Robert T. Tranquillo Distinguished McKnight University Professor Professor and Head 612/625-6868 tranquillo@cems.umn.edu Research Group

Cardiovascular and neural tissue engineering

• B.S., Chemical Engineering, Pennsylvania State University, 1979
• M.S., Chemical Engineering, Stanford University, 1980
• Ph.D., Chemical Engineering, University of Pennsylvania, 1986
• Postdoctoral Fellow, Mathemartical Biology, Oxford University, 1987

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, Pei, and Letourneau).

Selected Publications

Cytokine Induction of Functional Smooth Muscle Cells from Multipotent Adult Progenitor Cells
Ross J.J., Zhigang H., Willenbring B., Zeng L., Isenberg B., Lee E.H., Reyes M., Keirstead S.A., Weir E.K., Tranquillo R.T., Verfaillie C.M.
J Clin Invest. 2006 116:3139-3149. (abstract) (pdf)

Small-diameter artificial arteries engineered in vitro {Review}
Isenberg, B.C., Williams, C. and R.T. Tranquillo
Circ Res. 2006 Jan 6;98(1):25-35. (abstract) (pdf)

Endothelialization and Flow Conditioning of Fibrin-based Media-equivalents
Isenberg, B.C., Williams, C. and R.T. Tranquillo
Ann Biomed Eng. 2006 Jun;34(6):971-85. (abstract) (pdf)

Cell Sourcing for Fibrin-Based Valve Constructs
Williams, C., Johnson, S. L., Robinson, P. S. and R. T. Tranquillo
Tissue Eng. 2006 Jun;12(6):1489-502. (abstract) (pdf)

Tissue engineered valves with commissural alignment
Neidert, M.R. and Tranquillo, R.T.
Tissue Eng. 2006 Apr;12(4):891-903. (abstract) (pdf)

Schwann cell behavior in three-dimensional collagen gels: Evidence for differential mechano-transduction and the influence of TGF-beta1 in morphological polarization and differentiation
Rosner, B. I., Hang, T-C., and R. T. Tranquillo
Exp Neurol. 2005 Sep;195(1):81-91.

Cryopreservation of collagen-based tissue equivalents. II. Improved freezing in the presence of cryoprotective agents.
Neidert MR, Devireddy RV, Tranquillo RT, Bischof JC.
Tissue Eng. 2004 Jan-Feb;10(1-2):23-32.

Rational design of contact guiding, neurotrophic matrices for peripheral nerve regeneration.
Rosner BI, Siegel RA, Grosberg A, Tranquillo RT.
Ann Biomed Eng. 2003 Dec;31(11):1383-401.

Cryopreservation of collagen-based tissue equivalents. I. Effect of freezing in the absence of cryoprotective agents.
Devireddy RV, Neidert MR, Bischof JC, Tranquillo RT.
Tissue Eng. 2003 Dec;9(6):1089-100.

Elastic fiber production in cardiovascular tissue-equivalents.
Long JL, Tranquillo RT.
Matrix Biol. 2003 Jun;22(4):339-50.

Long-term cyclic distention enhances the mechanical properties of collagen-based media-equivalents.
Isenberg BC, Tranquillo RT.
Ann Biomed Eng. 2003 Sep;31(8):937-49.

A fibrin-based arterial media equivalent.
Grassl ED, Oegema TR, Tranquillo RT.
J Biomed Mater Res. 2003 Sep 1;66A(3):550-61.

Temporal variations in cell migration and traction during fibroblast-mediated gel compaction.
Shreiber DI, Barocas VH, Tranquillo RT.
Biophys J. 2003 Jun;84(6):4102-14.

Fiber alignment imaging during mechanical testing of soft tissues.
Tower TT, Neidert MR, Tranquillo RT.
Ann Biomed Eng. 2002 Nov-Dec;30(10):1221-33.

Confined compression of a tissue-equivalent: collagen fibril and cell alignment in response to anisotropic strain.
Girton TS, Barocas VH, Tranquillo RT.
J Biomech Eng. 2002 Oct;124(5):568-75.

A novel implantable collagen gel assay for fibroblast traction and proliferation during wound healing.
Enever PA, Shreiber DI, Tranquillo RT.
J Surg Res. 2002 Jun 15;105(2):160-72.

Enhanced fibrin remodeling in vitro with TGF-beta1, insulin and plasmin for improved tissue-equivalents.
Neidert MR, Lee ES, Oegema TR, Tranquillo RT.
Biomaterials. 2002 Sep;23(17):3717-31.

