SBIR-STTR Award

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. Current clinical experience indicates that young age, in particular, is an important risk factor for shortened intervention free survival in patients requiring these conduits as part of their initial surgical repair. The goal of creating a conduit that will overcome these limitations has not been achieved. We propose to develop a commercializable prototype and test the regenerative potential of decellularized and pentagalloyl glucose (PGG) crosslinked novel BJV valved conduit 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. Our specific aims for STTR Phase I are: Specific Aim 1: Scale-up our laboratory-based decellularization and PGG crosslinking method to a batch manufacturing process for TxGuard from a verified supplier with certification in ISO 13485. This includes dissemination of treatment protocol to the manufacturing partner to standardize manufacturing process for obtaining a consistent product. Specific Aim 2: Compare TxGuard that is made under ISO 13485 conditions with a commercially available device (Contegra) for material properties (suture pull out test, biaxial mechanical testing, and creep), cytotoxicity, and hemocompatibility assessment (ISO 10993 testing). Specific Aim 3: Test TxGuard for in vivo biocompatibility and functional assessment. This will include a) 90-day subdermal implantation in juvenile rats to assess calcification resistance and b) implantation in sheep as a pulmonary-valved conduit for three months to assess safety, function, biocompatibility, and cellularization by the host animal in a circulatory environment.

Public Health Relevance Statement:
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). Current replacement materials are suboptimal with high failure rate requiring reoperations. This research proposal is designed to develop a new pulmonary-valved conduit (TxGuard) that resists early degeneration and allows regeneration with host cells so that the device would grow with the pediatric patient.

Project Terms:
Adolescent; Affect; Age; Anastomosis - action; Aneurysm; Animals; Aortic Valve Stenosis; Arteries; base; biomaterial compatibility; Blood Vessels; calcification; Caliber; Cattle; Cells; Cellular Infiltration; Certification; Clinical; clinical practice; congenital heart disorder; crosslink; cytotoxicity; dacron; Data; Defect; design; Development; Devices; Dilatation - action; Distal; Double Outlet Right Ventricle; Environment; experience; Failure; Fatigue; flexibility; Fontan Procedure; Glucose; Glutaral; Goals; Growth; hemocompatibility; homograft; implantable device; implantation; improved; in vivo; Infant; Infection; infection risk; Inflammation; Intervention; Laboratories; Legal patent; manufacturing process; mechanical properties; Mechanics; Mediastinum; Membrane; Methods; Natural regeneration; neonate; Newborn Infant; non-Native; novel; off-patent; operation; Operative Surgical Procedures; Patients; pediatric patients; Pericardial body location; Periodicity; Phase; Population; Positioning Attribute; Predisposition; Procedures; Property; prototype; Pseudoaneurysms; pulmonary valve replacement; Pulmonary valve structure; Quality of life; Rattus; Reaction; reconstruction; regenerative; repaired; Repeat Surgery; Reporting; Research Proposals; Resistance; Risk Factors; Safety; scale up; Sheep; Small Business Technology Transfer Research; Standardization; Stenosis; Structure; Structure of jugular vein; Surgeon; Surgical sutures; Technology; Testing; Tetralogy of Fallot; Thinness; thrombogenesis; Thrombosis; Time; Tissues; Treatment Protocols; Tube; viscoelasticity; Xenograft procedure

Congenital heart disease affects approximately 40,000 newborns each year in the U.S. Valve and conduitreplacements are needed for absent pulmonary valve, aortic stenosis (Konno procedure, Ross procedure), double outlet right ventricle (Rastelli operation), extracardiac conduit (Fontan operation), pulmonary valvereplacement (Tetralogy of Fallot). Materials in current use include homograft blood vessels; glutaraldehydetreated 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 toinfection, 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 andlimited space in the mediastinum combine with the relatively thin immature native vascular tissues to createtissue-materials mechanical mismatches, which can compromise the ability to achieve a successful surgicalrepair. 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 ofBJV. All the preclinical testing shows that TxGuard valved conduit is viscoelastic, biocompatible, resistscalcification, 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 besubmitted to the FDA for HDE application. Towards this goal, we propose the following specific aims for SBIRPhase 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 hydrodynamicperformance and fatigue resistance of TxGuard conduits, Aim 4: Perform long-term preclinical in-vivo testing forTxGuard conduits. The ovine model of TxGuard pulmonary valved conduit placement (n=6) will be conductedfor 150 days in growing lambs and compared to the clinically available Contegra BJV conduits (n=3) under GLPconditions for FDA submission. The proposed Phase II SBIR project will spearhead the development of a novelBJV device (TxGuard) that would repopulate with host cells and slowly regenerate and grow with the patientwithout unwanted inflammation and degeneration in contrast to the existing devices.

Public Health Relevance Statement:
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). Current replacement materials are suboptimal, with a high failure rate requiring reoperations. This research proposal is designed to develop a new pulmonary-valved conduit (TxGuard) that resists early degeneration and allows regeneration with host cells so that the device would grow with the pediatric patient. The Phase II SBIR proposal will allow us to get data needed for FDA humanitarian device exemption (HDE) submission.

Project Terms:
<0-4 weeks old>