Biomechanical and biophysical environment of bone from the macroscopic to the pericellular and molecular level.

“Bones with complicated hierarchical configuration and microstructures constitute the load-bearing system. Mechanical loading plays an essential role in maintaining bone health and regulating bone mechanical adaptation (modeling and remodeling). The whole-bone or sub-region (macroscopic) mechanical signals, including locomotion-induced loading and external actuator-generated vibration, ultrasound, oscillatory skeletal muscle stimulation, etc., give rise to sophisticated and distinct biomechanical and biophysical environments at the pericellular (microscopic) and collagen/mineral molecular (nanoscopic) levels, which are the direct stimulations that positively influence bone adaptation. While under microgravity, the stimulations decrease or even disappear, which exerts a negative influence on bone adaptation. A full understanding of the biomechanical and biophysical environment at different levels is necessary for exploring bone biomechanical properties and mechanical adaptation. In this review, the mechanical transferring theories from the macroscopic to the microscopic and nanoscopic levels are elucidated. First, detailed information of the hierarchical structures and biochemical composition of bone, which are the foundations for mechanical signal propagation, are presented. Second, the deformation feature of load-bearing bone during locomotion is clarified as a combination of bending and torsion rather than simplex bending. The bone matrix strains at microscopic and nanoscopic levels directly induced by bone deformation are critically discussed, and the strain concentration mechanism due to the complicated microstructures is highlighted. Third, the biomechanical and biophysical environments at microscopic and nanoscopic levels positively generated during bone matrix deformation or by dynamic mechanical loadings induced by external actuators, as well as those negatively affected under microgravity, are systematically discussed, including the interstitial fluid flow (IFF) within the lacunar-canalicular system and at the endosteum, the piezoelectricity at the deformed bone surface, and the streaming potential accompanying the IFF. Their generation mechanisms and the regulation effect on bone adaptation are presented. The IFF-induced chemotransport effect, shear stress, and fluid drag on the pericellular matrix are meaningful and noteworthy. Furthermore, we firmly believe that bone adaptation is regulated by the combination of bone biomechanical and biophysical environment, not only the commonly considered matrix strain, fluid shear stress, and hydrostatic pressure, but also the piezoelectricity and streaming potential. Especially, it is necessary to incorporate bone matrix piezoelectricity and streaming potential to explain how osteoblasts (bone formation cells) and osteoclasts (bone resorption cells) can differentiate among different types of loads. Specifically, the regulation effects and the related mechanisms of the biomechanical and biophysical environments on bone need further exploration, and the incorporation of experimental research with theoretical simulations is essential.”

“bone  adaptation is regulated by the combination of bone biomechanical and biophysical environment, not only the commonly considered matrix strain, fluid shear stress, and hydrostatic pressure, but also the piezoelectricity and streaming potential”

“At the macroscopic level in long bone such as the femur, cortical bone with compact structures
and low porosity forms the hard shell, and trabecular bone with a three-dimensional interconnected  network of trabecular rods and plates forms the inner surface.  In flat bone, e.g. the calvaria and iliac crest, the cortical bone and trabecular bone form the cortical-trabecular-cortical sandwich structure”

the pericellular spaces between osteocytes and the lacunar-canalicular wall are filled with interstitial fluid and pericellular matrix (PCM), which is a gel-like fiber matrix thought to be composed of proteoglycans and other matrix molecules ”

” Due to  the low permeability of mineralized bone matrix, interstitial fluid flow (IFF) is principally generated during alteration of intramedullary pressurization (ImP) and bone matrix deformation ”

” Uniform pressurization [such as that due to decreased intramedullary cavity resulting from elevated bone marrow lipids induced by high level of corticosteroid administration will generate radial flow from the intramedullary compartment to the endosteal surface and into the LCS due to the pressure gradient from the marrow cavity to the bone matrix”

” Non-uniform pressure gradients within the intramedullary cavity [such as those due to local heterogeneous permeability or fluid displacement changes in the intramedullary compartment from the interaction between mechanical loading/oscillatory muscle stimulation and capillary filtration in bone tissue  will cause tangential fluid flow to the endosteal surface ”

“The matrix deformation generated pressure gradient within LCS stimulates the interstitial fluid to move towards the lower pressure zone”

“the profiles of IFF within the LCS are sophisticated and can be considered as a combination of
oscillating and unidirectional fluid flow ”

“Three stimuli induced by fluid flow, namely chemotransport effects, IFF-induced shear stress, and fluid drag on the PCM, have been shown to regulate osteocyte activity”

“IFF within the LCS serves as the primary transport mechanism between the blood supply and osteocytes. Furthermore, the shear stress induced by IFF provides potent mechanical stimulation for osteocytes ”

” In the inverse piezoelectric effect, subjecting bone to an electric field induces deformation”

“varying degrees of deformations, or even irreversible deformations, will also be evoked in collagen fibrils and mineral crystals oriented in different directions”