Transdermal drug delivery via microneedles to mediate wound microenvironment.

Due to local overactive inflammatory response and impaired angiogenesis, current treatments for diabetic wounds remain unsatisfactory. M2 macrophage-derived exosomes (MEs) have shown considerable potential in biomedical applications, especially since they have anti-inflammatory properties that modulate macrophage phenotypes. However, exosome-based strategies still have limitations, such as short half-lives and instability. Herein, we develop a double-layer microneedle-based wound dressing system (MEs@PMN) by encapsulating MEs in the needle tips and polydopamine (PDA) nanoparticles in backing layer to simultaneously suppress inflammation and improve angiogenesis at the wound site. In vitro, released MEs increased macrophage polarization towards the M2 phenotype. In addition, mild heat (40 ​°C) generated by the photosensitive PMN backing layer contributed to improved angiogenesis. More importantly, MEs@PMN also showed promising effects in diabetic rats. The uncontrolled inflammatory response at the wound site was inhibited by MEs@PMN during a 14-day period; in addition, MEs and the photothermal effects produced by PMN provided a combined proangiogenic effect by improving the expression of CD31 and vWF. Collectively, this study provides a simple and efficient cell-free strategy for suppressing inflammation and promoting vascular regeneration to treat diabetic wounds. 

https://doi.org/10.1016/j.mtbio.2023.100649

M2 macrophage-derived exosome-encapsulated microneedles with mild photothermal therapy for accelerated diabetic wound healing

Injuries to our skin trigger a cascade of spatially- and temporally-synchronized healing processes. During such endogenous wound repair, the role of fibroblasts is multifaceted, ranging from the activation and recruitment of innate immune cells through the synthesis and deposition of scar tissue to the conveyor belt-like transport of fascial connective tissue into wounds. A comprehensive understanding of fibroblast diversity and versatility in the healing machinery may help to decipher wound pathologies whilst laying the foundation for novel treatment modalities. In this review, we portray the diversity of fibroblasts and delineate their unique wound healing functions. In addition, we discuss future directions through a clinical-translational lens.

Fibroblasts – the cellular choreographers of wound healing

Abstract Even with many advances in design strategies over the past three decades, an enormous gap remains between existing tissue engineering skin and natural skin. Currently available in vitro skin models still cannot replicate the three-dimensionality and heterogeneity of the dermal microenvironment sufficiently to recapitulate many of the known characteristics of skin disorder or disease in vivo. Three-dimensional (3D) bioprinting enables precise control over multiple compositions, spatial distributions and architectural complexity, therefore offering hope for filling the gap of structure and function between natural and artificial skin. Our understanding of wound healing process and skin disease would thus be boosted by the development of in vitro models that could more completely capture the heterogeneous features of skin biology. Here, we provide an overview of recent advances in 3D skin bioprinting, as well as design concepts of cells and bioinks suitable for the bioprinting process. We focus on the applications of this technology for engineering physiological or pathological skin model, focusing more specifically on the function of skin appendages and vasculature. We conclude with current challenges and the technical perspective for further development of 3D skin bioprinting.

/pdf/advances-in-3d-skin-bioprinting-for-wound-healing-and-3ow17i6k.pdf

Advances in 3D skin bioprinting for wound healing and disease modeling

Abstract Inflammatory skin disorders can cause chronic scarring and functional impairments, posing a significant burden on patients and the healthcare system. Conventional therapies, such as corticosteroids and nonsteroidal anti-inflammatory drugs, are limited in efficacy and associated with adverse effects. Recently, nanozyme (NZ)-based hydrogels have shown great promise in addressing these challenges. NZ-based hydrogels possess unique therapeutic abilities by combining the therapeutic benefits of redox nanomaterials with enzymatic activity and the water-retaining capacity of hydrogels. The multifaceted therapeutic effects of these hydrogels include scavenging reactive oxygen species and other inflammatory mediators modulating immune responses toward a pro-regenerative environment and enhancing regenerative potential by triggering cell migration and differentiation. This review highlights the current state of the art in NZ-engineered hydrogels (NZ@hydrogels) for anti-inflammatory and skin regeneration applications. It also discusses the underlying chemo-mechano-biological mechanisms behind their effectiveness. Additionally, the challenges and future directions in this ground, particularly their clinical translation, are addressed. The insights provided in this review can aid in the design and engineering of novel NZ-based hydrogels, offering new possibilities for targeted and personalized skin-care therapies. 

Nanozyme-Engineered Hydrogels for Anti-Inflammation and Skin Regeneration

Wound healing is a dynamic and highly regulated process that can be separated into three overlapping and interdependent phases: inflammation, proliferation, and remodelling. This review focuses on the inflammation stage, as it is the key stage of wound healing and plays a vital role in the local immune response and determines the progression of wound healing. Inflammatory cells, the main effector cells of the inflammatory response, have been widely studied, but little attention has been paid to the immunomodulatory effects of wound healing in non-inflammatory cells and the extracellular matrix. In this review, we attempt to deepen our understanding of the wound-healing microenvironment in the inflammatory stage by focusing on the interactions between cells and the extracellular matrix, as well as their role in regulating the immune response during the inflammatory stage. We hope our findings will provide new ideas for promoting tissue regeneration through immune regulation.

