Infection-driven proliferative phase impairment in chronic wounds: a mechanistic framework for precision regenerative therapy

Chronic wounds represent a major clinical challenge characterized by persistent failure of tissue repair, a phenomenon that cannot be fully explained by infection and inflammation alone. Emerging evidence indicates that wound-associated microbial communities establish stable pathogenic ecosystems that specifically disrupt the proliferative phase of healing, the critical stage responsible for cellular expansion, angiogenesis, and extracellular matrix reconstruction. Here, we propose the conceptual framework of infection-driven proliferative phase impairment (IDPPI), which describes a pathological state in chronic wounds wherein sustained microbial pathogenic activities continuously compromise host regenerative programs. We synthesize current evidence showing that coordinated virulence factor deployment, biofilm persistence, and host immune-metabolic dysregulation converge to induce proliferative arrest. They do so through direct cellular injury, suppression of repair-related signaling pathways, and disruption of cell-cycle control. This integrated pathogenic cascade ultimately locks wounds into a state of low-efficiency or arrested regeneration. Building on this mechanistic framework, we outline a sequential, targeted therapeutic paradigm encompassing three interconnected levels: targeted suppression of virulence and biofilm functions, restoration of immune-metabolic homeostasis within the wound microenvironment, and spatiotemporally controlled promotion of regeneration using responsive biomaterials and cell-free regenerative strategies. Rather than prioritizing non-selective microbial eradication, this approach emphasizes functional disarmament of pathogenic ecosystems and reactivation of host proliferative capacity. Finally, we discuss how advances in spatial multi-omics, biomimetic human-relevant models, artificial intelligence, and real-time sensing technologies can enable dynamic assessment and adaptive intervention, supporting a paradigm shift in chronic wound management from static staging toward feedback-guided (closed-loop), mechanism-informed regenerative medicine. IDPPI is presented as an integrative framework that reorders causality by placing infection-driven disruption of proliferative repair execution as the proximal failure mode.