Wireless, closed-loop, smart bandage with integrated sensors and stimulators for advanced wound care and accelerated healing.

'Smart' bandages based on multimodal wearable devices could enable real-time physiological monitoring and active intervention to promote healing of chronic wounds. However, there has been limited development in incorporation of both sensors and stimulators for the current smart bandage technologies. Additionally, while adhesive electrodes are essential for robust signal transduction, detachment of existing adhesive dressings can lead to secondary damage to delicate wound tissues without switchable adhesion. Here we overcome these issues by developing a flexible bioelectronic system consisting of wirelessly powered, closed-loop sensing and stimulation circuits with skin-interfacing hydrogel electrodes capable of on-demand adhesion and detachment. In mice, we demonstrate that our wound care system can continuously monitor skin impedance and temperature and deliver electrical stimulation in response to the wound environment. Across preclinical wound models, the treatment group healed ~25% more rapidly and with ~50% enhancement in dermal remodeling compared with control. Further, we observed activation of proregenerative genes in monocyte and macrophage cell populations, which may enhance tissue regeneration, neovascularization and dermal recovery.

Disrupting mechanotransduction decreases fibrosis and contracture in split-thickness skin grafting.

Burns and other traumatic injuries represent a substantial biomedical burden. The current standard of care for deep injuries is autologous split-thickness skin grafting (STSG), which frequently results in contractures, abnormal pigmentation, and loss of biomechanical function. Currently, there are no effective therapies that can prevent fibrosis and contracture after STSG. Here, we have developed a clinically relevant porcine model of STSG and comprehensively characterized porcine cell populations involved in healing with single-cell resolution. We identified an up-regulation of proinflammatory and mechanotransduction signaling pathways in standard STSGs. Blocking mechanotransduction with a small-molecule focal adhesion kinase (FAK) inhibitor promoted healing, reduced contracture, mitigated scar formation, restored collagen architecture, and ultimately improved graft biomechanical properties. Acute mechanotransduction blockade up-regulated myeloid CXCL10-mediated anti-inflammation with decreased CXCL14-mediated myeloid and fibroblast recruitment. At later time points, mechanical signaling shifted fibroblasts toward profibrotic differentiation fates, and disruption of mechanotransduction modulated mesenchymal fibroblast differentiation states to block those responses, instead driving fibroblasts toward proregenerative, adipogenic states similar to unwounded skin. We then confirmed these two diverging fibroblast transcriptional trajectories in human skin, human scar, and a three-dimensional organotypic model of human skin. Together, pharmacological blockade of mechanotransduction markedly improved large animal healing after STSG by promoting both early, anti-inflammatory and late, regenerative transcriptional programs, resulting in healed tissue similar to unwounded skin. FAK inhibition could therefore supplement the current standard of care for traumatic and burn injuries.

Pullulan-Collagen hydrogel wound dressing promotes dermal remodelling and wound healing compared to commercially available collagen dressings.

Biological scaffolds such as hydrogels provide an ideal, physio-mimetic of native extracellular matrix (ECM) that can improve wound healing outcomes after cutaneous injury. While most studies have focused on the benefits of hydrogels in accelerating wound healing, there are minimal data directly comparing different hydrogel material compositions. In this study, we utilized a splinted excisional wound model that recapitulates human-like wound healing in mice and treated wounds with three different collagen hydrogel dressings. We assessed the feasibility of applying each dressing and performed histologic and histopathologic analysis on the explanted scar tissues to assess variations in collagen architecture and alignment, as well as the tissue response. Our data indicate that the material properties of hydrogel dressings can significantly influence healing time, cellular response, and resulting architecture of healed scars. Specifically, our pullulan-collagen hydrogel dressing accelerated wound closure and promoted healed tissue with less dense, more randomly aligned, and shorter collagen fibres. Further understanding of how hydrogel properties affect the healing and resulting scar architecture of wounds may lead to novel insights and further optimization of the material properties of wound dressings.

Inhibiting Fibroblast Mechanotransduction Modulates Severity of Idiopathic Pulmonary Fibrosis.

Objective: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that affects 63 in every 100,000 Americans. Its etiology remains unknown, although inflammatory pathways appear to be important. Given the dynamic environment of the lung, we examined the significance of mechanotransduction on both inflammatory and fibrotic signaling during IPF. Innovation: Mechanotransduction pathways have not been thoroughly examined in the context of lung disease, and pharmacologic approaches for IPF do not currently target these pathways. The interplay between mechanical strain and inflammation in pulmonary fibrosis remains incompletely understood. Approach: In this study, we used conditional KO mice to block mechanotransduction by knocking out Focal Adhesion Kinase (FAK) expression in fibroblasts, followed by induction of pulmonary fibrosis using bleomycin. We examined both normal human and human IPF fibroblasts and used immunohistochemistry, quantitative real-time polymerase chain reaction, and Western Blot to evaluate the effects of FAK inhibitor (FAK-I) on modulating fibrotic and inflammatory genes. Results: Our data indicate that the deletion of FAK in mice reduces expression of fibrotic and inflammatory genes in lungs. Similarly, mechanical straining in normal human lung fibroblasts activates inflammatory and fibrotic pathways. The FAK inhibition decreases these signals but has a less effect on IPF fibroblasts as compared with normal human fibroblasts. Conclusion: Administering FAK-I at early stages of fibrosis may attenuate the FAK-mediated fibrotic response pathway in IPF, potentially mediating disease progression.

Xenogeneic skin transplantation promotes angiogenesis and tissue regeneration through activated Trem2+ macrophages.

Skin allo- and xenotransplantation are the standard treatment for major burns when donor sites for autografts are not available. The relationship between the immune response to foreign grafts and their impact on wound healing has not been fully elucidated. Here, we investigated changes in collagen architecture after xenogeneic implantation of human biologic scaffolds. We show that collagen deposition in response to the implantation of human split-thickness skin grafts (hSTSGs) containing live cells recapitulates normal skin architecture, whereas human acellular dermal matrix (ADM) grafts led to a fibrotic collagen deposition. We show that macrophage differentiation in response to hSTSG implantation is driven toward regenerative Trem2+ subpopulations and found that hydrogel delivery of these cells significantly accelerated wound closure. Our study identifies the preclinical therapeutic potential of Trem2+ macrophages to mitigate fibrosis and promote wound healing, providing a novel effective strategy to develop advanced cell therapies for complex wounds.