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1. Anisotropy and Heterogeneity in Finite Element Models of Trabecular Bone Alters Expected Failure Outcomes

   Hammond, MA; Wallace, JA; Allen, MR; Siegmund, T. (March 2017, Proccedings of the 2017 Annual Meeting of the Orthopedic Research Society)

   At the nanoscale bone is composed of aligned mineralized collagen fibrils organized into packets along the surface of trabecular bone creating an anisotropic tissue microstructure. Newer packets at the trabecular surfaces are usually less mineralized than older bone in the interior of the trabeculae, which along with irregular mineral deposition within packets, forms a heterogeneous material across the span of a trabeculae. However, finite element (FE) models of bone typically use homogenous isotropic material properties, because it is challenging to build anisotropy and heterogeneity into a model in a way that is applicable to the complex geometries of trabecular bone. Both the material anisotropy and heterogeneity may influence the stress state of trabecular bone, and it is important to understand the implications of such differences for determining bone biomechanical failure. It was hypothesized that taking into consideration both the tissue anisotropy and heterogeneity of bone’s biomechanical properties would alter the expected failure locations by reducing tensile stress on near surface elements of an FE model of canine trabecular bone. The objective of this study was to test this hypothesis and to develop a method to apply anisotropic and heterogeneous material properties to a model automatically from micro-computed tomography (μCT) data. 

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2. Effects of novel raloxifene analogs alone or in combination with mechanical loading in the Col1a2G610c/+ murine model of osteogenesis imperfecta

   https://doi.org/10.1016/j.bone.2023.116970  

   Kohler, Rachel; Creecy, Amy; Williams, David R; Allen, Matthew R; Wallace, Joseph M (February 2024, Bone)

   Osteogenesis imperfecta (OI) is a hereditary bone disease in which gene mutations affect collagen formation, leading to a weak, brittle bone phenotype that can cause severe skeletal deformity and increased fracture risk. OI interventions typically repurpose osteoporosis medications to increase bone mass, but this approach does not address compromised tissue-level material properties. Raloxifene (RAL) is a mild anti-resorptive used to treat osteoporosis that has also been shown to increase bone strength by a-cellularly increasing bone bound water content, but RAL cannot be administered to children due to its hormonal activity. The goal of this study was to test a RAL analog with no estrogen receptor (ER) signaling but maintained ability to reduce fracture risk. The best performing analog from a previous analog characterization project, named RAL-ADM, was tested in an in vivo study. Female wildtype (WT) and Col1a2G610C/+ (G610C) mice were randomly assigned to treated or untreated groups, for a total of 4 groups (n=15). Starting at 10 weeks of age, all mice underwent compressive tibial loading 3×/week to induce an anabolic bone formation response in conjunction with RAL-ADM treatment (0.5 mg/kg; 5×/week) for 6 weeks. Tibiae were scanned via microcomputed tomography then tested to failure in four-point bending. RAL-ADM had reduced ER affinity, and increased post-yield properties, but did not improve bone strength in OI animals, suggesting some properties can be improved by RAL analogs but further development is needed to create an analog with decidedly positive impacts to OI bone. 

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3. Germ‐Free C57BL /6 Mice Have Increased Bone Mass and Altered Matrix Properties but Not Decreased Bone Fracture Resistance

   https://doi.org/10.1002/jbmr.4835  

   Vahidi, Ghazal; Moody, Maya; Welhaven, Hope D.; Davidson, Leah; Rezaee, Taraneh; Behzad, Ramina; Karim, Lamya; Roggenbeck, Barbara A.; Walk, Seth T.; Martin, Stephen A.; et al (June 2023, Journal of Bone and Mineral Research)

