Mice with a heterozygous Lrp6 deletion have impaired fracture healing.

Bone fracture non-unions, the failure of a fracture to heal, occur in 10%-20% of fractures and are a costly and debilitating clinical problem. The Wnt/ß-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 (LRP6), a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density. As fracture healing closely models embryonic skeletal development, we investigated the process of fracture healing in mice heterozygous for Lrp6 (Lrp6 (+/-)) and hypothesized that the heterozygous deletion of Lrp6 would impair fracture healing. Mid-diaphyseal femur fractures were induced in Lrp6 (+/-) mice and wild-type controls (Lrp6 (+/+)). Fractures were analyzed using micro-computed tomography (µCT) scans, biomechanical testing, and histological analysis. Lrp6 (+/-) mice had significantly decreased stiffness and strength at 28 days post fracture (PF) and significantly decreased BV/TV, total density, immature bone density, and mature area within the callus on day-14 and -21 PF; they had significantly increased empty callus area at days 14 and 21 PF. Our results demonstrate that the heterozygous deletion of Lrp6 impairs fracture healing, which suggests that Lrp6 has a role in fracture healing.

Biomechanical evaluation of fracture fixation constructs using a variable-angle locked periprosthetic femur plate system.

BACKGROUND: In the United States there are more than 230,000 total hip replacements annually, and periprosthetic femoral fractures occur in 0.1-4.5% of those patients. The majority of these fractures occur at the tip of the stem (Vancouver type B1). The purpose of this study was to compare the biomechanically stability and strength of three fixation constructs and identify the most desirable construct. METHODS: Fifteen medium adult synthetic femurs were implanted with a hip prosthesis and were osteotomized in an oblique plane at the level of the implant tip to simulate a Vancouver type B1 periprosthetic fracture. Fractures were fixed with a non-contact bridging periprosthetic proximal femur plate (Zimmer Inc., Warsaw, IN). Three proximal fixation methods were used: Group 1, bicortical screws; Group 2, unicortical screws and one cerclage cable; and Group 3, three cerclage cables. Distally, all groups had bicortical screws. Biomechanical testing was performed using an axial-torsional testing machine in three different loading modalities (axial compression, lateral bending, and torsional/sagittal bending), next in axial cyclic loading to 10,000 cycles, again in the three loading modalities, and finally to failure in torsional/sagittal bending. RESULTS: Group 1 had significantly greater load to failure and was significantly stiffer in torsional/sagittal bending than Groups 2 and 3. After cyclic loading, Group 2 had significantly greater axial stiffness than Groups 1 and 3. There was no difference between the three groups in lateral bending stiffness. The average energy absorbed during cyclic loading was significantly lower in Group 2 than in Groups 1 and 3. CONCLUSIONS: Bicortical screw placement achieved the highest load to failure and the highest torsional/sagittal bending stiffness. Additional unicortical screws improved axial stiffness when using cable fixation. Lateral bending was not influenced by differences in proximal fixation. CLINICAL RELEVANCE: To treat periprosthetic fractures, bicortical screw placement should be attempted to maximize load to failure and torsional/sagittal bending stiffness.

Mice lacking pten in osteoblasts have improved intramembranous and late endochondral fracture healing.

The failure of an osseous fracture to heal (development of a non-union) is a common and debilitating clinical problem. Mice lacking the tumor suppressor Pten in osteoblasts have dramatic and progressive increases in bone volume and density throughout life. Since fracture healing is a recapitulation of bone development, we investigated the process of fracture healing in mice lacking Pten in osteoblasts (Ocn-cre(tg/+;)Pten(flox/flox) ). Mid-diaphyseal femoral fractures induced in wild-type and Ocn-cre(tg/+;)Pten(flox/flox) mice were studied via micro-computed tomography (µCT) scans, biomechanical testing, histological and histomorphometric analysis, and protein expression analysis. Ocn-cre(tg/+;)Pten(flox/flox) mice had significantly stiffer and stronger intact bones relative to controls in all cohorts. They also had significantly stiffer healing bones at day 28 post-fracture (PF) and significantly stronger healing bones at days 14, 21, and 28 PF. At day 7 PF, the proximal and distal ends of the Pten mutant calluses were more ossified. By day 28 PF, Pten mutants had larger and more mineralized calluses. Pten mutants had improved intramembranous bone formation during healing originating from the periosteum. They also had improved endochondral bone formation later in the healing process, after mature osteoblasts are present in the callus. Our results indicate that the inhibition of Pten can improve fracture healing and that the local or short-term use of commercially available Pten-inhibiting agents may have clinical application for enhancing fracture healing.

