Skin is innervated by a multitude of sensory nerves that are important to the function of this barrier tissue in homeostasis and injury. The role of innervation and neuromediators has been previously reviewed so here we focus on the role of the transient receptor potential cation channel, subfamily V member 1 (TRPV1) in wound healing, with the intent of targeting it in treatment of non-healing wounds. TRPV1 structure and function as well as the outcomes of TRPV1-targeted therapies utilized in several diseases and tissues are summarized. In skin, keratinocytes, sebocytes, nociceptors, and several immune cells express TRPV1, making it an attractive focus area for treating wounds. Many intrinsic and extrinsic factors confound the function and targeting of TRPV1 and may lead to adverse or off-target effects. Therefore, a better understanding of what is known about the role of TRPV1 in skin and wound healing will inform future therapies to treat impaired and chronic wounds to improve healing.

Evaluating and tracking wound size is a fundamental metric for the wound assessment process. Good location and size estimates can enable proper diagnosis and effective treatment. Traditionally, laboratory wound healing studies include a collection of images at uniform time intervals exhibiting the wounded area and the healing process in the test animal, often a mouse. These images are then manually observed to determine key metrics —such as wound size progress— relevant to the study. However, this task is a time-consuming and laborious process. In addition, defining the wound edge could be subjective and can vary from one individual to another even among experts. Furthermore, as our understanding of the healing process grows, so does our need to efficiently and accurately track these key factors for high throughput (e.g., over large-scale and long-term experiments). Thus, in this study, we develop a deep learning-based image analysis pipeline that aims to intake non-uniform wound images and extract relevant information such as the location of interest, wound only image crops, and wound periphery size over-time metrics. In particular, our work focuses on images of wounded laboratory mice that are used widely for translationally relevant wound studies and leverages a commonly used ring-shaped splint present in most images to predict wound size. We apply the method to a dataset that was never meant to be quantified and, thus, presents many visual challenges. Additionally, the data set was not meant for training deep learning models and so is relatively small in size with only 256 images. We compare results to that of expert measurements and demonstrate preservation of information relevant to predicting wound closure despite variability from machine-to-expert and even expert-to-expert. The proposed system resulted in high fidelity results on unseen data with minimal human intervention. Furthermore, the pipeline estimates acceptable wound sizes when less than 50% of the images are missing reference objects.

Chronic wounds exhibit persistent inflammation with markedly delayed healing. The significant burden of chronic wounds, which are often resistant to standard therapy, prompts further research on novel therapies. Since the interleukin-17 family has been implicated as a group of proinflammatory cytokines in immune-mediated diseases in the gut and connective tissue, as well as inflammatory skin conditions, we consider here if it may contribute to the pathogenesis of chronic wounds. In this review, we discuss the interleukin-17 family’s signaling pathways and role in tissue repair. A PubMed review of the English literature on interleukin-17, wound healing, chronic wounds, and inflammatory skin conditions was conducted. Interleukin-17 family signaling is reviewed in the context of tissue repair, and preclinical and clinical studies examining its role in the skin and other organ systems are critically reviewed. The published work supports a pathologic role for interleukin-17 family members in chronic wounds, though this needs to be more conclusively proven. Clinical studies using monoclonal interleukin-17 antibodies to improve healing of chronic skin wounds have not yet been performed, and only a few studies have examined interleukin-17 family expression in chronic skin wounds. Furthermore, different interleukin-17 family members could be playing selective roles in the repair process. These studies suggest a therapeutic role for targeting interleukin-17A to promote wound healing; therefore, interleukin-17A may be a target worthy of pursuing in the near future.

Diabetic foot ulcers are a major health care concern with limited effective therapies. Mesenchymal stem cell (MSC)‐based therapies are promising treatment options due to their beneficial effects of immunomodulation, angiogenesis, and other paracrine effects. We investigated whether a bioengineered scaffold device containing hypoxia‐preconditioned, allogeneic human MSCs combined with the beta‐adrenergic antagonist timolol could improve impaired wound healing in diabetic mice. Different iterations were tested to optimize the primary wound outcome, which was percent of wound epithelialization. MSC preconditioned in 1 μM timolol at 1% oxygen (hypoxia) seeded at a density of 2.5 × 10⁵ cells/cm² on Integra Matrix Wound Scaffold (MSC/T/H/S) applied to wounds and combined with daily topical timolol applications at 2.9 mM resulted in optimal wound epithelialization 65.6% (24.9% ± 13.0% with MSC/T/H/S vs 41.2% ± 20.1%, in control). Systemic absorption of timolol was below the HPLC limit of quantification, suggesting that with the 7‐day treatment, accumulative steady‐state timolol concentration is minimal. In the early inflammation stage of healing, the MSC/T/H/S treatment increased CCL2 expression, lowered the pro‐inflammatory cytokines IL‐1B and IL6 levels, decreased neutrophils by 44.8%, and shifted the macrophage ratio of M2/M1 to 1.9 in the wound, demonstrating an anti‐inflammatory benefit. Importantly, expression of the endothelial marker CD31 was increased by 2.5‐fold with this treatment. Overall, the combination device successfully improved wound healing and reduced the wound inflammatory response in the diabetic mouse model, suggesting that it could be translated to a therapy for patients with diabetic chronic wounds.

Diabetic foot ulcers represent a significant source of morbidity in the U.S., with rapidly escalating costs to the health care system. Multiple pathophysiological disturbances converge to result in delayed epithelialization and persistent inflammation. Serotonin (5-hydroxytryptamine [5-HT]) and the selective serotonin reuptake inhibitor fluoxetine (FLX) have both been shown to have immunomodulatory effects. Here we extend their utility as a therapeutic alternative for nonhealing diabetic wounds by demonstrating their ability to interact with multiple pathways involved in wound healing. We show that topically applied FLX improves cutaneous wound healing in vivo. Mechanistically, we demonstrate that FLX not only increases keratinocyte migration but also shifts the local immune milieu toward a less inflammatory phenotype in vivo without altering behavior. By targeting the serotonin pathway in wound healing, we demonstrate the potential of repurposing FLX as a safe topical for the challenging clinical problem of diabetic wounds.