Pulmonary valved conduit xenograft with regeneration potential

具有再生潜力的肺动脉瓣导管异种移植物

• 批准号: 10491195
• 负责人: Ajay Houde
• 金额: $ 104.2万
• 依托单位: ANNOVIANT, INC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-03-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10491195
• 关键词: Affect; Anastomosis - action; Aneurysm; Aortic Valve Stenosis; Arteries; Bacteria; Bioreactors; Blood Vessels; Brain; Caliber; Cattle; Cells; Cellular Infiltration; Chronic; Clinical; Data; Defect; Development; Devices; Dilatation - action; Distal; Double Outlet Right Ventricle; Drops; Elastases; Extravasation; Failure; Fatigue; Fontan Procedure; Glucose; Glutaral; Goals; Growth; Image; In Vitro; Infant; Infection; Infectious Agent; Inflammation; Kidney; Legal patent; Liver; Lung; Mechanics; Mediastinum; Membrane; Methods; Mycoplasma; Natural regeneration; Newborn Infant; Operative Surgical Procedures; Organ; Patients; Peracetic Acid; Performance; Pericardial body location; Phase; Population; Preclinical Testing; Predisposition; Procedures; Pseudoaneurysms; Pulmonary valve structure; Pulsatile Flow; Quality Control; Quality of life; Reaction; Repeat Surgery; Reporting; Research Proposals; Resistance; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Spleen; Stenosis; Sterility; Sterilization; Structure; Structure of jugular vein; Surgeon; Technology; Testing; Tetralogy of Fallot; Thick; Thinness; Thrombosis; Thymus Gland; Tissues; Toxic effect; Tube; Validation; Velocimetries; Xenograft procedure; base; biomaterial compatibility; calcification; clinical practice; collagenase; congenital heart disorder; crosslink; dacron; design; feasibility testing; flexibility; fungus; homograft; implantable device; implantation; improved; in vivo; in vivo evaluation; infection risk; mechanical properties; neonate; non-Native; novel; operation; particle; pediatric patients; pre-clinical; pressure; prototype; pulmonary valve replacement; reconstruction; regeneration potential; repaired; sheep model; stability testing; subcutaneous; thrombogenesis; viscoelasticity

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.

先天性心脏病每年在美国阀门和导管中影响约40,000名新生儿 缺乏肺动脉瓣，主动脉狭窄（Konno手术，Ross手术）需要替换 双出出口右心室（Rastelli操作），外心管道（Fontan操作），肺动脉瓣 替代（法洛的四部曲）。目前使用的材料包括同源血管；戊二醛 处理过的牛颈静脉（BJV，CONTEGRA），聚氟乙烯（PTFE）和编织或针织的Dacron管。 这些材料的局限性在不同程度上涉及其血栓形成性，耐用性，易感性 感染和缺乏增长潜力。这些材料也具有不同程度的刚度和柔韧性， 这给外科医生带来了技术挑战 纵隔中有限的空间与相对较薄的不成熟的天然血管组织结合 组织物质机械不匹配，这可能会损害成功手术的能力 维修。在I阶段STTR中，我们测试了脱细胞和五核葡萄糖的原型的可行性 （PGG）稳定的新型BJV阀导管装置（TXGUARD），以增强已经公认的品质 BJV。所有临床前测试表明，TXGuard阀导管是粘弹性的，生物相容性的，抵抗 钙化和血栓形成，同时允许宿主细胞浸润以及重塑和生长的潜力。 要使TXGUARD导管商业化，我们需要在GMP和GLP条件下获得数据 提交给FDA进行HDE申请。为了实现这一目标，我们提出了以下针对SBIR的特定目标 第二阶段。目标1：实施质量控制SOP文档以处理GMP下的TXGuard管道， AIM 2：验证TXGUARD导管的灭菌，包装和存储，AIM 3：测试流体动力学 TXGUARD导管的性能和疲劳抗性，AIM 4：对长期临床前体内测试 TXGUARD导管。将进行TXGUARD肺动脉阀导管放置（n = 6）的卵子模型 在生长的羔羊中使用150天，并与GLP下的临床上可用的contegra bjv导管（n = 3）进行了比较 FDA提交条件。拟议的II阶段SBIR项目将率先开发新颖 BJV设备（TXGUARD）将用宿主细胞重新填充并缓慢再生并随患者生长 与现有设备相比，没有多余的炎症和变性。