Skip to main content

Bioreactor and Biomaterial Platforms for Investigation of Mitral Valve Biomechanics and Mechanobiology

  • Chapter
  • First Online:
Molecular Biology of Valvular Heart Disease

Abstract

Understanding the biomechanics of mitral valves (MVs) has significance for both surgical treatment and regenerative medicine. The biomechanics and mechanobiology of MVs is influenced by their complex anatomy, together with their extracellular matrix (ECM) composition and organization. Valve cells are mechanoresponsive, both to the hemodynamically active environment which the valve tissue is constantly exposed, as well as the altered hemodynamics of valve disease. This chapter will discuss the various tissue and cell level culture techniques and biomechanical approaches to date for examining MV biomechanics and mechanobiology, as well as directions for future studies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 54.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Barber JE, Kasper FK, Ratliff NB, Cosgrove DM, Griffin BP, Vesely I. Mechanical properties of myxomatous mitral valves. J Thorac Cardiovasc Surg. 2001;122:955–62.

    Article  PubMed  CAS  Google Scholar 

  2. Barber JE, Ratliff NB, Cosgrove DM, Griffin BP, Vesely I. Myxomatous mitral valve chordae. I: mechanical properties. J Heart Valve Dis. 2001;10:320–4.

    PubMed  CAS  Google Scholar 

  3. Barzilla JE, Acevedo FE, Grande-Allen KJ. Organ culture as a tool to identify early mechanisms of serotonergic valve disease. J Heart Valve Dis. 2010;19:626–35.

    PubMed  Google Scholar 

  4. Barzilla JE, McKenney AS, Cowan AE, Durst CA, Grande-Allen KJ. Design and validation of a novel splashing bioreactor system for use in mitral valve organ culture. Ann Biomed Eng. 2010;38:3280–94.

    Article  PubMed  Google Scholar 

  5. Benton J, Fairbanks B, Anseth K. Characterization of valvular interstitial cell function in three dimensional matrix metalloproteinase degradable peg hydrogels. Biomaterials. 2009;30:6593–603.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  6. Bhattacharya S, He Z. Annulus tension of the prolapsed mitral valve corrected by edge-to-edge repair. J Biomech. 2012;45:562–8.

    Article  PubMed  Google Scholar 

  7. Brand NJ, Roy A, Hoare G, Chester A, Yacoub MH. Cultured interstitial cells from human heart valves express both specific skeletal muscle and non-muscle markers. Int J Biochem Cell Biol. 2006;38:30–42.

    Article  PubMed  CAS  Google Scholar 

  8. Butcher JT, Penrod AM, García AJ, Nerem RM. Unique morphology and focal adhesion development of valvular endothelial cells in static and fluid flow environments. Arterioscler Thromb Vasc Biol. 2004;24:1429–34.

    Article  PubMed  CAS  Google Scholar 

  9. Chen L, May-Newman K. Effect of strut chordae transection on mitral valve leaflet biomechanics. Ann Biomed Eng. 2006;34:917–26.

    Article  PubMed  Google Scholar 

  10. Chen L, McCulloch AD, May-Newman K. Nonhomogeneous deformation in the anterior leaflet of the mitral valve. Ann Biomed Eng. 2004;32:1599–606.

    Article  PubMed  Google Scholar 

  11. Chester AH, Taylor PM. Molecular and functional characteristics of heart-valve interstitial cells. Philos Trans R Soc Lond B Biol Sci. 2007;362:1437–43.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  12. Croft LR, Jimenez JH, Gorman RC, Gorman JH, Yoganathan AP. Efficacy of the edge-to-edge repair in the setting of a dilated ventricle: an in vitro study. Ann Thorac Surg. 2007;84:1578–84.

    Article  PubMed  Google Scholar 

  13. Fornes P, Heudes D, Fuzellier JF, Tixier D, Bruneval P, Carpentier A. Correlation between clinical and histologic patterns of degenerative mitral valve insufficiency: a histomorphometric study of 130 excised segments. Cardiovasc Pathol. 1999;8:81–92.

