Tissue engineering9

Human Tissue Engineered Products – Today's Markets and Future Prospects Final Report for Work Package 1: Analysis of the actual market situation – Mapping of industry and products

Dr. Bärbel Hüsing Dr. Bernhard Bührlen Dr. Sibylle Gaisser Fraunhofer Institute for Systems and Innovation Research Karlsruhe, Germany April 28, 2003

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Table of contents

Page

List of tables.............................................................................................................. v

List of figures .........................................................................................................viii

1. Terms of reference ............................................................................................ 1

2. Methodology applied......................................................................................... 3

2.1 Definition of tissue engineering ....................................................... 3

2.2 List of tissue engineering companies ............................................... 3

2.3 List of tissue engineering products on the market and in clinical trials ..................................................................................... 4

2.4 Market volumes................................................................................ 4

2.5 Interviews ......................................................................................... 5

3. Market volumes for tissue engineering ........................................................... 6

3.1 Overview of potential applications .................................................. 6

3.2 Challenges in estimating market volumes in tissue engineering ....................................................................................... 6

3.2.1 Characteristics of tissue engineering................................................ 6

3.2.2 Purpose of market estimations ......................................................... 6

3.2.3 Sources of information for market estimations ................................ 6

3.2.4 Consequences for market estimations in this study ......................... 6

3.3 Actual sales and potential market volumes ...................................... 6

3.3.1 Actual sales ...................................................................................... 6

3.3.2 Potential market volumes ................................................................. 6

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4. Tissue engineered skin products ...................................................................... 6


4.2 Overview of important companies and products.............................. 6

4.2.1 Treatment of full-thickness burns .................................................... 6

4.2.2 Treatment of chronic wounds........................................................... 6

4.2.3 Aesthetic surgery, cosmetic dermatology ........................................ 6

4.2.4 In-vitro human skin models.............................................................. 6


4.3.1 Actual sales of tissue-engineered skin products............................... 6


4.3 Factors influencing the market situation .......................................... 6

5. Tissue engineered cartilage products .............................................................. 6




5.3.1 Actual sales of tissue-engineered cartilage products........................ 6



6. Tissue engineered bone products..................................................................... 6



6.3 Potential market volumes ................................................................. 6


7. Tissue engineered cardiovascular products.................................................... 6


7.1.1 Heart valves...................................................................................... 6

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7.1.2 Blood vessels.................................................................................... 6

7.1.3 Myocardial infarction....................................................................... 6

7.2 Overview of companies and their R&D activities ........................... 6

7.2.1 Heart valves...................................................................................... 6

7.2.2 Blood vessels.................................................................................... 6

7.2.3 Myocardial infarction....................................................................... 6

7.3 Potential market volumes ................................................................. 6

7.3.1 Prevalences and incidences for cardiovascular diseases .................. 6

7.3.2 Market figures related to CVD......................................................... 6

8. Tissue engineered organs.................................................................................. 6


8.1.1 Tissue-engineered pancreas for the treatment of Diabetes mellitus ............................................................................................. 6

8.1.2 Bioartificial liver assist devices........................................................ 6


8.2.1 Tissue-engineered pancreas.............................................................. 6

8.2.2 Bioartificial liver assist devices........................................................ 6

8.3 Overview of potential market volumes ............................................ 6

8.3.1 Overview of organ donation and organ transplantation internationally................................................................................... 6

8.3.2 Diabetes mellitus .............................................................................. 6

8.3.3 Acute hepatic failure ........................................................................ 6

9. Tissue engineered CNS products ..................................................................... 6



9.3 Overview of potential market volumes ............................................ 6

10. Characterization of the tissue engineering industry ...................................... 6

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10.1 Structure of the tissue engineering industry..................................... 6

10.1.1 Europe .............................................................................................. 6

10.1.2 USA.................................................................................................. 6

10.1.3 Common features of the European and US-American tissue engineering industry............................................................... 6

10.2 Differences between Europe and the USA....................................... 6

10.2.1 Science and technology base............................................................ 6

10.2.2 Companies........................................................................................ 6

10.2.3 Regulatory situation ......................................................................... 6

10.2.4 Market .............................................................................................. 6

10.3 Business models and business strategies.......................................... 6

11. Overview of tissue engineering products on the market and in clinical trials....................................................................................................... 6

11.1 Skin products.................................................................................... 6

11.2 Cartilage products ............................................................................ 6

11.3 Bone products................................................................................... 6

11.4 Cardiovascular products................................................................... 6

11.5 Tissue engineered organs ................................................................. 6

11.6 CNS products ................................................................................... 6

11.7 Miscellaneous products .................................................................... 6

12. Cited Literature................................................................................................. 6

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List of tables

Page

vi

Table 3.1: Revenue from tissue engineering products, cell therapies and biomolecules 1997................................................................ 6

Table 3.2: Overall potential market for tissue engineering ............................... 6

Table 3.3: Potential US markets for tissue engineering and organ regeneration products 1999......................................................... 6

Table 4.1: Sales figures for selected tissue engineered skin products............... 6

Table 4.2: World wound management sales market and its segments .............. 6

Table 4.3: Maximum market potential for tissue engineered skin products worldwide/USA............................................................ 6

Table 4.4: Realistic market potential for tissue engineered skin products for the treatment of chronic wounds, model calculation for Germany.............................................................. 6

Table 5.1: Sales figures of autologous chondrocyte implants ........................... 6

Table 5.2: Overview of frequencies of cartilage defects ................................... 6

Table 5.3: Market sizes correlated with cartilage defects/cartilage repair ........................................................................................... 6

Table 6.1: Comparison of different bone repair approaches ............................. 6

Table 6.2: Sales 2002 of bone products by tissue engineering companies.................................................................................... 6

Table 6.3: Market for bone replacement and repair .......................................... 6

Table 7.1: Global heart valve market 2001 ....................................................... 6

Table 8.1: Artificial and bioartificial liver assist devices with clinical experience ................................................................................... 6

Table 8.2: Overview of organ transplantations (absolute numbers) in 2001............................................................................................. 6

Table 8.3: Overview of organ transplantations in 2001 (numbers per 1 mio. inhabitants).......................................................................... 6

Table 8.4: Organ donations in selected countries in 2001................................. 6

Table 10.1: Tissue engineering companies in Europe......................................... 6

Table 10.2: Overview of tissue engineering companies in European countries ...................................................................................... 6

Table 10.3: Categorisation of SME European tissue engineering companies according to employee numbers ............................... 6

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Table 10.4: Economic parameters for contemporary tissue engineering (2001) .......................................................................................... 6

Table 10.5: Sector analysis of tissue engineering companies in the USA 2001.................................................................................... 6

Table 10.6: Differences in the regulatory situation in the USA and the EU ............................................................................................... 6

Table 10.7: Business models for pharmaceuticals, medical devices and tissue engineering products ......................................................... 6

Table 11.1: Skin products of European companies ............................................. 6

Table 11.2: Skin products of US companies ....................................................... 6

Table 11.3: Clinical trials on skin products of European and US companies.................................................................................... 6

Table 11.4: Autologous chondrocyte transplantation products of European companies ................................................................... 6

Table 11.5: Autologous chondrocyte transplantation products of US companies.................................................................................... 6

Table 11.6: Clinical trials on cartilage products of European and US companies.................................................................................... 6

Table 11.7: Bone products of European companies............................................ 6

Table 11.8: Bone products of US companies ...................................................... 6

Table 11.9: Clinical trials on bone products of European and US companies.................................................................................... 6

Table 11.10: Cardiovascular products of European and US companies ............... 6

Table 11.11: Clinical trials on cardiovascular products of European and US companies ............................................................................. 6

Table 11.12: Clinical trials on tissue engineered organs of European and US companies ............................................................................. 6

Table 11.13: Tissue engineered CNS products of US companies......................... 6

Table 11.14: Clinical trials on tissue engineered CNS products of US companies.................................................................................... 6

Table 11.15: Miscellanous products on the market and in clinical trials .............. 6

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List of figures

Page Figure 4.1: Contribution of cost factors to overall cost of healing in

sectors of the wound management market .................................. 6

Figure 8.1: Evolutionary cladogram on commercial efforts to develop a bioartificial pancreas ................................................................ 6

Figure 10.1: Tissue engineering companies in European countries ..................... 6

Figure 10.2: Company size of European tissue engineering companies .............. 6

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3

5 2

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

All TE companies Core TE companies

Shar

e of

com

pani

es (%

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not knownLargeSME

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Figure 10.3: Company type of European tissue engineering companies.............. 6

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1. Terms of reference

Tissue engineering (TE) is an emerging interdisciplinary area comprising different specialties such as medicine, materials science, cell biology, genomics and chemical engineering. Its aim is to develop biological substitutes to restore, maintain or im-prove tissue function, thus offering patients the chance to regain a normally func-tioning body. The European Commission, DG Enterprise, is considering a directive to cover human tissue-engineered products to harmonise legislation in the EU and to enable a common European market while safeguarding consumer protection. As the whole field of tissue engineering is relatively young, a comprehensive pic-ture of the state-of-the-art of tissue engineering in the EU in terms of research ac-tivities, actual market-industry structure and probable future developments will be prepared. This report is part of this comprehensive study. It maps the relevant industry and products on the market or in clinical trials, respectively, and analyses the actual market situation. In order to compile the report, the following tasks were carried out:

• Listing and description of products already on the market or in clinical trial phase (I to III), as well as their present market volume where applicable.

• Categorization of the companies involved according to their main production portfolio (medical devices industry, biotech industry, pharmaceutical industry) and according to size (SME, large company). The most important companies should be described in more detail (e.g. size, turnover, product portfolio…).

• Analysis of the potential market volume for different product categories, for ex-ample: − Skin substitutes − Orthopaedic cartilage and bone replacement − Cardiovascular substitutes − Organs (e.g. kidney, liver, lung) − Nervous system − Soft tissue (e.g. breast implants)

• The possible influences tissue-engineered products might have on the markets for medical devices and medicinal products should be analysed. What products might be replaced, how would the respective market shares change?

Demographical changes as well as lifestyle changes should be taken into account and fed into the analysis of potential market volumes.

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The scope of the analysis is the EU member states, the first round enlargement countries (Czech Republic, Estonia, Hungary, Latvia, Lituania, Poland, Slovenia and Slovakia) and the USA as a reference. Any visible trends that distinguish American approaches from European ones should be pointed out.

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2. Methodology applied

2.1 Definition of tissue engineering

The following defininition was agreed upon consultation with IPTS and DG Enter-prise and applied in this study: Tissue engineering is the regeneration of biological tissue through the use of cells, with the aid of supporting structures and/or biomolecules (Scientific Committee on Medicinal Products and Medical Devices 2001). The definition chosen for this study primarily relates to therapeutic applications of tissue engineering, not to in vitro applications. It excludes gene therapy and simple transplantations. It includes autologous and allogeneic human cells, tissues and or-gans, and also xenogeneic cells, tissues and organs, that have been substantially modified by treatments. In addition, autologous chondrocyte transplants are inclu-ded.

2.2 List of tissue engineering companies

In order to compile a list of companies in EU member states as well as in the acces-sion countries Czech Republic, Estonia, Hungary, Latvia, Lituania, Poland, Slove-nia and Slovakia involved in tissue engineering, the following sources were ana-lysed:

• analysis of international and national biotechnology directories,

• analysis of reports on national biotechnology innovation systems, compiled by research groups or foreign investment bureaus,

• analysis of internet tissue engineering platforms and link lists,

• analysis of scientific literature on tissue engineering, identified by data base searches,

• analysis of market studies and company reports, identified by data base and internet searches,

• in some countries direct requests for information on TE companies in academic research institutes and/or national biotechnology associations.

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Despite several efforts, it was not possible to obtain information from member lists of several professional societies (European Tissue Engineering Society (ETES), European Society for Biomaterials (ESB)) due to data protection reasons. After identification of company names from the above mentioned sources, the rele-vance of the company was checked by obtaining more detailed information from its internet home page where available.

2.3 List of tissue engineering products on the market and in clinical trials

In order to compile a list of products on the market or in clinical trials the following sources were analysed:

• analysis of scientific literature on tissue engineering, identified by data base searches,

• analysis of tissue engineering companies' home pages in the internet,

• analysis of market studies and company reports, identified by data base and internet searches,

• interviews with tissue engineering experts.

2.4 Market volumes

The actual and potential market volumes for tissue engineering as a whole or differ-ent product categories, respectively, were compiled by analysing existing market studies and company reports. Moreover, factors which influence market develop-ment and dynamics (e. g. scientific-technical developments, legal situation, compet-ing technologies, trends in health care systems, demographical and lifestyle changes) were assessed through literature analysis and interviews with tissue engi-neering experts from companies. In addition, health statistics and scientific litera-ture were analysed for figures on disease prevalences and incidences for certain diseases which are representative for selected tissue engineering market segments, and put into perspective with published market estimations and with influencing factors. Foreign currencies were transformed into €. The following exchange reference rates were used (Source: European Central Bank, http://www.ecb.int/stats/eurofxref/eurofxref-xml.html, retrieved March 27, 2003,

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and for the conversion rates of the EURO-Member Countries: http://www.ecb.int/change/conversion.htm, retrieved March 27, 2003): AUD Australian dollar 1.7852 GBP Pound sterling 0.68110 BEF Belgian Francs 40.3399 SEK Swedish krona 9.2527 CAD Canadian dollar 1.5711 USD US dollar 1.0000 FRF Francs Français 6.55957

2.5 Interviews

The information compiled in desk research were verified and completed during questionnaire-guided telephone interviews with management staff from leading companies (see annex). Each of these interviews lasted one to 1.5 hours. In addition, interim results were presented and discussed with the EuropaBio cells and tissues expert group in April 2003.

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3. Market volumes for tissue engineering

3.1 Overview of potential applications

Tissue engineering is the regeneration of biological tissue through the use of cells, with the aid of supporting structures and/or biomolecules (SCMPMD 2001). It of-fers the potential of a paradigm shift in medicine: new forms of therapy can be en-visioned which allow the repair or regeneration of cells, tissues and organs which have lost their function due to disease, injury or congenital defects. Potential applications of tissue engineering are envisioned in the following fields:

• Skin,

• Cartilage,

• Bone,

• Cardiovascular diseases,

• Organs,

• Central nervous system,

• Miscellanous, e. g. soft tissue, ligaments. Although tissue engineering research is being carried out in all these fields, only few products have already entered the market, and the present state of the art in science and technology does not allow a precise assessment which of these deve-lopments will finally yield new therapeutic options and commercially viable pro-ducts. Therefore, a broad variety of information sources and methods has to be used in order to estimate the actual and potential market volumes for tissue engineering. The following chapter gives an overview how this task can be addressed.

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3.2 Challenges in estimating market volumes in tissue engi-neering

3.2.1 Characteristics of tissue engineering

Tissue engineering is a new, emerging, highly dynamic and interdisciplinary field. Due to its infant stage of development and its continuing evolution, no clear and generally recognised definition has emerged, and no established "official" statistics are available which provide tissue-engineering specific data. Moreover, most of its potentials still remain to be revealed in the future, so that the present database and knowledge regarding future applications, products and potentials is incomplete and uncertain.

3.2.2 Purpose of market estimations

In emerging technologies such as tissue engineering, two different types of market estimations can be distinguished which fulfill two different purposes:

• Analysis of potential applications and markets. The analysis of potential applica-tions and markets is the only type of market estimations which can be carried out in very early stages of development. These potential market estimations can pro-vide information on the overall scope of tissue engineering, the significance of this field, and its potential for solving health problems and for commercial activi-ties. The main purpose of these estimations of potential markets is to mobilize ressources and to support decisions whether and to which extent to engage in this field.

• Analysis of actual applications and markets. The analysis of actual applications and markets can only be performed if tissue engineered products have already been developed and brought onto the market. Comparing actual and potential market analysis makes it possible to assess how far the development has already progressed, to which extent the potential has already been realised, to which ex-tent the potentials may have to be reassessed, and whether there are hindrances which cause a deviation of actual markets from potential markets.

3.2.3 Sources of information for market estimations

Market estimations require the combination of two types of information: informati-on on the number or frequency for the (actual or potential) application of the tissue engineered product, and monetary information regarding the price or costs. These types of information can be retrieved from a broad variety of sources.

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For the analysis of potential applications and markets, a broad scope of information sources and data can be used. For information on the number or frequency, for e-xample the following data can be used

• prevalences and incidences of the diseases which could be targeted by tissue en-gineering products,

• number of conventional treatments for the given disease; number of conventio-nally treated patients with the given disease,

• number of conventional drug doses/medical devices etc. sold for the targeted diseases.

For the corresponding monetary information, sources such as

• retail prices for conventional drugs/medical devices,

• expenditures of the health care system for a given treatment/disease,

• willingness of users/patients to pay for treatments of a given disease can be used. For the analysis of actual applications and markets,

• the number of tissue engineering treatments or the number of patients treated with the tissue engineering product,

• the expenditure of the health care system for tissue engineering treatments,

• sales figures for tissue engineering products or sales figures of tissue engineering companies

can be used. Often, combinations of the above mentioned approaches and data sources are ap-plied. The resulting market figures depend on which sources of data were used for calculating the market figures. Therefore, different market figures may be due to the fact that – for example – they were calculated in case 1 by using prevalence data for the given disease, and by using sold conventional drug doses in case 2. Moreover, consistent data of good quality are often not available for all aspects required in the market analysis. Then extrapolations of existing data (e. g. extrapolations of data from country A to region B) and plausible assumptions must be made.

3.2.4 Consequences for market estimations in this study

In this study, a secondary analysis of published market data was carried out by compiling and analysing existing market studies for tissue engineering. A secondary analysis has several inherent limitations:

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• Incomplete information of data sources and methodology applied. Most publis-hed market studies present their results in aggregated form, but do not reveal in detail which definitions, data sources, calculation methods, and assumptions in extrapolations have been applied. Therefore, it is often not possible to explain differences in the results which may be due to methodological reasons.

• Definition of tissue engineering. Due to the dynamic development of tissue engi-neering, several definitions are in use which differ from one another regarding the scope of included subfields. In this study, tissue engineering was defined as "the regeneration of biological tissue through the use of cells, with the aid of supporting structures and/or biomolecules". However, the secondary analysis of published market studies also had to rely on studies which used other definitions of tissue engineering. In several cases, no information was available how tissue engineering had precisely been defined for the respective study. This makes comparison of the results of different studies difficult.

• Regional scope. Most market estimations relate to the USA. If one assumes that worldwide disease incidence and prevalence rates were equal to those in the USA, the estimated number of patients worldwide would be about 20 times lar-ger than the US figures. However, in general, it is assumed that the worldwide market is at two to three times that in the USA, because incidences and preva-lences vary widely and in most parts of the world there is a lack of access to ad-vanced health care services. If the European market is considered in the market studies, it is assumed that it is as big as the US market, and is appr. 30-40 % of the worldwide market (Medtech Insight 2000).

• Scenarios for market dynamics. In most published market studies on tissue engi-neering, no information is available to which extent and with which level of methodological sophistication market dynamics have been taken into account. Dynamic factors are, among others, increase or decrease in disease prevalence and incidence due to demographic trends, limited regional availability of certain tissue engineered products, competition with established products and treatments etc.

Due to these limitations inherent in secondary analysis of published market studies, differences and inconsistencies between market estimations from different studies can be explained or compensated only to a limited extent.

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3.3 Actual sales and potential market volumes

3.3.1 Actual sales

Although tissue engineering offers the potential to provide novel treatments in the areas of skin, cartilage, bone, cardiovascular disease, central nervous system, and organs, only tissue engineered skin and cartilage (and to a limited extent bone) products have been commercialised until today. These are markets in which the value of the products is primarily based on quality of life, not survival. Although the data base is fragmentary, total annual worldwide sales for tissue engineered skin replacement products are in the order of magnitude of € 20 millions, and worldwide sales of autologous chondrocyte transplants are presently unlikely to exceed the order of magnitude of € 40 mio./year1. Therefore, actual sales of tissue engineered products amount to approximately € 60 millions/year.

Table 3.1: Revenue from tissue engineering products, cell therapies and bio-molecules 1997

Revenue 1997 Estimated Market 2007

Average an-nual growth

rate (%)

€ mio. € mio. 1997-2007 Cell therapies (Bone marrow transplants, stem cell transplants, lymphocyte therapy, xeno-grafts for treatment of Parkinson’s dis-ease)

0 14,572 --

Tissue Engineering 61 3,867 55 Proteins and peptides (cytokines, morphogenetic proteins, aner-genic peptides used in supporting thera-pies)

91 1,819 35

Total 152 20,258 60

Source: (Business Communication Company 1998)

Similar market assessments have also been published: according to (Lysaght 2002), the total sales of tissue engineered products (i. e. skin and cartilage products) were about € 40 mio. in 2001, with European combined sales under € 1 mio. Revenues from tissue engineering products (which were not specified in detail) were esti-

1 For a detailed presentation and discussion of the underlying figures and factors influencing the

market situation please refer to chapters 4-6.

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mated at € 61 mio. in 1997 (table 3.1). However, the estimated annual growth rate of 55 %, leading to a global € 3,867 mio. market ten years later, seems over-optimistic. A different source uses a narrower definition of tissue engineering and estimates the global cell-based tissue engineering market at € 47 mio. in 2001. It also assumes vital growth over the following years, with a € 270 mio. market in skin repair alone by 2007 (Medmarket Diligence 2002).

3.3.2 Potential market volumes

When estimating the overall potential market for tissue engineering, most publica-tions refer to estimates for the USA published in 1993 (Langer et al. 1993) and up-dated in 1999 (Vacanti et al. 1999). In this publication, medical procedures were taken into account which require some type of replacement structure for the area of defect or injury, and it was assumed that these medical procedures in principle could also be amenable to tissue engineering applications. Table 3.2 gives an over-view of the indications and procedures or patients per year in the USA. In total, annually more than 11 mio. medical procedures which are also potentially relevant for tissue engineering are performed in the USA. This corresponds to a total na-tional health care cost of appr. € 400 billion/year (this estimation only includes costs for patients with cardiovascular disease and coronary artery disease, for stents used in angioplasty and costs of care for diabetes). A different definition of tissue engineering was applied by (Lysaght et al. 2000), who additionally included organ transplantations and dialysis, but excluded neuro-logical disorders and skin replacement. They concluded that worldwide, more than 20 mio. patients are affected, and the costs associated with organ replacement therapies amount to more than € 300 billion /year worldwide, with appr. € 100 billion/year in the USA. This amounts to appr. 8 % of the worldwide medical spending (Lysaght et al. 2000). These two studies focus on the total health care costs caused by organ replacement therapies. Another market study focuses on potential industry sales. It estimates the Human Tissue Products Market at more than € 80 billion in the USA alone. This is put into perspective with the global medical devices market, estimated at € 130 billion and the global pharmaceuticals market of € 265 billion (Medtech In-sight 2000). In another study, however, the total market for the regeneration and repair of tissues and organs is estimated to be € 25 billion worldwide (Bassett 2001). It is not known whether different definitions of tissue engineering were used which could explain these differences in market potentials.

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Table 3.2: Overall potential market for tissue engineering

Vacanti and Langer 1999 Lysaght and Loughlin 2000 USA World

Patient Population 2000 Indication

Procedures or pa-tients/year (1996)

prevalence treatment cost/a (mio. €) Incidence Prevalence at Midyear

Total Therapy Cost 2000 (mio €)

Cardiovascular 58,000,000 Heart-Including coronary artery bypass graft-ing

1,821,000 14,000,000 274,000

heart-lung 733,000 6,000,000 65,000 Angioplasty of coronary vessels, stents 1,000,000 2,000 1,750,000 2,500,000 48,000 Blood vessels 272,000 Valves 245,000 2,400,000 27,000 Pacemakers 670,000 5,500,000 44,000 Spinal cord (neural and neuromuscular) 469,000 Orthopaedic and plastic reconstructive Bone, cartilage, tendon, and ligament 1,977,000 Hips 610,000 7,000,000 41,000 Knees 675,000 Breast 479,000 Gastrointestinal Liver, gallbladder, bile duct 205,000 Pancreas (diabetes)† 728,000 100,000 Intestinal 100,000 Other

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Urinary system including kidney 740,000 Maintenance dialysis 188,000 1,030,000 67,000 Skin 2,509,000 Hernia 988,000 Organ transplants 48,000 275,000 13,000 Total 11,288,000 376,000 4,919,000 24,705,000 305,000

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Tissue Engineering has the potential to offer new treatment options for orthopedic indications (cartilage, bone), skin damage, cardiovascular diseases, neurological disorders and organ failure. Table 3.3 gives an overview of the number of affected patients, and, based on these numbers, estimation of the tissue engineering and or-gan regeneration market in the USA. These derived market figures take into account to which extent the tissue engineered products could satisfy unmet medical needs (e. g. above average in the case of neurological disorders, where currently mostly symptomatic treatments are available), which degree of market penetration and re-placement of existing therapies could be achieved (e. g. below average in the case of skin repair), and willingness to pay/prices and costs of existing treatments (e. g. assessment of pancreas regeneration as a very profitable market segment due to the high health care costs of diabetes management in these chronically ill patients and the increasing incidence and prevalence of diabetes in the US).

