Spinal cord injury (SCI) leads to sustained oxidative damage and inflammatory activation, processes that are mutually reinforcing and ultimately hinder neural regeneration. This paper introduces cerium–kaempferol coordination nanoparticles (CeKaeNCs), a nanotherapeutic platform specifically engineered through metal–phenol coordination to concurrently neutralize reactive oxygen species and modulate the inflammatory microenvironment. CeKaeNCs integrate the enzyme-mimetic antioxidant capabilities of redox-active cerium with the anti-inflammatory attributes of the natural flavonoid kaempferol into a singular, stable nanostructure. CeKaeNCs demonstrate broad-spectrum ROS scavenging and effectively diminish pro-inflammatory macrophage activation, while simultaneously promoting a shift toward an anti-inflammatory phenotype. These effects surpass those observed with either free cerium or kaempferol alone. Furthermore, these beneficial actions preserve tissue integrity, promote axonal repair and remyelination, reduce glial scar formation, facilitate synaptic reconstruction, and ultimately enhance functional recovery. This research highlights the potential of rationally designed metal–polyphenol nanoplatforms to interrupt the detrimental feedback loop of oxidative stress and inflammation, thereby presenting a versatile, multifunctional approach for central nervous system repair.

Spinal cord injury could trigger an excessive reactive oxygen species formation and a sustained inflammatory response, both of which disrupt neural repair processes. Therefore, it is urgent that exploiting a therapeutic intervention that can simultaneously neutralize ROS and restore immune balance. This study reports a hyaluronic acid-based diselenide cross-linked nanogel (Se-Se@HA) designed to integrate catalytic ROS scavenging and immunomodulatory properties to reconstruct the damaged microenvironment and promote repair. Se-Se@HA exhibits significant structural stability and selectively responds to ROS, demonstrating strong free radical scavenging capabilities. By inhibiting M1 polarization and enhancing the M2 phenotype, Se-Se@HA reduces the levels of pro-inflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-6, exhibiting potent anti-inflammatory effects. In vitro, Se-Se@HA protects neurons from oxidative stress damage and promotes neurite growth and axonal bridging. In vivo, this nanogel has demonstrated strong ROS scavenging and anti-inflammatory effects. Transcriptome analysis revealed downregulation of NF-kappa B, TNF, and MAPK signaling pathways, while enrichment of gene pathways related to synaptic transmission and regeneration. Functionally, Se-Se@HA significantly improved BMS scores, gait indices, and gait regularity, enhanced motor evoked potentials and electromyographic signals, reduced muscle atrophy; increased axonal continuity, restored serotonergic and synaptic-related signals at the injury site, and reduced scar formation. These findings suggest that Se-Se@HA is a multifunctional nanozyme platform capable of coordinating oxidative stress relief, immune homeostasis, and neuroregeneration, providing a promising therapeutic strategy for SCI.

Spinal cord injury (SCI) results in irreversible neurological damage primarily due to secondary processes such as oxidative stress, inflammation, and mitochondrial dysfunction, which hinder functional recovery and currently lack effective targeted treatments. Developing bioactive scaffolds that can dynamically reshape this pathological environment is essential for facilitating neural repair. In this study, we present a ROS-responsive hydrogel scaffold synthesized from quaternized chitosan (QCS) and tannic acid (TA), which is further functionalized with Cu/Zn MOF, designed to create a neuro-permissive microenvironment. By taking advantage of the elevated oxidative levels present at the injury site, this hydrogel functions as an "on-demand" therapeutic system. It demonstrates significant antioxidative properties by effectively scavenging intracellular ROS and preserving mitochondrial function, thereby preventing neuronal apoptosis. Concurrently, the composite regulates the immune microenvironment by inhibiting the polarization of pro-inflammatory M1 macrophages while promoting the reparative M2 phenotype. This dual approach of anti-inflammatory and antioxidative regulation significantly reduces astrogliosis and establishes a favorable permissive environment for tissue reconstruction. In vivo assessments reveal that the Cu/Zn MOF@gel significantly enhances axonal regeneration and remyelination, leading to considerable improvements in both electrophysiological conduction and locomotor function recovery. This study underscores the potential of ROS-responsive hydrogels functionalized with MOFs as a promising therapeutic strategy for addressing oxidative and inflammatory challenges in SCI.

