Engineering a heparan sulfate-based medical device for use in spinal fusion

Due to their instability and poor delivery kinetics, high doses of growth factors are frequently required for the successful treatment of many type of skeletal injuries. As such, there is high demand for therapeutic strategies that stabilize these factors, prolong their bioactivity and lower the efficacious dose. Likewise, carrier systems used to deliver growth factors have been suboptimal and often lack the mechanical strength necessary for load-bearing applications. To address these shortcomings we developed a spinal fusion device consisting of bone morphogenetic protein 2 (BMP-2) complexed with a heparan sulfate (HS) variant previously shown to enhance bone healing (Murali et al., 2013) in combination with a silane-modified PCL-TCP/collagen scaffold (sPTC) that has enhanced load-bearing capacity. The efficacy of this novel combination product was first examined in vitro, followed by in vivo proof of concept studies using rodent ectopic bone assays, and then a porcine anterior interbody fusion model. Assays (proliferation, mRNA transcripts, ALP activity) with progenitor cells in vitro showed higher ALP induction and enhanced osteogenic gene expressions (RUNX2, Col1a2, ALP, OCN) when the fusion device contained BMP-2/HS complexes, compared to devices containing BMP-2 alone. This translated to a 2-fold increase in the amount of ectopic bone when sPTC/BMP-2/HS combination devices were implanted into a rat hamstring muscle model as determined by 2D radiography, 3D μCT and histological analyses. Further, preliminary studies of spinal fusion showed that the sPTC/BMP-2/HS combination device resulted in the formation of a fusion mass, highlighting their potential for clinical application.