Abstract
In recent years, synthetic calcium phosphate (CaP) ceramics have emerged as an alternative to bone grafts in the treatment of large critical-sized bone defects. To successfully substitute for bone grafts, materials must be osteoinductive, that is, they must induce osteogenic differentiation and subsequent bone formation in vivo. Although a set of osteoinductive CaP ceramics has been developed, the precise biological mechanism by which a material directs cells toward osteogenesis and the role of individual chemical and physical properties in this mechanism remain incompletely understood. Here, we used proteomics to compare serum protein adsorption to two CaP ceramics with different osteoinductive potential, namely an osteoinductive β-tricalcium phosphate (TCP) and a non-osteoinductive hydroxyapatite (HA). Moreover, we analyzed the protein profiles of human mesenchymal stromal cells (hMSCs) cultured on these two ceramics. The serum protein adsorption experiments in the absence of cells highlighted the proteins that are highly abundant in the serum and/or have a high affinity to CaP. The extent of adsorption was suggested to be affected by the available surface area for binding and by the ion exchange dynamics on the surface. Several proteins were uniquely expressed by hMSCs on TCP and HA surfaces. Proteins identified as enriched on TCP were involved in processes related to wound healing, cell proliferation, and the production of extracellular matrix. On the other hand, proteins that were enriched on HA were involved in processes related to protein production, translation, localization, and secretion. In addition, we performed a separate proteomics analysis on TCP, HA, and two biphasic calcium phosphates with known osteoinductive potential and performed a clustering analysis on a combination of a set of proteins found to be enriched on osteoinductive materials with a set of proteins already known to be involved in osteogenesis. This yielded two protein networks potentially involved in the process of osteoinduction – one consisting of collagen fragments and collagen-related enzymes and a second consisting of endopeptidase inhibitors and regulatory proteins. The results of this study show that protein profiling can be a useful tool to help understand the effect of biomaterial properties on the interactions between a biomaterial and a biological system. Such understanding will contribute to the design and development of improved biomaterials for (bone) regenerative therapies.
Highlights
Regenerative medicine comprises methods which harness and stimulate the body's own natural capacity to regenerate to restore damaged organs and tissues to normal function
Previous studies have shown that upon sintering in air, phosphate evaporation occurs on the surface of calcium phosphate (CaP) ceramics, leading to the formation of a calcium-rich phase, which in turn can convert to Ca(OH)2 and eventually CaCO3 upon exposure to ambient air [57,58,59,60,61,62] The extent of this process and the spatial organization of the formed layer are dependent on the bulk composition of the ceramic and the sintering conditions
While we did not perform a detailed analysis of the surface chemistry of the ceramics, the possible effects of the differences in surface chemical composition on the protein adsorption and production by human mesenchymal stromal cells (hMSCs) cannot be fully excluded
Summary
Regenerative medicine comprises methods which harness and stimulate the body's own natural capacity to regenerate to restore damaged organs and tissues to normal function. Synthetic biomaterials have already shown some clinical success in the area of bone regeneration, where they substitute for either donor cadaveric bone or the patient's own grafted bone to allow the repair of large, critical-sized bone defects. CaP ceramics have been developed with the intrinsic ability to induce de novo bone formation in vivo even at ectopic implantation sites. This property, known as osteoinductivity, is considered imperative for the capacity of a biomaterial to regenerate large, clinically relevant bone defects [7,8,9]. Chemical phase and surface chemistry, surface microstructural properties such as grain size, nanocrystal morphology, and microporosity, and the presence and architecture of ‘protected’ areas such as pores and channels in which local concentrations of calcium and inorganic phosphate ions can be modified have all been suggested as potentially playing a role in osteoinduction [10,11,12,13,14,15,16]
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