Sustained delivery of a heterodimer bone morphogenetic protein-2/7 via a collagen hydroxyapatite scaffold accelerates and improves critical femoral defect healing

Research output: Contribution to journalResearch articleContributedpeer-review


  • Yang Liu - , Chair of Hydrochemistry and Water Technology, Lund University (Author)
  • Manoj Puthia - , Lund University (Author)
  • Eamon J Sheehy - , Royal College of Surgeons in Ireland, Trinity College Dublin (Author)
  • Ines Ambite - , Lund University (Author)
  • Jitka Petrlova - , Lund University (Author)
  • Sujeethkumar Prithviraj - , Wallenberg Center for Molecular Medicine (Author)
  • Maria Wimer Oxborg - , Lund University (Author)
  • Sujeesh Sebastian - , Lund University (Author)
  • Corina Vater - , University Center for Orthopedics, Trauma and Plastic Surgery (Author)
  • Stefan Zwingenberger - , University Center for Orthopedics, Trauma and Plastic Surgery (Author)
  • André Struglics - , Lund University (Author)
  • Paul E Bourgine - , Wallenberg Center for Molecular Medicine (Author)
  • Fergal J O'Brien - , Royal College of Surgeons in Ireland, Trinity College Dublin (Author)
  • Deepak Bushan Raina - , Lund University (Author)


Despite the glimmer of hope provided by the discovery and commercialization of bone morphogenetic protein-2 (BMP-2) as a bone graft substitute, side effects related to the use of supraphysiological doses have hindered its clinical usage. In this study, we compared the osteoinductive potential of BMP-2 homodimer with a heterodimer of BMP-2/7, both delivered via a collagen-hydroxyapatite (CHA) scaffold delivery system, with the aim to reduce the overall therapeutic BMP doses and the associated side-effects. We first show that the incorporation of hydroxyapatite in collagen-based BMP delivery systems is pivotal for achieving efficient BMP sequestration and controlled release. Using an ectopic implantation model, we then showed that the CHA+BMP-2/7 was more osteoinductive than CHA+BMP-2. Further evaluation of the molecular mechanisms responsible for this increased osteoinductivity at an early stage in the regeneration process indicated that the CHA+BMP-2/7 enhanced progenitor cell homing at the implantation site, upregulated the key transcriptomic determinants of bone formation, and increased the production of bone extracellular matrix components. Using fluorescently labelled BMP-2/7 and BMP-2, we demonstrated that the CHA scaffold provided a long-term delivery of both molecules for at least 20 days. Finally, using a rat femoral defect model, we showed that an ultra-low dose (0.5 µg) of BMP-2/7 accelerated fracture healing and performed at a level comparable to 20-times higher BMP-2 dose. Our results indicate that the sustained delivery of BMP-2/7 via a CHA scaffold could bring us a step closer in the quest for the use of physiological growth factor doses in fracture healing. STATEMENT OF SIGNIFICANCE: • Incorporation of hydroxyapatite (HA) in a collagen scaffold dramatically improves bone morphogenic protein (BMP) sequestration via biophysical interactions with BMP, thereby providing more controlled BMP release compared with pristine collagen. • We then investigate the molecular mechanisms responsible for increased osteoinductive potential of a heterodimer BMP-2/7 with is clinically used counterpart, the BMP-2 homodimer. • The superior osteoinductive properties of BMP-2/7 are a consequence of its direct positive effect on progenitor cell homing at the implantation site, which consequently leads to upregulation of cartilage and bone related genes and biochemical markers. • An ultra-low dose of BMP-2/7 delivered via a collagen-HA (CHA) scaffold leads to accelerated healing of a critical femoral defect in rats while a 20-times higher BMP-2 dose was required to achieve comparable results.


Original languageEnglish
Pages (from-to)164-181
Number of pages18
JournalActa biomaterialia
Publication statusPublished - May 2023

External IDs

Scopus 85151531379



  • Rats, Animals, Durapatite/pharmacology, Collagen/pharmacology, Osteogenesis, Bone and Bones, Fracture Healing, Bone Substitutes/pharmacology, Bone Morphogenetic Protein 2/pharmacology, Bone Regeneration