An Off-the-Shelf Artificial Proregenerative Macrophage for Pressure Ulcer Treatment.

Abstract

Cell therapy is a promising approach in regenerative medicine. However, maintaining the survival and function of injected or implanted therapeutic cells remains a substantial challenge to success. In vivo modulatory strategy for cell therapeutics has been recently developed, but suffers from limited regenerative efficacy in injured tissue microenvironment with chronic inflammation. Here, an off-the-shelf artificial macrophage (artM) assembled by M2 macrophages-derived lysate proteins-loaded poly (lactic-co-glycolic acid) (PLGA) microspheres coated by macrophage cell membrane is developed. The synthetic artM fabricated in batches maintains its bioactivity with long-term cryostorage. Significantly, artM recapitulates the essential inflammation-regulatory and proregenerative characteristics of endogenous macrophages, including initiating M2 macrophage polarization, resolving excessive inflammation by releasing anti-inflammatory cytokines and growth factors, neutralizing endotoxins and proinflammatory cytokines, augmenting T-helper 2 (T2) immune response, and coordinating cell migration and proliferation. In mouse model of deep tissue pressure injury (DTPI), the artM induces tissue regeneration by modulating the inflammatory microenvironment, promoting angiogenesis, reducing scar deposition, and accelerating the renewal of skin appendages. Depletion of macrophages in mice with skin ulcers highlights the immunomodulatory and proangiogenic functions of artM as effective as autogenous macrophages. Collectively, the engineered artM represents a cell-free, proreparative alternative to immune cell therapy in chronic wound management.