Decellularized cartilage and progenitor cells for laryngotracheal reconstruction

用于喉气管重建的脱细胞软骨和祖细胞

• 批准号: 10704303
• 负责人: Riccardo Gottardi
• 金额: $ 61.67万
• 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: 2022-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704303
• 关键词: Address; Adolescent; Affect; Air Movements; Allogenic; Animals; Autologous; Back; Benchmarking; Biopsy; Blood Vessels; Cadaver; Cartilage; Cell Differentiation process; Cells; Child; Childhood; Chondrocytes; Clinic; Clinical; Cognitive; Cytoplasmic Granules; Deposition; Development; Diagnosis; Digestion; Dimensions; Disease; Ear; Ear Cartilages; Elastic Cartilage; Elastin Fiber; Endoscopy; Engineering; Ensure; Event; Exhibits; Face; Family suidae; Gene Expression; Goals; Hand; Harvest; Heart Valves; Histology; Hormones; Human; Immunohistochemistry; Implant; In Vitro; Incidence; Infection; Intubation; Joints; Larynx; Legal patent; Longitudinal Studies; Longterm Follow-up; Mechanics; Meniscus structure of joint; Mesenchymal Stem Cells; Modeling; Monitor; Morbidity - disease rate; Mus; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Patients; Phenotype; Pilot Projects; Premature Birth; Procedures; Production; Proliferating; Property; Quality of life; Risk; Shapes; Site; Source; Speech; Stenosis; Surgeon; Technology; Testing; Time; TimeLine; Tissue Engineering; Tissues; Trachea; Tracheotomy procedure; Translations; Triiodothyronine; United States; Work; adverse outcome; base; calcification; cartilage cell; cartilage implant; cartilage repair; cartilage transplantation; cartilaginous; clinical translation; clinically relevant; costal cartilage; efficacy validation; extracellular; graft failure; implantation; improved; in vivo; innovation; mechanical properties; minimally invasive; pediatric patients; porcine model; pre-clinical; preclinical safety; premature; reconstruction; response; restenosis; restoration; rib bone structure; safety study; scaffold; stem cells; subcutaneous; success; therapeutically effective; tool; 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 miniature pig 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 follow up long term studies to eventually apply this technology to restore children’s airway.

项目摘要/摘要 严重的亚平瓣狭窄，即声音褶皱下方的气道的狭窄，是为了回应 在美国，插管近20,000个早产的近10％。严重的案件需要 喉气管重建（LTR），其中外科医生将cricoid分开，并添加一块自体患者 - 派生的软骨以扩大气道并恢复适当的气流。但是，在儿童中，成功率是 低至50％的重新狭窄事件需要修订手术。移植失败直接与缺乏有关 儿童中足够尺寸的自体软骨，并提出了组织工程来发展 小儿LTR的替代嫁接选择。一些方法，包括我们以前的一些工作， 有效地生产功能软骨，但是结构匹配所需的整体时间框架 天然软骨的机械性能（> 24周）与临床翻译不兼容（<8周）。 此外，当前的细胞源，例如扩展的自体软骨细胞和间质干细胞 经常导致肥厚和计算的组织。我们的目标是设计一种新型的软骨 由患者细胞填充的植入物，机械可行，适用于临床内的LTR 相关时间范围。我们的方法是利用独特存在的血管和弹性纤维 半月板的纤维弹性软骨形成微通道以在酶促后有效卷积 脱皮化。我们正在申请专利的半月板脱细胞脚手架（MEND）技术确实可以是 易于重新细化，并具有与天然气管软骨相同的机械性能。 此外，已经提出了软骨祖细胞作为快速增殖的高度软骨细胞 来源。为了利用这些细胞，我们开发了一种微创的活检程序来收获耳朵 软骨祖细胞（ECPC）。我们的总体假设是，可以将修订和ECPC合并到 以适当的机械强度，尺寸和表型稳定性创建软骨 个性化的，微创的LTR。我们建议使用与ECPC进行修补的延误来工程师 软骨具有与天然软骨相匹配的组织特性。然后，我们将验证修补工程 微型猪LTR模型中的软骨。我们期望我们的发现将为临时证据提供 通过我们创新的ECPC Mend Technology，功能性喉气管软骨维修，从而迅速 跟进长期研究，最终将这项技术应用于恢复儿童气道。