Application of AMOR in Craniofacial Rabbit Bone Bioengineering

Abstract

Endogenous molecular and cellular mediators modulate tissue repair and regeneration. We have recently described antibody mediated osseous regeneration (AMOR) as a novel strategy for bioengineering bone in rat calvarial defect. This entails application of anti-BMP-2 antibodies capable of in vivo capturing of endogenous osteogenic BMPs (BMP-2, BMP-4, and BMP-7). The present study sought to investigate the feasibility of AMOR in other animal models. To that end, we examined the efficacy of a panel of anti-BMP-2 monoclonal antibodies (mAbs) and a polyclonal Ab immobilized on absorbable collagen sponge (ACS) to mediate bone regeneration within rabbit calvarial critical size defects. After 6 weeks, de novo bone formation was demonstrated by micro-CT imaging, histology, and histomorphometric analysis. Only certain anti-BMP-2 mAb clones mediated significant in vivo bone regeneration, suggesting that the epitopes with which anti-BMP-2 mAbs react are critical to AMOR. Increased localization of BMP-2 protein and expression of osteocalcin were observed within defects, suggesting accumulation of endogenous BMP-2 and/or increased de novo expression of BMP-2 protein within sites undergoing bone repair by AMOR. Considering the ultimate objective of translation of this therapeutic strategy in humans, preclinical studies will be necessary to demonstrate the feasibility of AMOR in progressively larger animal models.

Collagen Sponge Functionalized with Chimeric Anti-BMP-2 Monoclonal Antibody Mediates Repair of Critical-Size Mandibular Continuity Defects in a Nonhuman Primate Model

“…There were no side effects or adverse events detected in the current study. This is consistent with previous studies conducted in other animal models [17–20], suggesting the safety of local administration of anti-BMP-2 mAbs.…”

“…Using this animal model, which is closely associated with human, we demonstrated the capacity of collagen scaffold functionalized with anti-BMP-2 mAb to mediate de novo bone formation within mandibular continuity defects. These data confirmed and extended our previous studies, demonstrating the efficacy of AMOR in rodents and rabbits [17–20]. …”

“…Recent studies from our research group have demonstrated a tissue engineering strategy involving immobilization of anti-BMP-2 mAb on various scaffolds implanted into surgical defect sites [14, 15, 17–20]. AMOR has been validated in calvarial defects of rats and rabbits [14, 15, 17–20]. In order to advance this translational project toward our ultimate goal of clinical trial, the present investigation sought to utilize a clinically relevant defect in an animal model that is phylogenetically closer to human.…”

“…Our results provide further evidence in support of AMOR as a translational approach. Its efficacy and reproducibility have been demonstrated in a number of animals with different defect models [14–20]. …”

“…In addition, it was confirmed that anti-BMP-2 mAb can trap and tether endogenous BMP-2 ligands for the directed osteodifferentiation of mesenchymal stem cells through in vitro and in vivo studies [16]. In previous studies, murine and chimeric anti-BMP-2 mAb has been used in mice, rat, and rabbit models and confirmed to be effective in promoting bone repair and regeneration through calvaria defect models [17–20]. However, there has been a need for more clinically relevant animal models.…”