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Collagen

Dressings

or:

The Great

Coverup

Mary Vercellino, MSN, RN, CWON,

ACNS-BC

• Objectives:– Proteins vs Cells

– Structure of the dermis

– Structure of collagen

– Mechanism of collagen dressings

– Types of collagen dressings• Acellular

• Biologic or Cellular

– Research on collagen-containing dressing

• Disclaimer:

– Not an exhaustive review of all collagen-containing dressings

– Conclusions are mine alone, and alternate conclusions could be a good topic for your DNP project or PhD thesis

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• Disclaimer:– Not an exhaustive review of all collagen-

containing dressings

– Conclusions are mine alone, and alternate conclusions could be a good topic for your DNP project or PhD thesis

• Reviews:– Just a lot of numbers!

– I wanted to know what collagen dressing to use!

– I didn’t like that the product names weren’t used!

Biochemistry Review!

• Biochemistry review!

• Amino acids consist of Carbon atom with amino group (NH2), Carboxyl group (COOH), a hydrogen atom, and a side chain, which can be variable

• Sometimes called residues

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• Biochemistry review!

– Peptides consist of short chain of amino acids (20 kinds of amino acids)

– Polypeptides consist of a long peptide chain

• Biochemistry review!

• Protein:

– A building block of the cell (but NOT A CELL!)

– A structural hierarchy of strings of amino acids which comprise a protein

– The STRUCTURAL SHAPE of the protein helps determine it function

• Protein structures:

– Primary: The linear sequence of amino acids

– Secondary: The folding into a secondary structure

• Alpha helix

• Beta sheet

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• Collagen is a protein with a helix structure: – A triple alpha helix

– Which then assemble into fibrils

– Which then assemble into fibers

https://bionanotech2012.wordpress.com/2012/10/29/the-effects-of-strain-on-collagens-banding-structure/

• Collagen is:

– A protein molecule (not a cell)

– 2/3 of the dry weight of skin

– 1/3 of the protein in humans

Collagen Molecule

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• What does the body do with collagen?

– Tendon

– Ligaments

– In our case, is part of the composition of the ECM (extracellular matrix) which makes up the DERMIS

• ECM (extracellular matrix)– Secreted proteins that

provide structural support of tissue, secreted by fibroblasts• Collagen

– Types 1,2, and 3 (Fibular collagens)

– Type 4 (sheet type)

• Laminin

• Elastin

• Skin:

– Epidermis

• Cells are building blocks

• Cells densely packed

– Dermis

• Cells are supported by ECM, lower density

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– In dermis, cell density (Fibroblasts) is sparse

Biology.clc.uc.edu

– In epithelium, cells are densely packed

– In dermis, cell density (Fibroblasts) is sparse, supported by collagen in the ECM

• Fibroblasts in the dermis synthesize and maintain:

– Collagen

– Elastin

– Hyaluronic acid

– MMPs

– TIMPs

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• Maintenance of the ECM

– Regulation of the ECM

– TIMPs

• Tissue inhibitor of metalloproteanase

– MMPs

• Matrix metalloproteases

– Proteins, not cells

ECM maintenance is a delicate dance between MMPs and TIMPS

“Groot”

• MMP functions in wound healing– Removal of damaged ECM

– Help enable angiogenesis in wound by breaking down basement membrane around capillaries

– Contraction of scar tissue

– Remodeling of scar tissue

"Protein MMP1 PDB 1ayk" by Emw - Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons -http://commons.wikimedia.org/wiki/File:Protein_MMP1_PDB_1ayk.png#/media/File:Protein_MMP1_PDB_1ayk.png

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• Collagen dressings:– Acellular: are usually less expensive.

