Skin Substitutes and Wound Healing: Current Status and Challenges

David Eisenbud, MD, CWS; Ngan F. Huang, BS; Sunny Luke, DSc; Melvin Silberklang, PhD

Disclosures

Wounds. 2004;16(1) 

In This Article

Clinical Results

Diabetic Neuropathic Wounds

Lipkin and colleagues[61] have reported the results of a multicenter pilot trial of BCM for the treatment of neuropathic plantar wounds in 40 patients with diabetes mellitus. At the 12-week study end point, 7 of 20 treated wounds and 4 of 20 control wounds were completely reepithelized. Healing rate was nearly double (1.8% per day vs. 1.0% per day, p=0.008) in the treated compared with the control group, which received moist saline gauze and other standard wound care including debridement and offloading. The protocol, which prescribed up to six weekly applications of BCM, resulted in acceleration of wound closure that was highly statistically significant during the first four weeks before dropping closer to control levels. Benefits of the cellular skin substitute wound therapy were restricted to wounds smaller than 6cm2 (47% BCM patients healed vs. 23% control patients.) The FDA has granted approval for a pivotal trial of cryopreserved BCM in diabetic wounds.

Veves, et al.,[62] reported the results of a prospective, randomized multicenter trial of LSE in treating neuropathic diabetic plantar foot wounds that provided the basis for FDA approval of this product. The primary end point -- complete wound closure at 12 weeks -- was reached by 56 percent of LSE treated patients versus 38 percent of patients treated with standard wound care including debridement, offloading, and daily saline dressings. Median time to complete wound healing was lower in the LSE group (65 vs. 90 days, p=0.0026.)

The effectiveness of a dermal substitute (Dermagraft) in healing plantar foot wounds associated with diabetes mellitus was reported by Hanft and Surprenant.[38] Patients randomized to the dermal substitute treatment had up to eight applications of the bioengineered skin. At week 12, 71 percent of dermal substitute patients were healed compared with 14 percent of saline gauze-treated controls (p=0.004.) More recently, Marston and colleagues[39] reported a trial of the dermal substitute in 245 diabetic patients with plantar wounds. The incidence of complete healing was increased (30% vs. 18%; p=0.023) in the dermal substitute-treated wounds.

Venous Leg Ulcers

Very good results have been reported using bioengineered skin products to heal venous leg ulcers. Multiple weekly applications of LSE (average 3.3 per patient) plus compression induced complete healing in 63 percent of patients compared with 49 percent of those treated with compression alone (p=0.02).[63] Median time to healing was shorter (61 vs. 181 days, p=0.003) in the LSE group. The rate of wound recurrence at 12 months was not statistically different between study groups. The relative beneficial effect of this cellular skin substitute wound therapy was notable primarily in larger wounds and those of longer duration. Later analysis of patients meeting these criteria within the trial demonstrated that healing at six months was doubled using LSE.[64,65] The re-analysis of pivotal trial data on the effectiveness of LSE for hard-to-heal (greater than one year's duration) venous wounds was reported by Falanga and Sabolinski in 1999.[66] At six months, 47 percent of LSE-treated patients were completely healed compared with 19 percent of control patients (p< 0.005); median times to wound closure also showed a substantial advantage for LSE. Various subsequent reports from individual centers have confirmed similar good results using LSE on hard-to-heal ulcers of venous etiology.

BCM has also demonstrated excellent healing of venous wounds to date. In 2000, the pilot trial of BCM use in 36 venous ulcers showed that, compared with controls treated with foam dressings and standard compression, the product resulted in significantly more patients totally healed, by investigator assessment, at 12 (53% vs. 26%) and 26 (71% vs. 37%) weeks. Most patients received four applications of the skin substitute at weekly intervals. Wounds, as assessed by the investigators, were healed in a median 87 days with BCM, while more than half of control wounds were still unhealed at 180 days (p=0.033.) The efficacy of BCM was further supported by measurement of mean percent daily wound healing (2.0% for treated vs. 1.0% for control, p<0.0001.) Based upon these results, a pivotal trial using the cryopreserved form of BCM was initiated. Patient enrollment was completed in July, 2003. Preliminary analysis of the first 48 patients showed that 64 percent of BCM-treated patients had achieved complete wound closure by 12 weeks, compared with 39 percent of controls. The company is preparing its pre-market approval (PMA) submission as of January 2004.

Small series of venous ulcer patients treated with cultured epithelial allografts have been reported, noting good results,[48,67] but this technique has yet to be subjected to a prospective, multicenter, controlled, randomized trial.

Burns

Because of the life-threatening nature of deep, extensive burns and also because, in such situations, patients have limited sites for autologous skin graft donation, clinicians have had a low threshold for testing skin substitutes in this population. Many burn centers have tinkered with variations of CEA for wound coverage. Epicel has been used with excellent success, as noted above; typical "take" onto debrided burn wounds is 50 to 70 percent.[68]

In pilot, single-center studies, frozen cultured allogeneic keratinocyte sheets (Celaderm) have been noted to reduce healing time of partial-thickness burns by 44 percent (5.6 vs. 12.2 days), and were judged to obviate the need for autologous skin grafting in several of nine patients.[48] In a side-by-side comparison of cultured epithelial allograft applied to one section of skin graft donor sites and partial-thickness burns and control dressings applied to adjacent parts of the respective wound, healing was significantly improved in the cell-based wound therapy group (6.9 vs. 11.1 days, p<0.005.)[69] Severely burned patients treated with a regimen that included application of allograft and autograft epidermal cultures showed a survival advantage and reduced hospital stay compared with similar patients treated by other standard means at the same center.[70] Split-thickness donor sites for autologous graft harvest in burn patients have also been studied as suitable indications for intervention with skin substitute wound therapy. In a controlled matched-pairs design study of 82 burn patients, a single application of BCM was found to accelerate 100-percent epithelization of a donor site by an average of seven days, and with less scarring as compared to an acellular matrix product (Biobrane-L) control donor site in the same patient.[71] LSE has also been studied in this indication.[72]

Other Indications

Wounds associated with several rare conditions have been successfully treated with cell-based wound therapies or skin substitutes. The original FDA-approved indication for BCM was in the surgical treatment of mitten hand deformity secondary to recessive dystrophic epidermolysis bullosa;[73] subsequent reports have indicated the utility of LSE in this condition as well.[74,75] Bullous morphea,[76] actinic purpura,[77] polyarteritis nodosa,[78] sarcoidosis,[79] corneal wounds,[80] and sickle cell disease[81] have reportedly been treated successfully with bioengineered skin. Another report cites both LSE and BCM as effective in accelerating healing of saphenous vein harvest wound complications.[82]

While the main focus in clinical trials of skin substitutes has been on the kinetics of wound closure (time to complete closure, rate of closure etc.), clinicians have also begun to consider more critically the quality of the healed wound. Waymack,[83] for example, used LSE over meshed split-thickness autologous skin grafts and noted that while controls healed as quickly as LSE-treated sites, those that had LSE demonstrated more normal pigmentation, vascularity, pliability and scar height after healing.

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