Synthetic hydrogel for satellite cell delivery to the dystrophic diaphragm

用于将卫星细胞递送至营养不良隔膜的合成水凝胶

• 批准号: 9901554
• 负责人: Woojin Han
• 金额: $ 5.65万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901554
• 关键词: 3-Dimensional; Adhesions; Adhesives; Affect; Atelectasis; Atrophic; Binding; Biochemical; Biocompatible Materials; Biomedical Engineering; Biophysics; Breathing; Bypass; CRISPR/Cas technology; Caring; Cell Adhesion; Cell Transplantation; Cell physiology; Cells; Cessation of life; Clinic; Collagen; Coupling; Cues; Deterioration; Dimensions; Disease; Disease Progression; Duchenne muscular dystrophy; Dystroglycan; Dystrophin; Encapsulated; Engineering; Engraftment; Extracellular Matrix; Foundations; Gel; Genes; Genetic Diseases; Goals; Health; Heart failure; Hydrogels; In Vitro; Inferior; Injections; Integrins; Life Expectancy; Ligands; Link; Location; Luciferases; Maleimides; Mechanical ventilation; Mechanics; Mediating; Mus; Muscle; Muscle Contraction; Muscle Weakness; Muscle function; Muscle satellite cell; Muscular Atrophy; Neuromuscular Diseases; Neuromuscular Junction; Newborn Infant; Outcome; Outcomes Research; Patients; Peptides; Pharmaceutical Preparations; Pneumonia; Polyethylene Glycols; Proteins; Quality of life; Respiratory Diaphragm; Respiratory Failure; Respiratory physiology; Role; Sarcolemma; Structure; Surface; Technology; Testing; Therapeutic; Thinness; Translating; Treatment Efficacy; Work; X-Linked Genetic Diseases; aged; base; biomaterial compatibility; clinical application; crosslink; design; disability; emerging adult; healthspan; improved; improved functioning; in vivo; induced pluripotent stem cell; male; migration; muscle regeneration; palliative; premature; receptor binding; respiratory; restoration; satellite cell; syndecan; syndecan 3; synthetic peptide; treatment strategy; ventilation

ABSTRACT Duchenne muscular dystrophy is an X-linked genetic disorder that begets debilitating health consequences. Most affected patients do not live past their early adulthood primarily due to respiratory complications (e.g., decreased breathing, pneumonia and atelectasis) caused by deterioration of the diaphragm muscle. Current respiratory care therapies, such as mechanically assisted ventilation, remain palliative, and an effective therapeutic strategy targeting the diaphragm muscle to restore the respiratory capacity is a critical need. The objective of this project is to develop a biomaterial-mediated strategy to deliver and engraft muscle satellite cells to the diaphragm to reinstate the respiratory function through restoration of dystrophin, excitation-contraction coupling, and mechanical stability. This objective will be achieved by (1) engineering a synthetic biomaterial that is capable of maintaining and directing muscle satellite cell function in 3D and (2) delivering satellite cells encapsulated in the engineered biomaterial to stimulate engraftment of donor cells, thereby rescuing dystrophin expression, neuromuscular junction formation, and contractile function of the dystrophic diaphragm of young (2 months) and aged (12 months) mdx/mTR mice. The central hypothesis guiding this project is that the engineered niche- containing biomaterial designed to increase satellite cell adhesion, survival, proliferation, and differentiation will enable precise delivery of cells to the inferior surface of the diaphragm, enhance subsequent local cell retention, survival, expansion, migration, and engraftment of the donor cells, and further provide mechanical support to the aged/atrophied dystrophic diaphragm. The outcomes of this work will be significant in advancing the respiratory treatment strategy in the context of Duchenne muscular dystrophy. Salvaging the failing diaphragm muscle, and thereby the respiratory function, will positively impact patients healthspan and quality of life by providing opportunities to bypass the need for mechanically assisted ventilation. Successful completion of this work will also provide an opportunity to further synergize this platform with induced pluripotent stem cells and emergent gene editing technologies to treat diseased diaphragm function of patients suffering from various forms of neuromuscular diseases.

摘要