Nanoparticle/Hydrogel Composite for Growth Factor Delivery and Oligodendrocyte Regeneration

            Stroke affects 15 million people worldwide each year, and is the third leading cause of death and disability in the United States^1,2. Patient loss of function post-stroke results from cell death and deterioration of myelin, the electrically insulating layer surrounding axons. Regrowth of oligodendrocytes, the cells responsible for making myelin, is critical for functional recovery. As a result, many regeneration strategies aim to simultaneously deliver drug and transplant oligodendrocyte precursor cells (OPCs) to the injury site³. Biomaterials comprised of poly(ethylene glycol) (PEG) based hydrogels encapsulating poly(lactic-co-glycolic acid) (PLGA) nanoparticles provide one promising option for delivery of protein therapeutics to OPCs. Platelet derived growth factor (PDGF) is a protein that promotes cell survival and is believed to stimulate OPC differentiation to mature myelinating oligodendrocytes⁴. Here, we introduce a protein therapeutic drug delivery system encapsulating PDGF in nanoparticles dispersed in a PEG-based hydrogel, and determine its efficacy at promoting cell survival and differentiation in-vitro.

            PLGA particles co-encapsulating bovine serum albumin (BSA) and PDGF were synthesized using the double emulsion solvent evaporation method. BSA was incorporated to increase stability of PDGF in the particles. The release profile of PDGF and BSA into solution was then measured over several weeks, and quantified using enzyme linked immunosorbent assay (ELISA) and the Bradford assay, respectively. The influence of varying lactide to glycolide ratio (L:G ratio) in the particle was investigated. Particles with the highest L:G ratio (85:15) showed the slowest PDGF release, whereas particles with 50:50 L:G ratio released 90% of the PDGF in the first 24 hours. Additionally, dynamic light scattering (DLS) was used to determine average particle diameter. From this, it was determined that the 85:15 particles were the largest, with an average diameter of 118±21nm. Following characterization experiments, the particles were co-encapsulated with OPCs in 7.5wt% PEG hydrogels.  Current studies are using quantitative real time polymerase chain reaction to measure the differentiation of the OPCs following delivery of PDGF.

References: ¹Wang et al. J. Con. Rel. 172:1-11 (2013); ²Yang et al. Methods Mol. Biol. 814:451-66 (2012). ³Murphy et al. J Mater Chem.B 3:7867-80 (2015); ⁴Donaghue et al. Acta Biomat. 25:35-42 (2015).