Cardiac Regeneration through Growth Factor Eluting Microrod Scaffolds

通过生长因子洗脱微棒支架实现心脏再生

• 批准号: 8294454
• 负责人: PAUL H GOLDSPINK
• 金额: $ 35.47万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294454
• 关键词: Accounting; Address; Adverse effects; Affect; Amino Acids; Animal Model; Animals; Apoptosis; Biological; Biomedical Engineering; Bone Marrow; Cardiac; Cardiac Myocytes; Cell Differentiation process; Cell Lineage; Cell Maturation; Cell Proliferation Regulation; Cell Survival; Cell physiology; Cells; Cellular biology; Characteristics; Chemicals; Cicatrix; Clinical; Collaborations; Cues; Development; Engraftment; Evaluation; Family; Gene Expression; Goals; Growth; Growth Factor; Healed; Health Care Costs; Heart; Heart failure; Hospitalization; Human; Hypertrophy; Hypoxia; In Vitro; Infarction; Injectable; Injection of therapeutic agent; Injury; Insulin-Like Growth Factor I; Kinetics; Legal patent; Measures; Mechanics; Mesenchymal; Mesenchymal Stem Cells; Modeling; Molecular; Mus; Muscle; Muscle Cells; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Neonatal; Outcome; Pathologic; Pathway interactions; Patients; Peptides; Physiological; Physiology; Prevention; Primary idiopathic dilated cardiomyopathy; Pump; Rattus; Recovery; Recovery of Function; Recruitment Activity; Research; Shipping; Ships; Somatomedins; Staging; Stem cells; Stress; System; Techniques; Technology; Tertiary Protein Structure; Testing; Time; Tissue Engineering; Tissues; United States; Variant; Ventricular; Ventricular Function; Work; abstracting; base; cardiac repair; cellular engineering; design; disability burden; functional gain; healing; hypertensive heart disease; improved; in vivo; member; migration; mortality; muscle regeneration; novel; novel strategies; novel therapeutics; physical property; prevent; progenitor; prohormone; public health relevance; repaired; scaffold; stem; stem cell differentiation; stem cell population; three-dimensional modeling; tissue regeneration; Accounting; Address; Adverse effects; Affect; Amino Acids; Animal Model; Animals; Apoptosis; Biological; Biomedical Engineering; Bone Marrow; Cardiac; Cardiac Myocytes; Cell Differentiation process; Cell Lineage; Cell Maturation; Cell Proliferation Regulation; Cell Survival; Cell physiology; Cells; Cellular biology; Characteristics; Chemicals; Cicatrix; Clinical; Collaborations; Cues; Development; Engraftment; Evaluation; Family; Gene Expression; Goals; Growth; Growth Factor; Healed; Health Care Costs; Heart; Heart failure; Hospitalization; Human; Hypertrophy; Hypoxia; In Vitro; Infarction; Injectable; Injection of therapeutic agent; Injury; Insulin-Like Growth Factor I; Kinetics; Legal patent; Measures; Mechanics; Mesenchymal; Mesenchymal Stem Cells; Modeling; Molecular; Mus; Muscle; Muscle Cells; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Neonatal; Outcome; Pathologic; Pathway interactions; Patients; Peptides; Physiological; Physiology; Prevention; Primary idiopathic dilated cardiomyopathy; Pump; Rattus; Recovery; Recovery of Function; Recruitment Activity; Research; Shipping; Ships; Somatomedins; Staging; Stem cells; Stress; System; Techniques; Technology; Tertiary Protein Structure; Testing; Time; Tissue Engineering; Tissues; United States; Variant; Ventricular; Ventricular Function; Work; abstracting; base; cardiac repair; cellular engineering; design; disability burden; functional gain; healing; hypertensive heart disease; improved; in vivo; member; migration; mortality; muscle regeneration; novel; novel strategies; novel therapeutics; physical property; prevent; progenitor; prohormone; public health relevance; repaired; scaffold; stem; stem cell differentiation; stem cell population; three-dimensional modeling; tissue regeneration

