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

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Bob Tranquillo

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 (fibrin) 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.  Bioreactors are used to create tissue-equivalent tubes by simulating the cells to replace the aligned fibrin with an aligned collagenous matrix.  Upon decellularization, they are sufficiently strong to be implanted as vascular grafts and tubular hearts valves and are conducive to recellularization by the host, leading to growth capacity.  Engineered human cardiac tissue that beats via entrapped iPSC-cardiomyocytes and contains a self-assembled microvascular network has been created using the same tissue-equivalent approach.

Our current research in cardiovascular tissue engineering focuses creating transcatheter heart valves and vein valves, combining our unique tubes of cell-produced matrix with stent technology, and conferring immediate or rapid hemocompatibility of the matrix using autologous stem cell and small molecule strategies. 

Contact guidance -- the ability of cells to sense and aligned with aligned fibers -- is crucial to our ability to create tissues with prescribed alignment, such as the circumferentially-aligned tubes. The underlying mechanism of contact guidance is also 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.

Selected Publications

  1. Somatic growth of "off-the-shelf" tissue-engineered pediatric conduit in the lamb
    Syedain, Z.H., Reimer, J. M., Lahti, M., Berry, J., and R.T. Tranquillo 
    Nat Comm (in press).

  2. Inosculation and perfusion of pre-vascularized tissue patches containing aligned human microvessels after myocardial infarction
    Riemenschneider, S.B., Mattia, D.J., Wendel, J.S., Schaefer, J.A., Ye, L., Guzman, P.A., and R.T. Tranquillo
    Biomaterials 97:51-61 (2016). (abstract)

  3. Implantation of a tissue-engineered tubular heart valve in growing lambs
    Reimer, J.M., Syedain, Z.H., Haynei, B., Lahti, M., Berry, J. and R.T. Tranquillo
    Ann Biomed Eng (accepted). (abstract)

  4. Cyclic stretch and perfusion bioreactor for conditioning large diameter engineered tissue tubes
    Schmidt, J.B. and R.T. Tranquillo
    Ann Biomed Eng 44(5):1785-97 (2016). (abstract)

  5. Tissue contraction force microscopy for optimization of engineered cardiac tissue
    Schaefer, J.A. and R.T. Tranquillo
    Tissue Eng Part C 22:76-83 (2016). (abstract)

  6. 6-month aortic valve implantation of an off-the-shelf tissue-engineered valve in sheep
    Syedain, Z.H., Reimer, J.M., Schmidt, J.B., Lahti, M., Berry, J., Bianco, R. and R.T. Tranquillo
    Biomaterials 73:175-84 (2015). (abstract)

  7. Functional effects of a tissue-engineered cardiac patch from human induced pluripotent stem cell-derived cardiomyocytes in a rat infarct model
    Wendel, J., Ye, L., Rao, T. Zhang, J., Zhang, J., Kamp, T.J. and R.T. Tranquillo
    STEM CELLS Transl Med 4:1324-32 (2015). (abstract)

  8. Effects of intermittent and incremental cyclic stretch on ERK signaling and collagen production in engineered tissue
    Schmidt, J.B. and R.T. Tranquillo
    Cell Molec Bioeng 9:55-64 (2015). (abstract)

  9. Pediatric tubular pulmonary heart valve from decellularized engineered tissue tubes
    Reimer, J.M., Syedain, Z.H., Haynie, B and R.T. Tranquillo
    Biomaterials 62: 88-94 (2015). (abstract)

  10. Automated image analysis programs for the quantification of microvascular network characteristics
    Morin, K.T., Carlson, P. C. and R. T. Tranquillo
    Methods 84: 76-83 (2015). (abstract)

  11. 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 137: 051003 (2015). (abstract)

  12. 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 9: 605-18 (2015). (abstract)

  13. 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)

  14. 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)

  15. 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)

  16. 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)

  17. 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)

  18. 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)

  19. 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)

  20. 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)

  21. 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)

  22. 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)

  23. 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)

  24. 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)

  25. 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)

  26. 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)

  27. 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)

  28. 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).

  29. 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)

  30. 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)

  31. 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)

  32. 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)