Structural and biochemical modification of a collagen scaffold to selectively enhance MSC tenogenic, chondrogenic, and osteogenic differentiation

Adv Healthc Mater. 2014 Jul;3(7):1086-96. doi: 10.1002/adhm.201300646. Epub 2014 Feb 25.


Biomaterial approaches for engineering orthopedic interfaces such as the tendon-bone junction (TBJ) are limited by a lack of understanding of how insoluble (microstructure, composition) and soluble regulators of stem cell fate work in concert to promote bioactivity and differentiation. One strategy for regenerating the interface is to design biomaterials containing spatially graded structural properties sufficient to induce divergent mesenchymal stem cell (MSC) differentiation into multiple interface-specific phenotypes. This work explores the hypothesis that selective structural modification to a 3D collagen-glycosaminoglycan (CG) scaffold combined with biochemical supplementation can drive human bone-marrow-derived MSC differentiation down tenogenic, osteogenic, and chondrogenic lineages. Tenogenic differentiation is enhanced in geometrically anisotropic scaffolds versus a standard isotropic control. Notably, blebbistatin treatment abrogates this microstructurally driven effect. Further, enhanced osteogenic differentiation and new mineral synthesis are achieved by incorporation of a calcium phosphate mineral phase within the CG scaffold along with the use of osteogenic induction media. Finally, chondrogenic differentiation is optimally driven by combining chondrogenic induction media with a reduced density scaffold that promotes increased cellular condensation, significantly higher expression of chondrogenic genes, and increased GAG deposition. Together these data provide critical insight regarding design rules for elements of an integrated biomaterial platform for orthopedic interface regeneration.

Keywords: collagen scaffolds; differentiation; mesenchymal stem cells; osteotendinous junction; tendon.

Publication types

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

MeSH terms

  • Cell Differentiation / drug effects*
  • Cell Shape / drug effects
  • Cells, Cultured
  • Collagen / chemistry*
  • Collagen / pharmacology
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Gene Expression Profiling
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Histocytochemistry
  • Humans
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / drug effects*
  • Osteogenesis / drug effects
  • Tissue Scaffolds / chemistry*


  • Extracellular Matrix Proteins
  • Heterocyclic Compounds, 4 or More Rings
  • blebbistatin
  • Collagen