DESCRIPTION (provided by applicant): Five million heart failure patients in the US have poor cardiac pumping due to irreversible damage of the contractile myocytes. Thus, recovery of cardiac function by cell and tissue engineering is highly desirable. The novel approach proposed in this application combines bioengineering and cell biology-based techniques to directly target the regeneration of heart muscle, which is an important clinical problem not well addressed by current therapies. We have systemically delivered an artificial stabilized form of the mechano-growth factor (MGF), (24 amino acid, E-domain peptide from the prohormone) that is a member of the insulin-like growth factor (IGF) family and shown recovery of function in failing mouse hearts along with the mobilization of resident progenitor cells. We take advantage of the natural repair capacity of the heart by providing a microrod scaffold (MRS) to not only deliver the native, rapidly degradable MGF, but also provide local mechanical and topographic cues necessary for proper cellular connectivity and differentiation. Our overall hypothesis is that timed release of MGF and IGF-1 delivered locally by the MRS regenerates and strengthens the damaged myocardium without harmful side effects. This is tested on progenitor/stem cells and cardiac myocytes in culture and in animal models. Specific Aim 1 determines the effect of stiffness variation on cells grown in 3D microrod scaffolds. We optimize MRS characteristics for regulation of cell proliferation, lineage commitment, differentiation, contractile maturity and connectivity of stem cells and cardiac myocytes. Specific Aim 2 determines the effect of growth factor (GF)-loaded MRS in environmental conditions that mimic the normal and ischemic heart. We characterize encapsulation efficiency, GF biostability, and acellular release kinetics of the eluting MRS in vitro. We determine effects of GF release from MRS on proliferation and migration of progenitor/ stem and neonatal rat ventricular myocytes to establish changes in gene expression and cell survival under culture conditions that mimic the normal and ischemic heart. Specific Aim 3 determines the cellular, molecular and functional gains that occur at different stages following myocardial infarction after MRS delivery of GFs to the border zone of an infarct. We examine how GF release affects the migration and differentiation of cardiac progenitor cells in vivo. We examine the beneficial effects of localized MGF peptide delivery on cardiac function, prevention of cardiac myocyte apoptosis, prevention of adverse cardiac remodeling, and reduced scar formation. Our long-term goal is to develop microrod MGF therapy that supports the regeneration of cardiac muscle to regain cardiac function in the failing human heart. Public Health Relevance Statement (provided by applicant): Heart failure is a common condition carrying a high burden of disability and mortality. Current estimates are that heart failure accounts for approximately one million hospitalizations and $10 billion in health care costs in the United States per year. The main underlying causes of heart failure are ischemic heart disease, hypertension and idiopathic dilated cardiomyopathy, whose common pathophysiologic characteristic is an inadequate mass of functional myocytes. This proposal develops and tests a novel therapeutic 3D eluting microrod scaffold (MRS) system to deliver a natural cardiac growth factor for aiding in the regeneration and recovery of damaged cardiac muscle in culture and animal models.

描述（由申请人提供）： 由于收缩肌细胞的不可逆转损害，美国有500万心力衰竭患者的心脏泵送差。因此，非常需要通过细胞和组织工程来恢复心脏功能。该应用中提出的新方法结合了生物工程和基于细胞生物学的技术，以直接靶向心肌的再生，这是当前疗法无法很好地解决的重要临床问题。我们已系统地传递了机械增长因子（MGF）的人造稳定形式，（24个氨基酸，e域的肽从蛋白激素中）是胰岛素样生长因子（IGF）家族的成员，并显示出失败小鼠心脏中功能的恢复，以及居住的幼儿子细胞的动员。我们通过提供微型支架（MRS）来利用心脏的自然修复能力，不仅可以传递天然，迅速降解的MGF，而且还提供了适当的细胞连接性和分化所需的局部机械和地形线索。我们的总体假设是，MRS再生局部在本地传递的MGF和IGF-1的定时释放，并增强了受损的心肌而没有有害副作用。这对培养物和动物模型中的祖细胞/干细胞和心肌细胞进行了测试。 具体目标1决定了刚度变化对3D微型支架中生长的细胞的影响。我们优化了MRS特征，以调节细胞增殖，谱系承诺，分化，收缩成熟度以及干细胞和心肌细胞的连通性。 具体目标2决定了模仿正常和缺血性心脏的环境条件下，生长因子（GF）的MRS的影响。我们表征了封装效率，GF的生物稳定性和体外洗脱MRS的细胞释放动力学。我们确定GF从MRS释放对祖细胞/茎和新生大鼠心室心肌细胞的增殖和迁移的影响，以在模仿正常和缺血性心脏的培养条件下建立基因表达和细胞存活的变化。 特定目标3决定了MRS将GF递送到梗塞边界区后，在心肌梗塞后在不同阶段发生的细胞，分子和功能增长。我们研究了GF释放如何影响体内心脏祖细胞的迁移和分化。我们检查了局部MGF肽递送对心脏功能，预防心肌细胞凋亡，预防不良心脏重塑以及减少疤痕形成的有益作用。 我们的长期目标是开发微型MGF疗法，该疗法支持心脏肌肉的再生以恢复失败的人心心脏功能。 公共卫生相关性声明（由申请人提供）：心力衰竭是承担较高残疾和死亡负担的常见状况。目前的估计是，每年美国的心力衰竭约占住院和100亿美元的医疗费用。心力衰竭的主要根本原因是缺血性心脏病，高血压和特发性扩张性心肌病，其常见的病理生理特征是功能性肌细胞的质量不足。该建议开发和测试了一种新型的治疗3D洗脱微型支架（MRS）系统，以提供自然的心脏生长因子，以帮助培养和动物模型中受损的心脏肌肉的再生和恢复。