Bioengineered grafts for laryngotracheal reconstruction

用于喉气管重建的生物工程移植物

• 批准号: 10452927
• 负责人: Riccardo Gottardi
• 金额: $ 22万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452927
• 关键词: Affect; Air Movements; Allogenic; Autologous; Benchmarking; Biochemistry; Biomedical Engineering; Biopsy; Blood Vessels; Cadaver; Caliber; Cartilage; Cells; Central Nervous System Diseases; Child; Childhood; Chondrocytes; Clinical; Cognitive; Collagen; Compressive Strength; Cytoplasmic Granules; DNA; Deposition; Digestion; Dimensions; Disease; Ear Cartilages; Elastic Cartilage; Elastic Fiber; Elastin Fiber; Engineering; Ensure; Excision; Exhibits; Extracellular Matrix; GAG Gene; Gene Expression; Glycosaminoglycans; Hand; Harvest; Heart Valves; Histology; Human; Immunohistochemistry; Implant; In Vitro; Incidence; Infection; Instruction; Intubation; Joints; Larynx; Legal patent; Light; Mechanics; Meniscus structure of joint; Mesenchymal Stem Cells; Modeling; Monitor; Morbidity - disease rate; Nose; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Patients; Phenotype; Premature Birth; Procedures; Proliferating; Property; Quality of life; Quantitative Reverse Transcriptase PCR; Reconstructive Surgical Procedures; Risk; Shapes; Site; Source; Speech; Stenosis; Structure; Surgeon; Technology; Tensile Strength; Testing; Time; Tissue Engineering; Tissues; Trachea; Undifferentiated; United States; Work; adverse outcome; articular cartilage; calcification; cartilage implant; cartilage repair; cartilage transplantation; clinical translation; clinically relevant; comorbidity; congenital heart disorder; costal cartilage; graft failure; implantation; improved; improved outcome; in vivo; innovation; mechanical properties; minimally invasive; neonate; pre-clinical; premature; progenitor; reconstruction; response; restenosis; rib bone structure; scaffold; stem cells; success; therapeutically effective; tool; translational study; vocal cord

PROJECT SUMMARY/ABSTRACTS Severe subglottic stenosis, the narrowing of the airway just below the vocal folds, develops as a response to intubation in close to 10% of the > 20,000 premature births per year in the United States. Severe cases require laryngotracheal reconstruction (LTR), in which surgeons split the cricoid and add a piece of autologous patient- derived cartilage to expand the airway and restore proper airflow. However, in children, the success rate is as low as 50% with a high incidence of restenosis requiring revision surgery. Graft failure is tied directly to the lack of sufficiently sized autologous cartilage in the child, and tissue engineering has been proposed to develop alterative grafting options for pediatric LTR. Some approaches, including some of our previous work, have been effective in producing functional cartilage, but the overall timeframe required for the construct to match the mechanical properties of native cartilage (>24 weeks) is not compatible with clinical translation (<8 weeks). Furthermore, current cell sources such as expanded autologous chondrocytes and mesenchymal stem cells frequently result in hypertrophic and calcified tissue. Our objective is to engineer a new type of cartilage implant that is populated with patients’ cells, mechanically viable and suitable for LTR within a clinically relevant timeframe. Our approach is to exploit the blood vessels and elastin fibers that are uniquely present in the fibro-elastic cartilage of the meniscus to form microchannels for effective recellularization after enzymatic decellularization. Our patent-pending Meniscal Decellularized scaffold (MenD) technology can indeed be easily recellularized and has mechanical properties of the same order as native tracheal cartilage. Furthermore, cartilage progenitor cells have been proposed as a rapidly proliferating, highly chondrogenic cell source. To harness these cells, we have developed a minimally invasive biopsy procedure to harvest ear Cartilage Progenitor Cells (eCPCs). Our overarching hypothesis is that MenD and eCPCs can be combined to create cartilage implants with suitable mechanical strength, dimensions, and phenotypic stability for personalized, minimally invasive LTR. We propose to use MenD recellularized with eCPCs to engineer cartilage with tissue properties matching those of native cartilage. We will then validate the MenD-engineered cartilage in a proof- of-concept rabbit LTR model. We expect that our findings will provide strong pre-clinical evidence of functional laryngotracheal cartilage repair by our innovative eCPC-MenD technology and will thereby prompt further studies to eventually apply this technology to restore children’s airway.

项目总结/摘要