CEMS Faculty

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. An anisotropic biphasic continuum-mechanical theory has been developed based on constitutive models from rheological testing of collagen and fibrin gels and cell behavior assays. Parameter estimation has been performed on data from cell compaction of gels of various geometries and subject to different mechanical constraints that drive the alignment. In addition to guiding the design of molds presenting appropriate mechanical constraints for tissue-equivalent fabrication, parameter estimates have been obtained to characterize the properties of different fibroblast phenotypes and chemical stimuli (growth factors and cytokines) considered important to the related process of wound contraction.

Our current research in vascular tissue engineering focuses on the use of fibrin gel as an alternative to the traditional use of collagen gel for fabricating tissue equivalents 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 recognize the alignment of the degrading fibrin fibrils, and how does this depend on exposure to cyclic mechanical stretching as well as soluble chemical stimuli? Bioreactors are being developed and used to answer these questions. A related question is how does the resultant composition and structure translate into functional properties of interest, such as proper compliance and sufficient burst pressure for the media-equivalent (the medial layer of a replacement artery)? In order to address such questions, 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. Barocas). Another current focus is assessing the possibility of fabricating the media-equivalent entirely from cells derived from adult stem cells, in particular, inducing a cell of smooth muscle phenotype that exhibits the requisite traction and extracellular matrix production. In addition, the influence of endothelial cells on media-equivalent fabrication is being investigated (with Prof. Verfaillie).

More recent research in cardiac engineering seeks to apply the methods and strategies developed for the media-equivalent to the fabrication of a valve-equivalent. The more complicated geometry and 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 valve-equivalent function (with Profs. Barocas, Ebbini, and Longmire). A new project similarly seeks to generate a myocardium-equivalent, or myocardial patch, by exploiting the contact guidance features of tissue-equivalent fabrication to attain requisite electro-mechanical function (with Profs. Barocas and Zhang).

In the area of neural tissue engineering, our approach is based on magnetically aligned rods of collagen or fibrin gel, with fibril alignment being along the rod axis. The goal is to induce highly guided nerve regeneration by exploiting the contact guidance properties of growth cones at the tips of axons that extend into a gel rod serving as a bridge between the two stumps of a severed nerve. A current focus is to promote axon growth in addition to guiding it by supplying appropriate chemical stimuli, such as nerve growth factor, either by controlled release or entrapped Schwaan cells (with Profs. Siegel and Letourneau).