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.

与肝病相关的健康问题困扰着数百万人，并导致超过 70,000 人死亡每年在美国。部分由于人口老龄化，肝脏疾病预计会增加未来二十年显着增加对更有效治疗方法的需求提高移植的成功率。不幸的是，没有有效的治疗方法来抑制病理学用于移植的肝脏仍然短缺。这一挑战进一步加剧同种异体反应导致移植排斥。然而，一个可行的解决方案是使用模型肝脏准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增受体自体肝细胞的替代方法将作为生成用于移植的肝脏系统的有效方法。然而，虽然体内肝脏模型已经尝试过使用，但尚未成功地在体外扩增自体肝细胞使用体内模型系统成功植入以减轻受体的肝衰竭。我的实验室有最近证明了这种方法的成功，我们建立了有效的体外 3D 肝细胞文化体系快速扩张。此外，我们的前期工作显示出应用该方法的巨大前景使用我们创新的内部设计的 3D 支架系统进行体内过继植入的系统。所以，该提案的目标是开发一种在新型 3D 打印肝细胞中快速扩增的方法用于组装肝脏类器官的生物支架，用于体内组织修复和离体药物筛选。这中心假设是，接种在新型生物材料支架中的原代肝细胞将表现出类似的特征代谢功能、结构和生物力学特性与原始肝组织的代谢功能、结构和生物力学特性相同。的成功这种方法将在肝损伤小鼠模型移植后恢复肝功能。这流变生物材料调节、3D 生物打印和培养方法的创新组合，利用新型生物支架将用于实现两个具体目标：1）设计用于筛选的离体模型通过 3D 打印生物支架靶向肝细胞的治疗药物以及 2) 开发可植入的用于体内组织修复以减轻小鼠模型肝衰竭的肝类器官。这些调查将建立一个新型 3D 培养系统平台，用于严格的体外诊断筛选和体内体内过继转移方法可在生理上恢复衰竭的肝功能。拟议的工作是意义重大，因为预期结果将为利用生物材料的未来研究建立一个平台工程化细胞接种支架以恢复组织功能并追求药物发现。