In the area of cardiovascular tissue engineering, we have developed the use of the "tissue-equivalent" as a replacement for a diseased or damaged small diameter artery, heart valve, and myocardium. Tissue-equivalents are fabricated from entrapping the relevant tissue cell into a biopolymer gel and constraining the cell-mediated gel compaction to engineer the alignment of the gel fibrils, so as to mimic the alignment of the target tissue. In prior work we have extensively researched the process by which cell traction exerted on gel fibrils by cells causes fibril reorganization on the microscale and contraction of the fibril network on the macroscale, inducing fibril alignment and thereby cell contact guidance in a complicated but fascinating biomechanical feedback loop. This understanding guides the design of molds presenting appropriate mechanical constraints for fabrication of tissue-equivalents with prescribed alignment.
Our current research in cardiovascular tissue engineering focuses on the use of fibrin gel as an alternative to the traditional use of collagen gel because of the extensive compositional remodeling that can be realized in addition to the structural remodeling described above. Major questions are how do the collagen fibrils and elastic fibers being produced depend on exposure to cyclic mechanical stretching, transmural flow, and soluble chemical stimuli? Bioreactors are being developed and used to answer these questions. A related question is how does the resultant tissue composition and structure translate into functional properties of interest, such as proper compliance and sufficient burst pressure for our artery-equivalent or bending properties of the leaflets in our valve-equivalent? In order to address such questions in tissue growth and remodeling, we have developed a high-speed tissue alignment imaging system that we are using in conjunction with biaxial mechanical testing and electron microscopy of tissue-equivalents with systematically varied composition and alignment (with Prof. Victor Barocas).
The more complicated geometry and mechanical function related to leaflet bending for valve opening and closing poses new challenges being addressed in a collaborative effort to relate optimal mold design to ultimate function of the valve-equivalent (with Profs. Barocas, Ellen Longmire, and Fotis Sotiropoulos). We are developing a novel controlled-stretch bioreactor and use of photo-crosslinked fibrin as complementary strategies to achieve greater bending stiffness and strength of the valve leaflets. A newer project similarly seeks to generate a myocardium-equivalent, or “heart patch”, by exploiting the contact guidance features of tissue-equivalent fabrication to attain requisite electro-mechanical function (with Prof. Doris Taylor).
In all these projects, the use of blood-derived endothelial cells is being explored to provide a quiescent endothelium at implantation and possibly a functional microvasculature within the tissue as well (with Prof. Robert Hebbel). Also, animal studies are also being conducted (with Experimental Surgical Services).
A new direction aims to integrate “systems biology” with tissue engineering for developing a rationale approach to the use of stimuli to drive tissue growth. Cell signals are being measured in response to stimulation (mechanical or chemical) to determine the optimal stimulation regimen for maximizing outcomes of interest.