Multifunctional Printed Scaffolds for Enhancing Hepatocyte Viability and Function

用于增强肝细胞活力和功能的多功能印刷支架

• 批准号: 9118273
• 负责人: Ramille N Shah
• 金额: $ 13.03万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-13 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118273
• 关键词: 3D Print; Address; Adherent Culture; Adhesions; Affect; Anabolism; Appointment; Architecture; Area; Award; Behavior; Binding; Biochemical; Biocompatible Materials; Biological Assay; Biology; Biomedical Research; Cell Aggregation; Cell Culture Techniques; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cellular Morphology; Cellular biology; Cessation of life; Chemistry; Clinical; Coculture Techniques; Collagen; Collagen Type I; Controlled Study; Cues; DNA; Data; Deposition; Dermal; Development; Doctor of Philosophy; Engineering; Evaluation; Excision; Extracellular Matrix; FGF2 gene; Faculty; Fibroblasts; Foundations; Funding; Gelatin; Gene Expression; Genes; Geometry; Goals; Grant; Growth; Growth Factor Gene; HGF gene; Health; Healthcare; Heparin Binding; Hepatic; Hepatocyte; Hepatology; Human; Image; Immunocompromised Host; Implant; In Vitro; Institutes; Investigation; Joints; Journals; Knowledge; Learning; Life; Liver; Liver Regeneration; Liver diseases; Manuscripts; Massachusetts; Medicine; Mentors; Mentorship; Methods; Modeling; Molecular Biology; Mus; Musculoskeletal; Musculoskeletal System; Nanostructures; Natural regeneration; Nutrient; Operative Surgical Procedures; Organ; Pathology; Patients; Pattern; Peptides; Polymerase Chain Reaction; Postdoctoral Fellow; Preparation; Printing; Process; Property; Regenerative Medicine; Research; Research Design; Research Methodology; Research Personnel; Research Training; Rodent Model; Role; SCID Mice; Secure; Services; Signal Transduction; Soy Proteins; Spatial Design; Staging; Staining method; Stains; Stromal Cells; Structure; Supporting Cell; System; Techniques; Technology; Testing; Tissue Donors; Tissue Engineering; Tissues; Training Programs; Transplantation; Universities; Vascular Endothelial Growth Factors; Work; alternative treatment; angiogenesis; articular cartilage; base; biomaterial compatibility; biomaterial development; bioprinting; career; cartilage regeneration; cell behavior; design; experience; geometric structure; in vivo; induced pluripotent stem cell; intercellular communication; interest; liver cell proliferation; liver repair; liver transplantation; materials science; medical schools; migration; mouse model; nanobiotechnology; nanofiber; nanomedicine; novel; paracrine; professor; programs; research facility; research study; response; scaffold; self assembly; skills; subcutaneous; symposium; three dimensional cell culture; tissue regeneration; trend

DESCRIPTION (provided by applicant): The long-term career goal of the candidate, Dr. Ramille Shah, is to become an independent investigator and leader at the forefront of the liver regeneration field. Her immediate objective is to gain the knowledge, skill and experience needed to perform relevant and impactful research in the area of liver tissue engineering. Dr. Shah is completely committed to biomedical research, as demonstrated by completion of her Ph.D. involving the development of gene-supplemented collagen scaffolds for articular cartilage regeneration at the Massachusetts Institute of Technology and with two years of post-doctoral research involving the investigation of self-assembling peptide amphiphile nanostructures for regenerative medicine at Northwestern University's Institute for BioNanotechnology in Medicine. Currently, she is an Assistant Professor with joint appointments in the Department of Materials Science and Engineering and Department of Surgery (Transplant Surgery division) at Northwestern University. Dr. Shah's past research had mainly focused on the development of biomaterial systems for musculoskeletal regeneration, and she is now venturing into a new area of liver regeneration. Although her regenerative medicine target has changed, she has an excellent foundation in biomaterials and tissue engineering to apply what she has learned and experienced over the years in musculoskeletal tissue engineering to this new target area. This award will give her the opportunity to receive the research training, institutional support, and mentorship she needs to be able to transition into an independent investigator in the liver regeneration field. Dr. Shah's mentors in this K01 proposal consist of well-established and recognized clinicians (Dr. Janardan Reddy-Pathology and Dr. Richard Green-Hepatology) in the hepatic biology field, as well as a world- renowned researcher (Dr. Samuel Stupp-Materials Science and Engineering, Chemistry and Medicine) in the field of self-assembly and nanomedicine. She has their full support in helping hr develop into a successful independent investigator by providing valuable input on research design and methods, troubleshooting, scientific direction, and guidance in the preparation of manuscripts, grants, and presentations. Through interactions with both her mentors and collaborators she will be able to develop molecular biology and biochemical assay techniques, as well as in vitro and in vivo evaluation methods to characterize the behavior of hepatocytes, assess normal function, and understand the mechanisms behind cell-matrix interactions. With NU's strong research and training programs she will also have opportunities to interact with other faculty in the engineering and medical schools who share similar research interests through seminars, conferences, and journal clubs. NU's state of-the-art research facilities and technical support staff will also help Dr. Shah accomplish her proposed research aims. Furthermore, through formal coursework offered by NU's Graduate Program, Dr. Shah will be able to increase her knowledge in basic cell and molecular biology to help her interpret her research results. In addition, she has the opportunity to participate in seminars and conferences within the Hepatology service in the medical school to increase her knowledge of clinical hepatology. The proposed research aims to use multifunctional 3D bioprinted scaffolds incorporating bioactive agents such peptide nanostructures and support cells to enhance the viability and function of hepatocytes fr liver tissue engineering. The lack of liver donors for patients with end stage liver disease (ESLD) is a major healthcare obstacle. Developing organ replacements or functional liver units using tissue engineering strategies as an alternative treatment is a promising possibility to alleviate this significant need. The interplay between microenvironmental cues and cell behavior in liver tissue engineering, however, is still not well understood. This research hopes to establish and understand trends in 3D scaffold design and bioactive agent delivery to start to identify key components in the microenvironment that can enhance liver cell function and normal liver tissue formation both in vitro and in vivo. The hypothesis is that the viability and function of hepatocytes can be significantly enhanced by: 1) optimizing scaffold architecture, which can alter hepatocyte aggregation and cell-cell contact~ 2) including functional moieties for growth factor delivery via self-assembling peptide amphiphile (PA) nanofibers~ and 3) co-culturing stromal cells and hepatocytes with 3D spatial control. Small "liver units" will be created using 3D bioplotted scaffolds of varying pore size and geometry, peptide- based nanostructures and growth factors for bioactive signaling, and liver cells (primary hepatocytes, induced pluripotent stem cell-derived hepatocytes, and stromal cells) that are spatially patterned in 3D to change microenvironmental cues and determine what conditions promote optimal hepatocyte viability and function. Materials characterization, in vitro evaluation of viability, proliferation, and function, as well as in vivo assessment of angiogenesis, scaffold degradation, and tissue synthesis will be performed to evaluate the potential of these multifunctional scaffolds for liver tissue engineering. The reslts from this research will provide the necessary preliminary data for securing R01 funding that will help establish Dr. Shah as an independent investigator in the liver tissue engineering field.

