Advanced Therapies for Traumatic Central Nervous System Injury: Delivery Strategy Reinforced Efficient Microglial Manipulation.

Traumatic central nervous system (CNS) injuries, including spinal cord injury and traumatic brain injury, are challenging enemies of human health. Microglia, the main component of the innate immune system in CNS, can be activated postinjury and are key participants in the pathological procedure and development of CNS trauma. Activated microglia can be typically classified into pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. Reducing M1 polarization while promoting M2 polarization is thought to be promising for CNS injury treatment. However, obstacles such as the low permeability of the blood-brain barrier and short retention time in circulation limit the therapeutic outcomes of administrated drugs, and rational delivery strategies are necessary for efficient microglial regulation. To this end, proper administration methods and delivery systems like nano/microcarriers and scaffolds are investigated to augment the therapeutic effects of drugs, while some of these delivery systems have self-efficacies in microglial manipulation. Besides, systems based on cell and cell-derived exosomes also show impressive effects, and some underlying targeting mechanisms of these delivery systems have been discovered. In this review, we introduce the roles of microglia play in traumatic CNS injuries, discuss the potential targets for the polarization regulation of microglial phenotype, and summarize recent studies and clinical trials about delivery strategies on enhancing the effect of microglial regulation and therapeutic outcome, as well as targeting mechanisms post CNS trauma.

An antioxidative sophora exosome-encapsulated hydrogel promotes spinal cord repair by regulating oxidative stress microenvironment.

Spinal cord injury (SCI) is a severe traumatic disease because of its complications and multi-organ dysfunction. After the injury, the disruption of microenvironment homeostasis in the lesion demolishes the surrounding healthy tissues via various pathways. The microenvironment regulation is beneficial for neural and functional recovery. Sustained release, cellular uptake, and long-term retention of therapeutic molecules at the impaired sites are important for continuous microenvironment improvement. In our study, a local-implantation system was constructed for SCI treatment by encapsulating exosomes derived from Flos Sophorae Immaturus (so-exos) in a polydopamine-modified hydrogel (pDA-Gel). So-exos are used as nanoscale natural vehicles of rutin, a flavonoid phytochemical that is effective in microenvironment improvement and nerve regeneration. Our study showed that the pDA-Gel-encapsulated so-exos allowed rapid improvement of the impaired motor function and alleviation of urination dysfunction by modulating the spinal inflammatory and oxidative conditions, thus illustrating a potential SCI treatment through a combinational delivery of so-exos.

Transplantation of Human Mesenchymal Stem-Cell-Derived Exosomes Immobilized in an Adhesive Hydrogel for Effective Treatment of Spinal Cord Injury.

Spinal cord injury is among the most fatal diseases. The complicated inhibitory microenvironment requires comprehensive mitigation. Exosomes derived from mesenchymal stem cells (MSCs) are natural biocarriers of cell paracrine secretions that bear the functions of microenvironment regulation. However, the effective retention, release, and integration of exosomes into the injured spinal cord tissue are poorly defined. Herein, an innovative implantation strategy is established using human MSC-derived exosomes immobilized in a peptide-modified adhesive hydrogel (Exo-pGel). Unlike systemic admistration of exosomes, topical transplantation of the Exo-pGel provides an exosome-encapsulated extracellular matrix to the injured nerve tissue, thereby inducing effecient comprehensive mitigation of the SCI microenvironment. The implanted exosomes exhibit efficient retention and sustained release in the host nerve tissues. The Exo-pGel elicits significant nerve recovery and urinary tissue preservation by effectively mitigating inflammation and oxidation. The Exo-pGel therapy presents a promising strategy for effective treatment of central nervous system diseases based on exosome implantation.

A Pluripotential Neutrophil-Mimic Nanovehicle Modulates Immune Microenvironment with Targeted Drug Delivery for Augmented Antitumor Chemotherapy.