/pdf/inflammatory-microenvironment-of-skin-wounds-3dmp6yx8.pdf

Inflammatory Microenvironment of Skin Wounds

Abstract Background Schwann cell-like cells (SCLCs), differentiated from mesenchymal stem cells, have shown promising outcomes in the treatment of peripheral nerve injuries in preclinical studies. However, certain clinical obstacles limit their application. Hence, the primary aim of this study was to investigate the role of exosomes derived from SCLCs (SCLCs-exo) in peripheral nerve regeneration. Methods SCLCs were differentiated from human amniotic mesenchymal stem cells (hAMSCs) in vitro and validated by immunofluorescence, real-time quantitative PCR and western blot analysis. Exosomes derived from hAMSCs (hAMSCs-exo) and SCLCs were isolated by ultracentrifugation and validated by nanoparticle tracking analysis, WB analysis and electron microscopy. A prefabricated nerve graft was used to deliver hAMSCs-exo or SCLCs-exo in an injured sciatic nerve rat model. The effects of hAMSCs-exo or SCLCs-exo on rat peripheral nerve injury (PNI) regeneration were determined based on the recovery of neurological function and histomorphometric variation. The effects of hAMSCs-exo or SCLCs-exo on Schwann cells were also determined via cell proliferation and migration assessment. Results SCLCs significantly expressed the Schwann cell markers glial fibrillary acidic protein and S100. Compared to hAMSCs-exo, SCLCs-exo significantly enhanced motor function recovery, attenuated gastrocnemius muscle atrophy and facilitated axonal regrowth, myelin formation and angiogenesis in the rat model. Furthermore, hAMSCs-exo and SCLCs-exo were efficiently absorbed by Schwann cells. However, compared to hAMSCs-exo, SCLCs-exo significantly promoted the proliferation and migration of Schwann cells. SCLCs-exo also significantly upregulated the expression of a glial cell-derived neurotrophic factor, myelin positive regulators (SRY-box transcription factor 10, early growth response protein 2 and organic cation/carnitine transporter 6) and myelin proteins (myelin basic protein and myelin protein zero) in Schwann cells. Conclusions These findings suggest that SCLCs-exo can more efficiently promote PNI regeneration than hAMSCs-exo and are a potentially novel therapeutic approach for treating PNI.

Neural grafts containing exosomes derived from Schwann cell-like cells promote peripheral nerve regeneration in rats

Abstract Complete wound regeneration preserves skin structure and physiological functions, including sensation and perception of stimuli, whereas incomplete wound regeneration results in fibrosis and scarring. Amniotic fluid stem cells (AFSCs) would be a kind of cell population with self-renewing and non-immunogenic ability that have a considerable role in wound generation. They are easy to harvest, culture, and store; moreover, they are non-tumorigenic and not subject to ethical restrictions. They can differentiate into different kinds of cells that replenish the skin, subcutaneous tissues, and accessory organs. Additionally, AFSCs independently produce paracrine effectors and secrete them in exosomes, thereby modulating local immune cell activity. They demonstrate anti-inflammatory and immunomodulatory properties, regulate the physicochemical microenvironment of the wound, and promote full wound regeneration. Thus, AFSCs are potential resources in stem cell therapy, especially in scar-free wound healing. This review describes the biological characteristics and clinical applications of AFSCs in treating wounds and provide new ideas for the treatment of wound healing.

Applications of human amniotic fluid stem cells in wound healing

Pseudomonas aeruginosa is a widely distributed non-fermentative Gram-negative opportunistic pathogen that is often responsible for nosocomial infections. Gene interference is a potentially valuable tool for investigating essential genes in P. aeruginosa. To establish a gene interference platform in P. aeruginosa, CRISPR system was used with an inactive Cas9 protein. The CRISPR-dCas9 system was cloned into pHERD20T, a shuttle vector with arabinose inducible promoter, and was further modified to target a regulatory gene prtR that is essential for the viability of P. aeruginosa. Cells expressing the prtR-targeting CRISPR interference (CRISPRi) showed growth defect in an arabinose dose-dependent manner. A high-throughput RNA sequencing analysis of bacterial cells with or without the CRISPRi-mediated prtR inhibition indicated that prtRis a global regulator affecting multiple biological processes. In conclusion, the CRISPR-dCas9-based gene knockdown system has been successfully implemented in P. aeruginosa and demonstrated to be an effective tool in the investigation of essential or difficult-to-inactivate genes in this species.

CRISPR-dCas9-mediated knockdown of prtR, an essential gene in Pseudomonas aeruginosa

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Papers

Inflammatory Microenvironment of Skin Wounds

Neural grafts containing exosomes derived from Schwann cell-like cells promote peripheral nerve regeneration in rats

Applications of human amniotic fluid stem cells in wound healing

CRISPR-dCas9-mediated knockdown of prtR, an essential gene in Pseudomonas aeruginosa