PLGA-BMP-2 and PLA-17β-Estradiol Microspheres Reinforcing a Composite Hydrogel for Bone Regeneration in Osteoporosis

Patricia García-García; Ricardo Reyes; Elisabet Segredo-Morales; Edgar Pérez-Herrero; Araceli Delgado; Carmen Évora

doi:10.3390/pharmaceutics11120648

PLGA-BMP-2 and PLA-17β-Estradiol Microspheres Reinforcing a Composite Hydrogel for Bone Regeneration in Osteoporosis

Pharmaceutics. 2019 Dec 3;11(12):648. doi: 10.3390/pharmaceutics11120648.

Authors

Patricia García-García¹, Ricardo Reyes^{2

3}, Elisabet Segredo-Morales¹, Edgar Pérez-Herrero^{1

2}, Araceli Delgado^{1

2}, Carmen Évora^{1

2}

Affiliations

¹ Department of Chemical Engineering and Pharmaceutical Technology, University of La Laguna, 38206 La Laguna, Spain.
² Institute of Biomedical Technologies (ITB), University of La Laguna, 38206 La Laguna, Spain.
³ Department of Biochemistry, Microbiology, Cell Biology and Genetics. University of La Laguna, 38206 La Laguna, Spain.

Abstract

The controlled release of active substances-bone morphogenetic protein 2 (BMP-2) and 17β-estradiol-is one of the main aspects to be taken into account to successfully regenerate a tissue defect. In this study, BMP-2- and 17β-estradiol-loaded microspheres were combined in a sandwich-like system formed by a hydrogel core composed of chitosan (CHT) collagen, 2-hidroxipropil γ-ciclodextrin (HP-γ-CD), nanoparticles of hydroxyapatite (nano-HAP), and an electrospun mesh shell prepared with two external electrospinning films for the regeneration of a critical bone defect in osteoporotic rats. Microspheres were made with poly-lactide-co-glycolide (PLGA) to encapsulate BMP-2, whereas the different formulations of 17β-estradiol were prepared with poly-lactic acid (PLA) and PLGA. The in vitro and in vivo BMP-2 delivered from the system fitted a biphasic profile. Although the in vivo burst effect was higher than in vitro the second phases (lasted up to 6 weeks) were parallel, the release rate ranged between 55 and 70 ng/day. The in vitro release kinetics of the 17β-estradiol dissolved in the polymeric matrix of the microspheres depended on the partition coefficient. The 17β-estradiol was slowly released from the core system using an aqueous release medium (D_eff = 5.58·10^-16 ± 9.81·10^-17m²s^-1) and very fast in MeOH-water (50:50). The hydrogel core system was injectable, and approximately 83% of the loaded dose is uniformly discharged through a 20G needle. The system placed in the defect was easily adapted to the defect shape and after 12 weeks approximately 50% of the defect was refilled by new tissue. None differences were observed between the osteoporotic and non-osteoporotic groups. Despite the role of 17β-estradiol on the bone remodeling process, the obtained results in this study suggest that the observed regeneration was only due to the controlled rate released of BMP-2 from the PLGA microspheres.

Keywords: 17-βestradiol release; BMP-2-microspheres; bone regeneration; hydrogel system; osteoporosis; poly-lactide-co-glycolide; polylactic acid.

Grants and funding

MAT2014-55657-R/Ministerio de Ciencia, Innovación y Universidades