Cutaneous innervation in impaired diabetic wound healing.

Type 2 diabetes is associated with several potential comorbidities, among them impaired wound healing, chronic ulcerations, and the requirement for lower extremity amputation. Disease-associated abnormal cellular responses, infection, immunological and microvascular dysfunction, and peripheral neuropathy are implicated in the pathogenesis of the wound healing impairment and the diabetic foot ulcer. The skin houses a dense network of sensory nerve afferents and nerve-derived modulators, which communicate with epidermal keratinocytes and dermal fibroblasts bidirectionally to effect normal wound healing after trauma. However, the mechanisms through which cutaneous innervation modulates wound healing are poorly understood, especially in humans. Better understanding of these mechanisms may provide the basis for targeted treatments for chronic diabetic wounds. This review provides an overview of wound healing pathophysiology with a focus on neural involvement in normal and diabetic wound healing, as well as future therapeutic perspectives to address the unmet needs of diabetic patients with chronic wounds.

Functional recovery after peripheral nerve injury via sustained growth factor delivery from mineral-coated microparticles.

The gold standard for treating peripheral nerve injuries that have large nerve gaps where the nerves cannot be directly sutured back together because it creates tension on the nerve, is to incorporate an autologous nerve graft. However, even with the incorporation of a nerve graft, generally patients only regain a small portion of function in limbs affected by the injury. Although, there has been some promising results using growth factors to induce more axon growth through the nerve graft, many of these previous therapies are limited in their ability to release growth factors in a sustained manner and tailor them to a desired time frame. The ideal drug delivery platform would deliver growth factors at therapeutic levels for enough time to grow axons the entire length of the nerve graft. We hypothesized that mineral coated microparticles (MCMs) would bind, stabilize and release biologically active glial cell-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) in a sustained manner. Therefore, the objective of this study was to test the ability of MCMs releasing growth factors at the distal end of a 10 mm sciatic nerve graft, to induce axon growth through the nerve graft and restore hind limb function. After sciatic nerve grafting in Lewis rats, the hind limb function was tested weekly by measuring the angle of the ankle at toe lift-off while walking down a track. Twelve weeks after grafting, the grafts were harvested and myelinated axons were analyzed proximal to the graft, in the center of the graft, and distal to the graft. Under physiological conditions in vitro, the MCMs delivered a burst release of NGF and GDNF for 3 days followed by a sustained release for at least 22 days. In vivo, MCMs releasing NGF and GDNF at the distal end of sciatic nerve grafts resulted in significantly more myelinated axons extending distal to the graft when compared to rats that received nerve grafts without growth factor treatment. The rats with nerve grafts incorporated with MCMs releasing NGF and GDNF also showed significant improvement in hind limb function starting at 7 weeks postoperatively and continuing through 12 weeks postoperatively when compared to rats that received nerve grafts without growth factor treatment. In conclusion, MCMs released biologically active NGF and GDNF in a sustained manner, which significantly enhanced axon growth resulting in a significant improvement of hind limb function in rats. The animal experiments were approved by University of Wisconsin-Madison Animal Care and Use Committee (ACUC, protocol# M5958) on January 3, 2018.