An in vivo model of a mechanically-induced bone marrow lesion.

Bone marrow lesions (BMLs) are radiologic abnormalities in magnetic resonance images of subchondral bone that are correlated with osteoarthritis. Little is known about the physiologic processes within a BML, although BMLs are associated with mechanical stress, bone tissue microdamage and increased bone remodeling. Here we establish a rabbit model to study the pathophysiology of BMLs. We hypothesized that in vivo loads that generate microdamage in cancellous bone would also create BMLs and increase bone remodeling. In vivo cyclic loading (0.2-2.0 MPa in compression for 10,000 cycles at 2 Hz) was applied to epiphyseal cancellous bone in the distal femurs of New Zealand white rabbits (n=3, right limb loaded, left limb controls experienced surgery but no loading). Magnetic resonance images were collected using short tau inversion recovery (STIR) and T1 weighted sequences at 1 and 2 weeks after surgery/loading and histological analysis of the BML was performed after euthanasia to examine tissue microdamage and remodeling. Loaded limbs displayed BMLs while control limbs showed only a small BML-like signal caused by surgery. Histological analysis of the BML at 2 weeks after loading showed increased tissue microdamage (p=0.03) and bone resorption (p=0.01) as compared to controls. The model described here displays the hallmarks of load-induced BMLs, supporting the use of the model to examine changes in bone during the development, progression and treatment of BMLs.

Romosozumab Treatment Converts Trabecular Rods into Trabecular Plates in Male Cynomolgus Monkeys.

Treatment with sclerostin antibody (romosozumab) increases bone formation while reducing bone resorption, leading to increases in bone volume and bone mineral density. Sclerostin antibody treatment may also provide beneficial changes in trabecular microarchitecture and strength that are not reflected in bone volume and density. Here we use three-dimensional dynamic histomorphometry to determine longitudinal changes in vertebral trabecular microarchitecture in adolescent male cynomolgus monkeys (4-5 years old) treated with sclerostin antibody. Animals were treated bi-weekly with either sclerostin antibody (30 mg/kg, sc, n = 6) or vehicle (n = 6) for 10 weeks. Animals were administered fluorochrome bone formation labels on days 14 and 24 (tetracycline) and on days 56 and 66 (calcein), followed by necropsy on day 70. Cylindrical specimens of cancellous bone from the 5th lumbar vertebrae were used to generate high-resolution, three-dimensional images of bone and fluorescent labels of bone formation (0.7 × 0.7 × 5.0 µm/voxel). The three-dimensional images of the bone formation labels were used to determine the bone volume formed between days 14 and 66 and the resulting alterations in trabecular microarchitecture within each bone. Treatment with sclerostin antibody resulted in a conversion of rod-like trabeculae into plate-like trabeculae at a higher rate than in vehicle-treated animals (p = 0.01). Plate bone volume fraction was greater in the sclerostin antibody group relative to vehicle (mean 43 vs. 30%, p < 0.05). Bone formation increased the thickness of trabeculae in all three trabecular orientations (axial, oblique, and transverse, p < 0.05). The volume of bone formed between days 14 to 66 was greater in sclerostin antibody-treated groups (9.0 vs. 5.4%, p = 0.02), and new bone formation due to sclerostin antibody treatment was associated with increased apparent stiffness as determined from finite element models. Our results demonstrate that increased bone formation associated with sclerostin antibody treatment increases plate-like trabecular morphology and improves mechanical performance.

Material heterogeneity in cancellous bone promotes deformation recovery after mechanical failure.

Many natural structures use a foam core and solid outer shell to achieve high strength and stiffness with relatively small amounts of mass. Biological foams, however, must also resist crack growth. The process of crack propagation within the struts of a foam is not well understood and is complicated by the foam microstructure. We demonstrate that in cancellous bone, the foam-like component of whole bones, damage propagation during cyclic loading is dictated not by local tissue stresses but by heterogeneity of material properties associated with increased ductility of strut surfaces. The increase in surface ductility is unexpected because it is the opposite pattern generated by surface treatments to increase fatigue life in man-made materials, which often result in reduced surface ductility. We show that the more ductile surfaces of cancellous bone are a result of reduced accumulation of advanced glycation end products compared with the strut interior. Damage is therefore likely to accumulate in strut centers making cancellous bone more tolerant of stress concentrations at strut surfaces. Hence, the structure is able to recover more deformation after failure and return to a closer approximation of its original shape. Increased recovery of deformation is a passive mechanism seen in biology for setting a broken bone that allows for a better approximation of initial shape during healing processes and is likely the most important mechanical function. Our findings suggest a previously unidentified biomimetic design strategy in which tissue level material heterogeneity in foams can be used to improve deformation recovery after failure.

Bi-unicondylar knee replacement laxity with changes to simulated soft tissue constraints.

Unicondylar knee replacement systems have been shown to perform comparably to total knee replacements, while being much less surgically invasive. Proper ligament balancing, as well as knee laxity, has been shown to play an important role in optimizing kinematic behavior of these implant systems and improving long-term survival of the implant. This study investigates the effect of different simulated ligament laxity conditions of the anterior cruciate ligament and the posterior cruciate ligament on the resulting anteroposterior and mediolateral contact kinematics for medial and lateral pairs of UKR implants with flat and symmetric ultrahigh-molecular-weight polyethylene inserts during force-controlled ISO-14243-1 knee testing simulation. A novel method of capturing the tibiofemoral lowest point contact path was used to calculate the shear plane lowest point contact path kinematics in both the anteroposterior and the mediolateral directions. The results illustrated that multiple clinically relevant soft tissue configurations produce statistically different measured knee kinematics in unicondylar knee replacement systems than is seen in accepted "standard" knee simulator protocols with 95% confidence interval. The observed kinematic differences in anteroposterior and mediolateral movement from what was observed using standard wear testing protocols could aid in the development of unicondylar knee replacement design enhancements that are resistant to varying soft tissue deficiencies.