   ABSTRACT The gut microbiome impacts bone mass, which implies a disruption to bone homeostasis. However, it is not yet clear how the gut microbiome affects the regulation of bone mass and bone quality. We hypothesized that germ‐free (GF) mice have increased bone mass and decreased bone toughness compared with conventionally housed mice. We tested this hypothesis using adult (20‐ to 21‐week‐old) C57BL/6J GF and conventionally raised female and male mice (n = 6–10/group). Trabecular microarchitecture and cortical geometry were measured from micro–CT of the femur distal metaphysis and cortical midshaft. Whole‐femur strength and estimated material properties were measured using three‐point bending and notched fracture toughness. Bone matrix properties were measured for the cortical femur by quantitative back‐scattered electron imaging and nanoindentation, and, for the humerus, by Raman spectroscopy and fluorescent advanced glycation end product (fAGE) assay. Shifts in cortical tissue metabolism were measured from the contralateral humerus. GF mice had reduced bone resorption, increased trabecular bone microarchitecture, increased tissue strength and decreased whole‐bone strength that was not explained by differences in bone size, increased tissue mineralization and fAGEs, and altered collagen structure that did not decrease fracture toughness. We observed several sex differences in GF mice, most notably for bone tissue metabolism. Male GF mice had a greater signature of amino acid metabolism, and female GF mice had a greater signature of lipid metabolism, exceeding the metabolic sex differences of the conventional mice. Together, these data demonstrate that the GF state in C57BL/6J mice alters bone mass and matrix properties but does not decrease bone fracture resistance. © 2023 The Authors.Journal of Bone and Mineral Researchpublished by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). 

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4. Alginate Conjugation Increases Toughness in Auricular Chondrocyte Seeded Collagen Hydrogels

   https://doi.org/10.3390/bioengineering10091037  

   Slyker, Leigh; Bonassar, Lawrence (September 2023, Bioengineering)

   Current auricular cartilage replacements for pediatric microtia fail to address the need for long-term integration and neocartilage formation. While collagen hydrogels have been successful in fostering neocartilage formation, the toughness and extensibility of these materials do not match that of native tissue. This study used the N-terminal functionalization of collagen with alginate oligomers to improve toughness and extensibility through metal–ion complexation. Alginate conjugation was confirmed via FTIR spectroscopy. The retention of native collagen fibrillar structure, thermal gelation, and helical conformation in functionalized gels was confirmed via scanning electron microscopy, oscillatory shear rheology, and circular dichroism spectroscopy, respectively. Alginate–calcium complexation enabled a more than two-fold increase in modulus and work density in functionalized collagen with the addition of 50 mM CaCl2, whereas unmodified collagen decreased in both modulus and work density with increasing calcium concentration. Additionally, the extensibility of alginate-functionalized collagen was increased at 25 and 50 mM CaCl2. Following 2-week culture with auricular chondrocytes, alginate-functionalization had no effect on the cytocompatibility of collagen gels, with no effects on cell density, and increased glycosaminoglycan deposition. Custom MATLAB video analysis was then used to quantify fracture toughness, which was more than 5-fold higher following culture in functionalized collagen and almost three-fold higher in unmodified collagen. 

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5. Incorporating tissue anisotropy and heterogeneity in finite element models of trabecular bone altered predicted local stress distributions

   https://doi.org/10.1007/s10237-017-0981-8  

   Hammond, Max A.; Wallace, Joseph M.; Allen, Matthew R.; Siegmund, Thomas (November 2017, Biomechanics and Modeling in Mechanobiology)

   Trabecular bone is composed of organized mineralized collagen fibrils, which results in heterogeneous and anisotropic mechanical properties at the tissue level. Recently, biomechanical models computing stresses and strains in trabecular bone have indicated a significant effect of tissue heterogeneity on predicted stresses and strains. How-ever, the effect of the tissue-level mechanical anisotropy on the trabecular bone biomechanical response is unknown. Here, a computational method was established to automatically impose physiologically relevant orientation inherent in trabecular bone tissue on a trabecular bone microscale finite element model. Spatially varying tissue-level anisotropic elastic properties were then applied according to the bone mineral density and the local tissue orientation. The model was used to test the hypothesis that anisotropy in both homogeneous and heterogeneous models alters the predicted distribution of stress invariants. Linear elastic finite element computations were performed on a 3 mm cube model isolated from a microcomputed tomography scan of human trabecular bone from the distal femur. Hydrostatic stress and von Mises equivalent stress were recorded at every element, and the distributions of these values were analyzed. Anisotropy reduced the range of hydrostatic stress in both tension and compression more strongly than the associated increase in von Mises equivalent stress. The effect of anisotropy was independent of the spatial redistribution high compressive stresses due to tissue elastic heterogeneity. Tissue anisotropy and heterogeneity are likely important mechanisms to protect bone from failure and should be included for stress analyses in trabecular bone. 

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