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.

先天性心脏病影响大约40，000新生儿每年在美国瓣膜和导管 肺动脉瓣缺失、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 法洛四联症（Tetralogy of Fallot）目前使用的材料包括同种移植血管;戊二醛 经处理的牛颈静脉（BJV，Contegra）、聚四氟乙烯（PTFE）和编织或针织涤纶管。 这些材料的局限性在不同程度上涉及它们的促凝性、耐久性、对血栓的敏感性、对血栓的耐受性和对血栓的耐受性。 感染和缺乏生长潜力。这些材料还具有不同程度的刚度和柔性， 这对外科医生提出了技术挑战，特别是在新生儿和婴儿中， 纵隔中的有限空间联合收割机与相对薄的未成熟的天然血管组织结合 组织-材料机械不匹配，这可能会影响实现成功手术的能力 修复.在I期STTR中，我们测试了脱细胞葡萄糖和五没食子酰葡萄糖原型的可行性。 (PGG)稳定新型BJV带瓣管道装置（TxGuard），以增强已经公认的质量， BJV。所有临床前试验均表明，TxGuard带瓣管道具有粘弹性、生物相容性、耐 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。 为了使TxGuard导管商业化，我们需要在GMP和GLP条件下获得数据， 向FDA提交HDE申请。为了实现这一目标，我们建议SBIR的具体目标如下 第二阶段。目标1：根据GMP实施TxGuard导管处理的质量控制SOP文件， 目标2：TxGuard导管的灭菌、包装和储存，目标3：流体动力学试验 TxGuard导管的性能和抗疲劳性，目标4：进行长期临床前体内试验， TxGuard导管。将进行TxGuard肺动脉带瓣管道放置的绵羊模型（n=6） 在生长羔羊中持续150天，并与GLP下临床可用的Contegra BJV导管（n=3）进行比较 FDA提交的条件。拟议的第二阶段SBIR项目将率先开发一种新的 BJV器械（TxGuard），可与宿主细胞一起重新填充，并与患者一起缓慢再生和生长 与现有装置相比没有不希望的炎症和退化。