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Point-Counterpoint: Are Biologic Therapies Better Closers Than Split-Thickness Skin Grafts For DFUs?

Yes.

These authors note that advances with biologic dressings in recent years have led to quicker healing and long-term cost savings without the challenges and risks inherent to split-thickness skin grafts.

By Harry Schneider, DPM, FACFAS, and David Liou, DPM

Diabetic foot ulcerations are a major consequence of diabetes, secondary to the neuropathic and vasculopathic nature of the disease. These chronic, difficult to heal, neuropathic foot ulcerations arise in approximately 15 percent of the diabetic population.1

Foot ulcers affect a patient’s quality of life and incur tremendous medical costs. The treatment of diabetes and its associated complications in the United States generates at least $116 billion in direct costs. Approximately 33 percent of these costs are linked to the treatment of foot ulcers.2 Therefore, improved treatment of diabetic foot ulcerations is of paramount importance.

The difficulty of treating diabetic ulcerations stems from intrinsic and extrinsic factors that affect ulcer healing. Extrinsic factors include ulcer infection, callus formation and excessive pressure to the wound site. Intrinsic factors include neuropathy, vascular compromise and ulcer cell abnormalities.3 Advancements in biological dressings address these factors and have allowed for an improved environment for expedited ulcer healing.

Key Insights On Advancements In Biological Dressings

There are many factors that are desirable in an ideal ulcer dressing, including thermal insulation, gaseous exchange, drainage facilitation, debris removal and protection from secondary infection.
Another important factor, which has only become a relevant concern in recent years due to the use of biological dressings, is ensuring the biocompatibility of the dressing without provoking a host immune response reaction.3,4 Autologous skin graft is considered the gold standard as it meets all the aforementioned criteria.3

Historically, all other dressings were designed to replicate the properties of autologous skin grafts.3 However, more recently, advancement in biological dressings has led to the inclusion of additional growth factors, collagen and stem cells to allow ulcers to heal faster without the comorbidity of a donor site.

Placental membranes. Placental membrane, which consists of both amnion and chorion layers, is harvested from caesarean section. The membrane contains mesenchymal stem cells, collagen and growth factors. Researchers have shown that placental membranes aid in angiogenesis, decrease inflammation, enhance chemoattractive activities, confer mild antibacterial activity and provide anti-adhesion properties.3,5

The majority of placental membranes do not contain viable stem cells. This is due to technical difficulty with processing of the grafts and concern for tumorigenicity with implantation of allogeneic stem cells. Only one company, Osiris Therapeutics, currently manufactures and sells placental membranes with cryopreserved mesenchymal stem cells.

Despite the retaining of viable stem cells in the placental membrane, keep in mind that the stem cells do not differentiate into neighboring tissue type cells.6,7 This is contrary to prior beliefs. Both in vitro and in vivo studies have shown increased native stem cell recruitment by the introduction of allogeneic mesenchymal stem cells.8 These recruited stem cells then differentiate into neighboring host cell types in repairing the ulceration. Therefore, the presence of stem cells in the placental membrane merely aids in the attraction of other cell types to the site of injury.

Recent research has shown convincing results for the use of placental membranes to facilitate the healing of ulcerations, regardless of the presence of stem cells in the graft. In a multicenter, randomized, controlled, blinded clinical trial involving 97 patients, Grafix (Osiris Therapeutics) achieved 62 percent complete ulcer closure in comparison to only 21 percent in patients who had standard of care after 12 weeks.9

Another smaller study involving 25 patients had a similar result.10 Study authors noted 92 percent complete ulcer closure after four weeks with Epifix (MiMedx) in comparison with standard of care treatment, which achieved only 8 percent complete closure in the same time period.