Background: Spinal cord injury (SCI) leads to permanent sensory and motor function loss, characterized by inflammation and neuronal loss. A promising therapeutic strategy involves delivering anti-inflammatory and neuroregenerative agents tailored to these phases. Methods: GelMA-AFN hydrogel microspheres were prepared by a UV-crosslinked microfluidic chip. Immunofluorescence was performed to assess the effect of GelMA-AFN on apoptosis, axonal growth in dorsal root ganglion (DRG) neurons. Immunohistochemistry, flow cytometry, electrophysiology, RNA-seq, and behavioral testing were used to evaluate histological and functional recovery in a rat SCI model. Results: In this study, we developed GelMA-AFN with a dual-layer structure and an mean diameter of 50 µm. The outer layer, containing low-concentration gelatin methacryloyl (GelMA, 5%) and annexin A1 (ANXA1), provided sustained ANXA1 released for up to 7 days, while the inner layer, with high-concentration GelMA (10%), nanoclay, fibronectin (FN), and nerve growth factor (NGF), releases FN and NGF over 6 weeks. In vitro, GelMA-AFN inhibits neuronal apoptosis, promoted axonal growth, and enhances survival under oxidative stress. In vivo, it reduced early inflammation by limiting neutrophil recruitment and promoting macrophage M2 polarization. Eight weeks post-SCI in a rat model, GelMA-AFN enhanced axonal extension, myelin regeneration, beneficial ECM deposition, and reduced glial scar formation, leading to significant neural electrical signal conduction and motor function recovery. mRNA-seq analysis confirmed GelMA-AFN upregulates genes associated with anti-inflammatory responses and axonal extension while downregulating pro-inflammatory genes. Conclusion: These results suggest GelMA-AFN as a promising therapeutic approach for SCI by providing spatiotemporal delivery aligned with the injury's dynamic stages.

Rationale:Spinal cord injury (SCI) triggers a complex secondary injury process characterized by inflammation, neuronal loss, extracellular matrix (ECM) disruption, and limited endogenous repair. Although cell-based therapies hold potential for SCI treatment, their efficacy is often constrained by poor lesion targeting, inadequate persistence after delivery, and limited temporal control over therapeutic factor release. Methods:To address these limitations, we developed a macrophage-based mRNA delivery platform by electroporating CCR2 positive (CCR2+) macrophages with ANXA1, GDNF, and CTGF mRNAs. In vitro, we assessed transfection efficiency, cell viability, secretion kinetics of therapeutic proteins, anti-inflammatory activity, and neuroprotective and regenerative effects. In vivo, using a mouse SCI model, we evaluated lesion-site accumulation, inflammatory regulation, tissue repair, electrophysiological recovery, transcriptomic alterations, and behavioral outcomes. Results:Following electroporation, CCR2⁺ macrophages efficiently expressed ANXA1, GDNF, and CTGF while maintaining high viability, with no marked shift toward CD86- or CD206-associated phenotypes. These engineered macrophages showed enhanced accumulation at the lesion site and sustained therapeutic protein secretion for up to 14 days. In vitro, they protected neuronal cells against oxidative stress-induced injury and promoted neurite outgrowth. In vivo, they attenuated inflammation, improved the local repair microenvironment, and promoted axonal regeneration, remyelination, and ECM remodeling, accompanied by partial recovery of electrophysiological and motor function after SCI. RNA-seq analysis further supported broad changes in pathways related to immune regulation, neural repair, myelination, and matrix remodeling. Conclusions:CCR2-enriched macrophages engineered with reparative mRNAs may represent a promising treatment strategy for SCI. By linking CCR2-associated lesion accumulation with multimodal reparative activity, this cell-based platform provides a potential approach for coordinated microenvironmental regulation and tissue repair.

