Outcomes of allogenic acellular matrix therapy in treatment of diabetic foot wounds: an initial experience

Abstract

The purpose of this study was to evaluate outcomes of persons with UT grade 2A neuropathic diabetic foot wounds treated with an acellular matrix. Data were abstracted for 17 consecutive patients with diabetes – 76·5% males, aged 61·5 ± 8·5 years with a mean glycated haemoglobin of 9·2 ± 2·2% presenting for care at a large, multidisciplinary wound care centre. All patients received surgical debridement for their diabetic foot wounds and were placed on therapy consisting of a single application of an acellular matrix graft (GraftJacket™; Wright Medical Technologies, Arlington, TN, USA) with dressing changes taking place weekly. Outcomes evaluated included time to complete wound closure and proportion of patients achieving wound closure in 20 weeks. Acellular matrix therapy was used as initial therapy and was sutured or stapled in place under a silicone‐based non adherent dressing. Therapy was then followed by a moisture‐retentive dressing until complete epithelialisation. In total, 82·4% of wounds measuring a mean 4·6 ± 3·2 cm² healed in the 20‐week evaluation period. For those that healed in this period, healing took place in a mean 8·9 ± 2·7 weeks. We conclude that a regimen consisting of moist wound healing using an acellular matrix dressing may be a useful adjunct to appropriate diabetic foot ulcer care for deep, non infected, non ischaemic wounds. We await the completion of further trials in this area to confirm or refute this initial assessment.

Introduction

Diabetic foot ulcerations are among the most common severe complications of diabetes (1). Approximately, one quarter of all hospital days for persons with diabetes are related to foot complications 2, 3, 4). In the United States, 45–83% of all lower extremity amputations involve diabetics 5, 6, 7, 8). Overall, patients with diabetes are 15–46 times more likely to have an amputation compared with patients without diabetes (5, 9, 10, 11). The direct cost of amputations has been conservatively estimated to be approximately $1·6 billion a year without considering physician fees, cost of prosthetics or rehabilitation costs (12). Lower extremity complications in persons with diabetes are common, costly and associated with a high rate of recurrence, morbidity and mortality (1, 13). Prevention and treatment of foot ulcers may be considered a major public health goal.

One of the most common causes to limb amputation in persons with diabetes is neuropathic foot ulcer (14). Diabetic foot ulcerations are notoriously difficult to heal secondary to abnormal fibroblast and matrix protein function found in the skin, the poor nutritional blood flow, peripheral neuropathy and decreased inflammatory response (15, 16). Over the past generation, there have been a number of potentially revolutionary advances in wound healing. The advent of tissue engineering has provided clinicians the ability to transplant human tissues to assist in the closure of ulcerations. Research in tissue engineering has shown that there may be benefits to using allografts to achieve quicker wound healing as compared with local conservative care (15, 17, 18).

Several human skin matrixes and metabolically active human dermal replacement graft have been shown to be effective at wound closure; however, several applications of the skin matrix may be required 17, 18, 19).

GraftJacket™ (Wright Medical Technology, Arlington, TN, USA), a novel acellular regenerative tissue matrix, has been designed to aid wound closure where only a single administration of the tissue matrix was required. The purpose of this study was to evaluate outcomes of persons with UT grade 2A neuropathic diabetic foot wounds treated with an acellular matrix.

Methods

In this study, data from 17 consecutive patients with UT grade 2A neuropathic diabetic foot wounds treated with acellular matrix were abstracted. All patients presented for care at a large, multidisciplinary wound care centre. All patients had a diagnosis of diabetes prior to abstraction. This was confirmed by either communication with primary care providers or review of medical records. All patients had loss of protective sensation (>25 V) as measured with a VPT meter (Xilas, Inc., San Antonio, TX, USA) (20, 21), at least one palpable foot pulse and a neuropathic plantar diabetic foot ulcer corresponding to grade 2A of the University of Texas Diabetic Foot Wound Classification System (22, 23). Wound size was evaluated by measuring the maximum length by the maximum width. Patients with active infection, unable to walk without a wheelchair, with wounds in locations on the heel, rearfoot or other than the plantar aspect of the foot, or with severe peripheral vascular disease (diagnosed by the criteria listed above based on the absence of both foot pulses on the affected extremity) were excluded. If patients had more than one plantar wound, the largest wound was used as the index ulcer for abstraction.

Of the patients evaluated, 76·5% were male, aged 61·5 ± 8·5 years with a mean glycated haemoglobin of 9·2 ± 2·2%. All patients received surgical debridement for their diabetic foot wounds and were placed on therapy consisting of a single application of an acellular matrix graft (GraftJacket™) with dressing changes taking place weekly. All necrotic tissue was removed from the wound, and a granular wound base was created. GraftJacket™ therapy was used as initial therapy and was sutured or stapled in place under a silicone‐based non adherent dressing. Therapy was then followed by a moisture‐retentive dressing until complete epithelialisation. Outcomes evaluated included time to complete wound closure and proportion of patients achieving wound closure in 20 weeks. This time point was selected in order to allow for better comparison with previous studies of wound‐healing agents, which have evaluated diabetic foot wound‐healing prevalence between 12 and 20 weeks 24, 25, 26). We selected 20 weeks because of the deep nature (UT grade 2A) of these wounds.