Collagen dressings. Collagen is a main structural protein of the connective tissue and is vital for ulcer healing.11 A major complication of diabetes wound healing is ulcer site cell dysfunction. The dysfunction hinders fibroblast migration and subsequent establishment of new collagen.12,13 By introducing exogenous collagen to the site through collagen dressings, researchers have shown increased migration of fibroblasts to the ulcer sites and enhanced metabolic activity of granulation tissue.14

In vitro and in vivo studies have also indicated reduced protease activities within the wound sites and protection of growth factors.15,16 In a large randomized controlled study by Veves and colleagues involving 276 patients with chronic diabetic plantar ulcers from 11 treatment centers, patients who received collagen dressings saw a 45 percent full closure rate in comparison to only 33 percent in the control group after 12 weeks.15

Growth factor dressings. With an increasing understanding of the vital roles that growth factors play in the healing cascade, biological dressings containing growth factors are now increasingly available on the market for the treatment of diabetic foot ulcerations.

Most growth factor dressings include platelet-derived growth factor (PDGF) and transforming growth factor beta (TGFβ).17 Research has shown these two factors facilitate the healing of ulcerations in patients with diabetes.18 In a randomized controlled trial involving 382 patients with type or type 2 diabetes and chronic ulcers, Wieman and coworkers found that becaplermin gel (Regranex, Smith and Nephew), which includes both aforementioned growth factors, significantly increased complete wound closure by 43 percent.19 Becaplermin also decreased the time to achieve complete wound closure by 32 percent in comparison to placebo.

A Closer Look At The Disadvantages Of Split-Thickness Skin Grafts

Autologous split-thickness skin graft (STSG) is the gold standard for the reconstruction of diabetic foot ulcerations. However, there are multiple limitations and disadvantages associated with STSGs.
First, the application of STSG is contraindicated over exposed bones, joints or tendons because these wound beds often lack the local vascularity required for STSG survival.20 Split-thickness skin grafts also require a wound bed that is free of infection and are typically located at a non-weightbearing aspect of the diabetic foot. Unfortunately, the majority of diabetic foot ulcers occur on weightbearing surfaces and are prone to infection, making STSG unsuitable for the majority of diabetic ulcerations.

Furthermore, harvesting autologous STSG can be a challenge and grafts need to originate from the host. One would harvest the skin graft in the operating room, which induces patient stress and also increases the cost of treatment. In the case of graft failure, additional STSG harvest might be necessary, which compounds aforementioned complications. In comparison to STSG, biological dressings are readily available with a virtually limitless supply and do not involve harvest from the patient.

Moreover, there is a risk of infection at the harvest site. A study by Mahmoud and colleagues found an infection rate of 4 percent at the harvest site.21 Also, there are complications associated with the STSG application sites. A study by Ramanujam and coworkers found the postoperative complication rate at the STSG application sites to be 35 percent.22 Complications mainly consist of infections and graft failures leading to ulcer recurrence. The complication rate is even higher in smokers, reportedly as high as 58 percent at the application site. Complications further increase the time to complete healing from 6.4 to 9.5 weeks. Lastly, there are the commonly known complications of the STSG sites including graft contracture, seroma and hematoma formation.

Examining The Economics Of Biological Dressings

Diabetes-related foot pathology is the most frequent cause of hospitalization among patients with diabetes.23 The total cost of ulcer treatment ranges from $10,000 to nearly $60,000 depending on ulcer severity and clinical outcome.24 Ulcer infections that result in any amputation have significantly higher long-term medical costs.24 Therefore, aggressive treatment of the ulcers in a cost-effective manner is important.  

Currently, there is no direct economic study comparing biological dressings to split-thickness skin grafts in the closure of diabetic foot ulceration. However, economic studies are available comparing biological dressings to other conventional wound care methods.

In a study by Steinberg and colleagues, the authors found the use of Apligraf (Organogenesis) for the treatment of diabetic and venous stasis ulcerations decreases the rate of amputation from 12.5 percent to 5.4 percent.25 The study compared moistened gauze to the application of Apligraf. The use of Apligraf decreased the treatment cost from $86,226 to $6,683 when factoring in the prevention of amputation.

