Biofunctionalizing devitalized bone allografts through polymer‐mediated short and long term growth factor delivery

Abstract

According to 5- and 10-year clinical follow-up studies large-scale bone allografts have a high failure rate, largely due to poor allograft incorporation with adjacent bone and subsequent poor remodeling. The goal of this study was to develop a methodology to deliver growth factors from large-scale bone allografts in a temporally controlled manner. Intact long bone allografts were coated with a micron-scale thick layer of degradable polymer that maintained inherent pore structures and acted as a delivery vehicle for bone morphogenetic protein-2 and vascular endothelial growth factor. VEGF was loaded onto the surface of the polymer to produce rapid release, to encourage initial vascularization at the defect site, while BMP-2 was encapsulated within the polymer layer to promote a more sustained release, to encourage bone formation over time. Release kinetics from factor-loaded polymer-coated allografts show an early burst release of VEGF over the first 7 days followed by a more sustained release of BMP-2 over the second and third week. In vitro cell studies using human mesenchymal stem cells confirm the bioactivity of the released BMP-2. In-vivo results show robust bone formation over the first 8 weeks of healing in femoral segmental defects in rats implanted with BMP-2 loaded polymer-coated allografts. A microscale thin coating of degradable polymer on a large-scale bone allograft provides temporal control over the delivery of growth factor loaded onto one allograft, while maintaining its microscale pore structure. Enhancing the incorporation and subsequent remodeling of allografts would reduce the incidence of allograft failure over time, and potentially speed healing at the earliest stages after implantation.

Dual growth factor delivery from biofunctionalized allografts: Sequential VEGF and BMP-2 release to stimulate allograft remodeling

“…Given this, we have developed a method through which a thin, polymeric coating capable of retaining and delivering growth factors is applied to all surfaces of large‐scale structural allografts, with the intention of delivering therapeutic molecules capable of enhancing bone‐allograft healing. We have previously demonstrated the ability to deliver either VEGF or BMP‐2 with two distinct delivery kinetics; short‐ and long‐term . Our studies demonstrated that BMP‐2 released from the polymer‐coated allograft resulted in robust bone formation in a rat segmental defect.…”

“…To address these concerns, we have developed a novel procedure where a very thin coating of degradable polymer has been added to the surface of long bone allografts and loaded with relevant growth factors such that they elute with a temporal precision shown to benefit bone repair . By modifying an implant that is clinically viable and currently used in regular practice, and using materials and molecules that have long track records of safety and efficacy, we believe our approach may be accepted in the clinic, and by applying this to a known clinical challenge by directly addressing the issues at the heart of the challenge, we believe this approach has the potential to be an important tool to the orthopedic surgeon.…”

“…Allograft harvesting and preparation was based on previous work . Briefly, tibial and femoral bone samples were harvested from male Sprague–Dawley rats (150–250 g).…”

“…Our studies demonstrated that BMP‐2 released from the polymer‐coated allograft resulted in robust bone formation in a rat segmental defect. However, the release of BMP‐2 alone failed to show any significant bone resorption in vivo substantiating the need to stimulate osteoclastogenesis.…”

BMP2-modified injectable hydrogel for osteogenic differentiation of human periodontal ligament stem cells

“…A number of attempts to develop alternative drug delivery formulations have been made to minimize unfavorable side effects and to optimize the remedial effects of BMP2 8–10 . Generally, BMP2 can be loaded in drug delivery formulations by simple mixing (physical adsorption via non-covalent bonding).…”