Table 3.3: Potential US markets for tissue engineering and organ regeneration products 1999

Affected patients 1999 Potential US Sales

Disease/Application Segment mio. % of

total billion € % of total

Orthopedics (repair of joints and cartilage, fracture fixation, bone repair, vertebral disc repair)

3.2 22 7.8 20

Cardiovascular disease (tissue-engineered bypass grafts, regeneration of damaged cardiac muscle tissue, restenosis prevention, angiogenesis for revascularization, repair of heart valves, repair of congenital ab-normalities of the heart, treatment of stroke)

3.2 22 6.8 17

Neurological disorders (Parkinson's Disease, Huntington's Disease, epilepsy, regeneration of nerves)

1.6 11 7.2 18

Ulcers, skin repair (diabetic foot ulcers, pressure sores, venous ulcers)

2.8 20 4.3 11

Muscle repair 1.8 13 4.5 11 Pancreas Regeneration (Diabetes) 0.1 1 2.5 6

Other (bladder, renal tubule, small intestine replace-ment, skin, breast and urethra repair, liver, ureter and bone marrow regeneration, penile prosthesis)

1.6 11 6.8 17

Total 14.3 100 39.9 100

Source: (Medtech Insight 2000)

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The above mentioned figures, however, have to be met with caution. They refer to a potential market which could in principle be addressed by tissue engineering. How-ever, these estimations include several indications or application areas which are still in the early R&D phase and far from market entry (e. g. all organ replacement approaches, treatments for CNS disorders, see also chapters 8 and 9 of this report). Moreover, it is not clear to which extent it has been (unrealisticly) assumed that every patient is treated with the tissue engineering option although tissue engineer-ing products will have to compete with other treatment options. Although most markets for tissue engineering products have not yet emerged, two important characteristics can already be noted:

• The value of most products which are already commercialised or are likely to do so in the coming years is based on quality of life, not patient survival. Superior-ity regarding quality of life may, however, be rather difficult to prove if there are already conventional, established treatments which have to be outcompeted.

• Most tissue engineering products target markets which are much more focussed than attractive market for pharmaceuticals (> € 1 billion/year).

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4. Tissue engineered skin products


The human skin is a complex organ composed of three principal components (Schulz et al. 2000):

• Epidermis. The epidermis is the superficial layer of the skin. It is the interface with the environment, providing immediate protection from microbial entry and loss of water, electrolytes, and proteins. The epidermis, if damaged, can regene-rate.

• Dermis. The dermis is the inner and thicker of the two skin layers. it is responsi-bel for the strength, elasticity, and tactile qualities attributed to skin. If damaged, the dermis can only regenerate to a limited extent.

• Epidermal appendages. Epidermal appendages are hair follicles, sweat glands and sebaceous glands. They are involved in maintaining the barrier and thermo-regulatroy functions of the skin.

For the past 30 years, attempts have been made to develop products that can be used as a temporary or permanent natural skin substitute. These artificial skin substitutes should ideally fulfill the following functions (Schulz et al. 2000):

• Thermoregulation,

• microbial defense (both mechanical barrier and immune defense),

• desiccation barrier,

• mechanical defense and wound repair, elicit a regeneration response from the wound bed without evoking an inflammatory or rejection response,

• cosmetic appearance, pigmentation and control of contraction,

• durable and elastic to provide normal function and cosmetic appearance,

• be easy to use, be readily available immediately after damage of the natural skin. Indications and market segments for tissue engineered skin sustitutes are • Burns. Severe burns can be life-threatening. In the USA every year 75,000 of

burned patients require inpatient care, and 5,000-12,000 die of their injuries (Schulz et al. 2000). The number of burnt patients requiring tissue engineered skin grafts is estimated at appr. 150 patients/year in Western Europe. Although there is a medical need for skin replacement therapies in burns treatment, prod-

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ucts aimed at burn wound closure are unlikely to be as economically profitable as products that could be used for chronic wounds, which are substantially more prevalent (see below) (Jones et al. 2002).

• Chronic wounds. Chronic wounds are defined as wounds which do not heal within six weeks. Chronic wounds can be devided into − pressure ulcers, which form during sitting or lying without moving. Especially

elderly and severely ill people are at risk. − Ulcus cruris, venous ulcers, which are caused by venous insufficiency. − Diabetic ulcers, diabetic foot, which can emerge in diabetic patients with an

ill-controlled blood glucose level.

Chronic wounds often prevail for several years, require cost-intensive treatments and can also have significant psychosocial consequences for the affected patient. From epidemiological studies it is known that underlying diseases which result in the development of chronic wounds (e. g. venous diseases, diabetes) are among the most frequent disorders in Western populations, are increasing due to the prevailing life style changes, and are also age-correlated. Therefore, the demographic development will also lead to an increase in chronic wounds. It is estimated that appr. 2-3 mio. people suffer from chronic wounds in Germany (pressure ulcers 46 %, Ulcus Curis 28 %, diabetic foot 21 %, others 5 %) (Landesbank Baden-Württemberg Equity Research 2001). The direct and indi-rect costs of leg ulcers in the UK as well as Germany are higher than one bil-lion € per year (Augustin et al. 1999).

• Indications in plastic surgery or with cosmetic character. Indications are e. g. the treatment or prevention of scarring and the treatment of vitiligo or other pigmentation disorders. The worldwide incidence of vitiligo is 1-2 % of the population with marked regional differences (incidences of 3-4 % in In-dia/Asia/Arabia versus 0.5 % in Scandinavia) (Landesbank Baden-Württemberg Equity Research 2001).

• Defects in oral mucosa. Large and painful defects in oral mucosa are associated with certain forms of cancer. In addition, they play a role in dental surgery (e. g. tooth implantation).

4.2 Overview of important companies and products

Several different approaches have been pursued, many of them involving tissue engineering, to generate skin substitutes that fulfill at least some of the functions outlined in chapter 4.1. At present, approximately two dozens of tissue engineering products for skin replacement are already on the market in Europe and the USA. At least seven additional products are in clinical trials (for details see chapter 11.1). US companies concentrate on allogenic skin products, European companies favour autologous skin products.

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4.2.1 Treatment of full-thickness burns

The first products on the market were for the treatment of severe, full-thickness burns, e. g.

• Epicel, produced by Genzyme Biosurgery (formerly Genzyme Tissue Re-pair)(USA). Genzyme Biosurgery brought one of the first tissue engineered skin products on the market. This was Epicel® for the treatment of life-threatening burns. Approximately 75 burn patients are treated with Epicel® per year. Over 600 patients have been treated worldwide since the product was introduced in 1987.

• Integra, produced by Integra Life Sciences (USA).

• Transcyte, marketed by Smith & Nephew (UK). However, these products are unlikely to be economically as profitable as skin re-placements that could be used for chronic wounds, due to their being much more prevalent (Jones et al. 2002).

4.2.2 Treatment of chronic wounds

Several products are on the market which target chronic wounds, such as venous or diabetic ulcers. Products in this category are e. g.:

• Apligraf, developed and manufactured by Organogenesis (USA), marketed by Novartis (CH/USA) until June 2003. The worldwide distribution and marketing rights of Apligraf will then be transferred back to Organogenesis.

• Dermagraft, developed by Advanced Tissue Sciences, marketed by Smith & Nephew (UK)

• Hyalograft™ 3D, Laserskin™, produced by Fidia Advanced Biopolymers (Italy)

• BioSeed-S, produced by BioTissueTechnologies (Germany), marketed by Baxter Healthcare

• autologous Autoderm and allogeneic CryoCeal, produced by XCELLentis (Bel-gium)

• Epidex, production stopped by Modex Therapeutics, product licensed to Auto-derm (Germany) in spring 2003

• Collatamp, produced by Innocoll GmbH (Germany)

• Epibase, produced by Laboratoire Genevrier (France)

• CellActiveSkin, production stopped in late 2002 by IsoTis SA, because product was not profitable

• OrCell, produced by Ortec (USA)

19

• VivoDerm, produced by Convatec (USA) As will be explained in more detail in the following chapter and in WP 2, the cost-effectiveness of tissue engineered skin replacements for the treatment of chronic wounds has – in general – not yet been clearly established. Therefore, statutory and private health insurance schemes do not routinely cover the costs for these treat-ments which is a major restriction in realising the full market potential (see below). As a consequence, tissue engineering companies increasingly develop products which target the "self-payer" patients' segment.

4.2.3 Aesthetic surgery, cosmetic dermatology

In order to develop economically profitable products, tissue engineering companies increasingly target the "self-payer" patients' segment by specifically tailored appli-cations in aesthetic surgery or cosmetic dermatology. Such products comprise treatment or prevention of scarring, treatment of pigmentation disorders such as vitiligo, and others. Products in this category are e. g.

• BioSeedM, produced by BioTissueTechnologies (Germany)

• MelanoSeed, produced by BioTissueTechnologies (Germany)

4.2.4 In-vitro human skin models

Several companies develop in-vitro applications of skin replacement products. The products can be used as skin models for in vitro testing for toxicity, pharmacology and cosmetics. Products in this category are e. g.

• Skin model developed by Biopredic (France)

• Skin model developed by SkinEthicLaboratories (France)


4.3.1 Actual sales of tissue-engineered skin products

No comprehensive data on actual sales figures of tissue-engineered skin replace-ment products is publicly available. However, some data can be obtained from pub-lic sources by scanning literature or making educated guesses from data in compa-

20

nies' annual reports. Table 4.1 gives the best available, albeit very fragmentary overview of actual sales figures.

Table 4.1: Sales figures for selected tissue engineered skin products

Trade name Company Year Sales (€)

Apligraf Organogenesis Inc (USA), Novartis (USA/CH) 2000 12,000,000

Dermagraft Advanced Tissue Sciences (USA)2, Smith & Nephew (UK) 2002 4,405,000

CellActiveSkin IsoTis (NL) 2002 545,000 Epidex Modex Therapeutics (CH) 2002 157,000 BioSeedS, BioSeedM, MelanoSeed

BioTissueTechnologies (D) 2002 450,000

Epicel Genzyme Biosurgery (USA) 2001 n.a.

75 patients treated annually worldwide

Source: Fraunhofer ISI, compiled from literature and companies' annual reports

Although the data in table 4.1 only cover some of the tissue engineered skin re-placement products which are commercially available, it can be deduced that the total annual worldwide sales for tissue engineered skin replacement products will at present be in the order of magnitude of € 20 millions. However, none of the products on the market seems to have reached profitability yet. As a consequence, two leading US companies, Organogenesis Inc and Ad-vanced Tissue Sciences, which were the first to introduce tissue-engineered skin replacements into the market, had to file for bancruptcy in autumn 2002. The prod-ucts CellActiveSkin and Epidex were not profitable, and their commercialisation by IsoTis SA (recent merger of IsoTis BV and Modex Therapeutics) has been stopped by the end of 2002. BioTissueTechnologies which commercialises the products BioSeedS, BioSeedM, and MelanoSeed, in spring 2003 is at risk of not being able to meet its financial obligations.

2 Advanced Tissue Sciences (USA); had a marketing agreement with Smith & Nephew for Der-

magraft and Transcyte; both products were completely taken over by Smith & Nephew in 2002 after Advanced Tissue Sciences had to file for bancrupcy.

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Most tissue engineered skin replacement and repair products target the wound care market. The wound care market can be devided into three segments:

• Traditional wound management, such as traditional gaze and tape, first aid dress-ings.

• Advanced wound management, e. g. moist wound healing, hydrocolloid dress-ings.

• Active wound management, e. g. tissue engineered skin, growth factors, antim-icrobials, enzymes (e. g. collagenase).

Advanced and active wound management concepts aim at actively stimulating the biological processes of wound healing and at removing the barriers to normal heal-ing present in these types of wounds. Tissue engineered skin products are a sub-segment of the active wound management market. Table 4.2 gives an overview of the worldwide wound management sales market and its segments.

Table 4.2: World wound management sales market and its segments

Wound Management Market Segment

Sales in 2001 (mio. €)

Share of overall market (%)

Annual growth rate (%)

Traditional 1,950 50.5 -3 Advanced 1,515 39.3 + 8 Active 392 10.2 + 28 Total 3,857 100.0 + 6

Source: Smith & Nephew 2002

Table 4.2 shows that traditional wound care is still the largest segment of the worldwide wound care market. However, dynamic growth comes from both the advanced and active wound management segments. Their growth is coming largely at the expense of the traditional wound care products. The leading companies in the advanced and active wound management market are Smith & Nephew (market share 21 %), Johnson & Johnson (16 %), Convatec (13 %), 3M (12 %) and KCI (9 %). Key drivers in the advanced and active wound care market are

• demographic development,

• quality of life,

• health economics,

• improved outcomes,

• nursing shortages, and

• technological developments.

22

The market leader, Smith & Nephew, follows the strategy to be well represented with its products and services in all stages of the treatment process (wound assess-ment and diagnosis, systemic stabilisation, wound bed preparation, wound healing and aftercare/prevention). The most differentiating factor between traditional and advanced wound treatment strategies are staff costs, because traditional wound dressings required daily dressing changes while advanced hydrocolloid dressings are changed only every 2-4 days (Augustin et al. 1999). Therefore, it is assumed that the cost of healing will be reduced in advanced and active wound management as compared to traditional management due to the above mentioned driving factors, but that the proportion of the "material" of the total cost base will increase (fig-ure 4.1).

Figure 4.1: Contribution of cost factors to overall cost of healing in sectors of the wound management market

Driving factors: demographic development quality of life, health economics, technological developments, improved outcomes, nursing shortages

0

10

20

30

40

50

60

70

80

90

100

Traditional Advanced Active

Wound care

Cos

t of H

ealin

g

OtherMaterialsNursing Time

Source: Smith and Nephew 2002 Another source assumes that the global wound management market potential sums up to appr. € 6,250 mio., and that a maximum of 10 % can be accessed by – the relatively costly – tissue engineered skin products which will remain restricted to chronic wound management (Landesbank Baden-Württemberg Equity Research 2001, p. 17). Therefore, a maximum global market potential of € 625 mio. is calcu-lated. This is in the same order of magnitude as estimations from other sources (Russell et al. 2001).

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Table 4.3: Maximum market potential for tissue engineered skin products worldwide/USA

Market Market Size 2001 (mio. €) Region Source

Global wound management market po-tential 6,250 world

Maximum market potential for tissue engineered skin, only applicable to chronic wounds

625 world

(Landesbank Baden-Württemberg Equity Research 2001, p. 17)

Global market for skin replacement products for wound repair 800 world (Russell et al. 2001)

Market for skin substitutes 300 USA (Russell et al. 2001) Although tissue engineered skin products are already on the market for several years, the annual worldwide sales are in the order of magnitude of € 20 mio. (see above) and thus stay far behind the market potentials listed in table 4.3. Reasons for this discrepancy between forcasted market potentials and actual sales figures are given in chapter 4.3.

4.3 Factors influencing the market situation

Although the incidence and prevalence of acute and chronic wounds is high (see chapter 4.1), tissue engineered skin is not the preferred treatment for most of these wounds. Generelly, skin defects can be treated by three therapeutic options:

• classical wound treatment by traditional and advanced dressings and ointments,

• surgical procedures, such as split skin transplantation,

• transplantation of tissue engineered skin. Approximately 80 % of chronic wounds can be treated with classical wound treat-ments which have direct material costs in the order of € 1/day. The remaining 10-20 % therapy-resistant wounds can in principle be treated with tissue-engineered skin products. To which extent this potential market can be accessed depends heav-ily on the fact whether the health insurances pay the treatment. Experts estimate that only up to 15 % of the patients suffering from chronic wounds are willing to pay the wound treatment by themselves, even if sustainable healing could be expected. The skin transplant costs are appr. € 2,000/treatment. Up to now, in Europe no general cost coverage by health insurance companies has been achieved. An application for general reimbursement for EpiDex (produced by Modex Therapeutics, Switzerland) was turned down by the Swiss Federal Office for Social Security in late 2002. Ex-perts have different views whether the existing skin products are likely to gain ap-proval at all, regarding reimbursement. At least, this is unlikely to be achieved be-

24

fore 2005 because additional data from clinical trials supporting application for re-imbursement approval cannot be expected earlier. Table 4.4 gives a model calcula-tion for the "realistic" market potential, based on data for Germany. The model cal-culation yields a market potential of appr. € 40 mio. to max. 120 mio./year tissue engineered skin products for hard-to-heal wounds for Germany.

Table 4.4: Realistic market potential for tissue engineered skin products for the treatment of chronic wounds, model calculation for Germany

Patients with chronic wounds 2 mio. patients Wounds resistant to conventional wound treatment procedures

10-20 % of all patients 200,000 – 400,000 patients

Patients with therapy-resistant wounds willing to pay the treatment by themselves

10 % to max. 15% 20,000 to max. 60,000 patients

Real market potential for tissue engineered skin products

2,000 € transplant costs/treatment 40 mio. € to max. 120 mio. €/year

According to experts‘ opinion, the general reimbursement of tissue engineered skin treatments by health insurance companies would be a prerequisite to fully explore the real market potential. In addition, structural changes in patient care are required: treatment with tissue engineered skin products will largely be confined to special-ized wound healing centres – at least in the beginning – and not readily available from general practitioners who, however, care for the majority of chronic wound patients. Experts‘ opinions are devided over the question whether significant cost reductions can be achieved by using allogenic instead of autologous grafts. Allogenic grafts should allow for a continuous, automated graft production. However, actual prices are in the same order of magnitude, irrespective of whether the cell source is al-logenic or autologous. Allogenic Apligraf costs appr. € 1.000/50 cm², autologous BioSeedS € 2000/100 cm² (sales prices only for the transplant; treatment costs addi-tionally include preparation of the wound, transplantation of the skin graft, and costs for aftercare). Other market segments which do not rely so heavily on the reimbursement policy of health insurances are products which traditionally must be paid by the patients themselves (e. g. aesthetic surgery, dental implants) or which are paid from hospital budgets (e. g. oral mucosa products used in the treatment of oral cancer). However, the number of affected patients for these indications is much lower than the number of patients with chronic wounds. In 2002, sales of BioTissueTechnologies products MelanoSeed and BioSeedM which target the above mentioned niche markets were in the order of magnitude of € 150,000/year and product.

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5. Tissue engineered cartilage products


Cartilage tissue is composed of chondrocytes and an extracellular matrix that con-sists of proteoglycans, collagen, and water. It is avascular and has no nerve struc-tures (Laurencin et al. 1999). One can distinguish

• unstressed cartilage, e. g. ear and nose,

• stressed cartilage, e. g. in joints or intervertebral discs. Once damaged, cartilage is generally considered to have a limited capacity for self-repair. Therefore, tissue-engineered cartilage products aim at cultivating chondro-cytes in vitro, and to reintroduce the cultured cartilage tissue into the damaged re-gion. In the field of unstressed cartilage, few patients have been treated with tissue-engineered cartilage grown on preformed scaffolds. In these cases, cartilaginous parts of the maxillofacial region (e. g. outer ear, nasal septum) have been recon-structed. Due to the still limited clinical success, these applications seem to be re-stricted to single cases (Bücheler 2002). At present commercially more important are tissue-engineered cartilage products which target defects of stressed cartilage. Defects of stressed cartilage can be due to trauma, and over time even minor lesions of the articular cartilage may progress to chronic defects, such as osteoarthritis. Defects of stressed cartilage can, however, be also due to rheumatoid arthritis. In addition to causing pain and restricted mobility, chronic injuries to joint cartilage may lead to further deterioration of the joint sur-faces. These manifestations can severly hinder a person's normal activities and oc-cupation. Established forms of therapy for cartilage damage in joints are

• arthroscopic surgery to smooth the surface of the damaged cartilage area,

• surgical procedures, such as microfracture, drilling, abrasion, in order to let bone marrow cells infiltrate the defect, resulting in the formation of fibrous cartilage tissue,

• analgesic therapy,

• full or partial artificial joint prostheses, often after years of progredient joint de-fects. As artificial joints generally last 10-15 years and revision surgery is prob-

26

lematic, joint replacement therapy is recommended mainly for patients over the age of 50.

In 1994, another treatment option, based on tissue engineered cartilage, became available for cartilage defects in the knee joint which are due to traumatic injury: autologous chondrocyte implantation, also termed autologous chondrocyte trans-plantation (ACT) (Brittberg et al. 1994). This technique and several modifications of it are presently the most important clinical application of tissue engineered carti-lage. The following applications may become relevant in the future:

• further development and adaptation of the ACT technique for the treatment of traumatic cartilage defects in other joints than the knee,

• further development and adaptation of the ACT technique for the treatment of joint cartilage defects with different etiology (e. g. osteoarthritis, rheumatoid ar-thritis),

• development of tissue-engineered grafts combining cartilage and bone,

• tissue engineered products for the treatment of intervertebral disc damage.


At present, most tissue engineered cartilage products target cartilage defects in the knee joint which are due to traumatic injury. They are based on the method devel-oped in 1994 (Brittberg et al. 1994). At present, at least three types of ACT are commercially available:

• "Classical" ACT. In a first arthroscopic surgery, a biopsy of healthy cartilage is taken from the patient's knee from a minor load bearing area. The chondrocytes are isolated and cultured in vitro for about three weeks. In a second, this time open-knee surgery, a periosteal flap is taken from the patient and is sutured over the cartilage lesion. Then the cultured chondrocytes are injected under the flap into the lesion. The knee is surgically closed. Movement of the knee and weight bearing must be gradually introduced and increased to the full extent over a pe-riod of 2-6 months after surgery.

• ACT with artificial cover. This variant of the classical ACT uses an artificial cover, e. g. a collagen or hyaluronic acid membrane, instead of a periosteal flap.

• Matrix-induced ACT. In this variant of the classical ACT, the cultured chondro-cytes are applied to a biodegradable three-dimensional scaffold before retrans-plantation. The pre-formed graft is then cut to the required size and fitted into the defect with the aid of anchoring stitches. This method does no longer require the

27

complicated sueing of the periosteal flap or artificial cover, therefore signifi-cantly reduces the surgery time and also makes arthroscopic instead of open-knee surgery possible. It is assumed, but not yet proven, that the three-dimensional scaffold also yields a hyaline cartilage of superior biomechanical properties than in "classical" ACT, so that the treatment of osteoarthritic defects will also become possible in this way.

At present, all autologous chondrocyte products on the market fall into one of these three categories. Additionally, the commercially available products differ in their technical specifications (e. g. details and duration of the cell culturing process, addi-tives to the cell transplant (e. g. antibiotics)), the extent of quality standards and quality control applied to the production process and resulting product, the logistic service provided by the company, and the educational support provided by the company for the orthopedic surgeons. At present, it is difficult to assess whether and which of these factors give companies a clear market advantage over their competitors. There is a large number of companies which offer autologous chondrocyte trans-plants. The most important companies for chondrocyte transplants are described below.

• Genzyme Biosurgery (USA). Genzyme Biosurgery is a division of Genzyme Corporation. It develops, produces and sells biotherapeutic and biomaterial products especially in the markets of orthopaedics and heart disease, and in broader surgical applications. Genzyme Biosurgery was the first company which introduced autologous chondrocyte transplantation into the market. With its product Carticel®, Genzyme Biosurgery is market leader in the USA. Activities with Carticel in Europe seem to have been terminated recently. Genzyme Bio-surgery had treated appr. 4,000 patients worldwide with its product Carticel® in the period from 1995 to 2000. This corresponds to cumulated sales of appr. 20 mio. US-$ in five years. Sales of Carticel® amounted to 18.4 mio. US-$ in 2001 and 20.4 mio. US-$ in 2002, which corresponds to 2,000-3,000 transplants/year.

• Fidia Advanced Biomaterials (IT). Fidia Advanced Biomaterials is one of the European market leaders and has a good market position in Europe, especially in Italy. FAB sells about 300-400 transplants/year. Its product HYALOGRAFT® C is a cartilage substitute made of autologous chondrocytes delivered on a biocom-patible tridimensional matrix, entirely composed of a derivative of hyaluronic acid (HYAFF®).

• Verigen (Germany). Verigen, founded in 1999 and headquartered in Leverku-sen, Germany with offices in the United Kingdom, Denmark, Italy, and Austra-lia, is one of the European market leaders. It has currently three chondrocyte products for the treatment of knee cartilage defects on the market: CACI (cultu-red autologous chondrocytes which are covered by a collagen membrane), MACI

28

(matrix-induced autologous chondrocyte implantation), and MACI® (A) which is the minimally-invasive variant of MACI®, in which the implantation is done by arthroscopy. By 2002, more than 800 patients in Europe and Australia have been treated with Verigen products. Verigen has a cooperation with Mitek for marketing MACI® (A) in the USA. No data on sales figures and revenues are available.

• co.don (Germany). co.don was one of the first companies to offer autologous chondrocyte transplantations in Europe and is one of the European market lead-ers. Its product is co.don chondrotransplant®. In 2000, sales of chondrotrans-plant® were appr. 550,000 € (corresponding to sales of 100 transplants plus ap-plication of 100 without reimbursement (e. g. in clinical trials), and appr. 1 mio. € in 2001 (corresponding to ca. 260 transplants plus 80 transplants with-out reimbursement).

• BioTissueTechnologies (Germany). BioTissueTechnologies is a tissue-engineering company founded in 1997. Its chondrocyte product is BioSeedC®, an autologous 3D chondrocyte graft which can also be applied by arthroscopy. BioSeedC® is in controlled clinical use since 2001. Sales in 2002 were approxi-mately 500.000 €. BioSeed®-C is currently available throughout Germany. In 2003, in co-operation with industrial partners, the company plans to increase its availability to include other European countries.

• TETEC® AG (Germany). TETEC® AG was founded in 2000. It develops and manufactures autologous cell transplants for cartilage repair which are distrib-uted by its co-operation partner AESCULAP® AG, a medical device company specialised as a system supplier in the surgical area ("All it takes to operate"). TETEC® has a manufacturing permit for the autologous chondrocyte product NOVOCART® in accordance with the German Drug Act (AMG). TETEC® AG has one product on the market, NOVOCART®. TETEC's R&D activities comprise a scaffold implant technology for ACT which can be applied by arthroscopic surgery, treatment of larger articular cartilage defects including me-niscal lesions, degenerative arthritis or osteoarthritis by cartilage cells seeded on scaffolds in the medium-term, and treatment for Intervertebral disk (IVD) lesi-ons.

