Advancing the Science of Wound Care in the At-Risk Patient ... · VLUs, peripheral arterial disease, and wound care. He has written numer-ous peer-reviewed articles and text chapters

This publication was not subject to the WOUNDS® peer-review process.

Supplement to WOUNDS® September 2016

Supported by Osiris Therapeutics, Inc.

Charles G. Marchese, DPM, FACFAS, FAPWH – Moderator

R. Daniel Davis, DPM, ABFAS, ABPS, ABPM, CMET

Robert G. Frykberg, DPM, MPH

Howard E. Kashefsky, DPM, FACFAS

Alexander M. Reyzelman, DPM, FACFAS

Asaad H. Samra, MD, FACS

Gary W. Gibbons, MD, FACS

Advancing the Science of Wound Care in the At-Risk Patient

Optimizing Clinical Outcomes by Combining Advanced Cellular Therapy With Standard of CareProceedings from an Expert Panel Meeting

2 WOUNDS® September 2016

EXPERT PANELCharles G. Marchese, DPM, FACFAS, FAPWH – Moderator

Dr. Marchese has been in private practice for 28 years. In addi-tion, he is a Staff Podiatrist, Surgical Services at the Department of Veterans Affairs New York Health Harbor System in Brooklyn, New York and a consultant to Vascular Management Associ-ates, LLC, in New Brunswick, New Jersey. Dr. Marchese is a

Fellow of the American College of Foot and Ankle Surgeons, a Diplomat of the American Board of Foot and Ankle Surgery and is certified in foot surgery by that Board. He is also a Fellow of the Academy of Physicians in Wound Healing. Dr. Marchese attended the New York College of Podiatric Medicine Foot Clinics of New York, and completed his surgical training at the New York Methodist Hospital in Brooklyn, New York.

R. Daniel Davis, DPM, ABFAS, ABPS, ABPM, CMETDr. Davis is currently the President of the American Podiatric Medical Association (APMA). He is a Past President of the Connecticut Podiatric Medical Association and served as the Chairman of its Education Committee for thirty years. Dr. Davis is board certified by the American Board of Foot and Ankle Sur-

geons and the American Board of Podiatric Medicine. He is a Fellow of the American Board of Podiatric Surgery and the American College of Foot and Ankle Surgeons. He is board certified in wound care by the Council for Medical Education and Testing (CMET) and is certified in HBO therapy by the Undersea and Hyperbaric Medical Society. He is a Fellow of the Acad-emy of Physicians in Wound Healing. Dr. Davis earned his undergraduate degree at Bucknell University and his Doctorate in Podiatric Medicine at the Temple University School of Podiatric Medicine. He completed his res-idency at Parkview Hospital in Philadelphia, PA.

Robert G. Frykberg, DPM, MPHDr. Frykberg is Chief of the Podiatry Section and Podiatric Res-idency Director at the Carl T. Hayden Veterans Affairs Medical Center in Phoenix, Arizona. He is also an Adjunct Professor at the Midwestern University Program in Podiatric Medicine and the Professor of Practice at the University of Arizona College

of Medicine-Phoenix. Dr. Frykberg’s practice is devoted primarily to pa-tients with high-risk foot problems. His research and writing interests are in diabetic foot disorders, including ulcers, infections and the Charcot foot, VLUs, peripheral arterial disease, and wound care. He has written numer-ous peer-reviewed articles and text chapters and has published several textbooks. He is the former Chair of the Foot Care Council of the Ameri-can Diabetes Association and a Past President of the American College of Foot and Ankle Surgeons. He was the 2011 recipient of the Roger Pecoraro Award from the Foot Care Council of the American Diabetes Association. Dr. Frykberg received his Doctor of Podiatric Medicine degree from the California College of Podiatric Medicine and completed his residency in podiatric surgery at the New England Deaconess Hospital/Harvard Med-ical School. He received his Master of Public Health degree from the Har-vard School of Public Health.

Howard E. Kashefsky, DPM, FACFASDr. Kashefsky is Director of Podiatry Services and Assistant Pro-fessor of the Division of Vascular Surgery at the University of North Carolina Hospitals in Chapel Hill. Dr. Kashefsky has had a clinical interest in wound care for over 20 years and has partic-ipated in many clinical trials,including the Grafix Diabetic Foot

Ulcer Study. His focus of practice includes evidence and outcome based medicine. Dr. Kashefsky has worked on the advancement of standard of care, and has published data related to combining contact casting with bi-ological dressings. He earned his medical degree from New York College of Podiatric Medicine and completed his residency at Catholic Medical Center of Brooklyn and Queens.

Alexander M. Reyzelman, DPM, FACFASDr. Reyzelman is Associate Professor in the Department of Medicine at the California School of Podiatric Medicine at Samuel Merritt University. He is also the Co-director of the University of California San Francisco Center for Limb Preser-vation. He has been practicing for 18 years. Dr. Reyzelman re-

ceived his Bachelor’s degree from the University of San Francisco, earned his doctorate from the California College of Podiatric Medicine, and com-pleted his residency at the University of Texas Health Science Center at San Antonio.

Asaad H. Samra, MD, FACSDr. Samra is Chief of Surgery at Bayshore Community Hospi-tal, Holmdel, New Jersey, and Medical Director for the hos-pital’s Center for Wound Healing where he has led that team to receive four Center of Distinction awards, and two Center of Excellence awards (Healogics). In addition to his clinical

experience, Dr. Samra conducts research and gives lectures on a variety of topics ranging from cosmetic treatments, to wound care and extensive reconstructive surgery. Dr. Samra received his Bachelors degree from the Johns Hopkins University, and his medical degree from Rutgers – Robert Wood Johnson Medical School. He received his training in Plastic and Re-constructive Surgery at Baylor College of Medicine’s integrated residency program.

Gary W. Gibbons, MD, FACSDr. Gibbons is Medical Director at the South Shore Hospital Center for Wound Healing in Weymouth, Massachusetts, and Professor of Surgery at the Boston University School of Med-icine. Dr. Gibbons is a vascular surgeon by training and has been in practice for over 40 years. He was the first Director

of the Deaconess/Joslin Diabetic Wound Center, and has dedicated his career to diabetic patients with lower extremity wounds, especially those complicated by peripheral arterial disease. Dr. Gibons has published and spoken extensively on the subject and has been honored with the Roger Pecoraro (ADA), Olmos, and Georgetown Distinguished Achievement awards for his work.

WOUNDS® September 2016 3

INTRODUCTIONIn July of 2015, a multidisciplinary group

of practitioners with expertise in wound care convened in Newark, New Jersey to discuss the pathophysiology of chronic wounds, and to review the science, clini-cal evidence, and potential indications and benefits for advanced cellular therapy with placental membranes. The main objective of the expert panel was to discuss how the incorporation of advanced cellular thera-py with placental membranes into current standards of wound care could benefit the growing patient populations most at risk of developing chronic and complex wounds. This topic is especially relevant today as we are at the convergence of new research bringing forward expanded knowledge of the underlying pathologies of chronic wounds, and innovative new treatment op-tions that have the potential to change the future of wound care.