The limited therapeutic outcomes and severe systemic toxicity of chemotherapy remain major challenges to the current clinical antitumor therapeutic regimen. Tumor-targeted drug delivery that diminishes the undifferentiated systemic distribution is a practical solution to ameliorating systemic toxicity. However, the tumor adaptive immune microenvironment still poses a great threat that compromises the therapeutic efficacy of chemotherapy by promoting the tolerance of the tumor cells. Herein, a pluripotential neutrophil-mimic nanovehicle (Neutrosome(L)) composed of an activated neutrophil membrane-incorporated liposome is proposed to modulate the immune microenvironment and synergize antitumor chemotherapy. The prominent tumor targeting capability inherited from activated neutrophils and the improved tumor penetration ability of Neutrosome(L) enable considerable drug accumulation in tumor tissues (more than sixfold that of free drug). Importantly, Neutrosome(L) can modulate the immune microenvironment by restricting neutrophil infiltration in tumor tissue, which may be attributed to the neutralization of inflammatory cytokines, thus potentiating antitumor chemotherapy. As a consequence, the treatment of cisplatin-loaded Neutrosome(L) performs prominent tumor suppression effects, reduces systemic drug toxicity, and prolongs the survival period of tumor-bearing mice. The pluripotential neutrophil-mimic nanovehicle proposed in this study can not only enhance the tumor accumulation of chemotherapeutics but also modulate the immune microenvironment, providing a compendious strategy for augmented antitumor chemotherapy.

Nanozyme-Integrated Thermoresponsive In Situ Forming Hydrogel Enhances Mesenchymal Stem Cell Viability and Paracrine Effect for Efficient Spinal Cord Repair.

Mesenchymal stem cell (MSC)-based therapy has emerged as a promising strategy for the treatment of spinal cord injury (SCI). However, the hostile microenvironment of SCI, which can adversely affect the survival and paracrine effect of the implanted MSCs, severely limits the therapeutic efficacy of this approach. Here, we report on a ceria nanozyme-integrated thermoresponsive in situ forming hydrogel (CeNZ-gel) that can enable dual enhancement of MSC viability and paracrine effect, leading to highly efficient spinal cord repair. The sol-gel transition property of the CeNZ-gel at body temperature ensures uniform coverage of the hydrogel in injured spinal cord tissues. Our results demonstrate that the CeNZ-gel significantly increases the viability of transplanted MSCs in the microenvironment by attenuating oxidative stress and, more importantly, promotes the secretion of angiogenic factors from MSCs by inducing autophagy of MSCs. The synergy between the oxidative stress-relieving effect of CeNZs and the paracrine effect of MSCs accelerates angiogenesis, nerve repair, and motor function recovery after SCI, providing an efficient strategy for MSC-based SCI therapy.

Biomaterials reinforced MSCs transplantation for spinal cord injury repair.

Due to the complex pathophysiological mechanism, spinal cord injury (SCI) has become one of the most intractable central nervous system (CNS) diseases to therapy. Stem cell transplantation, mesenchymal stem cells (MSCs) particularly, appeals to more and more attention along with the encouraging therapeutic results for the functional regeneration of SCI. However, traditional cell transplantation strategies have some limitations, including the unsatisfying survival rate of MSCs and their random diffusion from the injection site to ambient tissues. The application of biomaterials in tissue engineering provides a new horizon. Biomaterials can not only confine MSCs in the injured lesions with higher cell viability, but also promote their therapeutic efficacy. This review summarizes the strategies and advantages of biomaterials reinforced MSCs transplantation to treat SCI in recent years, which are clarified in the light of various therapeutic effects in pathophysiological aspects of SCI.

Correction: Implantation of a functional TEMPO-hydrogel induces recovery from rat spinal cord transection through promoting nerve regeneration and protecting bladder tissue.

Correction for 'Implantation of a functional TEMPO-hydrogel induces recovery from rat spinal cord transection through promoting nerve regeneration and protecting bladder tissue' by Yu Zhang et al., Biomater. Sci., 2020, 8, 1695-1701, https://doi.org/10.1039/C9BM01530B.

Stimulation by Exosomes from Hypoxia Preconditioned Human Umbilical Vein Endothelial Cells Facilitates Mesenchymal Stem Cells Angiogenic Function for Spinal Cord Repair.

Revascularization treatment is a critical measure for tissue engineering therapies like spinal cord repair. As multipotent stem cells, mesenchymal stem cells (MSCs) have proven to regulate the lesion microenvironment through feedback to the microenvironment signals. The angiogenic capacities of MSCs have been reported to be facilitated by vein endothelial cells in the niche. As emerging evidence demonstrated the roles of exosomes in cell-cell and cell-microenvironment communications, to cope with the ischemia complication for treatment of traumatic spinal cord injury, the study extracts the microenvironment factors to stimulate angiogenic MSCs through using exosomes (EX) derived from hypoxic preconditioned (HPC) human umbilical vein endothelial cells (HUVEC). The HPC treatment with a hypoxia time segment of only 15 min efficiently enhanced the function of EX in facilitating MSCs angiogenesis activity. MSCs stimulated by HPC-EX showed significant tube formation within 2 h, and the in vivo transplantation of the stimulated MSCs elicited effective nerve tissue repair after rat spinal cord transection, which could be attributed to the pro-angiogenic and anti-inflammatory impacts of the MSCs. Through the simulation of MSCs using HPC-tailored HUVEC exosomes, the results proposed an efficient angiogenic nerve tissue repair strategy for spinal cord injury treatment and could provide inspiration for therapies based on stem cells and exosomes.

