Bone Tissue Engineering Bioreactors: A Role in the Clinic?

ArticleinTissue Engineering Part B Reviews 18(1):62-75 · September 2011with39 Reads
DOI: 10.1089/ten.TEB.2011.0209 · Source: PubMed
Tissue engineered bone grafts have the potential to be used to treat large bone defects due to congenital abnormalities, cancer resections, or traumatic incidents. Recent studies have shown that perfusion bioreactors can be used to generate grafts of clinically relevant sizes and shapes. Despite these scientific and technological successes, there is uncertainty regarding the translational utility of bioreactor-based approaches due to the perceived high costs associated with these procedures. In fact, experiences over the past two decades have demonstrated that the widespread application of cell-based therapies is heavily dependent on the commercial viability. In this article, we directly address the question of whether bioreactors used to create bone grafts have the potential to be implemented in clinical approaches to bone repair and regeneration. We provide a brief review of tissue engineering approaches to bone repair, clinical trials that have employed cell-based methods, and advances in bioreactor technologies over the past two decades. These analyses are combined to provide a perspective on what is missing from the scientific literature that would enable an objective baseline for weighing the benefit of extended in vitro cultivation of cells into functional bone grafts against the cost of additional cultivation. In our estimation, the cost of bioreactor-based bone grafts may range from $10,000 to $15,000, placing it within the range of other widely used cell-based therapies. Therefore, in situations where a clear advantage can be established for engineered grafts comprising patient-specific, autologous cells, engineered bone grafts may be a clinically feasible option.
    • "The cells lining these spaces are then influenced by the mechanical stimulation provided by the fluid flow, differentiating or proliferating accordingly [125, 126]. Based on this knowledge, it is clear that the recapitulation of these mechanisms in vitro is essential for the growth and the regenerative properties of human osteoprogenitor cells seeded onto scaffolds [127]. In vitro, mechanical stimulation can encourage cells to produce extracellular matrix (ECM) in a shorter time period and in a more homogeneous manner than in static culture [128]. "
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    • "In order to further enhance successful manufacturing of sensitive TE products, we should not only aim to define and maintain optimum bioprocess conditions but to also minimize or eliminate all possible sources of variation (Mason and Hoare, 2007). Minimizing bioreactor batch-to-batch variability by ensuring process reproducibility has been highlighted as an important factor for the further maturation of TE and successful translation into the clinic (Salter et al., 2012). Furthermore preventing the development of localized " hot zones " within scaffolds (either excessive shear stress development or detrimental low mass transport regions) could be minimized by optimizing scaffold positioning and perfusion chamber geometry. "
    [Show abstract] [Hide abstract] ABSTRACT: Perfusion bioreactors have shown great promise for tissue engineering applications providing a homogeneous and consistent distribution of nutrients and flow-induced shear stresses throughout tissue-engineered constructs. However, non uniform fluid-flow profiles found in the perfusion chamber entrance region have been shown to affect tissue-engineered construct quality characteristics during culture. In this study a whole perfusion and construct, three dimensional (3D) computational fluid dynamics approach was used in order to optimize a critical design parameter such as the location of the regular pore scaffolds within the perfusion bioreactor chamber. Computational studies were coupled to bioreactor experiments for a case-study flow rate. Two cases were compared in the first instance seeded scaffolds were positioned immediately after the perfusion chamber inlet while a second group was positioned at the computationally determined optimum distance were a steady state flow profile had been reached. Experimental data showed that scaffold location affected significantly cell content and neo-tissue distribution, as determined and quantified by contrast enhanced nanoCT, within the constructs both at 14 and 21 days of culture. However gene expression level of osteopontin and osteocalcin was not affected by the scaffold location. This study demonstrates that the bioreactor chamber environment, incorporating a scaffold and its location within it, affects the flow patterns within the pores throughout the scaffold requiring therefore dedicated optimization that can lead to bone tissue engineered constructs with improved quality attributes.
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    • "It is estimated that the introduction of automated systems, would both decrease the capital and operation expenditure approximately by 50%, mainly due to decreased amounts of FTEs and building space. In particular, the cost of a bioreactor grown cell based ATMP for bone repair -based on currently available technology -is estimated within the range of $10 000 to $15 000 [163], thus finally resulting in premium price commercial products. Furthermore, it might be argued A C C E P T E D M A N U S C R I P T "
    [Show abstract] [Hide abstract] ABSTRACT: The development of cell based Advanced Therapeutic Medicinal Products (ATMPs) for bone repair has been expected to revolutionize the health care system for the clinical treatment of bone defects. Despite this great promise, the clinical outcomes of the few cell based ATMPs that have been translated into clinical treatments have been far from impressive. In part, the clinical outcomes have been hampered because of the simplicity of the first wave of products. In response the field has set-out and amassed a plethora of complexities to alleviate the simplicity induced limitations. Many of these potential second wave products have remained “stuck” in the development pipeline. This is due to a number of reasons including the lack of a regulatory framework that has been evolving in the last years and the shortage of enabling technologies for industrial manufacturing to deal with these novel complexities. In this review, we reflect on the current ATMPs and give special attention to novel approaches that are able to provide complexity to ATMPs in a straightforward manner. Moreover, we discuss the potential tools able to produce or predict ‘Goldilocks’ ATMPs, which are neither too simple nor too complex.
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