The field of wound care has made great advances in recent years, propelled forward by scientific breakthroughs in the under-standing of wound healing. Additionally, technological advances have produced im-proved diagnostic tools and sophisticated wound care products. Despite these ad-vances, wounds have been referred to as a “major and snowballing threat to public

health and the economy.”1 Today’s popula-tion is living longer, with life expectancy at an all-time high of 78.8 years.2 Coupled with the baby boom generation born be-tween 1946 and 1964 now turning 65 years of age, the number of people over the age of 65 in the U.S. is growing at an increased rate. According to the 2010 U.S. census, there were 40 million people over the age of 65 in 2010,3 which is predicted to in-crease to 74 million in 2030.4

The aging population is at risk of im-paired wound healing due to normal age-related cellular senescence, plus age-re-lated comorbidities. Over a third (34.9%) of the U.S. adult population is obese,5 and in 2012 it was reported that 9.3% of the overall adult population and 25.9% of

the population aged 65 and older had di-abetes mellitus.6 These risk factors are not exclusive to the adult population; approx-imately 17% of children and adolescents in the U.S. are obese,5 and diabetes in populations under the age of 20 is on the rise.7 Current estimates indicate that ap-proximately 29 million people in the U.S. and 347 million people worldwide have diabetes; of those, millions remain undiag-nosed.6,8 Aging, obesity, diabetes, and the additional comorbidities commonly linked to these conditions are among the many factors associated with a higher risk of im-paired wound healing.9

Current advances in the understand-ing of wound physiology have been a key driver in developing new and innovative advanced therapies designed to address the specific needs and deficiencies in patients with non-healing wounds.10 The most re-cent of these advancements are in the area of placental membranes.

Placental membranes were first noted as a therapy in wound healing in 1910.11 Signif-icant research on the cellular composition and functions of placental membranes, plus advances in tissue processing methods that allow live cells to be retained have brought us to the present, with cellular placental membrane products commercially available

As our understanding of wounds at the cellular level continues to

expand, so does our appreciation for treatment options that

address the pathophysiology and intrinsic factors of the non-

healing wound. (Marchese)

Advancing the Science of Wound Care in the At-Risk Patient

Optimizing Clinical Outcomes by Combining Advanced Cellular Therapy With Standard of CareProceedings from an Expert Panel Meeting


to clinicians.12 Incorporating advanced cel-lular therapies using placental membranes into standard of wound care can provide clinicians with a powerful tool to optimize patient outcomes, and improve the quality of life of the growing patient population at risk for and living with chronic and com-plex wounds.

THE SCIENCE AND PATHOPHYSIOLOGY OF THE CHRONIC AND COMPLEX WOUND

Our expanded knowledge of wound healing at a cellular level has helped us un-derstand the reasons wounds fail to heal. Normal wound healing proceeds through overlapping phases of inflammation, pro-liferation, and remodeling, as illustrated in Figure 1.13

The main cellular activities in the inflam-matory phase support the removal of de-bris and devitalized tissue from the wound, and prepare the wound for tissue regener-ation.14 Damaged cells at the site of injury release inflammatory cytokines that trig-ger migration of inflammatory cells such as polymorphonuclear leukocytes, mostly neutrophils, and monocytes (the precursors

to macrophages) to the area. Broken skin may allow entry of bacteria, and antigens shed from bacterial cells will further trigger cells in the wound to secrete more inflam-matory cytokines and attract more inflam-matory cells. Proteinases such as matrix metalloproteinases (MMPs) are released by inflammatory cells in the initial phase of wound healing to degrade damaged tis-sues in the wound area.15,16 Neutrophils are the main cell types that internalize and kill bacteria within phagosomes with free oxy-gen radicals and enzymes. Macrophages are the main cell types that clean debris and dead cells from the wound. Macrophages also attract and activate other cells needed for healing by secreting growth factors, cy-tokines and chemokines.13,14 In the initial 24-48 hours, a fibronectin-rich provisional matrix is synthesized. Fibroblasts will mi-grate into the matrix at the end of the in-flammatory phase and in the beginning of the proliferative phase, and thereby initiate granulation of the wound bed.14 The in-flammatory phase lasts only from hours to several days in normal wound healing, but it is a key phase in triggering the powerful tissue regeneration process. Inflammatory

cytokines, MMPs, and oxygen radicals are all necessary for wound healing, but when present in excess for a prolonged period of time, they can cause a wound to stall in the inflammatory phase (Figure 2).12,17,18

During the proliferative phase, fibro-blasts become the key cells in the wound healing process. Fibroblasts adhere to the fi-bronectin rich provisional matrix and start producing collagen. During this phase, collagen is constantly being synthesized by fibroblasts and degraded by MMPs in a finely balanced process. An imbalance in the process will cause scar tissue to form, or conversely, a failure to heal. Another factor that can negatively affect wound healing is oxidative stress. Oxidative stress triggers cell senescence and death, and impairs cell functionality; for instance, the secretion of extracellular matrix proteins such as the collagen required for wound repair.19 At the same time, new microvasculature (capillar-ies) is forming to restore blood circulation to the wound bed, and to provide oxygen and nutrients for cells in the wound area. Macrophages and platelets secrete factors that recruit endothelial cells to the wound to initiate angiogenesis.15 Granulation tis-

Figure 1. Key events and factors in the phases of wound healing.

Phases of Wound Healing

• Platelet de-granulation • Wound infiltration with

inflammatory cells • Neutrophil’s phagocytosis• Provisional matrix (fibrin,

fibrinogen, HA)

• Fibroblasts and endothelial cells migrate into the provisional matrix

• Growth factors stimulate cell proliferation, ECM synthesis

• Angiogenesis, granulation, and re-epithelialization

PDGF, IGF-1, EGF , TGFβ, TGFα, VEGF, bFGF, KGF, HGF, PLGF, TIMPs, Interleukins, and interferons

• Matrix remodeling: collagen cross-linking

• Increase in tensile strength, cellularity, and vascularity

PDGF, IGF-1, TGFβ, FGFs, KGF, MMPs/TIMPs

Time

Mag

nitu

de o

f res

pons

e

Months - YearsRemodeling

Phase

WeeksProliferative

Phase

Inflammatory Phase

Days

Key Events:

Key Factors:

Injury and Coagulation

TNF-α, IL-1, IL-6, IL-8, MCP-1, PF-4, IP-10, SDF-1, MMPs, elastase, PDGF, IGF-1, EGF, TGFβ


sue consisting of collagen and new blood vessels is slowly formed to fill the wound. This process is controlled by a number of different growth factors, including vascu-lar endothelial growth factor (VEGF) and fibroblast growth factor (FGF2). Healthy granulation and wound margins are a vi-sual cue to a clinician that a wound has progressed from the inflammatory phase to the early proliferative phase. Epithelial cells migrate on the top of granulation tis-sue and form a barrier to protect the new layer of tissue and close the wound. At this point, the proliferative phase is complete, and the remodeling phase goes on under-neath the newly formed epithelial layer. During the remodeling phase of wound healing, cells present at the wound site remodel the provisional collagen matrix into mature tissue. Collagen is synthesized and degraded at a precisely balanced rate with no increase in amount of collagen produced; rather, the collagen fibers are being organized into bundles of increasing diameter. When the process of collagen re-modeling is not balanced, scar tissue may form, which has approximately 80% of the tensile strength of normal skin.20 This can leave the area vulnerable to future wound development.

The overall time frame for complete wound healing depends on local and system-ic factors that can impact the effectiveness of the wound healing process.9 The panel agreed that clinical signs of a stalled wound are fail-ure to decrease in size, borders which are everted, rolled or unattached, lack of gran-ulation tissue, or tissue of poor consistency which appears frail and pale in color.