• Sometimes called “dermal template”

• “Wound Matrix”

• “Scaffold”

• Collagen from animal sources

– Cellular or Biologic • May contain fibroblasts, epithelial cells, growth

factors, and cytokines

• Collagen from human tissue

• Sources of collagen

– Bovine

– Ovine

– Porcine

– Human

• Acellular

– Promogran, Prisma, and Fibracol

– Oasis

– Endoform

• Cellular or Biologic

– Dermagraft

– Apligraf

– Theraskin

– Epifix

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• Acellular collagen dressings:

– Processed to removes cells

• Leaving only the collagen matrix

• May degrade the structure of the collagen

• Sterilized

– More than just trying to replace missing human collagen

• Does NOT replace human collagen permanently

• Provides a TEMPORARY “scaffold” or matrix

• A “sacrificial substrate” to bind MMPs”, which then break down the dressing, and not the wound collagen

• Collagen processing

• “Claim to fame”

– Collagen/ORC denatured

– Vs Minimally processed

• Mode of action of collagen dressing

– Recruit fibroblasts (chemotaxis)

– Promotes fibroblast attachment to the scaffold

– Binds MMPs

– Provides structure for wound healing

– May stimulate angiogenesis

– May provide growth factors

Haycocks, S., Chadwick, Pl, & Cutting, K. F. (2013). Collagen matrix wound dressings and the treatment of DFUs. Journal of Wound Care, 22(7).

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• So let’s examine some acellularcollagen dressings first– And will review some of the evidence

• But first…– Mary’s pet peeve:

– “I was taught”…

• Research

– Not big money in wounds

– Many studies sponsored by manufacturer

• Most are for DFUs or venous ulcers

– Small n

– Research designs less rigorous (least to most)

• Case study or series

• Retrospective

• Prospective

• Randomized, controlled

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• Research

– There’s no money in wounds!

• Research

– Most studies seem to compare dressing to “standard of care”

• Debridement

• Offloading

• Wet to dry (ugh)

– More recently:

• Comparative effectiveness research– 2009 ACA

– Compares two treatments for effectiveness in clinical arena

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• Comparative Effectiveness Research

– ACA established PCORI

• Patient-centered Outcomes Research Institute– Funded by a tax on Medicare and private health insurance

companies

– Hoping to find most effective treatments through research

– Some find this controversial

• A slippery slope to health care rationing?

• Promoran: Collagen/ORC 45% ORC (Oxidized regenerated cellulose)

– 55% collagen

• Prisma: Collagen/ORC/silver 44% ORC/55% collagen/1% silver

• Fibracol: Collagen/alginate

– 90% collagen/10%

• Collagen source:

– Bovine split hides from Australia

• These are “early” dressings

– Approved by the FDA in the 90’s

– Are less expensive

– Evidence:

• Difficult to compare

• Small n

• Some studies just tested the quantity of MMPs in the dressing, not wound healing

• No big insurance hurdles

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Year n Results More results

1998Donaghue et al.

DFUs:39 collagen/alginate15 saline gauze

78% had 75% or greater size reduction vs60%

Complete healing:48% vs 36%

2002Veves, et. al

DFUs:138 collagen/ORC138 saline gauze

After 12 weeks:37% healed vs28.3%(not stat sig)

45% vs 33% if wound less than 6 months is duration(stat sig)

2013Gottrup, et. alRCT

DFUs:24 collagen/ORC/silver14 foam

>50% wound area reduction:79% vs 43%(p 0.035)

Healed by week 1452% vs 31%

Not considered significant

Holmes, C., Wrobel, J. S., MacEachern, M. P., & Boles, B. R. (2013) . Collagen-based wound dressings for the treatment of diabetes-related foot ulcers: a systematic review. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 6.

• Hey! What’s this p-value thing?

– A statistic

– Indication that the answer to the research question has a significant result

– Usually p <= 0.05 is considered significant

• Oasis (acellular)

– Approved by FDA in 2006

– Described as both a “scaffold” and a “matrix”

– Collagen source is small intestine submucosaof pigs (SIS)

– Includes growth factors and other dermal proteins (not cells)

– Comes in dry sheets

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• Oasis Evidence

– 2005: Randomized trial

– Diabetic foot ulcers

– Oasis vs Regranex gel (becaplermin)

– N=73

– 49% closure in 12 weeks with product O

– 28% with becaplermin

– p = 0.055 (almost statistically significant)

• Oasis Evidence– 2010: Randomized trial (UK)

– Some funding from manufacturer (editorial assistance)

– N=50, ABI >=0.6, no infection

– Mixed venous/arterial LE ulcers

– Compared to “standard of care” (petrolatum gauze)

– 80% closure in 8 weeks with product O

– 65% with “standard of care”

Romanelli, M., Dini, V., & Bertone, M. S. (2010). Randomized comparison of Oasis wound matris versus moist wound dressing in the treatment of difficult to heal wounds of mixed arterial/venous etiology. Advances in Skin and Wound Care, 23(1).

