Engineering a Novel Bio-Scaffold for Hepatic Tissue Restoration and Drug Screening

设计用于肝组织恢复和药物筛选的新型生物支架

基本信息

批准号：
10631238
负责人：
Jamel Ali
金额：
$ 14.8万
依托单位：
FLORIDA AGRICULTURAL AND MECHANICAL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10631238
关键词：
3-Dimensional 3D Print Adoptive Transfer Animal Experiments Animal Model Autologous Biochemical Biocompatible Materials Biological Models Biomechanics Biomedical Engineering Cells Cessation of life Development Dialysis procedure Disease Drug Compounding Drug Screening Drug Targeting Engineering Evaluation Future Graft Rejection Health Hepatic Hepatic Tissue Hepatocyte Hepatotoxicity Human Immune response Implant In Vitro Individual Investigation Laboratories Legal patent Liver Liver Failure Liver diseases Measures Metabolic Methods Modeling Monitor Mus Organoids Pathology Persons Physiological Printing Property Publishing Reporting Structure System Therapeutic Tissue Donors Tissues Toxic effect Transplantation United States Work aging population bioprinting bioscaffold copolymer design diagnostic screening drug discovery effective therapy high throughput screening implantation in vitro Model in vivo in vivo Model in vivo engraftment in-vitro diagnostics indexing innovation liver function liver injury liver transplantation mimetics mouse model novel rapid technique response restoration scaffold screening success three dimensional cell culture tissue support frame tool viscoelasticity

项目摘要

Health issues associated with liver diseases afflict millions of individuals and account for over 70,000 deaths annually in the United States. Due in part to an aging population, liver diseases are expected to rise significantly over the next two decades, increasing the need for more effective treatment therapies and increased success rates with transplants. Unfortunately, there are no effective treatments to curb the pathology and there remains a shortage of available livers for transplantation. This challenge is further compounded with alloreactive responses leading to transplant rejection. However, a viable solution is the use of a model liver systems that accurately mimic the biomechanical and biochemical functioning of in vivo liver tissue. Additionally, alternative methods to expand recipient autologous hepatic cells while maintaining function would serve as efficient methods to generate liver systems for transplantation. However, while liver models for in vivo use have been attempted, none have yet successfully expanded autologous hepatic cells in vitro followed by successful implantation to alleviate liver failure in recipients using an in vivo model system. My laboratory has recently demonstrated success in this approach, where we have established an effective in vitro 3D hepatocyte culture system for rapid expansion. Furthermore our preliminary work shows great promise in applying the system for in vivo adoptive implantation using our innovative in-house designed 3D scaffold system. Therefore, this proposal's objective is to develop a method for rapid expansion of hepatic cells in a novel 3D printed bioscaffold for assembly of a liver organoid for in vivo tissue restoration and ex vivo drug screening. The central hypothesis is that primary hepatic cells seeded in a novel biomaterial scaffold will display similar metabolic function, structure, and biomechanical properties to that of the original liver tissues. The success of this approach will restore liver function following transplantation in a liver-damaged mouse model. The innovative combination of rheological biomaterial tuning, 3D bioprinting, and culture methods that utilize a novel bioscaffold will be applied in pursuit of two specific aims: 1) Engineering an ex vivo model for screening therapeutic drugs targeting hepatocytes through 3D printed bioscaffolds and 2) Development of an implantable hepatic organoid for in vivo tissue restoration to alleviate liver failure in a mouse model. These investigations will establish a platform for novel 3D culture systems for both rigorous in vitro diagnostic screening and for in vivo adoptive transfer approaches to physiologically restore failed liver function. The proposed work is significant as the anticipated results will establish a platform for future investigations utilizing the biomaterial for engineering cell seeded scaffolds to restore tissue function and in pursuit of drug discovery.

与肝脏疾病相关的健康问题折磨了数百万个人，并占70,000多人死亡每年在美国。部分原因是人口老龄化，肝病有望增加在接下来的二十年中，显着地增加了对更有效的治疗疗法的需求，随着移植的成功率提高。不幸的是，没有有效的治疗方法来遏制病理而且仍然缺乏可用的肝脏移植。这个挑战进一步加剧了同种反应反应导致移植排斥。但是，可行的解决方案是使用模型肝精确模拟体内肝组织的生物力学和生化功能的系统。此外，在维持功能的同时扩展受体自体肝细胞的替代方法将用作生成肝系统进行移植的有效方法。但是，肝脏模型用于体内尝试使用过，在体外没有成功扩展自体肝细胞，然后使用体内模型系统成功植入以减轻受体中的肝脏衰竭。我的实验室有最近在这种方法中证明了成功，在该方法中，我们建立了有效的体外3D肝细胞快速扩张的培养系统。此外，我们的初步工作在应用使用我们创新的内部设计的3D脚手架系统的体内收养植入系统。所以，该提议的目标是开发一种在新颖的3D印刷中快速扩展肝细胞的方法用于组装肝癌的Bioscaffold，用于体内组织恢复和体内药物筛查。这中心假设是，在新型生物材料支架中播种的原代肝细胞将显示相似原始肝组织的代谢功能，结构和生物力学特性。成功的成功这种方法将在肝脏受损的小鼠模型中移植后恢复肝功能。这利用一种利用一种的创新组合，3D生物印刷和培养方法的创新组合新颖的Bioscaffold将用于追求两个具体目标：1）工程筛查的离体模型通过3D印刷的生物效应靶向肝细胞的治疗药物和2）开发可植入用于体内组织恢复的肝癌，以减轻小鼠模型中的肝衰竭。这些调查将建立一个新型3D培养系统的平台，用于严格的体外诊断筛查和IN 生理恢复肝功能失败的体内收养转移方法。拟议的工作是意义重大，因为预期的结果将建立一个使用生物材料的未来调查平台工程细胞种子支架以恢复组织功能并追求药物发现。