Remodeling Microenvironment for Endogenous Repair through Precise Modulation of Chondroitin Sulfate Proteoglycans Following Spinal Cord Injury.

The fluid-filled cystic cavity sealed by a dense scar developed following traumatic spinal cord injury (SCI) has been a major obstacle to neural regeneration and functional recovery. Here the transected lesion is bridged using a functional self-assembling peptide (F-SAP) hydrogel loaded with membrane-permeable intracellular sigma peptide (ISP) and intracellular LAR peptide (ILP), targeted at perturbing chondroitin sulfate proteoglycan (CSPG) inhibitory signaling. As compared to F-SAP hydrogel loaded with chondroitinase ABC, the F-SAP+ISP/ILP promotes a beneficial anti-inflammatory response via manipulation of microglia/macrophages infiltration and assembly of extracellular matrix (ECM) molecules into fibrotic matrix rather than scarring tissues. The remodeled ECM creates a permissive environment that supports axon regrowth and the formation of synaptic connections with neurons derived from endogenous neural stem cells. The remodeled networks contribute to functional recovery, as demonstrated by improved hind limb movements and electrophysiological properties. This work proposes a unique mechanism that ECM remodeling induced by CSPG-manipulation-based anti-inflammation can construct a permissive environment for neural regeneration, and shed light on the advancement of manipulation of cascading cellular and molecular events potential for endogenous repair of SCI.

Integrating hydrogels manipulate ECM deposition after spinal cord injury for specific neural reconnections via neuronal relays.

A bioinspired hydrogel composed of hyaluronic acid-graft-dopamine (HADA) and a designer peptide HGF-(RADA)4-DGDRGDS (HRR) was presented to enhance tissue integration following spinal cord injury (SCI). The HADA/HRR hydrogel manipulated the infiltration of PDGFRß+ cells in a parallel pattern, transforming dense scars into an aligned fibrous substrate that guided axonal regrowth. Further incorporation of NT3 and curcumin promoted axonal regrowth and survival of interneurons at lesion borders, which served as relays for establishing heterogeneous axon connections in a target-specific manner. Notable improvements in motor, sensory, and bladder functions resulted in rats with complete spinal cord transection. The HADA/HRR + NT3/Cur hydrogel promoted V2a neuron accumulation in ventral spinal cord, facilitating the recovery of locomotor function. Meanwhile, the establishment of heterogeneous neural connections across the hemisected lesion of canines was documented in a target-specific manner via neuronal relays, significantly improving motor functions. Therefore, biomaterials can inspire beneficial biological activities for SCI repair.

A Bioinspired Injectable, Adhesive, and Self-Healing Hydrogel with Dual Hybrid Network for Neural Regeneration after Spinal Cord Injury.

Hydrogel-based regenerated scaffolds show promise as a platform for neural regeneration following spinal cord injury (SCI). Nevertheless, the persistent problem of poor mechanical strength and limited integration with the host tissue still exists. In this study, a bioinspired hydrogel with highly sophisticated features for neural regeneration after SCI is developed. The hydrogel is composed of dihydroxyphenylalanine (DOPA)-grafted chitosan and a designer peptide, offering a unique set of qualities such as being injectable, having self-healing abilities, and adhering to tissues. Compared to conventional hydrogels, this hydrogel ensures a significant promotion of immune response modulation and axon regrowth while featuring synapse formation of various neurotransmitters and myelin regeneration. Subsequently, functional recoveries are enhanced, including motor function, sensory function, and particularly bladder defect repair. These positive findings demonstrate that the hydrogel has great potential as a strategy for repairing SCI. Moreover, the versatility of this strategy goes beyond neural regeneration and holds promise for tissue regeneration in other contexts. Overall, this proposed hydrogel represents an innovative and multifaceted tool for engineering structures in the biomedical field.

Cooperative assembly of a designer peptide and silk fibroin into hybrid nanofiber gels for neural regeneration after spinal cord injury.

