Scar Tissue-Targeting Polymer Micelle for Spinal Cord Injury Treatment.

Spinal cord injury (SCI) is a devastating disorder, leading to permanent motor and sensory deficit. Despite recent advances in neurosciences, the treatment efficacy on SCI patients remains unsatisfactory, mainly due to the poor accumulation, short retention, and lack of controlled release of therapeutics in lesion tissue. Herein, an injured spinal cord targeting prodrug polymer micelle is built. An esterase-responsive bond is used to link apocynin (APO) monomer, because of the enhanced esterase activity found in microglia cells after activation, which ensures a controlled degradation of APO prodrug (Allyloxypolyethyleneglycol-b-poly [2-(((4-acetyl-2-methoxyphenoxy)carbonyl)oxy)ethyl methacrylate], APEG-PAPO or PAPO) by activated microglia cells. A scar tissue-homing peptide (cysteine-alanine-glutamine-lysine, CAQK) is introduced to the PAPO to endow the polymer micelle the lesion tissue-targeting ability. As a result, this CAQK-modified prodrug micelle (cPAM) exhibits an improved accumulation and prolonged retention in lesion tissue compared to the control micelle. The cPAM also leads to superior tissue protection and sustained motor function recovery than the control groups in a mouse model of SCI. In conclusion, the cPAM induces an effective treatment of SCI by the lesion tissue specific delivery of the prodrug polymer via its robust scar binding effect, making the scar tissue a drug releasing platform for sustained treatment of SCI.

Swelling-Mediated Mechanical Stimulation Regulates Differentiation of Adipose-Derived Mesenchymal Stem Cells for Intervertebral Disc Repair Using Injectable UCST Microgels.

Mechanical stimulation is an effective approach for controlling stem cell differentiation in tissue engineering. However, its realization in in vivo tissue repair remains challenging since this type of stimulation can hardly be applied to injectable seeding systems. Here, it is presented that swelling of injectable microgels can be transformed to in situ mechanical stimulation via stretching the cells adhered on their surface. Poly(acrylamide-co-acrylic acid) microgels with the upper critical solution temperature property are fabricated using inverse emulsion polymerization and further coated with polydopamine to increase cell adhesion. Adipose-derived mesenchymal stem cells (ADSCs) adhered on the microgels can be omnidirectionally stretched along with the responsive swelling of the microgels, which upregulate TRPV4 and Piezo1 channel proteins and enhance nucleus pulposus (NP)-like differentiation of ADSCs. In vivo experiments reveal that the disc height and extracellular matrix content of NP are promoted after the implantation with the microgels. The findings indicate that swelling-induced mechanical stimulation has great potential for regulating stem cell differentiation during intervertebral disc repair.

PHBV/PLA/Col-Based Nanofibrous Scaffolds Promote Recovery of Locomotor Function by Decreasing Reactive Astrogliosis in a Hemisection Spinal Cord Injury Rat Model.

OBJECTIVES: Biomaterials are used to aid in the regeneration of damaged tissue and in promotion of axonal guidance following spinal cord injury (SCI). In the present study, electrospun composite poly(hydroxybutyrate-cohydroxyvalerate) (PHBV), poly(lactic acid) (PLA), and collagen (Col) nanofibrous scaffolds were applied to determine their roles in neural regeneration and recovery in a rat model of SCI. METHODS: The morphological and chemical properties of the electrospun scaffolds were investigated. The growth and proliferation of astrocytes on the scaffolds were assessed by MTT assay. The differentiation and gene expression of astrocytes on the scaffolds were measured by immunofluorescence and quantitative real-time polymerase chain reaction (q-PCR) assays. In a rat spinal cord hemisection model with 3-mm defects, 80 Sprague-Dawley rats were randomly divided into five groups: Sham group, SCI group, SCI+PHBV/PLA group, SCI+PHBV/PLA/Col (70:30) group, and SCI+PHBV/PLA/Col (50:50) group. The Basso-Beattie-Bresnahan (BBB) scores were evaluated every week postsurgery, and (immuno) histological and protein analyses were performed on specimens at 8 weeks. RESULTS: PHBV/PLA/Col scaffolds strongly inhibited the activation of astrocytes without decreasing their proliferation. qPCR assays revealed significant increases in the expression of brain lipid-binding protein (BLBP), glutamate transporter 1 (GLT-1) and S100 calcium-binding protein B (S100-ß), but decreases in the expression of glial fibrillary acidic protein (GFAP), chondroitin sulphate sulfate proteoglycan (CSPG), neurocan, and phosphacan in the PHBV/PLA/Col scaffold group. In a series of in vivo experiments, PHBV/PLA/Col scaffold-treated SCI groups showed significant reductions in the numbers of CD68- and GFAP-immunopositive astrocytes within the interface of the remodeled tissue layer, but increased expression of NF-200 in residual neurons with better locomotor functional recovery. However, there were no significant differences between the PHBV/PLA/Col (70:30) and PHBV/PLA/Col (50:50) groups, except in BBB scores. CONCLUSIONS: PHBV/PLA/Col nanofibrous scaffolds were biocompatible and significantly promoted astrocyte differentiation but decreased astrocyte activation. The topographic structures of the PHBV/PLA/Col (70:30 and 50:50) nanofibers were favorable for neural regeneration due to a decrease in astrogliosis in SCI rats.