Current drug discovery and development practices have resulted in considerably long development time frames and low success rates of new drugs reaching market. Few improvements on efficiency and poor cost versus benefits in R&D have also caused post approval costs as high as $2.87 billion in 2013. Together, these factors drive the demand to improve current practices and turn to new innovative technologies that are able to facilitate the introduction of more successful drugs with higher efficiency and cost effectiveness. It is well recognized that a key bottleneck in the pharmaceutical R&D sector is the lack of appropriate validation tools for accurate selection of prime drug candidates in the early stages. To circumvent this issue, new technologies such as high throughput screening (HTS) platforms are emerging. In addition, pharmaceutical companies are adapting 3D tissue culture platforms to better recapitulate the in vivo microenvironment to provide more physiologically relevant predictive data. Ultimately, an HTS system that incorporates 3D biomimetic tissue cultures would be a significant advancement to current technologies in early stage drug development. This proposal aims to develop a high throughput optical projection (hTOP) bioprinter that can directly print human liver tissue models within conventional multi-well cell culture plates for applications in high throughput preclinical drug screening. Specific Aim 1 will focus on the development of the hTOP bioprinter and its use to create 3D hydrogel constructs within a 24-well cell culture plate. In Specific Aim 2, we will optimize and characterize the ability to reproducibly print identical constructs within multiple wells and also the flexibility to print various designs. In Specific Aim 3, we will demonstrate the use of hTOP to bioprint 3D human liver tissues in a high throughput manner using iPSC-derived hepatocytes and liver-specific supportive cells to produce a physiologically relevant biomimetic model. Cell viability and hepatic function will be investigated along with studies on drug metabolism and drug-induced hepatotoxicity using our 3D biomimetic human liver model. Our hTOP bioprinting platform will serve as a commercially powerful instrument for the mass production of in vitro 3D tissue models for early-stage high throughput drug screening. More specifically, the hTOP bioprinter offers microscale printing resolution and superior printing speed compared to traditional bioprinters. Furthermore, the bioprinted iPSC-derived human liver model will provide a more reliable and clinically relevant platform to test drug-induced hepatotoxicity during preclinical trials. While the hTOP will be used to demonstrate the fabrication of a human liver biomimetic model in this work, it can also be readily adapted to print other biomimetic tissue models such as heart, kidney, and nerve tissues. Success of this project will significantly improve the predictive accuracy of preclinical drug studies and lower the cost of drug development towards improving public health.
Public Health Relevance Statement: Project Narrative The project seeks to develop a high-throughput 3D bioprinting platform to create in vitro functional human liver tissues using human induced pluripotent stem cells. Such tissue models can facilitate preclinical drug screening and disease studies. Success of this proposal would lead to significant reduction in cost for drug development and time to clinical use.
Project Terms: 3-Dimensional; Address; Animal Model; Animal Testing; Automation; base; Basic Science; Biocompatible Materials; Biological; Biomimetics; bioprinting; Cell Culture System; Cell Culture Techniques; Cell Density; Cell Survival; cell type; Cells; Clinical; clinically relevant; Complex; cost; cost effectiveness; culture plates; Custom; Data; Deposition; design; Development; Disease; drug candidate; Drug Costs; drug development; drug discovery; Drug Industry; drug metabolism; Drug Screening; drug testing; Encapsulated; Endothelial Cells; Ensure; Failure; feeding; flexibility; Gelatin; glycidyl methacrylate; Heart; Hepatic; Hepatic Stellate Cell; Hepatocyte; Hepatotoxicity; high throughput screening; Human; Hyaluronic Acid; Hydrogels; improved; In Vitro; in vivo; induced pluripotent stem cell; innovation; innovative technologies; instrument; Island; Kidney; Lasers; Lead; light intensity; lightspeed; Liver; Lobule; mechanical properties; Methacrylates; Methods; miniaturize; Modeling; Molecular Target; Nerve Tissue; new technology; novel; novel therapeutics; Optics; Pattern; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiological; pre-clinical; Preclinical Testing; preclinical toxicity; preclinical trial; Predictive Value; Printing; Process; Production; Public Health; Reproducibility; research and development; Resolution; Speed; success; System; Technology; Thick; Time; tissue culture; Tissue Model; Tissues; tolcapone; tool; Toxicity Tests; troglitazone; two-photon; Validation; Viscosity; Work
