Immunosuppressive microparticles for allogeneic transplantation in nerve repair.

Peripheral nerve damage affects millions of people each year, possibly resulting in long-term functional deficits and chronic pain. Severe nerve injury is largely treated with autologous grafting, which produces donor site morbidity and has limited supply. Although cell therapies and living allografts are promising alternatives, their clinical translation is hampered in part due to their immunogenicity. Local delivery of immunosuppressants via controlled-release microparticles could protect both allografts and cellular constructs, while potentially avoiding the detrimental effects of systemically administered immunosuppressants. To produce immunosuppressant-loaded engineered nerve grafts, tacrolimus-loaded microparticles were encapsulated into Schwann cell-laden Engineered Neural Tissue (EngNT) constructs. We investigated cell viability and alignment, then used these constructs to repair 10 mm nerve defects in major histocompatibility complex (MHC) mismatched rats. Schwann cell viability and alignment in EngNT remained robust in the presence of the microparticles, although CD4+ and CD8+ T cell infiltration into the grafts was not significantly reduced by the tacrolimus-loaded material. To produce immunosuppressant-coated nerve allografts, tacrolimus microparticles were incorporated into alginate to form a coating. We studied the mechanical behaviour of native and coated nerve grafts, then implanted these grafts in 25 mm nerve defects in MHC-I and II mismatched rats. The coating did not significantly alter tensile nerve stiffness, and we observed a significant reduction in CD8+ T cell infiltration into the allografts with a tacrolimus-loaded microparticle coating. These findings demonstrate the feasibility of preparing allogeneic nerve grafts pre-loaded with local immunosuppressant and the potential for these biomaterials to locally modulate the immune response, enhancing the translational potential for allogeneic grafting in nerve repair.