In vitro and in vivo preclinical testing of pericyte-engineered grafts for correction of congenital heart defects

Lead Research Organisation: University of Bristol


Congenital heart disease (CHD) is the most common type of birth defect, with a reported prevalence ranging from 6 to 13 per 1,000 live births. In UK alone, 4,600 babies are diagnosed with a cardiac defect each year. Despite considerable progresses in surgical techniques and medical treatments, CHD remains the first cause of mortality associated with a congenital defect. In addition, the material used by cardiac surgeons to correct cardiac defects has limited durability. Hence, patients are grown through repeated risky operations. We propose a definitive solution which is based on the incorporation of patient's own stem cells in grafts currently used to correct cardiac defects. Stem cells shall confer the graft with capability to grow and adapt to the need of the young heart. We will initially work to set up the protocol for optimal incorporation of cells in the graft and then test the therapeutic activity of the new grafts in animal models, in view of a therapeutic application in CHD patients.

Technical Summary

Unmet clinic needs: Congenital heart disease (CHD) is the most common type of and the first cause of mortality due to a congenital defect. In 2004, the U.S. hospital costs for CHD totalled $1.4 billion, with surgical costs for repeated operations being estimated to be over $2.4 million for every 100 cases. The main problem is that prostheses employed in congenital cardiac surgery are not perfect, e.g. they need to be substituted a few years after implantation.
How this new technology will fill the gap: Incorporation of stem cells (SCs) shall confer prosthetic grafts with the characteristics of a living tissue that grows and remodels in a physiologic manner in parallel with cardiac and whole body growth. We gathered promising data, prior and after our initial outline application to the MRC, regarding the unique properties of pericytes from neonatal heart and umbilical cord. Here, we propose to use pericytes to engineer valved vascular conduits to be used for the reconstruction of right ventricular/pulmonary artery defects.
Experimental plan: The project consists of three objectives. Objective 1 (workpackages [WP] 1&2): generate stocks of quality assured swine pericytes and determine the reproducibility of graft manufacture. Objective 2 (WP3): provide proof of principle of feasibility of the pericyte-based approach in a newly developed piglet model. Objective 3 (WP4): preparatory engagement with regulatory bodies. WP include milestones (M) and contingency measures (CM) for risk containment.

Planned Impact

Who will benefit
Despite a continuous decline in mortality rate, congenital heart defects still represent the primary cause of death among infants in North America and Europe. Concomitantly, the impact of CHD on the adult population is growing. According to the Department of Health, in 2006 there were around 135,000 adults living in England with CHD. Unfortunately, surgical repair is not as definitive as previously thought. In fact, prosthetic materials and valves used to reconstruct complex cardiac defects are unable to match the growth of an infant's heart and become dysfunctional over time, with obstruction, pulmonary regurgitation, or both. As a consequence, CHD patients usually undergo repeated risky, distressing and costly operations for replacement of failed grafts. The number of patients undergoing cardiac reoperation for CHD has continuously increased over the last 10 years. Reoperation mortality rate is still up to 5% and risk of complications can be as high 20%, with prolonged intensive care and hospital stay, higher rate of blood product transfusion and more importantly a negative impact on the child neuro-development. The cost of reoperation on healthcare budget is substantial. According to a recent US study, the direct healthcare expenditure for every 100 cases undergoing cardiac reoperation is over $2.4 million. With the ongoing constraints in healthcare budgets, differentiating the value of existing and future approaches in terms of clinical benefits, costs, and impact on resource utilization will become increasingly important. Patients with Tetralogy of Fallot/pulmonary atresia represent the biggest group responsible for the exponential increase of young adults undergoing reoperation. The major challenge in these patients is to create a definitive valvular conduit connecting the right ventricle to the pulmonary circulation. The whole conduit should be able to grow as the patient's heart grows without undergoing degeneration, calcification, obstruction or valve failure.
How will they benefit
Our project proposes a pericyte-engineered prosthetic material as a definitive solution to avoid or reduce the number of reoperations in this growing and high risk surgical population. The engineered valvular conduit could significantly impact on patients clinical outcomes and improve resources utilization for the NHS. Beyond this patient group, cell-engineered scaffolds could be effective for a wide range of conditions requiring reconstitution of a damaged heart. In Bristol, we have gathered a team of experts in translational cardiovascular medicine, stem cell therapy and cardiac surgery who focuses on practical solutions to patients' needs. Prof Madeddu is leading several research projects of pericytes for cardiovascular repair in liaison with the NHSBT. Prof. Caputo and Angelini are leading experts in cardiac surgery and have conducted many pioneering surgery trials. By extending and adapting the methodology used to reconstruct the human trachea, Prof Caputo has developed a novel bioreactor technology to create tissue-engineered conduits for correction of neonatal heart defects. At the same time, Prof Caputo has established a piglet model for the implantation and testing of these grafts into the pulmonary arteries, which closely mimics the type of reconstruction performed in infants with CHD. Therefore, the team is perfectly positioned to deliver benefit from this research through animal studies to the patient. We see the route to clinical translation and commercial sustainability to be pursued through a partnership between the University of Bristol and the NHSBT as a logical follow-up of established contractual agreements covering ongoing studies on saphenous vein pericytes. We are also involving the Cell Therapy Catapult as a key facilitator in the translation/exploitation plan.


10 25 50

publication icon
Carrabba M (2018) Current Strategies for the Manufacture of Small Size Tissue Engineering Vascular Grafts. in Frontiers in bioengineering and biotechnology

Description Pump-Priming Award: Discovery of a novel angiomiR -miR-532- from screening of human pericytes
Amount £75,307 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2016 
End 09/2017
Description Translational Research Project Grant: Umbilical cord pericyte-engineered grafts for correction of congenital heart defects
Amount £76,054 (GBP)
Funding ID RG2656/17/20 
Organisation Heart Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2017 
End 02/2020