• Endoform (acellular)

– Approved by FDA in 2010 (New Zealand)

– Collagen source is sheep

• Propria submucosa of ovine forestomach tissue

– 90% intact collagen, 10% secondary ECM components

– Inexpensive

– Comes in dry sheets

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• Endoform

– “Dermal template” (acellular)

– Approved by FDA 2010

– Referred to as an “intact collagen ECM”

– Different processing than other acellular collagens

– 90% collagen, 10% other “ECM components”

• Endoform (acellular)

– Now being distributed by large wound dressing company

– Evidence:

• Scant due to new dressing

• 2 case series found

• Research #1:

– Prospective case series

– n=19 patients, 24 wounds

– Venous, arterial, DFUs, and incisional wounds

– Debridement and compression(for VLUs)

– 50% of wounds closed at 12 weeks

Liden, B. A., & May, B. C. (2013). Clinical outcomes following the use of ovine forestomach matrix … to treat chronic wounds. Advances in Skin and Wound Care, 26(4).

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• Research #2:

– Retrospective case series

– n=14 patients, 23 wounds

– Venous ulcers

– Debridement and compression

– 97% of wounds closed at 12 weeks vs:

• 71% pig SIS

• 46% standard of care

Bohn, G. A., & Gass, K. (2014). Leg ulcer treatment outcomes with new ovine collagen extracellular matrix dressing: a retrospective case series. . Advances in Skin and Wound Care, 27(10).

• Issues?

– No control groups

– n is small

– Study #1 had a wide assortment of wounds

– Both studies acknowledge need controlled studies with large n

• Biologic collagen dressings:

– Have the properties of the acellular dressings AND MORE!

– May contain:

• Collagen

• Fibroblasts

• Growth factors

• Cytokines

• Keratinocytes

• Epithelial tissue

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• Biologic collagen dressings

– Some have viable human cells

– Come in a variety of media

• Frozen

• Dry sheets

• In petri dish

– More expensive

– Less applications

– More requirements from insurers

• Cytokines– Low molecular weight proteins– Act as signaling agents

• Cellular communication

– Bind to receptor on cell– Triggers “second messenger” within the

cell– Directs the cell to do something

• Produce/secrete protein• Alter membrane• Proliferate

– Sometimes also considered growth factors

Cytokine Function Notes

TNF-alpha Collagen synthesis MMP regulation

IL-1 Signals presence of an injury

Attracts neutrophils to wound to clean up

IL-2, IL-6 Fibroblast infiltration

IL-4 Inhibits TNF

Barrientos, S., Stojadinov, O, Golino, M. S., Brem, H. & Tomic-Canic, M. (2008). Growth factors and cytokines in wound healing . Wound Repair and Regeneration, 16.

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• Growth factors

– Proteins

– Function

• Stimulate cell proliferation

• Stimulate cell differentiation

– Mechanism

• Like cytokines, bind to receptor on cell membrane

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Growth factor Full name Notes

EGF Epidermal growth factor 53 amino acid proteinNormal cell growth, wound healing

VEGF Vascular endothelialgrowth factor

Attracts neutrophils to wound to clean up

PDGF Platelet derived growth factor

Secreted by platelets and other cells

FGF Fibroblast growth factor Proliferation of fibroblasts, angiogenesis, endothelial cells, and others100 + amino acids

Werner, S., & Grose, R. (2003). Regulation of wound healing by growth factors and cytokines. Physiology Review , 80.

• Biologic Product Dermagraft

– Approved by FDA in 2001 for DFUs

– Grown from neonatal foreskin tissue fibroblasts

– Supplied frozen, must be thawed

• Biologic Product Dermagraft

– Culture of neonatal dermal fibroblasts onto a bioabsorbable mesh scaffold.

