Injection site dictates the immune response to a biodegradable polymer and corresponding collagen regeneration

While the in vivo biocompatibility and efficacy of regenerative biomaterials are typically assessed using a subcutaneous (SC) implantation model, the profound impact of the implantation site's microenvironment is often overlooked, hindering the translational medicine of some new biomaterials. Here, we report that the injection location of a thermosensitive poly( D,L -lactide- co -glycolide)-poly(ethylene glycol)-poly( D,L -lactide- co -glycolide) hydrogel (T-gel) dictates tissue regeneration by spatiotemporally modulating local lactate accumulation and immune response in rats. Compared to SC injection, intradermal (ID) injection of T-gel significantly enhanced collagen generation, driven by a denser tissue architecture and more abundant stromal components. The compact ID niche intensified early cell–material interactions, triggering the release of damage-associated molecular patterns that activated resident macrophages via the TLRs–MyD88–NF-κB pathway, leading to amplified macrophage recruitment. Notably, T-gel underwent accelerated degradation in ID tissue, elevating local lactate levels, which concurrently promoted M2 macrophage polarization and directly stimulated fibroblast-mediated collagen biosynthesis. Our findings challenge the sole reliance on SC models for evaluating biomaterial efficacy and establish implantation site selection as a critical, yet underutilized, issue in regenerative strategy. This study highlights that the assessment of biomaterials for dermal regeneration and aesthetic applications must distinguish between ID and SC microenvironments, as they dictate different regenerative outcomes through distinct immunometabolic mechanisms.