Other companies, also active in this sector are

• IsoTis SA (Switzerland/The Netherlands). Before the merger with the Swiss company Modex Therapeutics, IsoTis BV (NL) had the autologous chondrocyte product CellActive Cart on the market, mainly in Spain. Sales amounted to 187,000 € in 2002. As the product was not profitable, the production and marke-ting of CellActive Cart was stopped in late 2002.

• ARS ARTHRO AG® (Germany). The company was founded in 2001, received manufacturing approval according to the German drug act in October 2002 and

29

has its product CaReS® (Cartilage Repair System) in clinical use since Novem-ber 2002. CaReS® is a 3D mechanically stable chondrocyte transplant based on cultured autologous cartilage cells and a collagen matrix. It is applied by mini-mally invasive surgery. Since late 2002 a prospective randomized study compar-ing ACT with the ARS ARTHRO® transplant is carried out at the University Hospital in Aachen (Germany) for the indication of focal defects of the articular cartilage of the knee joint.

• Ormed (Germany). Ormed is a medical device company specialised in thera-pies in orthopaedics, traumatology, athroscopy, sports medicine and rehabilita-tion. It offers the autologous chondrocyte transplant ARTROcell®. The autolo-gous chondrocytes are cultured by the cooperation partner Metreon Bioproducts GmbH , a subsidy of the biotechnology company CellGenix Technologie Trans-fer GmbH. The chondrocyte implant is covered by a collagen matrix derived from porcine type-I and type III collagen (Chondro-Gide®, supplied by Geist-lich). Ormed also offers training courses for ACT and carries out R&D on AR-TROcell® follow-up products.

• Orthogen AG (Germany). Founded in 1993, Orthogen develops and produces "molecular orthopaedics" products for orthopaedic specialists and surgeons, such as genetic diagnostic tests and autologous chondrocyte transplants. Since 2000, Orthogen AG has the authorization of a GMP-clean room, where it manufactures Arthromatrix®. Arthromatrix® is being distributed by Arthrex Biosystems (Germany).

• CellTec (Germany). CellTec, founded in 1997, holds a manufacturing permit in compliance with §13 AMG (German Drug Act) to manufacture culture chondrocytes according to GMP since 1999. CellTec has one autologous chondrocyte product on the market, ChondroTec™ which is applied by open-knee surgery and covered with a periosteal flap. In an ongoing research project, CellTec develops Matrix-Bound Chondrocyte Transplantation (MACT).

• TiGenix (Belgium). TiGenix develops cell-based tissue-engineered products in the areas of joint-surface defects, bone defects and heart valves. Its lead product is ChondroCelect®, an ACI, which entered randomised, prospective, multicenter clinical trials in March 2002. In preclinical development are ChondroCelect-P® (i. e. ChondroCelect with introduction of adult stem cell technology), Chon-droSealTM (use of a biodegradable membrane to replace the periosteal flap in the ACI-procedure), and Osteochondral Repair (Expanded osteoprogenitor cell populations, combined with adequate biomaterials, to be used in combination with ChondroCelect products in order to treat osteochondral defects).

• Osiris Therapeutics, Inc (USA). Osiris Therapeutics is a privately held devel-opment stage company, focusing on cellular therapeutic products for the regen-eration and functional restoration of damaged and diseased tissue. The therapeu-tic products are derived from human mesenchymal stem cells (hMSCs) ex-tracted, isolated and purified from adult bone marrow. Osiris specialises in the

30

differentiation of hMSCs into different specialised cell types, among them carti-lage. Osiris has a preclinical research programme to develop a treatment for me-niscal injury in the knee, based on human mesenchymal stem cells. The product Chondrogen is an injectable preparation of Mesenchymal Stem Cells suspended in hyaluronan which is delivered to the joint by simple intraarticular injection. A clinical trial is planned.


5.3.1 Actual sales of tissue-engineered cartilage products

No comprehensive data on actual sales figures of tissue-engineered cartilage repair products is publicly available. However, some data could be obtained from expert interviews, and they were backed up and checked for plausibility by data from pub-lic sources, such as literature or data from companies' annual reports. Table 5.1 gives the best available, albeit very fragmentary overview of actual transplantation and sales figures. The sales volume per country is calculated from the number of performed ACTs/year, assuming average prices of the transplants of € 5,000 in Europe and € 8,000 in the USA. As a plausibility check, sales information on indi-vidual products are also given. As can be seen from table 5.1, worldwide sales of autologous chondrocyte transplants are presently unlikely to exceed the order of magnitude of € 40 mio./year.

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Table 5.1: Sales figures of autologous chondrocyte implants

Country n ACT/year Calculated sales volume* Important companies/products Sales information from important companies

USA 2,000-3,000 € 16 – 24 mio. Genzyme Biosurgery/Carticel® Sales of Carticel ®: Sales 2001: 18.4 mio. US-$ Sales 2002: 20.4 mio. US-$

Germany 600 € 3 mio. Verigen/ACI/MACI/MACI-A co.don/co.don chondrotransplant® BioTissue Technologies/BioSeedC®

Sales of co.don chondrotransplant®: 2000: 550,000 € (ca. 100 transplants plus 100 without reimbursement), 2001: 1,000,000 € (260 transplants plus 80 without re-imbursement) Sales by BioTissueTechnologies 2002: 500.000 €, ca. 100 transplants

UK 300-850** € 1.5-4.3 mio. Verigen/ACI/MACI/MACI-A **Estimates by NICE of the number of potential ACT operations in England and Wales

Italy 300-400 € 1.5-2 mio. Fidia Advanced Biomaterials/ HYALOGRAFT® C

Spain 40 € 187,000 IsoTis/CellActive Cart Sales of IsoTis' CellActive Cart: 187,000 € in 2002 Total 3,240-4,850 € 22.2-33.3 mio.

* retail prices of € 5,000 /autologous chondrocyte transplant in Europe and € 8,000/transplant in USA. These costs do not include costs for sur-gery and rehabilitation.

Source: Fraunhofer ISI Research 2003

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Tissue-engineered cartilage products aim at repairing defects in stressed cartilage, due to trauma or progressive degeneration. Table 5.2 gives an overview of the inci-dences and prevalences of these defects, table 5.3 gives an overview of the corre-lated monetary markets.

Table 5.2: Overview of frequencies of cartilage defects

Region Size Year Source

Germany 1.5 mio. annual incidence of treatable arthrosis3 2000 (Landesbank Baden-Württemberg

Equity Research 2001, p. 19)

Germany 1.4 mio. patients suffering from arthrosis 2002 (Concord Corporate Finance Re-

search 2002)

Germany 1.5 mio patients suffering from osteoarthrosis 2002 (Concord Corporate Finance Re-

search 2002)

Europe 7 mio.* annual incidence of treatable arthrosis 2000

USA 5 mio.* annual incidence of treatable arthrosis 2000

World 15-20 mio. annual incidence of treatable arthrosis 2000

(Landesbank Baden-Württemberg Equity Research 2001, p. 19)

World 20 mio. patients with joint cartilage defects 2002 (Concord Corporate Finance Re-

search 2002)

Germany 50.000 annual incidence for knee injuries 2000 (Landesbank Baden-Württemberg

Equity Research 2001, p. 19)

Germany 40.000 annual joint re-placements with knee prosthesis

1999 Biomet Merck

Europe 250.000* annual incidence for knee injuries 2000 (Landesbank Baden-Württemberg

Equity Research 2001)

USA 600.000 arthroscopies linked to cartilage defects or injuries

2000 (Landesbank Baden-Württemberg Equity Research 2001)

USA 400.000 articular cartilage procedures 1997 (Isotis Corporate Communications

& Investor Relations 2003)

World 1.000.000** injuries or defects of the knee 2000 (Landesbank Baden-Württemberg

Equity Research 2001) * estimation based on incidence in Germany **estimation based on data from Germany and USA

3 Due to the limited availibitiy of effective therapeutic options, patients with symptoms of arthrosis

are often not treated until the disease has progressed to a stage in which analgesic therapy or a knee implant is indicated.

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Table 5.3: Market sizes correlated with cartilage defects/cartilage repair

Region Market size (€) Year Remarks Source

Europe 2 billions 1999 Market value for joint implants (prosthesis costs only) Biomet Merck

World 1.5 billions 1999 Market value for knee implants (prosthesis costs only) Datamonitor

USA 5.2 billions 2001

annual spending for total knee replacement; estimation based on incidence (200.000 patients/year) and cost per treatment (26.000 US-$)

(Russell et al. 2001)

World 6.5 billions 2001 market potential of surgical pro-cedures for cartilage regeneration

(Landesbank Baden-Württemberg Equity Research 2001)

World 25 billions 2011 market potential of surgical pro-cedures for cartilage regeneration

(Landesbank Baden-Württemberg Equity Research 2001)

As can be seen from table 5.3, the potential markets for cartilage repair amount to several billion €, and are thus very attractive. However, actual worldwide sales fig-ures for ACT are unlikely to exceed € 40 mio. That the presently accessible market for cartilage repair by tissue engineering is much smaller than the potential market is due to the following factors:

• Restriction to traumatic cartilage defects. With the present technology of trans-planting autologous chondrocytes in suspension and covering the transplanted cells with a cover (e.g. periosteum, artificial cover), only those joint cartilage de-fects can be treated which are due to traumatic injury (e. g. sports injuries). However, the majority of joint defects is due to osteoarthritis or rheumatoid ar-thritis.

• Restriction to knee joints. The surgical techniques by which the chondrocytes can be introduced into the damaged joint are established only for knees, but can-not readily be applied to other joints (e. g. hip, shoulder etc.). Due to these two reasons approximately 90 % of the joint cartilage defects in the affected popula-tion are not an indication for autologous chondrocyte transplantation using cell suspensions.

• Compliance of patients. As it takes approximately six months of rehabilitation, during which the treated knee cannot be fully used, a high compliance of the pa-tients with a strict rehabilitation protocol is required. This restricts the market to highly motivated, mostly younger patients. An artificial knee prosthesis, how-ever, can bear weight already a few days after the surgery.

• Alternative treatment options. Because a partial or full knee prosthesis can bear weight already a few days after the surgery, this option is preferred especially for

34

elder patients whose life expectancy correlates with the life span of the prosthe-sis. The suppliers of joint prostheses continually optimize their products so that the competition between cell based and prosthesis-based treatment options will continue.

Company experts interviewed for this study assumed that the ACT variant of ma-trix-induced ACT, which has recently become clinically and commercially avail-able, much larger and lucrative market segments could be opened up which are not accessible for cell suspensions:

• on the one hand, the easier surgical technique of matrix-induced ACT will sup-port the further use of this technique among orthopedic surgeons,

• on the other hand, it may be possible to treat also osteoarthritic defects in the knee, and perhaps also several types of cartilage lesions in other joints than the knee.

In addition, new tissue-engineered products are in preclinical development which combine cartilage and bone and might be used for the treatment of defects which affect both cartilage and bone. If the above mentioned assumptions proved true, matrix-induced chondrocyte trans-plants could partially replace knee prostheses, could also offer an option for defects which are presently not treated at all, and could – in the long term – postpone the need for joint prosthesis for several years. The size of this additional segment can-not be estimated with accuracy because the results from the ongoing clinical trials must still be awaited. For the USA, the annual market for effective new repair tech-niques is estimated at € 300 mio. to € 1 billion (Russell et al. 2001). Given the fact, that actual worldwide sales for ACT do not exceed € 40 mio., this would be a more than tenfold increase over the present market.


In orthopedic surgery, the concept of cell therapy is rather new. Therefore, a certain scepticism among orthopedic surgeons who are more used to prostheses, screws and plates, must be overcome. Therefore, relatively large efforts have to be taken to educate, convince and train these medical doctors. This also implies that the market-ing activities are knowledge-intensive and must be carried out by relatively highly qualified staff. Although strategic cooperations with medical device companies which are active in the orthopedics market have been formed to improve the access to the customers, experts are sceptical whether their marketing activities are appro-priate for cell-based products.

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The therapeutic success does not only depend on the quality of the chondrocyte transplant, but also on the quality of the surgical procedure and the rehabilitation protocol. Some companies, e. g. co.don in Germany, therefore follow a "Centre of Excellence" concept. This means that also their customers must comply with quality standards. This concept also makes it easier to obtain reimbursement for the trans-plants either from health insurers or hospital funds. At present, the main hindrance for expanding the ACT sales in the segment of traumatic knee injuries is the fact that no general reimbursement of this treatment by health insurances has been obtained so far in Europe, the only exception up to now being Austria. In Austria, autologous chondrocyte transplantation is listed in the "Leistungskatalog BMSG 2003 – Leistungsorientierte Krankenanstaltenfinan-zierung" (Editor Bundesministerium für soziale Sicherheit und Generationen) as an "costly diagnostic or therapeutic procedure". Since January 2003, Austrian hospitals must document their health services according to this Leistungskatalog in order to get reimbursement. As this "Leistungskatalog" came into force not before January 2003, figures are not yet available whether this different reimbursement practice in Austria corresponds to an increase in autologous chondrocyte transplant sales. Moreover, Austria is not the market which has been primarily targeted by the lead-ing companies. Review and approval procedures have been initiated e. g. in Germany with the Bundesausschuss der Ärzte und Krankenkassen and in the UK with the National Institute of Clinical Excellence (NICE). However, in 2000, these institutions came to the conclusion that the evidence on ACT does not yet support the widespread introduction of this technology into the respective national health systems (Geschäftsführung des Arbeitsausschusses "Ärztliche Behandlung" des Bunde-sausschusses der Ärzte und Krankenkassen 2000; Gibis et al. 2001; NHS Centre for Reviews and Dissemination 2003; Jobanputra et al. 2003; Jobanputra et al. 2001). Reviews of these decisions are ongoing, and may be due in 2003. As decisions on general reimbursement of ACT are still pending, in the present situation the reimbursement of the treatment costs has to be negotiated on a case-by-case basis. Moreover, the policy of the health insurers seems to differ from country to country, with companies perceiving Germany as being more prohibitive and the Benelux countries as being more permissive. Some companies hold special "reimbursement departments" which support patients and doctors in obtaining treatment cost reimbursements.

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6. Tissue engineered bone products


Tissue engineered bone addresses the bone repair market which is in principle a very huge market of several billion €/year worldwide. Indications and market seg-ments for tissue engineered bone products are (Concord Corporate Finance Re-search 2002)

• Bone fractures. Most bone fractures are treated by standard therapies (see be-low); however, appr. 10 % cannot be treated this way because the damaged sites are too big. If tissue engineered bone could be used, it could be applied world-wide in 1.5 mio. patients per annum. The most important markets are the USA with 700,000 patients and Europe with 600,000 patients.

• Jaw bone surgery and periodontal surgery. The number of patients in this field amounts to approximately 1.5 mio. patients in Europe and 4.5 mio. patients worldwide.

• Osteoporosis and bone tumors. In Europe there are 10 mio. cases annually, the worldwide potential sums up to 30 mio. applications.

Most bone fractures are treated by standard therapies. These are gypsum/plaster, tape, nailing, screws and plates. Larger defects, due to fractures, surgery or tumors, can be treated with autologous bone grafts which are taken from another site of the patient’s body in a second surgical procedure. These grafts normally give the best clinical results compared to other options. Another option are allogenic bone grafts which are taken from other patients undergoing bone surgery or from cadavers and stored in bone banks until used. Problems with these allogenic grafts lie in risk of infection, higher bone resorption rates and variations in quality due to donor varia-tion. A third option are synthetic bone materials such as calcium phosphate, hy-droxylapatite etc. These materials, however, lack the power of rapidly inducing bone formation. Moreover, bone from animal sources is being used. Most of these xenogeneic bone materials are prepared from deproteinized bovine bone. In general, xenogeneic bone can have better toxicological and bone-inducing properties than synthetic bone materials, but bear the risk of infections (e. g. viruses, prions) and rejection. Table 6.1 gives an overview of the advantages and disadvantages of the different treatment options in bone repair.

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Table 6.1: Comparison of different bone repair approaches

type of graft

rejection type of material

infection availabil-ity

type of surgery

size of grafting

shaping

autolo-gous grafts

no rejec-tion

own ma-terial

no risk of infection

immedi-ate but limited

large biopsy and transplan-tation

limited no indi-vidual shaping

alloge-neic grafts

risk of rejection

foreign substance

risk of infection

immedi-ate but limited

only transplan-tation


synthetics generally no rejec-tion

transfor-mation into own material


immedi-ate, un-limited


not lim-ited

special shape available

xenoge-neic grafts

risk of rejection

foreign substance

risk of infection

immedi-ate, un-limited



autolo-gous TE products

no rejec-tion

own ma-terial with os-teoblasts


unlimited but de-layed

small biopsy and transplan-tation

not lim-ited

shaping by in-jectable bone material


There are only few companies which have tissue engineered bone development programmes. These companies are

• IsoTis SA (CH/NL). Until recently, IsoTis had a research programme for the autologous bone product VivescOs, and an associated bioreactor production plat-form. However, in the course of the recent restructuring and reorganisation, this programme was cancelled. Instead, the scaffold OsSatura (without cells) has been brought onto the market in 2003 after receiving approval in Europe. Os-Satura is osteoconductive, i.e., it guides bone formation through its macroporous structure, and also osteoinductive, i.e., it actively induces bone to grow in and on the scaffold. OsSatura replaces an earlier product launched in late 2001, Os-Satura PCH. The company expects OsSatura to become a major product. The sales expectations are > 10 mio. € by 2005/2006, equivalent to 15-20 % of the synthetic bone substitute market (see table 6.3). Although OsSatura is less pow-erful than the tissue engineering approach followed until recently, the company assesses OsSatura's cost of goods as much more favourable than the tissue engi-neering option, whose additional therapeutic benefit would not justify the addi-

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tional high costs (IsoTis press releases January 7, 2003; February 5, 2003; March 27, 2003). IsoTis best selling product in 2002 was SynPlug, a cement restrictor for cemented hip replacements. It is CE certified. It was launched in 2001 and is presently being sold through orthopaedic companies such as Smith & Nephew, Centerpulse France, and ScandiMed (Biomet Merck), as well as through a range of national distributors. Sales for the SynPlug in Europe amounted to € 646,000 in 2002.

• BioTissue Technologies (Germany). This company has an autologous bone product on the market since November 2001. BioSeed®-Oral Bone is a three-dimensional, jawbone graft from cultured autologous periosteum cells. It can be used in the treatment of tooth loss with fixed dental prostheses. By strengthening and replacing missing upper jaw bone material it supports the anchoring of den-tal implants firmly into the jaw. Sales of BioSeed®-Oral Bone amounted to € 250,000 in 2002.

• co.don (Germany). Since 1997, co.don® has been manufacturing autologous osteoblast transplants according to the German Drug Act (AMG) under the brand name co.don osteotransplant®. The product is indicated in complicated fractures, tumour based bone damages, pseudoarthroses, sarcomata and calcifications in loosening or change of prostheses. Further indications are the reconstructive and plastic surgery, jaw bone surgery and bonechip blocking of spine segments in case of severe degenerated disks.

• Osiris Therapeutics, Inc (USA). Osiris Therapeutics is a privately held devel-opment stage company, focusing on cellular therapeutic products for the regen-eration and functional restoration of damaged and diseased tissue. The therapeu-tic products are derived from human mesenchymal stem cells (hMSCs) ex-tracted, isolated and purified from adult bone marrow. Osiris specialises in the differentiation of hMSCs into different specialised cell types, among them bone. The product Osteocel is bone regenerated from autologous mesenchymal stem cells for orthopedic and dental defects. In 2002, a small Phase 1 human safety trial was completed in which autologous hMSCs were delivered on a hydroxya-patite matrix into the jaw to promote new bone formation in preparation for den-tal implants. The results of that study demonstrated significant new bone forma-tion with no adverse events. Moreover, the feasibility of fully MHC mis-matched allogeneic MSCs to repair large segmental defects have been demonstrated in a baboon preclinical model. Ongoing studies are focused on the ideal composition of a matrix and the Adult Universal Cell hMSC product for delivery to load-bearing, long bone defects.

• CellFactors (UK). CellFactors focusses on the development of human cell-based therapies by generation and manipulation of immortalized, partially diffe-rentiated human cells. One of the company's areas of focus are protein matrices (orthobiologics) for bone regeneration. CellFactors lead product for bone regene-ration is SkeletexTM. This osteoinductive material consisting of growth factors

39

and collagens has the potential to increase the strength of weak or damaged bo-nes, or to create new bone where required. CellFactors is developing Skeletex™ for use in conjunction with existing orthopaedic devices and prosthetics (e.g. in spinal fusion, artificial hips and knees), as well as for dental applicati-ons.CellFactors plc demonstrated its ability in January 2003 to manufacture Ske-letex™ consistently to meet industrial requirements so that the material can be produced in sufficient quantities for full-scale commercial production. CellFac-tors is currently in negotiations with a number of orthopaedic companies to supply Skeletex™ for a range of applications. Contract Manufacturing Organisa-tions have now been identified and assessed for commercial-scale production of Skeletex™.

Several companies are offering growth factors and bone morphogenic proteins. Among them are

• Curis, Inc. (USA). Curis resulted from a merger of Creative BioMolecules Inc. (USA) with Ontogeny, Inc. (USA) and Reprogenesis Inc. (USA) in July 2000. Curis is a therapeutic drug development company. The Company's technology focus is on regulatory pathways that control repair and regeneration, among them the Hedgehog (Hh) pathway and the Bone Morphogenetic Protein (BMP) path-way. Development of several therapeutic products is in early to late preclinical stages.

• Wyeth (USA). Wyeth carries out discovery, development, manufacture, distribu-tion and sale of pharmaceuticals and over-the-counter consumer health care products. Among its products in the pipeline is hBMP-2, a recombinant human bone morphogenetic protein 2. It is approved in the EU and is currently in U.S. regulatory review for treating patients with acute long-bone fractures requiring surgical management. Its use in spinal fusion is being investigated in cooperation with Medtronic Sofamor Danek. The product is approved and launched in the U.S. for lumbar interbody spinal fusion. It is in Phase III trials for lumbar poster-olateral spinal fusion. Additional uses for rhBMP-2 are being investigated in ear-lier development phases.

• Medtronic Sofamor Danek (USA). Medtronic Sofamor Danek develops and manufactures products that treat a variety of disorders of the cranium and spine, including traumatically induced conditions, degenerative conditions, deformities and tumors. In 2002, U.S. Food and Drug Administration (FDA) approved Med-tronic Sofamor Danek's INFUSE™ Bone Graft/LT-CAGE™ Lumbar Tapered Fusion Device. This device is used to apply INFUSE™ Bone Graft in spine sur-gery in order to treat degenerative disc disease. The bone graft contains recombi-nant human bone morphogenetic protein (rhBMP-2), that is capable of initiating bone growth, or bone regeneration, in specific, targeted areas in the spine. De-velopment projects of combining threaded cortical dowels and Bone Morphoge-netic Proteins (BMP) are underway.

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• Stryker Corporation (USA). Stryker Corporation develops, manufactures and markets specialty surgical and medical products globally. The products include orthopaedic implants, trauma and spinal systems, powered surgical instruments, endoscopic systems, and the bone growth factor osteogenic protein-1 (OP-1). Marketing authorization was obtained in 2001 for OP-1 by Australia, the Euro-pean Union and the United States for specific indications involving long-bone fractures. Stryker is also investigating spinal applications for OP-1 through clini-cal trials in North America and Japan.

• Orquest, Inc. (USA). Founded in 1994 and employing a staff of 25, Orquest, Inc. is a orthobiologics company that designs, develops, manufactures and sells materials that accelerate and enhance bone repair and regeneration. Orquest's unique product portfolio is based on two proprietary core technologies. Its bone graft substitute Healos® is approved for sale in Europe, and Ossigel®, an in-jectable product designed to improve fracture healing, is currently under clinical investigation in Europe. Healos®MP52 is combination of Healos and the bone inducing protein MP52. MP52 is under clinical investigation in Europe.

There are many companies which offer biomaterials and synthetic bone fillers. Among them are

• Biomet Merck Group (The Netherlands). Founded in 1998 as a joint venture of Biomet Inc. (USA) and Merck KGaA (Germany), the company is specialised in the development, production and marketing of products for the therapy of bone and soft tissue diseases. It combines expertise in pharma and chemistry, biomaterials, drugs, orthopaedics and implants.

• Interpore Cross International (USA). Interpore Cross International develops and applies biologic biomaterials to speed bone repair. It has three products on the market: AGF technology, which allows the surgeon to collect autologous growth factors from the patient's blood and to combine it with bone grafting ma-terial in order to support healing. ProOsteon is a hydroxyapatite bone grafting material harvested from marine coral exoskeletons. BonePlast is an extrudable, moldable bone void filler based on calcium sulfate.

• Orthovita (USA). Orthovita is a biomaterials company which develops novel products for use in spine surgery and in the repair of osteoporotic fractures. It has two products on the European market: VITOSS®, a resorbable calcium phos-phate bone void filler, and CORTOSS®, a Synthetic Bone Void Filler, is a high-strength, bone-bonding, self-setting composite engineered specifically to mimic the strength characteristics of human cortical bone.

Other players and competitors in the field are large orthopedic companies, which offer “conventional” treatments, e. g.

• Stryker Corporation (see above).

