Techniques for Multiscale Neuronal Regulation via Therapeutic Materials and Drug Design

Abstract

Neurotrauma is a common source for a host of neurological disorders, including chronic pain. Pathological changes underlying neural injury and pain are complex due to the multiscale spatiotemporal nature of the nervous system and its response to insults. Understanding the combined influence of tissue mechanics, neuronal and glial activation, and molecular processes on the development and maintenance of pain has recently gained attention. The growing knowledge about nociceptive mechanisms has inspired the design of novel therapeutic materials and compounds for neuronal regulation. Primary mechanical insults and secondary inflammatory responses can induce morphological changes, electrophysiological abnormalities, and altered neurotransmitter release associated with neuronal dysfunction, degeneration, and/or death in both central and peripheral nervous systems. Such responses in afferent and spinal dorsal horn neurons directly and indirectly potentiate pain. Using separate radiculopathy and joint pain models, the mechanical, nociceptive, and inflammatory aspects of pain are reviewed. In that context, biomaterials and compounds with material advantages, neuroprotective benefits, or anti-inflammatory effects to mitigate pain are identified. Several promising techniques to promote neuronal survival and axonal regeneration after injury, including bioactive scaffolds, blocking growthinhibitory molecules, and active drug delivery, are highlighted. Similar biomaterials-based strategies and molecular intervention have shown promise in attenuating various types of pain. Advancing these and other approaches will help advance and deepen the mechanistic understanding underlying trauma-induced pain across different length scales.

Pre-treatment with Meloxicam Prevents the Spinal Inflammation and Oxidative Stress in DRG Neurons that Accompany Painful Cervical Radiculopathy

“…5) after selective COX-2 inhibition by meloxicam(Furst, 1997; Hawkey, 1999; Kimura and Kontani, 2009) may be due to a reduction in peripheral inflammation. In fact, decreased sPLA2 production and macrophage infiltration in the DRG has been found with this same meloxicam pre-treatment paradigm, along with prevention of the upregulation of spinal sPLA2 and activation of spinal glial cells that is typically observed after painful nerve root injury (Zhang et al, 2017). Together, these findings suggest that downregulation of sPLA2 in the spinal cord and DRG may contribute to the analgesic effects of meloxicam; further, the spinal changes may be due to regulation of neuroinflammation in the periphery.…”

“…5 & 6), providing further evidence that peripheral oxidative stress, specifically oxidative DNA and RNA damage in neurons, is associated with nerve root compression as with neuropathic pain (Dirig et al, 1998; Takeda et al, 2005; Gmitterová et al, 2018). Interestingy, in addition to macrophage infiltration, painful compresson of the nerve root also induces production of sPLA2 by DRG neurons (Zhang et al, 2017). Because the use of metabolites (i.e.…”

Integrated Multiscale Biomaterials Experiment and Modeling

“…However, Zhang et al are pioneering methods for identifying pathways to neuronal regulation through careful multiscale analysis, an approach that has much potential. 34 The study of how cells interact with their environment is deeply connected to the development of hierarchical scaffolds and of textured, structures, and tailored substrata. A contribution from Nasrollahi et al highlights this, showing how the nanoscale matrix topography of a substratum affects cell motility, a strong function of adhesion disposition, actin organization, and cell shape.…”

“…This field has proceeded almost entirely by experiment on living systems and numerical experiments simulating protein docking. However, Zhang et al are pioneering methods for identifying pathways to neuronal regulation through careful multiscale analysis, an approach that has much potential …”

A Nociceptive Role for Integrin Signaling in Pain After Mechanical Injury to the Spinal Facet Capsular Ligament

“…19,29 For instance, blocking the 2 1 integrin expressed on peripheral nerve endings has been shown to reduce the reactivity of cutaneous mechanoreceptors to skin stretch. 29,30 Further, recent data suggests that integrin subunit 1-mediated cell-ECM adhesion affects neuronal processing of noxious stretch (nociception) 66 (Figure 1). Since integrins can be mechanically and chemically coupled to the ECM and the cell cytoskeleton, 10,20 they may be important for the translation of tissue deformation to neuronal loading and intracellular signaling in the facet capsule.…”