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: 8731232
• 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/8731232
• 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; Commit; Controlled Study; Cues; DNA; Data; Deposition; Dermal; Development; Doctor of Philosophy; Engineering; Evaluation; Excision; Extracellular Matrix; Faculty; Fibroblast Growth Factor 2; Fibroblasts; Foundations; Funding; Gelatin; Gene Expression; Genes; Geometry; Goals; Grant; Growth; Growth Factor; Growth Factor Gene; Healthcare; Heparin Binding; Hepatic; Hepatocyte; Hepatocyte Growth Factor; 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; Science; 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; 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; medical schools; migration; mouse model; nanobiotechnology; nanofiber; nanomedicine; novel; paracrine; poly(L-lactide); professor; programs; public health relevance; research facility; research study; response; scaffold; self assembly; skills; subcutaneous; symposium; 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独立的调查员和领导者 肝脏再生场。 她的直接目标是获得在肝组织工程领域进行相关和有影响力的研究所需的知识，技巧和经验。 Shah博士完全致力于生物医学研究，如她的博士学位所证明的那样。 涉及马萨诸塞州技术研究所的关节软骨再生基因供应胶原蛋白支架的开发，并进行了两年的博士后研究，涉及研究自组装肽的研究 西北大学医学研究所再生医学的两亲纳米结构。 目前，她是西北大学材料科学与工程系和外科（移植手术部）联合任命的助理教授。 Shah博士过去的研究主要集中于用于肌肉骨骼再生的生物材料系统的发展，现在她正在进入肝脏再生的新领域。 尽管她的再生医学靶标发生了变化，但她在生物材料和组织工程方面拥有出色的基础，以应用她多年来在肌肉骨骼组织工程工程中学到的知识和经验。 该奖项将使她有机会接受研究培训，机构支持和指导，以便能够过渡到肝脏再生领域的独立研究者。 Shah博士在这项K01提案中的导师包括肝生物学领域的公认和公认的临床医生（Janardan Reddy-Parogy博士和Richard Green-Hepotology），以及世界知名的研究员（Samuel Stupp-Materials科学与工程学，化学和医学，化学，化学和医学）和自占自给自足的领域。 她通过提供有关研究设计和方法，故障排除，科学方向和指导的有价值的意见，在准备手稿，赠款和演示文稿方面提供宝贵的意见，以帮助人力资源发展成为成功的独立研究者。 通过与她的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，以表征肝细胞的行为，评估正常功能，并了解细胞 - 矩阵相互作用背后的机制。 通过NU的强大研究和培训计划，她还将有机会与通过研讨会，会议和期刊俱乐部分享类似研究兴趣的工程和医学院的其他教师互动。 NU的状态 艺术研究机构和技术支持人员还将帮助Shah博士实现她拟议的研究目标。 此外，通过NU研究生课程提供的正式课程，Shah博士将能够提高她在基本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，她有机会参加医学院肝脏学服务中的研讨会和会议，以提高她对临床肝病学的了解。 拟议的研究旨在使用掺入此类肽纳米结构和支持细胞的多功能3D生物打印支架，以增强肝脏肝组织工程的生存能力和功能。 缺乏针对末期肝病（ESLD）患者的肝脏供体是主要的医疗障碍。 使用组织工程策略作为替代方法开发器官替换或功能性肝单元是减轻这种巨大需求的有希望的可能性。 然而，微环境提示与肝组织工程中细胞行为之间的相互作用尚不清楚。 这项研究希望建立和理解3D支架设计和生物活性剂传递的趋势，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组成部分 体外和体内。 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. 小型“肝单元”将使用不同的孔径和几何形状，基于肽的纳米结构以及生物活性信号传导的纳米结构和生长因子以及肝细胞（原发性肝细胞，诱导多能干细胞衍生的肝细胞）和肝细胞的生长因子以及生长因子，这些小型肝脏和生长因子具有不同的毛孔和生长因子，这些孔隙和肝细胞是小型的“肝单元”。 以3D模式改变微环境提示，并确定哪些条件促进了最佳的肝细胞生存力和功能。 材料表征，体外评估生存力，增殖和功能以及血管生成，支架降解和组织合成的体内评估，以评估这些多功能支架的肝脏组织工程的潜力。 这项研究的Reslts将提供必要的初步数据，以确保R01资金，这将有助于将Shah博士确立为肝组织工程领域的独立研究人员。