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• Johnson & Johnson (USA). Johnson & Johnson is a comprehensive and broadly based manufacturer of health care products, and a provider of related services, for the consumer, pharmaceutical and medical devices and diagnostics markets. Johnson & Johnson has 198 operating companies in 54 countries. Johnson & Johnson's business segment "Medical Devices and Diagnostics" includes surgical implants, instruments, needles and sutures; blood glucose monitoring systems; wound closure devices; endoscopic instruments; orthopaedic products for joint repair and replacement and for correcting spinal deformities; contact lenses; clinical chemistry systems; medical devices, including cardiovascular monitoring and vascular access products; intravenous catheters and shunts; coronary and bil-iary stents; and diagnostics.

• Smith & Nephew (UK) (see annex).

• Zimmer Inc. (USA). Zimmer Inc. is a global player in the design, development, manufacture and marketing of reconstructive orthopaedic implants and fracture management products.

• Biomet Merck (see above).

• Synthes-stratec (Switzerland). Synthes-Stratec is an international medical device company, specializing in the development, manufacturing and marketing of in-struments and implants for the surgical treatment of bones (osteosynthesis). Syn-thes-Stratec’s activities also include new technologies such as implant coatings, synthetic bone replacement materials, bioresorbable implants, and computer-assisted surgery.

• Mitek (USA). Mitek Worldwide is a developer, manufacturer and marketer of innovative medical devices for surgery, with focus on sports medicine and re-construction. It is a division of Ethicon, a Johnson & Johnson company. The company's main products, suture anchoring implants are primarily used to reat-tach damaged ligaments and tendons in the shoulder, rotator cuff, wrist, thumb and ankle.

In hip and knee prostheses, important companies are mainly from the USA, while in trauma repair, European companies are better positioned.

6.3 Potential market volumes

Most bone products on the market do not fall into the definition of core tissue engi-neering products used in this study, because they either use only cells or growth factors or scaffolds, but not combinations thereof. Moreover, only few figures on actual sales could be retrieved from publicly available sources (table 6.2). However, market data on conventional bone replacement materials are available (table 6.3). The worldwide market is in the order of magnitude of € 300 mio. These market fig-

42

ures may represent the market potential for tissue engineered bone as long as no unique applications for tissue engineered bone emerge.

Table 6.2: Sales 2002 of bone products by tissue engineering companies

Company Product Description Sales 2002 (€)

IsoTis BV SynPlug CE certified cement restrictor for cemented hip replacements. 646,000

BioTissue Technologies

BioSeed OralBone

three-dimensional, jawbone graft from cul-tured autologous periosteum cells for use of fixing dental implants into the jaw bone

250,000

Table 6.3: Market for bone replacement and repair

Type of bone replacement USA 1998 World 2002

Autologous bone € 105 mio. 47 % Allogenic bone € 97 mio. 43 % Xenogeneic bone no data available no data available

€ 249 mio.

Synthetic bone material € 23 mio. 10 % € 51 mio. Total € >225 mio. € 300 mio.

Source (Concord Corporate Finance Research 2002) IsoTis 2003


Although tissue engineered bone can be grown successfully, experts are of opinion that at present there are only minor applications for commercialisation due to the following reasons: At the present state of the art in bone tissue engineering, only smaller defects could be treated. However, for these defects existing treatments (autologous or allogenic bone grafts, synthetic bone fillers) fulfil the clinical needs satisfactory, so that tissue engineered bone would have to edge out these established options. In addition, most bone defects come from trauma and accident and require acute treatment, so that there is not enough time to grow an autologous bone by tissue engineering. Only a minor fraction of bone surgery are planned operations. This is mainly the case in revision surgery when a prosthesis is replaced by a sec-ond one. Then the gaps between the prosthesis and the bone could be filled with tissue engineered bone. Nevertheless, experts have doubts that tissue engineered bone in the mentioned applications could be competitive on a monetary cost bases because its production costs would be in the order of magnitude of chondrocyte transplants (appr. 5,000 €). Therefore, a significant reduction in costs of the tissue engineered bone would be required. It is discussed controversially among experts

43

how this can be achieved (e. g. highly automated graft production procedures in specially designed bioreactors). As a consequence, present applications seem to be restricted to rather small niche markets, e. g. in dental and maxillofacial surgery. This market is targeted e. g. by BioTissue Technologies product BioSeed®-Oral Bone. Here, making the surgery easier and giving the patient less pain are advantages that the patients are willing to pay for. Established bone defect treatment options have relative weaknesses in the treatment of large bone defects, so that there would be a medical need for new treatments for this type of defects. However, the technology of bone tissue engineering is not yet advanced enough to provide such large bones with the required biomechanical properties. According to the experts interviewed, medical device companies which are active in the orthopedics market have recognised the potentials of tissue engineering for the future development of their field, and they closely monitor the progress of tissue engineering in this area. However, despite being aware of the future relevance of tissue engineering for the competitiveness of these companies, present investment into tissue engineering research projects is still rather limited. This is due to the fact that decisions must be made regarding the allocation of research funds to different projects. In these decision process, R&D projects in advanced "traditional" medical devices are often preferred over tissue engineering projects, because in direct com-parison, the "traditional" projects promise a larger, quicker and less risky return of investment. In addition, it is difficult for these companies to carry out tissue engi-neering, because tissue engineering requires different "thinking", competencies and procedures than those established in medical device companies.

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7. Tissue engineered cardiovascular products


Cardiovascular diseases (CVD) include hypertension, coronary heart disease, stroke (cerebrovascular disease), peripheral vascular disease, heart failure, rheumatic heart disease, congenital heart disease and cardiomyopathies. In the EU, 240-260 deaths per 100,000 population must be attributed to cardiovascular diseases. Thus, CVD are responsible for about half of the total mortality and therefore remain one of the main causes of death (World Health Organization (WHO) 2002). At present, tissue engineering R&D in the field of CVD comprises three fields of activities:

• Heart valves,

• Vessel grafts,

• Cell grafting into the heart muscle after myocardial infarction. To grow complete hearts by tissue engineering will remain science fiction for at least several decades. At present, there are no tissue engineered cardiovascular products on the market; they are all still in the R&D phase.

7.1.1 Heart valves

The surgical replacement of a heart valve is a common treatment for end-stage val-vular diseases. Currently, three major types of valves are available for replacement (Zeltinger et al. 2001; Von Oppell et al. 2001):

• Mechanical heart valves. Mechanical heart valves are manufactured primarily from titanium steel and pyrolytic carbon. They have superior durability com-pared to biological valves. However, life-long anticoagulation therapy is required to reduce the risk of thromboembolic complications due to the thrombogenic po-tential of the mechanical prostheses. This anticoagulation therapy is associated with a dose-related risk of bleeding complications. Moreover, they are suscepti-ble to infection.

• Biological tissue valves. Biological valves show better haemodynamic properties than mechanical valves, therefore do not require administration of anticoagula-

45

tion drugs, but in general have a shorter life-span than mechanical valves due to calcification and non-calcium-related degeneration. Therefore, reoperation sur-gery is often required to replace degenerated biological valves. Biological valves from different sources are in clinical use: − Allogeneic valves from human cadaver. Biological allogeneic valves are in

clinical use which were taken from human cadavers. They are processed by different processes, such as cryopreservation, freeze-drying, irradiation, fixa-tion with glutaraldehyde or sterilisation with ethylene-oxide). A major draw-back in comparison with the other valve options is their limited availability, most pronounced for children. Moreover, there is a risk of rejection.

− Biological xenogeneic valves from porcine or bovine sources. Biological valves have predominantly been manufactured from bovine pericardium or porcine aortic valves. They are preserved and sterilised by different tech-niques (e. g. fixation with glutaraldehyde) and therefore do not contain any living cells.

− Autografts. Autografts are valves that have been moved from one position to another position within the same individual (such as transferring of a pulmo-nary valve to the aortic position).

So far, none of these valves is ideal, having problems of thrombogenicity, limited durability and shortage of supply, respectively. They are not able to grow, repair and remodel to the functional needs. To overcome this, tissue engineered heart valve replacements are being developed. The general goal is to provide a "custom-made", living valve replacement with growth potential, non-thrombogenicity and lifetime durability. The general approach is to seed a scaffold with cells in vitro, to "condition" the cell culture with special emphasis on dynamic tissue culture, and to transplant these "cell-coated" structures into the patient, where the scaffold is gradually replaced by a new matrix produced by the cultured cells. However, TE research on heart valves is still in the preclinical phase, yielding first results from large animal models. Research issues comprise (Stock et al. 2002):

• Choice of appropriate cells and cell sources. Cells from arteries, veins, microvas-cular endothelial cells, progenitor cells and stem cells both from allogeneic and autologous sources are being tested,

• Choice of an appropriate scaffold. Several approaches use decellularized biologi-cal allogeneic and xenogeneic matrixes, others use scaffolds from biomaterials. Here, still unsolved problems are materials with appropriate biomechanical and biocompatible properties as well as the optimal design of the scaffold. 3D imag-ing, injection molding and stereolithography are being researched.

• Achieving long-term function and adaptability as well as absence of degenera-tion, thrombogenicity, and infection in large animal models as well as humans.

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7.1.2 Blood vessels

Atherosclerosis, a process that causes narrowing of the arteries, is a risk factor for myocardial infarction. For coronary arteries, this narrowing leads to a weaking of the myocardium (i. e. the wall of the heart), and ultimately to myocardial infarction. When a myocardial infarction is either imminent or occurs, the most common form of treatment is coronary bypass surgery. Usually, the patient's internal mammary artery or the saphenous vein is used (auto-graft). However, autologous vessels are not always available, either because of be-ing diseased themselves, or because of previous surgery. If autologous vessels are unavailable, then synthetic blood vessel substitutes can be used. They are made from Dacron or expanded polytetra fluoroethylene (ePTFE). When replacing larger vessels, i. e. 6-10 mm in diameter, these grafts can be successfully used, but when used in the coronary system where diameters are 3-4 mm, thrombotic events rapidly close them off (Nerem et al. 2001). Against this background, R&D is underway to develop tissue engineered blood ves-sels which may be used as a small vessel diameter substitute. The significance of developing tissue engineered blood vessels, however, reaches far beyond vessels for bypass grafts. As blood is the major form of supplying tissues and organs with nu-trients and of removing metabolic products, blood vessels are of crucial importance for the tissue engineering of more complicated tissues and structures. Tissue engineering of blood vessels aims at developing blood vessel substitutes, which exhibit all the functional characteristics of a natural blood vessel, especially

• no thrombogenicity,

• vasoactivity,

• appropriate mechanical properties (Nerem et al. 2001). Several approaches are being followed in order to engineer a blood vessel substitute (Nerem et al. 2001):

• EC-seeded synthetic grafts. This approach remains the most studied vascular tissue-engineering application. In this approach, synthetic blood vessel substi-tutes made from ePTFE or Dacron are coated with a monolayer of endothelial cells (EC). This approach is presently limited to the use of autologous endothe-lial cells. Autologous cells are required because immunological complications associated with nonautologous EC cannot be controlled satisfactory. These EC-seeded synthetic grafts lack vasoactivity. Long-term experience with clinical ap-plication in humans has been published (Deutsch et al. 1999; Meinhart et al. 2001). Clinical trials have been carried out involving the in vitro endothelializa-tion of vascular grafts prior to implantation which have shown conclusively that

47

tissue engineering results in a significantly enhanced clinical performance in small-diameter grafts (Seifalian et al. 2002).

• Collagen-based blood vessel grafts. In this approach, collagen instead of syn-thetic polymers act as substrate for cell attachment. This approach, in principle, offers the potential to engineer a vasoactive graft with cell-mediated in vivo re-modelling. However, these properties still remain to be demonstrated. Moreover, the inherent physical weakness of collagen must be overcome in order to grow vessel substitutes which are able to withstand the physical load imposed by he-modynamics. Today, the collagen-based constructs can withstand a pressure of approximately 225 mm Hg, which is not acceptable for arterial replacement sur-gery.

• Biodegradable synthetic polymer based blood vessel grafts. This approach uses biodegradable synthetic polymers such as polyglycolic acid as biodegradable scaffold on which the cells are grown. Cultivation under pulsatile conditions was required to generate vessels with significant rupture strength.

• Cell self-assembly blood vessel grafts. In this approach, vascular cells are cul-tured to form a continuous sheet of cells and extracellular matrix and then rolled over a central mandrel. The construct is matured over several weeks, allowing the cells to organise into a mechanically stable tubular construct. Layers of dif-ferent cell types can be combined.

• Decellularized approaches to blood vessel grafts. In this approach, a noncellular construct is implanted and thereafter recruits cells from the surrounding host tis-sue. Due to the presently poor understanding of in vivo vascular cell migration and of engineering this response into a vascular construct, this approach is likely to require several more years until clinical application.

As the growing of tissue engineered blood vessel graft in the laboratory is still the objective of research, few R&D efforts have been devoted to the question how to produce these vessel grafts on a commercial and cost-competitive scale. Recent research results indicate that bioreactors will be required which provide engineered vessels with mechanical stimulation. Moreover, the long-term integration of a living cell construct into a living system still remains to be demonstrated in large animal models and man, overcoming – among others – also the immunological response when using non-autologous constructs. Therefore, the approval of a small-diameter blood vessel substitute by regulatory authorities is at least a decade from now (Nerem et al. 2001).

7.1.3 Myocardial infarction

Even with current medical management, over one third of acute heart attacks are fatal. After a non-lethal coronary infarction a rehabilitation of the patient is possible

48

to a certain extent, but larger impairments cannot be fully healed. Treatments to prevent tissue damage after a heart attack include drugs that break down fibrin clots and open up blocked arteries. These drugs have greatly influenced morbidity and mortality, but must be administered within a short interval after a heart attack to be effective. Cardiac catheterization and angioplasty to dislodge the clot and open the blocked vessel have proven effective in restoring blood flow, but cannot reverse preexisting tissue damage. The transplantation of a healthy donor heart is a compli-cated surgery, which is also severely limited by the lack of donor organs. In order to complement these established therapies, there is a medical need for treatments that contribute to the restoration of the damaged heart. One option is the transplantation of healthy cells into the area where the infarction took place. For this purpose, different types of cells can be considered, among them (Rosenthal et al. 2001; Kessler et al. 1999):

• Fibroblasts.

• Skeletal muscle cells. Of all approaches listed here, this approach is the most advanced one at present. A clinical trial phase I was successfully completed by Prof. Menasché, Paris (Menasche et al. 2001; Pouzet et al. 2001; Menasche 2002; Hagège et al. 2003). A clinical trial phase II has started in 2002 in coop-eration with Genzyme Biosurgery (see below).

• Primary heart muscle cells.

• Hematopoietic stem cells. The therapeutic concept to implant autologous blood stem cells after an infarction to restore the damaged area has already been tested in humans (Strauer et al. 2001; Stamm et al. 2003).

• Embryonic stem cells. Embryonic stem cell transplantation for heart failure has been tested in rodent models (Roell et al. 2002), but not yet in humans.

7.2 Overview of companies and their R&D activities

7.2.1 Heart valves

There is a large number of companies which offer heart valves. Strong market posi-tions are occupied by

• Centerpulse (Switzerland)

• Edwards Lifesciences (USA)

• Medtronic, Inc. (USA)

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• Sorin Biomedica (Italy)

• St. Jude Medical, Inc (USA) Other companies, also offering heart valves, are

• ATS Medical, Inc. (USA)

• CryoLife, Inc (USA/UK)

• Jostra AG (Germany)

• Jyros Medical Devices (UK)

• Labcor Laboratories (Canada)

• Medical Carbon Research Institute, LLC (USA)

• Medical Incorporated (USA)

• Shelhigh, Inc. (USA)

• Sulzer (Switzerland) It can be assumed that leading heart valve companies closely monitor the develop-ment in tissue engineering of heart valves, and may also have own R&D activities in this field. However, due to the preclinical stage of tissue engineered heart valve R&D, information of companies' activities in this field is scarce. The following companies have been reported to have R&D activities in the tissue engineering of heart valves:

• AorTech International, plc (UK/Australia). The company investigates the use of its polymer Elast-EonTM and other polyurethanes for use e. g. in heart valves, but presently undergoes a change in its business strategy.

• Autogenics (USA). Autogenics is a start-up company which carries out R&D in the field of autologous tissue cardiac valves.

• CryoLife, Inc (USA/UK). The company has proprietary processes for preserving human heart valves, veins and connective tissue making them available for car-diac, vascular and orthopaedic surgical reconstruction. Over 75% of all cardio-vascular procedures involving allograft (homograft) tissue in the U.S. are per-formed with cryopreserved human heart valves from CryoLife (Product Cry-oValve®). Since 1996 and 1998, the company offers the CryoLife-O'Brien® stentless porcine aortic heart valve and the CryoLife-Ross® pulmonary porcine heart valve on the European market. Both valves have been awarded the Euro-pean CE (product certification) mark, allowing distribution throughout the Euro-pean Union. CryoLife's Research Staff has developed a tissue engineered heart valve and vascular graft replacement called the SynerGraft® family of products.

• TiGenix (Belgium). TiGenix develops cell-based tissue-engineered products in the areas of joint-surface defects, bone defects and heart valves. It carries out a

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collaborative research project with the Centre for Experimental Surgery and An-aesthesiology of the University of Leuven, a leading test centre for heart valves, to develop tissue engineered heart valves. Upon selection of the appropriate cell lines and scaffolds, TiGenix aims to further develop these valves into a stage where they can be out-licensed to a partner specialising in cardiac valve re-placement.

7.2.2 Blood vessels

Due to the mostly preclinical or early clinical stage of tissue engineered blood ves-sel R&D, information of companies' activities in this field is scarce. The following companies have been reported to have activities in the tissue engineering of blood vessels:

• Advanced Tissue Sciences (USA). ATS had tissue-engineered vascular grafts in development (Huynh et al. 1999), but most probably stopped this programme af-ter filing for bancruptcy in autumn 2002.

• Organogenesis (USA). Organogenesis did research into cell self-assembly blood vessel grafts (Huynh et al. 1999), but most probably stopped this programme af-ter filing for bancruptcy in autumn 2002.

• Vascular Biotech GmbH (Germany). Founded in 1998, Vascular Biotech GmbH is a tissue engineering company which focusses on the development, production and marketing of products for the treatment of vascular and heart diseases. Since 2001, the company has their patented tissue-engineered aorto-coronary bypass graft in clinical trials. The vessel graft consists of cryopreserved donor veins, lined with recipient-own endothelial cells.

• co.don (Germany). co.don has endothelialized vessels in clinical trials, phase I.

• BioTissueTechnologies (Germany). BioTissueTechnologies intends to commer-cialize vessel prostheses coated with autologous cells which are in preclinical development at Cell-Lining (Germany).

• Angio Genetics AB (Sweden). Probably not working in the core area of tissue-engineering of blood vessels is Angio Genetics AB. Founded in 2001 as a spin-out from Gothenburg University and the Karolinska Institute, Angio Genetics AB is a drug discovery company focusing on the formation of new blood vessels (angiogenesis). The focus of Angio Genetics AB is early drug discovery in the area of angiogenesis regulation, for pro- or anti-angiogenic therapies, which could be applied in the treatment of e. g. cancer, ischemic heart disease, diabetic microangiopathy and chronic wounds.

• Ark Therapeutics Oy (Finland). Probably not working in the core area of tissue-engineering of blood vessels is Ark Therapeutics. Ark Therapeutics is a Europe-an biotechnology company. It focuses on research, development and commercia-

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lisation of therapeutic products for vascular disease and cancer. Its product Tri-nam™ is in preparation for a Phase II/III study. It is a combination of a vascular endothelial growth factor gene packaged in an adenoviral vector and Ark's bio-degradable local drug delivery device (termed EG001). Once the VEGF gene is transfected locally, muscle cells in the vessel wall express the VEGF protein which triggers the release of nitric oxide and prostacyclin. These two agents have a protective effect, preventing the blocking of the blood vessels. The product will initially target the market for haemodialysis graft access surgery. Trinam™ has been granted Orphan Drug Status by the FDA.

7.2.3 Myocardial infarction

At present, no cell therapy for the treatment of myocardial infarction has been ap-proved. All activities in this field are preclinical research, or phase I to phase II clinical trials. The following companies have reported R&D activities in this field:

• Genzyme Biosurgery (USA/Europe). In December 2002, Genzyme Biosurgery started a randomized, double blind, placebo controlled clinical trial phase II with the aim of testing the safety and effectiveness of cardiac myoblast cell transplan-tation for the prevention of the progression of heart failure in patients who have had a heart attack. The trial uses the methodology developed by Prof. Menasché: autologous skeletal muscle cells are taken from the patient prior to bypass sur-gery through a small biopsy in the leg. The cells are multiplied over the course of three weeks in the laboratory, and injected into a scarred region of the heart dur-ing a coronary artery bypass operation. It is planned to enroll up to 300 patients in 30 medical centers throughout Europe and North America during the first half of 2003. Measures to be evaluated include monitoring the area into which the cells were injected to determine whether the engrafted cells restore the heart's ability to contract in that area; changes in left ventricular ejection fraction; and a comparison of the incidence of Major Adverse Cardiac Events (MACE) between treated and non-treated groups. Monitoring of all patients will continue for up to two years after treatment. The trial is being principally funded by Genzyme Biosurgery, with support from Assistance Publique - Hôpitaux de Paris. It is be-ing conducted in partnership with Myosix SA of Paris.

• Diacrin (USA). Diacrin develops a treatment for ischemia damaged myocardium with autologous skeletal myoblasts. In 2002, two Phase 1 clinical trials were car-ried out treating patients with damaged heart muscle. In one clinical trial six pa-tients are treated with the implantation of 300 million myoblasts at the same time they receive a ventricular assist device (VAD) in order to maintain heart function while they wait for a donor heart to become available. The other trial is a dose escalation trial, in which 12 patients, as they undergo coronary bypass surgery (CABG), receive cell implant doses ranging from 10 million to 300 million cells. The trials are carried out at six medical centers in the USA.

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• BioHeart Inc. (USA). Bioheart, Inc. is a privately held company which is focused on the discovery, development and commercialization of cell-based therapy products for the treatment of cardiovascular diseases. Bioheart's lead product candidates are: − MyoCell, an autologous cell-based product used for the treatment of myocar-

dial infarction, currently in clinical trials in the United States and Europe. Since May 2001, Bioheart has completed 13 MyoCell™ cases at various cen-ters in The Netherlands, Germany and Italy. These Phase I/II studies were primarily designed to evaluate safety and provide preliminary efficacy infor-mation for the therapy and the delivery systems used in the procedure. The company plans to continue its trials in the USA in 2003, expand it to phase III by late 2003, resulting in a commercial release in 2006.

− MyoCath - SR 200, a percutaneous needle injection catheter for delivering cell therapy or other compounds to the myocardial tissue, currently in clinical trials in Europe.

− MyoCell VT, a cell-based product for the treatment of ventricular tachycardia, currently in pre-clinical development.

− BioPace, a cell-based product used for the treatment of sinoatrial nodal dysfunction disease, currently in pre-clinical development.

• Osiris Therapeutics, Inc (USA). Osiris Therapeutics is a privately held develop-ment stage company, focusing on cellular therapeutic products for the regenera-tion and functional restoration of damaged and diseased tissue. The therapeutic products are derived from human mesenchymal stem cells (hMSCs) extracted, isolated and purified from adult bone marrow. Osiris specialises in the differen-tiation of hMSCs into different specialised cell types, among them myocardial tissue. Financed by a research award from the Department of Commerce, Na-tional Institute of Standards and Technology/Advanced Technologies Program (NIST/ATP), Osiris has developed culture conditions to induce myogenic differ-entiation of hMSCs and has implanted hMSCs into the hearts of small and large animal models. Clinical trials are scheduled to start in 2003 in the USA to exam-ine the ability of MSCs to prevent the progression to heart failure following in-farction. In March 2003, Osiris and Boston Scientific Corporation (USA), a worldwide developer, manufacturer and marketer of medical devices which are used in a broad range of interventional medical specialties announced their alli-ance in this field. Osiris will manufacture the MSCs. Boston Scientific will pro-vide a specialized injection catheter for the safe and effective injection of the cells to the affected area of the heart, and will sell both the cells and the injection catheters globally.

Other companies with preclinical R&D programmes are Morphogen (USA), Geron (USA) and Cardion (Germany).

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7.3 Potential market volumes

7.3.1 Prevalences and incidences for cardiovascular diseases

In the EU, cardiovascular diseases are responsible for about half of the total mortal-ity and are therefore one of the main causes of death. Giving CVD high priority in health politics has already yielded some success: The mortality from CVD in the EU is now 240-260 deaths per 100,000 population. This is a remarkable decline, because it is only around half the 1970 level. Nevertheless, CVD are the leading cause of disease burden in 2000, accounting for 33.4 million DALYs4 (this is 21.8 % of the overall burden of disease and injury). Mortality indicators for cardio-vascular disease reflect aspects of health status that are influenced more by determi-nants such as lifestyles and the socioeconomic situation rather than performance of health care services (World Health Organization (WHO) 2002). The surgical replacement of a heart valve is a common treatment for end-stage val-vular diseases. More than 50,000 heart valve replacement procedures are conducted annually in the United States alone. Worldwide, there are about 175,000 valve re-placements performed each year. Coronary and peripheral vascular bypass grafting are now performed approximately 240,000-320,000 annually in Europe for cardiovascular diseases, and 560,000-480,000 of these procedures performed in the USA. In 2001, approximately 4,600 heart transplantations were carried out in Europe and the USA. Of these, 1,900 were performed in the EU.

7.3.2 Market figures related to CVD

In most of the industrialised countries, cardiovascular diseases cause relatively high health costs. Despite a decrease of the mortality caused by cardiovascular diseases, growing patient populations and more sophisticated treatments lead to an increase of health expenditures caused by CVD. The direct costs for the treatment of cardio-vascular diseases in the USA amounted to € 171 billions in 1998 (Reuters Business Insights 1999). According to an estimation of the US-Centers for Medicaid and Medicare, heart failure alone costs € 10 billion a year and accounts for roughly 60,000 deaths (Jahania et al. 2002). In Germany, CVD caused total costs of 4 DALY (disability-adjusted life-years) is a measure of disease burden. The DALY expresses years

fo life lost to premature death and years lived with a disability of specified severity and duration. One DALY is thus one lost year of healthy life.