Spinal cord injury (SCI) leads to extensive neuronal loss and substantial neurological impairment within the spinal cord. The acute inflammatory response and the limited regenerative capacity of neurons are major barriers to neural repair. In this study, we developed bilayer hydrogel microspheres (PC-GEN) with a core-shell structure through droplet microfluidics. The shell layer, composed of PEG-4MAL hydrogels embedded with cerium oxide nanoparticles (CONPs), was released during the first week. The GelMA hydrogel core, containing spinal white matter extracellular matrix (swm-ECM) and nerve growth factor (NGF), provides sustained release for up to eight weeks. PC-GEN mitigates early inflammation during the acute phase by enhancing macrophage/microglia M2 polarization and reducing inflammatory cell infiltration. PC-GEN promoted axonal extension, myelin regeneration, and functional neural network reconstruction in the SCI rat model, resulting in substantial functional recovery. Notably, swm-ECM significantly improved the inhibitory microenvironment following SCI by increasing permissive ECM deposition and decreasing glial scar formation. Furthermore, mRNA-seq analysis confirmed that PC-GEN elevated the expression of genes associated with ECM proteins and neurogenesis, while simultaneously downregulating pro-inflammatory gene transcription. The sequential release of PC-GEN provides a biomimetic delivery strategy tailored to the dynamic pathological changes in SCI, positioning it as a promising therapeutic approach for SCI.

Calcium phosphate cement (CPC) is an injectable bone cement with excellent biocompatibility, widely used for filling bone defects of various shapes. However, its slow degradation, insufficient mechanical strength, and poor osteoinductivity limit its further clinical applications. In this study, we developed a novel composite magnesium-based calcium phosphate cement by integrating magnesium microspheres into PLGA fibers obtained through wet spinning and incorporating these fibers into CPC. The inclusion of magnesium-based PLGA fibers enhanced the compressive strength and degradation rate of CPC, with the degradation rate of the magnesium microspheres being controllable to allow for the sustained release of magnesium ions. In vitro experiments showed that magnesium-based CPC enhanced the proliferation and migration of MC3T3-E1 and HUVECs. Additionally, the magnesium-based composite CPC not only enhanced osteogenic differentiation of MC3T3-E1 cells but also promoted angiogenesis in HUVECs. In vivo experiments using a vertebral bone defect model in Bama miniature pigs showed that the magnesium-based composite CPC significantly increased new bone formation. Additionally, compared to the CPC group, this composite exhibited significantly higher levels of osteogenic and angiogenic markers, with no inflammation or necrosis observed in the heart, liver, or kidneys, indicating good biocompatibility. These results suggest that magnesium-based composite CPC, with its superior compressive strength, biodegradability, and ability to promote vascularized bone regeneration, holds promise as a minimally invasive injectable material for bone regeneration.

Spinal cord organoids are of significant value in the research of spinal cord-related diseases by simulating disease states, thereby facilitating the development of novel therapies. However, the complexity of spinal cord structure and physiological functions, along with the lack of human-derived inducing components, presents challenges in the in vitro construction of human spinal cord organoids. Here, we introduce a novel human decellularized placenta-derived extracellular matrix hydrogel (DPECMH) and, combined with a new induction protocol, successfully construct human spinal cord organoids. The human placenta-sourced decellularized extracellular matrix (dECM), verified through hematoxylin and eosin staining, DNA quantification, and immunofluorescence staining, retained essential ECM components such as elastin, fibronectin, type I collagen, laminin, and so forth. The temperature-sensitive hydrogel made from human placenta dECM demonstrated good biocompatibility and promoted the differentiation of human induced pluripotent stem cell (hiPSCs)-derived spinal cord organoids into neurons. It displayed enhanced expression of laminar markers in comparison to Matrigel and showed higher expression of laminar markers compared to Matrigel, accelerating the maturation process of spinal cord organoids and demonstrating its potential as an organoid culture substrate. DPECMH has the potential to replace Matrigel as the standard additive for human spinal cord organoids, thus advancing the development of spinal cord organoid culture protocols and their application in the in vitro modeling of spinal cord-related diseases.

Bone tissue engineering considers bone scaffolds as a key method for repairing critical-sized bone defects. Bone's unique combination of organic and inorganic elements, porous structure, and mechanical strength is crucial. However, many artificial scaffolds overlook the potential disruption to the natural bone repair process, hindering clinical translation. We propose a biomimetic perspective to design scaffolds that closely replicate natural bone's composition, structure, strength, and physiological process of bone repair. The biomimetic design of bone scaffolds across four dimensions significantly extends the concept of bone tissue engineering. In this review, the evolution of the bone repair concept is first briefly summarized. Then, we analyze the characteristics of bone composition, structure, mechanics, and bone repair in the physiological state based on the biomimetic concept. Comprehensive strategies for biomimetic scaffold fabrication are discussed, and future development perspectives are offered, advocating the biomimetic concept as a guiding principle for future scaffold design and fabrication.