The key molecular and cellular charac-teristics of chronic wounds versus healing wounds are summarized in Figure 3.17

THE ROLE OF MESENCHYMAL STEM CELLS IN WOUND HEALING

In the past 10 years, our understanding of the role of mesenchymal stem cells (MSCs) in wound healing has expanded dramatical-ly. MSCs are multifunctional cells that can differentiate into multiple different types of mesenchymal tissues to repair bone, skeletal muscle, tendon, or cartilage, as needed;21 or can remain undifferentiated and regulate im-mune and inflammatory responses.21 Initial-

ly, MSCs were discovered in bone marrow, but it is now known that they are present throughout the body and have been found in numerous tissues of non-mesenchymal or-igin including the skin.23 MSCs are mature stem cells, not embryonic. This makes MSCs

a non-controversial source of stem cells for both research and therapies. Although MSCs may differentiate into other types of cells in wounds,24 accumulated data support that paracrine secretion of growth factors is the main mechanism MSCs use to orchestrate

Figure 3. Chronic wounds versus healing wounds.

Figure 2. Pathophysiology of a chronic wound.

PNM – Polymorphonuclear Leukocytes (Neutrophils)MØ – Macrophages/MonocytesROS – Reactive Oxygen Species

TNF-α – Tumor Necrosis Factor alphaIL-1 – Interleukin-1MMP – metalloproteinase

Chronic WoundsExcess of pro-inflammatory (TNF-α, IL-1), Reactive Oxygen

Species (ROS) and proteases (MMPs)

Matrix (collagen) and growth factor degradation

Cell senescence and death

Lack of vascularization, granulation and re-epithelialization

Healing WoundsAnti-inflammatory cytokines (IL-10, IL-4)

Proteases Inhibitors (TIMPs)

Active cells secreting new matrix and growth factors and supporting new blood vessel formation, granulation and re-epithelialization


wound healing and regulate activity of other cells such as fibroblasts, endothelial and ep-ithelial cells.13 The role of MSCs in wound healing is summarized in Figure 4.25

MSCs can migrate to an area of inflamma-tion in response to cytokines, chemokines and growth factors present in the wound, including PDGF, interleukin-1 (IL-1), IL-8 and tissue necrosis factor-alpha (TNF-α), stromal cell-derived factor-1 (SDF-1) and

others.26,27 Extensive research has shown that MSCs play a vital role in wound healing by regulating inflammatory cell activities; neutralizing excess oxygen radicals; recruit-ing endothelial cells, dermal fibroblasts and epithelial cells to support wound vascular-ization, granulation tissue formation, and re-epithelialization, and producing factors that prevent fibrosis and improve the quality of healed tissue.28-31

Several studies have illustrated that there is a decline in MSC number and func-tionality in certain patient populations. A study by Rodriguez-Menocal compared MSCs in patients with chronic wounds over two years in duration to MSCs of healthy donors.32 MSC-mediated migra-tion of fibroblasts in vitro assay was select-

ed for assessment of MSC functionality. Fi-broblasts were placed in the upper chamber of a Transwell (Corning) insert, MSCs were placed in the bottom, and the migration of fibroblasts through the permeable mem-brane in response to growth factors released by MSCs was measured. The study showed a significant decrease in fibroblast migra-tion in response to MSCs derived from patients with chronic wounds, supporting a conclusion that MSCs in these patients do not function properly (Figure 5). A study by Caplan showed a steep decline in number of MSCs present in bone marrow as we age (Figure 6),33 and Cianfarini and colleagues studied MSCs in diabetic mice, and found that not only were the number of stem cells reduced, but levels of key wound healing growth factors released by stem cells derived from diabetic animals were also significantly lower (Figure 7).34

Evidence from in vitro, preclinical, and clinical research supports the effectiveness of adding exogenous MSCs to promote wound healing.13 The data indicate that delivering potent MSCs derived from young healthy donors directly to a wound, should promote wound healing in aged patients with under-lying co-morbidities impacting the number and functionality of their own MSCs.

ACELLULAR VERSUS CELLULAR PLACENTAL MEMBRANE THERAPIES

The panel reviewed the science of acellu-lar and cellular placental membrane ther-

Figure 4. The role of MSCs in wound healing.

Tissue Protective

Anti-inflammatory

Tissue Regenerative

Blocks T Cell Proliferation

IL-4 Production

IL-10 Production

TNF Suppression

Anti-apoptic

Anti-fibrotic

Bone

Ligament

Cartilage

Tendon

StromaFat

Extensive research has shown that MSCs play a vital role in wound healing.

Figure 5. Migration of fibroblasts in response to bone marrow MSCs derived from healthy donors and patients with chronic wounds.

MSCs from healthy donors

MSCs from patients with chronic wounds


apies and discussed the important differ-ences between these categories of advanced therapies in the context of the pathophys-iology of chronic wounds, and the role of MSCs in wound healing.

Acellular placental therapies provide a structural matrix that serves as an anchor for host cells to migrate to the area of a wound and bind MMPs, thereby preserving collagen and growth factors in the wound bed from degradation.35 Some acellular products, in addition to a structural matrix, also provide growth factors that stimulate migration, proliferation and differentiation of host cells at the wound site. Examples of acellular therapies are placental membrane products processed using dehydration or cryopreservation without a cryoprotectant. Neither of these techniques preserves via-ble cells. Because acellular products do not provide living cells, they may be less suited for patients with impaired native cell func-tionality, such as patients with advanced age or diabetes.36,37 The panel agreed that the majority of patients seen in their prac-

tice have underlying metabolic perturba-tions that impact the cellular functions required for progression of wound healing through its stages. Therefore, an acellular product that only coordinates the activity of poorly functioning host cells may not be enough to heal the wound.

Cellular placental membrane therapies provide structural matrix, growth factors, and viable cells, including MSCs. The liv-

ing cells offer a dynamic response to the changing wound microenvironment.38 In vivo studies provide overwhelming evidence that MSCs can accelerate wound closure by modulating the inflammatory environment, promoting the formation of a vascularized granulation matrix, inducing the migra-tion of keratinocytes and fibroblasts, and inhibiting cell apoptosis in the wound.39 An example of cellular therapy is a placen-

Figure 6. MSC prevalence in bone marrow by age. (Journal of cellular physiology by Wistar Institute of Anatomy and Biology. Reproduced with permission of John Wiley& Sons Ltd. in the format journal/magazine via Copyright Clearance Center.)

Newborn Teen 30 50 80

Age (Years)

12,000,000

1400,000

1250,000

1100,000

MSC

s per

Mar

row

Cel

ls

110,000

Estimates Obtained by CFU-f assay

Figure 7. Number and functionality of stem cells in diabetic versus normal mice. (Wound repair and regeneration: official publication of the Wound Healing Society and the European Tissue Repair Society by Wound Healing Society; European Tissue Repair Society. Reproduced with permission of Blackwell Publishing, Inc. in the format journal/magazine via Copyright Clearance Center.)

Cellular placental membrane therapies provide structural matrix, growth factors and viable cells, including MSCs.


tal membrane product that is processed to preserve viable cells. Data suggest that placental membranes serve as a temporary wound cover and do not become incorpo-rated into the host tissue.40 Rather, the liv-ing cells participate in the healing process and improve the wound environment by a paracrine mechanism via secretion of bio-logically active factors in response to wound stimuli.22,41

STRUCTURE AND COMPOSITION OF PLACENTAL MEMBRANES

Placental membrane-based cellular ther-apy is a natural yet powerful tool for heal-ing chronic wounds. Fresh placental mem-branes are a rich source of collagen-based extracellular matrix, growth factors, cyto-kines and living cells, including fibroblasts, epithelial cells and MSCs as shown in Fig-ure 8.12,42,43 Placental membranes are gen-erally immune-privileged and do not elic-it an immune response, which allows for

allogenic use.44,45 There are two placental membranes: the amnion and the chorion. Composition of the amnion and chorion is illustrated in Figure 9.35

The amnion is made up of a single-cell epithelial layer, and the stromal layer that contains fibroblasts and MSCs embedded in a collagen matrix.12 Between the amnion and chorion is a loose spongy matrix that al-lows the amnion to be easily separated from

the rest of the placenta. The chorion is com-posed of the stromal layer, which like the amnion contains fibroblasts and MSCs in a collagen rich matrix, and the chorionic tro-phoblast layer which forms the choriodecid-ua where the maternal and fetal systems are interconnected. The similarity of amnion and the stromal layer of chorion composi-tion suggest functional similarity and inter-changeable use for both membranes. The main difference between these membranes is the presence of the epithelial layer and the basement membrane in amnion that are ab-sent in chorion.42 These structural elements make amnion mechanically stronger than chorion42 and thus more appropriate when the tissue will serve as mechanical support or as a barrier. The jelly-like consistency of chorion makes it a better option for deep tunneling wounds.