Bilateral patellar component shear failure of highly cross-linked polyethylene components: report of a case and laboratory analysis of failure mechanisms.

A case of bilateral patellar component failure due to fatigue fracture of the all-polyethylene fixation pegs in a highly cross-linked ultra-high-molecular-weight polyethylene design is presented. To recreate this failure mode, a novel test method was developed to investigate the effects of peg orientation and cement technique on patella fatigue strength under cyclic compression and shear loading. Patellar peg orientation had a minor effect on shear strength, whereas lack of cement in the backside patellar groove had a substantial effect. The shear fatigue strength exceeded in vivo force estimates when the patellar groove was fully cemented. The test results and retrieval analysis suggest that high activity level and inadequate cement fixation of the patellar component may contribute to all-polyethylene patellar component peg fractures.

SOST and DKK: Antagonists of LRP Family Signaling as Targets for Treating Bone Disease.

The study of rare human genetic disorders has often led to some of the most significant advances in biomedical research. One such example was the body of work that resulted in the identification of the Low Density Lipoprotein-Related Protein (LRP5) as a key regulator of bone mass. Point mutations were identified that encoded forms of LRP5 associated with very high bone mass (HBM). HBM patients live to a normal age and do not appear to have increased susceptibility to carcinogenesis or other disease. Thus, devising methods to mimic the molecular consequences of this mutation to treat bone diseases associated with low bone mass is a promising avenue to pursue. Two groups of agents related to putative LRP5/6 functions are under development. One group, the focus of this paper, is based on antagonizing the functions of putative inhibitors of Wnt signaling, Dickkopf-1 (DKK1), and Sclerostin (SOST). Another group of reagents under development is based on the observation that LRP5 may function to control bone mass by regulating the secretion of serotonin from the enterrochromaffin cells of the duodenum.

Improved fatigue life of acrylic bone cements reinforced with zirconia fibers.

Poly(methyl methacrylate) (PMMA) bone cements have a long and successful history of use for implant fixation, but suffer from a relatively low fracture and fatigue resistance which can result in failure of the cement and the implant. Fiber or particulate reinforcement has been used to improve mechanical properties, but typically at the expense of the pre-cured cement viscosity, which is critical for successful integration with peri-implant bone tissue. Therefore, the objective of this study was to investigate the effects of zirconia fiber reinforcement on the fatigue life of acrylic bone cements while maintaining a relatively low pre-cured cement viscosity. Sintered straight or variable diameter fibers (VDFs) were added to a PMMA cement and tested in fully reversed uniaxial fatigue until failure. The mean fatigue life of cements reinforced with 15 and 20 vol% straight zirconia fibers was significantly increased by approximately 40-fold, on average, compared to a commercial benchmark (Osteobond) and cements reinforced with 0-10 vol% straight zirconia fibers. The mean fatigue life of a cement reinforced with 10 vol% VDFs was an order of magnitude greater than the same cement reinforced with 10 vol% straight fibers. The time-dependent viscosity of cements reinforced with 10 and 15 vol% straight fibers was comparable to the commercial benchmark during curing. Therefore, the addition of relatively small amounts of straight and variable diameter zirconia fibers was able to substantially improve the fatigue resistance of acrylic bone cement while exhibiting similar handling characteristics compared to current commercial products.

Patellofemoral interactions in walking, stair ascent, and stair descent using a virtual patella model.

Restoration of normal patella kinematics is an important clinical outcome of total knee arthroplasty. Failure of the patella within total knee systems has been documented and, upon occurrence, often necessitates revision surgery. It is thus important to understand patella mechanics following implantation, subject to load states that are typically realized during walking and other gaits. Here, a computational model of the patella is developed and used to examine the effects of walking, stair ascent, and stair descent on the development of stress and contact pressure in the patella throughout the gait cycle. Motion of the patella was governed by a combination of kinematic and force control, based on knee flexion and patellofemoral joint reaction force data from the literature. Unlike most previous analyses of full gait, quasi-static equilibrium was enforced throughout the cycle. Results indicate that, though peak forces vary greatly between the three gaits, maximum contact pressure and von Mises stress are roughly equivalent. However, contact area is larger in stair ascent and descent than walking, as patellofemoral loading, implant geometry, and polyethylene yield increase conformity between the femoral component and patella. Additionally, maximum contact pressure does not coincide with maximum load except for the case of walking. Though specific to the implant design considered here, this result has important ramifications for patella testing and emphasizes the need to characterize patella mechanics throughout gait.

Static and fatigue mechanical characterizations of variable diameter fibers reinforced bone cement.