The intricate electrophysiological functions and anatomical structures of spinal cord tissue render the establishment of in vitro models for spinal cord-related diseases highly challenging. Currently, both in vivo and in vitro models for spinal cord-related diseases are still underdeveloped, complicating the exploration and development of effective therapeutic drugs or strategies. Organoids cultured from human induced pluripotent stem cells (hiPSCs) hold promise as suitable in vitro models for spinal cord-related diseases. However, the cultivation of spinal cord organoids predominantly relies on Matrigel, a matrix derived from murine sarcoma tissue. Tissue-specific extracellular matrices are key drivers of complex organ development, thus underscoring the urgent need to research safer and more physiologically relevant organoid culture materials. Herein, we have prepared a rat decellularized brain extracellular matrix hydrogel (DBECMH), which supports the formation of hiPSC-derived spinal cord organoids. Compared with Matrigel, organoids cultured in DBECMH exhibited higher expression levels of markers from multiple compartments of the natural spinal cord, facilitating the development and maturation of spinal cord organoid tissues. Our study suggests that DBECMH holds potential to replace Matrigel as the standard culture medium for human spinal cord organoids, thereby advancing the development of spinal cord organoid culture protocols and their application in in vitro modeling of spinal cord-related diseases.

Abstract Active artificial bone substitutes are crucial in bone repair and reconstruction. Calcium phosphate bone cement (CPC) is known for its biocompatibility, degradability, and ability to fill various shaped bone defects. However, its low osteoinductive capacity limits bone regeneration applications. Effectively integrating osteoinductive magnesium ions with CPC remains a challenge. Herein, we developed magnesium malate-modified CPC (MCPC). Incorporating 5% magnesium malate significantly enhances the compressive strength of CPC to (6.18 ± 0.49) MPa, reduces setting time and improves disintegration resistance. In vitro, MCPC steadily releases magnesium ions, promoting the proliferation of MC3T3-E1 cells without causing significant apoptosis, proving its biocompatibility. Molecularly, magnesium malate prompts macrophages to release prostaglandin E2 (PGE2) and synergistically stimulates dorsal root ganglion (DRG) neurons to synthesize and release calcitonin gene-related peptide (CGRP). The CGRP released by DRG neurons enhances the expression of the key osteogenic transcription factor Runt-related transcription factor-2 (RUNX2) in MC3T3-E1 cells, promoting osteogenesis. In vivo experiments using minipig vertebral bone defect model showed MCPC significantly increases the bone volume fraction, bone density, new bone formation, and proportion of mature bone in the defect area compared to CPC. Additionally, MCPC group exhibited significantly higher levels of osteogenesis and angiogenesis markers compared to CPC group, with no inflammation or necrosis observed in the hearts, livers, or kidneys, indicating its good biocompatibility. In conclusion, MCPC participates in the repair of bone defects in the complex post-fracture microenvironment through interactions among macrophages, DRG neurons, and osteoblasts. This demonstrates its significant potential for clinical application in bone defect repair.

