Abstract
Critical size skeletal defects resulting from trauma and pathological disorders still remain a major clinical problem worldwide. Bone engineering aims at generating unlimited amounts of viable tissue substitutes by interfacing osteocompetent cells of different origin and developmental stage with compliant biomaterial scaffolds, and culture the cell/scaffold constructs under proper culture conditions in bioreactor systems. Bioreactors help supporting efficient nutrition of cultured cells and allow the controlled provision of biochemical and biophysical stimuli required for functional regeneration and production of clinically relevant bone grafts. In this review, the authors report the advances in the development of bone tissue substitutes using human cells and bioreactor systems. Principal types of bioreactors are reviewed, including rotating wall vessels, spinner flasks, direct and indirect flow perfusion bioreactors, as well as compression systems. Specifically, the review deals with: (i) key elements of bioreactor design; (ii) range of values of stress imparted to cells and physiological relevance; (iii) maximal volume of engineered bone substitutes cultured in different bioreactors; and (iv) experimental outcomes and perspectives for future clinical translation.
Highlights
The human skeleton consists of 206 distinct bones, which support and protect the body, and plays a role in metabolism, calcium storage and blood cell production [1]
Human embryonic stem cells and human induced pluripotent stem cells possess virtually unlimited expansion potential and ability to differentiate toward all specialized cell types constituting the human body [15,16,17] including cells of the vascular systems, with an increasing number of scientific reports lately demonstrating the potential of pluripotent stem cells and their mesenchymal derivatives for bone engineering in vitro and in vivo [18,19,20,21,22,23,24,25]
Independent studies using bone marrow (BM)-derived Human mesenchymal stem cells (hMSCs)-TERT seeded onto porous poly(lactic-co-glycolic acid) scaffolds (8 × 8 × 5 mm) and cultured in spinner flasks (30 rpm) up to 21 days showed similar results [57], characterized by a positive effect provided by the dynamic conditions on cell distribution and differentiation toward the osteogenic lineage, as evidenced by increased alkaline phosphatase (ALP) activity and calcium deposition
Summary
The human skeleton consists of 206 distinct bones, which support and protect the body, and plays a role in metabolism, calcium storage and blood cell production [1]. Conversion of physical stimuli into molecular signals and biological responses is termed mechanotransduction, which principally relies on the regulation of stretch-activated ion channels and integrin-initiated cytoskeleton deformations and organelle displacement (for a review see [32]) that triggers the initiation of a cascade of events culminating in the activation of genes involved in osteogenic pathways [31] Based on this knowledge, it is clear that the recapitulation of these mechanisms in vitro is essential for fostering the regenerative properties of human osteocompetent cells seeded onto biomaterial scaffolds, enabling the formation of mature tissue substitutes for enhanced skeletal reconstructions. The construction of viable bone substitutes using bioreactor systems opens new opportunities for the generation of valid experimental models to study bone development and pathologies, screen new drugs and test biomaterials within a context that better reflects the native tissue environment
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