Abstract

In situ tissue engineering using biodegradable scaffolds is an emerging approach to create living heart valve replacements inside the human body. This breakthrough technology entails the implantation of a cell-free scaffold that gradually transforms into a living valve at the site of implantation.

Our approach is based on the notion that the natural inflammatory response to a scaffold can be harnessed to induce physiological healing and neo-tissue formation. The challenge is to develop instructive scaffolds capable of host cell repopulation and that provide biochemical and/or biophysical cues for a stable cellular phenotype and load-bearing extracellular matrix formation. We use electrospun scaffolds consisting of supramolecular polymers that can be functionalized with bioactive moieties to elicit specific responses of host cells, typically recruited from the blood stream. Biomimetic in vitro models and computational analyses are being used in direct comparison with in vivo experiments to optimize scaffold biochemical, biophysical, and degradation properties. Using in vitro models we demonstrated the modulation of inflammatory responses via the release of bioactive moieties to favor the recruitment of beneficial macrophage subpopulations. This modulation resulted in functional vessel formation by circulating cells only, as demonstrated in preclinical studies. Subsequent optimization of scaffold structural-mechanical properties resulted in the creation of heart valve scaffolds that gradually transform into living heart valves and maintain mechanical and biological function during long-term follow up in large animal studies.   

(This project was made possible by the research program of the BioMedical Materials institute, co-funded by the Dutch Ministry of Economic Affairs. Financial contribution of Netherlands Heart Foundation is gratefully acknowledged.)