Placental membranes for wound healing products are donated by mothers undergo-ing cesarean section at full-term of a nor-mal pregnancy. As the placenta reaches full-term, levels of pro-inflammatory cytokines and MMPs in the trophoblast increase to facilitate the post-partum separation of the placenta from the uterus.46 Consequently, products that include the trophoblast layer of placental membranes will have high levels of MMPs and pro-inflammatory cytokines, which are already present in excess in chron-ic wounds and are correlated with poor wound healing.47 The causal effect of exoge-nous MMPs on delaying wound healing was also demonstrated in a mouse wound mod-el.48 As a maternal tissue, the trophoblast layer will also be immunogenic when used as an allogenic implant. For these reasons, the panel recommends that clinicians consider the layers of the placental membrane includ-ed in commercial wound care products, as this can affect clinical outcomes.

COMPARATIVE PROCESSING TECHNIQUES FOR PLACENTAL MEMBRANE WOUND THERAPIES

Processing techniques used to sterilize and preserve the placental membrane also influence the composition and properties of the final wound therapy product. Pla-cental tissue can be processed using aseptic techniques, in which the processed tissue is not terminally sterilized and requires

Figure 8. Composition of placental membranes.

There are several methods of preserving placental membranes that are utilized to manufacture

commercial wound care products, however, with only one

exception, all methods result in destruction of viable cells.51

Figure 9. Layers and composition of the placental membrane (Courtesy of Osiris/ Lavery).


bioburden and sterility testing. Chemical treatment or radiation is often used for tis-sue sterilization; however, these have both been shown to destroy cells in the tissue and may alter the structure and functional-ity of the remaining components.45,49,50

There are several methods of preserving placental membranes that are utilized to manufacture commercial wound care prod-ucts, however, with only one exception, all methods result in destruction of viable cells.51 Effects of different commercial tis-sue processing techniques on composition and properties of placental membranes can be seen in Table 1 and Figure 10.51

Dehydration is the method most com-monly used for placental membrane preser-vation. Numerous studies have investigated the composition of dehydrated amniotic membranes in vitro, and show the partial degradation of the basement membrane during the dehydration process.49,50 The thickness of the placental matrix after de-hydration is two- to three-fold less than fresh placental tissue.51 In addition to alter-ing the structure of the tissue, dehydration also kills endogenous living cells,51,57 result-ing in a devitalized product.

A second method of processing placental tissue is cryopreservation in glycerol with a freezing step.51 Like dehydration, this method preserves structural matrix but

kills endogenous living cells, resulting in a devitalized product. These devitalized pla-cental membrane products do not provide living cells, but it has been shown in vi-tro that they can stimulate migration and proliferation of MSCs, suggesting that it may contribute to wound healing58 which may be sufficient in healthy patients with functional MSCs, but not in patients with poorly functioning native MSCs.

Currently, there is only one method of tissue processing that results in a cellular placental membrane product containing viable cells. This cryopreservation method developed by Osiris Therapeutics retains structural matrix, growth factors, and live cells including MSCs in their native state. It therefore preserves the key properties of fresh placental membranes, resulting in the only viable cryopreserved placental mem-

Figure 10. Cell viability is maintained with BioSmart process. Cell viability was evaluated post-thaw (BioSmart & CryoTek) or after re-hydration (Purion) using LIVE/DEAD cell viability/cytotoxicity kit. Green indicates live cells. Red indicates dead cells.

Images provided by Osiris Therapeutics, Inc. (Columbia, MD). Data were published by Duan-Arnold et al. 15-17 and presented at SAWC spring 2015.14

Table 1. Summary of properties of placental membranes processed by different methods

Description Cryopreservation Freezing followed by Cryopreservation Dehydration

Commercial Processing Method29-31,52-56

Biosmart Cryotek Purion

Tissue Source55,56 Amnion, trophoblast-free chorion

Amnion and umbilical cord Amnion and chorion with trophoblast

Structural Matrix29-31,55-56 Intact Intact Altered

Viable endogenous cells13,29-31,56

Preserved Destroyed Destroyed

MMP level56 Low Low High

Sustained release of growth factors over time13,56

Yes No No

Dynamic response to changing wound environment29-13,56

Yes No No

Commercial product (Company)52-54

Grafix Prime and Core (Osiris Therapeutics, Inc)

Neox and Clarix (Amniox Medical)

Epifix (MiMedex Group)


brane (vcPM) product.59 Placental mem-brane products containing live cells are particularly suited for patients who are ex-pected to have a reduced number or poorly functioning resident MSCs due to age, dia-betes or other comorbidities.

The panel recommends that when eval-uating placental membrane products, clinicians consider both the layers of the placental membrane used, as well as the method of processing and sterilization used to prepare it for use in wound care. The method of processing and sterilization has an enormous impact on the properties of the end product, and its potential to suc-cessfully heal chronic wounds in compro-mised patients.

THE EVIDENCE SUPPORTING USE OF VIABLE CRYOPRESERVED PLACENTAL MEMBRANE

Evidence supporting adoption of new therapies travels up the evidence-based medicine pyramid, starting with scientif-ic evidence and clinician experience on a small scale, expanding next to single-center trials, then to randomized, controlled mul-ticenter trials, and finally to multi-study reviews (Figure 11).60

Clinical trials in wound care are a chal-lenge because the patient population with chronic wounds is heterogeneous in wound type and comorbidities.14 High-quality ran-domized, controlled trials can explore com-parative efficacy, but the panel cautions that the study inclusion and exclusion criteria ensuring a relatively homogeneous popu-lation across treatments groups often ex-cludes the very patients of particular inter-est – those with multiple comorbidities who are at high risk of failing standard therapies.

Although patients with comorbidities may have been excluded from clinical stud-ies with advanced therapies, panel members confirm that the therapies are not contra-indicated. In fact, early intervention with viable cryopreserved placental membrane (vcPM) containing live cells could con-tribute to efficient wound healing in these

high-risk patients. The panel expressed that clinical experience is currently outpac-ing research, and encouraged generation of further data to support use of vcPM in high-risk patients.

The panel reviewed and discussed exist-ing clinical data for vcPM, focusing on re-cent publications supporting the efficacy of vcPM for healing chronic wounds. Reguls-ki and colleagues conducted a single-center retrospective database analysis in a spe-cialized outpatient foot and ankle wound care center to evaluate the initial clinical experience with vcPM for the treatment of chronic wounds.61 Patients were included if they received at least one application of vcPM (Osiris Therapeutics, Inc.) during the study time period, and site-standard practice was use of this advanced therapy in wounds of 28 days or greater duration after resolution of underlying morbidities.

