Marozas, Ian A.

Characterizing the release profile for materials-directed local delivery of bioactive molecules and its effect on bone regeneration is an important step to improve our understanding of, and ability to optimize, the bone healing response. This study examined the local delivery of parathyroid hormone (PTH) using a thiol-ene hydrogel embedded in a porous poly(propylene fumarate) (PPF) scaffold for bone regeneration applications. The aim of this study was to characterize the degradation-controlled in vitro release kinetics of PTH from the thiol-ene hydrogels, in vivo hydrogel degradation in a subcutaneous implant model, and bone healing in a rat critical size bone defect. Tethering PTH to the hydrogel matrix eliminated the early timepoint burst release that was observed in previous in vitro work where PTH was free to diffuse out of the matrix. Only 8% of the tethered PTH was released from the hydrogel during the first 2 weeks, but by day 21, 80% of the PTH was released, and complete release was achieved by day 28. In vivo implantation revealed that complete degradation of the hydrogel alone occurred by day 21; however, when incorporated in a three-dimensional printed osteoconductive PPF scaffold, the hydrogel persisted for >56 days. Treatment of bone defects with the composite thiol-ene hydrogel–PPF scaffold, delivering either 3 or 10 μg of tethered PTH 1-84, was found to increase bridging of critical size bone defects, whereas treatment with 30 μg of tethered PTH resulted in less bone ingrowth into the defect area. Continued development of this biomaterial delivery system for PTH could lead to improved therapies for treatment of nonunion fractures and critical size bone defects.

ABSTRACTNeither allograft nor commercially available bone graft substitutes provide the same quality of bone healing as autograft. Incorporation of bioactive molecules like parathyroid hormone (PTH) within bone graft substitute materials may provide similar, if not better treatment options to grafting. The goal of this work was to develop a biomaterial system for the local delivery of PTH to large bone defects for promoting bone regeneration. PTH was loaded in a thiol‐ene hydrogel at several concentrations and polymerized in and around an osteoconductive poly(propylene fumarate) (PPF) scaffold. PTH was shown to be bioactive when released from the hydrogel for up to 21 days. Eighty percent of the PTH was released by day 3 with the remaining 20% released by day 14. Bone healing was quantified in rat critical size femoral defects that were treated with hydrogel/PPF and 0, 1, 3, 10, or 30 µg of PTH. Although complete osseous healing was not observed in all samples in any one treatment group, all samples in the 10 µg PTH group were bridged fully by bone or a combination of bone and cartilage containing hypertrophic chondrocytes and endochondral ossification. Outcome measures indicated improved defect bridging by a combination of bony and cartilaginous tissue in the 10 μg treatment group compared with empty bone defects and defects treated with only hydrogel/PPF (i.e., without PTH). Given the tailorability of the hydrogel, future studies will investigate the effects of prolonged gradual PTH release on bone healing. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:536–544, 2020