Melt Electrowritten Scaffold-Reinforced Affibody-Conjugated Hydrogels for Controlled Bone Morphogenetic Protein-2 Delivery

Abstract Bone morphogenetic protein-2 (BMP-2) is clinically used to promote bone regeneration but suffers from uncontrolled release when delivered from collagen sponges, necessitating high doses that can cause adverse effects. Hydrogels offer tunable protein release but are limited by weak mechanics and poor stability during storage and handling. Here, we introduce a two-part protein delivery platform that integrates mechanical reinforcement with affinity-controlled protein release. We developed a melt electrowritten (MEW) scaffold–reinforced, affibody-conjugated polyethylene glycol maleimide (PEG-mal) hydrogel for affinity-controlled BMP-2 delivery. MEW scaffolds improved hydrogel handling, compressive resistance, and stability during lyophilization and rehydration, without altering bulk stiffness. Engineered BMP-2-specific affibodies provided affinity-based control over BMP-2 release. This ability to control BMP-2 release was preserved after lyophilization and rehydration of the hydrogels. In vivo, affibody conjugation of high-affinity affibodies to the hydrogels significantly enhanced BMP-2 retention in subcutaneous implants, while MEW reinforcement significantly increased bone volume and defect bridging in rat femoral bone defects. This affibody-conjugated, MEW scaffold-reinforced hydrogel system effectively integrates mechanical reinforcement with tunable protein-material affinity interactions, advancing hydrogel-based delivery strategies for BMP-2 and other protein therapeutics in musculoskeletal repair. Competing Interest Statement J.D. and M.H.H. are authors on a pending patent application encompassing some of this work (U.S. Patent Application No. 18/340,754). Footnotes This version of the manuscript has been revised to address reviewer comments, including new methods, results, and figures.