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16 billion € in 1990, about half of them direct costs for drugs, ambulant treatments, hospital stays and rehabilitation. The other half were indirect costs due to mortality, inability to work and disablement (Kohlmeier et al. 1993). The prescribed pharmaceuticals have a relatively small share of the total costs, but can easily be determined. In the USA, the share of prescribed drugs for the treat-ment of CVD were only 9 % of the total direct costs in 1998, amounting to drug sales of € 14.8 billions (Reuters Business Insights 1999). The world-wide market for pharmaceuticals prescribed for cardiovascular diseases reached approx. € 64 billions in 1998. This corresponds to 23 % of the market for pharmaceutical products world-wide. 50 % of the market volume are made up by anti-hypertensives (Reuters Business Insights 1999). For the future it is expected, that on the one hand the leading cardiovascular medicines will get under substantial pressure by generic medicines what will lead to a limited growth of the market for pharmaceuticals against cardiovascular diseases. On the other side, under a global perspective, an increase in prevalence and incidence of cardiovascular diseases is expected (Reuters Business Insights 1999). In 2001, global heart valve sales amounted to 830 mio. US-$, with tissue valves and mechanical valves contributing about equally to the total sales: Global sales in tis-sue valves were 390 mio. US-$ in 2001. Due to progress regarding the lifetime of tissue valves, especially in the prevention of calcification, the tissue heart valve segment is expected to grow at the expense of the mechanical heart valve segment. Table 7.1 gives an overview of the market segmentation.

Table 7.1: Global heart valve market 2001

Type of heart valve Global sales 2001

Tissue heart valve (allogeneic, xenogeneic) 390 mio. US-$ Mechanical heart valve 380 mio. US-$ Repair 60 mio. US-$ Total 830 mio. US-$ Source: Edwards Lifesciences, Investor Conference 2002

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8. Tissue engineered organs


The "holy grail" of tissue engineering is the tissue engineering of entire organs. Re-search activities have been published regarding the tissue-engineering of

• urinary bladder (Oberpenning et al. 1999),

• kidney (Humes 1996; Woods et al. 1997; Humes 2000),

• heart valves and heart muscle (see chapter 7),

• liver (see this chapter),

• pancreas (see this chapter). Despite high medical needs, tissue engineering of complete organs is far from the market. Important scientific-technical hurdles must be overcome, e. g. vasculariza-tion of tissue engineered organs, controlled three-dimensional structure, coordinated action of different cell types. The concept of "organ printing", i. e. computer-aided, jet-based 3D tissue engineering of organs, has been proposed as a possible means to achieve this goal (Mironov et al. 2003). If feasible at all, those organs are most likely to be the first to be developed whose function can be replaced by cell thera-pies or in bioartificial biomedical devices. Belonging to this category are free or encapsulated islet cells for diabetes therapy and extracorporal bioartificial liver as-sist devices. At the present stage of development, high scientific-technical hurdles must be overcome before diabetes or acute hepatic failure can be treated by tissue engineering approaches.

8.1.1 Tissue-engineered pancreas for the treatment of Diabetes mel-litus

Diabetes mellitus is the most frequent metabolic disease in the world. It is a chronic disease caused by inherited and/or acquired deficiency in production of insulin by the pancreas, or by the ineffectiveness of the insulin produced. Such a deficiency results in increased concentrations of glucose in the blood, which in turn damage many of the body's systems, in particular the blood vessels and nerves. The standard therapy for type I diabetes is the regular injection of insulin. Currently, research is carried out in different fields to optimise the standard therapy of diabetes in two areas: on the one hand, the quality of life of the patients would be

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enhanced by making them independent of the periodic injection of insulin. On the other hand a regulation of the blood glucose level is strived for which is more pre-cise and sustainable compared to the state that can be reached by manual insulin injection, to prevent long term damage. The following therapeutic options are avail-able or are under development:

• New insulin delivery forms. Among the options are inhalation as an aerosol; in-sulin as tablets; devices that release insulin automatically ("artificial pancreas").

• Gene therapy.

• Pancreas transplantation. Since the first pancreas transplantation in 1966, up to now more than 14,000 pancreas transplantations have been carried out world-wide. At the moment, approx. 1,000 pancreases are transplanted per year, most of them in the USA. The surgical procedure is complicated and stressful for the patient. Therefore, only in few cases is this the therapeutic option of choice, as compared to the established treatment with insulin.

• Transplantation of allogenic insulin producing cells. An alternative to the trans-plantation of the whole pancreas is the transfer of isolated islet cells, which is much less traumatic for the patient. Between 1990 and 2000, 394 allogenic islet cell transplantations took place world-wide. Only 81 transplants worked for more than one year. Therefore, only in 20 % of the treated patients was the treatment successful on the long run. Recently, a new and improved therapy protocol has been developed which is perceived by experts as a break-through in the trans-plantation of allogenic islet cell transplantation. In a first study, this protocol, that does without steroids as immuno-suppressive agents and that makes use of a larger amount of unencapsulated islet cells, has led to a long-term independence from insulin in 18 out of 19 patients (Shapiro et al. 2000; Ryan et al. 2001). A multicenter clinical trial in the USA and Europe is underway in order to confirm and extend these results, to standardize procedures of islet isolation and trans-plantation, and to implement cell processing standards in accordance with clini-cal good manufacturing practice.

• Transplantation of xenogeneic insulin producing cells. If diabetes cell therapies based on allogeneic islet cells prove to be successful in larger patient popula-tions, the need for additional islet sources (xenogenic, from stem cells) becomes more urgent. Preclinical research into xenogeneic islet transplantation has been carried out for many years, but was even less successful than allogeneic islet transplantation regarding the achievement of long-term insulin independence. Moreover, the use of xenogeneic cell sources is controversially discussed due to the fact that a risk of infection with unknown infectious agents cannot totally be ruled out. There is a general consensus in the scientific community that at the present knowledge, xenotransplantations of solid organs should not be performed (see e. g. (Cooper et al. 2000)). However, the clinical application of cellular xe-notransplantation is not totally excluded at present because the risk-benefit as-sessment may come to more favourable results than for organ xenotransplantati-

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on (Hüsing et al. 2001). Nevertheless, concern has been expressed on clinical tri-als for the treatment of diabetes in which porcine islet cells are transplanted into diabetes patients. Because they are performed in Mexico, and may be expanded in cooperation with the New Zealand based company Diatranz to the Cook Is-lands, doubts have been raised whether these trials are in line with high interna-tional safety and ethics standards (Archer et al. 2002; Mckenzie et al. 2002; Col-lignon 2002; Valdes 2002; Dalton 2002; Valdes Gonzalez 2002; Anonymous 2002).

In diabetes, neither pancreas transplantation nor islet transplantation has become the preferred therapeutic option, because they do not compare favourably with estab-lished insulin replacement therapies. However, since 2000, there are encouraging results from allogenic islet transplantation which may indicate that the concept of cellular therapy may work for diabetes. Transplantation of insulin producing cells and a bioartificial pancreas are options where tissue engineering approaches can contribute. It is investigated in preclinical and clinical trials whether insulin produc-ing cells isolated from pigs (Hüsing et al. 2001) or differentiated from human adult stem cells (Bonner-Weir et al. 2000) or human embryonic stem cells can be used (Schuldiner et al. 2000; Assady et al. 2001). According to (Lysaght et al. 2001), more than 200 mio. US-$ of private sector funds have been invested in the devel-opment of a bioartificial pancreas in the USA. However, no design capable of rou-tine success in large animal models could be developed.

8.1.2 Bioartificial liver assist devices

In Europe, around one thousand people develop acute liver failure each year – an illness that can appear suddenly, as a result of poisoning for example, or develop slowly following chronic jaundice, for example. Acute liver failure causes progredi-ent brain dysfunction leading to the patient's death. This development occurs usu-ally within 2-10 days. Acute hepatic failure can only be treated reliably by liver transplantation although 10-30 % of the affected patients could recover without transplantation. However, reliable markers are not available which could predict which patients definitively require a liver transplant for recovery. Although it does not seem feasible in the nearer future to develop a tissue engi-neered liver, tissue engineering could provide important contributions to the devel-opment of some type of artificial liver support. This liver support has the following aims:

• stabilize the patient's condition so that a liver transplantation can be performed,

• bridging the time until a liver transplant becomes available,

• support the patient's liver function to make regeneration of the patient's own liver possible.

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Over the last four decades, several approaches have been taken to support liver function. Initially, the development of extracorporeal liver support was focused on purely physical and chemical systems or processes. These included hemodialysis, plasmapheresis, hemofiltration, plasma exchange, resin perfusion, and charcoal he-moperfusion. There are at least two artificial liver support systems on the market which do not incorporate a biological component (table 8.1). In addition, extracor-poreal perfusions of whole or partial livers showed promising results, but have sig-nificant limitations to its practical application. As a result, the concept of hybrid bioartificial devices evolved in which technical systems are equipped with a bio-logical component. Tissue engineering can contribute to engineer this biological component in order to perform physiological functions similar to native livers. Al-though some implantable bioartificial systems have been developed and tested in animals, presently R&D focusses on extracorporeal liver assist devices which sup-port the detoxification functions performed by the liver for a limited period of time (in the order of hours to days) (Tzanakakis et al. 2000). At present, at least four types of extracorporeal bioartificial liver support systems have been tested in clinical trials. These systems differ in the type of hepatocytes, the amount of hepatocytes incorporated into the devices, the design of the bioreac-tor, and whether the reactor is perfused with the patient's blood or plasma (see ta-ble 8.1). In the development of bioartificial liver assist devices which incorporate living cells, the following crucial points have not yet been solved satisfactory:

• Type and source of the used cells (human primary isolates; differentiated from human adult or embryonic stem cells; primary porcine isolates or porcine cell lines),

• Production of the required liver cells in suitable quantity, quality and physiologi-cal activity,

• Cultivation of the liver cells while maintaining their physiological activity,

• Appropriate bioreactor concept,

• Logistic aspects (e. g. shelflife of the cells, time to get the reactor running),

• Clinical application, outcome, safety and efficacy.

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Table 8.1: Artificial and bioartificial liver assist devices with clinical experience

Device Company Clinical Phase Design Cell Line

Liver Dialysis UnitTM (for-merly BioLogic-DT)

HemoTherapies (formerly HemoCleanse) (USA)

FDA approved Multicenter

Membrane Separated He-modialysis Unit

Noncellular (Charcoal)

Molecular Adsorbent Recy-cling System (MARS®)

Teraklin (Germany) I/II/II CE-approved Multicenter

Hollow Fiber Bioreactor Human Albumin

Extracorporeal Liver Assist Device (ELAD®)

Vitagen (USA) I/II Multicenter Hollow Fiber Membrane Bioreactor

Immortalized Human Hepa-tocytes

HepatAssist® 2000 System Circe Biomedical (USA) II Multicenter completed Hollow Fiber Membrane Bioreactor

Porcine Hepatocytes

Bioartificial Liver Support System (BLSS®)

Excorp Medical, Inc. (USA) I/II Multicenter Hollow Fiber Membrane Bioreactor

Primary Porcine Hepato-cytes

Modular Extracorporeal Liver System (MELS®)

Hybrid Organ (Germany) I/II Multicenter Hollow Fiber Membrane Bioreactor

Human Hepatocytes

LIVERX2000 System Algenix, Inc. (USA) I planned Hollow Fiber Membrane Bioreactor

Primary Porcine Hepato-cytes

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8.2.1 Tissue-engineered pancreas

According to (Lysaght et al. 2001), more than 200 mio. US-$ of private sector funds have been invested in the development of a bioartificial pancreas in the USA. How-ever, no design capable of routine success in large animal models could be devel-oped. As a consequence, there has been considerable change in the companies en-gaged in this field. Figure 8.1 gives an overview. In the last years, three large coop-erations (Baxter, Gore, WR Grace, all USA) have discontinued their pancreas pro-grammes, and other companies previously engaged in this field (Cytotherapeutics, Modex, BioHybrid, Metabolix, Encelle, Circe, Vivorx, Neocrin, all USA) either no longer exist or are no longer serious contenders in this area (Lysaght et al. 2001). Therefore, only few companies are still active with clinical R&D activities or have increased their preclinical research intensity. Whether bioartificial pancreas has the chance to become a market-relevant application of tissue engineering depends largely on the ability of these companies to achieve scientific-technical break-throughs (Lysaght et al. 2001).

• AmCyte, Inc. (USA). Founded in 1991, AmCyte is developing a cell therapy, BetaRxTM, for transplantation into patients with diabetes that require insulin. The company has preclinical and clinical experience with islet cell transplantation from allogeneic and xenogeneic sources: From 1993-1995, it carried out three clinical encapsulated human islet transplantations in the USA, and in 1997, a transplantation of porcine encapsulated islet cells in New Zealand. At present, it pursues a "proliferative human islet programme" BetaRxTM. Human insulin-producing cells are isolated, expanded in vitro, encapsulated in alginate and transplanted into the peritoneal cavity.

• Diatranz (New Zealand). Founded in 1994, Diatranz's core business is the devel-opment of alginate-encapsulated porcine insulin-producing islet cells suitable for transplantation into people with type 1 diabetes mellitus. Its product, DiaBcell®, are alginate-encapsulated porcine islet cells obtained from the pancreases of cus-tom-bred, disease-free pigs and isolated in a GMP manufacturing facility. This product has been transplanted into two patients. A second product, DiaVcell®, contains porcine islet cells together with porcine Sertoli cells. The latter cells serve as "nursery cells" to protect against rejection. These cells are injected into a stainless-steel mesh tube which is implanted under the skin of the patient. Since April 2000, 12 diabetic patients have been treated with DiaVcell® in Mexico City, and the company plans to extend the trials to the Cook Islands. Concern has

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been expressed by the scientific community whether these trials comply with in-ternational standards (see above).

• Novocell (USA). Novocell is a biopharmaceutical company which was formed in August 1999 by acquiring all of the assets and liabilities of a predecessor com-pany, Neocrin Company. It develops encapsulated human insulin producing cells for the treatment of diabetes. These cells are processed from primary human pancreases, expanded and differentiated, and encapsulated with polyethylen gly-col. The R&D is presently in the preclinical stage. Novocell hopes to receive FDA approval after completion of animal studies in order to begin human trials in 2003. Since 2000, Novocell has a cooperative R&D agreement with BD Technologies to study the feasibility of growing and differentiating human pan-creatic progenitor cells into insulin-producing cells, and since 2001, a collabora-tion with SurModics, Inc. for the development of encapsulation materials.

• Circe Biomedical (USA). Circe Biomedical is a privately held biomedical com-pany engaged in the development, production, and commercialization of extra-corporeal and implantable bioartificial organs and therapeutic cell systems. It has the PancreAssist® System in pre-clinical development. The PancreAssist® Sys-tem is an implantable, membrane-based system bioartificial pancreas incorporat-ing living pancreatic islets, and is designed to improve blood glucose control in diabetics by providing insulin in response to changes in the patient's blood glu-cose level. Circe Biomedical is designing the PancreAssist System to be im-planted near the kidney and surgically connected directly to the patient's circula-tory system.

• Islet Sheet Medical LLC (USA). Islet Sheet Medical is a research and develop-ment company which develops a thin-sheet bio-artificial pancreas for the treat-ment of diabetes. R&D is in the preclinical stage, no clinical trials are planned at present.

• MicroIslet Inc. (USA). MicroIslet Inc. is a biotechnology company engaged in the research, development, and commercialization of of insulin-producing islet cells from porcine sources. MicroIslet has licensed several technologies from Duke University Medical Center developed over the last decade for the isolation, culture, storage, and encapsulation (microencapsulation) of insulin-producing is-let cells from porcine sources. MicroIslet is working to develop, obtain FDA ap-proval for and commercialize a first product, called MicroIslet-P™. This is microencapsulated porcine islet cells used for islet transplantation for patients with insulin dependent diabetes. R&D is in the preclinical stage, no clinical trials are scheduled yet.

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Figure 8.1: Evolutionary cladogram on commercial efforts to develop a bio-artificial pancreas

Source: http://www.isletmedical.com/company_competition.htm, accessed March 31, 2003

8.2.2 Bioartificial liver assist devices

At present, there are no bioartificial liver assist devices on the market. The only products which have been FDA approved or were granted the CE mark do not in-corporate any living bio-components. Some companies, mainly in the USA, but also in Germany, are engaged in research and develop of bioartificial devices, and some have progressed to clinical trials:

• Circe Biomedical (USA). Circe Biomedical is a privately held biomedical com-pany engaged in the development, production, and commercialization of extra-corporeal and implantable bioartificial organs and therapeutic cell systems. The company's lead product is the HepatAssist® Liver Support System which is be-ing developed since 1994. The device has four components: a hollow fiber biore-actor containing primary porcine hepatocytes, two charcoal filters, a membrane oxygenator, and a pump. Additionally, the device must be used in conjunction with a commercially available plasma separation machine, a heater, and tempera-ture and oxygen monitors. Circe completed phase I/II clinical trials in 1997. These trials were found to demonstrate safety and showed encouraging signs in treatment of fulminant hepatic failure and primary liver nonfunction, either as a

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bridge to transplant or in some cases as a bridge to recovery of normal liver func-tion. Circe then proceeded on to phase II/III trials, which concluded enrollment in 2001 after a four-year run. The trials treated approximately 180 patients at 20 clinical centers in the US and Europe, with the desired endpoint being the 30-day survival of acute liver failure patients with or without transplant. Circe’s HepatAssist 2000 device was long considered the most promising of the bioarti-ficial liver devices currently in development, but has recently run into substantial roadblocks. In 1999, its corporate parent, W.R. Grace and Co., decided to with-draw as part of a unilateral withdrawal from the biotech industry. From then on, Circe was financed by venture capital funding as the HepatAssist went through phase II/III prospective, randomized, controlled clinical trials. In 2002, the FDA concluded that the device’s efficacy was still unproven making a full phase III efficacy trial the mandatory next step, if Circe wishes to continue the quest to bring the device to market. As of now, the company’s plans are unknown, and it remains unclear as to whether Circe will continue to invest in the HepatAssist product, divest, or keep the project shelved for an extended period.

• HybridOrgan GmbH (Germany). HybridOrgan GmbH was founded in 1997 as a university spin off in cooperation with the Virchow Clinic of the Humboldt Uni-versität of Berlin. It develops the liver support system BELS, which originally used primary porcine hepatocytes, but was then changed to using human hepato-cytes isolated from human donor livers which were not suitable for whole organ transplantation.

• Excorp Medical (USA). Excorp Medical develops a liver assist device BLSS in cooperations with the University of Pittsburgh Medical Center. The BLSS is an extracorporeal hemofiltration device. It contains a hollow fiber membrane (with 100kDa cutoff) bioreactor that separates the patient's blood from approximately 100 grams of primary porcine hepatocytes that have been harvested from pur-pose-raised, pathogen-free pigs (raised by Midwest Research Swine). The actual BLSS device consists of a blood pump, heat exchanger to control blood tempera-ture, an oxygenator to control oxygenation and pH, a hollow fiber bioreactor, and associated pressure and flow alarm systems. Since 1998, Excorp Medical is un-dergoing phase I/II clinical trials. At least nine patients have been treated this de-vice. Moreover, the risk of infection with porcine endogenous retroviruses has been assessed. However, there is still concern regarding the safety of such a de-vice, especially regarding the threat of viral infection from animal hepatocytes. While initial studies regarding the safety of the BLSS are promising, more stud-ies are required to prove safety to the FDA before the product can be approved for phase II/III trials.

• VitaGen Inc. (formerly Hepatix)(USA). VitaGen Incorporated, founded in 1990, is a biotechnology and medical products company, which develops the ELAD® (Extracorporeal Liver Assist Device) Artificial Liver. ELAD® is a two-chambered hollow-fiber cartridge containing a cultured human liver cell line (C3A). In April 1999, the company initiated the phase I/II clinical trial. The

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company anticipated the completion of a FDA approved Phase 2 Clinical trial to evaluate the safety and efficiency of the ELAD® artificial liver device in patients with Fulminant Hepatic Failure while bridging them to liver transplantation in March 2002. This trial was planned to enrol twenty-four patients at seven US sites.

• Algenix (USA). Algenix Inc. is a spin-off of the University of Minnesota. The company focusses on the development of the bioartifical liver LIVERx2000 which is the result of a 10 year preclinical research project at the University of Minnesota. Several patents have been obtained. LIVERx2000 uses fresh porcine hepatocytes. The company is planning to begin FDA approved Phase I Clinical Trials to evaluate the safety of the Algenix LIVERx 2000 Bioartifical Liver for the treatment of hepatic diseases such as fulminant hepatic failure.

• Diacrin (USA). At least until 2002, Diacrin developed porcine liver cells for acute liver failure (HepatoCell™) for the treatment of liver failure; no up-to-date information is available whether this programme is still continued, or whether the company now focusses on the transplantation of muscle cells for ischemic heart failure.

8.3 Overview of potential market volumes

8.3.1 Overview of organ donation and organ transplantation inter-nationally

During the past three decades transplantations of organs, tissues and cells have be-come routine surgical procedures. Irreversibly damaged organs, tissues and cells are replaced by functional ones. In many cases transplantations are life-saving, e. g. liver transplantation after fulminant hepatic failure. In addition, the patient's quality of life can be substantially improved, e. g. in the case of kidney transplantation which makes the transplant recipient independent of dialysis. Organs transplanted are heart, kidney, liver, lung, pancreas/islet cells and small in-testine. In Europe, the USA, Canada, and Australia a total of nearly 42,000 organs were transplanted in 2001 (Table 8.2). More than the half of these transplantations were kidney transplantations, followed by liver transplantations (nearly 11,000), hearts, lungs and pancreas. Bowels are very rarely transplanted (126 transplantations), nearly all of them in the USA. The transplantation of kid-neys, hearts and livers is surgical routine today while lung transplantation is in the process of achieving this phase.

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The number of organs transplanted per million inhabitants differs largely from country to country: leading countries with up to 80 organ transplantations per mil-lion inhabitants are Spain, Austria, Belgium, and the USA (Table 8.3).

Table 8.2: Overview of organ transplantations (absolute numbers) in 2001

Country Kidney+ Liver Heart* Lung* Pancreas Bowels Total

Germany 1964 757 409 139 200 3 3472 Spain 1893 972 341 143 56 3405 France 1921 803 342 117 53 2 3238 UK 1333 675 198 92 41 2 2341 Ireland 113 35 11 0 9 168 Italy 1447 792 316 62 61 5 2683 Belgium 358 201 84 46 21 710 Luxemburg 9 9 Austria 362 128 66 57 19 1 633 Sweden 188 102 25 21 5 341 Denmark 121 32 31 29 213 Finland 165 38 13 4 220 Greece 74 18 5 0 97 The Neth-erlands 337 107 37 27 23 1 532

Portugal 359 184 17 1 4 565 EU-15 total 10644 4844 1895 738 492 14 18627 Poland 843 103 129 17 1092 Czech Republic 310 58 49 10 20 447

Switzerland 156 88 38 25 12 319 Turkey 162 107 27 296 Norway 125 37 29 13 12 216 Hungary 259 19 9 0 7 294 Slovacia 0 Bulgaria 4 4 Croatia 61 20 9 0 90 Slovenia 47 9 4 0 60 Lithuania 0 Cyprus 0 Estonia 30 1 0 31 USA 8859 5177 2202 1054 884 112 18288 Canada 661 389 164 124 33 1371 Australia 328 120 68 74 21 611 Total 22489 10972 4623 2038 1498 126 41746 + kidneys from brain-dead donors; * including heart-lung transplantations Source: http://www.msc.es/ont/ing/f_data.htm, accessed Feb. 11, 2003

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Table 8.3: Overview of organ transplantations in 2001 (numbers per 1 mio. inhabitants)

Country Kidney+ Liver Heart* Lung* Pancreas Bowels Total

Germany 23.9 9.2 5.0 2.4 0.0 40.5 Spain 46.0 23.6 8.3 1.3 79.2 France 32.0 13.4 5.7 0.9 0.0 52.0 UK 22.6 11.4 3.4 0.7 0.0 38.1 Ireland 30.2 9.4 2.9 2.4 44.9 Italy 25.0 13.7 5.5 1.1 0.1 45.4 Belgium 35.8 19.7 8.2 2.0 65.7 Luxemburg 22.5 22.5 Austria 44.8 15.9 8.2 2.4 0.1 71.4 Sweden 21.1 11.4 2.8 35.3 Denmark 22.3 5.9 5.7 33.9 Finland 31.9 7.3 2.5 41.7 Greece 7.4 1.8 0.5 9.7 The Neth-erlands 21.1 6.7 2.3 1.4 0.1 31.6

Portugal 34.9 18.4 1.7 0.4 55.4 EU-15 total 28.1 12.0 4.5 1.5 0.1 44.5

Poland 21.8 2.7 3.3 0.4 28.2 Czech Republic 30.1 5.6 4.8 1.9 42.4

Switzerland 22.0 12.2 5.3 1.7 41.2 Turkey 2.4 1.6 0.4 4.4 Norway 27.7 8.2 4.0 2.7 42.6 Hungary 25.9 1.9 0.9 0.7 29.4 Slovacia 0.0 Bulgaria 0.5 0.5 Croatia 13.9 4.5 2.1 20.5 Slovenia 23.5 4.5 2.0 30.0 Lithuania 0.0 Cyprus 0.0 Estonia 21.4 0.7 22.1 USA 33.0 19.3 8.2 3.2 0.4 64.1 Canada 21.3 12.5 5.3 1.1 40.2 Australia 16.9 6.2 3.5 1.1 27.7 Total 24.4 9.5 4.1 1.5 0.1 34.2 * including heart-lung transplantations Source: http://www.msc.es/ont/ing/f_data.htm, accessed Feb. 11, 2003 The frequency of organ transplantations depends on – among other factors – the frequency of organ donation. The number of organ donors differs largely from country to country, as well as the share of multi-organ donations (Table 8.4). In Europe, Spain, Austria and Belgium/Luxembourg hold the leading positions with 32.5 to 23.7 donors per 1 mio. inhabitants. As a consequence of the gap between

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demand and supply of donated organs, the waiting times for an organ transplanta-tion have become longer. The longest waiting times exist for kidney- and heart-lung transplantations, the waiting times for heart transplantations are the shortest. World-wide, several thousand patients die while still on the waiting list because no suitable organ was available in time. This holds especially true for patients waiting for a heart or a lung, because for these organs there are hardly any life-saving alternatives to organ transplantation.