Results

Descriptive characteristics for this population are summarised in Table 1. In total, 14 of the 17 chronic wounds (82·4%) with a mean wound size of 4·5 ± 3·2 cm² healed in the 20‐week evaluation period with a single application of an acellular matrix graft. The mean duration of wounds prior to treatment was 29·8 ± 22·4 weeks. For those that healed within the 20‐week period, healing took place in a mean 8·9 ± 2·7 weeks.

Table 1.

Descriptive characteristics

	Minimum	Maximum	Mean (SD)
Age (years)	45·0	75·0	61·5 (8·5)
Duration of diabetes (years)	7·0	24·0	15·0 (5·1)
Glycosylated haemoglobin (%)	6·2	13·8	9·2 (2·2)
Wound size (sq cm)	1·2	12·5	4·5 (3·2)
Duration of wound (weeks)	3·0	81·0	29·8 (22·4)
Time to healing (weeks)	4·0	15·0	8·9 (2·7)

There were no device‐related adverse events in this group. Six of the 17 patients (35%) required oral antibiotics at some point during the life cycle of their wound. All of these patients were among those who had their wounds healed in the 20‐week period of assessment.

Discussion

The most common antecedent to lower extremity amputation in persons with diabetes is a foot ulcer (14). Besides the physical aspects of repetitive pressure over the wound site, these wounds are notoriously difficult to heal secondary to abnormal fibroblast and matrix protein function found in the skin, the poor nutritional blood flow, peripheral neuropathy and decreased inflammatory response (16, 27). Over the past generation, there have been a number of potentially promising advances in wound healing. The advent of tissue engineering has provided clinicians the ability to transplant human tissues to assist in the closure of ulcerations.

There may be several advantages to the use of an acellular dermal matrix (ADM) (28). ADM does not require an immediate blood supply but can transmit essential interstitial fluids for nourishment of overlying tissues with no detectable immune response either by histology or by lymphocyte proliferation assay (29). Huo et al. (30) showed no significant change between the content and proportion of type I–III collagen in the ADM they evaluated and suggested it to be a potentially ideal material for soft tissue filling. Collagen is a natural substrate for cellular attachment, growth and differentiation (31) and promotes cellular proliferation and differentiation. The specific construct employed in this project (GraftJacket™) is a bilaminate acellular regenerative tissue matrix in which there is a scaffold of collagen, laminin and elastin fibres that are preserved during the cryofreezing process that renders the graft acellular. The matrix of intact collagen network and preserved vascular channels in GraftJacket™ acts as a scaffold to facilitate angiogenesis and migration of growth factors that stimulate keratinocytes, melanocytes and other cell migration through a complex regulatory mechanism.

An et al. examined the effects of ADM on the closure of abdominal wounds and found that wounds treated with ADM showed a significant reduction in wound area. In addition, they noted that ADM became vascularised and incorporated into the wound bed and was partially or fully epithelialised without the need for skin grafting (32). Significant wound contraction has been noted at 14, 20 and 30 days after surgery in rat wounds receiving allogenic ADM (33).

Brigido et al. (34) in a prospective, randomised study reported faster healing of chronic, full‐thickness, lower extremity wounds at a significantly faster rate compared with conventional treatment when using an acellular matrix dressing.

Several human skin matrixes and metabolically active human dermal replacement graft have been shown to be effective at wound closure; however, several applications of the skin matrix may be required 17, 18, 19). In our study, 82·4% of deep wounds measuring a mean 4·6 ± 3·2 cm² healed in the 20‐week evaluation period following aggressive surgical debridement, a single application of an acellular matrix graft (GraftJacket™) and moisture‐retentive dressing. Of those that healed in this period, healing took place in a mean 8·9 ± 2·7 weeks.

The most obvious shortcoming to this study was the lack of a control group available to compare outcomes. The purpose of this study was to evaluate initial results using this novel therapy for wounds. This obviously limits any overt conclusions that might be drawn from this study. Additionally, as this was a retrospective study, any of the inherent biases that may be found in such a design may have entered into and affected these patients' assessments. While consecutive patients were reviewed from a centre that has a rigid, systematic method of assessment and highly consistent pathways for care, this remains a significant methodological weakness.

We conclude that a regimen consisting of moist wound healing using an acellular matrix dressing may be a useful adjunct to appropriate diabetic foot ulcer care for deep, non infected, non ischaemic diabetic foot wounds. There were no dressing‐related complications, and the healing rate in this survey was reasonable considering the deep (UT grade 2A) nature of the wounds. We await the completion of further trials in this area to confirm or refute this initial assessment.