Gutierrez Gonzalez, J. | Search bioRxiv

bioRxiv2024

3D-printed, biomimetic, conductive MXene-microfiber composite scaffolds enhance the axonal growth-promoting characteristics of electrical stimulation.

No effective treatments are currently available for central nervous system neurotrauma although recent advances in electrical stimulation suggest some promise in neural tissue repair. We hypothesized that structured integration of an electroconductive biomaterial into a tissue engineering scaffold could enhance electroactive signalling for neural regeneration. Electroconductive 2D Ti3C2Tx MXene nanosheets were synthesized from MAX-phase powder, demonstrating excellent biocompatibility with neurons, astrocytes and microglia. To achieve spatially-controlled distribution of these MXenes, melt-electrowriting was used to 3D-print highly-organized PCL micro-meshes with varying fibre spacings (low-, medium-and high-density), which were functionalized with MXenes to provide highly-tunable electroconductive properties (0.081{+/-}0.053-18.87{+/-}2.94 S/m). Embedding these electroconductive micro-meshes within a neurotrophic, immunomodulatory hyaluronic acid-based extracellular matrix (ECM) produced a soft, growth-supportive MXene-ECM composite scaffold. Electrical stimulation of neurons seeded on these scaffolds promoted neurite outgrowth, influenced by fibre spacing in the micro-mesh. In a multicellular model of cell behaviour, neurospheres stimulated for 7 days on high-density MXene-ECM scaffolds exhibited significantly increased axonal extension and neuronal differentiation, compared to low-density scaffolds and MXene-free controls. The results demonstrate that spatial-organization of electroconductive materials in a neurotrophic scaffold can enhance repair-critical responses to electrical stimulation and that these biomimetic MXene-ECM scaffolds offer a promising new approach to neurotrauma repair.

bioengineering↗

bioRxiv2022

Spinal cord and brain concentrations of riluzole after oral and intrathecal administration: a potential new treatment route for amyotrophic lateral sclerosis

Riluzole is the only treatment known to improve survival in patients with Amyotrophic Lateral Sclerosis (ALS). However, oral riluzole efficacy is modest at best, further it is known to have large inter-individual variability of serum concentration and clearance, is formulated as an oral drug in a patient population plagued with dysphagia, and has known systemic side-effects like asthenia (limiting patient compliance) and elevated liver enzymes. In this context, we postulated that continuous intrathecal (IT) infusion of low doses of riluzole could provide consistent elevations of the drug spinal cord (SC) concentrations at or above those achieved with oral dosing, without increasing the risk for adverse events associated with systemic drug exposure or off-target side effects in the brain. We developed a formulation of riluzole for IT delivery and conducted our studies in purpose-bred hound dogs. Our non-GLP studies revealed that IT infusion alone was able to increase SC concentrations above those provided by oral administration, without increasing plasma concentrations. We then conducted two GLP studies that combined IT infusion with oral administration at human equivalent dose, to evaluate SC and brain concentrations of riluzole along with assessments of safety and tolerability. In the 6-week study, the highest IT dose (0.2 mg/hr) was well tolerated by the animals and increased SC concentrations above those achieved with oral riluzole alone, without increasing brain concentrations. In the 6-month study, the highest dose tested (0.4 mg/hr) was not tolerated and yielded SC significantly above those achieved in all previous studies. Our data show the feasibility and safety profile of continuous IT riluzole delivery to the spinal cord, without concurrent elevated liver enzymes, and minimal brain concentrations creating another potential therapeutic route of delivery to be used in isolation or in combination with other therapeutics."

neuroscience↗