Hypoxia-stimulated mesenchymal stem cell-derived exosomes loaded by adhesive hydrogel for effective angiogenic treatment of spinal cord injury.

Due to the limited efficacy of current clinical treatment strategies, functional recovery after traumatic spinal cord injury (SCI) remains a knotty problem to be solved. Apart from anti-inflammation and cell replenishing treatments, accumulating evidence implies that promoting angiogenesis would also potentially benefit tissue regeneration after SCI. In this research, inspired by the role of exosomes in cell-cell communication and exosomal alteration resulting from cells under stress, exosomes were engineered through hypoxia stimulation to mesenchymal stem cells and were proposed as an alternative for promoting angiogenesis in SCI therapy. Hypoxia-stimulated exosomes (hypo-Exo) were transplanted into the injured spinal cord via encapsulation in a peptide-modified adhesive hydrogel for pro-angiogenic therapy of SCI. The adhesive peptide PPFLMLLKGSTR-modified hyaluronic acid hydrogel replenished the spinal cavity caused by SCI and achieved the local delivery of exosomes. The hypoxia-inducible factor 1-alpha content in hypo-Exo was significantly increased, resulting in the overexpression of vascular endothelial growth factor in the endothelial cells surrounding the transplant system. Ultimately, prominent angiogenesis and functional recovery after injury were demonstrated both in vitro and in vivo, indicating the immense potential of hydrogel-encapsulated hypo-Exo in treating central nervous system trauma and other ischemia diseases.

The design criteria and therapeutic strategy of functional scaffolds for spinal cord injury repair.

Spinal cord injury (SCI) remains a therapeutic challenge in clinic. Current drug and cell therapeutics have obtained significant efficacy but are still in the early stages for complete neural and functional recovery. In the past few decades, functional scaffolds (FSs) have been rapidly developed to bridge the lesion and provide a framework for tissue regeneration in SCI repair. Moreover, a FS can act as an adjuvant for locally delivering drugs in the lesion with a designed drug release profile, and supplying a biomimetic environment for implanted cells. In this review, the design criteria of FSs for SCI treatment are summarized according to their biocompatibility, mechanical properties, morphology, architecture, and biodegradability. Subsequently, FSs designed for SCI repair in the scope of drug delivery, cell implantation and combination therapy are introduced, respectively. And how a FS promotes their therapeutic efficacy is analyzed. Finally, the challenges, perspectives, and potential of FSs for SCI treatment are discussed. Hopefully, this review may inspire the future development of potent FSs to facilitate SCI repair in clinic.

Rapid and effective treatment of traumatic spinal cord injury using stem cell derived exosomes.

Traumatic spinal cord injury is a fatal acute event without effective clinical therapies. Following the trauma, immediate neural protection and microenvironment mitigation are vitally important for nerve tissue repair, where stem cell-based therapies could be eclipsed by the deficiency of cells due to the hostile microenvironment as well as the transport and preservation processes. Effective emergency strategies are required to be convenient, biocompatible, and stable. Herein, we assess an emergency cell-free treatment using mesenchymal stem cell-derived exosomes, which have proven capable of comprehensive mitigation of the inhibitory lesion microenvironment. The clinically validated fibrin glue is utilized to encapsulate the exosomes and in-situ gelates in transected rat spinal cords to provide a substrate for exosome delivery as well as nerve tissue growth. The emergency treatment alleviates the inflammatory and oxidative microenvironment, inducing effective nerve tissue repair and functional recovery. The therapy presents a promising strategy for effective emergency treatment of central nervous system trauma.

Iron Oxide Nanoparticles Promote Cx43-Overexpression of Mesenchymal Stem Cells for Efficient Suicide Gene Therapy during Glioma Treatment.

