Effects of controlled dual growth factor delivery on bone regeneration following composite bone-muscle injury

Abstract

Highlights• We developed a smart growth factor delivery system using heparin microparticles and alginate that facilitates tunable delivery of VEGF and BMP-2 in a simultaneous or sequential manner by merely varying the loading strategy.• In vitro, both VEGF and BMP-2 alone promoted vascular growth; however, VEGF was significantly more potent, and there was no detectable benefit of co-delivery.• In vivo, both BMP-2 alone and co-delivery of VEGF and BMP-2 promoted bone formation in the challenging bone/muscle polytrauma model; however, none of the treatment groups restored biomechanical properties to that of uninjured bone.

Local Application of Mineral-Coated Microparticles Loaded With VEGF and BMP-2 Induces the Healing of Murine Atrophic Non-Unions

“…In fact, the effect of additional application of VEGF to BMP-2 on bone healing is discussed controversially in the literature. It has recently been shown that the simultaneous or tunable co-delivery of low-dose BMP-2 and VEGF fails to fully restore the mechanics of bone in a bone defect model ( Subbiah et al, 2020 ). Moreover, Samee et al (2008) found that human periosteum-derived cells transfected with BMP-2 and VEGF in vitro do not show more bone formation at 8 weeks after implantation than human periosteum-derived cells transfected only with BMP-2.…”

Biomaterials for protein delivery for complex tissue healing responses

“…Since many proteins interact with ECM molecules, multiple proteins may interact with the same biomaterial, which may be advantageous for developing strategies to deliver multiple ECM-binding proteins. 84,85 However, the promiscuous binding of heparin and other ECM molecules to a variety of heparin binding proteins can also be disruptive when these biomaterials are delivered in vivo and non-specific, competitive binding to abundant serum proteins can result in accelerated payload release. 86 Thus, caution should be exercised when employing ECM-based biomaterials, which could unintentionally bind additional proteins involved in other cellular processes, resulting in off-target effects and unpredictable protein release in vivo.…”

Spatiotemporal regulation of angiogenesis/osteogenesis emulating natural bone healing cascade for vascularized bone formation

“…However, to achieve optimal bone formation, the coupling of osteogenesis and angiogenesis needs to be deliberately tailored in spatiotemporal manners [ 12 ]. To meet this demand, delivery systems with the ability to simultaneously supply osteogenic and angiogenic growth factors have been developed [ 13 , 14 ]. Unfortunately, current delivery systems do not effectively imitate the pattern by which growth factors appear and act in vivo but act as depots for high concentrations of growth factors.…”