Multifunctional nanoparticles for intracellular drug delivery and photoacoustic imaging of mesenchymal stem cells.

Strategies that control the differentiation of mesenchymal stem cells (MSC) and enable image-guided cell implantation and longitudinal monitoring could advance MSC-based therapies for bone defects and injuries. Here we demonstrate a multifunctional nanoparticle system that delivers resveratrol (RESV) intracellularly to improve osteogenesis and enables photoacoustic imaging of MSCs. RESV-loaded nanoparticles (RESV-NPs), formulated from poly (lactic-co-glycolic) acid and iron oxide, enhanced the stability of RESV by 18-fold and served as photoacoustic tomography (PAT) contrast for MSCs. Pre-loading MSCs with RESV-NP upregulated RUNX2 expression with a resultant increase in mineralization by 27% and 45% compared to supplementation with RESV-NP and free RESV, respectively, in 2-dimensional cultures. When grown in polyethylene glycol-based hydrogels, MSCs pre-loaded with RESV-NPs increased the overall level and homogeneity of mineralization compared to those supplemented with free RESV or RESV-NP. The PAT detected RESV-NP-loaded MSCs with a resolution of 1500 cells/µL, which ensured imaging of MSCs upon encapsulation in a PEG-based hydrogel and implantation within the rodent cranium. Significantly, RESV-NP-loaded MSCs in hydrogels did not show PAT signal dilution over time or a reduction in signal upon osteogenic differentiation. This multifunctional NP platform has the potential to advance translation of stem cell-based therapies, by improving stem cell function and consistency via intracellular drug delivery, and enabling the use of a promising emerging technology to monitor cells in a clinically relevant manner.

Localized and sustained release of brain-derived neurotrophic factor from injectable hydrogel/microparticle composites fosters spinal learning after spinal cord injury.

Damaged axons in the adult mammalian central nervous system (CNS), including those of the spinal cord, have extremely limited endogenous capacity to regenerate. This is the result of both the intrinsic and extrinsic inhibitory factors that limit the regeneration of adult neurons. Despite attempts to limit or eliminate the extrinsic inhibitory components, regeneration of adult neurons in the CNS is still limited. Therefore, additional factors that can further enhance the intrinsic plasticity of adult neurons need to be considered. Herein, we examine the effects of brain-derived neurotrophic factor (BDNF), a known growth factor for neuronal survival and plasticity, using an in vivo delivery method for a localized and sustained delivery to the spinal cord. A highly versatile injectable biomaterial platform for the sustained delivery of BDNF was developed using a physical blend of hyaluronic acid (HA) and methylcellulose (MC), in combination with poly-lactic-co-glycolic acid (PLGA) microparticles. Contemporary studies examining the plasticity of the CNS suggest that the spinal cord is an important site for activity-dependent learning that can mediate motor function after injury or disease. Here we utilized such a learning paradigm in combination with local and sustained BDNF application (at L3-S2) to foster spinal learning after complete spinal cord injury in rodents. Our data suggest that composite biomaterial systems such as the one described herein can be utilized for the sustained and localized delivery of therapeutics following damage to the spinal cord.