Point-Counterpoint: Extracellular Matrices: Are They Worth It?

Yes. By Dr. Steven R. Kravitz, DPM. This author says podiatrists should consider extracellular matrix enhancement for chronic, complex wounds that do not respond to standard of care therapy.
Over the past 10 years, there have been paradigm shifts in intervention for chronic non-healing wounds. There has been an increased emphasis on moist wound healing,wound bed preparation and managing the wound microenvironment through bone factor enhancement, matrix metalloprotease (MMP) management and bioload reduction.
There has also been a new emphasis on extracellular matrix (ECM) enhancement. In past years, the prevailing thinking on extracellular matrix was that it was primarily structural relative to its involvement with wound healing. However, researchers have demonstrated increasing evidence that the ECM also plays an important regulatory role in the wound healing process.
There are distinct differences in the biochemical interactions that occur between healing and non-healing wounds. Healing wounds provide increased cellular mitosis, a tight regulation on pro-inflammatory cytokines, tight regulation of matrix metalloproteases, and the release of growth factors, which ultimately provide normal extracellular matrix formation.
In contrast, non-healing wounds demonstrate decreased cellular mitoses or the complete absence of cellular mitoses with quiescent cells in the Go (pronounced “Jee–Oh”) phase. There is an increased abundance of both pro-inflammatory cytokines and MMPs, and a decrease in growth factors, all of which lead to abnormal extracellular matrix formation and delayed epithelialization.
All chronic wounds contain significant necrosis, which is essentially premature cell death, and quiescent cells that are in a Go phase and non-mitotic. Stating that these cells are senescent is a common misstatement in wound care literature. Senescence occurs before cellular apoptosis, which is normal cell death due to maturity. Both senescence and apoptosis are irreversible, and accordingly cannot be the objectives of a wound care regimen.
In contrast, quiescence and necrosis are both reversible. Therefore, addressing these cells is the goal of all treatment for chronic wounds. Treatment that replaces or, in another matter, addresses the extracellular matrix is an effective method of decreasing cellular necrosis and converting cells from a quiescent Go phase into actively mitotic cells. Stopping necrosis and enhancing mitosis are the essential goals to converting a chronic wound into one that is actively healing.
Non-healing wounds are in a cyclical phase of degradation.This cycle starts with any one or more of the following factors: repeated trauma, local tissue ischemia, edema, maceration and desiccation with tissue breakdown (necrosis) and an associated increase in bioburden.The result of all this is prolonged inflammation with inflammatory white cells. There is activation of macrophages with an increased release of MMPs. This results in impaired connective tissue deposition and degradation of the extracellular matrix.

How The Extracellular Matrix Affects The Wound Healing Process

As stated above, the extracellular matrix acts as a scaffold to support cellular migration and production, and angiogenesis. It also serves as an active director and coordinator to the wound healing cascade. It activates receptor mediated bonding sites, and regulates the release and activation of growth factors. Molecular composition of the extracellular matrix includes:

• structural proteins (collagen and elastin);
• specialized proteins (fibronectin and fibrillin);
• proteoglycans (long chain glycosaminoglycans attached to a protein core); and
• integrins (adhesive molecules).

The extracellular matrix is involved in all phases of wound healing. This includes hemostasis, the inflammatory phase, the proliferative phase and the phase of remodeling in which fibronectin breaks down and collagen replaces it. The ECM guides and directs all these phases of wound healing and their cellular components: the migration of macrophages, the migration of fibroblasts, the release of growth factors, the migration of endothelial cells and the production of angiogenesis.
There are essentially two types of deficits that occur to the ECM in chronic wounds. There is either a lack of ECM production or ECM dysfunction. A dysfunctional ECM results in unresponsive fibroblasts that do not lay down appropriate structural components and are unresponsive to growth factors.A dysfunctional ECM also leads to a wound bed containing high levels of activated MMPs and high levels of proteases that degrade fibronectin, growth factors and other surface proteins. There is an associated lack of epithelial migration, all of which result in a nonhealing wound.
The goals of intervention to address ECM malfunction includes decreasing ECM breakdown, increasing ECM production and replacement of the ECM.
It is important to realize that reduction in ECM breakdown alone does not necessarily convert a non-healing wound to one that goes onto active wound healing. Replacement of the ECM is often helpful or required to convert a non-healing wound into one that resumes active wound healing to closure.

