A novel ex vivo assay to define charge-balanced electrical stimulation parameters for neural precursor cell activation in vivo.

Endogenous neural stem cells and their progeny (together termed neural precursor cells (NPCs)) are promising candidates to facilitate neuroregeneration. Charge-balanced biphasic monopolar stimulation (BPMP) is a clinically relevant approach that can activate NPCs both in vitro and in vivo. Herein, we established a novel ex vivo stimulation system to optimize the efficacy of BPMP electric field (EF) application in activating endogenous NPCs. Using the ex vivo system, we discerned that cathodal amplitude of 200 µA resulted in the greatest NPC pool expansion and enhanced cathodal migration. Application of the same stimulation parameters in vivo resulted in the same NPC activation in the mouse brain. The design and implementation of the novel ex vivo model bridges the gap between in vitro and in vivo systems, enabling a moderate throughput stimulation system to explore and optimize EF parameters that can be applied to clinically relevant brain injury/disease models.

Bio-inspired conductive adhesive based on calcium-free alginate hydrogels for bioelectronic interfaces.

Electrode impedance is one of the greatest challenges facing neural interfacing medical devices and the use of electrical stimulation-based therapies in the fields of neurology and regenerative medicine. Maximizing contact between electronics and tissue would allow for more accurate recordings of neural activity and to stimulate with less power in implantable devices as electric signals could be more precisely transferred by a stable interfacial area. Neural environments, inherently wet and ion-rich, present a unique challenge for traditional conductive adhesives. As such, we look to marine mussels that use a 3,4-dihydroxyphenyl-L-analine (DOPA)-containing proteinaceous excretion to adhere to a variety of substrates for inspiration. By functionalizing alginate, which is an abundantly available natural polymer, with the catechol residues DOPA contains, we developed a hydrogel-based matrix to which carbon-based nanofiller was added to render it conductive. The synthesized product had adhesive energy within the range of previously reported mussel-based polymers, good electrical properties and was not cytotoxic to brain derived neural precursor cells.

Facile Fabrication of Injectable Alginate and Poly(3,4-ethylenedioxythiophene)-Based Soft Electrodes toward the Goal of Neuro-Regenerative Applications.

Resident brain neural precursor cells (NPCs) are electrosensitive cells that respond to electric field application by proliferating, differentiating, and undergoing rapid and directed cathodal migration. Harnessing NPC potential is a promising strategy to facilitate neural repair following injury or disease. The use of electric fields to activate NPCs is limited by current electrode designs which are typically made of conductive metals that are stiff and can lead to neuroinflammation following implantation, in part due to the mechanical mismatch between physiological conditions and material. Herein, the design of a novel, injectable biobased soft electrode with properties suitable for electrical stimulation in vivo is explored. The recent interest in using biologically derived polymers which are relatively abundant and afford economic feasibility have been built upon. Sodium alginate is utilized to form soft hydrogels, thereby addressing the issue of mechanical mismatch, and the conductive polymer, poly(3,4-ethylenedioxythiophene) (PEDOT), to generate an innovative new material. It is demonstrated that the optimized alginate PEDOT blend matches the modulus of the brain and is suitable for injection and is not cytotoxic to neural cells. Furthermore, in vivo studies demonstrate minimal activation of inflammatory cells upon implantation in the brain compared to classically used platinum-based electrodes.

Regulating Endogenous Neural Stem Cell Activation to Promote Spinal Cord Injury Repair.

Spinal cord injury (SCI) affects millions of individuals worldwide. Currently, there is no cure, and treatment options to promote neural recovery are limited. An innovative approach to improve outcomes following SCI involves the recruitment of endogenous populations of neural stem cells (NSCs). NSCs can be isolated from the neuroaxis of the central nervous system (CNS), with brain and spinal cord populations sharing common characteristics (as well as regionally distinct phenotypes). Within the spinal cord, a number of NSC sub-populations have been identified which display unique protein expression profiles and proliferation kinetics. Collectively, the potential for NSCs to impact regenerative medicine strategies hinges on their cardinal properties, including self-renewal and multipotency (the ability to generate de novo neurons, astrocytes, and oligodendrocytes). Accordingly, endogenous NSCs could be harnessed to replace lost cells and promote structural repair following SCI. While studies exploring the efficacy of this approach continue to suggest its potential, many questions remain including those related to heterogeneity within the NSC pool, the interaction of NSCs with their environment, and the identification of factors that can enhance their response. We discuss the current state of knowledge regarding populations of endogenous spinal cord NSCs, their niche, and the factors that regulate their behavior. In an attempt to move towards the goal of enhancing neural repair, we highlight approaches that promote NSC activation following injury including the modulation of the microenvironment and parenchymal cells, pharmaceuticals, and applied electrical stimulation.

Associations Between Time After Stroke and Exercise Training Outcomes: A Meta-Regression Analysis.

Background Knowledge gaps exist regarding the effect of time elapsed after stroke on the effectiveness of exercise training interventions, offering incomplete guidance to clinicians. Methods and Results To determine the associations between time after stroke and 6-minute walk distance, 10-meter walk time, cardiorespiratory fitness and balance (Berg Balance Scale score [BBS]) in exercise training interventions, relevant studies in post-stroke populations were identified by systematic review. Time after stroke as continuous or dichotomized (≤3 months versus >3 months, and ≤6 months versus >6 months) variables and weighted mean differences in postintervention outcomes were examined in meta-regression analyses adjusted for study baseline mean values (pre-post comparisons) or baseline mean values and baseline control-intervention differences (controlled comparisons). Secondary models were adjusted additionally for mean age, sex, and aerobic exercise intensity, dose, and modality. We included 148 studies. Earlier exercise training initiation was associated with larger pre-post differences in mobility; studies initiated ≤3 months versus >3 months after stroke were associated with larger differences (weighted mean differences [95% confidence interval]) in 6-minute walk distance (36.3 meters; 95% CI, 14.2-58.5), comfortable 10-meter walk time (0.13 m/s; 95% CI, 0.06-0.19) and fast 10-meter walk time (0.16 m/s; 95% CI, 0.03-0.3), in fully adjusted models. Initiation ≤3 months versus >3 months was not associated with cardiorespiratory fitness but was associated with a higher but not clinically important Berg Balance Scale score difference (2.9 points; 95% CI, 0.41-5.5). In exercise training versus control studies, initiation ≤3 months was associated with a greater difference in only postintervention 6-minute walk distance (baseline-adjusted 27.3 meters; 95% CI, 6.1-48.5; fully adjusted, 24.9 meters; 95% CI, 0.82-49.1; a similar association was seen for ≤6 months versus >6 months after stroke (fully adjusted, 26.6 meters; 95% CI, 2.6-50.6). Conclusions There may be a clinically meaningful benefit to mobility outcomes when exercise is initiated within 3 months and up to 6 months after stroke.