Engineering therapeutic angiogenesis in impaired tissues is critical for chronic wound healing. Materials can be engineered to deliver specific biological cues that enhance angiogenesis. However, currently available materials have limitations for use in angiogenesis engineering since the complex inflammation environment of wounds requires spatiotemporal control. Immune cells are the central component of wound microenvironment and orchestrate immune responses to wound healing. This study presents a novel approach of using a delivery system comprising living Lactococcus, incorporated in a heparin‐poloxamer thermoresponsive hydrogel, designed to bioengineer the wound microenvironment and enhance the angiogenesis in a highly dynamic‐temporal manner. The living system can produce and protect vascular endothelial growth factor (VEGF) to increase proliferation, migration, and tube formation of endothelial cells, as well as secrete lactic acid to shift macrophages toward an anti‐inflammatory phenotype, resulting in successful angiogenesis in diabetic wounds. Further, the delivery system confines the bacterial population to wounds, thereby minimizing the risk of systemic toxicities. Therefore, this living hydrogel system can be harnessed for safe and efficient delivery of therapeutics that drive the wound microenvironment toward rapid healing and may serve as a promising scaffold in regenerative medicine.

Excessive extracellular matrix deposition drives fibroblasts into a state of high mechanical stress, exacerbating pathological fibrosis and hypertrophic scar formation, leading to tissue dysfunction. This study reports a minimally invasive and convenient approach to obtaining scarless tissue using a silk fibroin microneedle patch (SF MNs). We found that by tuning the MN size and density only, the biocompatible MNs significantly decreased the scar elevation index in the rabbit ear hypertrophic scar model and increased ultimate tensile strength close to regular skin. To advance our understanding of this recent approach, we built a fibroblast-populated collagen lattice system and finite element model to study MN-mediated cellular behavior of fibroblasts. We found that the MNs reduced the fibroblasts generated contraction and mechanical stress, as indicated by decreased expression of the mechanical sensitive gene ANKRD1. Specifically, SF MNs attenuated the integrin-FAK signaling and consequently down-regulated the expression of TGF-β1, α-SMA, collagen I, and fibronectin. It resulted in a low-stress microenvironment that helps to reduce scar formation significantly. Microneedles’ physical intervention via the mechanotherapeutic strategy is promising for scar-free wound healing.

Myocardial infarction (MI), as one of the leading causes of global death, urgently needs effective therapies. Recently, hydrogen sulfide (H 2 S) has been regarded as a promising therapeutic agent for MI, while its spatiotemporally controlled delivery remains a major issue limiting clinical translation. To address this limitation, we designed and synthesized a novel H 2 S donor (HSD-R) that can produce H 2 S and emit fluorescence in response to reactive oxygen species (ROS) highly expressed at diseased sites. HSD-R can specifically target mitochondria and provide red fluorescence to visualize and quantify H 2 S release in vitro and in vivo . Therapeutically, HSD-R significantly promoted the reconstruction of cardiac structure and function in a rat MI model. Mechanistically, myocardial protection is achieved by reducing cardiomyocyte apoptosis, attenuating local inflammation, and promoting angiogenesis. Furthermore, inhibition of typical pro-apoptotic genes (Bid, Apaf-1, and p53) played an important role in the anti-apoptotic effect of HSD-R to achieve cardioprotection, which were identified as new therapeutic targets of H 2 S against myocardial ischemia injury. This ROS-responsive, self-immolative, and fluorescent H 2 S donor can serve as a new theranostic agent for MI and other ischemic diseases.

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