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A contrast in Poisson ratio is a possible strategy to enhance the stiffness of composite structures. In solid materials Poisson ratio is hardly tailorable unless cellular architectures are considered. Here, we first investigated the effect of a single re-entrant inclusion acting as a defect into a regular (non-re-entrant) honeycomb lattice. Building on this, we generated regular patterns of re-entrant inclusions into a regular hexagonal cellular matrix and we characterized the apparent stiffness and Poisson ratio of the obtained structures. We also explored the role of the intrinsic material properties of the inclusion as well as of its closest environment on the interplay between the deformations of different phases in the lattice. Our main finding is that a small fraction of re-entrant inclusions (around 12%) is sufficient to generate a substantial augmentation in stiffness (300%) at constant overall relative density and without inducing strong anisotropy. Eventually, we fabricated by 3D polyjet printing bi-material composite architectures to demonstrate the superior mechanical behavior obtained exploiting the Poisson effect.

14 www.nature.com/bonekey P33 Wolff’s Law and the Interplay between Bone Structure and External Loading Davide Ruffoni1, Patrik Christen2, Heike Scherf3, Richard Weinkamer4 1Department of Aerospace and Mechanical Engineering, University of Liege, Liege, Belgium, 2Institute for Biomechanics, ETH Zurich, Zurich, Switzerland, 3Institute for Archaeological Sciences, University of Tubingen, Tubingen, Germany, 4Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany

Anchorage of orthopedic implants depends on the interfacial bonding between the implant and the host bone as well as on the mass and microstructure of peri-implant bone, with all these factors being continuously regulated by the biological process of bone (re)modeling. In osteoporotic bone implant integration may be jeopardized not only by lower peri-implant bone quality but also by reduced intrinsic regeneration ability. The first aim of this review is to provide a critical overview of the influence of osteoporosis on bone regeneration post-implantation. Mechanical stimulation can trigger bone formation and inhibit bone resorption; thus, judicious administration of mechanical loading can be used as an effective non-pharmacological treatment to enhance implant anchorage. Our second aim is to report recent achievements on the application of external mechanical stimulation to improve the quantity of peri-implant bone. The review focuses on peri-implant bone changes in osteoporotic conditions and following mechanical loading, prevalently using small animals and in vivo monitoring approaches. We intend to demonstrate the necessity to reveal new biological information on peri-implant bone mechanobiology to better target implant anchorage and fracture fixation in osteoporotic conditions. This article is protected by copyright. All rights reserved

Biomedical Engineering / Biomedizinische Technik, 58 (Supplement 1), ISSN:0013-5585, ISSN:1862-278X

Although mechanical stimulation is considered a promising approach to accelerate implant integration, our understanding of load-driven bone formation and resorption around implants is still limited. This lack of knowledge may delay the development of effective loading protocols to prevent implant loosening, especially in osteoporosis. In healthy bone, formation and resorption are mechanoregulated processes. In the intricate context of peri-implant bone regeneration, it is not clear whether bone (re)modelling can still be load-driven. Here, we investigated the mechanical control of peri-implant bone (re)modelling with a well-controlled mechanobiological experiment. We applied cyclic mechanical loading after implant insertion in tail vertebrae of oestrogen depleted mice and we monitored peri-implant bone response by in vivo micro-CT. Experimental data were combined with micro-finite element simulations to estimate local tissue strains in (re)modelling locations. We demonstrated that a substantial increase in bone mass around the implant could be obtained by loading the entire bone. This augmentation could be attributed to a large reduction in bone resorption rather than to an increase in bone formation. We also showed that following implantation, mechanical regulation of bone (re)modelling was transiently lost. Our findings should help to clarify the role of mechanical stimulation on the maintenance of peri-implant bone mass.

Stem cell-mediated gene therapy for fracture repair, utilizes genetically engineered mesenchymal stem cells (MSCs) for the induction of bone growth and is considered a promising approach in skeletal tissue regeneration. Previous studies have shown that murine nonunion fractures can be repaired by implanting MSCs over-expressing recombinant human bone morphogenetic protein-2 (rhBMP-2). Nanoindentation studies of bone tissue induced by MSCs in a radius fracture site indicated similar elastic modulus compared to intact murine bone, eight weeks post treatment. In the present study we sought to investigate temporal changes in microarchitecture and biomechanical properties of repaired murine radius bones, following the implantation of MSCs. High resolution micro computed tomography (Micro-CT) was performed 10 and 35 weeks post MSC implantation, followed by micro finite element (Micro-FE) analysis. The results have shown that the regenerated bone tissue remodels over time, as indicated by a significant decrease in bone volume, total volume and connectivity density combined with an increase in mineral density. In addition, the axial stiffness of limbs repaired with MSCs was 2 to 1.5 times higher compared to the contralateral intact limbs, at 10 and 35 weeks post treatment. These results could be attributed to the fusion that occurred between in the ulna and radius bones. In conclusion, although MSCs induce bone formation, which exceeds the fracture site, significant remodeling of the repair callus occurs over time. In addition, limbs treated with an MSC graft demonstrated superior biomechanical properties, which could indicate the clinical benefit of future MSC application in nonunion fracture repair.

