Pulmonary valved conduit xenograft with regeneration potential

先天性心脏病每年在美国瓣膜和管道中影响大约4万名新生儿 肺动脉瓣缺如，主动脉瓣狭窄(Konno手术，Ross手术)， 右室双出口(Rastelli手术)、心外管道(Fontan手术)、肺动脉瓣 替换术(法洛四联症)。目前使用的材料包括同种血管；戊二醛 经处理的牛颈静脉(BJV、Contiga)、聚四氟乙烯(PTFE)以及机织或针织涤纶管。 这些材料的局限性在不同程度上涉及到它们的血栓形成能力、耐久性、对 感染，缺乏生长潜力。这些材料还具有不同程度的刚性和柔韧性， 这给外科医生带来了技术挑战，特别是在新生儿和婴儿中，尺寸限制和 纵隔中有限的空间与相对较薄的未成熟的天然血管组织相结合，形成了 组织-材料机械不匹配，这可能会损害实现成功手术的能力 修理。在第一阶段STTR中，我们测试了脱细胞和五没食子酰基葡萄糖的原型的可行性 (PGG)稳定的新型BJV阀门管道装置(TxGuard)，以增强已经公认的 BJV。所有的临床前测试表明，TxGuard带瓣管道具有粘弹性、生物相容性和抵抗力 钙化和血栓形成，同时允许宿主细胞渗透和重塑和生长的可能性。 为了将TxGuard管道商业化，我们需要在GMP和GLP条件下获得数据，这些条件可以 已向FDA提交HDE申请。为了实现这一目标，我们对SBIR提出了以下具体目标 第二阶段：目标1：根据GMP为TxGuard导管的加工实施质量控制SOP文件； 目标2：验证TxGuard管道的灭菌、包装和储存，目标3：测试流体力学 TxGuard导管的性能和抗疲劳性，目标4：进行长期的临床前体内试验 TxGuard管道。建立绵羊TxGuard带瓣肺导管置入模型(n=6) 在生长羔羊中使用150天，并与GLP下临床可用的Contiga BJV管道(n=3)进行比较 FDA提交的条件。拟议的SBIR第二阶段项目将带头开发一种 BJV设备(TxGuard)，可用宿主细胞重新填充，并随患者缓慢再生和生长 与现有设备相比，没有不必要的炎症和退化。

Congenital heart disease affects approximately 40,000 newborns each year in the U.S. Valve and conduit replacements are needed for absent pulmonary valve, aortic stenosis (Konno procedure, Ross procedure), double outlet right ventricle (Rastelli operation), extracardiac conduit (Fontan operation), pulmonary valve replacement (Tetralogy of Fallot). Materials in current use include homograft blood vessels; glutaraldehyde treated bovine jugular veins (BJV, Contegra), polytetrafluorethylene (PTFE), and woven or knitted Dacron tubes. The limitations of these materials involve to varying degrees their thrombogenicity, durability, susceptibility to infection, and lack of growth potential. These materials also have varying degrees of stiffness and flexibility, which present technical challenges for surgeons, particularly in neonates and infants where size constraints and limited space in the mediastinum combine with the relatively thin immature native vascular tissues to create tissue-materials mechanical mismatches, which can compromise the ability to achieve a successful surgical repair. In Phase I STTR, we tested the feasibility of a prototype from decellularized and pentagalloyl glucose (PGG) stabilized novel BJV valved conduit device (TxGuard) to augment the already recognized qualities of BJV. All the preclinical testing shows that TxGuard valved conduit is viscoelastic, biocompatible, resists calcification, and thrombosis while allowing host cellular infiltration and the potential for remodeling and growth. To commercialize the TxGuard conduit, we need to obtain data under GMP and GLP conditions that can be submitted to the FDA for HDE application. Towards this goal, we propose the following specific aims for SBIR Phase II. Aim 1: Implement quality control SOPs documents for processing of the TxGuard conduit under GMP, Aim 2: Validate sterilization, packaging, and storage of the TxGuard conduits, Aim 3: Test hydrodynamic performance and fatigue resistance of TxGuard conduits, Aim 4: Perform long-term preclinical in-vivo testing for TxGuard conduits. The ovine model of TxGuard pulmonary valved conduit placement (n=6) will be conducted for 150 days in growing lambs and compared to the clinically available Contegra BJV conduits (n=3) under GLP conditions for FDA submission. The proposed Phase II SBIR project will spearhead the development of a novel BJV device (TxGuard) that would repopulate with host cells and slowly regenerate and grow with the patient without unwanted inflammation and degeneration in contrast to the existing devices.