描述（由申请人提供）： 候选人 Ramille Shah 博士的长期职业目标是成为一名独立调查员和前沿的领导者 肝脏再生领域。 她的近期目标是获得在肝组织工程领域进行相关且有影响力的研究所需的知识、技能和经验。 Shah 博士完全致力于生物医学研究，她完成博士学位就证明了这一点。 涉及在麻省理工学院开发用于关节软骨再生的基因补充胶原蛋白支架，并进行了两年的博士后研究，涉及自组装肽的研究 西北大学医学生物纳米技术研究所用于再生医学的两亲性纳米结构。 目前，她是西北大学材料科学与工程系和外科系（移植外科部）的助理教授。 Shah 博士过去的研究主要集中在肌肉骨骼再生生物材料系统的开发上，现在她正在尝试进入肝脏再生的新领域。 尽管她的再生医学目标发生了变化，但她在生物材料和组织工程方面拥有良好的基础，可以将多年来在肌肉骨骼组织工程方面学到的知识和经验应用到这个新的目标领域。 该奖项将使她有机会接受她所需的研究培训、机构支持和指导，以便她能够转变为肝再生领域的独立研究者。 Shah 博士在此 K01 提案中的导师包括肝脏生物学领域知名且公认的临床医生（病理学 Janardan Reddy 博士和肝病学 Dr. Richard Green），以及世界知名的研究人员（Samuel Stupp 博士） -材料科学与工程、化学与医学）自组装和纳米医学领域。 她得到了他们的全力支持，通过在研究设计和方法、故障排除、科学方向以及手稿、资助和演示文稿准备方面的指导提供宝贵的意见，帮助人力资源部发展成为一名成功的独立研究者。 通过与导师和合作者的互动，她将能够开发分子生物学和生化测定技术，以及体外和体内评估方法来表征肝细胞的行为，评估正常功能，并了解细胞基质背后的机制互动。 凭借国立大学强大的研究和培训项目，她还将有机会通过研讨会、会议和期刊俱乐部与工程学院和医学院的其他具有相似研究兴趣的教师进行互动。 NU的状态 最先进的研究设施和技术支持人员也将帮助沙阿博士实现她提出的研究目标。 此外，通过NU研究生项目提供的正式课程，Shah博士将能够增加她在基础细胞和分子生物学方面的知识，以帮助她解释她的研究结果。 此外，她还有机会参加医学院肝病学服务范围内的研讨会和会议，以增加她的临床肝病学知识。 拟议的研究旨在使用多功能3D生物打印支架，结合肽纳米结构和支持细胞等生物活性剂，以增强肝脏组织工程中肝细胞的活力和功能。 终末期肝病（ESLD）患者缺乏肝脏捐献者是一个主要的医疗障碍。 使用组织工程策略作为替代治疗开发器官替代品或功能性肝脏单元是缓解这一重大需求的有希望的可能性。 然而，肝脏组织工程中微环境线索和细胞行为之间的相互作用仍不清楚。 这项研究希望建立并了解 3D 支架设计和生物活性剂递送的趋势，以开始识别微环境中可以增强肝细胞功能和正常肝组织形成的关键成分 体外和体内。 假设肝细胞的活力和功能可以通过以下方式显着增强：1）优化支架结构，这可以改变肝细胞聚集和细胞与细胞的接触〜2）包括通过自组装肽两亲物（PA）输送生长因子的功能部分) 纳米纤维~ 和 3) 通过 3D 空间控制共培养基质细胞和肝细胞。 将使用不同孔径和几何形状的 3D 生物标绘支架、基于肽的纳米结构和用于生物活性信号传导的生长因子以及肝细胞（原代肝细胞、诱导多能干细胞衍生的肝细胞和基质细胞）来创建小型“肝脏单位”在空间上 3D 模式化以改变微环境线索并确定哪些条件可以促进最佳肝细胞活力和功能。 将进行材料表征、活力、增殖和功能的体外评估，以及血管生成、支架降解和组织合成的体内评估，以评估这些多功能支架在肝组织工程中的潜力。 这项研究的结果将为获得 R01 资金提供必要的初步数据，这将有助于 Shah 博士成为肝脏组织工程领域的独立研究者。