Nanogel-based scaffold delivery of prostaglandin E(2) receptor-specific agonist in combination with a low dose of growth factor heals critical-size bone defects in mice

Arthritis Rheum. 2011 Apr;63(4):1021-33. doi: 10.1002/art.30151.

Abstract

Objective: Regeneration of bone requires the combination of appropriate drugs and an appropriate delivery system to control cell behavior. However, the delivery of multiple drugs to heal bone is complicated by the availability of carriers. The aim of this study was to explore a new system for delivery of a selective EP4 receptor agonist (EP4A) in combination with low-dose bone morphogenetic protein 2 (BMP-2).

Methods: Combined delivery of EP4A and BMP-2 was carried out with a nanogel-based scaffold in the shape of a disc, to repair critical-size circle-shaped bone defects in calvariae that otherwise did not heal spontaneously.

Results: Combination treatment with EP4A and low-dose BMP-2 in nanogel efficiently activated bone cells to regenerate calvarial bone by forming both outer and inner cortical plates as well as bone marrow tissue to regenerate a structure similar to that of intact calvaria. EP4A enhanced low-dose BMP-2-induced cell differentiation and activation of transcription events in osteoblasts.

Conclusion: These data indicate that combined delivery of EP4A and low-dose BMP-2 via nanogel-based hydrogel provides a new system for bone repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaline Phosphatase / blood
  • Animals
  • Bone Diseases / drug therapy*
  • Bone Diseases / physiopathology
  • Bone Morphogenetic Protein 2 / pharmacology
  • Bone Morphogenetic Protein 2 / therapeutic use*
  • Bone and Bones / drug effects
  • Bone and Bones / physiology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Intercellular Signaling Peptides and Proteins / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Nanogels
  • Osteogenesis / drug effects
  • Osteogenesis / physiology
  • Phosphorylation
  • Polyethylene Glycols / pharmacology
  • Polyethylene Glycols / therapeutic use*
  • Polyethyleneimine / pharmacology
  • Polyethyleneimine / therapeutic use*
  • Receptors, Prostaglandin E, EP4 Subtype / agonists*
  • Regeneration / drug effects
  • Regeneration / physiology
  • Smad4 Protein / metabolism
  • Tissue Scaffolds

Substances

  • Bmp2 protein, mouse
  • Bone Morphogenetic Protein 2
  • Intercellular Signaling Peptides and Proteins
  • Nanogels
  • Receptors, Prostaglandin E, EP4 Subtype
  • Smad4 Protein
  • polyethylene glycol polyethyleneimine nanogel
  • Polyethylene Glycols
  • Polyethyleneimine
  • Alkaline Phosphatase