Enhancing Nervous System Recovery through Neurobiologics, Neural Interface Training, and Neurorehabilitation.

After an initial period of recovery, human neurological injury has long been thought to be static. In order to improve quality of life for those suffering from stroke, spinal cord injury, or traumatic brain injury, researchers have been working to restore the nervous system and reduce neurological deficits through a number of mechanisms. For example, neurobiologists have been identifying and manipulating components of the intra- and extracellular milieu to alter the regenerative potential of neurons, neuro-engineers have been producing brain-machine and neural interfaces that circumvent lesions to restore functionality, and neurorehabilitation experts have been developing new ways to revitalize the nervous system even in chronic disease. While each of these areas holds promise, their individual paths to clinical relevance remain difficult. Nonetheless, these methods are now able to synergistically enhance recovery of native motor function to levels which were previously believed to be impossible. Furthermore, such recovery can even persist after training, and for the first time there is evidence of functional axonal regrowth and rewiring in the central nervous system of animal models. To attain this type of regeneration, rehabilitation paradigms that pair cortically-based intent with activation of affected circuits and positive neurofeedback appear to be required-a phenomenon which raises new and far reaching questions about the underlying relationship between conscious action and neural repair. For this reason, we argue that multi-modal therapy will be necessary to facilitate a truly robust recovery, and that the success of investigational microscopic techniques may depend on their integration into macroscopic frameworks that include task-based neurorehabilitation. We further identify critical components of future neural repair strategies and explore the most updated knowledge, progress, and challenges in the fields of cellular neuronal repair, neural interfacing, and neurorehabilitation, all with the goal of better understanding neurological injury and how to improve recovery

Spinal Progenitor-Laden Bridges Support Earlier Axon Regeneration Following Spinal Cord Injury.

Impact statementSpinal cord injury (SCI) results in loss of tissue innervation below the injury. Spinal progenitors have a greater ability to repair the damage and can be injected into the injury, but their regenerative potential is hampered by their poor survival after transplantation. Biomaterials can create a cell delivery platform and generate a more hospitable microenvironment for the progenitors within the injury. In this work, polymeric bridges are used to deliver embryonic spinal progenitors to the injury, resulting in increased progenitor survival and subsequent regeneration and functional recovery, thus demonstrating the importance of combined therapeutic approaches for SCI

Harnessing the power of cell transplantation to target respiratory dysfunction following spinal cord injury.

The therapeutic benefit of cell transplantation has been assessed in a host of central nervous system (CNS) diseases, including disorders of the spinal cord such as traumatic spinal cord injury (SCI). The promise of cell transplantation to preserve and/or restore normal function can be aimed at a variety of therapeutic mechanisms, including replacement of lost or damaged CNS cell types, promotion of axonal regeneration or sprouting, neuroprotection, immune response modulation, and delivery of gene products such as neurotrophic factors, amongst other possibilities. Despite significant work in the field of transplantation in models of SCI, limited attention has been directed at harnessing the therapeutic potential of cell grafting for preserving respiratory function after SCI, despite the critical role pulmonary compromise plays in patient outcome in this devastating disease. Here, we will review the limited number of studies that have demonstrated the therapeutic potential of intraspinal transplantation of a variety of cell types for addressing respiratory dysfunction in SCI

Differential expression of ADAMTS -1, -4, -5 and TIMP -3 in rat spinal cord at different stages of acute experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is an animal model of inflammatory demyelination, a pathological event common to multiple sclerosis (MS). During CNS inflammation there are alterations in the extracellular matrix (ECM). A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS) -1, -4 and -5 are proteases present in the CNS, which are able to cleave the aggregating chondroitin sulphate proteoglycans, aggrecan, phosphacan, neurocan and brevican. It is therefore important to investigate changes in their expression in different stages of EAE induction. We have investigated expression of ADAMTS-1, -4, -5 and Tissue inhibitor of metalloproteinase (TIMP) -3, by real-time RT-PCR. We have also examined protein expression of ADAMTS-1, -4 and -5 by western blotting and immunocytochemistry in spinal cord from animals at different stages of disease progression. Our study demonstrated a decrease in ADAMTS-4 mRNA and protein expression. TIMP-3 was decreased at the mRNA level although protein levels were increased in diseased animals compared to controls. Our study identifies changes in ADAMTS expression during the course of CNS inflammation which may contribute to ECM degradation and disease progression.</p

Tissue-type plasminogen activator-primed human iPSC-derived neural progenitor cells promote motor recovery after severe spinal cord injury.

The goal of stem cell therapy for spinal cord injury (SCI) is to restore motor function without exacerbating pain. Induced pluripotent stem cells (iPSC) may be administered by autologous transplantation, avoiding immunologic challenges. Identifying strategies to optimize iPSC-derived neural progenitor cells (hiNPC) for cell transplantation is an important objective. Herein, we report a method that takes advantage of the growth factor-like and anti-inflammatory activities of the fibrinolysis protease, tissue plasminogen activator tPA, without effects on hemostasis. We demonstrate that conditioning hiNPC with enzymatically-inactive tissue-type plasminogen activator (EI-tPA), prior to grafting into a T3 lesion site in a clinically relevant severe SCI model, significantly improves motor outcomes. EI-tPA-primed hiNPC grafted into lesion sites survived, differentiated, acquired markers of motor neuron maturation, and extended βIII-tubulin-positive axons several spinal segments below the lesion. Importantly, only SCI rats that received EI-tPA primed hiNPC demonstrated significantly improved motor function, without exacerbating pain. When hiNPC were treated with EI-tPA in culture, NMDA-R-dependent cell signaling was initiated, expression of genes associated with stemness (Nestin, Sox2) was regulated, and thrombin-induced cell death was prevented. EI-tPA emerges as a novel agent capable of improving the efficacy of stem cell therapy in SCI

Exploring the properties and potential of the neural extracellular matrix for next‐generation regenerative therapies

The extracellular matrix (ECM) is a dynamic and complex network of proteins and molecules that surrounds cells and tissues in the nervous system and orchestrates a myriad of biological functions. This review carefully examines the diverse interactions between cells and the ECM, as well as the transformative chemical and physical changes that the ECM undergoes during neural development, aging, and disease. These transformations play a pivotal role in shaping tissue morphogenesis and neural activity, thereby influencing the functionality of the central nervous system (CNS). In our comprehensive review, we describe the diverse behaviors of the CNS ECM in different physiological and pathological scenarios and explore the unique properties that make ECM-based strategies attractive for CNS repair and regeneration. Addressing the challenges of scalability, variability, and integration with host tissues, we review how advanced natural, synthetic, and combinatorial matrix approaches enhance biocompatibility, mechanical properties, and functional recovery. Overall, this review highlights the potential of decellularized ECM as a powerful tool for CNS modeling and regenerative purposes and sets the stage for future research in this exciting field. This article is categorized under: Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Implantable Materials and Surgical Technologies > Nanomaterials and Implant

Biomechanical properties of the spinal cord: implications for tissue engineering and clinical translation

Spinal cord injury is a severely debilitating condition which can leave individuals paralyzed and suffering from autonomic dysfunction. Regenerative medicine may offer a promising solution to this problem. Previous research has focused primarily on exploring the cellular and biological aspects of the spinal cord, yet relatively little remains known about the biomechanical properties of spinal cord tissue. Given that a number of regenerative strategies aim to deliver cells and materials in the form of tissue-engineered therapies, understanding the biomechanical properties of host spinal cord tissue is important. We review the relevant biomechanical properties of spinal cord tissue and provide the baseline knowledge required to apply these important physical concepts to spinal cord tissue engineering