Engineering Three-Dimensional Nanofiber Heart Valve Scaffolds to Fine-Tune Valvular Interstitial Cell Morphology and Phenotype

Abstract

Regenerative tissue engineered heart valves have emerged as a promising alternative to mechanical and bioprosthetic valve replacements, especially for pediatric patients. In designing and fabricating these regenerative heart valves, a primary goal has been ensuring that upon implantation, the valve replacement seamlessly integrates into, and has the capacity to grow with, a patient’s dynamic cardiovascular system. To achieve this, tissue engineers have turned to acellular heart valve scaffolds as a means of stimulating and directing in situ tissue regeneration, thereby resulting in the creation of a substitute valve composed entirely of the patient’s tissues. In spite of positive preliminary results, a central challenge associated with this approach is ensuring that the scaffold design can promote physiological remodeling, especially at the micro-structural level. Here, we show that by fine-tuning these acellular scaffolds’ mechanical and chemical properties to recapitulate those of the native valve, we can attain physiological valvular tissue regeneration. Specifically, we found that valvular interstitial cells (VICs) demonstrated physiological morphology and cytoskeletal organization when cultured on scaffolds with an elastic modulus and chemical structure similar to that in the native leaflet. At the same time, VIC infiltration was improved when cultured on scaffolds containing gelatin, a derivative of the extracellular matrix protein collagen. In turn, these results assist in understanding how valve cells respond to micro-environmental mechanical and chemical cues, thereby guiding the design of a regenerative tissue-engineered heart valve.