Heparin microparticle-mediated delivery of BMP-2 and pluripotent stem cell morphogens for bone repair

Abstract

The delivery of bone morphogenetic protein-2 (BMP-2) offers a promising means of stimulating endogenous repair mechanisms to heal severe bone injuries. However, clinical application of growth factor therapy is hindered by the lack of adequate biomaterials to localize BMP-2 delivery. Glycosaminoglycans, such as heparin, have the capacity to strongly bind BMP-2 and other growth factors implicated in bone regeneration, and present the opportunity to locally deliver growth factors to injury sites. Moreover, pluripotent stem cells (PSCs) secrete many potent heparin-binding growth factors that have been implicated in tissue regeneration following cell transplantation and may provide cues for repair. Thus, heparin can also be used to concentrate and deliver PSC-derived morphogens to tissue injury sites, thereby overcoming challenges associated with PSC transplantation. The goal of this work was to improve growth factor delivery for bone repair by both (1) creating an effective biomaterial for BMP-2 delivery and (2) investigating PSC morphogens as a novel source of therapeutic growth factors. We developed heparin-based microparticles that could bind and retain large amounts of bioactive BMP-2 in vitro and improve BMP-2 retention in vivo, resulting in spatially localized bone formation in a critically sized rat femoral defect. Furthermore, heparin microparticles could also sequester and concentrate complex mixtures of bioactive PSC-secreted proteins, which may be developed into cell-free therapies in the future. Overall, this work broadens current understanding of bone tissue engineering, biomaterial delivery strategies, and stem cell-based therapeutics, and provides valuable insight into developing affinity-based biomaterials for clinical applications.