Tissue Regeneration via Growth Factor Delivery

Abstract

Growth factors (GFs) -- signalling proteins that regulate cell proliferation, differentiation, and migration -- are essential mediators of tissue repair, yet clinical application is limited by their short biological half-lives (minutes to hours in vivo), supraphysiological doses required for efficacy, systemic side effects (ectopic bone formation with BMP-2, tumourigenicity concerns with VEGF), and costs exceeding $5,000 per treatment. Controlled delivery systems that release GFs at physiological concentrations over therapeutically relevant timescales promise to overcome these barriers. This study developed and evaluated five GF delivery platforms -- bolus injection (free GF), collagen sponge adsorption, PLGA microsphere encapsulation, heparin-binding nanofibre hydrogel, and a proposed sequential dual-GF delivery system (Seq-DDS) releasing BMP-2 (osteogenic) followed by VEGF (angiogenic) from core-shell PLGA-alginate microspheres - for critical-size calvarial bone defect regeneration in rats (8 mm, n = 72). Seq-DDS achieved the highest bone volume fraction (BV/TV 68.4 +- 6.8% at 12 weeks) compared to collagen sponge (42.6 +- 8.4%; p < 0.001), simultaneous dual-GF delivery (54.8 +- 7.2%; p = 0.004), and empty defect controls (12.4 +- 4.6%; p < 0.001). The sequential release profile -- early VEGF burst (days 1-7, establishing vascular supply) followed by sustained BMP-2 release (weeks 2-8, driving osteogenesis in pre-vascularised tissue) -- recapitulated the natural temporal sequence of fracture healing. Histomorphometry confirmed 82.4 +- 6.2% defect bridging with mature lamellar bone and active vascular networks (CD31+ vessel density 34.8 +- 5.4 vessels/mm2). These results establish sequential multi-GF delivery as a biomimetic strategy for tissue regeneration and provide an optimised platform for clinical bone repair applications.