Rapid healing of a critical-sized bone defect using a collagen-hydroxyapatite scaffold to facilitate low dose, combinatorial growth factor delivery

The healing of large, critically sized bone defects remains an unmet clinical need in modern orthopaedic medicine. The tissue engineering field is increasingly using biomaterial scaffolds as 3D templates to guide the regenerative process, which can be further augmented via the incorporation of recombinant growth factors. Typically, this necessitates supraphysiological doses of growth factor to facilitate an adequate therapeutic response. Herein, we describe a cell-free, biomaterial implant which is functionalised with a low dose, combinatorial growth factor therapy that is capable of rapidly regenerating vascularised bone tissue within a critical-sized rodent calvarial defect. Specifically, we demonstrate that the dual delivery of the growth factors bone morphogenetic protein-2 (osteogenic) and vascular endothelial growth factor (angiogenic) at a low dose (5 μg/scaffold) on an osteoconductive collagen-hydroxyapatite scaffold is highly effective in healing these critical-sized bone defects. The high affinity between the hydroxyapatite component of this biomimetic scaffold and the growth factors functions to sequester them locally at the defect site. Using this growth factor-loaded scaffold, we show complete bridging of a critical-sized calvarial defect in all specimens at a very early time point of 4 weeks, with a 28-fold increase in new bone volume and seven-fold increase in new bone area compared with a growth factor-free scaffold. Overall, this study demonstrates that a collagen-hydroxyapatite scaffold can be used to locally harness the synergistic relationship between osteogenic and angiogenic growth factors to rapidly regenerate bone tissue without the need for more complex controlled delivery vehicles or high total growth factor doses.