Synthetic helical peptides on nanofibers to activate cell-surface receptors and synergistically enhance critical-sized bone defect regeneration

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Abstract
More than 500,000 bone grafting procedures are performed annually in the USA. Considering the significant limitations of available bone grafts, we previously invented a phase-separation technology to generate nanofibrous poly(l-lactic acid) (PLLA) scaffolds that mimic the bone matrix collagen in nanofiber geometry and enhance bone regeneration. Here we report the development of nanofibrous scaffolds with covalently attached synthetic peptides that mimic native collagen peptides to activate the two main collagen receptors in bone cells, discoidin domain receptor 2 (DDR2) and β1 integrins. We synthesized a PLLA-based graft-copolymer to enable covalent peptide conjugation via a click reaction. Using PLLA and the graft-copolymer, we developed 3D scaffolds with interconnected pores and peptides-containing nanofibers to activate DDR2 and β1 integrins of osteogenic cells. The degradation rate and mechanical properties of the scaffolds are tunable. The peptides-decorated nanofibrous scaffolds demonstrated 7.8 times more mineralized bone regeneration over the control scaffolds without the peptides in a critical-sized bone defect regeneration model after 8 weeks of implantation, showing a synergistic effect of the two peptides. This study demonstrates the power of scaffolds to mimic ECM at both nanometer and molecular levels, activating cell surface receptors to liberate the innate regenerative potential of host stem/progenitor cells.
Funding Information
  • National Institutes of Health (R01AR075770)
  • National Institutes of Health (R01DE029465)
  • U.S. Department of War (W81XWH-20-1-0571)
  • U.S. Department of War (W81XWH-20-1-0572)

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