Strict standard of care (SOC) to diag-nose and address underlying comorbidities was implemented at the start of the study. Weekly follow-up and routine wound care included sharp debridement at each visit as indicated, preparation of the vcPM accord-ing to instructions and placement directly on the wound surface, and dressing with a non-adherent dressing, saline-moistened gauze, and dry gauze. Offloading utilizing total contact cast, surgical shoe, specialized walker, and compression were used as ap-propriate for wound location.

The 66 patients included were elderly (mean age 71.1 years), with wounds that had not healed for a substantial duration of time (mean 38.0 weeks, range 4-416 weeks). Wound types included were Diabetic Foot Ulcers (DFU) at 40.3%, Venous Leg Ulcers (VLU) 50.7%, and ‘other’ at 9%, including pressure ulcers, traumatic and postsurgical

A majority (76.1%) of wounds that had failed to heal with

other therapies for an extended period of time were fully closed

after 12 weeks of study therapy with vcPM.61

Figure 11. EBM levels of evidence. EBM Pyramid and EBM Page Generator, © 2006 Trustees of Dartmouth College and Yale University. All Rights Reserved. Produced by Jan Glover, David Izzo, Karen Odato, and Lei Wang.

quality

of evid

ence

UNFILTERED INFORMATION

FILTERED INFORMATION

TRIP Database searches these simultaneously

Systematic Reviews

Critically-Appraised Topics

[Evidence Syntheses]

Critically-Appraised Individual Articles [Article Synopses]

Randomized Controlled Trials (RCTs)

Cohort Studies

Case-Controlled Studies Case Series / Reports

Background Information / Expert Opinion

Placental membrane products containing live cells are particularly suited for patients who are expected to have a reduced number or poorly functioning resident MSCs due to age, diabetes or other comorbidities.


wounds, and non-venous vascular wounds. Nearly 75% of the patients receiving study treatment with vcPM previously received advanced therapies including acellular ma-trices, skin grafts, artificial cellular skin sub-stitutes, collagen dressings, HBO, wound vacuum, and topical growth factors, all of which failed to close the wound.

A majority (76.1%) of wounds that had failed to heal with other therapies for an extended period of time were fully closed after 12 weeks of study therapy with vcPM (Figure 12). Follow-up data on 47 of the 54 wounds that completely closed using the study therapy showed no recurrences at mean follow-up time of 20.4 months.

Benchmark healing rates for DFU using SOC showed only 24.2% of wounds healed at 12 weeks.62 The healing rate seen with study therapy at 12 weeks for the DFU subset of patients was 85.2%, which is es-pecially noteworthy considering the mean age of the DFUs subset at the start of vcPM was 24.5 weeks.

Consistent with these results, a prospec-tive, multicenter, randomized, single-blind-ed study conducted by Lavery and the Grafix Diabetic Foot Ulcer Study Group showed that vcPM was a safe and effective treatment for chronic DFUs.63 The study included patients with Type 1 or Type 2 diabetes be-tween the ages of 18-80 years old, with index wound between four and 52 weeks in dura-tion, located below the malleoli on planter or dorsal surface, between one and 15 cm2 in size. Patients were excluded from the study for HbA1c >12%, evidence of active infec-tion, inadequate circulation to the affect-ed foot, exposed muscle, tendon, bone, or joint capsule, or reduction of wound area by ≥30% during the screening period. Patients were randomized to either the study group with SOC plus vcPM (Osiris Therapeutics, Inc.) applied once per week for up to 12 weeks, or the control group with SOC alone once per week. All patients received SOC that included wound cleaning and surgical debridement, offloading, and non-adherent dressings. The primary endpoint was com-plete closure of the wound, as evaluated by the investigator and confirmed by blinded experts at a central wound care laboratory. Control patients with wounds that did not heal during the 12-week period were able to

Figure 12. Healing rates in chronic wounds with vcPM.

Figure 13. Healing rates in vcPM versus SOC after 12 weeks.

Figure 14. Safety of vcPM versus control.

Baseline (mean Week 12 Week 26 38.0 weeks)

0

76.1%

100%

80%

60%

40%

20%

0%

80.6%

vcPM Control

70%

60%

50%

40%

30%

20%

10%

0%

21%

62%

P = 0.0001 vs

Adverse Events Wound-related Infection-related (All) infections hospitalizations

100%

80%

60%

40%

20%

0%

44%36%

18%

6%

15%

66%P = 0.031

P = 0.044

vcPM

Control

P = 0.15


receive vcPM therapy in an open-label 12-week cross-over period.

Ninety-seven patients were included from 20 centers, with 50 patients random-ized to the study group and 47 to the con-trol group. Patient baseline characteristics were similar across groups. All primary

and secondary endpoints demonstrated the clinical benefit of vcPM. There was a significant increase in the proportion of patients achieving complete wound closure at 12 weeks in the active treatment group compared to the control group (62% vs 21%; P=0.0001) (Figure 13). The control group was representative of normal clinical practice and the rate of healing at 12 weeks in the control group was comparable to the standard rate reported by Margolis and col-leagues of 24% with SOC.62

Median time to wound closure was also decreased by almost four weeks with active therapy (vcPM 42.0 days vs Control 69.5 days; P=0.019), and 50% wound size re-duction at day 28 was increased (62% vs. 40.4%; P=0.035). Patients in the study group also required fewer visits in the

blinded phase (vcPM 6 visits vs Control 12 visits; P<0.001).

Superior wound healing was achieved in fewer visits with vcPM, which can de-crease utilization of healthcare services and reduce overall cost of care. Follow-up vis-its for an additional 12 weeks showed that 82.1% of wounds during the initial period remained closed in the study group, versus 70% in the control group. Safety was also improved with use of vcPM as shown in Figure 14. There were significantly fewer adverse events (vcPM 44.0% vs. Control 66.0%; P=0.031), including wound relat-ed infections (18.0% vs. 36.2%; P=0.044) and fewer hospitalizations related to in-fections (6% vs. 15%; P=0.15) in patients randomized to the study group. This posi-tive result seen with the use of vcPM can

Compared to high-quality standard of care, weekly application of vcPM increased the rate of complete closure in DFUs by 62% versus 21% with standard care alone.65

Table 2. Risk factors for reduced wound healing capacity and supporting evidence

Risk Factor Supporting Evidence

Aging • MSC, fibroblasts and neutrophils play a major role in wound healing, and cell senescence is expected with the normal aging process.

• Number of MSCs and their functionality declines over time.33,37

Obesity • An accumulation of senescent cells has been found in the diabetic and obese patient populations.67

• Body Mass Index (BMI) is a predictor of wound complications, with increased BMI and obesity linked to increased risk of complications68 and increased wound healing time.69

• Hypertension often accompanies high BMI, and has been linked to delayed wound healing time.70

Diabetes • Immunodeficiency, neuropathy, ischemia, and inflammation contribute to poor healing in DFU.9

• Impaired fibroblast function negatively affects the synthesis of collagen.71

• Inadequate production of inhibitors of matrix metalloproteinase (MMP) allows MMP to break down extracellular matrix.35,72

• Reduced number and poorly functioning stem cells and reduced growth factor production.34

Chronic renal failure (CRF)

• CRF impacts most body systems including dermatologic, endocrine/metabolic, cardiovascular, pulmonary, and hematologic.73

• Protein consumption is critical to wound healing, and increase in protein consumption is often recommended in patients with wounds in opposition to recommendations for patients with renal failure.74

Smoking and nicotine use

• Smoking, and nicotine in particular, has detrimental effects on blood vessels and the efficiency of the oxygen transport to the cells in the body that slows wound and bone healing processes.75

• Smokers have a higher risk of infection and delayed wound healing.76,77

• Smoking is a predictor of wound complications.68

Impaired Circulation

• Impaired circulation impacts wounds of the lower extremities leading a hypoxic wound environment.78

• An ABI <0.9 indicate risk of ischemia, borderline ischemia at <0.6–0.8, severe ischemia at <0.5, and critical ischemia at <0.4.