    Article  PubMed  CAS  Google Scholar 

  14. Gheewala N, Grande-Allen KJ. Design and mechanical evaluation of a physiological mitral valve organ culture system. Cardiovasc Eng Technol. 2010;1:123–31.

    Article  Google Scholar 

  15. Gould RA, Sinha R, Aziz H, Rouf R, Dietz HC, Judge DP, Butcher J. Multi-scale biomechanical remodeling in aging and genetic mutant murine mitral valve leaflets: insights into Marfan syndrome. PLoS One. 2012;7:e44639.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  16. Grande-Allen KJ, Barber JE, Klatka KM, Houghtaling PL, Vesely I, Moravec CS, McCarthy PM. Mitral valve stiffening in end-stage heart failure: evidence of an organic contribution to functional mitral regurgitation. J Thorac Cardiovasc Surg. 2005;130:783–90.

    Article  PubMed  Google Scholar 

  17. Grande-Allen KJ, Liao J. The heterogeneous biomechanics and mechanobiology of the mitral valve: implications for tissue engineering. Curr Cardiol Rep. 2011;13:113–20.

    Article  PubMed  Google Scholar 

  18. Grashow JS, Sacks MS, Liao J, Yoganathan AP. Planar biaxial creep and stress relaxation of the mitral valve anterior leaflet. Ann Biomed Eng. 2006;34:1509–18.

    Article  PubMed  Google Scholar 

  19. Grashow JS, Yoganathan AP, Sacks MS. Biaixal stress-stretch behavior of the mitral valve anterior leaflet at physiologic strain rates. Ann Biomed Eng. 2006;34:315–25.

    Article  PubMed  Google Scholar 

  20. Gupta V, Grande-Allen KJ. Effects of static and cyclic loading in regulating extracellular matrix synthesis by cardiovascular cells. Cardiovasc Res. 2006;72:375–83.

    Article  PubMed  CAS  Google Scholar 

  21. Gupta V, Werdenberg JA, Blevins TL, Grande-Allen KJ. Synthesis of glycosaminoglycans in differently loaded regions of collagen gels seeded with valvular interstitial cells. Tissue Eng. 2007;13:41–9.

    Article  PubMed  CAS  Google Scholar 

  22. He S, Fontaine AA, Schwammenthal E, Yoganathan AP, Levine RA. Integrated mechanism for functional mitral regurgitation. Circulation. 1997;96:1826.

    Article  PubMed  CAS  Google Scholar 

  23. Hockaday LA, Kang KH, Colangelo NW, Bonassar LJ, Malone E, Wu J, Chu CC, Lipson H, Duan B, Cheung PYC, Girardi LN, Butcher JT. Rapid 3d printing of anatomically accurate and mechanically heterogeneous aortic valve hydrogel scaffolds. Biofabrication. 2012;4:035005.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  24. Hu Y, Shi L, Parameswaran S. Left ventricular vortex under mitral valve edge-to-edge repair. Cardiovasc Eng Technol. 2010;1:235–43.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Itoh A, Krishnamurthy G, Swanson JC, Ennis DB, Bothe W, Kuhl E, Karlsson M, Davis LR, Miller DC, Ingels NB. Active stiffening of mitral valve leaflets in the beating heart. Am J Physiol Heart Circ Physiol. 2009;296:H1766–73.

    Article  PubMed  CAS  Google Scholar 

  26. Jimenez JH, Liou SW, Padala M, He Z, Sacks M, Gorman RC, Gorman JH, Yoganathan AP. A saddle-shaped annulus reduces systolic strain on the central region of the mitral valve anterior leaflet. J Thorac Cardiovasc Surg. 2007;134:1562–8.

    Article  PubMed  Google Scholar 

  27. Jimenez JH, Soerensen DD, He Z, He S, Yoganathan AP. Effects of a saddle shaped annulus on mitral valve function and chordal force distribution: an in vitro study. Ann Biomed Eng. 2003;31:1171–81.

