RT Journal Article
SR Electronic
T1 Local BDNF delivery to the injured cervical spinal cord using an engineered hydrogel enhances diaphragmatic respiratory function
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3084-17
DO 10.1523/JNEUROSCI.3084-17.2018
A1 Biswarup Ghosh
A1 Zhicheng Wang
A1 Jia Nong
A1 Mark W. Urban
A1 Zhiling Zhang
A1 Victoria A. Trovillion
A1 Megan C. Wright
A1 Yinghui Zhong
A1 Angelo C. Lepore
YR 2018
UL http://www.jneurosci.org/content/early/2018/06/11/JNEUROSCI.3084-17.2018.abstract
AB 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 C4/5 contusion-type spinal cord injury (SCI) in female rats robustly preserved diaphragm function, as assessed by in vivo recordings of compound muscle action potential (CMAP) and electromyography (EMG) 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 (NMJ) morphological analysis and retrograde PhMN labeling from diaphragm using cholera toxin B (CTB). 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.SIGNIFICANCE STATEMENTRespiratory compromise is a leading cause of morbidity and mortality following traumatic SCI. We utilized 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 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 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.