Local BDNF Delivery to the Injured Cervical Spinal Cord using an Engineered Hydrogel Enhances Diaphragmatic Respiratory Function

Abstract

We developed an innovative biomaterial-based approach to repair the critical neural circuitry that controls diaphragm activation by locally delivering brain-derived neurotrophic factor (BDNF) to injured cervical spinal cord. BDNF can be used to restore respiratory function via a number of potential repair mechanisms; however, widespread BDNF biodistribution resulting from delivery methods such as systemic injection or lumbar puncture can lead to inefficient drug delivery and adverse side effects. As a viable alternative, we developed a novel hydrogel-based system loaded with polysaccharide-BDNF particles self-assembled by electrostatic interactions that can be safely implanted in the intrathecal space for achieving local BDNF delivery with controlled dosing and duration. Implantation of BDNF hydrogel after C4/C5 contusion-type spinal cord injury (SCI) in female rats robustly preserved diaphragm function, as assessed by recordings of compound muscle action potential and electromyography amplitudes. However, BDNF hydrogel did not decrease lesion size or degeneration of cervical motor neuron soma, suggesting that its therapeutic mechanism of action was not neuroprotection within spinal cord. Interestingly, BDNF hydrogel significantly preserved diaphragm innervation by phrenic motor neurons (PhMNs), as assessed by detailed neuromuscular junction morphological analysis and retrograde PhMN labeling from diaphragm using cholera toxin B. Furthermore, BDNF hydrogel enhanced the serotonergic axon innervation of PhMNs that plays an important role in modulating PhMN excitability. Our findings demonstrate that local BDNF hydrogel delivery is a robustly effective and safe strategy to restore diaphragm function after SCI. In addition, we demonstrate novel therapeutic mechanisms by which BDNF can repair respiratory neural circuitry. Respiratory compromise is a leading cause of morbidity and mortality following traumatic spinal cord injury (SCI). We used an innovative biomaterial-based drug delivery system in the form of a hydrogel that can be safely injected into the intrathecal space for achieving local delivery of brain-derived neurotrophic factor (BDNF) with controlled dosing and duration, while avoiding side effects associated with other delivery methods. In a clinically relevant rat model of cervical contusion-type SCI, BDNF hydrogel robustly and persistently improved diaphragmatic respiratory function by enhancing phrenic motor neuron (PhMN) innervation of the diaphragm neuromuscular junction and by increasing serotonergic innervation of PhMNs in ventral horn of the cervical spinal cord. These exciting findings demonstrate that local BDNF hydrogel delivery is a safe and robustly effective strategy to maintain respiratory function after cervical SCI.

Advances in Tissue Engineering and Innovative Fabrication Techniques for 3-D-Structures: Translational Applications in Neurodegenerative Diseases

“…Amongst the neuroprotective factors incorporated in hydrogels, promising results have been obtained with the delivery of neurotrophin-3 [ 263 , 264 , 265 ], nerve growth factor [ 266 ], BDNF [ 267 ], and neuregulin [ 268 ]. One of the most innovative research works in this field required a complex combinatorial system of growth factors and bio-scaffolds.…”

Neural Stimulation and Molecular Mechanisms of Plasticity and Regeneration: A Review

“…BDNF is widely implicated as a major driver of neuronal plasticity that directly contributes to learning. For example, TrkB signaling is required for spatial memory formation in mice (Lai et al, 2012 ), BDNF signaling contributes to the conversion of early to late phase long-term memory (Lu et al, 2008 ), BDNF signaling facilitates cocaine-seeking addictive behavior in mice (Im et al, 2010 ), and BDNF administration has even been implicated in functional recovery after stroke (Berretta et al, 2014 ) and SCI (Ghosh et al, 2018 ) in rodents.…”

Combination of a Gellan Gum-Based Hydrogel With Cell Therapy for the Treatment of Cervical Spinal Cord Injury

“…They showed that serotonergic and other descending axons could be traced throughout the scaffolds. Ghosh et al (2018) have recently demonstrated that local BDNF delivery using an FIGURE 5 | Staircase test for the right paw, performed at 2 and 5 weeks after injury. There are no significant differences among groups in none of the time points evaluated, for both the staircase test (upper graphs) and the forced choice task of the test (bottom graphs).…”