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Biofabrication of three-dimensional liver cell-embedded tissue constructs for in vitro drug metabolism models

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ABSTRACT In their normal in vivo matrix milieu, tissues assume complex well-organized threedimensional architectures. Therefore, a primary aim in the tissue engineering design process is to fabricate an optimal analog of the in vivo scenario. This challenge can be addressed by applying emerging layered biofabrication approaches in which the precise configuration and composition of cells and bioactive matrix components can recapitulate the well-defined three-dimensional biomimetic microenvironments that promote cell-cell and cell-matrix interactions. Furthermore, the advent of and refinements in microfabricated systems can present physical and chemical cues to cells in a controllable and reproducible fashion unrealizable with conventional tissue culture, resulting in highfidelity, high-throughput in vitro models. As such, the convergence of layered solid freeform fabrication (SFF) technologies along with microfabrication techniques, a threedimensional micro-organ device can serve as an in vitro platform for cell culture, drug screening, or to elicit further biological insights, particularly for NASA’s interest of a flight-suitable high-fidelity microscale platform to study drug metabolism in space and planetary environments. A proposed model in this thesis involves the combinatorial setup of an automated syringe-based, layered direct cell writing bioprinting process with micropatterning techniques to fabricate a microscale in vitro device housing a chamber of bioprinted three-dimensional cell-encapsulated hydrogel-based tissue constructs in defined design patterns that biomimics the cell’s natural microenvironment for enhanced performance and functionality. In order to assess the structural formability and biological feasibility of such a micro-organ, reproducibly fabricated tissue constructs are biologically characterized for both viability and cell-specific function. Another key facet of the in vivo microenvironment that is recapitulated with the in vitro system is the necessary dynamic perfusion of the three-dimensional microscale liver analog with cells probed for their collective drug metabolic function and suitability as a drug metabolism model. This thesis details the principles, methods, and engineering science basis that undergird the direct cell writing fabrication process development and adaptation of microfluidic devices for the creation of a drug screening model, thereby establishing a novel drug metabolism study platform for NASA’s interest to adopt a microfluidic microanalytical device with an embedded three-dimensional microscale liver tissue analog to assess drug pharmacokinetic profiles in planetary environments.

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    ABSTRACT: Advances in micro-electro-mechanical systems (MEMS) have led to an increased fabrication of micro-channels. Microfabrication techniques are utilized to develop microfluidic channels for continuous nutrition supply to cells inside a micro-environment. The ability of cells to build tissues and maintain tissue-specific functions depends on the interaction between cells and the extracellular matrix (ECM). SU-8 is a popular photosensitive epoxy-based polymer in MEMS. The patterning of bare SU-8 alone does not provide the appropriate ECM necessary to develop microsystems for biological applications. Manipulating the chemical composition of SU-8 will enhance the biological compatibility, giving the fabricated constructs the appropriate ECM needed to promote a functional tissue array. This article investigates three frequently used surface treatment techniques: (1) plasma treatment, (2) chemical reaction, and (3) deposition treatment to determine which surface treatment is the most beneficial for enhancing the biological properties of SU-8. The investigations presented in this article demonstrated that the plasma, gelatin, and sulfuric acid treatments have a potential to enhance SU-8's surface for biological application. Of course each treatment has their advantages and disadvantages (application dependent). Cell proliferation was studied with the use of the dye Almar Blue, and a micro-plate reader. After 14 days, cell proliferation to plasma treated surfaces was statistically significantly enhanced (p < 0.00001), compared to untreated surfaces. The plasma treated surface is suggested to be the better of the three treatments for biological enhancement followed by gelatin and sulfuric acid treatments, respectively. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2014.
    Journal of Biomedical Materials Research Part B Applied Biomaterials 02/2015; 103(2). DOI:10.1002/jbm.b.33223 · 2.33 Impact Factor

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