The tissue-engineered small-diameter artery.
Tranquillo RT.
Ann N Y Acad Sci. 2002 Jun;961:251-4.

Macrophages influence a competition of contact guidance and chemotaxis for fibroblast alignment in a fibrin gel coculture assay.
Bromberek BA, Enever PA, Shreiber DI, Caldwell MD, Tranquillo RT.
Exp Cell Res. 2002 May 1;275(2):230-42.

Fibrin as an alternative biopolymer to type-I collagen for the fabrication of a media equivalent.
Grassl ED, Oegema TR, Tranquillo RT.
J Biomed Mater Res. 2002 Jun 15;60(4):607-12.

Alignment maps of tissues: II. Fast harmonic analysis for imaging.
Tower TT, Tranquillo RT.
Biophys J. 2001 Nov;81(5):2964-71.

Alignment maps of tissues: I. Microscopic elliptical polarimetry.
Tower TT, Tranquillo RT.
Biophys J. 2001 Nov;81(5):2954-63.

Neuronal contact guidance in magnetically aligned fibrin gels: effect of variation in gel mechano-structural properties.
Dubey N, Letourneau PC, Tranquillo RT.
Biomaterials. 2001 May;22(10):1065-75.

Effects of pdgf-bb on rat dermal fibroblast behavior in mechanically stressed and unstressed collagen and fibrin gels.
Shreiber DI, Enever PA, Tranquillo RT.
Exp Cell Res. 2001 May 15;266(1):155-66.

A self-consistent cell flux expression for simultaneous chemotaxis and contact guidance in tissues.
Wagle MA, Tranquillo RT.
J Math Biol. 2000 Oct;41(4):315-30.

Mechanisms of stiffening and strengthening in media-equivalents fabricated using glycation.
Girton TS, Oegema TR, Grassl ED, Isenberg BC, Tranquillo RT.
J Biomech Eng. 2000 Jun;122(3):216-23.

Guided neurite elongation and schwann cell invasion into magnetically aligned collagen in simulated peripheral nerve regeneration.
Dubey N, Letourneau PC, Tranquillo RT.
Exp Neurol. 1999 Aug;158(2):338-50.

Magnetically aligned collagen gel filling a collagen nerve guide improves peripheral nerve regeneration.
Ceballos D, Navarro X, Dubey N, Wendelschafer-Crabb G, Kennedy WR, Tranquillo RT.
Exp Neurol. 1999 Aug;158(2):290-300.

Exploiting glycation to stiffen and strengthen tissue equivalents for tissue engineering.
Girton TS, Oegema TR, Tranquillo RT.
J Biomed Mater Res. 1999 Jul;46(1):87-92.

Self-organization of tissue-equivalents: the nature and role of contact guidance.
Tranquillo RT.
Biochem Soc Symp. 1999;65:27-42.

A fibrin or collagen gel assay for tissue cell chemotaxis: assessment of fibroblast chemotaxis to GRGDSP.
Knapp DM, Helou EF, Tranquillo RT.
Exp Cell Res. 1999 Mar 15;247(2):543-53.

Engineered alignment in media equivalents: magnetic prealignment and mandrel compaction.
Barocas VH, Girton TS, Tranquillo RT.
J Biomech Eng. 1998 Oct;120(5):660-6.

A finite element solution for the anisotropic biphasic theory of tissue-equivalent mechanics: the effect of contact guidance on isometric cell traction measurement.
Barocas VH, Tranquillo RT.
J Biomech Eng. 1997 Aug;119(3):261-8.

An anisotropic biphasic theory of tissue-equivalent mechanics: the interplay among cell traction, fibrillar network deformation, fibril alignment, and cell contact guidance.
Barocas VH, Tranquillo RT.
J Biomech Eng. 1997 May;119(2):137-45.

Magnetically orientated tissue-equivalent tubes: application to a circumferentially orientated media-equivalent.
Tranquillo RT, Girton TS, Bromberek BA, Triebes TG, Mooradian DL.
Biomaterials. 1996 Feb;17(3):349-57.

Stochastic model of receptor-mediated cytomechanics and dynamic morphology of leukocytes.
Tranquillo RT, Alt W.
J Math Biol. 1996;34(4):361-412.

The fibroblast-populated collagen microsphere assay of cell traction force--Part 2: Measurement of the cell traction parameter.
Barocas VH, Moon AG, Tranquillo RT.
J Biomech Eng. 1995 May;117(2):161-70.