Similar results reportedly occur with the use of Dermagraft (Organogenesis) for diabetic ulceration.26 Moreover, Naughton and colleagues noted minimal difference when comparing the cost of conventional wound care ($12,128 per ulcer healed) to that of Dermagraft ($12,500 per ulcer healed).26 However, Dermagraft can decrease healing time and therefore significantly decrease cost in avoiding amputations.26

Lastly, research has shown that becaplermin increases the average number of ulcer-free months from 3.41 to 4.22 in comparison to the control group.27 The application of becaplermin also lowers the rate of amputation from 6.5 percent to 5.91 percent.27 Another study by Ghatnekar and coworkers reached similar conclusions.28 Despite the initial high cost of using biological dressings, economic studies of these products have indicated cost savings in the long term. This is due to shorter treatment periods, fewer complications and fewer hospitalizations.23   

In Conclusion

In the past, due to a limited understanding of the ulcer repair process, most dressings were designed to replicate the ideal characteristics of autologous skin graft. However, in the last few decades, there have been major breakthroughs in both the understanding and manufacturing of new biological dressings for the treatment of diabetic foot ulcerations. These products possess the same ideal characteristics of the skin graft with additional growth factors, collagen and stem cells that improve the closure of ulcers.

Furthermore, these products are not harvested from the host so there are minimal concerns regarding harvest site infection or the common complications associated with STSG including infection, seroma and hematoma. Biological dressings are cost-effective in the long term by preventing amputation. These biological dressings are effective in facilitating healing of the ulcers and are a superior alternative to partial thickness skin graft.

Dr. Schneider is the Director of the Cambridge Health Alliance Podiatric Medicine and Surgery Residency in Cambridge, Mass. He is a Fellow of the American College of Foot and Ankle Surgeons, and an Assistant Professor of Surgery at Harvard Medical School.

Dr. Liou is a second-year resident with the Cambridge Health Alliance Podiatric Medicine and Surgery Residency in Cambridge, Mass.