A Pertinent Review Of Available Modalities For ECM Enhancement

There are many methods that are helpful to correct ECM deficit and increase ECM production. While there are a number of products on the market, let us take a closer look at some of the modalities that we have used at the Leonard Abrams Center for Advanced Wound Healing at Temple University School of Podiatric Medicine.
The application of bilayered or single layered skin replacement therapy will provide living fibroblasts, which can rebuild ECM structural components, release growth factors and assist in creating an active wound healing environment. Porcine small intestine submucosa has the benefit of a long shelf life and provides ECM components that retain the natural composition of matrix molecules and many factors that are part of the human dermas. These include collagens type I, III, IV and VI, heparin, hyaluronic acid, elastin and several growth factors.
A regenerated tissue matrix from donated human skin can also provide structural components. Other methods of treatment include application of collagen particle or collagen wound gel to the wound surface, oxidized regenerated cellulose (ORC) with collagen and platelet derived growth factor (becaplermin, Regranex, Johnson and Johnson).
Oxidized regenerated cellulose with collagen actively removes MMP from the wound surface while providing the collagen matrix to the wound bed. A low dose silver form of the product is available to address bioburden but is not intended to treat acute infection.
A new triple helix form of collagen application therapy contains largely native collagen that combines MMPs but also reportedly has the benefit of binding elastase to a much larger degree. Elastase breaks down elastin and therefore hydrolyzes a wide variety of tissue proteins.The collagen triple helix structure and packaging of the collagen fiber bundles enhance collagen production by reverting fibroblasts out of their quiescent phase so they lay a new matrix for active wound healing. The new product is absorbent and will soon have an antimicrobial form available as well.

In Conclusion

The ECM has important structural as well as regulatory activity in wound healing. Wounds that do not heal either have a lack of formation of ECM or improper dysfunctional ECM formation. There are many methods and interventions that address ECM malfunction by decreasing ECM breakdown, increasing ECM production or replacing the ECM.
The result of this therapy is conversion of a chronic wound into an actively healing wound. Extracellular matrix is effective and there are a wide variety of treatment methods from which to choose. Extracellular matrix enhancement can be an efficacious method to help patients heal chronic and complex wounds.
Evidence-based practice suggests that approximately a 25 to 30 percent reduction of the cross-section area of a wound during the first four weeks of treatment is a predictor of complete healing at 12 to 14 weeks for diabetic ulcers and approximately 24 weeks for venous ulcers.
The initial care of a wound should include debridement to a clean wound bed, maintaining a moist wound environment, protection against infection and offloading areas of pressure as necessary. If these wounds do not respond to this standard of care and do not show a 25 percent reduction in size within three to four weeks, physicians should consider patient compliance issues and weigh the use of additional advanced treatment.
It is appropriate to consider ECM enhancement for wounds that are not responsive to standard of care therapy alone and as an additional component to the wound care protocol.

Dr. Kravitz is a Fellow of the American College of Foot and Ankle Surgeons, and a Fellow of the American Professional Wound Care Association. He is an Assistant Professor in the Department of Orthopedics and is on the clinical faculty for the Advanced Wound Healing Center at the Temple University School of Podiatric Medicine in Philadelphia.
For further reading, check out the archives at www.podiatrytoday.com.

No. By Khurram Khan, DPM, and Lawrence Harkless, DPM. These authors say the use of extracellular matrices should be extremely limited until further randomized controlled trials can prove that these modalities can close wounds in a costeffective manner.