The local interpretation of microfinite element (μFE) simulations plays a pivotal role for studying bone structure–function relationships such as failure processes and bone remodeling. In the past μFE simulations have been successfully validated on the apparent level, however, at the tissue level validations are sparse and less promising. Furthermore, intratrabecular heterogeneity of the material properties has been shown by experimental studies. We proposed an inverse μFE algorithm that iteratively changes the tissue level Young’s moduli such that the μFE simulation matches the experimental strain measurements. The algorithm is setup as a feedback loop where the modulus is iteratively adapted until the simulated strain matches the experimental strain. The experimental strain of human trabecular bone specimens was calculated from time-lapsed images that were gained by combining mechanical testing and synchrotron radiation microcomputed tomography (SRμCT). The inverse μFE algorithm was able to iterate the heterogeneous distribution of moduli such that the resulting μFE simulations matched artificially generated and experimentally measured strains.

Perfusion bioreactors are known to exert shear stresses on cultured cells, leading to cell differentiation and enhanced extracellular matrix deposition on scaffolds. The influence of the scaffold’s porous microstructure is investigated for a polycaprolactone (PCL) scaffold with a regular microarchitecture and a silk fibroin (SF) scaffold with an irregular network of interconnected pores. Their complex 3D geometries are imaged by micro-computed tomography and used in direct pore-level simulations of the entire scaffold–bioreactor system to numerically solve the governing mass and momentum conservation equations for fluid flow through porous media. The velocity field and wall shear stress distribution are determined for both scaffolds. The PCL scaffold exhibited an asymmetric distribution with peak and plateau, while the SF scaffold exhibited a homogenous distribution and conditioned the flow more efficiently than the PCL scaffold. The methodology guides the design and optimization of the scaffold geometry.

Trabecular bone is a highly dynamic tissue due to bone remodeling, mineralization and demineralization. The mineral content and its spatial heterogeneity are main contributors to bone quality. Using time-lapsed in vivo micro-computed tomography (micro-CT), it is now possible to resolve in three dimensions where bone gets resorbed and deposited over several weeks. In addition, the gray values in the micro-CT images contain quantitative information about the local tissue mineral density (TMD). The aim of this study was to measure how TMD increases with time after new bone formation and how this mineralization kinetics is influenced by mechanical stimulation. Our analysis of changes in TMD was based on an already reported experiment on 15-week-old female mice (C57BL/6), where in one group the sixth caudal vertebra was mechanically loaded with 8 N, while in the control group no loading was applied. Comparison of two consecutive images allows the categorization of bone into newly formed, resorbed, and quiescent bone for different time points. Gray values of bone in these categories were compared layer-wise to minimize the effects of beam hardening artifacts. Quiescent bone in the control group was found to mineralize with a rate of 8 ± 1 mgHA/cm3 per week, which is about half as fast as observed for newly formed bone. Mechanical loading increased the rate of mineral incorporation by 63% in quiescent bone. The week before bone resorption, demineralization could be observed with a drop of TMD by 36 ± 4 mgHA/cm3 in the control and 34 ± 3 mgHA/cm3 in the loaded group. In conclusion, this study shows how time-lapsed in vivo micro-CT can be used to assess changes in TMD of bone with high spatial and temporal resolution. This will allow a quantification of how bone diseases and pharmaceutical interventions influence not only microarchitecture of trabecular bone, but also its material quality.

Bone is probably the most frequently investigated biological material and finite element analysis (FEA) is the computational tool most commonly used for the analysis of bone biomechanical function. FEA has been used in bone research for more than 30 years and has had a substantial impact on our understanding of the complex behavior of bone. Bone is structured in a hierarchical way covering many length scales and this chapter reflects this hierarchical organization. In particular, the focus is on the applications of FEA for understanding the relationship between bone structure and its mechanical function at specific hierarchical levels. Depending on the hierarchical level, different issues have been investigated with FEA ranging from more clinically oriented topics related to bone quality (e.g., predicting bone strength and fracture risk) to more fundamental problems dealing with the mechanical aspects of biological processes (e.g., stress and strain around osteocyte lacunae) as well as with the micromechanical behavior of bone at its ultrastructure. A better understanding of the relationship between structure and mechanical function is expected to be important for the current trends in (bio)materials design, where the structure of biological materials is considered as a possible source of inspiration, as well as for more successful approaches in the prevention and treatment of age- and disease-related fractures.

The human parathyroid peptide fragment hPTH 134 is an anabolic drug which, given intermittently, turns on bone remodeling by increasing bone formation. Its exact mode of action is however still unclear to date. In an earlier study, we found that in mechanically loaded animals, formation occurs preferentially at highly loaded areas, and resorption at lowly strained areas [1]. Here we investigate if and how PTH combined with mechanical loading alters the mechanoregulation of bone remodeling. With this, we aimed at a better understanding of the effectiveness of PTH in the treatment of bone diseases such as osteoporosis.