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Table 8.4: Organ donations in selected countries in 2001

Country Number of or-

gan donors Organ donors per million inhabitants

Multiorgan donors

Spain 1335 32.5 84.4% Austria 191 23.7 77.8% USA 6081 22.6 n. a. Belgium 222 21.6 47.7% Portugal 202 20.2 78.7% R.Ireland 68 18.2 81% France 1066 17.8 n. a. Latvia 41 17.8 n. a. Italy 988 17.1 n. a. Finland 88 17 48.9% Czech.Rep 172 16.7 48.3% Malta 6 15 100% Norway 65 14.4 83% Hungary 137 13.7 19% Canada 420 13.5 n. a. Switzerland 95 13.2 76.8% Germany 1073 13.1 77% United Kingdom 777 13.1 83% Denmark 70 12.9 74.3% Luxemburg 5 12.5 100% Sweden 108 12.1 75.9% The Netherlands 187 11.7 61.4% Poland 450 11.6 38.4% Slovenia Rep. 23 11.5 85% Estonia 14 10 7.14% Australia 180 9.3 81% Israel 59 9 37.2% Croatia 32 7.3 62.5% Greece 32 3.2 n. a. Turkey 89 1.3 n. a. Romania 21 0.95 76.19% Bulgaria 2 0.26 n. a. n. a. data not available Source: Organización Nacional de Trasplantes; http://www.msc.es/ont/ing/data/

organo.asp?O=2&DO=DONORS&aO=2001; accessed on October 15, 2002

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8.3.2 Diabetes mellitus

Diabetes is a serious and costly disease which is becoming increasingly common, especially in developing countries and disadvantaged minorities. According to the latest WHO estimate worldwide 177 million people had diabetes mellitus in 2000 which is a sharp increase over the last decades (1985: 30 million people; 1995: 135 million people). In the European Region, about 22.5 million adults are affected. The number of affected people will double to at least 300 million worldwide by 2025. Much of this increase will occur in developing countries and will be due to population growth, ageing, unhealthy diets, obesity and sedentary lifestyles. By 2025, while most people with diabetes in developed countries will be aged 65 years or more, in developing countries most will be in the 45-64 year age bracket and affected in their most productive years. Generally, people suffering from diabetes have a 3-4 times higher risk of dying prematurely from cardiovascular disease than the rest of the population. The num-ber of deaths attributed to diabetes was previously estimated at just over 800,000. However, it has long been known that the number of deaths related to diabetes is considerably underestimated. A more plausible figure is likely to be around 4 mil-lion deaths per year related to the presence of the disorder. This is about 9% of the global total. Many of these diabetes related deaths are from cardiovascular compli-cations. Most of them are premature deaths when the people concerned are eco-nomically contributing to society. Besides mortality, Diabetes has additional severe impacts: it is the commonest cause of blindness in people of working age, one of the most commonest causes of kidney failure, and the commonest cause of leg amputation (World Health Organi-zation (WHO) 2002). Because of its chronic nature, the severity of its complications and the means required to control them, diabetes is a costly disease, not only for the affected individual and his/her family, but also for the health authorities. The total health care costs of a person with diabetes in the USA are between twice and three times those for people without the condition. It was calculated, for example, that the cost of treating diabetes in the USA in 1997 was US$ 44 billion. Overall, direct health care costs of diabetes range from 2.5% to 15% annual health care budgets, depending on local diabetes prevalence and the sophistication of the treatment available. For most countries, the largest single item of diabetes expenditure is hos-pital admissions for the treatment of long-term complications, such as heart disease and stroke, kidney failure and foot problems. Many of those are potentially prevent-able given prompt diagnosis of diabetes, effective patient and professional educa-tion and comprehensive long term care (WHO 2002, Fact Sheet N° 236). In 2000, world wide sales of therapeutics for the treatment of diabetes were 8.1 billion US-$, a growth of 19 % compared to the previous year. Nearly two thirds of this market are covered by oral antidiabetic drugs. The top selling product (Glu-

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cophage, distributed by the US pharmaceutical company Bristol-Myers Squibb) has sales of more than 1.6 billion US-$. Other leading companies are Novo Nordisk (Denmark) and Eli Lilly (USA).

8.3.3 Acute hepatic failure

In the EU, 4,844 liver transplantations were carried out in 2001. In France, the total cost (staff wages, pharmacy and blood, laboratory and radiology, supplies, overhead hospital services) for adults who received a liver transplant between 1994 and 1996 were € 85,500. Care outside the hospital induced 10% of the total cost (Fourquet et al. 2001). Assuming that costs in other European countries are similar to the costs in France, this corresponds to total costs for liver transplantation in the EU of 414 mio. € per year.

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9. Tissue engineered CNS products


During the past decades, knowledge on the regeneration of neural tissue has been enlarged considerably, bringing tissue engineering approaches to the repair of dis-eased or damaged neural tissue into the range of feasibility. Tissue engineering ap-proaches, especially approaches based on cell therapies, can exploit several mecha-nisms (Björklund et al. 2000):

• Structural and functional integration of the graft into the damaged tissue, form-ing of three-dimensional networks.

• Production of therapeutically active substances at the diseased or damaged site, e. g. neurotransmitters, neurotrophic or neuroprotective factors.

• Repair of damaged structures, e. g. coating nerves with a new myelin sheath. These tissue engineering approaches can target different types of CNS damage or disease:

• Neurodegenerative diseases. Neurodegenerative diseases comprise Parkinson's disease, Chorea Huntington, Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis.

• Paralysis, damage of nerve fibres, spinal cord injury.

• Epilepsy, impaired generation of nerve impulses.

• Stroke

• Pain. For most of these diseases and damages, no fully satisfactory treatments are avail-able. Drug treatment which is long-term effective, is often difficult to achieve or not possible at all. As the central nervous system is responsible for the cognitive abili-ties of a person and controls most body functions, diseases of the central nervous system severely impair a patient's life and that of his contact persons. The preva-lence of especially the neurodegenerative diseases increases with age and require intensive nursing, so that a significant increase in health care costs can be expected in the coming decades in industrialised nations due to the demographic develop-ment. On the other hand, multiple sclerosis (MS) or spinal cord injury can affect young persons and lead to life-long incapability to work and needs for nursing.

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At present, there are no approved cell therapies for CNS disorders available. How-ever, several clinical trials have been carried out, are underway or planned. The following companies are reported to be engaged in cell-therapy-related R&D of CNS disorders, however, most of them in the preclinical stage:

• Diacrin Inc. (USA). Diacrin is a biotechnology company which develops cell transplantations for treating human diseases. In 2001, Diacrin had several prod-ucts in development for treatment of CNS disorders. These products are: − NeuroCell-PD. NeuroCell-PD are porcine fetal neural cells for Parkinson’s

disease. in 1999 to 2001, Diacrin in cooperation with Genzyme carried out a phase 1 clinical trial with 12 patients and a double-blind, randomized, pla-cebo-controlled phase II trial for the evaluation of the safety and efficacy of NeuroCell-PD in 10 patients plus 8 patients in the placebo control group. No improvement in the treated group over the control group could be achieved.

− NeuroCell-HD for Huntington’s disease. Genzyme and Diacrin established a joint venture in 1996 to develop NeuroCell-PD and NeuroCell-HD for cell therapies for the treatment of Parkinson’s and Huntington’s diseases.

− Porcine neural cells for stroke, focal epilepsy and intractable pain. Diacrin carried out a phase I clinical trial using porcine neural cells for stroke, focal epilepsy, and intractable pain. In 2000, Diacrin halted the stroke trial after two patients had developed adverse events.

− Porcine spinal cord cells for spinal cord injury; In 2001, Diacrin received permission by the Food and Drug Administration for a phase I trial on trans-plantations of porcine fetal spinal cord cells from a pig, treated with antibod-ies to reduce the immunogenicity of the graft, into the spinal cord of a total of six quadriplegic patients in cooperation with two US medical centers.

All these trials seem to have been discontinued since 2001. It is not known whether they will be continued by Diacrin.

• StemCells Inc. (USA). The company carries out research and development into stem-cell based cell therapies based on human adult stem cells. It has – among others – a preclinical research programme on human neural stem cells for stroke and Parkinson's disease therapy. Its near-term goals in this programme are the es-tablishment of strategic alliances, and the filing of an IND.

• Neuronyx, Inc. (USA). Neuronyx, Inc. is a development-stage biopharmaceutical company. It discovers and develops treatments for diseases of the brain, central nervous system and heart utilizing human adult bone marrow-derived stem cells. It has a programme on Parkinson’s Disease in the research stage, is considering programmes on stroke and ALS, and plans filing an IND with FDA to com-mence human clinical trials of spinal cord injury therapy in 2003.

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• Acorda Therapeutics, Inc. (USA). Acorda Therapeutics, Inc. was established in March 1995 to develop therapeutic products for spinal cord injury and other cen-tral nervous system disorders. Among others, it also has a preclinical R&D pro-gramme on developing neural stem cell-based technologies and approaches based on L1 axonal guidance proteins for regeneration and repair of the spinal cord and brain.

• NeuroNova AB (Sweden). Founded in 1998, NeuroNova AB is a Swedish bio-pharmaceutical company engaged in both the discovery and the development of adult neural stem cell-based therapies for the treatment of disorders of the central nervous system such as Parkinson's disease, Alzheimer's disease, stroke, and spi-nal cord injury. NeuroNova is targeting Parkinson's disease as its first area for development. The research is in the preclinical stage.

• ReNeuron Holding (UK). Founded in 1997, ReNeuron is a bio-pharmaceutical company developing treatments for neurological disorders based on its murine and human conditionally immortalized neuroepithelial stem cell lines. The com-pany intends to develop cell lines for the treatment of stroke, followed by Park-inson's, Alzheimer's and Huntington's disease and cerebral palsy. These research programmes are in the preclinical stage; and the human transplantation pro-gramme had to be postponed because the cell lines became genetically unstable.

• CellFactors (UK). CellFactors focusses on the development of human cell-based therapies by generation and manipulation of immortalized, partially differenti-ated human cells. One of the company's focusses are whole cell therapies for neuro-degenerative disorders. It has its product Volante, a whole cell therapy for the treatment of Parkinson's disease, in preclinical development. Human fetal cells from aborted fetuses are immortalised, and the resulting dopamine-producing cell lines are genetically engineered to become temperature sensitive and to build in a molecular control mechanism.

• ReInnervate Limited (UK). Founded in 2002, ReInnervate Limited is a spin-off biotechnology company from the University of Durham. The company con-centrates on neural stem cell research and development to facilitate cell lines, as-says, enabling systems and therapeutic patents, which in turn are licensed and sold to major pharmaceutical and biotechnology companies for final commercia-lisation in the market place. ReInnervate is currently in the process of developing its core enabling technologies and of fund raising.

9.3 Overview of potential market volumes

For the year 2000, the world market for pharmaceuticals for the central nervous system (CNS) is estimated to approx. US$ 44 billion (Informa Pharmaceuticals 2000). Drugs with the highest sales volume globally target depression, schizo-

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phrenia and epilepsy. Therefore, medicines against neuro-degenerative diseases are not among top sellers (Informa Pharmaceuticals 2000; Pardridge 2002). The only exception are drugs for the treatment of multiple sclerosis. Several therapeutics are on the market which reduce the severety and frequency of disease episodes (e. g. interferon-beta-1a, marketed as Avonex and Rebif by Biogen (USA) or Serono (Switzerland), respectively; interferon-beta-1b, marketed as Betaseron by Schering (Germany), and other therapeutics such as Copaxone (Teva Pharmaceuticals, Israel) and Novantrone (Immunex, USA). The market for drugs for the treatment of multi-ple sclerosis is estimated at 2.3 Mrd. US-$ in 2001, with an estimated growth to 4 billion US-$ by 2005 (Frost & Sullivan 2001). Most of the actually authorised pharmaceuticals are not able to treat acute stroke. This is why in general medicines are used to prevent the development of blood clots or reduce the risk for coagulation. It is estimated that the market potential for phar-maceuticals to treat stroke is about € 5 billion per year (Frost & Sullivan 2002). For the years to come, mainly because of shifts in the age structure of the population in most of the industrialised countries the number of stroke patients is expected to grow (Reuters Business Insights 1999) The direct costs of a stroke for hospital treatment and primary care were estimated in the late 1980's to about € 10,000 (Isard et al. 1992). According to data from the USA the total costs (direct and indi-rect) of a stroke incident at the beginning of the 1990's were about € 113,000 (Taylor et al. 1996). The present market structure for CNS drugs reflects the present state of pharmaco-logy where only few effective drugs for the treatment of CNS diseases and damages are available. This can be interpreted as an – in principle – favourable market situa-tion for tissue engineering cell therapies, provided, they can be developed as effec-tive treatments. For the future, a rising number of patients with neuro-degenerative patients is expected, not least because of the shift in the age structure of the popula-tions in the industrialised countries. Several analysts estimate, that the market for CNS products will grow more quickly than the global pharma market. This assess-ment is based on the fact that up to now only for few diseases in this area adequate treatments exist and therefore rising pressure by patients and therapists on research in this field can be expected. The future growth of the market for CNS products significantly depends on the solution of scientific problems (e.g., a major part of the potential active substances for CNS-diseases cannot pass the blood-brain barrier), the potential of the pharmaceutical industry to develop effective and safe new pharmaceuticals as well as on politically motivated pressure to replace original me-dicaments by generic products.

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10. Characterization of the tissue engineering industry

10.1 Structure of the tissue engineering industry

10.1.1 Europe

In order to characterise European tissue engineering companies, three different categories were distinguished:

• Core TE companies: Core TE companies are companies whose activity fully complies with the tissue engineering definition chosen for this study: Their tissue engineering activities are carried out with the aid of cells and biomaterials and/or biomolecules, and have a therapeutic purpose.

• Broader TE definition: Companies which carry out actitivities which are di-rectly relevant for tissue engineering, but do not comply with the tissue engineer-ing definition chosen for this study. Companies in this category, for example, are primarily engaged in marketing and distribution of tissue engineering products, in biomaterials, or in bioreactors for tissue engineering. Moreover, medical de-vice or pharma companies are listed in this category if they are involved in joint R&D projects in tissue engineering, but if this is only a minor activity within their overall company activities.

• In-vitro-use of TE: Companies in this category carry out tissue engineering ac-tivities with the aid of cells and biomaterials and/or biomolecules, but without a therapeutic purpose. In general, these companies have developed in-vitro models of e. g. skin or liver through tissue engineering, and use these in-vitro models for screening of drugs, toxicity tests etc.

In these three categories, a total of 113 companies were identified in Europe (ta-ble 10.1, 10.2). 54 of these companies are core tissue engineering companies, 48 are companies in the category "Broader definition", and 11 companies focus on in-vitro use of tissue engineering (table 10.2). Most of the European tissue engineering companies are located in Germany (39), followed by the United Kingdom (18), France (10), the Scandinavian countries and the Benelux countries (table 10.2, fig-ure 10.1). Only few companies could be identified in the Mediterranian EU coun-tries, and, with the exception of the Czech Republic, no companies could be identi-fied in the first round accession countries (table 10.2).

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The large majority of tissue engineering companies are biotechnology companies (n=80). Moreover, medical device companies (n=24) and several pharmaceutical companies (n=9) are also involved (figure 10.3), but in most cases, they do not fall into the definition of core tissue engineering companies (table 10.1). Among the tissue engineering companies, small companies prevail (figure 10.2): 91 out of 113 companies are small and medium-sized companies with less than 500 employees. In fact, most of the companies are even significantly smaller: for 44 out of the 91 tissue engineering companies, more detailed data on employee num-bers were available (table 10.3). Table 10.3 shows that 75 % of these small and me-dium sized tissue engineering companies have less than 50 employees (expressed as full time equivalents). No significant difference regarding this size distribution can be discovered between the core tissue engineering companies and all TE SMEs (which also include the broader definition and in-vitro-use companies). Only one core tissue engineering SME could be identified which has more than 100 employees, this is IsoTis SA (Switzerland/The Netherlands). To sum up, the majority of the European tissue engineering companies can be char-acterised as young, small, research-based and technology-oriented companies. This structure of the European tissue engineering industry reflects that tissue engineering is a new, growing, dynamic field which is still in an infant stage of development. In order to put the situation in Europe into perspective, results from recent surveys of the US-American tissue engineering industry are presented in the following sec-tion.

Table 10.1: Tissue engineering companies in Europe

Country Company Company Type Company Size TE Relevance

Austria Educell Zellkultivierung F&E GmbH

Biotech SME Core

Austria InnovaCell Biotech SME Core Austria igor – Institut für Gewebe- und

Organrekonstruktion Biotech SME Core

Belgium Genzyme Europe Biotech large Core Belgium TIGenix NV Biotech SME Core Belgium beta-cell Biotech SME Core Belgium XCELLentis Biotech SME Core Czech Republic Altius Co.Ltd. Biotech SME Core Czech Republic Educell Biotech SME Core Czech Republic CPN, Ltd. Biotech unknown Core Denmark Interface Biotech SA Biotech SME Core Denmark Nordic Bioscience A/S Biotech SME Broader def. Denmark Coloplast A/S Medical Device large Broader def. Finnland Ark Therapeutics Oy Biotech SME Broader def.

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Finnland Cellomeda Oy Biotech SME Broader def. Finnland Fibrogen Europe Oy Biotech SME Broader def. France Imedex Biomateriaux Pharma SME Core France Laboratoires Genevrier Pharma SME Core France Myosix SA Biotech SME Core France Neurotech SA Biotech SME Core France Biopredic International Biotech unknown in vitro use France Coletica Biotech SME in vitro use France Galderma R & D Pharma large in vitro use France Groupe Dermscan Biotech SME in vitro use France L'Oreal Recherche Medical Device Large in vitro use France SkinEthic Laboratories Biotech SME in vitro use Germany Ars Arthro AG Biotech SME Core

Germany ARTISS GmbH Biotech SME Core Germany BioTissue Technologies AG Biotech SME Core Germany Cell Lining GmbH Biotech SME Core Germany CO.DON AG Biotech SME Core Germany MeGa Tec GmbH Biotech SME Core Germany Switch Biotech AG Biotech SME Core Germany TETEC Tissue Engineering

GmbH Technologies GmbH Biotech SME Core

Germany Vascular Biotech GmbH Biotech SME Core Germany Verigen Transplantation Ser-

vice International AG Biotech SME Core

Germany IBFB GmbH Biotech SME Core Germany Innocoll GmbH Medical Device SME Core Germany CellMed AG Biotech SME Core Germany Cytonet AG Biotech SME Core Germany DeveloGen Biotech SME Core Germany Trans Tissue Technologies

GmbH Biotech SME Core

Germany Kourion Therapeutics GmbH Biotech SME Core Germany CellTec GmbH Biotech SME Core Germany Hybrid Organs Biotech SME Core Germany CellSystems Biotechnologie

Vertrieb GmbH Biotech SME in vitro use

Germany ACM-Biotech GmbH Biotech SME in vitro use Germany EDI GmbH Biotech SME in vitro use Germany In Vitro Biotec GmbH Biotech SME in vitro use Germany ALVITO Biotechnologie

GmbH Biotech SME Broader def.

Germany B.Braun Melsungen Medical Device Large Broader def. Germany Biomet Merck Biomaterials

GmbH Medical Device SME-

Large Broader def.

Germany Aventis Behring GmbH Pharma Large Broader def. Germany Beiersdorf AG Pharma Large Broader def. Germany Biovision GmbH Biomaterial Biotech SME Broader def. Germany Cardion AG Biotech SME Broader def.

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Germany Curasan Biotech SME Broader def. Germany Dr. Suwelack Skin & Health

Care AG Pharma SME Broader def.

Germany Teraklin AG Medical Device SME Broader def. Germany Aesculap AG & Co. Medical Device Large Broader def. Germany In Vitro Systems & Services

GmbH Biotech SME Broader def.

Germany Innovent Technologieentwick-lung e.V.

Biotech SME Broader def.

Germany Osartis GmbH & Co. KG Biotech SME Broader def. Germany ProBioGen AG Biotech SME Broader def. Germany Minucells and Minutissue Ver-

triebs GmbH Biotech SME Broader def.

Italy Fidia Advanced Biopolymers srl

Pharma large Core

Italy Novamont SpA Medical Device unknown Broader def. Luxembourg Cellon S.A. Biotech SME Broader def. Spain Advancell Biotech SME in vitro use Spain Grupo Ferrer Internacional

S.A. Pharma Large Broader def.

Spain Genetrix SL Biotech SME Broader def. Sweden Cell Therapeutics Scandinavia Biotech SME Core Sweden Cellfactory Biotech SME Core Sweden Karocell Tissue Engineering

AB Biotech SME Core

Sweden Neuronova Biotech SME Core Sweden Vitrolife AB Medical Device SME Core Sweden AnaMar Medical Biotech SME Broader def. Sweden Biora AB Medical Device SME Broader def. Sweden Medicarb Biotech SME Broader def. Sweden Q-Med Medical Device SME Broader def. Sweden Angio genetics AB Biotech SME Broader def. Switzerland Kuros Biotech SME Core Switzerland/The Netherlands

IsoTis SA Biotech SME Core

Switzerland Novartis Pharma Large Broader def. Switzerland Centerpulse AG Medical Device large Broader def. Switzerland Degradable Solutions AG Medical Device SME Broader def. Switzerland Nisco Engineering Inc. Medical Device SME Broader def. Switzerland Synthes stratec AG Medical Device Large Broader def. Switzerland BD Biosciences Biotech Large Broader def. The Netherlands Matrix Medical BV Biotech SME Core The Netherlands Biomat BV Medical Device SME Broader def. The Netherlands Bioscan BV Medical Device SME Broader def. The Netherlands Leadd Biotech SME Broader def. The Netherlands Pharming Group NV Biotech SME Broader def. The Netherlands Polyganics BV Medical Device SME Broader def. United Kingdom Axordia Biotech SME Core United Kingdom Cell Factors Biotech SME Core

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United Kingdom Cerestem Biotech SME Core United Kingdom Intercytex Limited Biotech SME Core United Kingdom Multicell Biotech unknown Core United Kingdom Odontis Biotech SME Core United Kingdom Regentec Biotech SME Core United Kingdom ReInnervate Biotech SME Core United Kingdom Reneuron Biotech SME Core United Kingdom Renovo Ltd Biotech SME Core United Kingdom Smith & Nephew Ltd Medical Device large Core United Kingdom Advanced Medical Solutions Medical Device SME Broader def. United Kingdom Apatech Medical Device SME Broader def. United Kingdom Enact Pharma Biotech unknown Broader def. United Kingdom Johnson & Johnson Advanced

Wound Care Medical Device large Broader def.

United Kingdom PPL Therapeutics plc Biotech SME Broader def. United Kingdom Tissuemed Ltd Medical Device SME Broader def. United Kingdom TissueScience Laboratories Medical Device SME Broader def. SME: <500 employees, large: >500 employees

Table 10.2: Overview of tissue engineering companies in European countries

Number of TE companies

Country Core TE company

broader TE definition

in-vitro use of TE Total

Austria 3 0 0 3 Belgium 4 0 0 4 Czech Republic 3 0 0 3 Denmark 1 2 0 3 Finnland 0 3 0 3 France 4 0 6 10 Germany 19 16 4 39 Italy 1 1 0 2 Luxembourg 0 1 0 1 Spain 0 2 1 3 Sweden 5 5 0 10 Switzerland 2 6 0 8 The Netherlands 1 5 0 6 United Kingdom 11 7 0 18 Total 54 48 11 113

80

Figure 10.1: Tissue engineering companies in European countries

0

5

10

15

20

25

30

35

40

German

y

United

King

dom

France

Sweden

Switzerl

and

The N

etherl

ands

Belgium

Czech

Rep

ublic

Denmark

Finnlan

dSpa

inIta

ly

Austria

Luxe

mbourg

Country

Num

ber o

f Com

pani

es

Core TE company broader TE definition in-vitro use of TE

Figure 10.2: Company size of European tissue engineering companies

91

49

17

3

5 2

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

All TE companies Core TE companies

Shar

e of

com

pani

es (%

)

not knownLargeSME

81

Table 10.3: Categorisation of SME European tissue engineering companies according to employee numbers

Employees/company (full time equivalents) Total Number of SMEs ≤ 20 ≤ 50 ≤ 100 ≥ 100

all TE SMEs 25 8 7 4 44 Core TE SMEs 13 4 5 1 23 Share of SMEs all TE SMEs 57 % 18 % 16 % 9 % 100 % Core TE SMEs 57 % 17 % 22 % 4 % 100 %

Figure 10.3: Company type of European tissue engineering companies

Biotech71%

Pharma8%

Medical device21%

10.1.2 USA

A characterisation of the tissue engineering industry with significant emphasis on the USA based on several surveys has recently been published (Lysaght et al. 1998; Lysaght et al. 2001; The Pittsburgh Tissue Engineering Initiative 2000). Tissue en-gineering was defined as the development of products or services that

• combine living cells and biomaterials,

• utilize living cells as therapeutic or diagnostic reagents,

• generate tissues or organs in vitro for subsequent implantation, and/or

• provide materials or technologies to enable such approaches.

