Altered collagen chemical compositional structure in osteopenic women with past fractures: A case-control Raman spectroscopic study.

Incidences of low-trauma fractures among osteopenic women may be related to changes in bone quality. In this blinded, prospective-controlled study, compositional and heterogeneity contributors of bone quality to fracture risk were examined. We hypothesize that Raman spectroscopy can differentiate between osteopenic women with one or more fractures (cases) from women without fractures (controls). This study involved the Raman spectroscopic analysis of cortical and cancellous bone composition using iliac crest biopsies obtained from 59-cases and 59-controls, matched for age (62.0 ± 7.5 and 61.7 ± 7.3 years, respectively, p = 0.38) and hip bone mineral density (BMD, 0.827 ± 0.083 and 0.823 ± 0.072 g/cm3, respectively, p = 0.57). Based on aggregate univariate case-control and odds ratio based logistic regression analyses, we discovered two Raman ratiometric parameters that were predictive of past fracture risk. Specifically, 1244/1268 and 1044/959 cm-1 ratios, were identified as the most differential aspects of bone quality in cortical cases with odds ratios of 0.617 (0.406-0.938 95% CI, p = 0.024) and 1.656 (1.083-2.534 95% CI, p = 0.020), respectively. Both 1244/1268 and 1044/959 cm-1 ratios exhibited moderate sensitivity (59.3-64.4%) but low specificity (49.2-52.5%). These results suggest that the organization of mineralized collagen fibrils were significantly altered in cortical cases compared to controls. In contrast, compositional and heterogeneity parameters related to mineral/matrix ratios, B-type carbonate substitutions, and mineral crystallinity, were not significantly different between cases and controls. In conclusion, a key outcome of this study is the significant odds ratios obtained for two Raman parameters (1244/1268 and 1044/959 cm-1 ratios), which from a diagnostic perspective, may assist in the screening of osteopenic women with suspected low-trauma fractures. One important implication of these findings includes considering the possibility that changes in the organization of collagen compositional structure plays a far greater role in postmenopausal women with osteopenic fractures.

A paradigm for the development and evaluation of novel implant topologies for bone fixation: in vivo evaluation.

While contemporary prosthetic devices restore some function to individuals who have lost a limb, there are efforts to develop bio-integrated prostheses to improve functionality. A critical step in advancing this technology will be to securely attach the device to remnant bone. To investigate mechanisms for establishing robust implant fixation in bone while undergoing loading, we previously used a topology optimization scheme to develop optimized orthopedic implants and then fabricated selected designs from titanium (Ti)-alloy with selective laser sintering (SLS) technology. In the present study, we examined how implant architecture and mechanical stimulation influence osseointegration within an in vivo environment. To do this, we evaluated three implant designs (two optimized and one non-optimized) using a unique in vivo model that applied cyclic, tension/compression loads to the implants. Eighteen (six per implant design) adult male canines had implants surgically placed in their proximal, tibial metaphyses. Experimental duration was 12 weeks; daily loading (peak load of ±22 N for 1000 cycles) was applied to one of each animal's bilateral implants for the latter six weeks. Following harvest, osseointegration was assessed by non-destructive mechanical testing, micro-computed tomography (microCT) and back-scatter scanning electron microscopy (SEM). Data revealed that implant loading enhanced osseointegration by significantly increasing construct stiffness, peri-implant trabecular morphology, and percentages of interface connectivity and bone ingrowth. While this experiment did not demonstrate a clear advantage associated with the optimized implant designs, osseointegration was found to be significantly influenced by aspects of implant architecture.

A paradigm for the development and evaluation of novel implant topologies for bone fixation: implant design and fabrication.

