Synthetic vascularization and regeneration in engineered tissues

工程组织中的合成血管化和再生

基本信息

批准号：
10566387
负责人：
SANGEETA N. BHATIA
金额：
$ 56.52万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10566387
关键词：
3-Dimensional Address Automobile Driving Biological Models Biology Blood Vessels Blood capillaries Buffers Cell Communication Cell Signaling Process Cells Clinical Communities Complex Disease Endothelial Cells Endothelium Endowment Engineering Engraftment Environment Experimental Models Fiber Fibroblasts Gene Expression Generations Goals Growth Hepatic Hepatic Tissue Hepatocyte Human Human Engineering Implant In Vitro Injury Life Liver Liver parenchyma Mediating Microfluidics Modeling Mus Natural regeneration Organ Organ Size Organ Transplantation Oxygen Paracrine Communication Pattern Perfusion Physiological Play Process Regenerative Medicine Regenerative capacity Regenerative engineering Research Personnel Role Signal Transduction Solid Stromal Cells System Systems Integration Technology Therapeutic Tissue Engineering Tissue Grafts Tissues Transplantation Variant Vascular blood supply Vascularization cell type density dosage efficacy testing fitness implantation improved in vitro Model in vivo in vivo Model innovative technologies insight intercellular communication liver injury liver transplantation novel strategies paracrine regenerative release factor response synthetic biology tool transcription factor vascular tissue engineering

项目摘要

Project Description The goal of this NEW PROJECT is to engineer liver tissue grafts in which the timing and extent of graft vascularization and expansion in a living host is directly manipulable. In vivo, cell-to-cell communication mediated through paracrine signals is a hallmark of multicellular life, and in the liver is thought to play a critical role in driving tissue vascularization and growth. In collaborative studies, the investigators have recently established experimental models of liver tissue that incorporate hepatocytes, endothelial cells, and stromal cells spatially patterned to bolster these cell-cell interactions. These interactions enable vascularization regenerative expansion of engineered human liver tissue both in vitro, in a microfluidic human liver model, and in vivo, in an ectopically implanted human liver graft. In this proposal, the investigators will build upon these model systems by leveraging synthetic transcription factors to take control over the dynamics of paracrine signaling within the engineered livers to enable controlled, on-demand tissue vascularization and expansion. The specific aims of this new proposal are: (1) To build functional vasculature in engineered tissue through synthetic vascularization, (2) To establish on-demand expansion of engineered functional liver tissue through synthetic regeneration, and (3) To develop approaches for system integration and robustness in suboptimal host environments. Together, leveraging both in vitro and in vivo models, these efforts will endow precise control of function, expansion, and engraftment of engineered vasculature and hepatic parenchyma and will more generally establish a new approach for synthetic control of engineered tissues that will advance engineered organ grafts closer towards clinical utility.

项目描述这个新项目的目标是设计肝组织移植物，其中时间和程度活体宿主中移植血管的形成和扩张是可以直接操作的。体内、细胞间通过旁分泌信号介导的通讯是多细胞生命的一个标志，肝脏被认为在驱动组织血管化和生长方面发挥着关键作用。在协作中研究人员最近建立了肝组织实验模型结合肝细胞、内皮细胞和基质细胞，以空间模式支持这些细胞细胞与细胞的相互作用。这些相互作用使血管再生扩张在体外（微流体人类肝脏模型）和体内（在）中工程化人类肝脏组织异位移植的人类肝移植物。在这项提议中，研究人员将建立在这些模型系统通过利用合成转录因子来控制工程肝脏内旁分泌信号的动力学，以实现受控的、按需的组织血管化和扩张。这项新提案的具体目标是： (1) 建立通过合成血管形成工程组织中的功能性脉管系统，(2) 建立通过合成再生按需扩展工程功能性肝组织，以及 (3) 开发次优主机中的系统集成和鲁棒性方法环境。这些努力将共同利用体外和体内模型精确控制工程脉管系统和肝脏的功能、扩张和植入薄壁组织，并将更普遍地建立一种新的综合控制方法工程组织将推动工程器官移植更接近临床应用。