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• In addition, newer areas such as therapeutic cloning, regenerative medicine and stem cell-based organogenesis were specifically included.

The following activities were especially excluded: allotransplantation, transgenic organ xenotransplantation, gene therapy, blood substitutes, porcine heart valves, and blood banking as well as classic orthopedic biomaterials, bone marrow trans-plantation and basic research into stem cell biology. Thus, this scope is rather simi-lar to, but a bit broader than the definition applied in this report. Tables 10.4 and 10.5 give an overview of the results.

Table 10.4: Economic parameters for contemporary tissue engineering (2001)

Number of firms 73 (14 not in the USA) Number of scientists and support staff 3,300 Annual spending rate, calendar 2000 610 million € Compound annual growth rate, 1995-2001 16 % Capital value of post IPO companies (n=16) 2.6 billion € Cumulative investment, 1990-2001 3.5 billion €

Source: (Lysaght et al. 2001). Data are referenced to January 1, 2001, except where noted.

According to the 2001 survey conducted by (Lysaght et al. 2001), approximately 70 startups or business units are currently active in the field of tissue engineering. This figure includes 56 US companies and 14 non-US companies. These 70 companies employ a workforce of appr. 3,500 full time equivalents, which means an average of 50 full time equivalents per company. Most of the companies are young and small. Two fifth have less than 16 employees, two fifth less than 51 employees, and only one fifth has more than 51 employees. The spending is nearly € 600 mio. annually. The spending has been growing at a compound annual rate of 16 %, and the cumulative spending since 1990 exceeds € 3.5 billion. Appr. two dozens of companies are listed on stock exchanges; these publicly traded companies account for appr. 35 % of the workforce. On the other hand, no profitable product has yet been launched, and the size of sales stays far behind the high-flying expecta-tions and market potentials. For example, the FDA-approved products Carticel and Apligraf together had annual sales of less than 40 mio. US-$ in 2001 (Lysaght et al. 2001). Neither of them is profitable which led to the situation that the companies Advanced Tissue Sciences and Organogenesis went bancrupt in 2002 (Bouchie 2002). These low sales are in disproportion to the rate of investment that currently attends tissue engineering. The majority of companies focus on developing structural applications (skin, heart valves, bone, arteries, myocardial, particles) (2/3 of the companies in US), this sec-tor is expanding rapidly (table 10.5). Cellular applications (cell transplantation, therapeutic cloning) is the second largest segment. As it has remained about con-

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stant since 1998, the foundation of new companies with activities in the field of human embryonic stem cells and cell therapies based on human adult stem cells must have compensated the reduction of activities in other subfields of this sector (Hüsing et al. 2003). Metabolic applications (bioartificial organs and encapsulated cell therapies) have shrunken since 1998 and presently only represent 10 % of tissue engineering in the USA. This reflects the very early stage of development of this sector where basic research questions still have to be solved and break-throughs to be achieved before clinically applicable therapies or devices can be expected (Lysaght et al. 2001; Hüsing et al. 2001).

Table 10.5: Sector analysis of tissue engineering companies in the USA 2001

Sector Structural Cellular Metabolic

Examples Skin, bone, heart valves, arteries, myo-cardial particles

Cell transplantation, therapeutic cloning

Bioartificial organs, encapsulated cell therapy

Employees (Full Time Equivalents) 1980 890 570

Percent of total 60 % 27 % 11 % Spending in 2000 (€ mio.) 363 174 68

Growth since 1998 survey5 +85 % 0 % - 30 %

Source: (Lysaght et al. 2001)

10.1.3 Common features of the European and US-American tissue engineering industry

In Europe as well as in the USA, a rather similar structure of the tissue engineering industry can be observed: This structure reflects that tissue engineering is a new, growing, dynamic field which is still in an infant stage of development. As can be deduced from the information given in chapters 4-6, there are many com-panies firms with a similar technology base and similar products. They invest into R&D and market development to an extent which cannot sustainably be financed by current product sales: Sales are far too small to cover or outpace operating costs (high costs to produce, maintain and ship the products, high investments in R&D, spending of money for the development of marketable products and market devel-opment). The markets are not yet fully developed and amount to only several 5 Lysaght, M.; Nguy, N. A. P.; Sullivan, K. (1998): An Economic Survey of the Emerging Tissue

Engineering Industry. In: Tissue Engineering 4, No. 3, pp. 231-238

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€ mio./year. Thus, these markets are not only orders of magnitude smaller than ex-pected, but also orders of magnitude smaller than markets for pharmaceutical prod-ucts. In most markets, several tissue engineering companies compete with one an-other, and also with established simpler, cheaper, more familiar therapeutic options. Therefore, it can be concluded that there is significant redundancy and overcapac-ity. As a consequence of high operating costs and low sales revenues, firms run out of money or are chronically underfinanced and have to struggle for more funds from investors in the currently unfavourable economic climate (Petit-Zeman 2001). As is obvious from companies' press releases and company reports, most companies have implemented strict cost reduction programmes in the last few years, and have also started rationalization, downsizing, and realignment. This consolidation process will continue, and will also reduce the number of low-profit "me-too" companies and products in the coming years.

10.2 Differences between Europe and the USA

10.2.1 Science and technology base

Several experts interviewed for this study had the impression that tissue engineering is treated as a strategic R&D area in USA, which receives focussed and intensive support. Although tissue engineering also receives relatively intensive support on the R&D side in the EU, the experts felt this support to be not as intensive and fo-cussed as in the USA. Some were of opinion that funding is broad and - in the wish to advance the field - also second-class R&D and "me-too"-approaches get funding. According to the experts' characterisation of the EU situation, the R&D efforts seem not to be very well coordinated, and networks and cooperations can still be devel-oped significantly. Several experts noted that networking and cooperation recently had improved due to efforts to submit proposals for networks of excellence and integrated projects within the 6th framework programme. Most experts interviewed for this study were of opinion that the scientific and tech-nological level of R&D is on a comparable high level both in USA and Europe, and the scientific progress is at about the same pace in both regions. Due to shorter time to market in Europe (see below), Europe is in certain subfields and applications ahead of the USA because it already has experience with clinical application in hu-mans.

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In the USA; there are significantly more acedemic groups and companies which explore "borderline", controversial approaches (e. g. use of xenogeneic cells, tissues and organs, use of human embryonic stem cells, cell transplantations into the brain) than in Europe. Moreover, approaches based on allogeneic cell sources are favoured in the USA, companies in Europe focus on autologous cells.

10.2.2 Companies

In the USA as well as in Europe, the majority of tissue engineering companies are small, young, research-intensive, technology-based companies which are typically financed by venture capital or listing on the stock exchange. Few have products on the market. Most companies are characterised by a high burn rate and low income, and presently many run into severe financial problems because the public invest-ment markets are down. This company situation is typical for an emerging field such as tissue engineering, and is similar in the USA and Europe. The experts interviewed for this study are of opinion, that commercialisation of tissue engineering started earlier in the USA than in Europe. The reason given for this situation is a more favourable general climate for start-up companies and a spirit of entrepreneurship in the USA: In the past years, the conditions for founding biotechnology companies were better in the USA than in Europe (e. g. venture capi-tal, stock markets, entrepreneurship etc.); but the experts acknowledge that these conditions have significantly improved in Europe in recent years. Both in the USA and in Europe, the first of leading tissue engineering companies go bancrupt or run into severe financial problems. This, however, should not be overrated, according to experts' opinions, but is part of a healthy, necessary consolidation process within the tissue engineering field which will continue in the next years.

10.2.3 Regulatory situation

The experts interviewed for this study pointed out significant differences in the re-gulatory situation in the USA and the EU. The main points are summarised in table 10.6.

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Table 10.6: Differences in the regulatory situation in the USA and the EU

USA EU

centralized agency for approval approval procedure decentralised, on national level, in different institu-tions, country-specific approach required

clear regulatory scheme ("biologics" for tissue engineered products) with rather strict, yet clear criteria and requirements

no uniform approval procedure, regulatory scheme not uniformly applied in different countries, lack of an approval procedure especially tailored for innovative products and therapies

good support by regulatory bodies during the approval process, relatively open-minded to innovative treatments

unsatisfactory support from regulatory bodies bodies relatively conservative regarding innovative treatments

transparency regarding the requirements for and duration of the approval process

in case of successful approval, access to the largest and rather homoge-nous health market in the world

in case of successful approval, only access to the national market due to the country-specific approval approach

preclinical research must be completed before clinical trials in humans can be started. If in clinical trials, product costs can already be reimbursed (commercialisations during clinical trials), there is the possibility of pre-approval for first line treatments

In Europe, permission to distribution can be obtained with preclinical work (this gives European companies a clear time advantage over US companies because they can start trials in humans much earlier than in the USA).

in case of successful approval, reimbursement of product costs no major problem

However, this time advantage can in practice not be exploited commer-cially because successful biologics commercialization requires general reimbursement of costs in order to reach increased sales. General reim-bursement by health insurers requires the proof of safety, efficacy, and clinical durability in clinical trials which take 3-5 years.

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10.2.4 Market

The US market is the largest health market in the world which is – despite existing regional differences – much more homogenous than the European health market. The latter has pronounced national differences. After approval of an innovative treatment in the USA, in general, there is a rather quick diffusion and reimbursement of this treatment. According to experts' opin-ions, this is due to a health system in the USA which is more open to innovation than in Europe. In Europe, large national differences regarding openness towards innovative treatments, both on the side of potential users (medical doctors) and regulatory or financing bodies (e. g. health insurers) are noted by the experts.

10.3 Business models and business strategies

According to expert opinions, the tissue engineering field is too young and too dy-namic to already bet on companies or business strategies which will most likely develop successfully or which are in a "pole position". Nevertheless, several aspects which seem to be crucial for successful business in tissue engineering can be de-rived. These are:

• Ability to access and integrate the required scientific-technical know-how. A rather large share of the tissue engineering companies have a narrow and not unique scientific-technological basis, e. g. profound knowledge only in cell cul-ture. However, to be successful in tissue engineering business, a much broader knowledge base must be built, which encompasses cell culture, ma-trix/scaffolds/biomaterials, growth factors, surgical techniques, production and quality control according to GMP. The intellectual property and know-how is of-ten fragmented among different companies, and this limits them as to what they can achieve. Therefore, profound knowledge in all these fields must be creatively combined but it is too early to bet on a winning strategy of technology in tissue engineering. There are differences between technologies and different ap-proaches to achieving the same end point (Petit-Zeman 2001).

• Profound preclinical knowledge base. Another weak point of many small companies is that they are built on a narrow preclinical knowledge base. As a consequence, several companies cooperate with clinicians with year-long re-search experience in this field, and take over advanced research results to adapt them to marketable products.

• Excellent clinical outcome of products. The value of most tissue engineering products is often based on quality of life, not patient survival. Often, the prod-

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ucts cannot compete on a direct cost basis. As presently many products target markets where conventional treatment options are already available, they must offer at least a similar or an even better clinical performance than conventional therapies. Although from a regulatory perspective, for many tissue engineering products results from clinical trials are not necessarily required for commerciali-sation, clinical trials are required to convince users (medical doctors) of the su-periority of the tissue engineering application, and also to obtain cost reim-bursement from statutory and private health insurers.

• Excellent manufacturing and quality control standards. At present, the qual-ity requirements for manufacturing tissue engineered products seem to vary widely among companies and EU member states. It is not yet settled which quality standards will turn out to be necessary and sufficient.

• Very good logistic and service for users. Most tissue engineered products re-quire complicated logistic procedures which may be comparable to the shipment of living human organs. Moreover, the implants have a very limited shelflife. Therefore, it is important that the company which provides the implants is flexi-ble and reliable enough to adjust its implant production procedure to the sched-ule of the surgical procedure.

• Orientation towards market and customer needs and requirements. Accord-ing to experts' opinions, many companies are doing very good, also interdiscipli-nary science, but focus too much on scientifically challenging and interesting questions, whereas a clear focus on the market has often been neglected. Indica-tors for this conclusions are the investment of large sums of money (from down payments etc.) into research projects instead of product and market development, an inbalance between high burn rate and too low revenues from product sales, and neglecting intensive communication with the targeted medical community: too often high-tech solutions have been developed to a problem which can also be solved (by competing options) more simple. Therefore addressing the practi-cal aspects of product application (e. g. ease of handling the product in surgical procedures, shelflife and storability of the product, faster and/or more reproduci-ble production processes, cost savings in production processes) in product devel-opment is important. Therefore, a stronger focus on applications is required and a critical assessment of potential markets, applications and indications regarding the question whether the customers are really willing and able to pay for the product. If these markets can be identified, then the technologies can be looked for with which to address these applications.

• Willingness and ability to invest into the development of the market. On the one hand, the markets for individual tissue engineering products are by factor 10 to 100 smaller than "usual" markets for pharmaceuticals so that the interest of large pharmaceutical companies in tissue engineering products is limited. On the other hand, the resources required for R&D, clinical trials and marketing often exceed the resources of the small tissue engineering companies. Therefore, mar-keting is often done in cooperation with larger companies which have good ac-

89

cess to the targeted customers. However, according to expert opinions, the search for cooperations which really work for both partners is still ongoing. Experts raise doubts whether biomedical device companies which have good access to e. g. orthopedic surgeons are really the suitable marketing partner for e. g. chon-drocyte transplants. Good contacts with potential customers alone are not suffi-cient. Tissue engineering products differ in many marketing-relevant respects from biomedical devices and pharmaceuticals. They are more complicated, not yet very familiar to medical doctors and therefore require extensive education of the potential customers. As a consequence, highly educated marketing staff is re-quired, and also other marketing instruments (e. g. workshops, practical trainings instead of conferences) are required.

• Ability to cope with regulatory bottlenecks.

• Ability to cope with different corporate cultures and established procedures in tissue engineering companies, pharmaceutical companies and medical device companies.

The above mentioned aspects are mainly derived from the commercialisation of tissue engineering products which are currently on the market (especially skin and cartilage products). For such products, the successful business model is still to emerge: it must account for high development costs (biologics operating model) and relatively small margins (device-type business model) (Petit-Zeman 2001), ta-ble 10.7). However, tissue engineering can also deliver other types of products for which a pharmaceuticals of medical device business model can be applied.

Table 10.7: Business models for pharmaceuticals, medical devices and tissue engineering products

Pharmaceuticals Medical Devices Tissue Engineering products

High up-front investment in R&D

Lower up-front investment in R&D

Medium up-front investment in R&D

Long development times Short development times Medium to long develop-ment times

High gross margins Low gross margins Low gross margins Large markets Focused markets Focused markets

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11. Overview of tissue engineering products on the mar-ket and in clinical trials

In order to gain an overview of tissue engineering products which are already com-mercially available, or are likely to be introduced into the market in the foreseeable future, lists of products were compiled which are on the market or in clinical trials, conducted by tissue engineering companies. Although significant efforts were made to compile as comprehensive lists as possible, it cannot be ruled out that some pro-ducts and clinical trials have been missed. As the methodological approach focussed on tissue engineering companies and the clinical trials conducted by these compa-nies, especially clinical trials may be underrepresented which are conducted by re-search institutions, but not companies. In many cases, it was difficult to draw the line whether a given product is "on the market" or in clinical trials, because under certain regulatory regimes, both can be possible simultaneously. Moreover, the list of products in clinical trials must not be interpreted as "complete R&D pipeline" of products which are likely to be introdu-ced into the market in the foreseeable future. This would only hold true if an appro-val procedure which is based on the results of clinical trials would be required for market access (as it is the case for pharmaceuticals and biologics). Tissue enginee-ring products are, however, subject to different regulatory regimes. Therefore it depends on the product and on which regulatory regime is assigned to this product by the relevant national authorities, whether clinical trials are a prerequisite for market approval or not. In order to draw a picture as complete as possible, not only tissue engineered pro-ducts were included in the following tables which fully comply with the definition of tissue engineering chosen for this study6. In addition, products were also inclu-ded which are beyond the scope of the chosen definition, but can be understood as tissue engineering products if broader definitions are applied. Products which fully comply with the tissue engineering definition of this study are marked with "1" in the column "Relevance" in the following tables. Products which are a combination of either cells and scaffolds of cells and biomolecules or scaffolds and biomolecules are marked with "2", and tissue engineering products for in-vitro use or products which are only scaffolds or biomolecules are marked with "3" in the column "Rele-vance". 6 Tissue engineering is the regeneration of biological tissue through the use of cells, with the aid

of supporting structures and/or biomolecules. The definition chosen for this study primarily re-lates to therapeutic applications of tissue engineering, not to in vitro applications. It excludes gene therapy and simple transplantations. It includes autologous and allogeneic human cells, tis-sues and organs, and also xenogeneic cells, tissues and organs, that have been substantially mo-dified by treatments. In addition, autologous chondrocyte transplants are included (also see chapter 2.1)

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11.1 Skin products

Table 11.1: Skin products of European companies

Manufac-turer (product name)

Coun-try Status Indications Cells Biomaterials Rele-

vance

BioTissue Technolo-gies (Bio-Seed-M)

Ger-many

on the market (2001)

defects of the oral mucosa

autologous oral mucosal cells

gel-like biomatrix 1

BioTissue Technolo-gies (Bio-Seed-S)

Ger-many

on the market

chronic skin ul-cera (surface wounds)

autologous keratinocytes

gel-like bioadhe-sive

1

BioTissue Technolo-gies (Melano-Seed)

Ger-many

on the market

vitiligo autologous melanocytes

gel-like biomatrix 1

Fidia Ad-vanced Biopoly-mers (Hya-lograft™ 3D)

Italy on the market

non healing ul-cers, burns

autologous fibroblasts

hyaluronic acid ester biopolymer scaffold

1

Fidia Ad-vanced Biopoly-mers (La-serskin™)

Italy on the market

skin wounds, ulcers


hyaluronic acid ester biopolymer scaffold with or-derly arrays of laser-drilled mi-croperforations

1

Fidia Ad-vanced Biopoly-mers (TIS-SUEtech autograft systemTM)

Italy on the market

burns, chronic ulcers, loss of skin tissue

autologous fibroblasts and keratino-cytes

hyaluronic acid ester biopolymer scaffold

1

IsoTis, AB (cellActive Skin)

NL produc-tion stopped in late 2002

ulcer autologous fibroblasts and keratino-cytes

biodegradable PEG based poly-mer (polyactive)

1

Smith and Nephew (Derma-graft)

UK on the market (2002)

diabetic and ve-nous stasis ulcers

allogeneic fibroblasts

PLGA degradable polymer

1

92

Smith and Nephew (Trans-cyte)

UK on the market

burns fibroblasts skin matrix com-bined with nylon layer

1

XCELLen-tis (Auto-Derm)

Bel-gium

on the market

skin wounds, ulcers


epithelial sheets 1

XCELLen-tis (Cryo-Ceal)

Bel-gium

on the market

skin wounds, ulcers

allogeneic keratinocytes, cryopreserved

epithelial sheets 1

IsoTis SA (formerly Modex Therapeu-tics (Epi-dex))

NL/Switzerland

on the market (1999), with-drawn Decem-ber 2002

alternative to split thickness skin graft


none 2

Autoderm (Epidex, inlicensed product of IsoTis SA)

Ger-many

intended market introduc-tion spring 2003

alternative to split thickness skin graft


none 2

Innocoll GmbH (Col-latamp)

Ger-many

on the market

wound healing collagen matrix covered with spe-cific bioactive compounds

2

Karocell Tissue Engineer-ing

Sweden on the market

autologous skin cells, melanocytes

2

Labora-toire Genevrier (Epibase)

France on the market (2002)

wound healing autologous keratinocytes

none 2

MeGa Tec GmbH

Ger-many

on the market

burns, scars autologous skin cells

2

Biopredic France on the market

in vitro testing for toxicity and pharmacology

human kerati-nocytes, hu-man fibro-blasts

3

Skin Ethic Laborato-ries

France on the market

in vitro testing for toxicity and pharmacology

human cell cultures

3

"relevance" specifies the extent of compliance with the definition of tissue engineering applied in this study. 1 = tissue engineering product (core definition) 2 = tissue engineering product (broader definition) 3 = tissue engineering product for in-vitro use or with marginal relevance for tissue engineering

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Table 11.2: Skin products of US companies

Manufac-turer (product name)

Coun-try Status Indications Cells Biomaterials Rele-

vance

Novar-tis/Organogenesis (Apligraf)

USA on the market


allogeneic fi-broblasts and keratinocytes

bovine collagen 1

Ortec (OrCell)

USA on the market (2001)


allogeneic ke-ratinocytes and fibroblasts

bovine collagen 1

Smith and Nephew (Derma-graft)



allogeneic fi-broblasts

PLGA degrad-able polymer

1

Smith and Nephew (Trans-cyte)

USA on the market

burns fibroblasts skin matrix com-bined with nylon layer

1

Convatec (Vi-voderm)

USA on the market

skin ulcer, burns autologous skin cells

2

Genzyme Biosur-gery (Epicel)

USA on the market

burns autologous skin cells

2

LifeCell (Repli-form)


urological plastic surgery

acellular tissue derived from allogeneic skin cells

2

LifeCell Corpora-tion

USA on the market

wound dressing human skin proc-essed to remove epidermal and dermal cells while preserving the remaining biological dermal matrix

2

Fibrogen Inc

USA on the market

wound manage-ment

none; guided tissue regenera-tion

collagen with growth factors

2

Organo-genesis (Forta- Flex)


wound closure none; guided tissue regenera-tion

bioengineered collagen

3

LifeCell Corpora-tion (Cy-metra)

USA on the market

wound manage-ment

processed human tissue that results in micronized collagens, elastin,

3

94

and proteogly-cans

Cook Biotech (Oasis™)


wound manage-ment

porcine small intestinal submu-cosa acellular collagen matrix

3

Brennen Medical (EZ-Derm™)

USA on the market

partial thickness burns, skin ul-cers, abrasions

acellular porcine derived collagen matrix

3

Integra Life Sci-ences (Integra)

USA on the market

burns collagen com-bined with silicon layers

3

Apart from the products mentioned in table 11.1 and 11.2 there is a huge number of synthetic skin replacement products, that compete with the products from biological sources.

