PMID- 29891731
OWN - NLM
STAT- MEDLINE
DCOM- 20191028
LR  - 20191028
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 38
IP  - 26
DP  - 2018 Jun 27
TI  - Local BDNF Delivery to the Injured Cervical Spinal Cord using an Engineered 
      Hydrogel Enhances Diaphragmatic Respiratory Function.
PG  - 5982-5995
LID - 10.1523/JNEUROSCI.3084-17.2018 [doi]
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/C5 contusion-type spinal cord 
      injury (SCI) in female rats robustly preserved diaphragm function, as assessed by 
      in vivo 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.SIGNIFICANCE 
      STATEMENT 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.
CI  - Copyright (c) 2018 the authors 0270-6474/18/385983-14$15.00/0.
FAU - Ghosh, Biswarup
AU  - Ghosh B
AUID- ORCID: 0000-0001-9192-5081
AD  - Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, 
      Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, 
      Pennsylvania 19107.
FAU - Wang, Zhicheng
AU  - Wang Z
AD  - School of Biomedical Engineering, Science and Health Systems, Drexel University, 
      Philadelphia, Pennsylvania 19104, and.
FAU - Nong, Jia
AU  - Nong J
AD  - School of Biomedical Engineering, Science and Health Systems, Drexel University, 
      Philadelphia, Pennsylvania 19104, and.
FAU - Urban, Mark W
AU  - Urban MW
AD  - Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, 
      Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, 
      Pennsylvania 19107.
FAU - Zhang, Zhiling
AU  - Zhang Z
AD  - School of Biomedical Engineering, Science and Health Systems, Drexel University, 
      Philadelphia, Pennsylvania 19104, and.
FAU - Trovillion, Victoria A
AU  - Trovillion VA
AD  - Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, 
      Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, 
      Pennsylvania 19107.
FAU - Wright, Megan C
AU  - Wright MC
AD  - Department of Biology, Arcadia University, Glenside, Pennsylvania 19038.
FAU - Zhong, Yinghui
AU  - Zhong Y
AUID- ORCID: 0000-0002-1363-9466
AD  - School of Biomedical Engineering, Science and Health Systems, Drexel University, 
      Philadelphia, Pennsylvania 19104, and angelo.lepore@jefferson.edu 
      yz348@drexel.edu.
FAU - Lepore, Angelo C
AU  - Lepore AC
AD  - Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, 
      Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, 
      Pennsylvania 19107, angelo.lepore@jefferson.edu yz348@drexel.edu.
LA  - eng
GR  - R01 NS079702/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180611
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Hydrogels)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*administration & dosage
MH  - Cervical Cord/*drug effects
MH  - Diaphragm/drug effects
MH  - Drug Delivery Systems/*methods
MH  - Female
MH  - Hydrogels
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Recovery of Function/*drug effects
MH  - Respiration/*drug effects
MH  - *Spinal Cord Injuries
PMC - PMC6021996
OTO - NOTNLM
OT  - biomaterial
OT  - contusion
OT  - diaphragm
OT  - phrenic motor neuron
OT  - respiratory
OT  - spinal cord injury
EDAT- 2018/06/13 06:00
MHDA- 2019/10/29 06:00
PMCR- 2018/12/27
CRDT- 2018/06/13 06:00
PHST- 2017/10/24 00:00 [received]
PHST- 2018/05/16 00:00 [revised]
PHST- 2018/05/17 00:00 [accepted]
PHST- 2018/06/13 06:00 [pubmed]
PHST- 2019/10/29 06:00 [medline]
PHST- 2018/06/13 06:00 [entrez]
PHST- 2018/12/27 00:00 [pmc-release]
AID - JNEUROSCI.3084-17.2018 [pii]
AID - 3084-17 [pii]
AID - 10.1523/JNEUROSCI.3084-17.2018 [doi]
PST - ppublish
SO  - J Neurosci. 2018 Jun 27;38(26):5982-5995. doi: 10.1523/JNEUROSCI.3084-17.2018. 
      Epub 2018 Jun 11.