Evidence Corner: Biologic Dressings for Foot Ulcers

Dear Readers:   Healthy feet help us preserve our independence, earn our livelihood, and participate actively in our social environment. A foot ulcer can isolate and depress the individual who suffers it while increasing risk of amputation, infection, or mortality. Healing foot ulcers quickly helps limit the costs and burden of care and keeps patients active as contributing members of family and society. Most foot ulcers will decrease in area by at least 50% in 4 weeks and proceed to complete healing by 12 weeks^1,2 when their growth factor-rich, enzyme-laden fluid is sealed over the wound, cause(s) of injury stopped, and devitalized tissue removed.¹   Foot ulcers unresponsive to this best standard of care may need further impetus to heal. Biologic skin substitutes (BSS) containing different types of living or dead cells or matrices have been explored as interventions to speed foot ulcer healing. In a large randomized controlled trial (RCT) involving patients with full-thickness plantar diabetic foot ulcers (DFU), 56% of 112 subjects healed in 12 weeks when dressed with a BSS containing living allogeneic fibroblasts and keratinocytes, compared to 39% of the 96 subjects randomized to receive a porous wound contact layer covered by a saline gauze dressing,³ a dubious standard of care.^4-6 Interpretation of biologic dressing results has been clouded by use of removable offloading devices which delays healing⁷ and differences in test and control dressings’ capacity to seal moisture over the wound to permit moist healing.^5,6 The 2 recent studies reviewed below identify important variables to control and to study in clarifying effects of foot ulcer treatment with BSS.

Living Cells Improve Foot Ulcer Healing

Reference: Felder JM III, Goyal SS, Attinger CE. A systematic review of skin substitutes for foot ulcers. Plast Reconstr Surg. 2012;130(1):145-164. Rationale: The clinical and economic challenges of foot ulcers have been addressed in recent years by increasing numbers of biologically derived artificial skin substitutes as tissue culture technology progressed. Objective: Inform decisions about foot ulcer care with a systematic review describing the quality and quantity of evidence of safety and efficacy of BSS in treatment of chronic foot ulcers of all types. Methods: PubMed, MEDLINE, EBSCO, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for controlled or prospective comparative cohort studies and systematic reviews reporting outcomes of human controlled clinical trials including non-traumatic foot ulcers of any etiology treated with any form of BSS. Derivative references and trials known to experts were included. Three reviewers wrote structured abstracts of each reference, including standardized entries of study citation, design, procedures, and outcomes reported. Evidence quality was rated on the Jadad scale based on blinding, randomization, and subject withdrawal information. Results: Of 271 studies identified, 15 RCTs and 1 prospective comparative cohort study qualified for inclusion in the systematic review: 12 studies on DFUs, 3 on venous ulcers, and 1 on foot ulcers of unspecified etiology. Six studies of a neonatal fibroblast- and-keratinocyte-populated BSS on a bovine Type I collagen substrate supported its safety and effectiveness on DFUs and venous ulcers. Four studies of a fibroblast-derived BSS on a polyglactin substrate reported it safe and effective on DFUs only if the fibroblasts were metabolically active. Three studies reported more DFUs healed when dressed with an acellular dermal layer derived from human cadaver skin than control-treated DFUs. Better quality research is needed to support efficacy, because the treatment group in the largest study had smaller pre-treatment wound size, a lower proportion of foot wounds, and twice as many withdrawals as controls. One study each explored 1) allogeneic cryopreserved human cadaver split-thickness skin containing mature fibroblasts and keratinocytes (RCT underpowered for statistical significance); 2) a matrix composed of a benzyl esther of hyaluronic acid seeded with autologous keratinocytes and fibroblasts with no statistically significant effect overall but an effect on dorsal DFU healing; or 3) neonatal foreskin-derived keratinocytes and fibroblasts seeded onto a Type I bovine collagen sponge, effective only on the subset of DFUs Author’s Conclusions: There is likely no need for further RCTs to justify use of currently available cell-based BSS on foot ulcers. More BSS RCTs are needed with more consistent design, larger samples, and longer follow-up to facilitate future systematic reviews. Higher quality evidence is needed before one can compare one BSS to another or to more advanced control dressings as standards of care or to support firm conclusions about non-cell-based BSS.

Cultured Allogeneic Keratinocytes Improve Healing

Reference: You HJ, Han SK, Lee JW, Chang H. Treatment of diabetic foot ulcers using cultured allogeneic keratinocytes. A pilot study. Wound Repair Regen. 2012;20(4):491-499. Rationale: The need to stimulate healing in DFUs that fail to heal using conventional interventions may be met by therapies that stimulate local cellular activity. Cultured allogeneic keratinocytes (CAK) release growth factors and matrix molecules important in healing and have been reported to stimulate healing of burns and chronic leg ulcers. Objective: Conduct a stratified single-blind RCT exploring early clinical healing efficacy of sheets containing >2 x 10⁷ CAK backed by petrolatum gauze in a pilot study of patients with chronic DFUs. Methods: Subjects without Charcot foot deformity or other conditions delaying healing with Type 1 or 2 diabetes and an uninfected non-ischemic Wagner grade 1 or 2 DFU >1 cm² in area that failed to show signs of healing for 6 weeks were recruited from 3 hospitals in Korea. After consent, qualifying subjects were debrided to the level of bleeding tissue, then randomized stratified within the center to receive either a CAK or control primary dressing. Petrolatum gauze-backed CAK dressings were stored at -70○ C, thawed at room temperature for 5 to 10 minutes before cutting to wound size, applied to the wound surface, and then covered with a secondary dressing, mainly a polyurethane foam which could be changed up to 3 times weekly while leaving the CAK in place. Control DFUs received similar primary and secondary dressings without CAK. Both CAK and control primary dressings were changed only once weekly. No concomitant biologic or biochemical therapy was allowed during the study. All subjects with ulcers requiring protection from pressure received removable offloading or protective foot wear, crutches, or wheelchairs. Evaluators were not blinded to treatment. The primary efficacy measure was percent of ulcers completely healed at 12 weeks. Weekly mean percent wound area reduction from baseline area based on digital planimetry and Kaplan-Meier estimated time to healing were secondary efficacy measures. Recurrence was monitored for 6 months in 16 CAK and 15 control subjects. Safety was reported as adverse events. Results: The two groups were comparable on all safety measures. One DFU recurred during 6 months in each group. Intent-to-treat analysis (ITT) reported 85% of 27 CAK-treated subjects healed in 12 weeks, compared to 59% of the 32 control subjects (P P Author's Conclusions: Combined with a protocol that removes devitalized wound surface tissue and offloads pressure, CAK may be safe and effective for the treatment of non-infected, non-ischemic diabetic foot ulcers.