Spinal cord injuries (SCI) often cause severe inflammatory response and neuronal loss, which consequently deteriorates motor function. Although exogenous stem cells are considered to be vital seed cells for cell replacement therapy after SCI, their low survival rate and low efficiency of neuronal differentiation after in vivo transplantation limit their widespread application in clinical practice. To this end, this study proposed a new strategy for dramatically improving the efficiency of insulin-like growth factor 1 (IGF1c) mimetic peptide to activate its receptor by fabricating IGF1c mimetic peptide supramolecular hydrogel microspheres (IGF1c-PHM) using an innovatively designed piezoelectric ceramic-driven thermal electrospray device. IGF1c-PHM displayed an average size of 10 & mu;m and could activate the IGF1R of neural stem cells (NSCs) more effectively than IGF1c peptide block hydrogel (IGF1c-PH). In vitro, IGF1c-PHM exerted strong neuroprotective effects by maintaining the proliferation, inhibiting the apoptosis of NSCs, and promoting the efficiency of differentiation into neurons in presence of myelin extracts. In vivo, IGF1c-PHM improved the inflammatory environment by suppressing the recruitment of the inflammatory cells, altering the subtypes of the macrophages, and promoting the survival rate of endogenous cells and NSCs in the injury area. In particular, IGF1c-PHM enhanced the proliferation ability and neuronal differentiation of NSCs in vivo after SCI. In the presence of IGF1c-PHM, the transplanted NSCs could differentiate into several mature neurons at the injury site, and the axons regenerated in the injury site were remyelinated, all of which closely correlate with the improvement of the electrophysiological indices after SCI. Finally, at 8 weeks post-SCI, the gait analysis and behavioral scores confirmed the significant improvement in motor function in rats treated with IGF1c-PHM and NSCs. Therefore, IGF1c-PHM combined with NSCs is a promising therapy for treating SCI. & COPY; 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

This present study is aimed to investigate the role of microRNA-365 (miR-365) in the development of intervertebral disc degeneration (IDD). Nucleus pulposus (NP) cells were transfected by miR-365 mimic and miR-365 inhibitor, respectively. Concomitantly, the transfection efficiency and the expression level of miRNA were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Meanwhile, NP cells apoptosis was measured through propidium iodide (PI)-AnnexinV-fluorescein isothiocyanate (FITC) apoptosis detection kit. Subsequently, immunofluorescence (IF) staining was performed to assess the expression of collagen II, aggrecan and matrix metalloproteinase 13 (MMP-13). In addition, bioinformatic prediction and Luciferase reporter assay were used to reveal the target gene of miR-365. Finally, we isolated the primary NP cells from rats and injected NP-miR-365 in rat IDD models. The results showed that overexpression of miR-365 could effectively inhibit NP cells apoptosis and MMP-13 expression and upregulate the expression of collagen II and aggrecan. Conversely, suppression of miR-365 enhanced NP cell apoptosis and elevated MMP-13 expression, but decreased the expression of collagen II and aggrecan. Moreover, the further data demonstrated that miR-365 mediated NP cell degradation through targeting ephrin-A3 (EFNA3). In addition, the cells apoptosis and catabolic markers were increased in NP cells when EFNA3 upregulated. More importantly, the vivo data supported that miR-365-NP cells injection ameliorated IDD in rats models. miR-365 could alleviate the development of IDD by regulating NP cell apoptosis and ECM degradation, which is likely mediated by targeting EFNA3. Therefore, miR-365 may be a promising therapeutic avenue for treatment IDD through EFNA3.

Transplantation of curcumin-activated olfactory ensheathing cells (aOECs) improved functional recovery in spinal cord injury (SCI) rats. Nevertheless, little is known considering the underlying mechanisms. At the present study, we investigated the promotion of regeneration and functional recovery after transplantation of aOECs into rats with SCI and the possible underlying molecular mechanisms. Primary OECs were prepared from the olfactory bulb of rats, followed by treatment with 1µM CCM at 7–10 days of culture, resulting in cell activation. Concomitantly, rat SCI model was developed to evaluate the effects of transplantation of aOECs in vivo. Subsequently, microglia were isolated, stimulated with 100 ng/mL lipopolysaccharide (LPS) for 24 h to polarize to M1 phenotype and treated by aOECs conditional medium (aOECs-CM) and OECs conditional medium (OECs-CM), respectively. Changes in the expression of pro-inflammatory and anti-inflammatory phenotypic markers expression were detected using western blotting and immunofluorescence staining, respectively. Finally, a series of molecular biological experiments including knock-down of triggering receptor expressed on myeloid cells 2 (TREM2) and analysis of the level of apolipoprotein E (APOE) expression were performed to investigate the underlying mechanism of involvement of CCM-activated OECs in modulating microglia polarization, leading to neural regeneration and function recovery. CCM-activated OECs effectively attenuated deleterious inflammation by regulating microglia polarization from the pro-inflammatory (M1) to anti-inflammatory (M2) phenotype in SCI rats and facilitated functional recovery after SCI. In addition, microglial polarization to M2 elicited by aOECs-CM in LPS-induced microglia was effectively reversed when TREM2 expression was downregulated. More importantly, the in vitro findings indicated that aOECs-CM potentiating LPS-induced microglial polarization to M2 was partially mediated by the TREM2/nuclear factor kappa beta (NF-κB) signaling pathway. Besides, the expression of APOE significantly increased in CCM-treated OECs. CCM-activated OECs could alleviate inflammation after SCI by switching microglial polarization from M1 to M2, which was likely mediated by the APOE/TREM2/NF-κB pathway, and thus ameliorated neurological function. Therefore, the present finding is of paramount significance to enrich the understanding of underlying molecular mechanism of aOECs-based therapy and provide a novel therapeutic approach for treatment of SCI.

