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A new cell‐tissue technology uses a patient's skin to create an in vivo expanding and self‐organising full‐thickness skin autograft derived from potent cutaneous appendages. This autologous homologous skin construct (AHSC) is manufactured from a small full‐thickness skin harvest obtained from an uninjured area of the patient. All the harvested tissue is incorporated into the AHSC including the endogenous regenerative cellular populations responsible for skin maintenance and repair, which are activated during the manufacturing process. Without any exogenous supplementation or culturing, the AHSC is swiftly returned to the patient's wound bed, where it expands and closes the defect from the inside out with full‐thickness fully functional skin. AHSC was applied to a greater than two‐year old large (200 cm2) chronic wound refractory to multiple failed split‐thickness skin grafts. Complete epithelial coverage was achieved in 8 weeks, and complete wound coverage with full‐thickness functional skin occurred in 12 weeks. At 6‐month follow‐up, the wound remained covered with full‐thickness skin, grossly equivalent to surrounding native skin qualitatively and quantitatively equivalent across multiple functions and characteristics, including sensation, hair follicle morphology, bio‐impedance and composition, pigment regeneration, and gland production.

Introduction There is a clinical need to improve the outcomes of peripheral nerve regeneration and repair after injury. In addition to its immunosuppressive effects, FK506 (tacrolimus) has been shown to have neuroregenerative properties. To determine biologically relevant local FK506 and growth factor concentrations, we performed an in vitro bioassay using dorsal root ganglion (DRG) from chicken embryos. Methods Neurite elongation and neurite branching were analyzed microscopically after addition of FK506, glial cell line-derived neurotrophic factor (GDNF), and nerve growth factor (NGF), each alone and in combination. Results FK506 induced modest neurite elongation (~500–800 μm) without improving neurite branching significantly. The combination of FK506 with NGF, GDNF, or both, exerted a potentiating or competitive effect on neurite elongation (~700–1100 μm) based on dosage and competitive effect on neurite branching (~0.2–0.4). Conclusions These results strongly suggest that the interaction of FK506 with GDNF and NGF mediates distinct enhancement of neurite growth.

Autologous nerve grafts are the current "gold standard" for repair of large nerve gaps. However, they cause morbidity at the donor nerve site, only a limited amount of nerve can be harvested, and there is the potential for mismatches in size and fascicular patterns between the nerve stumps and the graft. Nerve conduits are a promising alternative to autografts and can act as guidance cues for the regenerating axons and allow for tension free bridging, without the need to harvest donor nerve. Separately, FK506, and FDA-approved small molecule, has been shown to enhance axon growth and peripheral nerve regeneration. This article describes the design of a novel drug delivery apparatus integrated with a poly lactic-co-glycolic acid (PLGA)-based nerve guide conduit for controlled local delivery of FK506. An FK506 dosage curve was acquired to determine the minimum in vitro concentration for optimal axonal outgrowth of dorsal root ganglion (DRG) cells, then PLGA devices were designed and tested in a diffusion chamber, and finally the bioactivity of the released media was evaluated by measuring axon growth in DRG cells exposed to the media for 72 h. The combined drug delivery nerve guide was able to release FK506 for 20 days at concentrations (1-20 ng/mL) that were shown to enhance DRG axon growth. Furthermore, the released FK506 was bioactive and able to enhance DRG axon growth. The combined drug delivery nerve guide can release FK506 for extended periods of time and enhance axon growth, and has the potential to improve nerve regeneration after a peripheral nerve injury.

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This integrated drug delivering nerve guide simplifies the design process and provides increased versatility for releasing a variety of different growth factors. This innovative device has the potential for broad applicability and allows for easier customization to change the type of drugs and dosage of individual drugs without devising a completely new biomaterial-drug conjugate each time.

Autologous nerve grafts are the current "gold standard" for repairing large nerve gaps. However, they cause morbidity at the donor nerve site and only a limited amount of nerve can be harvested. Nerve conduits are a promising alternative to autografts and can act as guidance cues for the regenerating axons, without the need to harvest donor nerve. Separately, it has been shown that localized delivery of GDNF can enhance axon growth and motor recovery. FK506, an FDA approved small molecule, has also been shown to enhance peripheral nerve regeneration. This paper describes the design of a novel hole-based drug delivery apparatus integrated with a polytetrafluoroethylene (PTFE) nerve conduit for controlled local delivery of a protein such as GDNF or a small molecule such as FK506. The PTFE devices were tested in a diffusion chamber, and the bioactivity of the released media was evaluated by measuring neurite growth of dorsal root ganglions (DRGs) exposed to the released drugs. The drug delivering nerve guide was able to release bioactive concentrations of FK506 or GDNF. Following these tests, optimized drug releasing nerve conduits were implanted across 10 mm sciatic nerve gaps in a BL6 yellow fluorescent protein (YFP) mouse model, where they demonstrated significant improvement in muscle mass, compound muscle action potential, and axon myelination in vivo as compared with nerve conduits without the drug. The drug delivery nerve guide could release drug for extended periods of time and enhance axon growth in vitro and in vivo.

Introduction The objective of this study is to assess the efficacy of local tacrolimus (FK506) delivery to improve outcomes in the setting of nerve transection injury. Methods FK506 embedded poly(lactide‐co‐caprolactone) films capable of extended, localized release of FK506 were developed. FK506 rate of release testing and bioactivity assay was performed. Mouse sciatic nerve transection and direct repair model was used to evaluate the effect extended, local delivery of FK506 had on nerve regeneration outcomes. Results Linear release of FK506 was observed for 30 days and released FK506 matched control levels of neurite extension in the dorsal root ganglion assay. Groups treated with local FK506 had greater gastrocnemius muscle weight, foot electromyogram, and number of axons distal of the repair site than non‐FK506 groups. Discussion Results of this study indicate that extended, localized delivery of FK506 to nerve injuries can improve nerve regeneration outcomes in a mouse sciatic nerve transection and repair.