Cyclic Flexure and Laminar Flow Synergistically Accelerate Mesenchymal Stem Cell-Mediated Engineered Tissue Formation: Implications for Engineered Heart Valve Tissues

Biomaterials. 2006 Dec;27(36):6083-95. doi: 10.1016/j.biomaterials.2006.07.045. Epub 2006 Aug 23.


Bone marrow-derived mesenchymal stem cells (BMSCs) are relatively accessible and exhibit a pluripotency suitable for cardiovascular applications such as tissue-engineered heart valves (TEHVs). Recently, Sutherland et al. [From stem cells to viable autologous semilunar heart valve. Circulation 2005; 111(21): 2783-91] demonstrated that BMSC-seeded TEHV can successfully function as pulmonary valve substitutes in juvenile sheep for at least 8 months. Toward determining appropriate mechanical stimuli for use in BMSC-seeded TEHV cultivation, we investigated the independent and coupled effects of two mechanical stimuli physiologically relevant to heart valves-cyclic flexure and laminar flow (i.e. fluid shear stress)-on BMSC-mediated tissue formation. BMSC isolated from juvenile sheep were expanded and seeded onto rectangular strips of nonwoven 50:50 blend poly(glycolic acid) (PGA) and poly(l-lactic acid) (PLLA) scaffolds. Following 4 days static culture, BMSC-seeded scaffolds were loaded into a novel flex-stretch-flow (FSF) bioreactor and incubated under static (n=12), cyclic flexure (n=12), laminar flow (avg. wall shear stress=1.1505 dyne/cm(2); n=12) and combined flex-flow (n=12) conditions for 1 (n=6) and 3 (n=6) weeks. By 3 weeks, the flex-flow group exhibited dramatically accelerated tissue formation compared with all other groups, including a 75% higher collagen content of 844+/-278 microg/g wet weight (p<0.05), and an effective stiffness (E) value of 948+/-233 kPa. Importantly, collagen and E values were not significantly different from values measured for vascular smooth muscle cell (SMC) -seeded scaffolds incubated under conditions of flexure alone [Engelmayr et al. The independent role of cyclic flexure in the early in vitro development of an engineered heart valve tissue. Biomaterials 2005; 26(2): 175-87], suggesting that BMSC-seeded TEHV can be optimized to yield results comparable to SMC-seeded TEHV. We thus demonstrated that cyclic flexure and laminar flow can synergistically accelerate BMSC-mediated tissue formation, providing a basis for the rational design of in vitro conditioning regimens for BMSC-seeded TEHV.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bioprosthesis*
  • Bioreactors
  • Cell Culture Techniques / instrumentation
  • Cell Culture Techniques / methods
  • Cell Proliferation
  • Cells, Cultured
  • Endothelial Cells / cytology*
  • Endothelial Cells / physiology*
  • Equipment Design
  • Heart Valve Prosthesis*
  • Mechanotransduction, Cellular / physiology
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / physiology*
  • Microfluidics / instrumentation
  • Microfluidics / methods
  • Prosthesis Design
  • Sheep
  • Stress, Mechanical
  • Tissue Engineering / instrumentation*
  • Tissue Engineering / methods