Many forms of extracellular matrix products (ECM) are available. These products act as a “scaffold” to allow wound closure to occur using the body’s natural healing response. The ECM collagen reduces elastase levels in the wound environment and this subsequently decreases matrix metalloproteinase (MMP) production. Extracellular matrices also rely on the collagen component to allow for more efficient angiogenesis and greater fibroblast chemotaxis.1
All chronic wounds are not the same since they evolve from the time they occur until closure. Currently, there is no diagnostic assay or study that one can perform to identify where the wound is in the healing process. Accordingly, the clinician’s judgment, based on his or her experience, will help guide therapy.
Understanding wound healing at the biochemical and cellular level can be the starting point for answers. Good wound care includes appropriate offloading, debridement to reduce the bioburden by eliminating biofilms, and adequate blood flow (perfusion). One should consider advanced wound care modalities only after good wound care has failed.
Margolis, et al., performed a metaanalysis on the control arm of studies looking at wound care products. They found that after 20 weeks of basic wound care, approximately 31 percent of diabetic neuropathic ulcers healed.2 In another study, Sheehan, et al., found that patients who had Wagner grade I and II ulcers that failed to reduce by half over the first four weeks of treatment were unlikely to achieve wound healing over a reasonable period.3
Longstanding chronic wounds become problem wounds that have many barriers to healing. Inflammation, fibrosis, cell senescence and apoptosis all occur at different stages, causing the wound to halt its natural progression toward closure. Wound healing uses a symphony of growth factors produced by a multitude of cells, all in synchronized fashion to help facilitate wound closure with the main cells being fibroblasts and keratinocytes. These cells are key in the signaling process.4,5 The ECM products are devoid of these cells (due to their processing) and accordingly rely on the wound bed for sufficient cells to facilitate the healing process.

A Quick Guide To Current ECM Products

The available ECM products include the Oasis® graft (Healthpoint), which is comprised of porcine-derived acellular small intestine submucosa. EZ-Derm® (Brennen Medical) is composed of crosslinked porcine collagen. Graftjacket® (Wright Medical Technology) is derived from human dermal membrane. Unite® (Pegasus) is derived from horse pericardium. AlloDerm® (LifeCell) is an acellular dermal matrix derived from donated human skin tissue.
Integra Bilayer Matrix Wound Dressing® (Integra LifeSciences) is a nonliving extracellular matrix of bovine tendon collagen and chondroitin-6-sulfate with silicone backing. Researchers have shown that Integra regenerates tissue in histopathology studies and this modality is FDA approved for burns.6
Other versions of ECM for soft tissue repair/tendon repair include Tissuemend® (TEI Bioscience), a fetal bovine dermis, and Restore® orthobiologic implant (Depuy), a porcine small intestine submucosa. Apligraf® (Organogenesis) and Dermagraft® (Advanced Biohealing) are considered living tissue and are separate from this discussion. Transcyte® (Smith and Nephew) is a human fibroblast derived temporary skin substitute indicated for burns.

Raising Questions On The Lack Of Quality Evidence For ECMs In Chronic Wounds

So which of the currently available wound care products should we utilize to facilitate wound closure? Many would argue in favor of using products with proven efficacy in randomized control trials. Which products can help achieve the most benefit with the least cost? Unfortunately, most of the ECM products are severely lacking in both their demonstrated efficacy and cost effectiveness.
Most major healthcare plan formularies require a pharmacoeconomic analysis before approving a given drug to be listed on their formularies. The number needed to treat (NNT) is an epidemiological measure used to assess the effectiveness of a healthcare intervention. The NNT is the number of patients who need to be treated in order to prevent one additional bad outcome (i.e. to reduce the expected number of cases of a defined endpoint by one).7 Is there enough data to show that a current modality works well enough to warrant its use and is it cost effective?
Indeed, a recent Business Week article on cholesterol drugs noted that the NNT for many of these statins was higher than once thought.8
How do these issues apply to the current topic? It comes down to evidenced- based medicine. Using this same standard for extracellular matrices, no randomized controlled trials (RCTs) with a cost benefit analysis have ever been performed.The current research is limited to a few RCTs on earlier ECM products and a plethora of smaller case studies demonstrating some evidence of statistically significant wound healing in comparison to the standard of care.
However, the numbers of subjects within these studies are relatively small and lack the ability to be applied to the entire population given the products’ exorbitant cost.
Should our limited funds be used for these modalities that lack data? The newest extracellular matrices lack level I evidence to support use and also have reimbursement issues, specifically with coverage being limited to an inpatient OR setting.

