The strategies concerning modification of the complex immune pathological inflammatory environment during acute spinal cord injury remain oversimplified and superficial. Inspired by the acidic microenvironment at acute injury sites, a functional pH-responsive immunoregulation-assisted neural regeneration strategy was constructed. With the capability of directly responding to the acidic microenvironment at focal areas followed by triggered release of the IL-4 plasmid-loaded liposomes within a few hours to suppress the release of inflammatory cytokines and promote neural differentiation of mesenchymal stem cells in vitro, the microenvironment-responsive immunoregulatory electrospun fibers were implanted into acute spinal cord injury rats. Together with sustained release of nerve growth factor (NGF) achieved by microsol core-shell structure, the immunological fiber scaffolds were revealed to bring significantly shifted immune cells subtype to down-regulate the acute inflammation response, reduce scar tissue formation, promote angiogenesis as well as neural differentiation at the injury site, and enhance functional recovery in vivo. Overall, this strategy provided a delivery system through microenvironment-responsive immunological regulation effect so as to break through the current dilemma from the contradiction between immune response and nerve regeneration, providing an alternative for the treatment of acute spinal cord injury.
Although
injectable hydrogel microsphere has demonstrated tremendous
promise in clinical applications, local overactive inflammation in
degenerative diseases could jeopardize biomaterial implantation’s
therapeutic efficacy. Herein, an injectable “peptide-cell-hydrogel”
microsphere was constructed by covalently coupling of APETx2 and further
loading of nucleus pulposus cells, which could inhibit local inflammatory
cytokine storms to regulate the metabolic balance of ECM in
vitro. The covalent coupling of APETx2 preserved the biocompatibility
of the microspheres and achieved a controlled release of APETx2 for
more than 28 days in an acidic environment. By delivering “peptide-cell-hydrogel”
microspheres to a rat degenerative intervertebral disc at 4 weeks,
the expression of ASIC-3 and IL-1β was significantly decreased
for 3.53-fold and 7.29-fold, respectively. Also, the content of ECM
was significantly recovered at 8 weeks. In summary, the proposed strategy
provides an effective approach for tissue regeneration under overactive
inflammatory responses.
We have proposed a technique for estimating image-derived input functions using independent component analysis without blood sampling. The results of our method were highly correlated with those from standard blood sampling, and more accurate than those of other methods proposed previously.
Current homogeneous bioscaffolds could hardly recapture the regenerative microenvironment of extracellular matrix. Inspired by the peculiar nature of dura matter, we developed an extracellular matrix–mimicking scaffold with biomimetic heterogeneous features so as to fit the multiple needs in dura mater repairing. The inner surface endowed with anisotropic topology and optimized chemical cues could orchestrate the elongation and bipolarization of fibroblasts and preserve the quiescent phenotype of fibroblasts indicated by down-regulated α–smooth muscle actin expression. The outer surface could suppress the fibrotic activity of myofibroblasts via increased microfiber density. Furthermore, integrin β1 and Yes-associated protein molecule signaling activities triggered by topological and chemical cues were verified, providing evidence for a potential mechanism. The capability of the scaffold in simultaneously promoting dura regeneration and inhibiting epidural fibrosis was further verified in a rabbit laminectomy model. Hence, the so-produced heterogeneous fibrous scaffold could reproduce the microstructure and function of natural dura.
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