Construction of a functional skeleton is accomplished through co-ordination of the developmental processes of chondrogenesis, osteogenesis, and synovial joint formation. Infants whose movement in utero is reduced or restricted and who subsequently suffer from joint dysplasia (including joint contractures) and thin hypo-mineralised bones, demonstrate that embryonic movement is crucial for appropriate skeletogenesis. This has been confirmed in mouse, chick, and zebrafish animal models, where reduced or eliminated movement consistently yields similar malformations and which provide the possibility of experimentation to uncover the precise disturbances and the mechanisms by which movement impacts molecular regulation. Molecular genetic studies have shown the important roles played by cell communication signalling pathways, namely Wnt, Hedgehog, and transforming growth factor-beta/bone morphogenetic protein. These pathways regulate cell behaviours such as proliferation and differentiation to control maturation of the skeletal elements, and are affected when movement is altered. Cell contacts to the extra-cellular matrix as well as the cytoskeleton offer a means of mechanotransduction which could integrate mechanical cues with genetic regulation. Indeed, expression of cytoskeletal genes has been shown to be affected by immobilisation. In addition to furthering our understanding of a fundamental aspect of cell control and differentiation during development, research in this area is applicable to the engineering of stable skeletal tissues from stem cells, which relies on an understanding of developmental mechanisms including genetic and physical criteria. A deeper understanding of how movement affects skeletogenesis therefore has broader implications for regenerative therapeutics for injury or disease, as well as for optimisation of physical therapy regimes for individuals affected by skeletal abnormalities. Cite this article: Bone Joint Res 2015;4:105–116

Introduction. Uncemented porous coated acetabular components have gained more research emphasis in recent years compared to their cemented counterparts, largely owing to the natural biological fixation they offer. Nevertheless, sufficient peri-prosthetic bone ingrowth is essential for long-term fixation of such uncemented acetabular components. The phenomenon of bone ingrowth can be predicted based on mechanoregulatory principles of primary bone fracture healing. Literature review reveals that the surface texture of implant plays a major role in implant-bone fixation mechanism. A few insilico models based on 2-D microscale finite elements (FE) were reported in literatures to predict the influence of surface texture designs on peri-prosthetic bone ingrowth. However, most of these studies were based on FE models of dental implants. The primary objective of this study, therefore, is to mechanobiologically predict the influence of surface texture on bone- ingrowth in acetabular components considering a novel 3-D mesh-shaped surface texture on the implant. Materials/Methods. The 3-D microscale model [Fig.1] of implant-bone interface was developed using CATIA. ®. V5R20 software (DassaultSystèmes, France) and was modelled in ANSYS V15.0 FE software (Ansys Inc., PA, USA) using coupled linear elastic ten-noded tetrahedral finite elements. The model consists of cast-inbeaded mesh textured implant having finely meshed inter-bead spacing. Linear, elastic and isotropic material properties considering Young's modulus of 210 GPa and Poisson's ratio of 0.3 for stainless steel implant were employed in the model. Boundary of bone was assumed to be rich in Mesenchymal Stem Cells(MSC) with periodic boundary conditions at contralateral surfaces. The linear elastic material properties in the model were updated iteratively through a tissue differentiation algorithm that works on the principle of mechanotransduction driven by local mechanical stimuli, e.g. hydrostatic pressure and equivalent deviatoric strain. Results. Results indicate that bone ingrowth is inhibited upon increasing the inter-bead spacing and upon decreasing the bead aspect ratio. It has been observed that there is a predominant influence of bead spacing diameter on the peri-acetabular bone ingrowth. The increase in bead spacing diameter has led to increased bead height that is found to promote higher bone ingrowth with an increase in average Young's modulus of neo-tissue layer. Conclusions. The present study focussed on the development of a new texture on the implant surface and to study the influence of surface texture on bone-ingrowth in acetabular components. Since there is a promising increase in average Young's modulus of the newly formed tissue layer, it predicts the increase in stiffness of the newly formed tissue. The increase in tissue stiffness reveals that, there is not much inhibition in bone ingrowth after the employment of the acetabular implant. The numerical study based on mechanoregulatory algorithm considering the appropriate mechanical stimuli responsible for bone ingrowth, reveals that, compared to hemispherical beaded surface texture, mesh shaped surface texture provides an improved fixation of the acetabular component. For any figures or tables, please contact the authors directly

Purpose. Adenosine triphosphate (ATP) has been implicated as an autocrine/paracrine signal in the mechanotransduction pathway of chondrocytes. In this study, human chondrocytes in a 3D agarose scaffold were cultured with exogenous ATP in varying doses to determine its effect on extracellular matrix synthesis by the cells. Further experiments determined basal ATP release, ATP degradation and expression of P2Y1 and P2Y2 purinoreceptors by the cultured cell constructs. Method. Human chondrocytes were obtained by enzymatic digestion of cartilage samples obtained at the time of total joint arthroplasty. The chondrocytes were cultured in a 3D agarose scaffold using standard tissue culture techniques. Various concentrations of exogenous ATP were added to the cultures, along with the radioisotopes to assess matrix synthesis. The cultures were harvested after a 24 hr incubation and radioisotope incorporation was determined by scintillation counting to determine proteoglycan ([35S]-sulfate) and collagen ([3H]-proline) synthesis, respectively. DNA content was determined by the Hoescht 33258 binding assay, and the proteoglycan and collagen synthesis were normalized to DNA content. Basal ATP release and degradation of exogenous ATP were determined by luciferase assay and luminometry. Expression of P2Y1 and P2Y2 purinoreceptors were determined by flow cytometry. Results. Cartilage was obtained and cultured from 22 patients. We identified responders (16/22) and non-responders (6/22) to ATP stimulation. Patients demographics, co-morbidities and medications were reviewed and no correlating characteristics were identified. The average increase in [3H]-proline incorporation was 242% the control (range 115%–388%, p<0.02) and the average increase in [35S]-sulfate incorporation was 238% (range 124%–711%, p<0.02). The expression of P2Y1 and P2Y2 receptors varied widely between individuals, with a range of 11–76% expression and of 3–67% expression for P2Y1 and P2Y2 receptors, respectively. Almost all cells expressing P2Y2 receptors also expressed P2Y1 receptors, and 4/8 patients also had significant cell populations expressing P2Y1 but not P2Y2 receptors (range of 4–17% of cells). Of the 8 patients studied, only 1 patient had measurable ATP within the culture media. ATP degradation within the culture media was measured, with the measured ATP half-life and elimination rate constants were determined. The ATP elimination rate constant values showed good correlation to P2Y1 receptor expression (R=0.99). Conclusion. P2Y1 and P2Y2 receptors were expressed on a significant proportion of chondrocytes from patients with osteoarthritis and there was a significant correlation of the expression of these receptors to the ATP elimination rate constants. The addition of exogenous ATP increased both the proteoglycan and collagen synthesis of the developing cartilage constructs in a subset of patients and appears to be a promising technique to improve extracellular matrix production in these constructs