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

Source: OAI
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.

Full-text preview

Available from:
  • Source
    • "The group at Drexel led by Chang et al. developed a three-dimensional liver micro-organ that consists of a microscale in vitro device housing a chamber of 3D liver cell-encapsuated hydrogelbased tissue that resembles the natural microenvironment of the hepatocyte in order to achieve biological functionality. A great enhancement of this system is that it included a dynamic perfusion in order to assess the cell metabolic function by perfusion of drugs [27] . Their model was developed to provide NASA with a liver tissue analog to assess drug pharmacokinetic profiles in planetary environments. "
    [Show abstract] [Hide abstract] ABSTRACT: In the field of transplantation, the demand for organs continues to increase and has far outpaced the supply. This ever-growing unmet need for organs calls for innovative solutions in order to save more lives. The development of new technologies in the field of biomedical engineering might be able to provide some solutions. With the advent of 3D bioprinting, the potential development of tissues or organ grafts from autologous cells might be within the reach in the near future. Based on the technology and platform used for regular 3D printing, 3D bioprinters have the ability to create biologically functional tissues by dispensing layer after layer of bioink and biogel that if left to mature with the proper environment will produce a functional tissue copy with normal metabolic activity. In the present day, 3D-bioprinted bladders, tracheal grafts, bone, and cartilage have proven to be functional after development and implantation in animal models and humans. Promising ongoing projects in different institutions around the world are focused on the development of 3D-bioprinted organs such as the livers and kidneys with integrated vasculature, in order for the tissue to be able to thrive once it has been transplanted. This review focuses on the background, the present, and the future of 3D bioprinting and its potential role in transplantation.
    Full-text · Article · Feb 2016
  • [Show abstract] [Hide abstract] 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.
    No preview · Article · Feb 2015 · Journal of Biomedical Materials Research Part B Applied Biomaterials