The future development of bio-integrated devices will improve the functionality of robotic prosthetic limbs. A critical step in the advancement of bio-integrated prostheses will be establishing long-term, secure fixation to the remnant bone. To overcome limitations associated with contemporary bone-anchored prosthetic limbs, we established a paradigm for developing and fabricating novel orthopedic implants undergoing specified loading. A topology optimization scheme was utilized to generate optimal implant macrostructures that minimize deformations near the bone-implant interface. Variations in implant characteristics and interfacial connectivity were investigated to examine how these variables influence the layout of the optimized implant. For enhanced tissue integration, the optimally designed macroscopic geometry of a titanium (Ti)-alloy implant was further modified by introducing optimized microstructures. The complex geometries of selected implants were successfully fabricated using selective laser sintering (SLS) technology. Fabrication accuracy was assessed by comparing volumes and cross-sectional areas of fabricated implants to CAD data. The error of fabricated volume to CAD design volume was less than 8% and differences in cross sectional areas between SEM images of fabricated implants and corresponding cross sections from CAD design were on average less than 9%. We have demonstrated that this computational design method, combined with solid freeform fabrication techniques, provides a versatile way to develop novel orthopedic implants.

Biomechanical stimulation of osteoblast gene expression requires phosphorylation of the RUNX2 transcription factor.

Bone can adapt its structure in response to mechanical stimuli. At the cellular level, this involves changes in chromatin organization, gene expression, and differentiation, but the underlying mechanisms are poorly understood. Here we report on the involvement of RUNX2, a bone-related transcription factor, in this process. Fluid flow shear stress loading of preosteoblasts stimulated translocation of extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) to the nucleus where it phosphorylated RUNX2 on the chromatin of target genes, and increased histone acetylation and gene expression. MAPK signaling and two RUNX2 phosphoacceptor sites, S301 and S319, were critical for this response. Similarly, in vivo loading of mouse ulnae dramatically increased ERK and RUNX2 phosphorylation as well as expression of osteoblast-related genes. These findings establish ERK/MAPK-mediated phosphorylation of RUNX2 as a critical step in the response of preosteoblasts to dynamic loading and define a novel mechanism to explain how mechanical signals induce gene expression in bone.

Hip resurfacing increases bone strains associated with short-term femoral neck fracture.

Short-term femoral neck fracture is a primary complication associated with contemporary hip resurfacing. Some fractures are associated with neck notching, while others occur in the absence of notching. These unexplained fractures may be due to large magnitude strains near the implant rim, which could cause bone damage accumulation and eventual neck fracture. We used statistically augmented finite element analysis to identify design and environmental variables that increase bone strains near the implant rim after resurfacing, and lead to strain magnitudes sufficient for rapid damage accumulation. After resurfacing, the compressive strains in the inferior, peripheral neck increased by approximately 25%, particularly when the implant shell was bonded. While the tensile strains in the peripheral neck were low in magnitude in the immediate postoperative models, they increased substantially following compressive damage accumulation. Low bone modulus, within the range of normal bone, and high head load contributed the most to large magnitude strains. Therefore, in some cases, hip resurfacing may cause a region of compressive bone damage to develop rapidly, which in turn leads to large tensile strains and potential neck fracture. Our study suggests that indications for surgery should account for bone material quality, and that rehabilitation protocols should avoid high-load activities.

Surgical variables affect the mechanics of a hip resurfacing system.

Recent clinical studies have linked failure to surgical variables of stemmed hip resurfacing systems. We used finite element analysis to investigate the effects of implant position, stem orientation, and extent of fixation both on the local stresses and strains associated with implant loosening, neck fracture, and stem fracture, as well as on the load transfer distribution in the bone-implant system. The range of peak stress in the cement was reduced from 11 to 13 MPa for the varus stem to 3.2 to 4.2 MPa for the valgus stem. The range of peak strain in the bone was also reduced from -0.35% to -0.45% strain for the varus stem to -0.19% to -0.27% strain for the valgus stem, but only when reamed cancellous bone remained exposed. Peak stresses in the stem were low for all cases. Additionally, the implant's load transfer distribution was generally insensitive to all variables examined and the femoral head was substantially unloaded. Our data indicate the local stresses and strains associated with implant loosening and neck fracture were reduced by placing the implant in a valgus orientation and covering reamed cancellous bone, but unloading of the femoral head, found for all variables examined, may lead to adverse bone remodeling.