In spite of recent success in tissue engineering blood vessels and patches for repairing damaged regions of the heart, there has been little success in tissue engineering supportive pumping systems that can produce one-way flow, which often require valves that prevent flow reversal. Chronic venous insufficiency, which can affect 20-30% of the people over the age of 50, is an example of such an unmet need. In chronic venous insufficiency, blood pools in affected veins and doesn't return to the heart efficiently, which can lead to swelling, skin changes, varicose veins, ulcerations, and even loss of limbs. The goal of this project is to perform exploratory work to tissue engineer a biological valveless pump based on recently discovered novel physical principles governing the functioning of an embryonic heart, in which there is one-way flow without significant valve control. Pumps of different designs will be systematically tested for their ability to create one-way flow. Key parameters, including the pump's outer radius and length, the thickness and consistency of a gelatinous inner layer and the position and the contraction frequency of its active segment (a rhythmic cuff made of cardiac muscle cells), will be examined. If successfully developed, valveless pumps can be useful in multiple other projects. On a microscale, ongoing efforts to build organs-on-a-chip devices to study various diseases and their treatment using patient-derived cells can clearly benefit from a more physiologically relevant version of circulation that involves energy efficient valveless pumping. On a macroscale, implantable valveless pumps might be able to aid venous blood or lymphatic flow since they can be made suitable to different anatomical scales, including the peripheral circulation.
The goal of this project is to use tissue-engineered cardiac muscle cuffs to create effective directional pumping action in a valveless fashion. Theoretically, this can be achieved in the presence of a sectional difference in mechanical compliance along the cuff and by asymmetric stimulation with respect to such gradients. The theoretical basis and a man-made impedance pump of this kind was first proposed by Gerhart Liebau in the 1950s. Later it was suggested that this mechanism can play an important role in heart development and aortic flow. The main goal of this EAGER project is to recreate this fascinating mechanism of valveless pumping by combining novel tools of tissue engineering tools and 3D bioprinting and to test theoretical predictions that addition of a gelatinous inner layer to the classic Liebau impedance pump can significantly improve the ability of these pumps to generate unidirectional flow. The work will involve 3D printing of live tissue constructs containing defined amounts of cardiac myocytes and fibroblasts. It will also rely on a newly developed 3D bioprinting approach that uses agarose slurry as a support bath to sustain free-standing hydrogel structures in cell culture environments. Pacing of the contractile segment of the tissue engineered Liebau pumps will be achieved by external electrical field or by light-based stimulation of myocytes expressing channelorhodopsin. If successful, such biomimetic pumps can i) serve as energy- efficient flow generators in microdevices such as human-on-the-chip, ii) be used as experimental models for modeling function of embryonic heart during normal development or in diseased states, iii) be recreated from patient's own cell for the purpose of improving flow of biological fluids at specific locations.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