Fibers can be used to improve the mechanical properties of bone cement for the long-term stability of hip prostheses. However, debonding of the fibers from the matrix due to the poor fiber/matrix interface is a major failure mechanism for such fiber reinforced bone cements. In this study, a novel fiber (variable diameter fibers or VDFs) technology for reinforced bone cement was studied to overcome the interface problem of short-fiber composites. These fibers change their diameters along their length to improve the fiber/matrix interfacial bond by the mechanical interlock between the VDFs and the matrix. A novel composite made from novel ceramic VDFs incorporated in PMMA matrix was developed. Both static and fatigue tests were carried out on the composites. Conventional straight fiber (CSF) reinforced bone cement was also tested for comparison purposes. Results demonstrated that both the stiffness and the fatigue life of VDF reinforced bone cement are significantly improved (P < 0.05) compared with the unreinforced bone cement. VDF contents of 10% by volume increased the fatigue life over unreinforced bone cement by up to 100-fold. Also, the fatigue life and modulus of toughness of VDF reinforced cement were significantly greater than those of CSF reinforced cement (P < 0.05 and P < 0.001, respectively). Scanning electron microscopy (SEM) micrographs revealed that VDFs can bridge the matrix cracks effectively and pullout of VDFs results in much more extensive matrix damage than pullout of CSFs increasing the resistance to fatigue. Therefore, VDF reinforced cement was significantly tougher, having a greater energy dissipation capacity than CSF reinforced cement. VDFs added to bone cement could potentially avoid implant loosening due to the mantle fracture of bone cement and delay the need for revision surgery.

The effect of entrapped bone particles on the surface morphology and wear of polyethylene.

Clinically retrieved highly cross-linked ultrahigh molecular weight polyethylene (HXPE) acetabular liners have demonstrated scratching, whereas conventional ultrahigh-molecular-weight polyethylene (UHMWPE) implants show a smoother surface early after implantation. In the present study, the potential of bone particles and soft tissues, rather than cement, to scratch the articular surface of HXPE and UHMWPE (gamma radiated) acetabular components was evaluated; multiple bone particles located at the articular surface for 3600 simulated walking cycles replicated the scratches observed on retrieved implants. By remelting, these scratches were confirmed to be due to plastic deformation of the polyethylene, not wear. Furthermore, it was shown using wear testing that these scratches did not affect the subsequent wear rate of HXPE or conventional UHMWPE. Wear rates of scratched conventional and cross-linked polyethylene were not significantly different from unscratched conventional and cross-linked polyethylene, respectively.

Preparation and mechanical characterization of a PNIPA hydrogel composite.

A poly (N-isopropylacrylamide) (PNIPA) hydrogel was synthesized by free radical polymerization and reinforced with a polyurethane foam to make a hydrogel composite. The temperature dependence of the elastic modulus of the PNIPA hydrogel and the composite due to volume phase transition was found using a uniaxial compression test, and the swelling property was investigated using an equilibrium swelling ratio experiment. The gel composite preserves the ability to undergo the volume phase transition and its elastic modulus has strong temperature dependence. The temperature dependence of the elastic modulus and swelling ratio of the gel composite were compared to the PNIPA hydrogel. Not surprisingly, the modulus and swelling ratio of the composite were less dramatic than in the gel.

A comparison of mechanical properties derived from multiple skeletal sites in mice.

Laboratory mice provide a versatile experimental model for studies of skeletal biomechanics. In order to determine the strength of the mouse skeleton, mechanical testing has been performed on a variety of bones using several procedures. Because of differences in testing methods, the data from previous studies are not comparable. The purpose of this study was to determine which long bone provides the values closest to the published material properties of bone, while also providing reliable and reproducible results. To do this, the femur, humerus, third metatarsal, radius, and tibia of both the low bone mass C57BL/6H (B6) and high bone mass C3H/HeJ (C3H) mice were mechanically tested under three-point bending. The biomechanical tests showed significant differences between the bones and between mouse strains for the five bones tested (p < 0.05). Computational models of the femur, metatarsal, and radius were developed to visualize the types of measurement error inherent in the three-point bending tests. The models demonstrated that measurement error arose from local deformation at the loading point, shear deformation and ring-type deformation of the cylindrical cross-section. Increasing the aspect ratio (bone length/width) improved the measurement of Young's modulus of the bone for both mouse strains (p < 0.01). Bones with the highest aspect ratio and largest cortical thickness to radius ratio were better for bending tests since less measurement error was observed in the computational models. Of the bones tested, the radius was preferred for mechanical testing because of its high aspect ratio, minimal measurement error, and low variability.