Local reconstruction of a permissive environment with biomaterials is a promising strategy to treat spinal cord injury (SCI). We reported a hybrid hydrogel fabricated from a small functional self-assembling peptide (F-SAP) and large silk fibroin (SF). The diffusion of SF micelles into F-SAP solution was driven by the dynamic synergy between osmotic pressure and F-SAP/SF electrostatic interactions, resulting in the rearrangement of SF micelles and the formation of rod-like filaments with axes nearly perpendicular to F-SAP nanofibers. Spectroscopy analysis, including circular dichroism, Raman and fluorescence, indicated conformation changes of SF from random coil to ß sheet, which contributed to enhanced mechanical properties of the resultant hybrid hydrogel. Furthermore, the F-SAP/SF hybrid hydrogel coupled with controlled release of NT-3 provided a permissive environment for neural regeneration by providing nanofibrous substrates for regenerating axons, inflammatory modulation and remyelination, consequently resulting in improved locomotion and electrophysiological properties. This hydrogel could be used as a long-term stent in vivo for the treatment of SCI.

On-demand release of the small-molecule TrkB agonist improves neuron-Schwann cell interactions.

Various extracellular factors jointly control a wide variety of neuronal functions. On-demand delivery system provides a platform to integrate multiple signals in one intervention. In this study, we fabricated an electrically controlled drug delivery nanocomposite composed of graphene oxide (GO) deposited inside a poly(3,4-ethylenedioxythiophene) (PEDOT) film. 7,8-dihydroxyflavone (7,8-DHF) was loaded on GO via π-π stacking and consequentially encapsulated into the electrochemically active film during deposition, which was followed by a Dopamine-graft-Chitosan (CD) coating to improve the biocompatibility. 7,8-DHF was released in response to voltage stimulation and the dosage was adjusted by altering the magnitude of stimulation. The on-demand delivery system promoted dorsal root ganglion (DRG) neurite outgrowth, Schwann cell migration, myelination, and synapse transmission. Neuronal mitochondrial biogenesis was enhanced as determined by immunofluorescence staining and gene expression of HSP60, a mitochondrial localized quality control protein. Therefore, we provided an on-demand delivery platform of temporal control and dosage flexibility to integrate multiple signals in the modulation of neural behaviors and functions.

An injectable and self-healing hydrogel with controlled release of curcumin to repair spinal cord injury.

The harsh local micro-environment following spinal cord injury (SCI) remains a great challenge for neural regeneration. Local reconstitution of a favorable micro-environment by biocompatible scaffolds with desirable functions has thus been an area of concern. Herein, a hybrid hydrogel was developed using Fmoc-grafted chitosan (FC) and Fmoc peptide (FI). Dynamic reversible π-π stacking interactions of the fluorenyl rings enabled the FC/FI hybrid hydrogel to exhibit excellent injectable and self-healing properties, as characterized by visual appearances and rheological tests. Furthermore, the FC/FI hybrid hydrogel showed a slow and persistent release of curcumin (Cur), which was named as FC/FI-Cur hydrogel. In vitro studies confirmed that with the support of FC/FI-Cur hydrogel, neurite outgrowth was promoted, and Schwann cell (SC) migration away from dorsal root ganglia (DRG) spheres with enhanced myelination was substantiated. The FC/FI-Cur hydrogel well reassembled extracellular matrix at the lesion site of rat spinal cord and exerted outstanding effects in modulating local inflammatory reaction by regulating the phenotypes of infiltrated inflammatory cells. In addition, endogenous SCs were recruited in the FC/FI-Cur graft and participated in the remyelination process of the regenerated nerves. These outcomes favored functional recovery, as evidenced by improved hind limbs movement and enhanced electrophysiological properties. Thus, our study not only advanced the development of multifunctional hydrogels but also provided insights into comprehensive approaches for SCI repair.

A colorimetric and absorption ratiometric anion sensor based on indole & hydrazide binding units.

A colorimetric and absorption ratiometric anion sensor (L) based on indole and hydrazide binding units was designed and synthesized, and its recognition & sensing properties towards different anions were studied by naked-eye observations, UV-vis and (1)H NMR titration spectra. Sensor L could selectively recognize biologically important F(-), AcO(-) and H2PO4(-) in DMSO over other anions, along with a significant change in its color and absorption spectrum, resulting from the formation of corresponding 1:2 (L/F(-)) and 1:1 (L/AcO(-) and L/H2PO4(-)) complexes. The (1)H NMR titration experiments proved that sensor L experienced deprotonation of NH fragment and produced [HF2](-) species, whereas a stable H-bonding complex was formed in the presence of AcO(-) and H2PO4(-).