– Cryopreserved

– Fibroblasts proliferate to fill the scaffold

• Secrete collagen

• Growth factors

• Cytokines

• Contains metabolically active living cells.

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• Dermagraft Evidence– 2003 RCT by Marston, et al

• 130 got Dermagraft, 115 got “conventional therapy”.

• At week 12, 30% of Dermagraft patients had full wound closure vs. 18.3% of control

– 2013 RCT by Harding, et al (from the UK) for venous• Product D + 4 layer compression for VLUs vs compression alone

• 186 in Dermagraft group, 180 in control group

• At 12 weeks:– 34% complete wound healing vs 31% control

– If ulcers < 12 months duration, 52% vs 37%

Marston, W. A., Hanft, J., Norwood, P., & Pollack, R. (2003). The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers. Diabetes Care, 26 (6).

Harding, K., Sumner, M., & Cardinal, M. (2013). A prospective, multicentre, randomised controlled study of human fibroblast-derived dermal substitute (Dermagraft) in patients with venous leg ulcers. International Wound Journal, 10: 132-137.

• Apligraf

– Venous ulcers and DFUs only

– Approved by FDA:

• 2000 for DFUs

• 1998 for for venous ulcers

– From neonatal foreskins in a bovine type 1 collagen matrix

– Neonatal dermis develops, with neonatal epidermis to cover

• Biologic Product Apligraf

– 2 layers

• Lower layer is bovine type 1 collagen and human fibroblasts

• Top layer is human epidermal cells– From human keratinocytes

• These are living cells

– Supplied in petri dish

– Not frozen, but has a shelf life

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• Apligraf Evidence for VLUs

– 1998 prospective, randomized, multicenter trial

– Apligraf (n=146) with compression vs standard of care (compression only) (n=129)

– 6 month follow up:

• 63% Apligraf complete wound closure

• 49% control group

• p=.003

Falanga, V. , Margolis, D., Alvarez, O. , & Human Skin Equivalent Investigators Group. (1998) Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Archives of Dermatology, 134(3).

• Apligraf Evidence for DFUs

– 2001 prospective, randomized, multicenter trial

– P Apligraf (n=112) vs standard of care (saline gauze) (n=96)

– For DFUs

– 12 week follow up:

• 56% product A complete wound closure

• 38% control group

Veves, A., Falanga, V., Armstrong, D., Sabolinski, D. and study group. (2001). Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers. Diabetes Care, 24(2).

• Comparative research

– Apligraf vs Oasis

• 2014 study

• Retrospective analysis, 2010-2012– Venous ulcers

– Data from WoundExpert

– 1451 wounds (1187 patients) got product A

– 350 wounds (302 patients) got product O

– Product A: Avg # treatments significantly lower than Product O (2.3 vs 3.8)

– Estimated incidence of wound closure at week 12: Product A (31%) vs Oasis (26%)

– At week 24: 50% vs 41%

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• Comparative research

– Apligraf vs Oasis

• Good n, however…

• No reliable measure whether compression was used or not

• Funded by Apligraf

• Subjects may have also been getting NPWT or HBOT, were not excluded from study

• Apligraf may be marginally better at obtaining wound closure

• Amnion/Chorioncontaining Dressings

– Amnion inner membrane

– Chorion is outer membrane

• Amnion contains:

– Cytokines

– Hyaluronan

– Growth factors

• Biologic Epifix

– Approved by FDA in 2013

– Dehydrated human amnion/chorion allografts (dHACM)

– Supplied in dry sheets

– DFUs and in some areas and some insurance plans, VLUs

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• Biologic Epifix

– Contains human dermal collagen, growth factors, cytokines

• PDGF, TGF, FGF, EGF, PLGF

• IL-4, 6, 8, & 10

• TIMP 1, 2, & 4

• Native ECM

• Both amnion and chorion layers

• Non-living cells

Koob, T. J., et al. (2013). Biological properties of dehydrated human amnion/chorion composite graft: Implications for chronic wound healing. International Wound Journal.

