Apligraf in the Treatment of Neuropathic Diabetic Foot Ulcers

Diabetic Foot Clinic, King's College Hospital, Denmark Hill, London, United Kingdom.
The International Journal of Lower Extremity Wounds (Impact Factor: 0.93). 02/2009; 8(1):11-8. DOI: 10.1177/1534734609331597
Source: PubMed


This study compared the efficacy and safety of Apligraf (Organogenesis, Inc., Canton, MA) in combination with standard therapy versus standard therapy alone in the treatment of neuropathic diabetic foot ulcers. Efficacy was assessed by time to complete wound healing (by 12 weeks) and incidence of complete wound closure (at 12 weeks). This was an international multi-center, randomized, controlled study. Patients were eligible for entry into the study if the following criteria were met: type 1 or type 2 diabetes mellitus, age 18 to 80 years, adequate glycemic control, and the presence of a full-thickness neuropathic ulcer for at least 2 weeks prior to the initial screening visit. Following the 2-week screening period, the 2 treatment groups received standard ulcer care consistent with international treatment guidelines that comprised sharp debridement, saline-moistened dressings, and a non-weight bearing regimen. There were 106 subjects screened for enrollment, 82 randomized to the treatment groups, and 72 treated (33 Apligraf subjects and 39 standard therapy subjects) before the study was terminated. Kaplan-Meier curves indicated a trend for shorter time to complete wound healing in the Apligraf group compared with the standard therapy group (p = .059; log-rank test). The median time to healing was 84 days in the Apligraf group, whereas no median time to healing could be determined for the standard therapy group because <50% of the standard therapy subjects healed. By 12 weeks, 51.5% (17/33) Apligraf subjects had achieved complete wound closure compared with 26.3% (10/38) of standard therapy subjects (p = .049; Fisher's exact test). Even though the study was halted prematurely, this study suggested that the use of Apligraf resulted in a higher incidence of wound closure by 12 weeks.

