Treatment of critically sized femoral defects with recombinant BMP-2 delivered by a modified mPEG-PLGA biodegradable thermosensitive hydrogel
Journal
BMC Musculoskeletal Disorders
Journal Volume
17
Journal Issue
1
Date Issued
2016
Author(s)
Abstract
Background: Reconstruction of a segmental fracture with massive bone loss is still a challenge for orthopaedic surgeons. The aim of our study was to develop a suitable biodegradable thermosensitive hydrogel system as a carrier for bone morphogenetic protein (BMP)-2 delivery in the treatment of critical-sized femoral defects. Methods: A block copolymer composed of monomethoxypoly(ethylene glycol) (mPEG), poly(lactic-co-glycolic acid) (PLGA) and 2, 2'-Bis (2-oxazolin) (Box) was synthesized by ring opening polymerization. The synthesized block copolymer was characterized by 1H-NMR spectroscopy and gel permeation chromatography (GPC). Different biophysical and biochemical properties of the synthesized copolymer, including temperature-induced structure changes, degradation rate, pH changes during hydrolytic degradation, cell toxicity, and the release profile of BMP-2, were also evaluated and/or were compared with those of a well-characterized mPEG-PLGA copolymer. In animal testing, rabbits (n = 36) that received critically sized (10 mm) femoral defects were divided into 6 groups. These experimental groups included an untreated group, autograft, and groups treated with the synthesized copolymer carrying different concentrations of BMP-2 (0, 5, 10, and 20 μg/ml). Bone repair was evaluated using X-ray radiography, histological staining, micro-computed tomography (μCT), biomarker examination and biomechanical testing in a 12-week treatment period. Results: A new thermosensitive mPEG-PLGA/Box/mPEG-PLGA block copolymer, or named as BOX copolymer, was successfully prepared. Compared to the reported mPEG-PLGA in vitro, the prepared BOX copolymer at the same weight percent concentrations exhibited wider temperature ranges of gelation, slower degradation rates, higher the pH values, as well as less cytotoxicity. Furthermore, the BMP-2 release from BOX hydrogel exhibited a near-linear release profile in vitro. In animal experiments, treatment of critical-sized bony defects with 25 wt% BOX hydrogel carrying BMP-2 effectively promoted fracture healing during the 12-week trial period and higher concentrations of BMP-2 treatment correlated with better bone quality. Most importantly, clinical outcome and bone healing in the BOX-hydrogel group with 20 μg/ml BMP-2 were nearly equivalent to those in the autograft group in a 12-week treatment course. Conclusion: These data support that the use of BOX hydrogel (25 wt%) as a drug delivery system is a promising method in the treatment of large bone defects. ? 2016 The Author(s).
Subjects
Biodegradable polymer; BMP-2; Fracture healing; mPEG-PLGA; Thermosensitive hydrogel
Other Subjects
monomethoxypoly(ethylene glycol); polyglactin; polymer; recombinant bone morphogenetic protein 2; unclassified drug; biodegradable plastic; biological marker; bone morphogenetic protein 2; drug carrier; macrogol derivative; poly(D,L-lactic-co-glycolic acid)-methoxy-poly(ethyleneglycol) copolymer; polyglactin; recombinant human bone morphogenetic protein-2; recombinant protein; transforming growth factor beta; animal cell; animal experiment; animal model; animal tissue; Article; biodegradability; biodegradation; biomechanics; bone defect; bone remodeling; chemical structure; controlled study; cytotoxicity; drug effect; drug efficacy; drug release; femur; fetus; fibroblast; fracture healing; gelation; heat sensitivity; histopathology; human; human cell; hydrogel; hydrolysis; in vitro study; mouse; New Zealand White (rabbit); nonhuman; osteoblast; pH; ring opening; animal; autograft; bone transplantation; cell line; chemistry; diagnostic imaging; disease model; drug effects; femur; femur fracture; fracture nonunion; hydrogel; Leporidae; micro-computed tomography; pathology; procedures; radiography; temperature; transplantation; Animals; Autografts; Biodegradable Plastics; Biomarkers; Biomechanical Phenomena; Bone Morphogenetic Protein 2; Bone Transplantation; Cell Line; Disease Models, Animal; Drug Carriers; Femoral Fractures; Femur; Fracture Healing; Fractures, Ununited; Humans; Hydrogels; Mice; Polyethylene Glycols; Polyglactin 910; Rabbits; Radiography; Recombinant Proteins; Temperature; Transforming Growth Factor beta; X-Ray Microtomography
Type
journal article