Clinical Perspective:

  Together, these two studies confirm the efficacy of BSS with living allogeneic human foreskin keratinocytes with or without the addition of fibroblasts in healing foot ulcers of diabetic or venous etiology^8,9 and suggest that BSS without living cells need higher quality research to support a similar conclusion. Future BSS studies need to use more advanced controls, increase sample size and follow-up time, and include cost effectiveness data to improve their capacity to inform care.⁸ Careful RCT design and conduct are important to avoid all sources of bias.¹⁰ A good quality RCT starts by using blinded allocation to randomized treatment groups on enrollment and matching or stratifying groups on key comorbid factors (eg, vascular perfusion, neuropathy, blood glucose) or ulcer parameters related to healing, such as size, depth, location, etiology, and duration; and finishes with blind evaluation of outcomes. Treatment factors to hold constant for both experimental and control groups include frequency and depth of debridement, consistency, and effectiveness of off-loading⁷ or compression, and moisture-retentive qualities of secondary dressings. All “advanced technologies” including BSS merit testing against best available standard of care dressings such as film or hydrocolloid dressings known to optimize healing outcomes.^5,6 Gauze is no longer a best clinical practice standard of care dressing.^5,6 Patients requiring pressure offloading in RCTs deserve consistent offloading⁷ for weight-bearing sites, not inconsistently used crutches or wheelchairs, which increase variability of outcomes and obscure results. Finally, a well-designed RCT answers a clear question by modifying a single aspect of care between active and control groups. You et al represented a good RCT design for BSS, in which the only difference between active and control groups was the addition of allogeneic keratinocytes in the active BSS group.⁹ A limitation was that persons evaluating the outcomes knew the treatment received. The clearest conclusion for BSS therapy is that it likely works, possibly due to living cells in the substrate or to the cytokines and/or matrix molecules they release.

References

1. Boulton AJ, Meneses P, Ennis WJ. Diabetic foot ulcers: A framework for prevention and care. Wound Rep Reg. 1999;7:7-16. 2. Sheehan P, Jones P, Caselli A, Giurini J, 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. Diabetes Care. 2003;26(6):1879-1882. 3. Veves A, Falanaga V, G. AD, Sabolinski ML, Study ADFU. Graftskin, a human skin equivalent, is effective in the managment of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care. 2001;24(2):290-295. 4. Margolis DJ, Kantor J, Berlin JA. Healing of diabetic neuropathic foot ulcers receiving standard treatment: A meta-analysis. Diabetes Care.1999;22(5):692-695. 5. van Rijswijk L. Bridging the gap between research and practice. American J Nursing. 2004;104(2):28-30. 6. Bolton LL. Evidence-based report card: Operational definition of moist wound healing. JWOCN. 2007;34(1):23-29. 7. Armstrong DG, Lavery LA, Wu S, Boulton AJ. Evaluation of removable and irremovable cast walkers in the healing of diabetic foot wounds: A randomized controlled trial. Diabetes Care. 2005;28:551–554. 8. Felder JM 3rd, Goyal SS, Attinger CE. A systematic review of skin substitutes for foot ulcers. Plast Reconstr Surg. 2012;130(1):145-164. 9. You HJ, Han SK, Lee JW, Chang H. Treatment of diabetic foot ulcers using cultured allogeneic keratinocytes: A pilot study. Wound Repair Regen. 2012;20:491-499. 10. Eskes AM, Brölmann FE, Sumpio BE, et al. Fundamentals of randomized clinical trials in wound care: Design and conduct. Wound Repair Regen. 2012;20(4):449-455. 9. Armstrong DG, Lavery LA, Wu S, Boulton AJ. Evaluation of removable and irremovable cast walkers in the healing of diabetic foot wounds: A randomized controlled trial. Diabetes Care. 2005;28:551–554. 10. Felder JM 3rd, Goyal SS, Attinger CE. A systematic review of skin substitutes for foot ulcers. Plast Reconstr Surg. 2012;130(1):145-164. 11. You HJ, Han SK, Lee JW, Chang H. Treatment of diabetic foot ulcers using cultured allogeneic keratinocytes: A pilot study. Wound Repair Regen. 2012;20:491-499. 12. Eskes AM, Brölmann FE, Sumpio BE, et al. Fundamentals of randomized clinical trials in wound care: Design and conduct. Wound Repair Regen. 2012;20(4):449-455.