Effect of cell origin and timing of delivery for stem cell-based bone tissue engineering using biologically functionalized hydrogels

Christopher R. Dosier, Brent A. Uhrig, Nick J. Willett, Laxminarayanan Krishnan, Mon Tzu Alice Li, Hazel Y. Stevens, Zvi Schwartz, Barbara D. Boyan, Robert E. Guldberg

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Despite progress in bone tissue engineering, the healing of critically sized diaphyseal defects remains a clinical challenge. A stem cell-based approach is an attractive alternative to current treatment techniques. The objective of this study was to examine the ability of adult stem cells to enhance bone formation when co-delivered with the osteoinductive factor bone morphogenetic protein-2 (BMP-2) in a biologically functionalized hydrogel. First, adipose and bone marrow-derived mesenchymal stem cells (ADSCs and BMMSCs) were screened for their potential to form bone when delivered in an RGD functionalized alginate hydrogel using a subcutaneous implant model. BMMSCs co-delivered with BMP-2 produced significantly more mineralized tissue compared with either ADSCs co-delivered with BMP-2 or acellular hydrogels containing BMP-2. Next, the ability of BMMSCs to heal a critically sized diaphyseal defect with a nonhealing dose of BMP-2 was tested using the alginate hydrogel as an injectable cell carrier. The effect of timing of therapeutic delivery on bone regeneration was also tested in the diaphyseal model. A 7 day delayed injection of the hydrogel into the defect site resulted in less mineralized tissue formation than immediate delivery of the hydrogel. By 12 weeks, BMMSC-loaded hydrogels produced significantly more bone than acellular constructs regardless of immediate or delayed treatment. For immediate delivery, bridging of defects treated with BMMSC-loaded hydrogels occurred at a rate of 75% compared with a 33% bridging rate for acellular-treated defects. No bridging was observed in any of the delayed delivery samples for any of the groups. Therefore, for this cell-based bone tissue engineering approach, immediate delivery of constructs leads to an overall enhanced healing response compared with delayed delivery techniques. Further, these studies demonstrate that co-delivery of adult stem cells, specifically BMMSCs, with BMP-2 enhances bone regeneration in a critically sized femoral segmental defect compared with acellular hydrogels containing BMP-2.

Original languageEnglish (US)
Pages (from-to)156-165
Number of pages10
JournalTissue Engineering - Part A
Volume21
Issue number1-2
DOIs
StatePublished - Jan 1 2015

ASJC Scopus subject areas

  • Bioengineering
  • Biochemistry
  • Biomaterials
  • Biomedical Engineering

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    Dosier, C. R., Uhrig, B. A., Willett, N. J., Krishnan, L., Li, M. T. A., Stevens, H. Y., Schwartz, Z., Boyan, B. D., & Guldberg, R. E. (2015). Effect of cell origin and timing of delivery for stem cell-based bone tissue engineering using biologically functionalized hydrogels. Tissue Engineering - Part A, 21(1-2), 156-165. https://doi.org/10.1089/ten.tea.2014.0057