    Article  PubMed  Google Scholar 

  28. Jimenez JH, Soerensen DD, He Z, Ritchie J, Yoganathan AP. Mitral valve function and chordal force distribution using a flexible annulus model: an in vitro study. Ann Biomed Eng. 2005;33:557–66.

    Article  PubMed  Google Scholar 

  29. Jimenez JH, Soerensen DD, He Z, Ritchie J, Yoganathan AP. Effects of papillary muscle position on chordal force distribution: an in-vitro study. J Heart Valve Dis. 2005;14:295–302.

    PubMed  Google Scholar 

  30. Jimenez JH, Forbess J, Croft LR, Small L, He Z, Yoganathan AP. Effects of annular size, transmitral pressure, and mitral flow rate on the edge-to-edge repair: an in vitro study. Ann Thorac Surg. 2006;82:1362–8.

    Article  PubMed  Google Scholar 

  31. Johnson CM, Hanson MN, Helgeson SC. Porcine cardiac valvular subendothelial cells in culture: cell isolation and growth characteristics. J Mol Cell Cardiol. 1987;19:1185–93.

    Article  PubMed  CAS  Google Scholar 

  32. Krishnamurthy VK, Guilak F, Narmoneva DA, Hinton RB. Regional structure-function relationships in mouse aortic valve tissue. J Biomech. 2011;44:77–83.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Kunzelman KS, Cochran RP. Stress/strain characteristics of porcine mitral valve tissue: parallel versus perpendicular collagen orientation. J Card Surg. 1992;7:71–8.

    Article  PubMed  CAS  Google Scholar 

  34. Lacerda CMR, Kisiday J, Johnson B, Orton EC. Local serotonin mediates cyclic strain-induced phenotype transformation, matrix degradation, and glycosaminoglycan synthesis in cultured sheep mitral valves. Am J Physiol Heart Circ Physiol. 2012;302:H1983–90.

    Article  PubMed  CAS  Google Scholar 

  35. Lacerda CMR, Maclea HB, Kisiday JD, Orton EC. Static and cyclic tensile strain induce myxomatous effector proteins and serotonin in canine mitral valves. J Vet Cardiol. 2012;14:223–30.

    Article  PubMed  Google Scholar 

  36. Lester WM. Interstitial cells from the atrial and ventricular sides of the bovine mitral valve respond differently to denuding endocardial injury. In Vitro Cell Dev Biol. 1993;29:41–50.

    Article  Google Scholar 

  37. Lester WM, Damji AA, Tanaka M, Gedeon I. Bovine mitral valve organ culture: role of interstitial cells in repair of valvular injury. J Mol Cell Cardiol. 1992;24:43–53.

    Article  PubMed  CAS  Google Scholar 

  38. Lester WM, Gotlieb AI. In vitro repair of the wounded porcine mitral valve. Circ Res. 1988;62:833–45.

    Article  PubMed  CAS  Google Scholar 

  39. Liao J, Yang L, Grashow J, Sacks MS. The relation between collagen fibril kinematics and mechanical properties in the mitral valve anterior leaflet. J Biomech Eng. 2007;129:78–87.

    Article  PubMed  Google Scholar 

  40. Lieber SC, Kruithof BPT, Aubry N, Vatner SF, Gaussin V. Design of a miniature tissue culture system to culture mouse heart valves. Ann Biomed Eng. 2010;38:674–82.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Little SH, Igo SR, Pirat B, McCulloch M, Hartley CJ, Nosé Y, Zoghbi WA. In vitro validation of real-time three-dimensional color Doppler echocardiography for direct measurement of proximal isovelocity surface area in mitral regurgitation. Am J Cardiol. 2007;99:1440–7.

    Article  PubMed Central  PubMed  Google Scholar 

  42. Little SH, Pirat B, Kumar R, Igo SR, McCulloch M, Hartley CJ, Xu J, Zoghbi WA. Three-dimensional color Doppler echocardiography for direct measurement of vena contracta area in mitral regurgitation: in vitro validation and clinical experience. JACC Cardiovasc Imaging. 2008;1:695–704.