References

1.     Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. J Clin Investig. 2007;117(5):1219-1222.
2.     Driver VR, Fabbi M, Lavery LA, Gibbons G. The costs of diabetic foot: The economic case for the limb salvage team. J Vasc Surg. 2010;52(3)17S–22S.
3.     Falanga V. Wound healing and its impairment in the diabetic foot. Lancet. 2005;366(9498):1736-1743.
4.     Morin RJ, Tomaselli NL. Interactive dressings and topical agents. Clin Plast Surg. 2007;34(4):643-658.
5.     Pradhan L, Nabzdyk C, Andersen ND, Logerfo FW, Veves A. Inflammation and neuropeptides: the connection in diabetic wound healing. Expert Rev Molec Med. 2009;11.
6.     Koob TJ, Rennert R, Zabek N, et al. Biological properties of dehydrated human amnion/chorion composite graft: implications for chronic wound healing. Int Wound J. 2013;10(5):493-500.
7.     Koob TJ, Lim JJ, Massee M, et al. Angiogenic properties of dehydrated human amnion/chorion allografts: therapeutic potential for soft tissue repair and regeneration. Vasc Cell. 2014;6(1):10.
8.     Koob TJ, Lim JJ, Massee M, Zabek N, Denozière G. Properties of dehydrated human amnion/chorion composite grafts: Implications for wound repair and soft tissue regeneration. J Biomed Materials Res Part B: Appl Biomat. 2014;102(6):1353-1362.
9.     Lavery LA, Fulmer J, Shebetka KA, et al. The efficacy and safety of Grafix® for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial. Int Wound J. 2014;11(5):554-560.
10.     Zelen CM, Serena TE, Denoziere G, Fetterolf DE. A prospective randomised comparative parallel study of amniotic membrane wound graft in the management of diabetic foot ulcers. Int Wound J. 2013;10(5):502-507.
11.     Moura LI, Dias AM, Carvalho E, Sousa HCD. Recent advances on the development of wound dressings for diabetic foot ulcer treatment—A review. Acta Biomaterialia. 2013;9(7):7093-7114.
12.     Lerman OZ, Galiano RD, Armour M, Levine JP, Gurtner GC. Cellular dysfunction in the diabetic fibroblast. Am J Pathol. 2003;162(1):303-312.
13.     Arul V, Kartha R, Jayakumar R. A therapeutic approach for diabetic wound healing using biotinylated GHK incorporated collagen matrices. Life Sciences. 2007;80(4):275-284.
14.     Midwood KS, Williams LV, Schwarzbauer JE. Tissue repair and the dynamics of the extracellular matrix. Int J Biochem Cell Biol. 2004;36(6):1031-1037.
15.     Veves A, Sheehan P, Pham HT. A randomized, controlled trial of Promogran (a collagen/oxidized regenerated cellulose dressing) vs standard treatment in the management of diabetic foot ulcers. Arch Surg. 2002;137(7):822.
16.     Lee CH, Singla A, Lee Y. Biomedical applications of collagen. Int J Pharma. 2001;221(1-2):1-22.
17.     Robson M, Phillips L, Robson L, Thomason A, Pierce G. Platelet-derived growth factor BB for the treatment of chronic pressure ulcers. Lancet. 1992;339(8784):23-25.
18.     Mustoe TA. A phase II study to evaluate recombinant platelet-derived growth factor-BB in the treatment of stage 3 and 4 pressure ulcers. Arch Surg. 1994;129(2):213.
19.     Wieman TJ, Smiell JM, Su Y. Efficacy and safety of a topical gel formulation of recombinant human platelet-derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers: a phase III randomized placebo-controlled double-blind study. Diabetes Care. 1998;21(5):822-827.
20.     Johnson TM, Ratner D, Nelson BR. Soft tissue reconstruction with skin grafting. J Am Acad Dermatol. 1992;27(2):151-165.
21.     Mahmoud S, Mohamed A, Mahdi S, Ahmed M. Split-skin graft in the management of diabetic foot ulcers. J Wound Care. 2008;17(7):303-306.
22.     Ramanujam CL, Stapleton JJ, Kilpadi KL, et al. Split-thickness skin grafts for closure of diabetic foot and ankle wounds. Foot Ankle Spec. 2010;3(5):231-240.
23.     Langer A, Rogowski W. Systematic review of economic evaluations of human cell-derived wound care products for the treatment of venous leg and diabetic foot ulcers. BMC Health Services Research. 2009;9(1).
24.     Singh N. Preventing foot ulcers in patients with diabetes. J Am Med Assoc. 2005;293(2):217.
25.     Steinberg J, Beusterien K, Plante K, et al. A cost analysis of a living skin equivalent in the treatment of diabetic foot ulcers. Wounds. 2002;14(4):142.
26.     Naughton G, Mansbridge J, Gentzkow G. A metabolically active human dermal replacement for the treatment of diabetic foot ulcers. Artificial Organs. 2008;21(11):1203-1210.
27.     Persson U, Willis M, Ödegaard K, Apelqvist J. The cost-effectiveness of treating diabetic lower extremity ulcers with becaplermin (Regranex): a core model with an application using Swedish cost data. Value Health. 2000;3(Suppl 1):39–46.
28.     Ghatnekar O, Persson U, Willis M, Odegaard K. Cost effectiveness of becaplermin in the treatment of diabetic foot ulcers in four European countries. PharmacoEconomics. 2001;19(7):767-778.

No.

Citing the lack of comparative trials to gauge the effectiveness of biologic therapies and the need for multiple, costly applications to achieve wound healing, this author says split-thickness skin grafts offer superior advantages when rapid wound coverage is required.

By Thanh Dinh, DPM, FACFAS

Despite advances in our understanding of the pathways to the development of diabetic foot ulcers (DFUs) and the abundance of advanced therapies developed to heal these complicated chronic wounds, DFUs remain a significant problem.

