Sustained Delivery of rhBMP-2 by Means of Poly(Lactic-co-Glycolic Acid) Microspheres

Abstract

Background Commercially available recombinant human bone morphogenetic protein 2 (rhBMP2) has demonstrated efficacy in bone regeneration, but not without significant side effects. In this study, we utilize rhBMP2 encapsulated in PLGA microspheres (PLGA-rhBMP2) placed in a rabbit cranial defect model to test whether low-dose, sustained, delivery can effectively induce bone regeneration. Methods rhBMP2 was encapsulated in 15% poly (lactic-co-glycolic acid), using a double emulsion, solvent extraction/evaporation technique, and its release kinetics and bioactivity were tested. Two critical-size defects (10mm) were created in the calvarium of New Zealand White rabbits (5-7 mos of age, M/F) and filled with a collagen scaffold containing one of four groups: 1) no implant, 2) collagen scaffold only, 3) PLGA-rhBMP2(0.1ug/implant), or 4) free rhBMP2 (0.1ug/implant). After 6 weeks, the rabbits were sacrificed and defects were analyzed by μCT, histology, and finite element analysis. Results RhBMP2 delivered via bioactive PLGA microspheres resulted in higher volumes and surface area coverage of new bone than an equal dose of free rhBMP2 by μCT and histology (p=0.025, 0.025). FEA indicated that the mechanical competence using the regional elastic modulus did not differ with rhBMP2 exposure (p=0.70). PLGA-rhBMP2 did not demonstrate heterotopic ossification, craniosynostosis, or seroma formation. Conclusions Sustained delivery via PLGA microspheres can significantly reduce the rhBMP2 dose required for de novo bone formation. Optimization of the delivery system may be a key to reduce the risk for recently reported rhBMP2 related adverse effects. Level of Evidence Animal Study

Drug‐Loaded Elastin‐Like Polypeptide–Collagen Hydrogels with High Modulus for Bone Tissue Engineering

“…With an rhBMP2 loading of 10 ng mL −1 , they observed an initial burst release of 15% and long‐term release of 70% over a 30‐day period. Wink et al encapsulated 0.1 µg rhBMP2 in PLGA microspheres and evidenced a release of 30% within the first day and the remainder delivered over 35 days . We observed a nearly linear release profile of rhBMP‐2 in all hydrogel compositions (Figure c).…”

Biocompatibility of poly(d,l-lactic-co-hydroxymethyl glycolic acid) microspheres after subcutaneous and subcapsular renal injection

“…Poly(D,L-lactic-co-glycolic acid) (PLGA) is a biodegradable aliphatic polyester that has been investigated for controlled delivery of low molecular weight drugs (Kim et al, 2011), peptides (Shmueli et al, 2013;Xuan et al, 2013), proteins (Menon et al, 2014;Reguera-Nuñez et al, 2014;Wink et al, 2014) and vaccine antigens (Huang et al, 2014;Joshi et al, 2013). PLGA is degraded by hydrolytic cleavage of ester bonds that connect the monomer units, and the final degradation products are lactic and glycolic acid, both endogenous compounds (Spenlehauer et al, 1989;Vert et al, 1994).…”

LIPUS-S/B@NPs regulates the release of SDF-1 and BMP-2 to promote stem cell recruitment-osteogenesis for periodontal bone regeneration

“…Therefore, BMP-2 may provide an effective bio-signal for osteogenesis of the recruited stem cells. In clinic, growth factors are usually directly injected into the defect area to promote bone healing, which may cause their rapid loss in the targeted area ( Wink et al, 2014 ; de Freitas et al, 2016 ). Moreover, bioactive molecules are generally unstable and easily degraded in vivo ( Dumic-Cule et al, 2018 ), and high concentrations of BMP-2 may lead to many side effects such as ectopic osteogenesis, local inflammation and hemangioma ( Wang B. et al, 2018a ).…”