    Article  PubMed Central  PubMed  Google Scholar 

  43. Liu AC, Joag VR, Gotlieb AI. The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology. Am J Pathol. 2007;171:1407–18.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  44. May-Newman K, Yin FC. Biaxial mechanical behavior of excised porcine mitral valve leaflets. Am J Physiol. 1995;269:H1319–27.

    PubMed  CAS  Google Scholar 

  45. Nielsen SL, Nygaard H, Fontaine AA, Hasenkam JM, He S, Andersen NT, Yoganathan AP. Chordal force distribution determines systolic mitral leaflet configuration and severity of functional mitral regurgitation. J Am Coll Cardiol. 1999;33:843–53.

    Article  PubMed  CAS  Google Scholar 

  46. Nielsen SL, Nygaard H, Mandrup L, Fontaine AA, Hasenkam JM, He S, Yoganathan AP. Mechanism of incomplete mitral leaflet coaptation—interaction of chordal restraint and changes in mitral leaflet coaptation geometry. J Biomech Eng. 2002;124:596.

    Article  PubMed  Google Scholar 

  47. Padala M, Gyoneva L, Yoganathan AP. Effect of anterior strut chordal transection on the force distribution on the marginal chordae of the mitral valve. J Thorac Cardiovasc Surg. 2012;144:624–33.

    Article  PubMed Central  PubMed  Google Scholar 

  48. Padala M, Hutchison RA, Croft LR, Jimenez JH, Gorman RC, Gorman JH, Sacks MS, Yoganathan AP. Saddle shape of the mitral annulus reduces systolic strains on the p2 segment of the posterior mitral leaflet. Ann Thorac Surg. 2009;88:1499–504.

    Article  PubMed Central  PubMed  Google Scholar 

  49. Padala M, Powell SN, Croft LR, Thourani VH, Yoganathan AP, Adams DH. Mitral valve hemodynamics after repair of acute posterior leaflet prolapse: quadrangular resection versus triangular resection versus neochordoplasty. J Thorac Cardiovasc Surg. 2009;138:309–15.

    Article  PubMed  Google Scholar 

  50. Padala M, Sacks MS, Liou SW, Balachandran K, He Z, Yoganathan AP. Mechanics of the mitral valve strut chordae insertion region. J Biomech Eng. 2010;132:081004.

    Article  PubMed  Google Scholar 

  51. Perloff JK, Roberts WC. The mitral apparatus: functional anatomy of mitral regurgitation. Circulation. 1972;46:227–39.

    Article  PubMed  CAS  Google Scholar 

  52. Quaini A, Canic S, Guidoboni G, Glowinski R, Igo SR, Hartley CJ, Zoghbi WA, Little SH. A three-dimensional computational fluid dynamics model of regurgitant mitral valve flow: validation against in vitro standards and 3d color Doppler methods. Cardiovasc Eng Technol. 2011;2:77–89.

    Article  PubMed Central  PubMed  Google Scholar 

  53. Rabbah J-P, Chism B, Siefert A, Saikrishnan N, Veledar E, Thourani VH, Yoganathan AP. Effects of targeted papillary muscle relocation on mitral leaflet tenting and coaptation. Ann Thorac Surg. 2013;95:621–8.

    Article  PubMed  Google Scholar 

  54. Rabbah J-P, Saikrishnan N, Yoganathan AP. A novel left heart simulator for the multi-modality characterization of native mitral valve geometry and fluid mechanics. Ann Biomed Eng. 2013;41:305–15.

    Article  PubMed Central  PubMed  Google Scholar 

  55. Rabkin E, Aikawa M, Stone JR, Fukumoto Y, Libby P, Schoen FJ. Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation. 2001;104:2525–32.

    Article  PubMed  CAS  Google Scholar 

  56. Sacks MS, Enomoto Y, Graybill JR, Merryman WD, Zeeshan A, Yoganathan AP, Levy RJ, Gorman RC, Gorman JH. In-vivo dynamic deformation of the mitral valve anterior leaflet. Ann Thorac Surg. 2006;82:1369–77.

