Congenital heart defects (CHD) affect approximately 1% of live births. Many complicated CHD require surgical correction to establish anatomic continuity and physiological restoration of flow. Although primary repair of the defect is sometimes possible, implementation of prosthetic replacement grafts in the form of new valves, conduits and patches, has allowed for establishment of anatomic continuity and physiological restoration in more complicated cases.
Overall the use of prosthetic material is very common in congenital cardiac surgery, and even though these grafts may be lifesaving, they have limited durability and are prone to infection, immunological reactivity, and thrombosis, which often require repeat operations in the future.
A very promising approach to solve the above problem may be the use of tissue engineering, in which cells are seeded in three-dimensional matrices to form living tissue products having structure and function properties that can be used to restore, maintain or improve tissue function. Induction of autologous stem cells provides a powerful source for all types of cell regeneration and would be of great advantage in cardiovascular tissue engineering. These cells are easy to obtain and can be manipulated for multiple passages. The repopulation of homograft with patient’s stem cells before surgery can potentially create a vital homograft with a physiological high replacement of all components and subsequent long-term preservation of mechanical and biological properties.
Hypothesis and aims of the project
Tissue-engineered cardiovascular structures, including valves, conduits and vascular patches would consist of viable and autologous tissue which could theoretically function like a native biological structure with the potential to grow, to repair, and to model, and thus providing a longer lasting therapeutic effect than acellular allografts and significantly improve the quality of lives in children with congenital heart disease.
The aim of this project is to upgrade the valved-conduits and patches commonly used in reconstructive CHD surgery, by creating biomaterials/medical devices endowed with potential to grow, remodel and regenerate the failing right ventricle in vivo. We will test different cell products, including autologous stem cells from neonatal heart and bone marrow and blood, and cardiovascular cells derived from autologous induced pluripotent cells, to verify the optimal regenerative component within the medical device. We shall then use an in vivo CHD piglet model to test the new devices for proof of concept of feasibility and efficacy. If feasibility and efficacy is demonstrated we will perform a first-in-human clinical trial, comparing bio-engineered and conventional scaffolds for reconstruction of the right ventricular outflow tract and pulmonary arteries which will be the subject of future applications for regulatory approval.
The research participants (parents) will be asked permission to use the small left over surgical specimens that are normally discarded during the operation for isolating and growing stem cells and populate the biomaterials for our tissue engineering experiments. Furthemore we will collect small samples of bone marrow removed from the sternum after the median sternotomy that is necessary to access the heart. We will also collect samples from the thymus, which is routinely removed during congenital heart surgery to gain access to the heart structures. A small amount of blood (2 mls) will be withdrawn from the venous neck line that is routinely used in cardiac surgery without any need for invasive procedure. The sample will be completely anonymized.
All participants will have congenital heart disease and be children (0-16 yrs old). All must be undergoing cardiopulmonary bypass operations.
-Sick children who need emergency operations
-Children who are not within the above diagnostic groups above
-Syndromes or genetic conditions other than Downs syndrome
-Children who have had recent cardiac intervention within the previous month.