Zhao, Yichao

Abstract Immune reactions to medical implants often lead to encapsulation by fibrotic tissue and impaired device function. This process is thought to initiate by protein adsorption, which enables immune cells to attach and mount an inflammatory response. Previously, several antifibrotic materials have been either designed to reduce protein adsorption or discovered via high‐throughput screens (HTS) to favorably regulate inflammation. The present work introduces antifouling immunomodulatory (AIM) copolymer coatings, which combine both strategies to effectively enhance implant protection. AIM copolymers synergistically integrate zwitterionic moieties to resist protein fouling, HTS‐derived antifibrotics for immunomodulation, and silane monomers for grafting to diverse substrates including elastomers, ceramics, and metals. Interestingly, simply combining these monomers into conventional random or block copolymer architectures yielded no significant advantage over homopolymers. By contrast, an unusual polymer chain architecture — a zwitterionic block flanked by a mixed zwitterionic immunomodulatory segment — showed superior fibrosis resistance in both peritoneal and subcutaneous sites over one month in immunocompetent mice. This architecture also improved the performance of two different HTS‐derived antifibrotic monomers, suggesting that tailoring AIM architectures may broadly complement immunomodulatory chemistries and provide a versatile approach to improving implant longevity.

The transplantation of engineered cells that secrete therapeutic proteins presents a promising method for addressing a range of chronic diseases. However, hydrogels used to encase and protect non-autologous cells from immune rejection often suffer from poor mechanical properties, insufficient oxygenation, and fibrotic encapsulation. Here, we introduce a composite encapsulation system comprising an oxygen-permeable silicone cryogel skeleton, a hydrogel matrix, and a fibrosis-resistant polymer coating. Cryogel skeletons enhance the fracture toughness of conventional alginate hydrogels by 23-fold and oxygen diffusion by 2.8-fold, effectively mitigating both implant fracture and hypoxia of encapsulated cells. Composite implants containing xenogeneic cells engineered to secrete erythropoietin significantly outperform unsupported alginate implants in therapeutic delivery over 8 weeks in immunocompetent mice. By improving mechanical resiliency and sustaining denser cell populations, silicone cryogel skeletons enable more durable and miniaturized therapeutic implants.