    Article  PubMed  Google Scholar 

  57. Schoen FJ. Evolving concepts of cardiac valve dynamics: the continuum of development, functional structure, pathobiology, and tissue engineering. Circulation. 2008;118:1864–80.

    Article  PubMed  Google Scholar 

  58. Sewell-Loftin M-K, Brown CB, Baldwin HS, Merryman WD. A novel technique for quantifying mouse heart valve leaflet stiffness with atomic force microscopy. J Heart Valve Dis. 2012;21:513–20.

    PubMed Central  PubMed  Google Scholar 

  59. Stephens E, Durst C, West J, Grande-Allen K. Mitral valvular interstitial cell responses to substrate stiffness depend on age and anatomic region. Acta Biomater. 2011;7:75–82.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  60. Stephens EH, Durst CA, Swanson JC, Grande-Allen KJ, Ingels NB, Miller DC. Functional coupling of valvular interstitial cells and collagen via α2β1 integrins in the mitral leaflet. Cell Mol Bioeng. 2010;3:428–37.

    Article  CAS  Google Scholar 

  61. Stephens EH, Grande-Allen KJ. Age-related changes in collagen synthesis and turnover in porcine heart valves. J Heart Valve Dis. 2007;16:672–82.

    PubMed  Google Scholar 

  62. Stephens EH, de Jonge N, McNeill MP, Durst CA, Grande-Allen KJ. Age-related changes in material behavior of porcine mitral and aortic valves and correlation to matrix composition. Tissue Eng Part A. 2010;16:867–78.

    Article  PubMed  Google Scholar 

  63. Tibbitt MW, Anseth KS. Hydrogels as extracellular matrix mimics for 3d cell culture. Biotechnol Bioeng. 2009;103:655–63.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  64. Tseng H, Balaoing LR, Grigoryan B, Raphael RM, Killian TC, Souza GR, Grande-Allen KJ. A three-dimensional co-culture model of the aortic valve using magnetic levitation. Acta Biomater. 2013;10:173–82.

    Article  PubMed  CAS  Google Scholar 

  65. Tedder ME, Simionescu A, Chen J, Liao J, Simionescu DT (2011) Assembly and testing of stem cell-seeded layered collagen constructs for heart valve tissue engineering. Tissue Eng Part A 17:25–36.

    Google Scholar 

  66. Waxman A, Kornreich B. Interactions between tgfβ1 and cyclic strain in modulation of myofibroblastic differentiation of canine mitral valve interstitial cells in 3d culture. J Vet Cardiol. 2012;14:211–21.

    Article  PubMed Central  PubMed  Google Scholar 

  67. Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 2007;117:524–9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  68. Yap CH, Kim H-S, Balachandran K, Weiler M, Haj-Ali R, Yoganathan AP. Dynamic deformation characteristics of porcine aortic valve leaflet under normal and hypertensive conditions. Am J Physiol Heart Circ Physiol. 2010;298:H395–405.

    Article  PubMed  CAS  Google Scholar 

  69. Yeung T, Georges PC, Flanagan LA, Marg B, Ortiz M, Funaki M, Zahir N, Ming W, Weaver V, Janmey PA. Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion. Cell Motil Cytoskeleton. 2005;60:24–34.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to K. Jane Grande-Allen PhD .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag London

About this chapter

Cite this chapter

Connell, P.S., Krishnamurthy, V.K., Grande-Allen, K.J. (2014). Bioreactor and Biomaterial Platforms for Investigation of Mitral Valve Biomechanics and Mechanobiology. In: Rajamannan, N. (eds) Molecular Biology of Valvular Heart Disease. Springer, London. https://doi.org/10.1007/978-1-4471-6350-3_12

Download citation

  • DOI: https://doi.org/10.1007/978-1-4471-6350-3_12

  • Published:

  • Publisher Name: Springer, London

  • Print ISBN: 978-1-4471-6349-7

  • Online ISBN: 978-1-4471-6350-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics