Bone regeneration using an alpha 2 beta 1 integrin-specific hydrogel as a BMP-2 delivery vehicle

Abstract

Non-healing bone defects present tremendous socioeconomic costs. Although successful in some clinical settings, bone morphogenetic protein (BMP) therapies require supraphysiological dose delivery for bone repair, raising treatment costs and risks of complications. We engineered a protease-degradable poly(ethylene glycol) (PEG) synthetic hydrogel functionalized with a triple helical, α2β1 integrin-specific peptide (GFOGER) as a BMP-2 delivery vehicle. GFOGER-functionalized hydrogels lacking BMP-2 directed human stem cell differentiation and produced significant enhancements in bone repair within a critical-sized bone defect compared to RGD hydrogels or empty defects. GFOGER functionalization was crucial to the BMP-2-dependent healing response. Importantly, these engineered hydrogels outperformed the current clinical carrier in repairing non-healing bone defects at low BMP-2 doses. GFOGER hydrogels provided sustained in vivo release of encapsulated BMP-2, increased osteoprogenitor localization in the defect site, enhanced bone formation and induced defect bridging and mechanically robust healing at low BMP-2 doses which stimulated almost no bone regeneration when delivered from collagen sponges. These findings demonstrate that GFOGER hydrogels promote bone regeneration in challenging defects with low delivered BMP-2 doses and represent an effective delivery vehicle for protein therapeutics with translational potential.

Polyaniline-poly(styrene sulfonate) conducting hydrogels reinforced by supramolecular nanofibers and used as drug carriers with electric-driven release

“…This indicates that the release of RhB can be conveniently modulated through simple voltage ''on-off''. An important application of conducting hydrogels is in the field of tissue engineering scaffold materials [47,48], especially bone graft or bone repair [49]. The pulse release of drugs has an important significance to the growth and recovery of tissues [48].…”

How to use BMP-2 for clinical applications? A review on pros and cons of existing delivery strategies

“…Another more complex material which was also studied in the context of bone regeneration, is a MMP cleavable PEG hydrogel functionalized with an α2β1 integrin-specific peptide (GFOGER; single letter amino acid code, O = hydroxyprolin). This material was shown to be effective for bone-healing in a mouse critical size defect model even in the absence of BMP-2 but doping the hydrogel with low BMP-2 doses (0.03 μg) resulted in higher bone formation capabilities and complete bridging of bone gaps after 8 weeks [83]. Hybrid nanofiber mesh/alginate delivery systems containing RGD (Arg-Gly-Asp) have been compared to collagen sponges for BMP-2 release [84].…”

Material-driven fibronectin fibrillogenesis to engineer cell function.

“…The material system that we use here is a very demanding one as we intend to promote bone regeneration in a critical size defect -a volume -by engineering the material surface of a tube where this volume is contained. This is very different to what has been done up to now to promote bone formation in vivo using engineered 3D environments such as hydrogels (Shekaran et al, 2014). …”

“…This bone repair model has significant advantages: i) the 2.5 mm defect does not spontaneously heal, providing a rigorous criticalsized model, ii) it allows for simple in vivo imaging approaches (e.g. Faxitron, and μ-CT), iii) the ulna provides sufficient stabilisation of the defect and no fixation plates/hardware are required, thereby simplifying the surgical procedure and reducing the risk of infection; a major advantage over the rat calvaria and segmental femur defect models (Shekaran et al, 2014).…”

“…GFOGER-functionalized PEGmaleimide (PEG-MAL) hydrogels, which have been shown to promote osteogenic differentiation and bone healing of radial segmental defects (Shekaran et al, 2014), were used as a positive control. Hydrogels were synthesised by reacting the four-arm, MAL-end functionalised (>95%) PEG macromer (PEG-MAL; 20 kD; Laysan Bio) with the adhesive peptide GYGGGPG(GPP)5GFOGER(GPP)5GPC (GFOGER) (Activotec) and BMP-2 (R&D Systems), followed by mixing with VPM cross-linker (AAPTEC) at a volume ratio of 2:1:1:1.…”