Table 11.3: Clinical trials on skin products of European and US companies

Manu-facturer (product name)

Country Status Indications Cells Biomaterials Rele-vance

XCEL-Lentis (Lypho-Derm)

Belgium phase II ulcers, burns lysate of al-logeneic kerati-nocytes

epithelial sheets 1

IsoTis SA (Al-lox)

CH/NL phase II skin leg ulcers allogeneic skin cells

allogeneic growth factors

1

IsoTis SA (Acu-Dress)

CH/NL phase I planned

burns; also plas-tic reconstruc-tive surgery, and other wound conditions in-tended

autologous epidermal sheet

fibrin also to be combi-ned with Ethi-con's (Johnson & Johnson) In-tegra® Template

1

Organo-genesis (Vitrix)

USA phase II/III (present status unknown after Organo-genesis filed for ban-crupcy in late 2002

diabetic and venous stasis ulcers

allogeneic fi-broblasts and keratinocytes

bovine collagen 1

95

medicarb Sweden phase II wound healing polysaccharide films and appli-cations partly coated with bio-active com-pounds

2

Colla-genesis (Derma-logen, Derma-plant, Urogen, Duraderm)

USA phase III aesthetic surgery collagen matrix from cadaver skin

3

11.2 Cartilage products

Table 11.4: Autologous chondrocyte transplantation products of European companies



Educell Zellkul-tivierung F&E GmbH (Chon-droArt™)

Austria on the market

cartilage repair autologous chondrocytes

1

Interface Biotech A/S(CartilinkTM-2)

Denmark on the market

cartilage repair autologous chondrocytes

collagen mem-brane

1

BioTis-sue Tech-nologies (Bio-Seed-C)

Germany on the market (2001)

cartilage replacement

autologous chondrocytes

gel-like bioma-trix

1

CellTec GmbH (Chon-droTec)


chrondrocyte transplantation


1

co.don Germany on the articular carti- autologous 1

96

(Chon-drotrans-plant)

market lage repair chondrocytes

TETEC AG (Novo-cart)

Germany on the market

chrondrocyte transplantation


1

Verigen Trans-plantation Service Interna-tional AG (CACI, MACI, MACI-A)


chrondrocyte transplantation, cartilage repair


Collagen mem-brane

1

Ar-sArthro (Ca-ReS®)




collagen matrix 1

Ormed (ARTROcell®)




collagen matrix (Chondro-Gide®)

1

Orthogen AG (Ar-throma-trix®)




1

Fidia Ad-vanced Biomate-rials (Hyalo-graft C®)

Italy on the market

Cartilage repair autologous chondrocytes

biocompatible tridimensional matrix composed of a derivative of hyaluronic acid ester

1

IsoTis NV (Cel-lActive Cart)

NL on the market (2001), produc-tion and market-ing stopped in 2002

cartilage repair (knee defects)


polyactive bio-degradable PEG based polymer

1

Karocell Tissue Engineer-ing

Sweden on the market


1

Vitrolife Sweden on the market

cell regenera-tion

cryopreserved chondrocytes

hyaluronic acid based support structures

1

97

Table 11.5: Autologous chondrocyte transplantation products of US companies

Manu-facturer (product

name)


Genzyme Biosur-gery (Carticel)

USA on the market

cartilage repair in the knee


1

Table 11.6: Clinical trials on cartilage products of European and US companies



TIGenix NV (ChondroCelect®)

Belgium phase II cartilage repair autologous chondrocytes

none 1

Ar-sArthro (Ca-ReS®)

Germany phase II 3 D cartilage repair, focal defects of the articular carti-lage of the knee joint


collagen matrix 1

Biomet Merck

Germany phase II 3 D cartilage repair


polymer scaffold 1

co.don (Chondrosphere)

Germany phase III 3D cartilage repair, arthritis therapy


spheroid tech-nology

1

Curis (Chon-drogel)

USA phase III cartilage repair autologous chondrocytes

hydrogel poly-mer

1

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11.3 Bone products

Table 11.7: Bone products of European companies



BioTissue Tech-nologies (BioSee-dOral Bone)


jawbone sur-gery

autologous jawbone graft

gel-like bioma-trix

1

co.don (osteotransplant)


bone repair autologous osteoblasts

none 1

aap Im-plantate AG (Ca-vat)

Germany on the market (2002, intended)

bone defects none autologous bone growth factors on a hydroxy apatit ceramic support

2

Tutogen Medical GmbH (Tuto-plast)

Germany / USA

on the market

bone repair allogeneic bone material proc-essed to remove cells

2

Biora AB Sweden on the market

wound healing after periodon-tal surgery

enamel matrix proteins in pro-pylene glycol alginate

2

Sulzer Medica (Puros Allograft)

Switzer-land

on the market

spinal surgery allogeneic bone material

2

IsoTis SA (SynPlug)

Switzer-land/The Nether-lands


hip replace-ment

cement restric-tor

cement restrictor 3

IsoTis SA (Os-Satura)

Switzer-land/The Nether-lands


bone substitute osteoconductive and osteoinduc-tive porous cal-cium phosphate scaffold

3

99

Table 11.8: Bone products of US companies


name)


Osteo-tech, Ea-tontown (Graftech)

USA on the market

bone repair allogenic bone 2

Osteotech (Grafton)

USA on the market

bone repair allogeneic de-mineralised bone material

2

Interpore Cross Interna-tional (AGF)

USA on the market

bone repair autologous growth factors from patient's blood to be com-bined with bone grafting material

2

Medtron-icSofamorDanek (INFUSE™)

USA on the market

lumbar inter-body spinal fusion

collagen matrix for use with bone growth factors

2

Regenera-tion Tech-nologies/ distrib-uted by MSD (Osteofil)


spinal fusion allogeneic bone material proc-essed to remove cells

2

Becton Dickinson Biosci-ences (BD Bio-Coat™)

USA on the market

bone repair scaffolds for cell cultivation

3

Interpore Cross Interna-tional (Bone-Plast)

USA on the market

bone repair extrudable bone void filler based on calcium sul-fate

3

Interpore Cross Interna-tional (ProOs-teon)

USA on the market

bone repair hydroxyapatite bone grafting material har-vested from marin coral exo-skeletons

3

100

Orquest (Hea-los®)

USA on the market

bone repair bone graft substi-tute

3

Orthovita (CORTOSS®)

USA on the market

spine surgery and repair of osteoporotic fractures

synthetic com-posite bone void filler

3

Orthovita (VITOSS®)

USA on the market

spine surgery and repair of osteoporotic fractures

resorbable cal-cium phosphate bone void filler

3

Stryker Corp. (OP-1)


long-bone frac-tures

3

Apart from the above mentioned materials which originate from human or animal biological materials there is a huge number of synthetic bone substitutes on the market. Most of them use hydroxyapatite, calcium phosphate, calcium sulfate, or polymers such as poly(lactic acid), poly(glycolic acid) or the copolymer poly(lactic co-glycolic acid). An alternative source for bone fillers are marine coral exoscele-tons (ProOsteon).

Table 11.9: Clinical trials on bone products of European and US companies


name)


Nordic Biosci-ence A/S

Denmark phase unknown

Monitoring bone turnover, osteoporosis, osteoarthritis

skin and bone cells

Collagen 1

Curasan Germany phase unknown

bone defects autologous osteoblasts

growth factors (PRP, BMP) on Cerasorb, a ce-ramic based ma-trix

1

IsoTis SA (Vivesc Os)

The Nether-lands

phase I/II (pro-gramme cancelled in 2003)

jawbone sur-gery, joint re-pair, spinal fusion

autologous bone marrow cells

biocompatible and biodegrad-able poly (ether ester) multiblock copolymers (polyactive)

1

Osiris Therapeu-tics (Al-logen)

USA phase II cancer therapy autologous human mesen-chymal stem cells (hMSCs) from human bone marrow

hydroxyapatite matrix

1

Osiris USA phase I jawbone sur- autologous hydroxyapatite 1

101

Therapeu-tics (Os-teocel)

gery human mesen-chymal stem cells (hMSCs) from human bone marrow

matrix

Aastrom Biosci-ence

USA phase I/II osteoporosis bone progenitor cells

2

Orquest (Healos MP52)

USA phase unknown

bone repair bone graft substi-tute with bone inducing protein MP52

2

Orquest (Ossigel)

USA phase III bone repair hyaluronic acid and fibroblast growth factors

2

Stryker Corp. (OP-1)

USA phase unknown

spinal applica-tions of OP-1

3

Wyeth (rhBMP-2)

USA phase III lumbar poster-olateral spinal fusion

3

11.4 Cardiovascular products

Table 11.10: Cardiovascular products of European and US companies


name)


CryoLife Europe (Cryo-Life-O'-Brien®, CryoLife-Ross®)

UK on the market

heart valves, vascular grafts

porcine heart valve processed to build neutral scaffolds

2

Edwards Life-sciences


heart valves various porcine and bovine heart valves (stented and stentless)

2

Cardiovascular products are dominated by mechanical solutions made from carbon or different metals as they are found to show higher stability.

102

Table 11.11: Clinical trials on cardiovascular products of European and US companies



co.don (vas-cuplant)

Germany phase I cardiovascular endoprothesis

endothel cells vessel graft 1

Vascular Biotech GmbH (aorto-coronary bypass graft)

Germany phase unknown

graft for by-pass surgery

recipient-own endothelial cells

allogeneic cryopreserved donor veins

1

Ark Thera-peutics Oy (Tri-nam™)

Finland phase II/III

haemodialysis graft access surgery

- biodegradable local drug deli-very device (termed EG001) vascular endo-thelial growth factor, delive-red as gene by an adenoviral vector

2

Osiris Thera-peutics (Cardio-cel)

USA phase I heart surgery autologous human mesen-chymal stem cells (hMSCs) from human bone marrow

2

Diacrin USA phase I cardiac disease human muscle cells

2

Genzyme Biosur-gery

USA phase II left ventricular dysfunction/ heart attack

autologous skeletal muscle cells

2

BioHeart (MyoCell TM)

USA phase I/II post-infarct deterioration of cardiac func-tion

autologous myoblasts

2

103

11.5 Tissue engineered organs

No tissue engineered organs could be identified which are currently on the Euro-pean or US market.

Table 11.12: Clinical trials on tissue engineered organs of European and US companies


name)


Amcyte (Be-taRx™)

USA phase I Diabetes encapsulated human insulin-producing cells

alginate 1

Diatranz (DiaB-cell®)

NZ phase I Diabetes encapsulated porcine insulin-producing cells

alginate 1

Diatranz (DiaVcell®)

NZ phase I Diabetes porcine insulin-producing and Sertoli cells

stainless-steel mesh tube

1

Novocell (formerly Neocrin)

USA phase I planned for 2003

Diabetes encapsulated human pancre-atic cels

Polyethylen glycol

1

Hybrid Organ (MELS)

Germany phase I/II fulminant he-patic failure

human hepato-cytes

Hollow Fiber Membrane Bioreactor

1

Circe-Biomedi-cal (Hepat Assist)

USA phase II/III (failed)

fulminant he-patic failure

cryopreserved porcine hepato-cytes


1

Vitagen (ELAD)

USA phase I/II fulminant he-patic failure

immortalized human hepato-cytes


1

Algenix (LIVE RX 2000)

USA phase I planned

fulminant he-patic failure

primary porcine hepatocytes


2

Diacrin (Hepato-Cell™)

USA phase I; present status unknown

acute liver failure

porcine hepato-cytes

2

Excorp Medical (BLSS)

USA phase I/II fulminant he-patic failure

primary porcine hepatocytes


2

104

11.6 CNS products

At present, there are no approved cell therapies for CNS disorders available. Several clinical trials have been carried out, are underway or planned. However, most of the cell-therapy-related R&D of CNS disorders is still in the preclinical stage.

Table 11.13: Tissue engineered CNS products of US companies

Manufac-turer

(product name)


Integra (Neura Gen)

USA on the market

spinal cord injury

absorbable collagen tube as a nerve guide

3

Integra (Dura Gen)

USA on the market

onlay graft for dural defects

collagen matrix for dural clo-sure

3

Table 11.14: Clinical trials on tissue engineered CNS products of US companies

Manufac-turer

(product name)


Diacrin USA phase I spinal cord injury

porcine spinal cord cells, treated with antibodies to reduce immu-nogenicity

2

Diacrin USA phase I (sus-pended)

stroke porcine neural cells

3

Diacrin USA phase I intractable pain

porcine neural cells

3

Diacrin USA phase I focal epilepsy porcine neural cells

3

Diacrin (Neuro-Cell-PD)

USA phase II (sus-pended)

Parkinson's disease

porcine fetal neural cells

3

105

11.7 Miscellaneous products

Table 11.15: Miscellanous products on the market and in clinical trials

Manufac-turer

(product name)

Country Status Indica-tions Cells Biomate-

rials Relevance

co.don (Chondro-Transplant Disc)

Germany phase III acute, her-niated in-tervertebral disks

autologous chondro-cytes

1

Articular Engi-neering (ARC)

USA phase un-known

articular cartilage and in-tervertebral disc disor-ders

autologous chondro-cytes

alginate 1

InnovaCell Austria Phase I-II urinary inconti-nence

autologous skeletal muscle cells

no infor-mation available

1

Artimplant (Artelon)

Sweden phase III ligament augmenta-tion in the knee and thumb

biodegrad-able poly-uretha-nurea

3

Imedex Biomateri-aux (Flore-ane)


surgery none; guided soft tissue re-generation

collagen as film, seal-ant and foam

3

Genopoi-etic


immun-stimulation for mela-noma treatment cartilage repair

transgeneic (estrogen producing) autologous cells

3

Q-Med Sweden on the market

Uro-Gynecol-ogy, ortho-pedics, estetics, cell therapy and encap-sulation

none; guided soft tissue re-generation

structures from hya-luronic acids

3

Integra USA on the regenera- none; type I col- 3

106

(BioMend) market (1999)

tion proce-dures in periodontal defects

guided soft tissue re-generation

lagen membrane processed from bo-vine achil-les tendon

Becton Dickinson BioScience (BD™3D Collagen Composite and OPLA® Scaffolds)

USA on the market

biological scaffolds for cell cultivation

3

Integra (Col-laTape)

USA on the market

dental sur-gery prod-ucts

absorbable collagen matrix

3

107

12. Cited Literature

Anonymous. (2002): Xenotransplantation: Labor in der Südsee? In: biomedpark 3, pp. 11-12

Archer, K.; McLellan, F. (2002): Controversy surrounds proposed xenotransplant trial. In: The Lancet 359, No. 9310

Assady, S.; Maor, G.; Amit, M. et al. (2001): Insulin production by human embryo-nic stem cells. In: Diabetes 50, No. 8, pp. 1691-1697

Augustin, M.; Siegel, A.; Heuser, A. et al. (1999): Chronic leg ulcers: cost evaluati-on of two treatment strategies. In: Journal of Dermatological Treatment 10, No. Supplement 1, pp. S21-S25

Bassett, P. (2001): Tissue Engineering - Technologies, Markets, and Opportunities. MarketResearch.com, 523 p.

Björklund, A.; Lindvall, O. (2000): Cell replacement therapies for central nervous system disorders. In: Nature Neuroscience 3, pp. 537-544

Bonner-Weir, S.; Taneja, M.; Weir, G. C. et al. (2000): In vitro cultivation of hu-man islets from expanded ductal tissue. In: Proc Natl Acad Sci U S A 97, No. 14, pp. 7999-8004

Bouchie, A. (2002): Tissue engineering firms go under. In: Nature Biotechnology 20, pp. 1178-1179

Brittberg, M.; Lindahl, A.; Nilsson, A. et al. (1994): Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. In: New England Journal of Medicine 331, pp. 889-895

Bücheler, M. (2002): Tissue Engineering in der Hals-Nasen-Ohrenheilkunde, Kopf- und Halschirurgie. In: Laryngo-Rhino-Otol 81, No. 1, pp. 61-80

Business Communication Company. (1998): Cell Therapy and Tissue Engineering: Emerging Products. Norwalk CT: Business Communication Company.

Collignon, P. (2002): Xenotransplantation trials. In: The Lancet 359, No. 9325, p. 2281

CONCORD Corporate Finance Research. (2002): Biomaterialien und Tissue Engi-neering am Neuen Markt. Frankfurt/M.: Concord Effekten AG, 91 p.

108

Cooper, D. K. C.; Keogh, A. M.; Brink, J. et al. (2000): Report of the Xe-notransplantation Advisory Committee of the International Society for Heart and Lung Transplantation: The Present Status of Xenotransplantation and Its Potential Role in the Treatment of End-Stage Cardiac and Pulmonary Disea-ses. In: The Journal of Heart and Lung Transplantation 19, No. 12, pp. 1125-1165

Dalton, R. (2002): Diabetes trial stirs debate on safety of xenotransplants. In: Na-ture 419, p. 5

Deutsch, M.; Meinhart, J.; Fischlein, T. et al. (1999): Clinical autologous in vitro endothelialization of infrainguinal ePTFE grafts in 100 patients: a 9-year ex-perience. In: Surgery 126, pp. 847-855

Fourquet, F.; Le Gales, C.; Rufat, P. et al. (2001): [Medical and economic evaluati-on of organ transplantation in France. The example of liver transplantation]. In: Rev Epidemiol Sante Publique 49, No. 3, pp. 259-72.

Frost & Sullivan. (2001): Multiple sclerosis therapies: poised for take-off. wysi-wyg://110/http://www.inpharm.com/intelligence/frost011101.html

Frost & Sullivan. (2002): The hunt for neuroprotection continues. wysi-wyg://96http://www.inpharm.com/intelligence/frost040202.html

Geschäftsführung des Arbeitsausschusses "Ärztliche Behandlung" des Bundesaus-schusses der Ärzte und Krankenkassen. (2000): Autologe Chondrozyte-nimplantation (ACI). Köln: Geschäftsführung des Arbeitsausschusses "Ärztli-che Behandlung" des Bundesausschusses der Ärzte und Krankenkassen, 29 p.

Gibis, B.; Gawlik, C.; Sander, G. et al. (2001): Autologe Chondrozytenimplantation - ein Verfahren für die vertragsärztlichen Versorgung? In: Z. ärztl. Fortbild. Qual.sich. (ZaeFQ) 95, pp. 219-223

Hagège, A. A.; Carrion, C.; Menasché, P. et al. (2003): Viability and differentiation of autologous skeletal myoblast grafts in schaemic cardiomyopathy. In: The Lancet 361, No. 9356, pp. 491-492

Humes, H. D. (1996): Application of gene and cell therapies in the tissue enginee-ring of a bioartificial kidney. In: The International Journal of Artificial Organs 19, No. 4, pp. 215-217

Humes, H. D. (2000): Bioartificial kidney for full renal replacement therapy. In: Seminars in Nephrology 20, No. 1, pp. 71-82

109

Hüsing, B.; Engels, E.-M.; Frietsch, R. et al. (2003): Menschliche Stammzellen. Bern: Zentrum für Technologiefolgen-Abschätzung, TA SWISS, 337 p.

Hüsing, B.; Engels, E.-M.; Gaisser, S. et al. (2001): Zelluläre Xenotransplantation. Bern: Zentrum für Technologiefolgen-Abschätzung beim Schweizerischen Wissenschafts- und Technologierat, 331 p.

Huynh, T.; Abraham, G.; Murray, J. et al. (1999): Remodeling of an acellular colla-gen graft into a physiologically responsive neovessel. In: Nature Biotechnolo-gy 17, No. 11, pp. 1083-6

Informa Pharmaceuticals. (2000): CNS-markets and therapies. wysi-wyg://138/http://www.inpharm.com/intelligence/inpharma011000.html

Isard, P. A.; Forbes, J. F. (1992): The costs of stroke to the national Health Service in Scotland. In: Cerebrovasc Dis. 2, pp. 47-50

IsoTis Corporate Communications & Investor Relations. (2003): Tissue engineered cartilage. www.isotis.com

Jahania, M. S.; Mentzer, R. M., Jr. (2002): Heart transplants: need versus availabili-ty. In: J Ky Med Assoc 100, No. 3, pp. 94-8.

Jobanputra, P.; Parry, D.; Fry-Smith, A. et al. (2001): Effectiveness of autologous chondrocyte transplantation for hyaline cartilage defects in knees: a rapid and systematic review. 5, No. 11, pp. 1-57

Jobanputra, P.; Parry, D.; Meads, C. et al. (2003): Autologous chondrocyte trans-plantation for cartilage defects in the knee joint. In: Development and Evalua-tion Service, Dept. of Public Health and Epidemiology, University of Bir-mingham, No. 1

Jones, I.; Currie, L.; Martin, R. (2002): A guide to biological skin substitutes. In: British Journal of Plastic Surgery 55, pp. 185-193

Kessler, P. D.; Byrne, B. J. (1999): Myoblast cell grafting into heart muscle: Cellu-lar biology and potential applications. In: Annu. Rev. Physiol. 61, No. 0, pp. 219-242

Kohlmeier, L.; Kroke, A.; Pötzsch, J. et al. (1993): Ernährungsabhängige Krankhei-ten und ihre Kosten. Baden-Baden: Nomos-Verlagsgesellschaft mbH und Co KG (Schriftenreihe des Bundesministeriums für Gesundheit).

110

Landesbank Baden-Württemberg Equity Research. (2001): Tissue Engineering. Stuttgart: Landesbank Baden-Württemberg Equity Research, 62 p.

Langer, R.; Vacanti, J. P. (1993): Tissue engineering. In: Science 260, pp. 920-926

Laurencin, C. T.; Ambrosio, A. M.; Borden, M. D. et al. (1999): Tissue enginee-ring: orthopedic applications. In: Annu Rev Biomed Eng 1, pp. 19-46

Lysaght, M. (2002): Tissue Engineering - Is the allure only skin deep? In: Science and Medicine, pp. 191-193

Lysaght, M.; Nguy, N. A. P.; Sullivan, K. (1998): An Economic Survey of the E-merging Tissue Engineering Industry. In: Tissue Engineering 4, No. 3, pp. 231-238

Lysaght, M.; O´Loughlin, J. A. (2000): Demographic Scope and Economic Magni-tude of Contemporary Organ Replacement Therapies. In: ASAIO Journal, pp. 515-521

Lysaght, M.; Reyes, J. (2001): The Growth of Tissue Engineering. In: Tissue Engi-neering 7, No. 5, pp. 485-493

McKenzie, F. C.; d´Apice, A.; Cooper, D. K. (2002): Xenotransplantation trials. In: The Lancet 359, No. 9325, pp. 2280-2281

MedMarket Diligence. (2002): Cell-Based Tissue Engineering. Foothill Ranch, CA: MedMarket Diligence LLC, 247 p.

MedTech Insight. (2000): Cost-Benefit New Approach to EU Regulation of Human Tissue Products. ES-2 Report #A101. without location: MedTech Insight, 1-5 pp.

Meinhart, J.; Deutsch, M.; Fischlein, T. et al. (2001): Clinical autologous in vitro endothelialization of 153 infrainguinal ePTFE Grafts. In: Ann Thorac Surg 71, pp. 327-331

Menasche, P. (2002): Cell therapy of heart failure. In: C R Biol 325, No. 6, pp. 731-738

Menasche, P.; Hagege, A. A.; Scorsin, M. et al. (2001): Myoblast transplantation for heart failure. In: The Lancet 357, pp. 279-280

111

Mironov, V.; Boland, T.; Trusk, T. et al. (2003): Organ printing: computer-aided jet-based 3D tissue engineering. In: Trends in Biotechnology 21, No. 4, pp. 157-161

Nerem, R.; Seliktar, D. (2001): Vascular Tissue Engineering. In: Annu. Rev. Bio-med. Eng. 3, pp. 225-243

NHS Centre for Reviews and Dissemination. (2003): Autologous chondrocyte transplantation for cartilage defects in the knee joint. In: The Cochrane Libra-ry, No. 1

Oberpenning, F.; Meng, J.; Yoo, J. J. et al. (1999): De novo reconstitution of a func-tional mammalian urinary bladder by tissue engineering. In: Nature Biotech-nology 17, No. 2, pp. 149-155

Pardridge, W. M. (2002): Why is the global CNS pharmaceutical market so under-penetrated? In: Drug Discovery Today 7, No. 1, pp. 5-7

Petit-Zeman, S. (2001): Regenerative medicine. In: Nature Biotechnology 19, pp. 201-206

Pouzet, B.; Ghostine, S.; Vilquin, J. T. et al. (2001): Is skeletal myoblast transplan-tation clinically relevant in the era of angiotensin-converting enzyme inhibi-tors? In: Circulation 104, No. 12 Suppl 1, pp. I223-8

Reuters Business Insights. (1999): The cardiovascular outlook. wysi-wyg://r142/http://www.inpharm.com/intelligence/bi010899.html

Roell, W.; Lu, Z. J.; Bloch, W. et al. (2002): Cellular Cardiomyoplasty Improves Survival After Myocardial Injury. In: Circulation 105, No. 20, pp. 2435-2441

Rosenthal, N.; Tsao, L. (2001): Helping the heart to heal with stem cells. In: Nature Medicine 7, No. 4, pp. 412-413

Russell, J.; Cross, S. (2001): Commercial Prospects for Tissue Engineering. Busi-ness Intelligence Program-SRI Consulting, 1-15 pp.

Ryan, E. A.; Lakey, J. R.; Rajotte, R. V. et al. (2001): Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. In: Diabetes 50, No. 4, pp. 710-719

112

Schuldiner, M.; Yanuka, O.; Itskovitz-Eldor, J. et al. (2000): Effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells. In: Proceedings of the National Academy of Sciences of the United Sta-tes of America 97, No. 21, pp. 11307-11312

Schulz, J. T.; Tompkins, R. G.; Burke, J. F. (2000): Artificial Skin. In: Annu. Rev. Med. 51, pp. 231-244

Seifalian, A. M.; Tiwari, A.; Hamilton, G. et al. (2002): Improving the clinical pa-tency of prosthetic vascular and coronary bypass grafts: the role of seeding and tissue engineering. In: Artif Organs 26, No. 4, pp. 307-320

Shapiro, A. M. J.; Lakey, J. R. T.; Ryan, E. A. et al. (2000): Islet Transplantation in Seven Patients with Type I Diabetes Mellitus Using a Glucocorticoid-free Immunosuppressive Regimen. In: New England Journal of Medicine 343, No. 4, pp. 230-238

Stamm, C.; Westphal, B.; Kleine, H.-D. et al. (2003): Autologous bone-marrow stem cell transplantation for myocardial regeneration. In: The Lancet 361, pp. 45-46

Stock, U. A.; Vacanti, J. P.; Mayer_Jr, J. E. et al. (2002): Tissue engineering of heart valves -- current aspects. In: The Thoracic and Cardiovascular Surgeon 50, No. 3, pp. 184-193

Strauer, B. E.; Brehm, M.; Zeus, T. et al. (2001): Intrakoronare, humane autologe Stammzelltransplantation zur Myokardregeneration nach Herzinfarkt. In: Dtsch. med. Wschr. 126, pp. 932-938

Taylor, T. N.; Davis, P. H.; Torner, J. C. et al. (1996): Lifetime cost of stroke in the United States. In: Stroke 27, pp. 1459-1466

The Pittsburgh Tissue Engineering Initiative. (2000): An industry emerges - A pro-file of Pittsburgh´s growing Tissue Engineering sector. Pittsburgh: PTEI - Pittsburgh Tissue Engineering Initiative, 1-29 pp.

Tzanakakis, E. S.; Hess, D. J.; Sielaff, T. D. et al. (2000): Extracorporeal tissue en-gineered liver-assist devices. In: Annu. Rev. Biomed. Eng. 2, pp. 607-632

Vacanti, J. P.; Langer, R. (1999): Tissue engineering: the design and fabrication of living replacement devices for surgical reconstruction and transplantation. In: The Lancet 354, No. Supplement 1, pp. S32-S34

113

Valdes Gonzalez, R. (2002): Xenotransplantation´s benefits outweigh risks. In: Na-ture 420, p. 268

Valdes, R. (2002): Xenotransplantation trials. In: The Lancet 359, No. 9325, p. 2281

von Oppell, U.; Zilla, P. (2001): Prosthetic Heart Valves: Why Biological? In: Jour-nal of Long-Term Effects of Medical Implants 11, No. 3-4, pp. 105-113

Woods, J. D.; Humes, H. D. (1997): Prospects for a bioartificial kidney. In: Semi-nars in Nephrology 17, No. 4, pp. 381-386

World Health Organization (WHO) (edt) (2002): The European Health Report 2002. In: WHO Regional Publications., No. European Series No. 97, p. 172

Zeltinger, J.; Landeen, L.; Alexander, H. et al. (2001): Development and characteri-zation of tissue-engineered aortic valves. In: Tissue Engineering 7, No. 1, pp. 9-22