Neural tissue engineering is an essential strategy to repair long-segment peripheral nerve defects. Modification of the nerve conduit is an effective way to improve the local microenvironment of the injury site and facilitate nerve regeneration. However, the concurrent release of multiple growth cues that regulate the activity of Schwann cells and neurons remains a challenge. The present study involved the fabrication of a composite hydrogel, specifically methacrylate-anhydride gelatin-ciliary neurotrophic factor/insulin-like growth factor-1 (GelMA-CNTF/IGF-1), with the aim of providing a sustained release of CNTF and IGF-1. The GelMA-CNTF/IGF-1 hydrogels exhibited a swelling rate of 10.2% following a 24 h incubation in vitro. In vitro, GelMA hydrogels demonstrated a high degree of efficiency in the sustained release of CNTF and IGF-1 proteins, with a release rate of 85.9% for CNTF and 90.9% for IGF-1 shown at day 28. In addition, the GelMA-CNTF/IGF-1 composite hydrogel promoted the proliferation of Schwann cells and the production of nerve growth factor (NGF), connective tissue growth factor (CTGF), fibronectin, and laminin and also considerably promoted the axonal growth of neurons. Furthermore, GelMA-CNTF/IGF-1 hydrogels were loaded into PCL electrospun nerve conduits to repair 15 mm sciatic nerve defects in rats. In vivo studies indicated that PCL-GelMA-CNTF/IGF-1 could efficiently accelerate the regeneration of the rat sciatic nerve, promote the formation of the myelin sheath of new axons, promote the electrophysiological function of regenerated nerves, and eventually improve the recovery of motor function in rats. Overall, the PCL-GelMA-CNTF/IGF-1 scaffold presents an attractive new approach for generating an optimal therapeutic alternative for peripheral nerve restoration.

Spinal cord injuries (SCI) often cause a severe inflammatory response and neuronal loss, which in turn lead to loss of motor function. Exogenous stem cells are considered to be vital seed cells for cell replacement therapy after spinal cord injury. However, the low survival rate and the low efficiency of neuronal differentiation of stem cells after in vivo transplantation limit their use in clinical practice. In this study, a new strategy to dramatically improve the efficiency of insulin-like growth factor 1 mimetic peptide to activate its receptor is proposed through fabrication of IGF1c mimetic peptide supramolecular hydrogel microspheres (IGF1c-PHM). IGF1c-PHM was fabricated by an innovative designed piezoelectric ceramic-driven thermal electrospray device. IGF1c-PHM have an average size of 10 μm and can activate the IGF1R of NSCs more remarkably than IGF1c peptide block hydrogel (IGF1c-PH). In vitro, IGF1c-PHM exerts strong neuroprotective effects by maintaining the proliferation, inhibiting the apoptosis of NSCs, and promoting the efficiency of differentiation to neurons in the presence of myelin extracts. In vivo, IGF1c-PHM improved the inflammatory environment by reducing the recruitment of inflammatory cells and altering the subtypes of macrophages, and elevated survival rate of endogenous cells and NSCs in the injury area. IGF1c-PHM enhanced proliferation ability and neuronal differentiation of NSCs in vivo after SCI. Transplanted NSCs can differentiate into a variety of mature neurons in the injury site in presence of IGF1c-PHM, and regenerated axons in the injury site have been remyelinated, all of which are closely correlated with the improvement of electrophysiological indices after SCI. Gait analysis and behavioral scores confirmed significant improvement of motor function in rats treated with IGF1c-PHM combined NSCs at 8 weeks post-SCI. Therefore, IGF1c-PHM combined with NSCs is a promising therapy for SCI repair.