Diabetic foot ulcers are the leading cause of hospitalization and amputation among patients with diabetes with a DFU preceding 85 percent of lower extremity amputations.1,2 In addition to the individual burdens the patient bears, the impact of DFUs on quality of life represents a significant financial impact to the healthcare system with an estimated $245 billion spent annually to treat this pathology.3

Before exploring the advanced wound therapies, it remains of paramount importance to recognize the fundamental principles of treatment. These principles include ensuring sufficient vascular supply, periodic debridement of all necrotic and nonviable tissue, treatment of infection, and wound offloading. The goals of therapy should be to facilitate the expeditious and reliable closure of these chronic wounds, prevent reulceration, and return to function. Successful and rapid wound closure can prevent the serious complications of infection that so often result in increased morbidity and mortality associated with treatment of these complicated wounds.

One should reserve the use of advanced therapies such as biologic therapies or surgical intervention with split- thickness skin grafts (STSG) in cases when the wound has stalled in observed healing. Additionally, wounds that are significantly large or deep may benefit from these advanced modalities in assisting in the formation of a granular bed or decreasing the wound size. However, the debate on which modality is best remains unclear.

Key Insights On The Use Of Biologic Therapies For DFUs

Biologic therapies in the form of bioengineered tissue and mesenchymal stem cell (MSC) therapies for DFUs have emerged as popular treatments, but have they lived up to their promise? The mechanism of action for these biologic therapies purportedly promotes complete closure of the ulcer through the addition of extracellular matrices that induce growth factors and cytokine expression although the exact mechanism is largely unknown.

A 2016 Cochrane Review evaluated the use of skin grafts and tissue replacements for DFUs, focusing on 17 randomized studies with 1,655 study participants.4 Based on the data, the authors concluded that “the overall therapeutic effect of skin grafts and tissue replacements used in conjunction with standard care shows an increase in the healing rate of foot ulcers and slightly fewer amputations in people with diabetes compared with standard care alone.” However, the data was insufficient to draw conclusions on the effectiveness of these therapies, and evidence for long-term effectiveness and cost-effectiveness is lacking.

While the use of biologic therapies may provide modest improvement in the healing of foot ulcers and decreased amputations, there are significant limitations for biologic therapy use.

1. There is a paucity of comparative clinical trials demonstrating effectiveness. Instead, the current literature is replete with small case series and cohort studies.

2. Biologic therapies do not provide a definitive closure and require repeat applications, resulting in increased time to heal.

3. Repeated applications of biologic therapies result in substantial cost, adding to the economic healthcare burden.

As a result of these limitations, it is my belief that when possible, STSG is the treatment of choice for expeditious and reliable closure of chronic DFUs.

What The Literature Says About STSG For DFUs

In contrast to the limited literature on biologic therapies, the medical literature has demonstrated both effectiveness and low complication rates for STSG on DFUs.  

When expeditious wound healing is preferred, the role of STSG trumps the use of biologic therapies. In 2008, Mahmoud and colleagues studied the difference in days to heal and days spent in the hospital in 100 patients with diabetes (50 in each group) using STSG in comparison with conservative wound care.5 All the patients in the study did heal completely but the STSG group healed in an average of 28 days in comparison to 122 days in the conservative group. The mean hospital stay was also 12 days fewer for the STSG group.   

There are anecdotal concerns regarding the effectiveness of STSG in patients with diabetes due to concerns with the integrity of the donor skin with regard to impaired wound healing common to those with diabetes. Puttirutvong and coworkers assessed meshed versus non-meshed skin grafts in the treatment of DFUs in 80 patients with diabetes.6 All 80 DFUs healed following application of both meshed and non-meshed skin grafts with no statistical difference between the two groups.  

Ramanujam and colleagues retrospectively analyzed STSG in 83 consecutive patients with diabetes.7 The authors found all of their patients healed successfully by the final follow-up at six months and concluded that STSG with an appropriate postoperative regimen is a beneficial procedure to achieve wound closure.