Background: Mesenchymal stem cells (MSCs) have been applied as a promising vehicle for tumour-targeted delivery of suicide genes in the herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV) suicide gene therapy against malignant gliomas. The efficiency of this strategy is largely dependent on the bystander effect, which relies on high suicide gene expression levels and efficient transportation of activated GCV towards glioma cells. However, up to now, the methods to enhance the bystander effect of this strategy in an efficient and safe way are still lacking and new approaches to improve this therapeutic strategy are required. Methods: In this study, MSCs were gene transfected using magnetosome-like ferrimagnetic iron oxide nanochains (MFIONs) to highly express HSV-tk. Both the suicide and bystander effects of HSV-tk expressed MSCs (MSCs-tk) were quantitatively evaluated. Connexin 43 (Cx43) expression by MSCs and glioma cells was measured under different treatments. Intercellular communication between MSCs and C6 glioma cells was examined using a dye transfer assay. Glioma tropism and the bio-distribution of MSCs-tk were observed. Anti-tumour activity was investigated in the orthotopic glioma of rats after intravenous administration of MSCs-tk followed by intraperitoneal injection of GCV. Results: Gene transfection using MFIONs achieved sufficient expression of HSV-tk and triggered Cx43 overexpression in MSCs. These Cx43 overexpressing MSCs promoted gap junction intercellular communication (GJIC) between MSCs and glioma cells, resulting in significantly inhibited growth of glioma through an improved bystander effect. Outstanding tumour targeting and significantly prolonged survival with decreased tumour size were observed after the treatment using MFION-transfected MSCs in glioma model rats. Conclusion: Our results show that iron oxide nanoparticles have the potential to improve the suicide gene expression levels of transfected MSCs, while promoting the GJIC formation between MSCs and tumour cells, which enhances the sensitivity of glioma cells to HSV-tk/GCV suicide gene therapy.

Implantation of a functional TEMPO-hydrogel induces recovery from rat spinal cord transection through promoting nerve regeneration and protecting bladder tissue.

Spinal cord injury is one of the most serious traumatic diseases. The current available clinical therapies are unable to provide effective recovery of nerve functions. Implantation of biomaterial scaffolds is a promising approach to bridge the damaged nerve tissue in the absence of the extracellular matrix. However, the treatments have been impaired by the increased generation of reactive oxygen species in the microenvironment of acute spinal cord injury. Efficient delivery of antioxidants and biocompatible materials and reagents has been a challenge. Herein, a novel hyaluronic acid (HA) hydrogel functionalized with the antioxidant compound 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) is fabricated for nerve tissue regeneration after serious spinal cord transection in rats. TEMPO is tethered onto HA chains to form HA-TEMPO through a Schiff base reaction between 4-amino-TEMPO and aldehyde modified HA chains. The TEMPO-hydrogel is constructed with a highly porous three-dimensional structure via the gelation between the residue aldehydes in HA-TEMPO and the amines in adipic dihydrazide modified HA. The functional TEMPO-hydrogel exhibits the antioxidant effect in an H2O2 simulated in vitro peroxidative microenvironment. Implantation of the functional hydrogel in vivo induces a significant motor function restoration, which could be attributed to the effective functions of the TEMPO-hydrogel in tissue reconnection as well as nerve fiber regeneration of the central nervous spinal cord tissue. Importantly, the treatment with the TEMPO-hydrogel effectively protects the bladder tissue from neurogenic damage. Therefore, the functional TEMPO-hydrogel provides a promising strategy for the treatment of central nervous system diseases through the antioxidant and lesion-bridging regulation of the pathological microenvironment.

A MnO2 Nanoparticle-Dotted Hydrogel Promotes Spinal Cord Repair via Regulating Reactive Oxygen Species Microenvironment and Synergizing with Mesenchymal Stem Cells.

Spinal cord injury (SCI) is one of the most debilitating injuries, and transplantation of stem cells in a scaffold is a promising strategy for treatment. However, stem cell treatment of SCI has been severely impaired by the increased generation of reactive oxygen species in the lesion microenvironment, which can lead to a high level of stem cell death and dysfunction. Herein, a MnO2 nanoparticle (NP)-dotted hydrogel is prepared through dispersion of MnO2 NPs in a PPFLMLLKGSTR peptide modified hyaluronic acid hydrogel. The peptide-modified hydrogel enables the adhesive growth of mesenchymal stem cells (MSCs) and nerve tissue bridging. The MnO2 NPs alleviate the oxidative environment, thereby effectively improving the viability of MSCs. Transplantation of MSCs in the multifunctional gel generates a significant motor function restoration on a long-span rat spinal cord transection model and induces an in vivo integration as well as neural differentiation of the implanted MSCs, leading to a highly efficient regeneration of central nervous spinal cord tissue. Therefore, the MnO2 NP-dotted hydrogel represents a promising strategy for stem-cell-based therapies of central nervous system diseases through the comprehensive regulation of pathological microenvironment complications.