What About Other Advanced Wound Care Modalities?

Over the past few years, there have been research articles with cost benefit analyses of certain wound care products. Currently only three treatments are FDA approved for diabetic foot ulcers. These three treatments are becaplermin (Regranex, Johnson and Johnson), Apligraf and Dermagraft.9-12 Recently, becaplermin has come to the public eye for links to cancer.13
While negative pressure wound therapy (NPWT) and hyperbaric oxygen (HBO) are not FDA approved, they are covered by Medicare and physicians are certainly using these modalities extensively. Negative pressure wound therapy has found a niche in postsurgical cases for staged closures but has weak evidence for chronic non-healing wounds. Hyperbaric oxygen has evidence for ischemic wounds but weak evidence for chronic wounds.14-18
If these advanced wound care modalities have proven track records and cost benefit analysis to demonstrate effectiveness at savings over the standard of care, then why would one pick an unproven therapy?
The number of ulcers and the associated cost is expected to increase with the Baby Boomer population entering the Medicare system and the rate of diabetes expected to rise to 12 percent by 2050. Accordingly, we have to be better stewards of our healthcare dollars. Medicare/Medicaid is the single largest cost to the United States government after the military.19-20 As the population ages, the resources will become sparse, requiring a more careful analysis of expenditures.

Other Key Points To Consider

The science of wound care is progressing to the point where we may see the development of an assay and its availability on the market in one to three years to determine what factors are missing at the biochemical and cellular levels. However, until diagnostics are available to determine the defect, physicians must rely on their experience and understanding of the pathobiology of type 2 complications of diabetes (chronic hyperglycemia).
In his clinical experience, the senior author suggests that patients who have macrovascular, microvascular, functional microvascular (endothelial dysfunction evidenced by gastroparesis and sexual dysfunction) and metabolic syndrome tend to have problem wounds.21-24 Given this insight, one can implement advanced wound care modalities sooner in the treatment plan before the wound becomes chronic.
To help prove this sentiment, Landsman, et al., demonstrated in a randomized control trial that the ECM Oasis was comparable to Dermagraft in the healing of diabetic ulcers.25 Unfortunately, the study failed to define what they considered to be a problem wound and why. This is key because if these wounds were non-healing due to a lack of keratinocytes and fibroblasts, then the group treated with Dermagraft should have been superior. However, if the wound had the necessary components but just needed a scaffold, then the published results would have been expected.Without defining the population, it is difficult to extrapolate the nature of the exact problem.
However, this exemplifies our point that one needs to assess why the wound is a problem wound and implement the appropriate therapy.

In Conclusion

It is not our contention to insist that extracellular matrix has no place in our armamentarium. However, the use of these products should be extremely limited until researchers perform further randomized control trials with cost benefit analysis.
Indeed, we need to facilitate the healing of recalcitrant wounds in an efficacious and cost effective manner that will ultimately save limbs and economic resources.

Dr. Khan is a Clinical Assistant Professor in the Department of Medical Sciences at the New York College of Podiatric Medicine.
Dr. Harkless is the Dean of the Western University of Health Sciences School of Podiatric Medicine in Pomona, Calif.

References:

