Optimizing 3D-printed Scaffold Geometry Decreases Foreign Body Response and Enhances Allogeneic Islet Transplant Outcomes

Abstract Cellular therapy, such as beta cell transplantation for Type 1 diabetes, is a promising approach to durably alleviate disease states. Implanting cells within porous scaffolds is beneficial as they distribute the cells and mechanically support implantation; however, scaffolds can exacerbate foreign body responses (FBR). While the geometric features of a scaffold are known to impact FBR, there is limited consensus on what makes an ideal implant. Some have explored the role of pore size and interconnectivity; however, the impact of rung thickness between pores on FBR is broadly understudied. To investigate this parameter, we created a scaffold with reproducible geometric features and high biostability by combining 3D-printing with the polymer polydimethylsiloxane (PDMS). We tested 3D-printed scaffold prototypes with identical pore sizes but distinct PDMS rung thicknesses ranging from 150 to 300 µm. Upon transplantation, biocompatibility screening in a mouse model revealed that scaffolds with thicker PDMS rungs led to increased intra-device fibrosis. Additional spatio-proteomic analysis revealed distinct differences in host responses to rung changes, with alterations in macrophage and adaptive immune cell markers, as well as fibrotic proteins, within scaffolds containing thicker rungs. Selecting the optimized rung size, we evaluated its efficacy in rat syngeneic and allogeneic islet transplant models. In the allogeneic model, 3D-printed scaffold islet implants demonstrated robust efficacy and stability, yielding improved outcomes compared to PDMS scaffolds without optimized geometric features. Results from this study reveal how specific geometric scaffold features critically influence FBR to biomaterial implants, accelerating or mitigating fibrotic responses, and ultimately determining transplant success. Competing Interest Statement The authors have declared no competing interest.