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    • "Several studies have described the use of Apligraf (Organogenesis Inc, Canton, MA) for treatment of DFU.20–23 Apligraf is a living bioengineered dressing that is bilayered, with cultured keratinocytes placed on the surface of a fibroblast-populated lattice made from type 1 bovine collagen. Edmonds21 studied 82 DFU patients with wounds present for at least 2 weeks. Following a 2-week screening period, patients were randomized to either a treatment group receiving Apligraf or a control group receiving sharp debridement, non-weight-bearing activity, and saline wet-to-dry dressings. "
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    ABSTRACT: Diabetic foot ulcers are a major source of morbidity, limb loss, and mortality. A prolonged inflammatory response, extracellular matrix degradation irregularities, and increased bacteria presence have all been hypothesized as major contributing factors in the delayed healing of diabetic wounds. Collagen components such as fibroblast and keratinocytes are fundamental to the process of wound healing and skin formation. Wound dressings that contain collagen products create a biological scaffold matrix that supports the regulation of extracellular components and promotes wound healing. A systematic review of studies reporting collagen wound dressings used in the treatment of Diabetic foot ulcers was conducted. Comprehensive searches were run in Ovid MEDLINE, PubMed, EMBASE, and ISI Web of Science to capture citations pertaining to the use of collagen wound dressings in the treatment of diabetic foot ulcers. The searches were limited to human studies reported in English. Using our search strategy, 26 papers were discussed, and included 13 randomized designs, twelve prospective cohorts, and one retrospective cohort, representing 2386 patients with diabetic foot ulcers. Our design was not a formal meta-analysis. In those studies where complete epithelialization, 58% of collagen-treated wounds completely healed (weighted mean 67%). Only 23% of studies reported control group healing with 29% healing (weighted mean 11%) described for controls. Collagen-based wound dressings can be an effective tool in the healing of diabetic foot wounds. The current studies show an overall increase in healing rates despite limitations in study designs. This study suggests that future works focus on biofilms and extracellular regulation, and include high risk patients.
    Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 01/2013; 6:17-29. DOI:10.2147/DMSO.S36024
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    • "Many studies reported that patients treated with skin substitutes, which acted as a temporary biological dressing, had a significantly faster wound closure time compared to their respective control groups. [13], [14], [15], [19], [20]. MyDerm™ is a fully autologous living bilayered skin substitutes that can be integrated completely with the patient's skin after grafting, thus is expected to have comparatively faster wound closer. "
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    ABSTRACT: Skin plays an important role in defense against infection and other harmful biological agents. Due to its fragile structure, skin can be easily damaged by heat, chemicals, traumatic injuries and diseases. An autologous bilayered human skin equivalent, MyDerm™, was engineered to provide a living skin substitute to treat critical skin loss. However, one of the disadvantages of living skin substitute is its short shelf-life, hence limiting its distribution worldwide. The aim of this study was to evaluate the shelf-life of MyDerm™ through assessment of cell morphology, cell viability, population doubling time and functional gene expression levels before transplantation. Skin samples were digested with 0.6% Collagenase Type I followed by epithelial cells dissociation with TrypLE Select. Dermal fibroblasts and keratinocytes were culture-expanded to obtain sufficient cells for MyDerm™ construction. MyDerm™ was constructed with plasma-fibrin as temporary biomaterial and evaluated at 0, 24, 48 and 72 hours after storage at 4°C for its shelf-life determination. The morphology of skin cells derived from MyDerm™ remained unchanged across storage times. Cells harvested from MyDerm™ after storage appeared in good viability (90.5%±2.7% to 94.9%±1.6%) and had short population doubling time (58.4±8.7 to 76.9±19 hours). The modest drop in cell viability and increased in population doubling time at longer storage duration did not demonstrate a significant difference. Gene expression for CK10, CK14 and COL III were also comparable between different storage times. In conclusion, MyDerm™ can be stored in basal medium at 4°C for at least 72 hours before transplantation without compromising its functionality.
    PLoS ONE 09/2012; 7(8):e40978. DOI:10.1371/journal.pone.0040978 · 3.23 Impact Factor
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    • "Following these technological breakthroughs , multiple collagen-based biomaterials were developed and designed for clinical and experimental purposes. The use of collagen gels (Apligraft™), collagen sponges (Integra™) and decellularized collagenous tissues (Alloderm™) have all been approved by the US Food and Drug Administration and shown to improve wound healing in clinical applications [9] [10] [11] [12]. These 3-D scaffolds and their derivatives were also used for multiple cell migration, proliferation and differentiation studies, since they allow cell culture in a physiologically and spatially relevant environment [13] [14] [15] [16]. "
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    ABSTRACT: Combining bovine collagen with chitosan followed by freeze-drying has been shown to produce porous scaffolds suitable for skin and connective tissue engineering applications. In this study collagen extracted from porcine and avian skin was compared with bovine collagen for the production of tissue engineered scaffolds. A similar purity of the collagen extracts was shown by electrophoresis, confirming the reliability of the extraction process. Collagen was solubilized, cross-linked by adding chitosan to the solution and freeze-dried to generate a porous structure suitable for tissue engineering applications. Scaffold porosity and pore morphology were shown to be source dependant, with bovine collagen and avian collagen resulting into the smallest and largest pores, respectively. Scaffolds were seeded with dermal fibroblasts and cultured for 35 days to evaluate the suitability of the different collagen-chitosan scaffolds for long-term tissue engineered dermal substitute maturation in vitro. Cell proliferation and scaffold biocompatibility were found to be similar for all the collagen-chitosan scaffolds, demonstrating their capability to support long-term cell adhesion and growth. The scaffolds contents was assessed by immunohistochemistry and showed increased deposition of extracellular matrix by the cells as a function of time. These results correlate with measurements of the mechanical properties of the scaffolds, since both the ultimate tensile strength and tensile modulus of the cell seeded scaffolds had increased by the end of the culture period. This experiment demonstrates that porcine and avian collagen could be used as an alternative to bovine collagen in the production of collagen-chitosan scaffolding materials.
    Acta biomaterialia 06/2011; 7(10):3757-65. DOI:10.1016/j.actbio.2011.06.020 · 6.03 Impact Factor
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