1. Fleck CA. Understanding the mechanism of collagen dressings. Advances in Skin & Wound Care 20(5). 2. Margolis DJ, Kantor J and Berlin JA. Healing of diabetic neuropathic foot ulcers receiving standard treatment.A meta-analysis. Diabetes Care 22(5):692-5, May 1999. 3. Sheehan P, Jones P, Caselli A, Giurini JM, Veves A. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Diab Care 26(6):1879-1882, June 2003. 4. Kane DP, Krasner D. Chronic Wound Care. 2nd ed. Health Management Publications Inc; 1997:1-4. 5. Falanga V. Chronic Wounds: Pathophysiologic and experimental considerations. J Invest Dermatol 100:721-5, 1993. 6. Stern R, McPherson M, Longaker MT. Histologic study of artificial skin used in the treatment of full thickness thermal injury. J Burn Rehabil. 11:7-13, 1990. 7. Laupacis A, Sackett DL, Roberts RS.An assessment of clinically useful measures of the consequences of treatment. N. Engl. J. Med. 318 (26): 1728-33, 1988. 8. Carey J. Do cholesterol drugs do any good? Business Week, January 17th 2008 9. Willis M, Persson U, Ödegaard, K, et al.The cost-effectiveness of treating diabetic lower extremity ulcers with becaplermin (Regranex): a core model with an application using Swedish cost data. Value Health 3 Suppl 1:39-46, Nov-Dec 2000. 10. Redekop WK, McDonnell J,Verboom P, Lovas K, Kalo Z.The cost effectiveness of Apligraf® treatment of diabetic foot ulcers. Pharmacoeconomics 21(16):1171-1183, 2003. 11. Fivenson D, Scherschun L. Clinical and economic impact of Apligraf® for the treatment of nonhealing venous leg ulcers. Int J Dermatol 42:960-965, 2003. 12. Allenet B, Parée F, Lebrun T, Carr L, Posnett J, Martini J,Yvon C. Cost-effectiveness modeling of Dermagraft for the treatment of diabetic foot ulcers in the french context. Diabetes Metab. 26(2):125-32,April 2000. 13. https://www.fda.gov/cder/drug/early_ comm/becaplermin.htm 14. Ubbink DT,Westerbos SJ, Evans D, Land L, Vermeulen H.Topical negative pressure for treating chronic wounds. Cochrane Database of Systematic Reviews 2001, Issue 1.Art. No.: CD001898. DOI: 10.1002/14651858.CD001898 15. Wang J, Li F, Calhoun JH, Mader JT.The role and effectiveness of adjunctive hyperbaric oxygen therapy in the management of musculoskeletal disorders. J Postgrad Med 48:226, 2002. 16. Hailey D, Jacobs P, Chuck A; Economic analysis of hyperbaric oxygen therapy for diabetic foot ulcers. Health Technology Assessment International. Meeting (3rd: 2006: Adelaide, S.Aust.). Handb Health Technol Assess 3: 4, 2006. 17. Philbeck TE,Whittington KT, Millsap MH, et al. The clinical and cost effectiveness of externally applied negative pressure wound therapy in the treatment of wounds in home healthcare Medicare patients. Ostomy Wound Manage 45(11):41-50, 1999. 18. Andros G,Armstrong DG, Attinger CE, et al. Tucson Expert Consensus Conference. Consensus statement on negative pressure wound therapy (V.A.C.Therapy) for the management of diabetic foot wounds. Ostomy Wound Manage Suppl:1-32, June 2006. 19. https://www.diabetes.org/diabetesstatistics/ prevalence.jsp 20. https://www.whitehouse.gov/omb/ budget/fy2009/index.html 21. Adler AI, Stevens RJ, Neil A, Stratton IM, Boulton AJ, Holman RR, et al UKPDS 59: Hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes. Diabetes Care 25(5): 894–99, 2002. 22. Boyko EJ,Ahroni JH, Davison D, Stensel V, Prigeon RL, Smith DG, et al. Diagnostic utility of the history and physical examination for peripheral vascular disease among patients with diabetes mellitus. J Clinical Epidemiology 50(6): 659–68, 1997. 23. Pham H, et al.The role of endothelial function on the foot. Clin Podiatr Med Surgery 15: 85–94, 1998. 24. Tooke JE. Microvascular haemodynamics in diabetes mellitus. Clinical Science 70: 119-25, 1986. 25. Landsman A, Roukis TS, DeFronzo DJ, Agnew P, Petranto RD, Surprenant M. Living Cells or Collagen Matrix:Which Is More Beneficial in the Treatment of Diabetic Foot Ulcers? Wounds 20(5):111- 116, May 2008. For related articles, see “A Closer Look At Bioengineered Alternative Tissues” in the July 2006 issue of Podiatry Today, “Current Concepts In Managing The Wound Microenvironment” in the September 2006 issue or “A Comprehensive Review Of Topical Agents” in the July 2002 issue. For other articles, please visit the archives at www.podiatrytoday.com