While successful closure occurred in all 83 cases, complications and delayed healing did occur in patients with these complex wounds.7 Of the 83 patients, 54 healed uneventfully, 23 required re-grafting and six had a complication resolved with conservative management. The time to complete wound healing ranged from 1.7 to 30.1 weeks with a median time to healing of 6.9 weeks, a longer duration of time to healing in comparison to healing times of two to four weeks reported in studies on STSG in those without diabetes. The authors postulate that we can attribute longer healing times in patients with diabetes to several factors, including impaired microcirculation, neuropathy and endothelial dysfunction.

Indeed, STSG failure can occur in patients with diabetes due to several factors that may be related to the underlying pathology of the chronic disease. Sanniec and coworkers retrospectively reviewed 43 DFUs treated with STSG.8 Of the 43 surgical sites, 27 healed with greater than 90 percent graft incorporation while 16 experienced graft failure. The authors noted that there was no statistically significant difference in HbA1c levels between the group that healed a skin graft in comparison to the group in which the skin graft failed to adhere. Despite those STSG failures, the authors concluded that the benefits of early wound closure outweigh the risks.

In addition to HbA1c, evaluation of risk factors for STSG failure also encompasses age, gender, race, wound size, wound location, illicit drug use, amputation history, Charcot history and preoperative infection. Ramanujam and colleagues also found that STSG failure was unassociated with HbA1c.7 The authors instead found that postoperative graft complications were significantly associated with current or previous smoking history, and the level of previous pedal amputation to which physicians applied the STSG.

In Conclusion

The treatment of complex chronic DFUs remains rooted in the basic cornerstones of debridement, infection control, wound offloading and enhancement of vascular perfusion. When rapid wound coverage is required, STSG offers superior advantages to biologic therapies with minimal complications. Furthermore, authors have rigorously studied and reported these advances in the medical literature, lending support to the superiority of STSG.

Dr. Dinh is an Assistant Professor of Surgery at Harvard Medical School. She is the Program Director of the Podiatric Surgical Residency Program at the Beth Israel Deaconess Medical Center in Boston. Dr. Dinh is a Fellow and a member of the Board of Directors for the American College of Foot and Ankle Surgeons.

References

1.     Pham HT, Rosenblum BI, Lyons TE, et al. Evaluation of a human skin equivalent for the treatment of diabetic foot ulcers in a prospective, randomized, clinical trial. Wounds. 1999;11(4):1044–6.
2.     Boulton AJ. The diabetic foot: grand overview, epidemiology and pathogenesis. Diabetes Metab Res Rev. 2008;24(Suppl 1):3–6.
3.     Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. J Am Med Assoc. 2005; 293(2):217-228.
4.     Santema TB, Poyck PPC, Ubbink DT. Skin grafting and tissue replacement for treating foot ulcers in people with diabetes. Cochrane Database Syst Rev. 2016;2:CD011255.
5.     Mahmoud SM, Mohamed AA, Mahdi SE, et al. Split-skin graft management of diabetic foot ulcers. J Wound Care. 2008;17(7):303-306.
6.     Puttirutvong P. Meshed skin graft versus split thickness skin graft in diabetic ulcer coverage. J Med Assoc Thai. 2004;87(1):66-72.
7.     Ramanujam CL, Stapleton JJ, Kilpadi KL, et al. Split-thickness skin grafts for closure of diabetic foot and ankle wounds: a retrospective review of 83 patients. Foot Ankle Spec. 2010;3(5):231-40.
8.     Sanniec K, Nguyen T, van Asten S, et al. Split thickness skin grafts to the foot and ankle of diabetic patients. J Am Podiatr Med Assoc. 2017;107(5):365-368.
9.     Krishnan ST, Quattrini C, Jeziorska M, et al. Neurovascular factors in wound healing in the foot skin of type 2 diabetic subjects. Diabetes Care. 2007;30(12):3058-3062.

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Harry Schneider, DPM, FACFAS, and David Liou, DPM; Thanh Dinh, DPM, FACFAS
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