Topic Area: This proposal will address a major unmet clinical need in the Peer Reviewed Medical Research Program (PRMRP) Fiscal Year 2019 topic area of Congenital Heart Disease (CHD): the development of a pediatric heart valve for infants and young children that adapts to their growth and reduces the number of open heart surgeries typically required for treatment.

Central Critical Problem: Approximately 1% of babies are born with CHD. In the U.S. alone, this equates to about 44,000 babies each year, 1,000 of which are military beneficiaries. One in four children with severe CHD will die before their first birthday. Heart valve defects are a major subset of CHD, requiring surgical intervention for survival. Often, valve replacement is the best or only viable option for defective valves. Unfortunately, there is no clinical standard for valve replacement in children under 5 years old because all valve prosthetics currently on the market have been designed for adults. Current devices are too large to fit young children and function at fixed sizes. However, children grow rapidly, and their heart valves double in size from birth to age 5-6 years old. These young patients will endure as many as 3-5 open heart surgeries throughout childhood as valve repairs or ill-fitting prosthetics fail or are outgrown. Young children need a valve prosthetic that not only fits them, but will grow with them. The goal of this work is to develop the LEAP Valve (Low-force Expanding/Adaptable Pediatric Valve), which will be appropriately sized for infants and toddlers while overcoming the challenge of growth through device expansion, resulting in fewer surgeries and improved quality of life.

Comprehensive Overview: The complex challenge of developing a “growing” pediatric device requires a multidisciplinary approach. This entails close collaboration among engineers, biomedical and materials scientists, and pediatric clinicians (who will eventually implant the device in children). Study design and assessments are steered by the International Organization for Standardization (ISO) and the Food and Drug Administration (FDA) requirements for pediatric devices and heart valves. Design iterations are expected as we move from laboratory bench tests to animal tests to account for needed changes based on our learnings.

The major goal of this 3-year proposal is to demonstrate that the LEAP Valve passively adapts to growth in the pulmonary valve position of growing piglets. LEAP Valve development can be separated into four major components: stent design, valve selection, stent-to-valve attachment, and surgical cuff design for implantation. Our “growth-adaptive” stent is designed to act like a low-force spring that will expand as the heart grows. Development of the stent will leverage our established computational models predicting spring force and will be guided by data generated via testing of the pulmonary valve annulus (the tissue “ring” where the native heart valve attaches and where the device will be implanted). In parallel, we will explore and identify an “expandable valve” source for our device. Selection efforts are based on clinical experience with venous valves, such as those found in the veins of legs and that can function over multiple diameters, including the required doubling in diameter for the LEAP Valve. Further, we must address one of the major challenges of all bioprosthetic valves: reliable attachment of the tissue valve to the stent. The current gold standard is suturing by hand, a time-intensive process that requires high skill and becomes more challenging at smaller device sizes, increasing product costs. We will develop a “sutureless” alternative based on adhesive microstructures: MANTIS (Mechanical AdhesioN to TISsue). The fourth component is the development of an expandable cuff that will facilitate surgical implantation of the LEAP Valve and protect the spring-like function of the device when implanted.

The full device (stent, valve, cuff) will undergo standard accelerated wear and functional tests that mimic conditions in the growing hearts of children from infancy through age 6 years. Once the LEAP Valve passes these bench tests, it will be deployed in two growing animal models that span the weight range of human infants and young children (6-18 kg). Two models must be used to effectively capture the growth effects and measure the biological response of the animals over the 90-day minimum requirement for FDA submission.

Ultimate Applicability and Impact: The bench tests and animal data resulting from this work will fulfill the requirements for Investigational Device Exemption submission to the FDA for First-in-Human Early Feasibility Studies. This would allow the youngest patients with the greatest need to receive the LEAP Valve soon after completing this award. In addition, we expect MANTIS sutureless adhesion technology will be positioned for further development for hemorrhage control applications that can be deployed in the battlefield to treat injured Soldiers. Through both of these technological innovations, we seek to have meaningful impact on the survival and quality of life of the youngest military beneficiaries to the bravest Warfighters who serve our country.