• Decreased ABI is a predictor of wound healing, with an ABI of less than 0.8 identified as a predictor of failure to heal within 24 weeks in venous leg ulcers.79


contribute to improved patient safety and decreased healthcare utilization, as wound infections increase a patient’s likelihood of hospitalization 56-fold, and the likelihood of amputation 155-fold.64

Patients who did not achieve wound clo-sure with standard of care alone were eli-gible to receive vcPM therapy in an open label period, and in these 26 patients, the rate of expected closure with study therapy after failure with SOC was 67.8% with a time to closure of 42 days.

This study was the first multi-center ran-domized controlled trial investigating the use of vcPM for the treatment of non-heal-ing DFU, and it showed that cryopreserved placental membrane with live cells is a safe and effective treatment. Compared to high-quality standard of care, weekly appli-cation of vcPM with live cells increased the rate of complete healing in DFUs by 191% (relative effect) over SOC alone. 65

A recently published prospective multi-center, open label, single arm clinical tri-al investigated the clinical effectiveness of vcPM for complex DFUs.66 Complex di-abetic foot wounds with exposed tendon, muscle, fascia, or bone remain a challenge and are more susceptible to complications such as infection and amputation due to their severity. In this study, after vcPM was applied weekly to complex DFUs with ex-posed deep structures (mean wound area 14.6 cm2), 96.3% of patients completing the protocol achieved the primary end-point of 100% wound granulation by week 16. The four week percent area reduction was 54.3%. Complete wound closure was obtained in 59.3% of these patients in a mean time of 9.1 weeks. Furthermore, no product-related adverse events occurred in this high-risk population. The findings from this study support that vcPM is a promising treatment option for chronic complex wounds in compromised patients, as well as for those uncomplicated DFUs usually studied in most clinical trials.

The data generated to date support that decreased healing time, decreased health-care resources required, and improved patient safety make therapy with cellular placental membrane products an import-ant new treatment option for patients with DFUs.65

EARLY USE OF VCPM IS RECOM-MENDED FOR AT-RISK PATIENTS

The panel extensively discussed the pa-tient populations who would benefit from vcPM and the timeframe to start the thera-py. Based on scientific and clinical data pre-sented in Table 2, patients with advanced age, obesity, diabetes, hypertension, chron-ic renal failure, malnutrition, smoking, and impaired circulation were identified as populations at risk for chronic wounds. Despite the fact that these populations are at highest risk of non-healing, there is lim-ited data available on the use of advanced therapies in these populations because these factors are typical clinical trial exclu-sion criteria.

Diabetic patients have multiple risk fac-tors for developing a chronic wound.9 Di-abetic patients have approximately 15 to 25% lifetime risk of developing a DFU and 15% of DFUs will result in amputation.68 Multiple clinical studies illuminate the re-ality of poor wound healing in the diabetic population. A meta-analysis of the con-trol groups from randomized controlled trials was completed by Margolis and col-leagues to investigate the standard healing rates of patients who received standard of care treatment.62 Nine studies met criteria for inclusion in the analysis, and overall showed healing rates of 24.2% at 12 weeks, and 31% at 20 weeks with standard of care. The panel was passionate about improving these poor odds of healing, and based on the current data, strongly recommends that along with strict adherence to good stan-dard of care, clinicians incorporate cellu-lar therapy with placental membranes into early therapy for at-risk patients.

The panel also shared clinical experienc-es using vcPM, and discussed additional patient populations and clinical situations that could benefit from this advanced thera-py. Based on their experiences, the scientific information known about the properties of vcPM and the physiology of wound healing, the panel proposes sickle cell anemia, rheu-matoid arthritis, pyoderma, incisional clo-sure, trauma, burns, breast reconstruction, amputation site closure, tendon repair, hypertrophic scars, wounds with bone ex-posed, tunneling, or dehiscence as areas of promise. With scientific background and

expert opinion established, evidence needs to be built, first with case studies, and then moving up the evidence-based medicine pyramid to randomized controlled trials. As evidence is being generated, use of cellular placental membrane products based on sci-ence and guided by clinical results can lead to better patient outcomes as well as to new applications.

The panel also discussed the optimal timeframe for starting vcPM in at-risk pa-tients and agreed that the decision to use this advanced therapy should be patient and wound based, rather than time based.

Research has shown that early wound progress is a predictor of complete healing, In a study of VLUs, Gelfand and colleagues found that patients not achieving at least a 40% reduction in wound size by week 4 were unlikely to achieve full wound closure at 24 weeks,80 and in DFUs, Sheehan and colleagues found that patients not achiev-ing at least a 50% reduction in wound size by week four were unlikely to achieve full wound closure at 12 weeks.81 Percent area reduction (PAR) for DFUs after four weeks of treatment has been suggested as a tool to help clinicians distinguish DFUs expected to heal within 12 weeks from those not ex-pected to heal despite standard wound care.

However, the panel proposes that based on the science available today, clinicians should not wait four weeks to see whether a wound will heal with standard care alone. While PAR was the best predictor for the science available at that time, the panel agreed and current scientific evidence supports that the risk factors outlined in Table 2 are reliable predictors of the patient populations who will experience impaired healing.9,82 In these at-risk patients, the panel recommends that

We have patients with comorbidities. The longer they

have to wait to receive placental membrane cellular therapy,

the higher the risk of their developing debilitating and

costly complications. (Davis)


vcPM be incorporated into early wound care, not reserved as a last resort therapy af-ter wounds have failed to close after a period of time, or have failed other treatments.10

Panel members agreed that patients with comorbidities who in all likelihood will de-velop a chronic wound deserve early inter-vention with placental membrane cellular therapy. “We do not see healthy patients in our wound care clinic” was a common sentiment across panel members, as most patients seeking specialized wound care are at high risk for delayed healing, and already have chronic wounds. Panel members felt that subjecting this advanced therapy to waiting periods was not in the best interest of patients.

The panel reported that it is often a chal-lenge to establish the start date of a wound and recommend that patients identified as at-risk be referred to a specialty wound care clinic sooner, since requiring patients to fail treatment before introducing a treatment with greater healing potential puts patients at unnecessary risk.

Chronic wounds can pose serious risks to patients including increased mortality, am-putation, and infection, all of which carry substantial cost burdens and impact patient quality of life.68,83 Quality clinical evidence of improved healing of chronic wounds with vcPM63 supports its use in mitigating these risks.

The panel recommends an aggressive early approach that includes a thorough assess-ment of wound status and management of

underlying issues that could impact healing, implementation of good standard of care according to established guidelines, plus the use of viable cryopreserved placental membranes for patients identified as being at high risk of developing a chronic or com-plex wound.

COMBINING VIABLE CRYOPRE-SERVED PLACENTAL MEMBRANE WITH STANDARD OF CARE

The basic tenets of standard of care used to diagnose underlying wound pathologies and manage progression of wound healing are relatively consistent across wound etiol-ogies. Clinicians should refer to the estab-lished evidence-based guidelines issued by various societies for detailed guidance on standards of wound care. Examples are pro-vided at the end of this article for further reading.