• Epifix Evidence• N = 25 DFUs

• 13 Product Ex, 12 Standard of care (silver gel or silver hydrofiber)

• Funded by Mimedx (Epifix manufacturer)

• At 6 weeks of treatment– 92% complete wound closure product EX

– 8% (standard of care)

– Subjects whose wounds failed to reduce by 50% after 6 weeks were exited

Zelen, C. M., Gould, L., Serena, T. E., Carter, M. J, Keller, J., & Li, W. W. (2013). A prospective, randomised, comparative parallel study of amniotic membrane wound graft in the management of diabetic foot ulcers. International Wound Journal.

• Epifix Evidence• N = 84 VLUs

• 53 Epifix + compression, 31 compression alone

• Funded by MiMedx (Epifix)

• At 4 weeks of treatment– 62% of Epifix group showed > 40% wound closure

– 32% of compression group showed > 40% wound closure

– 6 patients in Epifix group had complete wound closure

– 4 patients in the compression group had complete wound closure

Serena, T. E., Carter, M. J, Keller, J., Le, L. T., Sabo, M. J. DiMarco, D. T. (2014). A multicenter, randomized, controlled clinical trial evaluating the use of dehydrated human amnion/chorion membrane allografts and multilayer compression therapy vs. multilayer compression therapy alone in the treatment of venous leg ulcers. Wound Repair and Regeneration. 22.

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• Comparative research– Epifix vs Apligraf

• N = 60 DFUs

• Good design

• 20 Epifix, 20 Apligraf, 20 collagen/ORC

• Funded by MiMedx

• At 6 weeks of treatment– 95% complete wound closure Epifix

– 45% for Apligraf

– 35% collagen/ORC

– Subjects whose wounds failed to reduce by 50% after 6 weeks were exited

Zelen, C. M., Gould, L., Serena, T. E., Carter, M. J, Keller, J., & Li, W. W. (2014). A prospective, randomised, controlled, multi-centre comparative effectiveness study of healing usi nd dehydrated human amnion/chorionmembrane allograft, bioengineered skin substitue or standard of care for treatment of chronic lower extremity diabetic ulcers. International Wound Journal,.

• Comparative research

– Apligraf vs Epifix

• N = 226 DFUs

• 163 Apligraf, 63 Epifix

• Funded by Organogenesis

• Data culled from WoundExpert

• Median time to closure– 13.3 weeks for Apligraf

– 26 weeks for Epifix

Kirsner, R. S., Sabolinski, M. L, Parsons, N. B.k Skornicki, M., Marston, W. A. (2015). Comparative effectiveness of a bioengineered livign cellular construct vs. a dehydrated human amniotic membrane allograft for the treatment of diabetic foot ulcers in a real world setting. Wound Repair and Regeneration. International Wound Journal, (00).

• Biologic Theraskin

– From donated human tissue (cadaver)

– Contains:

• Fibroblasts

• Keratinocytes

• ECM (collagen)

– Can be used on any wound

• Not just DFUs or VLUs

– Shipped on dry ice

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• Theraskin Evidence– 2011 retrospective study, both DFUs and VLUs

– N=188 (134 VLUs, 54 DFUs)

– By 12 weeks• DFUs 60.38% of wounds had closed

• VLUs 60.77% of wounds had closed

– By 20 weeks• DFUs 74.1% of wounds had closed

• VLUs 74.6% of wounds had closed

– No controlLandsman, A. S., Cook, J., Cook, E., Landsman, A. R., Garrett, P., Yoon, J., Kirkwood, A., et al. (2011). A retrospective clinical study of 188 consecutive patients to examine the effectiveness of a biologically active cryopreserved human skin allograft (TheraSkin®) on the treatment of diabetic foot ulcers and venous leg ulcers. Foot and Ankle Specialist, 4(1).

