Tuning microenvironment modulus and biochemical composition promotes human mesenchymal stem cell tenogenic differentiation

Matthew S. Rehmann, Jesus I. Luna, Emanual Michael Maverakis, April M. Kloxin

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


Mesenchymal stem cells (MSCs) are promising for the regeneration of tendon and ligament tissues. Toward realizing this potential, microenvironment conditions are needed for promoting robust lineage-specific differentiation into tenocytes/ligament fibroblasts. Here, we utilized a statistical design of experiments approach to examine combinations of matrix modulus, composition, and soluble factors in human MSC tenogenic/ligamentogenic differentiation. Specifically, well-defined poly(ethylene glycol)-based hydrogels were synthesized using thiol-ene chemistry providing a bioinert base for probing cell response to extracellular matrix cues. Monomer concentrations were varied to achieve a range of matrix moduli (E 10-90 kPa), and different ratios of integrin-binding peptides were incorporated (GFOGER and RGDS for collagen and fibronectin, respectively), mimicking aspects of developing tendon/ligament tissue. A face-centered central composite response surface design was utilized to understand the contributions of these cues to human MSC differentiation in the presence of soluble factors identified to promote tenogenesis/ligamentogenesis (BMP-13 and ascorbic acid). Increasing modulus and collagen mimetic peptide content increased relevant gene expression and protein production or retention (scleraxis, collagen I, tenascin-C). These findings could inform the design of materials for tendon/ligament regeneration. More broadly, the design of experiments enabled efficient data acquisition and analysis, requiring fewer replicates than if each factor had been varied one at a time. This approach can be combined with other stimuli (for example, mechanical stimulation) toward a better mechanistic understanding of differentiation down these challenging lineages.

Original languageEnglish (US)
Pages (from-to)1162-1174
Number of pages13
JournalJournal of Biomedical Materials Research - Part A
Issue number5
StatePublished - May 1 2016


  • cell microenvironment
  • design of experiments
  • hydrogel
  • mesenchymal stem cell
  • tendon

ASJC Scopus subject areas

  • Ceramics and Composites
  • Biomaterials
  • Biomedical Engineering
  • Metals and Alloys


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