Publications

Peripheral nerve injuries, including motor neuron axonal injury, often lead to functional impairments. Current therapies are mostly limited to surgical intervention after lesion, yet these interventions have limited success in restoring functionality. Current activity-based therapies after axonal injuries are based on trial-error approaches in which the details of the underlying cellular and molecular processes are largely unknown. Here we show the effects of the modulation of both neuronal and muscular activity with optogenetic approaches to assess the regenerative capacity of cultured motor neuron (MN) after lesion in a compartmentalized microfluidic-assisted axotomy device. With increased neuronal activity, we observed an increase in the ratio of regrowing axons after injury in our peripheral-injury model. Moreover, increasing muscular activity induces the liberation of leukemia inhibitory factor and glial cell line-derived neurotrophic factor in a paracrine fashion that in turn triggers axonal regrowth of lesioned MN in our 3D hydrogel cultures. The relevance of our findings as well as the novel approaches used in this study could be useful not only after axotomy events but also in diseases affecting MN survival.

JTD Keywords: Neuromuscular junction, Microfluidics, Axotomy, Paracrine signaling

Movement of skeletal-muscle fibers is generated by the coordinated action of several cells taking part within the locomotion circuit (motoneurons, sensory-neurons, Schwann cells, astrocytes, microglia, and muscle-cells). Failures in any part of this circuit could impede or hinder coordinated muscle movement and cause a neuromuscular disease (NMD) or determine its severity. Studying fragments of the circuit cannot provide a comprehensive and complete view of the pathological process. We trace the historic developments of studies focused on in-vitro modeling of the spinal-locomotion circuit and how bioengineered innovative technologies show advantages for an accurate mimicking of physiological conditions of spinal-locomotion circuit. New developments on compartmentalized microfluidic culture systems (cμFCS), the use of human induced pluripotent stem cells (hiPSCs) and 3D cell-cultures are analyzed. We finally address limitations of current study models and three main challenges on neuromuscular studies: (i) mimic the whole spinal-locomotion circuit including all cell-types involved and the evaluation of independent and interdependent roles of each one; (ii) mimic the neurodegenerative response of mature neurons in-vitro as it occurs in-vivo; and (iii) develop, tune, implement, and combine cμFCS, hiPSC, and 3D-culture technologies to ultimately create patient-specific complete, translational, and reliable NMD in-vitro model. Overcoming these challenges would significantly facilitate understanding the events taking place in NMDs and accelerate the process of finding new therapies.

JTD Keywords: 3D-culture, Compartmentalized microfluidic culture systems (cμFCS), HiPSC, In-vitro models, Neuromuscular circuit

The poor rehabilitation success rate, including the cases of ineffective and detrimental adaptations, make stroke a leading cause of disability. Thus, it is essential to recognize the mechanisms driving healthy motor recovery to improve such rate. Stroke alters the Synergy Architecture (SA), the modular muscle control system. So SA analysis may constitute a powerful tool to design and assess rehabilitation procedures. However, current impairment scales do not consider the patient's neuromuscular state. To gain insights into this hypothesis, we recorded multiple myoelectric signals from upper-limb muscles, in healthy subjects, while executing a set of common rehabilitation exercises. We found that SA reveals optimized motor control strategies and the positive effects of the use of visual feedback (VF) on motor control. Furthermore we demonstrate that the right and left arm's SA share the basic structure within the same subject, so we propose using the unaffected limb's SA as a reference motion pattern to be reached through rehabilitation.

JTD Keywords: Bars, Electromyography, Motor drives, Neuromuscular, Vectors, Visualization