Page 13 - Physico-Chemical Niche Conditions for Bone Cells

use [8,9]. Moreover, mechanical stimuli also affect mesenchymal stem cell (C3H10T1/2) and pre-osteoblast behavior [10–12]. In bone, mesenchymal stem cells, (pre)osteoblasts, osteocytes, and osteoclasts are involved in bone adaptation to mechanical loading. Albeit the osteocyte is the main mechanosensor of bone, all mentioned cell types are capable of independently sensing mechanical signals and synergistically regulate adaptive changes in the physical micro-environment [13,14]. It is difficult, if not impossible, to distinguish specific effects of each different type of physical stimuli on these bone cell types. However, it is clear that those stimuli separately are capable to regulate cell behavior and affect remodeling events within bone [6]. Mechanical loading studies demonstrate that the parameters magnitude, frequency, and strain rate are very important factors to influence cell behavior [6,15].
During daily activities, any form of activity, e.g. standing, jogging, or climbing, directly or indirectly leads to bone skeletal loading and thus invariably affects the distribution of bone matrix [6,16]. During strenuous activities, maximum deformations of the bulk bone matrix have been measured in different vertebrates (e.g. human, sheep, horse, and goose) in a range of locations (e.g. femur, tibia, ulna, and humerus). Those strains are in a confined range of 2000- 3500 μe (10,000 μe = 1% change in length from the original length) [17]. Bulk strains on the matrix are likely to be amplified around lacunae of osteocytes, and strains in the niche of osteocytes are likely to be much higher [18]. Furthermore, the strains in the bone matrix drives the movement of fluid within the ultrastructural anatomy of bone, which also produces mechanical stimuli on bone cells [19]. Exogenous mechanical forces are likely the main driver of bulk fluid flow in bone, as opposed to e.g. blood pressure [20].
Effect of topography and matrix stiffness on bone cell behavior
Cells can actively sense the physical signals of matrix topography, e.g. shape and rigidity (stiffness) [21]. The interaction at the cell-matrix interface affects a range of cell processes, such as cell adhesion and differentiation [21]. The features of matrix topography presenting at different shape (e.g. fibers) and length scales (e.g. nanoscale, microscale) promote global (cell shape and spreading) and local (focal adhesions) changes in cell behavior. Changes in matrix topography at the microscale (single cell size) might affect the direction (degree) of cell adhesion and convert signals to nearby cells along a fibrillary matrix topography [22,23]. As such, micro-topography can give cell directionality, control cells towards a certain path, promote cell viability, and induce bone regeneration [23,24]. Matrix nano-topography presenting features at the size of a single cell could cause more local changes in focal adhesions and affect integrin clustering [22,25]. Those changes not only alter the number, size, and distribution of focal adhesions, but also affect cytoskeletal organization and cell fate [22,25]. The other feature of the matrix presenting rigidity (stiffness) is a vital factor to affect
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