Donahue, Seth W.

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

ABSTRACTIntracortical bone remodeling is persistent throughout life, leading to age related increases in osteon population density (OPD). Intracortical porosity also increases with age in many mammals including humans, contributing to bone fragility and fracture risk. Unbalanced bone resorption and formation during disuse (e.g., physical inactivity) also increases intracortical porosity. In contrast, hibernating bears are a naturally occurring model for the prevention of both age‐related and disuse osteoporoses. Intracortical bone remodeling is decreased during hibernation, but resorption and formation remain balanced. Black bears spend 0.25–7 months in hibernation annually depending on climate and food availability. We found longer hibernating bears demonstrate lower OPD and higher cortical bone mineralization than bears with shorter hibernation durations, but we surprisingly found longer hibernating bears had higher intracortical porosity. However, bears from three different latitudes showed age‐related decreases in intracortical porosity, indicating that regardless of hibernation duration, black bears do not show the disuse‐ or age‐related increases in intracortical porosity which is typical of other animals. This ability to prevent increases in intracortical porosity likely contributes to their ability to maintain bone strength during prolonged periods of physical inactivity and throughout life. Improving our understanding of the unique bone metabolism in hibernating bears will potentially increase our ability to develop treatments for age‐ and disuse‐related osteoporoses in humans. Anat Rec, 2013. © 2013 Wiley Periodicals, Inc.

SUMMARY Lack of activity causes bone loss In most animals. Hibernating bears have physiological processes to prevent cortical and trabecular bone loss associated with reduced physical activity, but different mechanisms of torpor among hibernating species may lead to differences in skeletal responses to hibernation. There are conflicting reports regarding whether small mammals experience bone loss during hibernation. To investigate this phenomenon, we measured cortical and trabecular bone properties in physically active and hibernating juvenile and adult 13-lined ground squirrels (Ictidomys tridecemlineatus, previous genus name Spermophilus). Cortical bone geometry, strength and mineral content were similar in hibernating compared with active squirrels, suggesting that hibernation did not cause macrostructural cortical bone loss. Osteocyte lacunar size increased (linear regression, P=0.001) over the course of hibernation in juvenile squirrels, which may indicate an osteocytic role in mineral homeostasis during hibernation. Osteocyte lacunar density and porosity were greater (+44 and +59%, respectively; P<0.0001) in hibernating compared with active squirrels, which may reflect a decrease in osteoblastic activity (per cell) during hibernation. Trabecular bone volume fraction in the proximal tibia was decreased (–20%; P=0.028) in hibernating compared with physically active adult squirrels, but was not different between hibernating and active juvenile squirrels. Taken together, these data suggest that 13-lined ground squirrels may be unable to prevent microstructural losses of cortical and trabecular bone during hibernation, but importantly may possess a biological mechanism to preserve cortical bone macrostructure and strength during hibernation, thus preventing an increased risk of bone fracture during remobilization in the spring.