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: 10257850
• 负责人: Ajay Houde
• 金额: $ 81.76万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10257850
• 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.

在美国，先天性心脏病每年影响大约 40,000 名新生儿。 肺动脉瓣缺失、主动脉瓣狭窄（Konno 手术、Ross 手术）需要置换术， 右心室双出口（Rastelli 手术）、心外导管（Fontan 手术）、肺动脉瓣 替代（法洛四联症）。目前使用的材料包括同种移植血管；戊二醛 处理过的牛颈静脉（BJV、Contegra）、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它们的血栓形成性、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度和柔韧性， 这给外科医生带来了技术挑战，特别是对于尺寸有限且尺寸有限的新生儿和婴儿。 纵隔内有限的空间与相对较薄的未成熟的原生血管组织相结合，形成 组织材料机械不匹配，这可能会影响成功手术的能力 维修。在第一阶段 STTR 中，我们测试了脱细胞和五没食子酰葡萄糖原型的可行性 (PGG) 稳定了新型 BJV 阀门导管装置 (TxGuard)，以增强已经公认的品质 BJV。所有临床前测试均表明 TxGuard 阀门导管具有粘弹性、生物相容性、抗腐蚀能力 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。 为了将 TxGuard 导管商业化，我们需要在 GMP 和 GLP 条件下获取数据，这些数据可以 向FDA提交HDE申请。为了实现这一目标，我们为 SBIR 提出以下具体目标 第二阶段。目标 1：根据 GMP 实施 TxGuard 导管加工的质量控制 SOP 文件， 目标 2：验证 TxGuard 导管的灭菌、包装和存储，目标 3：测试流体动力学 TxGuard 导管的性能和抗疲劳性，目标 4：执行长期临床前体内测试 TxGuard 导管。将进行 TxGuard 肺动脉瓣导管置入的绵羊模型 (n=6) 在生长中的羔羊中持续 150 天，并根据 GLP 与临床可用的 Contegra BJV 导管 (n=3) 进行比较 FDA 提交的条件。拟议的第二阶段 SBIR 项目将带头开发一种新型 BJV 设备 (TxGuard) 可以重新填充宿主细胞，并与患者一起缓慢再生和生长 与现有设备相比，没有不必要的炎症和变性。