University of Minnesota
Department of Biomedical Engineering
http://www1.umn.edu/bme
612-624-4507

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Alena Talkachova

Robert T. Tranquillo

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Cardiovascular Tissue Engineering

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. Jay Zhang). A distinctive feature of our heart patch is creating a self-assembled network of dense and aligned microvessels that allows for efficient nutrient transport (with George Davis, U Missouri)

In all these projects, the use of blood-derived endothelial cells (with Profs. Robert Hebbel and Gregory Vercellotti) and mesenchymal stem cells (with Prof. Jakub Tolar) is being explored to provide a quiescent endothelium at implantation and possibly a functional microvasculature within the tissue as well. Also, animal studies are also being conducted (with Experimental Surgical Services).

Contact guidance -- the ability of cells to sense and aligned with aligned fibers -- is crucial to our ability to create tissues with prescribed alignment. The underlying mechanism of contact guidance is being investigated using methods, including magnetic alignment and photo-crosslinking of fibrin, to systematically vary the chemical/physical cues contained in aligned fibers that cells might be sensing (with Prof. Elliot Botvinick, UC-Irvine).

Selected Publications

  1. A mathematical model for understanding fluid flow through engineered tissues containing microvessels
    Morin, K.T., Lenz, M.S., Labat, C. and R.T. Tranquillo
    J Biomech Eng (accepted).

  2. Influence of culture conditions and extracellular matrix alignment on human mesenchymal stem cell invasion into decellularized engineered tissues
    Weidenhamer, N.K., Moore, D.L., Lobo, F.L., Klair, N.T. and R.T. Tranquillo
    J Tissue Eng Regen Med (accepted)

  3. Engineered microvessels possessing alignment and high lumen density via cell-induced fibrin gel compaction and interstitial flow
    Morin, K.T., Dries-Devlin, J.L. and R.T. Tranquillo
    Tissue Eng Part A 20: 553-65 (2014). (abstract)

  4. Functional consequences of a tissue-engineered myocardial patch for cardiac repair in an acute rat infarct model
    Wendel, J., Ye, L., Zhang, P., Tranquillo, R.T. and J. Zhang
    Tissue Eng Part A 20: 1325-35 (2014). (abstract)

  5. Implantation of completely biological engineered grafts following decellularization into the sheep femoral artery
    Syedain, Z.H., Meier, L.A., Lahti, M.T., Johnson, S.L., Hebbel, R.P and R. T. Tranquillo
    Tissue Eng Part A 20: 1726-34 (2014). (abstract)

  6. Blood Outgrowth Endothelial Cells Alter Remodeling of Completely Biological Engineered Grafts Implanted into the Sheep Femoral Artery
    Meier, L.A., Syedain, Z.H., Lahti, M.T., Johnson, S.L., Chen, M.H., Hebbel, R.P and R. T. Tranquillo
    J Cardiovasc Trans Res A 7: 242-9 (2014). (abstract)

  7. A multiscale approach to modeling the passive mechanical contribution of cells in tissues
    Lai, V.K., Hadi, M.F., Tranquillo, R.T., and V.H. Barocas
    J Biomech Eng 135(7): 71007 (2013). (abstract)

  8. Combating adaptation to cyclic stretching by prolonging activation of extracellular signal-regulated kinase
    Weinbaum, J.S., Schmidt, J.B., and R.T. Tranquillo
    Cell Molec Bioeng 6(3): 279-86 (2013). (abstract)

  9. Aligned human microvessels formed in 3D fibrin gel by constraint of gel contraction
    Morin, K.T., Smith, A.O., Davis, G.E., and R.T. Tranquillo
    Microvasc Res 90:12-22 (2013). (abstract)

  10. Tubular heart valves from decellularized engineered tissue
    Syedain, Z.H., Meier, L.A., Reimer, J., and R.T. Tranquillo
    Ann Biomed Eng 41(12): 2645-54 (2013). (abstract)

  11. Influence of cyclic mechanical stretch and tissue constraints on cellular and collagen alignment in fibroblast-derived cell sheets
    Weidenhamer, N.K and R. T. Tranquillo
    Tissue Eng Part C 19(5): 386-95 (2013). (abstract)

  12. Decellularized tissue-engineered heart valve leaflets with recellularization potential
    Syedain, Z.H., Bradee, A.R., Kren S., Taylor, D.A. and R. T. Tranquillo
    Tissue Eng Part A 19:759 (2013). (abstract)

  13. Microstructural and mechanical differences between digested collagen-fibrin co-gels and pure collagen and fibrin gels
    Lai, V. K, Frey, C.R., Kerandi, A.M., Lake, S. P., Tranquillo, R.T. and V.H. Barocas
    Acta Biomat 8:4031 (2012). (abstract)

  14. Mechanical behavior of collagen-fibrin co-gels reflect transition from series to parallel interactions with increasing collagen content
    Lai, V. K, Lake, S. P., Frey, C.R., Tranquillo, R.T. and V.H. Barocas
    J Biomech Eng 134: 011004-1 (2012). (abstract)

  15. Hypoxic Culture and Insulin Yield Improvements to Fibrin-Based Engineered Tissue
    Bjork, J.W., Meier, L.A., Johnson, S.L., Syedain, Z.H., and R.T. Tranquillo
    Tissue Eng Part A, 18(7-8): 785-795 (2012). (abstract)

  16. Shear stress responses of adult blood outgrowth endothelial cells seeded on bioartifical tissue
    Ahmann, K. A., Johnson, S. L., Hebbel, R.P. and R.T. Tranquillo
    Tissue Eng Part A 17:2511 (2011). (cover photo) (abstract)

  17. Guided sprouting from endothelial spheroids in fibrin gels aligned by magnetic fields and cell-induced gel compaction
    Morin, K.T. and R.T. Tranquillo
    Biomaterials 32: 6111-6118 (2011). (abstract)

  18. Implantation of a Tissue-engineered Heart Valve from Human Fibroblasts Exhibiting Short Term Function in the Sheep Pulmonary Artery
    Syedain, Z.H., Lahti, M.T, Johnson, S.L., Robinson, P.S., Ruth, G.R., Bianco, R.W., and R.T. Tranquillo
    Cardiovascular Engineering and Technology 2(2): 101-112 (2011).

  19. Ruthenium-catalyzed photo cross-linking of fibrin-based engineered tissue
    Bjork, J.W., Johnson, S.L., and R.T. Tranquillo
    Biomaterials 32(10): 2479-2488 (2011). (abstract)

  20. TGF-B1 diminishes collagen production during long-term cyclic stretching of engineered connective tissue: Implication of decreased ERK signaling
    Syedain, Z.H. and R.T. Tranquillo
    JBiomech 44(5): 848-55 (2011). (abstract)

  21. Initial fiber alignment pattern laters extracellular matrix synthesis in fibroblast populated fibrin gel cruciforms and correlates with predicted tension
    Sander, E.A., Barocas, V.H., and R.T. Tranquillo
    Ann Biomed Eng (2010). (abstract)

  22. Implantable arterial grafts from human fibroblasts and fibrin using a multi-graft pulsed flow-stretch bioreactor with noninvasive strength monitoring
    Syedain, Z.H. Meier, L.A., Bjork, J.W, Lee, A. and R. T. Tranquillo
    Biomaterials, 32(3): 714-22 (2011). (abstract)