Page 36 - NNS 2014 Program & Abstract Book

inflammation in headache chronification with implications for the
management of post-concussion syndrome.
Key words
closed head injury, concussion, headache, post-concussion syndrome,
post-traumatic headache
T1-06
ADVANCED BIOMATERIAL STRATEGIES FOR MICRO-
TISSUE ENGINEERED NEURAL NETWORKS TO RESTORE
BRAIN CIRCUITS
Harris, J.P.1,2, Struzyna, L.A.1, Murphy, P.L.1, Cullen, D.K.1,2
1Center for Brain Injury and Repair, Dept of Neurosurgery, Uni-
versity of Pennsylvania, Philadelphia, PA, USA
2Philadelphia Veterans Administration Hospital, Philadelphia, PA,
USA
Disruption of the connectome is a prominent feature of many neu-
rological diseases and trauma. There is currently no strategy to repair
long-distance axonal connections in the brain; therefore, we have
developed micro-tissue engineering techniques to generate neurons
with long axonal tracts encased in miniature hydrogel tubes as a
strategy to restore long-distance axonal connections and neural
populations. We previously found that these preformed micro-tissue
engineered neural networks (TENNs) may be drawn into a needle
and stereotaxically delivered into the rodent brain to reconstruct lost
cortico-thalamic pathways, with evidence of transplant neuronal
survival, maintenance of axonal architected, and synaptic integration
into the cortex. Here, we have advanced the biomaterial encasement
strategy to allow for needle-less delivery of preformed micro-
TENNs to minimize insertion trauma. The micro-TENNs were
composed of a small hollow hydrogel shell ( £ 700 lm OD) with an
extracellular matrix interior (350 lm ID). These micro-TENNs
consisted of agarose coated with low viscosity carboxymethylcel-
lulose (CMC). Upon mild dehydration, coated micro-TENNs were
able to withstand a force of 0.89 + / - 0.45 N before buckling,
whereas a solid agarose cylinder of the same size only withstood a
force of less than 10 lN, thus the CMC coating increased the
stiffness by five orders of magnitude. The needle to insert control
(uncoated) micro-TENNs was almost 1/6 bigger than the needle-less
(coated) micro-TENN; therefore, we anticipate that the needle-less
method will minimize insertion damage due to a reduced form
factor. We are currently evaluating host responses and micro-TENN
neuronal survival and integration using needle versus needle-less
delivery. Our novel micro-TENNs are the first strategy capable of
facilitating nervous system repair by simultaneously providing
neuronal replacement and re-creating long-distance axon pathways
in the brain. The micro-TENN approach offers a new ability to treat
several disorders that disrupt the connectome, including Parkinson’s
disease, TBI, stroke, Gulf War Illness, and brain tumor excision.
Key words
axonal tracts, biomaterials, cell replacement, tissue engineering
T1-07
INCREASED CSF NLRP3 BUT NOT NLRP1 AFTER SEVERE
TRAUMATIC BRAIN INJURY IN CHILDREN
Simon, D.W.1,2, Wallisch, J.1, Bell, M.J.1,2, Bayir, H.1–3, Aneja,
R.K.1,2, Janesko-Feldman, K.2, Kochanek, P.M.1,2, Clark, R.S.1,2
1Departments of Critical Care and Pediatrics Children’s Hospital of
Pittsburgh of UPMC, Pittsburgh, USA
2Safar Center for Resuscitation Research, Pittsburgh, USA
3Center for Free Radical and Antioxidant Health, Pittsburgh, USA
The NOD-like receptor, pyrin domain containing (NLRP) 1 and 3
inflammasomes are implicated in inflammation and secondary injury
following traumatic brain injury (TBI). NLRPs recruit pro-caspase-1
and pro-interleukin-1b into the inflammasome, resulting in activation
of caspase-1 and formation of interleukin-1b, both shown to be in-
creased in cerebrospinal fluid (CSF) of children following severe TBI.
NLRP1 is classically recognized for activation by Bacillus anthracis
toxin, whereas in addition to microbial pathogens, NLRP3 is activated
by oxidative stress and b-amyloid. We sought to determine whether
one or both of the inflammasome proteins NLRP1 and NLRP3 were
detectable in CSF of pediatric patients following severe TBI. CSF was
obtained from children (n = 18) treated with CSF diversion via an
external ventricular drain after severe TBI in this IRB approved study.
Lumbar CSF from children without TBI or meningitis served as
controls (n = 8). CSF levels of NLRP1 and NLRP3 were determined at
four time intervals (0–24 h, 45–48 h, 49–72 h, and > 72 h after injury)
using enzyme-linked immunosorbent assay. CSF NLRP1 levels were
below level of detection (< 18.75pg/mL) in control subjects and were
detected in only 2/18 TBI patients and only at a single time point
(< 24 h). In contrast, CSF NLRP3 levels were increased vs. controls
across points (control = 0.36 – 0.04, 0–24 h = 14.13 – 2.90, 25–48 h =
4.08 – 1.01, 49–72 h = 5.80 – 1.67, > 72 h = 8.48 – 1.92 ng/mL; mean –
SEM; p < 0.001). However, CSF NLRP3 levels did not correlate with
age, sex, mechanism of injury, or outcome by univariate analysis. In
conclusion, NLRP3, but not NLRP1, was increased in CSF of pedi-
atric patients following severe TBI. To our knowledge, this represents
the first study evaluating specific NLRPs after pediatric TBI and
suggests prominent NLRP3 inflammasome formation, perhaps trig-
gered by oxidative stress and/or b-amyloid, after TBI. Support:
T32HD40686
Key words
inflammasome, NLRP3, traumatic brain injury
T1-08
THE POST TRAUMATIC BRAIN INJURY INFLAMMASOME
AND RESPONSE TO AUTOLOGOUS CELL THERAPY
Liao, G.P., Hetz, R.A., Jimenez, F., Chang, J.T., Moore, A.N.,
Kosmach, S.C., Day, M., Lee, D.A., Worth, L.L., Savitz, S.I., Dash, P.,
Cox, C.S.
University of Texas Medical School at Houston, Department of
Pediatric Surgery, Houston, USA
Traumatic brain injury (TBI) elicits a complex neurologic and sys-
temic inflammatory response. Cell therapy may have potential ad-
vantages over single agents as cellular bioreactors sense and respond
to numerous environmental signals. However, interpreting the in-
flammasome response using biomarker data in clinical trials is chal-
lenging. This study evaluates the ability of bioinformatic techniques to
evaluate cell therapy effects to relevant biomarkers during neu-
rointensive care.
Interval plasma samples from 24–96 hours post TBI were obtained
from three groups (TBI alone (n = 3), TBI + 6 million cells/kg (n = 4),
TBI + 9 million cells/kg (n = 5)) in the prospective Phase II Adult
Bone Marrow Derived Mononuclear Cell Therapy for TBI clinical
trial. The cell therapy groups were treated intravenously within 48
hours of injury. A multiplex magnetic bead-based assay was used to
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