Standard wound care successfully heals some wounds. However, the panel’s expe-rience is that a large proportion of wounds will remain stalled with the use of standard care alone. The panel emphasized that in patients with comorbidities, advanced therapies are required to interrupt the in-flammatory cycle of a stalled wound, and to correct the imbalance in the wound en-vironment to help a wound transition from chronic to healing.

The panel recommends that clinicians perform a thorough clinical examination and patient interview to understand wound history, surgeries, concurrent diseases, and current medication use; as well as uncover barriers to wound healing in the patient’s so-cial, family, and home lifestyle. Healing the wound is one goal, but an equally import-ant goal is to correct the underlying issues that led to formation of the wound. Patients will need coordinated management of any underlying conditions to control metabolic abnormalities, vascular peripheral arterial disease and other vascular deficiencies, in-fection/bioburden, autoimmune disease, and other factors such as tobacco use and nutritional deficiencies that may impact cel-lular function and impair wound healing. Resource limitations can impact nutrition and lifestyle; patients may split medications due to cost constraints, and financial lim-itations may be at the source of issues asso-

ciated with shoes, which can be a factor in formation of diabetic foot ulcers. A patient history is the first step to understanding out-side factors that may have contributed to the wound up to the current moment, and that may impede healing going forward despite best efforts and therapies. Social workers are an important part of the interdisciplinary team, and they can assist in getting patients the help they need to overcome barriers to wound healing. Wound management has become a multifactorial, multidisciplinary process,84,85 and synergy across the team can improve the efficiency of care and improve patient outcomes.

Diagnostic tools can uncover issues that may factor into the success of wound heal-ing – factors which can guide a clinician in identifying patients unlikely to heal on their own who are good candidates for vcPM. Commercial assays are under development for several proposed markers of inflamma-tion to assist in assessing wound activity on a cellular level. These advanced diagnostic tools will deepen understanding of the cel-lular function of wounds and help identi-fy what a specific stalled wound is lacking, and what it needs to progress. Until these tools are available, the panel feels that cur-rent diagnostic tools, clinical examination, and applying knowledge about how disease and aging affect the wound microenviron-ment, allow a clinician to identify patients at risk of non-healing who would benefit from vcPM.

Routine wound management with vigi-lant attention to SOC best practice is key to achieving optimal outcomes with cellu-

The science that is available to us now which wasn’t before,

and our clinical experience is telling us in no uncertain

terms, that the earlier you use advanced products in a patient identified as at risk, the greater

the chance that the patient will heal. (Gibbons)

Application of advanced cellular therapy as early as possible – especially in high risk patients, along with standard of care, in my experience, will save legs and ultimately be more cost efficient to the system. My goal is simply to heal patients as fast as possible, and the data supports the benefits of this approach. (Kashefsky)


lar therapy with placental membranes.10 The panel overwhelmingly stressed that ad-vanced therapy does not replace good SOC; rather the success of these therapies relies on well-executed SOC. They agreed that any treatment applied without good SOC is wasted care and will cause even the best and most advanced therapies to fail.

Thorough debridement of the wound prior to use of placental membrane cellular therapy is crucial to remove excess factors such as MMPs. The wound environment may still be imbalanced, but the MSCs in the vcPM will secrete factors needed to correct the environment. At the present time there are no data showing long-term persistence of MSCs in wounds. Available data support that MSCs improve the wound environment and support the functionality of host cells by a paracrine mechanism, and are cleared from the wound.86,87 At the next scheduled visit, the wound is again debrid-ed and vcPM is placed in the wound. The wound environment has been improved compared to the prior visit, which can be assessed by reduction of wound size and volume, wound bed color, reduction of ne-crotic tissue, and formation of wound bed granulation. Because the cells in vcPM are biologically active, they are responsive to dynamic changes in the wound, and they will secrete different factors in response to the needs of the wound as healing progress-es.22,43 Although most wounds are stalled in the inflammatory phase of healing, a wound can stall at any phase, therefore it is import-ant to maintain use of vcPM until a wound fully heals.

Offloading pressure, sheer and friction from the point of injury is also critical to the success of vcPM.10 A recent consensus document on the necessity for adequate offloading highlights this critical tenet of standard of care.88 Various devices are available depending on the location of the wound and patient mobility level, includ-ing specialty mattress support surfaces and pressure-relieving boots for pressure ulcers, and orthotics and devices such as walkers, casts, and boots for diabetic foot ulcers. Total contact casts are considered the gold standard for offloading DFUs and have pro-duced the highest healing rates compared to half shoes and removable cast walkers.89

Removable casts can be an effective offload-ing tool, but patient compliance with use of removable casts can be variable and can therefore impact effectiveness. Research has shown that patients only wear removable casts approximately 30% of the time they are walking.90 Strict prescription of offload-ing devices and compliant usage by patients is of critical importance with use of vcPM, which contains live cells. Direct contact between cells in the vcPM and the wound bed is required for successful cell signaling, and significant pressure on the wound sur-face has the potential to dislodge the vcPM, or even worse, shear the vcPM from the wound surface before the full benefit of the therapy can be received.

SOC guidelines are based on current ev-idence and experience available, and con-tinually evolve as new technologies and evidence emerge. As evidence with wound healing with vcPM continues to build, it is anticipated that guidelines will be updated to incorporate best practices in use of pla-cental membrane cellular therapy.

SUMMARYChronic wounds have a serious impact on

patient safety and quality of life,67 and carry a significant financial burden. Estimates of the cost of treating chronic wounds are in excess of $50 billion annually,91 including outpatient visits, medications and supplies, and serious complications that can require hospitalization, surgical intervention, and amputation. The serious consequences of chronic wounds, coupled with the growing population of at risk patients, deserve the attention of clinicians and the entire health-care system to consider new therapies that can positively impact healing outcomes.

Advances in understanding the patho-physiology of chronic wounds have revealed how age and comorbidities alter normal cell function, and shown the vital role that MSCs play in wound healing. This knowl-edge has been a key driver in the develop-ment of innovative therapies using placental membranes. The composition and proper-ties of placental membrane products can be distinguished by the layers of the membrane used, and by the processing and sterilization method used to prepare it. Currently, only one commercial processing method results

in a cellular product: a viable cryopreserved placental membrane (vcPM) that maintains the natural properties and function of the placental membrane tissues, retaining the native ECM, growth factors, and viable cells, including MSCs.

After reviewing the science and clinical outcomes evidence for vcPM, and discuss-ing their clinical experience using this ad-vanced therapy, the panel recommends that vcPM be incorporated into wound care protocols early for at-risk patients. This vi-able tissue should not be reserved as a last resort therapy after wounds have failed to close after a period of time or have failed other treatments. The panel proposes that the best interest of a patient can be met when good standard of care is practiced, and a cellular placental membrane product is used in patients with risk factors that in-crease the likelihood that they will develop a chronic or complex wound.35-37,79 These risk factors include advanced age, obesi-ty, diabetes, uncontrolled hypertension, chronic renal failure, malnutrition, smok-ing, and impaired circulation.

The science behind vcPM supports its early use in high-risk patients, and evidence continues to build through clinical stud-ies to support the incorporation of vcPM into existing clinical practice and advanced wound care treatment protocols. The pan-el concluded that combining vcPM with good standard of care has the potential to positively impact wound healing outcomes, substantially decrease healthcare costs, and improve the quality of life of patients at risk for, and living with chronic and com-plex wounds.

The serious consequences of chronic wounds, coupled with

the growing population of at risk patients, deserve the attention

of clinicians and the entire healthcare system to consider

new therapies that can positively impact healing outcomes.


