Organ engineering based on perfusion decellularized matrix

基于灌注脱细胞基质的器官工程

• 批准号: 8146680
• 负责人: HARALD C OTT
• 金额: $ 261.33万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8146680
• 关键词: Acute; Adult; Adverse effects; American; Americas; Architecture; Biopsy; Bioreactors; Cardiac Myocytes; Cardiovascular Diseases; Cell Transplants; Cells; Chronic Disease; Chronic Obstructive Airway Disease; Clinical; Diabetes Mellitus; Diagnosis; End stage renal failure; Endothelial Cells; Engineering; Engraftment; Epithelial Cells; Event; Extracellular Matrix; Goals; Healthcare; Heart; Heart failure; Human; Immunosuppression; Immunosuppressive Agents; Kidney Transplantation; Lung; Lung Transplantation; Organ; Organ Culture Techniques; Organ Donor; Organ Transplantation; Organ failure; Outcome; Patients; Perfusion; Population; Reporting; Research; System; Techniques; Technology; Time; Tissues; Transplantation; Western World; abstracting; base; cell assembly; cell type; design; flexibility; in vivo; innovation; liver transplantation; meetings; multidisciplinary; novel; patient population; pneumocyte; public health relevance; scaffold

DESCRIPTION (Provided by the applicant) Abstract: End organ failure is the leading health care challenge in the Western World. Improvements in management of acute events and chronic diseases led to a growing patient population suffering from single or multi organ failure. Nearly 6 million Americans suffer from heart failure with about 550,000 new cases diagnosed annually; 25 million Americans suffer from chronic obstructive pulmonary disease (COPD) with an estimated 12 million new yearly diagnoses; 530,000 Americans suffer from end stage renal disease. Organ transplantation is the only potentially curative therapy available. However, its outcomes are limited by donor organ shortage and the side effects of harsh immunosuppressive treatments. Organ engineering is a theoretical alternative to transplantation. Whole organs could be derived from patient's cells and transplanted similar to donor organs to overcome donor organ shortage, and the need for immunosuppression. Many important milestones have been met towards the goal to build replacement organs. Potential cell candidates have been derived from adult tissue biopsies and differentiated into some of the required cell types such as cardiomyocytes, endothelial cells, pneumocytes, epithelial cells. Culture conditions have been developed to induce the assembly of these cells into functional tissue constructs. However, construction of scaffolds that outline whole organ architecture and enable formation of human size grafts has been a major hurdle. The PI developed and reported a novel technique to isolate whole organ extracellular matrix (ECM) scaffolds by perfusion decellularization. In preliminary studies, these ECM scaffolds supported engraftment of cardiomyocytes and pneumocytes to form viable hearts and lungs that could be transplanted and function in vivo. Other groups have generated lung and liver grafts based on the same technology. We propose to further develop perfusion decellularized scaffolds as a platform for organ engineering by developing conditions suitable for human organs, deriving adult derived cell populations, designing human size bioreactor systems, and developing human organ culture conditions. The proposed research has a high potential clinical impact and may change the field of organ engineering. The project is highly innovative, and requires a creative and flexible multidisciplinary team. The PI as the inventor of the platform technology is an ideal candidate to perform the proposed research. Public Health Relevance: Cardiovascular disease, diabetes, and chronic obstructive pulmonary disease are the three most common chronic diseases in America. Organ transplantation is the only potentially curative therapy available. However, its outcomes are limited by donor organ shortage and the side effects of harsh immunosuppressive treatments. Indeed, there are today 91,000 total patients waiting for a heart, lung, or kidney transplant, with a 2003 median waiting time of 0.6, 2.5, and 3.3 years, respectively. As a result, 5237 Americans died waiting for a suitable donor organ in 2009. Organ engineering based on patient derived cells could offer an alternative to transplantation, potentially alleviating donor organ shortage, and the need for immunosuppression.

描述（由申请人提供） 摘要：终末器官衰竭是西方世界面临的主要医疗保健挑战。急性事件和慢性疾病管理的改进导致越来越多的患者遭受单一或多器官衰竭。近 600 万美国人患有心力衰竭，每年诊断出约 55 万例新病例； 2500 万美国人患有慢性阻塞性肺病 (COPD)，估计每年新增诊断人数为 1200 万； 530,000 美国人患有终末期肾病。器官移植是唯一可用的潜在治愈疗法。然而，其结果受到供体器官短缺和严厉的免疫抑制治疗的副作用的限制。器官工程是移植的理论上的替代方案。整个器官可以源自患者的细胞，并类似于供体器官进行移植，以克服供体器官短缺和免疫抑制的需要。朝着建造替代器官的目标已经实现了许多重要的里程碑。潜在的候选细胞来自成人组织活检，并分化为一些所需的细胞类型，如心肌细胞、内皮细胞、肺细胞、上皮细胞。已经开发出培养条件来诱导这些细胞组装成功能性组织结构。然而，构建勾勒出整个器官结构并能够形成人体大小移植物的支架一直是一个主要障碍。 PI 开发并报告了一种通过灌注脱细胞分离整个器官细胞外基质 (ECM) 支架的新技术。在初步研究中，这些 ECM 支架支持心肌细胞和肺细胞的植入，形成可移植并在体内发挥功能的活心脏和肺。其他小组也基于相同的技术进行了肺和肝移植。我们建议通过开发适合人体器官的条件、衍生成体细胞群、设计人体尺寸的生物反应器系统和开发人体器官培养条件，进一步开发灌注脱细胞支架作为器官工程的平台。拟议的研究具有很高的潜在临床影响，可能会改变器官工程领域。该项目具有高度创新性，需要一支富有创造力、灵活的多学科团队。作为平台技术发明者的 PI 是执行拟议研究的理想人选。 公共卫生相关性：心血管疾病、糖尿病和慢性阻塞性肺疾病是美国三种最常见的慢性疾病。器官移植是唯一可用的潜在治愈疗法。然而，其结果受到供体器官短缺和严厉的免疫抑制治疗的副作用的限制。事实上，目前共有 91,000 名患者等待心脏、肺或肾移植，2003 年的中位等待时间分别为 0.6 年、2.5 年和 3.3 年。结果，2009 年有 5237 名美国人在等待合适的捐赠器官时死亡。基于患者来源细胞的器官工程可以提供移植的替代方案，有可能缓解捐赠器官短缺和免疫抑制的需要。