Bone tissue engineering bioreactors: a role in the clinic?
ABSTRACT 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.
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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.Biotechnology and Bioengineering 06/2014; · 4.16 Impact Factor
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ABSTRACT: Online and non-invasive quantification of critical tissue engineering (TE) construct quality attributes in TE bioreactors is indispensable for the cost-effective up-scaling and automation of cellular construct manufacturing. However, appropriate monitoring techniques for cellular constructs in bioreactors are still lacking. This study presents a generic and robust approach to determine cell number and metabolic activity of cell-based TE constructs in perfusion bioreactors based on single oxygen sensor data in dynamic perfusion conditions. A data-based mechanistic modeling technique was used that is able to correlate the number of cells within the scaffold (R2 = 0.80) and the metabolic activity of the cells (R2 = 0.82) to the dynamics of the oxygen response to step changes in the perfusion rate. This generic non-destructive measurement technique is effective for a large range of cells, from as low as 1.0 × 105 cells to potentially multiple millions of cells, and can open-up new possibilities for effective bioprocess monitoring. Biotechnol. Bioeng. © 2014 Wiley Periodicals, Inc.Biotechnology and Bioengineering 04/2014; · 4.16 Impact Factor
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ABSTRACT: The use of multifactorial design of experiments (DoE) in tissue engineering bioprocess development will contribute to the robust manufacturing of tissue engineered constructs by linking their quality characteristics to bioprocess operating parameters. In this work, perfusion bioreactors were used for the in vitro culture and osteogenic differentiation of human periosteum-derived cells (hPDCs) seeded on three-dimensional titanium (Ti) alloy scaffolds. A CaP-supplemented medium was used to induce differentiation of the cultured hPDCs. A two-level, three-factor fractional factorial design was employed to evaluate a range of bioreactor operating conditions by changing the levels of the following parameters: flow rate (0.5–2 mL/min), cell culture duration (7–21 days) and cell seeding density (1.5 × 10^3–3 × 10^3 cells/cm2). This approach allowed for evaluating the individual impact of the aforementioned process parameters upon a range of genes that are related to the osteogenic lineage, such as collagen type I, alkaline phosphatase, osterix, osteopontin and osteocalcin. Furthermore, by overlaying gene-specific response surfaces, an integrated operating process space was highlighted within which predetermined values of the six genes of interest (i.e., gene signature) could be minimally met over the course of the bioreactor culture time.Processes. 08/2014; 2(3):639-657.