Marchese: While nothing replaces good standard of care and adherence to tried and true algorithms for treating chronic wounds, our current knowledge allows us to predict which patients are at risk of developing a chronic wound, as well to understand what is lacking in these wounds at the cellular level that is causing im-paired healing. This can guide our decisions on when to use the advanced products that will provide exoge-nously what we know the wound is inherently lacking. Relying on standard of care alone simply ignores what we now know about the microenvironment of a chronic wound. It is an exciting time in wound care as we now have a better understanding of these wounds, better tools to assay a wound and its needs, and can provide the right product at the right time to help wounds prog-ress to healing.

Davis: We currently practice wound care with a delayed approach, often having to wait four weeks to administer advanced cellular therapy. Statistics repeatedly show that conservative standard of care only heals a wound ap-proximately 25% of the time in 12 weeks of care, and less than one third of the time after twenty weeks. We hold 66 to 75% of wound care patients hostage, waiting for stan-dard of care to fail before administering advanced cellu-lar technology. There are several studies that show the longer a wound remains open, the higher the costly risk of infection, complications, hospitalization, and amputa-tion. We recommend that advanced cellular technology be initiated as soon as possible, especially when seeing a patient with comorbidities. Cryopreserved placental membrane with live cells offer a new, unique, advanced therapy with healthy, live mesenchymal stem cells that offer unparalleled accelerated wound healing capabili-ties. Earlier treatment with advanced cellular technolo-gy leads to earlier healing, less cost, fewer complications and better quality healing. Why are we waiting?

Frykberg: While we cannot ever disregard the necessity for effective standard care for all chronic wounds, there exists an increasing need for advanced wound therapies for many of our patients with associated comorbidities. In this regard, the incorporation of advanced cellular

therapies into our wound care protocols can significant-ly improve patient outcomes. Earlier appropriate use of such products with demonstrated efficacy rather than late stage “rescue” therapy should also be considered in many high-risk patients with problematic wounds.

Reyzelman: Treatment of chronic wounds is incredibly challenging due to the highly complex physiology of wound healing. In order to increase our success in heal-ing chronic wounds, we must understand what is hap-pening on the cellular level and be able to apply that understanding by choosing the appropriate advanced tissue product. Although we have many options, only a few have the high level evidence to support their use and even less have live cells as part of their construct.

Samra: The review of the most recent scientific findings and their significance toward clinical wound care are astounding. All of the experts on the panel agreed that once standard of care was implemented, the current sta-tus quo of waiting four weeks was, by far, too long. There is no question in my mind that in the right clinical set-ting, using advanced therapy would help heal wounds faster. We can all agree that that is in everyone’s best interest. The advanced cellular therapy available today is arguably game changing in wound care and beyond. The potential indications reach into the realm of other types of soft tissue reconstruction such as in the setting of trauma, burns or even breast reconstruction. There is preliminary data suggesting that mesenchymal stem cells found in advanced cellular therapy may have ben-efits in improving the radiation-induced tissue damage. This could potentially have a significant impact on breast reconstruction in the radiated patient. Keloid scarring is another condition that could potentially benefit from the use of advanced cellular therapy. It’s an exciting time in wound care and the field of plastic surgery as a whole.

Gibbons: Standard of care that’s currently being used is often fragmented, not uniform, and is often misapplied. In order to be successful, advanced cellular products have to be used on the right foundation. The right foun-dation is standard of care that is properly applied.

SUMMARY STATEMENTS FROM PANEL MEMBERS


For Further Reading: Society guidelines for reference

American Diabetes Association

Clinical Practice Guidelines. Diabetes Care 2015; 38(1).http://professional.diabetes.org/resourcesforprofessionals.aspx?cid=84160

American Venous Forum O’Donnell TF Jr, Passman MA, Marston WA, et al; Society for Vascular Surgery; American Venous Forum. Management of venous leg ulcers: clinical practice guidelines of the Society for Vascular Surgery® and the American Venous Forum. J Vasc Surg. 2014; 60(2), 3S–59S.

Association for the Advancement of Wound Care

Association for the Advancement of Wound Care (AAWC) Guideline of Pressure Ulcer Guidelines. Malvern, Pennsylvania: Association for the Advancement of Wound Care (AAWC) 2010.http://aawconline.org/wp-content/uploads/2015/11/AAWCPressureUlcerGuidelineofGuidelinesAug11.pdf

Association for the Advancement of Wound Care (AAWC) Venous Ulcer Guideline. Malvern, Pennsylvania: Association for the Advancement of Wound Care (AAWC).December 2010.http://aawconline.org/wp-content/uploads/2015/11/AAWC-Venous-Ulcer-Guideline-Update-Algorithm-v28-updated-11Feb2014.pdf

International Disease Society of America (IDSA)

Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Disease Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2012; 54(12): e132-173.http://cid.oxfordjournals.org/content/54/12/e132.full?sid=54d872f6-fe76-4e81-b7ce-0133a3fb4e96

Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014; 59(2): e10-52.http://cid.oxfordjournals.org/content/early/2014/06/14/cid.ciu296.full

National Pressure Ulcer Advisory Panel

Prevention and treatment of pressure ulcers: clinical practice guideline. NPUAP/EPUAP/PPPIA. 2014.http://www.npuap.org/resources/educational-and-clinical-resources/prevention-and-treatment-of-pressure-ulcers-clinical-practice-guideline/

National Institute for Health Care Excellence

Diabetic foot problems: prevention and management . NICE guidelines [NG19]; 2015. https://www.nice.org.uk/guidance/ng19

Society for Vascular Surgery Hingorani A, LaMuraglia GM, Henke P, et al. The management of diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine. J Vasc Surg. 2016; 63(2): 3S–21S.http://www.jvascsurg.org/article/S0741-5214%2815%2902025-X/fulltext

Wound Healing Society Barbul et al, Wound Healing Society, Wound treatment guidelines. Wound Repair Regen. 2006; 14(6): 645-711.Lavery LA, Davis, KE, Berriman, SJ, et al. WHS guidelines update: Diabetic foot ulcer treatment guidelines. Wound Rep Reg. 2016; 24: 112-126.Federman DG, Ladiiznski B, Dardik A, et al. Wound healing society 2014 update on guidelines for arterial ulcers. Wound Rep Reg. 2016; 24: 127-136.Marston W, Tang J, Kirsner RS, Ennis W. Wound healing society 2015 update on guidelines for venous ulcers. Wound Rep Reg. 2016; 24: 136-144.Gould,L, Stuntz M, Giovannelli M, et al. Wound healing society 2015 update on guidelines for pressure ulcers. Wound Rep Reg. 2016; 24: 145-162.

Wound Ostomy Continence Nursing Society

Crawford PE, Fields-Varnado M; WOCN Society. Guideline for the management of wounds in patients with lower-extremity neuropathic disease: an executive summary. J Wound Ostomy Continence Nurs. 2013 Jan-Feb;40(1):34-45.

Kelechi TJ, Johnson JJ; WOCN Society. Guideline for the management of wounds in patients with lower-extremity venous disease: an executive summary. J Wound Ostomy Continence Nurs. 2012 Nov-Dec;39(6):598-606.

Ratliff CR, Tomaselli N. WOCN update on evidence-based guideline for pressure ulcers. J Wound Ostomy Continence Nurs. 2010 Sep-Oct;37(5):459-60. doi: 10.1097/WON.0b013e3181f17cae.

Wounds International International Best Practice Guidelines: Wound Management in Diabetic Foot Ulcers. Wounds International, 2013. Available from: http://www.woundsinternational.com


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Advancing the Science of Wound Care in the At-Risk Patient ... · VLUs, peripheral arterial disease, and wound care. He has written numer-ous peer-reviewed articles and text chapters