Investigating novel drug delivery systems to enhance tissue regeneration in the central nervous system

Targeted drug delivery within the central nervous system (CNS) has gained increasing interests in treating neurological diseases, such as neurodegenerative and demyelinating diseases. However, the presence of multiple cell types in the CNS tissues may lead to nonspecific uptake and reduced efficiency in drug delivery. Therefore, an effective approach to target specific cell type in the disease treatment is necessary. In this work, we employed neural cell-derived membrane coating technique on DNA nanogels to improve target specificity. The efficacy of neural cell membrane-coated DNA nanogels (NCM-nanogels) were demonstrated by using four types of cell membranes derived from the CNS, namely, astrocytes, microglia, cortical neurons, and oligodendrocyte progenitor cells (OPCs). A successful coating of neural cell membrane over DNA nanogels was confirmed by dynamic light scattering and zeta potential. Subsequently, the cellular uptake results suggested an overall improvement in cellular uptake of NCM-nanogels over uncoated DNA nanogels (p < 0.005). Additionally, we observed a selective uptake of OPC membrane-coated DNA nanogels (NCM-O mem) by oligodendrocytes. Next, our biomimicking fiber platform was further examined in hope to discover new fiber material that closely mimic the mechanical properties of native neurons, hence allowing more accurate examination of therapeutic outcomes upon drug/gene delivery. Two scaffold materials, namely, polylactic acid-polycaprolactone copolymer (PLA-PCL), and dextran methacrylate (DexMA) were extensively examined. Lastly, an extensive review on injectable hydrogels was carried out to expand our therapeutic strategies in CNS diseases treatment. In this review, the development of injectable hydrogels in stroke and spinal cord injury treatment, focusing on the cellular response and tissue integration, was discussed.Master of Engineerin

A 3D fiber-hydrogel based non-viral gene delivery platform reveals that microRNAs promote axon regeneration and enhance functional recovery following spinal cord injury

Current treatment approaches toward spinal cord injuries (SCI) have mainly focused on overcoming the inhibitory microenvironment that surrounds lesion sites. Unfortunately, the mere modulation of the cell/tissue microenvironment is often insufficient to achieve desired functional recovery. Therefore, stimulating the intrinsic growth ability of injured neurons becomes crucial. MicroRNAs (miRs) play significant roles during axon regeneration by regulating local protein synthesis at growth cones. However, one challenge of using miRs to treat SCI is the lack of efficient delivery approaches. Here, a 3D fiber-hydrogel scaffold is introduced which can be directly implanted into a spinal cord transected rat. This 3D scaffold consists of aligned electrospun fibers which provide topographical cues to direct axon regeneration, and collagen matrix which enables a sustained delivery of miRs. Correspondingly, treatment with Axon miRs (i.e., a cocktail of miR-132/miR-222/miR-431) significantly enhances axon regeneration. Moreover, administration of Axon miRs along with anti-inflammatory drug, methylprednisolone, synergistically enhances functional recovery. Additionally, this combined treatment also decreases the expression of pro-inflammatory genes and enhance gene expressions related to extracellular matrix deposition. Finally, increased Axon miRs dosage with methylprednisolone, significantly promotes functional recovery and remyelination. Altogether, scaffold-mediated Axon miR treatment with methylprednisolone is a promising therapeutic approach for SCI.Ministry of Education (MOE)National Medical Research Council (NMRC)National Research Foundation (NRF)Published versionThis work is supported by the National Research Foundation, Singapore, under its Intra-CREATE Thematic Grant Programme (NRF2019-THE002-0001) and NMRC-CBRG grant (NMRC/CBRG/0096/2015), as well as the MOE Tier 1 grants (RG38/19 and RG37/20). N.Z. and J.L. would like to acknowledge NTU by providing Nanyang Research Scholarship to carry out these research works