Heparin-Conjugated Decellularized Bone Particles Promote Enhanced Osteogenic Signaling of PDGF-BB to Adipose-Derived Stem Cells in Tissue Engineered Bone Grafts

Alexandra N. Rindone, Bartlomiej Kachniarz, Chukwuebuka C. Achebe, Ryan Riddle, Aine N. O'Sullivan, Amir H. Dorafshar, Warren L Grayson

Research output: Contribution to journalArticle

Abstract

Adipose-derived stem cells (ASCs) are a promising cell source for regenerating critical-sized craniofacial bone defects, but their clinical use is limited due to the supraphysiological levels of bone morphogenetic protein-2 required to induce bone formation in large grafts. It has been recently reported that platelet-derived growth factor-BB (PDGF) directly enhances the osteogenesis of ASCs when applied at physiological concentrations. In this study, a biomimetic delivery system that tethers PDGF to decellularized bone matrix (DCB) is developed to enhance osteogenic signaling in bone grafts by colocalizing PDGF-extracellular matrix cues. Heparin is conjugated to DCB particles (HC-DCB) to promote sustained binding of PDGF via electrostatic interactions. HC-DCB particles bind to PDGF with >99% efficiency and release significantly less PDGF over 21 days compared to nonconjugated DCB particles (1.1% vs 22.8%). HC-DCB-PDGF signaling in polycaprolactone (PCL)-fibrin grafts promotes >40 µg Ca 2+ µg −1 DNA deposition by ASCs during in vitro osteogenic culture compared to grafts without HC-DCB or PDGF. Furthermore, more bone formation is observed in grafts with HC-DCB-PDGF at 12 weeks following implantation of grafts into murine critical-sized calvarial defects. Collectively, these results demonstrate that HC-DCB enhances the osteogenic signaling of PDGF to ASCs and may be applied to promote ASC-mediated bone regeneration in critical-sized defects.

Original languageEnglish (US)
Article number1801565
JournalAdvanced Healthcare Materials
DOIs
StatePublished - Jan 1 2019

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Bone Matrix
Platelets
Stem cells
Grafts
Heparin
Bone
Stem Cells
Tissue
Transplants
Bone and Bones
Osteogenesis
platelet-derived growth factor BB
Intercellular Signaling Peptides and Proteins
Defects
Bone Morphogenetic Protein 2
Biomimetics
Bone Regeneration
Fibrin
Static Electricity
Cues

Keywords

  • adipose-derived stem cells
  • bone extracellular matrix
  • bone tissue engineering
  • growth factor delivery
  • platelet-derived growth factors

ASJC Scopus subject areas

  • Biomaterials
  • Biomedical Engineering
  • Pharmaceutical Science

Cite this

Heparin-Conjugated Decellularized Bone Particles Promote Enhanced Osteogenic Signaling of PDGF-BB to Adipose-Derived Stem Cells in Tissue Engineered Bone Grafts. / Rindone, Alexandra N.; Kachniarz, Bartlomiej; Achebe, Chukwuebuka C.; Riddle, Ryan; O'Sullivan, Aine N.; Dorafshar, Amir H.; Grayson, Warren L.

In: Advanced Healthcare Materials, 01.01.2019.

Research output: Contribution to journalArticle

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abstract = "Adipose-derived stem cells (ASCs) are a promising cell source for regenerating critical-sized craniofacial bone defects, but their clinical use is limited due to the supraphysiological levels of bone morphogenetic protein-2 required to induce bone formation in large grafts. It has been recently reported that platelet-derived growth factor-BB (PDGF) directly enhances the osteogenesis of ASCs when applied at physiological concentrations. In this study, a biomimetic delivery system that tethers PDGF to decellularized bone matrix (DCB) is developed to enhance osteogenic signaling in bone grafts by colocalizing PDGF-extracellular matrix cues. Heparin is conjugated to DCB particles (HC-DCB) to promote sustained binding of PDGF via electrostatic interactions. HC-DCB particles bind to PDGF with >99{\%} efficiency and release significantly less PDGF over 21 days compared to nonconjugated DCB particles (1.1{\%} vs 22.8{\%}). HC-DCB-PDGF signaling in polycaprolactone (PCL)-fibrin grafts promotes >40 µg Ca 2+ µg −1 DNA deposition by ASCs during in vitro osteogenic culture compared to grafts without HC-DCB or PDGF. Furthermore, more bone formation is observed in grafts with HC-DCB-PDGF at 12 weeks following implantation of grafts into murine critical-sized calvarial defects. Collectively, these results demonstrate that HC-DCB enhances the osteogenic signaling of PDGF to ASCs and may be applied to promote ASC-mediated bone regeneration in critical-sized defects.",
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