No abstract

In diabetes-associated chronic wounds, the normal response to hypoxia is impaired and many cellular processes involved in wound healing are hindered. Central to the hypoxia response is hypoxia-inducible factor-1α (HIF-1α), which activates multiple factors that enhance wound healing by promoting cellular motility and proliferation, new vessel formation, and re-epithelialization. Prolyl hydroxylase domain-containing protein 2 (PHD2) regulates HIF-1α activity by targeting it for degradation under normoxia. HIF-1α also upregulates microRNA miR-210, which in turn regulates proteins involved in cell cycle control, DNA repair, and mitochondrial respiration in ways that are antagonistic to wound repair. We have identified a highly potent short synthetic hairpin RNA (sshRNA) that inhibits expression of PHD2 and an antisense oligonucleotide (antimiR) that inhibits miR-210. Both oligonucleotides were chemically modified for improved biostability and to mitigate potential immunostimulatory effects. Using the sshRNA to silence PHD2 transcripts stabilizes HIF-1α and, in combination with the antimiR targeting miR-210, increases proliferation and migration of keratinocytes in vitro. To assess activity and delivery in an impaired wound healing model in diabetic mice, PHD2-targeting sshRNAs and miR-210 antimiRs both alone and in combination were formulated for local delivery to wounds using layer-by-layer (LbL) technology. LbL nanofabrication was applied to incorporate sshRNA into a thin polymer coating on a Tegaderm mesh. This coating gradually degrades under physiological conditions, releasing sshRNA and antimiR for sustained cellular uptake. Formulated treatments were applied directly to splinted full-thickness excisional wounds in db/db mice. Cellular uptake was confirmed using fluorescent sshRNA. Wounds treated with a single application of PHD2 sshRNA or antimiR-210 closed 4 days faster than untreated wounds, and wounds treated with both oligonucleotides closed on average 4.75 days faster. Markers for neovascularization and cell proliferation (CD31 and Ki67, respectively) were increased in the wound area following treatment, and vascular endothelial growth factor (VEGF) was increased in sshRNA-treated wounds. Our results suggest that silencing of PHD2 and miR-210 either together or separately by localized delivery of sshRNAs and antimiRs is a promising approach for the treatment of chronic wounds, with the potential for rapid clinical translation.

Significance: Hypertrophic scars, keloids, and burn injuries of the skin have a significant impact on patients' lives and impact the health care system tremendously. Treating skin wounds and lesions can be challenging, with a variety of choices available for treatment. Scar and burn managements range from invasive, surgical options such as scar excision to less invasive, nonsurgical alternatives such as laser therapy or topical drug application. Recent Advances: Laser treatment has become increasingly popular, with a growing body of research supporting its use for scars and burns. Numerous methods are available for the treatment of these skin diseases, including different nonsurgical laser therapies. Critical Issues: To date, the optimal treatment method for scars, keloids, and burn injuries of the skin has not yet been established, although it is an area of increasing clinical concern. Future Directions: This review provides an updated summary of the treatment of scars and burn wounds of the skin using different laser treatments, including the most recent technologies. It addresses their indications, mechanisms of action, differences, efficacies, and complications.

Chronic wounds are a significant medical and economic problem worldwide. Individuals over the age of 65 are particularly vulnerable to pressure ulcers and impaired wound healing. With this demographic growing rapidly, there is a need for effective treatments. We have previously demonstrated that defective hypoxia signaling through destabilization of the master hypoxia-inducible factor 1α (HIF-1α) underlies impairments in both aging and diabetic wound healing. To stabilize HIF-1α, we developed a transdermal delivery system of the Food and Drug Administration-approved small molecule deferoxamine (DFO) and found that transdermal DFO could both prevent and treat ulcers in diabetic mice. Here, we demonstrate that transdermal DFO can similarly prevent pressure ulcers and normalize aged wound healing. Enhanced wound healing by DFO is brought about by stabilization of HIF-1α and improvements in neovascularization. Transdermal DFO can be rapidly translated into the clinic and may represent a new approach to prevent and treat pressure ulcers in aged patients.

Summary: Resection of large mandibular tumors followed by primary reconstruction using free tissue transfer is typically accomplished using transcutaneous cervical incisions, which provide access for ablation as well as inset of the osseous free flap. This approach offers wide exposure; however, it subjects the patient to potential facial scarring, marginal mandibular nerve injury, lip deformity/incompetence, formation of orocutaneous fistulae, as well as functional impairments to speech, mastication, and deglutition. To reduce morbidity and to preserve aesthetics, a transoral approach can be used in cases that do not require a neck dissection. This technique can be coupled with transoral dissection of the facial vessels for intraoral microanastomoses to avoid extraoral incisions altogether. We present a case of a large 17.2 cm subtotal mandibulectomy and 3-segment fibular free flap reconstruction using virtual surgical planning, with patient-specific cutting guides and reconstruction plate performed entirely transorally without any skin incisions. Although technically challenging, this is a safe and effective technique for large segmental mandibular defects, which provides superior cosmetic and functional outcomes.