Modified macroporous structures and active osteogenic substances are necessary to overcome the limited bone regeneration capacity and low degradability of self-curing calcium phosphate cement (CPC). Curcumin (CUR), which possesses strong osteogenic activity and poor aqueous solubility/bioavailability, esterifies the side chains in hyaluronic acid (HA) to form a water-soluble CUR-HA macromolecule. In this study, we incorporated the CUR-HA and glucose microparticles (GMPs) into the CPC powder to fabricate the CUR-HA/GMP/CPC composite, which not only retained the good injectability and mechanical strength of bone cements, but also significantly increased the cement porosity and sustained release property of CUR-HA in vitro. CUR-HA incorporation greatly improved the differentiation ability of bone marrow mesenchymal stem cells (BMSCs) to osteoblasts by activating the RUNX family transcription factor 2/fibroblast growth factor 18 (RUNX2/FGF18) signaling pathway, increasing the expression of osteocalcin and enhancing the alkaline phosphatase activity. In addition, in vivo implantation of CUR-HA/GMP/CPC into femoral condyle defects dramatically accelerated the degradation rate of cement and boosted local vascularization and osteopontin protein expression, and consequently promoted rapid bone regeneration. Therefore, macroporous CPC based composite cement with CUR-HA shows a remarkable ability to repair bone defects and is a promising translational application of modified CPC in clinical practice.

Neural stem cells (NSCs) are considered to be prospective replacements for neuronal cell loss as a result of spinal cord injury (SCI). However, the survival and neuronal differentiation of NSCs are strongly affected by the unfavorable microenvironment induced by SCI, which critically impairs their therapeutic ability to treat SCI. Herein, a strategy to fabricate PDGF-MP hydrogel (PDGF-MPH) microspheres (PDGF-MPHM) instead of bulk hydrogels is proposed to dramatically enhance the efficiency of platelet-derived growth factor mimetic peptide (PDGF-MP) in activating its receptor. PDGF-MPHM were fabricated by a piezoelectric ceramic-driven thermal electrospray device, had an average size of 9 μm, and also had the ability to activate the PDGFRβ of NSCs more effectively than PDGF-MPH. In vitro, PDGF-MPHM exerted strong neuroprotective effects by maintaining the proliferation and inhibiting the apoptosis of NSCs in the presence of myelin extracts. In vivo, PDGF-MPHM inhibited M1 macrophage infiltration and extrinsic or intrinsic cells apoptosis on the seventh day after SCI. Eight weeks after SCI, the T10 SCI treatment results showed that PDGF-MPHM + NSCs significantly promoted the survival of NSCs and neuronal differentiation, reduced lesion size, and considerably improved motor function recovery in SCI rats by stimulating axonal regeneration, synapse formation, and angiogenesis in comparison with the NSCs graft group. Therefore, our findings provide insights into the ability of PDGF-MPHM to be a promising therapeutic agent for SCI repair.

OBJECTIVES:The goal of this study was to determine whether electro-acupuncture (EA) stimulation might protect the motor endplate, minimize muscle atrophy in the hind limbs, and enhance functional recovery of rats with spinal cord injury (SCI).METHODS:Sprague-Dawley adult female rats (n = 30) were randomly assigned into Sham, SCI, and EA + SCI groups (n = 10 each). Rats in the Sham and SCI groups were bound in prone position only for 30 min, and rats in the EA + SCI group were treated with electro-acupuncture. The EA was conducted from the first day after surgery, lasted for 30 mins, once every day for 28 consecutive days.RESULTS:EA significantly prevented motor endplate degeneration, improved electrophysiological function, and ameliorated hindlimb muscle atrophy after SCI. Meanwhile, EA upregulated Tuj-1 expression, downregulated GFAP expression, and reduced glial scar formation. Additionally, after 4 weeks of EA treatment, the serum of SCI rats exhibited a reduced inflammatory response.CONCLUSION:These findings suggest that EA can preserve the motor endplate and reduce muscular atrophy. In addition, EA has been shown to improve the function of upper and lower neurons, reduce glial scar formation, suppress systemic inflammation, and improve axon regeneration.