Bone cements for treatment of fractures at weight-bearing sites are subjected to dynamic physiological loading from daily activities. An ideal bone cement rapidly sets after injection, exhibits bone-like strength, stimulates osteogenic differentiation of endogenous cells, and resorbs at a rate aligned with patient biology. However, currently available materials fall short of these targeted properties. Nanocrystalline hydroxyapatite (nHA) enhances osteogenic differentiation, new bone formation, and osteoclast differentiation activity compared to amorphous or micron-scale crystalline hydroxyapatite. However, the brittle mechanical properties of nHA precludes its use in treatment of weight-bearing bone defects. In this study, we report settable nHA-poly(ester urethane) (PEUR) nanocomposites synthesized from nHA, lysine triisocyanate (LTI), and poly(caprolactone) triol via a solvent-free process. The nanocomposites are easily mixed and injected using a double-barrel syringe, exhibit mechanical properties exceeding those of conventional bone cements, enhance mineralization of osteoprogenitor cells in vitro, and undergo osteoclast-mediated degradation in vitro. This combination of properties cannot be achieved using other technologies, which underscores the potential of nHA-PEUR nanocomposites as a new approach for promoting bone healing at weight-bearing sites.
Bone fractures at weight-bearing sites are challenging to treat due to the difficulty in maintaining articular congruency. An ideal biomaterial for fracture repair near articulating joints sets rapidly after implantation, stabilizes the fracture with minimal rigid implants, stimulates new bone formation, and remodels at a rate that maintains osseous integrity. Consequently, the design of biomaterials that mechanically stabilize fractures while remodeling to form new bone is an unmet challenge in bone tissue engineering. In this study, we investigated remodeling of resorbable bone cements in a stringent model of mechanically loaded tibial plateau defects in sheep. Nanocrystalline hydroxyapatite-poly(ester urethane) (nHA-PEUR) hybrid polymers were augmented with either ceramic granules (85% β-tricalcium phosphate/15% hydroxyapatite, CG) or a blend of CG and bioactive glass (BG) particles to form a settable bone cement. The initial compressive strength and fatigue properties of the cements were comparable to those of non-resorbable poly(methyl methacrylate) bone cement. In animals that tolerated the initial few weeks of early weight-bearing, CG/nHA-PEUR cements mechanically stabilized the tibial plateau defects and remodeled to form new bone at 16 weeks. In contrast, cements incorporating BG particles resorbed with fibrous tissue filling the defect. Furthermore, CG/nHA-PEUR cements remodeled significantly faster at the full weight-bearing tibial plateau site compared to the mechanically protected femoral condyle site in the same animal. These findings are the first to report a settable bone cement that remodels to form new bone while providing mechanical stability in a stringent large animal model of weight-bearing bone defects near an articulating joint.
Iliac crest autograft (AG) is the gold standard for bone grafting. Due to the limited supply of autograft, synthetic materials such as ceramics and polymers have been proposed as AG extenders to minimize the volume of AG required for induction of new bone formation. However, the feasibility of reactive polymers for use as settable AG extenders has not been previously investigated. In this study, a reactive oxygen species-degradable poly(thioketal urethane) (PTKUR) was evaluated as a settable AG extender. AG was anticipated to enhance infiltration of cells into the defect and induce new bone formation. Histological analysis of a preliminary study in a rat femoral segmental defect model showed that cells infiltrated PTKUR/AG implants at 4 weeks. In a second experiment, implantation into an intertransverse process model of bone formation showed bone remodeling from the superior and inferior transverse processes. Histological analysis combining data from stains and fluorochrome injections showed lamellar bone formation ongoing near the base of the transverse processes after 8 weeks. Similar findings were observed for a second group, in which 35% of the AG was replaced with calcium phosphate granules. These observations highlight the potential of PTKUR for use as a settable AG extender.
Resorbable bone cements are replaced by bone through osteoclastic resorption and osteoblastic new bone formation near the periphery. However, the ideal bone cement would be replaced by new bone through processes similar to fracture repair, which occurs by a variable combination of endochondral and intramembranous ossification. In this study, nanocrystalline hydroxyapatite (nHA)–poly(thioketal urethane) (PTKUR) cements were implanted in femoral defects in New Zealand White rabbits to evaluate ossification at 4, 12, and 18 months. Four formulations were tested: an injectable, flowable cement and three moldable putties with varying ratios of calcium phosphate to sucrose granules. New bone formation and resorption of the cement by osteoclasts occurred near the periphery. Stevenel’s Blue and Safranin O staining revealed infiltration of chondrocytes into the cements and ossification of the cartilaginous intermediate. These findings suggest that nHA–PTKUR cements support combined intramembranous and endochondral ossification, resulting in enhanced osseointegration of the cement that could potentially improve patient outcomes.
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