Engineering Pulmonary Valve Tissue for Pediatric Patients with Tetralogy of Fallot

出生时患有先天性心脏病的儿童，如法洛四联症，通常会有心脏瓣膜缺陷。例如，在法洛四联症中，肺动脉和瓣膜变窄。外科医生可以扩大动脉，通过使用心脏周围的心包组织或合成纤维制成的补片来增加瓣叶。虽然这为婴儿或儿童提供了暂时的缓解，但修复材料不能随着患者的生长而生长，容易结痂和钙化，导致患者终生需要再次手术和临床干预。在这里，我们建议使用心脏瓣膜组织工程的原理来生产可用作替代修复材料的活瓣叶组织片。这些床单将由生长在聚氨酯网状物上的婴儿脐带干细胞制成，这些干细胞最终会在体内溶解为无害的副产品，留下干细胞产生的活瓣叶。为了启动组织生产，我们将首先在生物反应器中培养瓣膜组织，以锻炼组织以提高其强度和灵活性。大多数工程瓣膜组织会因结疤而失败，因此为了防止这种情况，我们将在植入前向组织中注入装载了抗瘢痕药物的纳米颗粒。我们将在猪身上测试这种新型的替代组织，以评估该材料是否耐用、不会留下疤痕，并在体内保持功能。在接下来的三年里，我们由材料科学家、心脏瓣膜专家和心脏外科医生组成的跨学科团队将培训下一代工程师、科学家和外科医生，并将与我们在SickKids医院和组织再生治疗公司的合作伙伴合作，将这一新概念转化为先天性心脏缺陷修复的实践，显著提高当前的护理标准，并通过商业化产生经济影响。

Children born with congenital heart diseases, such as tetralogy of Fallot, often have defectiveheart valves. For example, in tetralogy of Fallot, the pulmonary artery and valve are narrowed.Surgeons can enlarge the artery and add a valve leaflet by using a patch made frompericardial tissue from around the heart or a synthetic fabric. While this provides temporaryrelief to the infant or child, the repair materials cannot grow with the patient and are prone toscarring and calcification, leading to a lifetime of reoperations and clinical interventions for thepatient.Here, we propose to use principles of heart valve tissue engineering to produce sheets ofliving valve leaflet tissue that can be used as an alternative repair material. The sheets will bemade from stem cells from the infants own umbilical cord grown on a polyurethane mesh,which will eventually dissolve away in the body to harmless byproducts, leaving behind aliving valve leaflet produced by the stem cells. To kickstart tissue production, we will first growthe valve tissue in bioreactors that exercise the tissue to improve its strength and flexibility.Most engineered valve tissue fails by scarring, so to prevent this, we will inject nanoparticlesloaded with an anti-scarring drug into the tissue prior to implantation. We will test this novelreplacement tissue in pigs to assess whether the material is durable, does not scar, andremains functional in the body.Over the next three years, our interdisciplinary team of material scientists, heart valveexperts, and cardiac surgeons will train next-generation engineers, scientists, and surgeonsand will collaborate with our partners at SickKids Hospital and Tissue RegenerationTherapuetics to translate this novel concept in congenital heart defect repair towards practice,significant improvement in the current standard of care, and economic impact throughcommercialization.