Remolding Microenvironmental Homeostasis for Enhancing Regenerative Hypertrophic Scar Treatment Based on Functionalized Microneedles

Abstract

Hypertrophic scar (HS) is a common pathological fibrous hyperplasia with high incidence and recurrence rates. The limited understanding of the pathological characteristics of HS restricts the therapeutic efficacy of current strategies. In this study, we first identified the elevated mitophagy and suppressed apoptosis in hypertrophic scar fibroblasts (HSFs), which combined with excess inflammation to constitute the pathological microenvironment of HS, driving us to develop a functionalized microneedle (MN) patch for inhibiting mitophagy, promoting apoptosis and modulating inflammation to adapt HS treatment. The MNs integrate curcumin-loaded HSFs-derived extracellular vesicles (Cur@EV) and a decellularized extracellular matrix from umbilical cord-derived mesenchymal stem cells (UC-MSCs-dECM, UdECM). The homologous Cur@EV with enhanced cellular uptake significantly induced HSFs apoptosis via mitophagy inhibition, meanwhile reducing collagen deposition. Meanwhile, the UdECM exerted immunomodulation capacity by facilitating the M2 polarization of macrophages, aiding in the suppression of HSFs. Notably, the Cur@EV/UdECM-functionalized MN patches exhibited regenerative therapeutic outcomes on a rabbit HS model, with HS inhibition and new hair follicle formation. Overall, this study presents a synergistic strategy based on the regulation of “mitophagy-apoptosis-inflammation,” offering a novel, minimally invasive approach for HS management. The integration of homologous Cur@EV and UdECM into an MN patch represents an innovative, multifunctional approach that combines mitophagy inhibition, apoptosis induction, and immunomodulation. The regenerative outcomes observed in the rabbit HS model, including hair follicle formation, further underscore the translational potential of this strategy. Future research will focus on optimizing patch design for scalable production, assessing long-term safety and efficacy, and exploring its broader applicability.