• Comparative research– Theraskin vs Dermagraft

• 2014 study

• Dermagraft:– Human fibroblast derived dermal skin

substitute

• Theraskin:– Human skin allograft, from cadaver skin

• Authors on advisory board of product Theraskin

• Prospective, multicenter, randomized clinical trial– DFUs

• Comparative research

– Theraskin vs Dermagraft

• N=23

• 12 to Dermagraft

• 11 to Theraskin

• At week 12:– 63.6% of Theraskin wounds closed

– 33.3% of Dermagraft wounds closed

Sanders, L., Landsman, A. S., Landsman, A., Keller, N., Cook, J., Cook, E., & Hopson, M. (2014). A prospective, multicenter, randomized, controlled clinical trial comparing a bioengineered skin substitute to a human skin allograft. Ostomy Wound Management. 60(9).

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• Comparative research

– Theraskin vs Apligraf

– 2011 study

• N=29 patients with DFUs

• 12 with Theraskin

• 17 with Apligraf

• At 12 weeks:– 41.3% of wounds closed with Apligraf

– 66.7% of wounds closed with Theraskin

DiDomenico, L., Landsman, A. R., Emch, K. J., & Landsman, A. (2011). A prospective comparison of diabetic foot ulcers treated with either a cryopreserved skin allograft or a bioengineered skin substitute. Wounds, 23(7).

• Other biologics (not a complete list)– Biovance

• Alliqua/Celgene

• Dehydrated amnion

– Amnioexcel/Amniomatrix• Derma Sciences

• Dehydrated amnion

– Grafix (frozen)• Osiris

• Cryopreserved placental tissue

• Large reviews

– NO Cochrane review on advanced wound dressings

– VA 2012: 177 page review of advanced wound care therapies

– AHRQ (2012) 64 page review

• Agency for Healthcare Research and Quality

Evidence-based synthesis program center, Department of Veterans Affairs. (2012). Advanced wound care therapies for non-healing diabeteic, venous, and arterial ulcers: A systematic review.

Snyder, D. L., Sullivan, N., Schoelles, K. M. (2012). Skin substitutes for treating chronic wounds: Technology assessment report. Evidence based Practice Center, Agency for Healthcare Research and Quality.

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• Conclusions

– Anything’s better than wet to dry

– Many studies have small n

• Few rigorous RCTs

• No money in wound care!

– Collagen/ORC/Silver/Alginate

• Minimal significant results

– Ovine dressing

• Too soon to tell

• Conclusions

– Biologics

• Better results from studies

• Obviously, more expensive

• Must wrestle with insurance to use them

• Sometimes, you just have to use your own clinical judgment!

• Because we WOC nurses are awesome!

WOC nurses are

AWESOME!

Thank you! Thank you very much!

mvercellino@sprynet.com if you want a copy of this presentation

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• References– Molecular Cell Biology, 7th edition, Lodish, etc.

– Advanced Wound Care Therapies for non-healing diabetic, venous and arterial ulcers: A systematic review. (2012). Department of Veterans’ Affairs, Quality Enhancement Research Initiative

– Bohn, G. A., & Gass, K. (2014). Leg ulcer treatment outcomes with new ovine collagen extracellular matrix dressing: A retrospective case series. Advances in Skin & Wound Care, 27(10).

– Chattopadhyay, S., & Raines, R. T. (2014). Review: Collagen-based biomaterials for wound healing. Biopolymers, 101(8).

– Fleck, C. A., Chakravarthy, D. (2007). Understanding the mechanisms of collagen dressings. Advances in Skin and Wound Care, 20(5).

– Fleck, C. A., & Simman, R. (2010). Modern collagen wound dressings: Function and purpose. Journal of the American College of Certified Wound Specialists. 2.

– Harding, K., Kirsner, R., Lee, D., Mulder, G., & Serena, T. (2010). International consensus: Acellularmatrices for the treatment of wounds: An expert working group review. Wounds International.

– Haycocks, S., Chadwick, Pl, & Cutting, K. F. (2013). Collagen matrix wound dressings and the treatment of DFUs. Journal of Wound Care, 22(7).

– Mulder, G. (ed). 2010. International consensus. Acellular matrices for the treatment of wounds. An expert working group review. Wounds International.

– Snyder, D. L., Sullivan, N., & Schoelles, K. M. (2012).Agency for Healthcare Research and Quality. (2012). Skin substitutes for treating chronic wounds.