molecular bioelectronics for neural interfacing and repair mario i. romero-ortega bioengineering,...
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Molecular Bioelectronics for Neural Interfacing and Repair
Mario I. Romero-Ortega
Bioengineering, University of Texas in Arlington and U.T. Southwestern Medical Center
UTARI March 20, 2014
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Peripheral Nerve Injury
Neurapaxia Axonotmesis Neurotmesis
Amputation
Aba and Cavalli, 2008
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The Grow/No Grow Dilemma in PNI
Transection Nerve Injury:- Paralysis- Anesthesia- Allodynia- Can be permanent
Neuroma- Excruciating pain- Responsive to thermal,
barometric, and other stimuli.
- Can lead to phantom limb perception
GROW NO-GROW
. Fot
o: O
tto
Boc
k/M
icha
el A
ppel
t
DIRECTED GROWTH
Peripheral Neural Interfaces- Control growth to MEAs- Modality specificity- Avoid pain or aesthesias- Prevent neuromas
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Peripheral Nerve Gap Injury
• Autografts remains the gold standard for bridging gap defects
• Limitations:– Available quantity of donor nerve– Scarring– Painful neuroma at donor site
– Graft thickness limited by revascularization
– Only 10% of axons after a nerve transection and ‘‘best’’ surgical apposition reach target organs (Witzel et al., 2005).
Peripheral nerve injuries that induce gaps larger than 2 cm require bridging strategies for repair
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FDA Approved Biosynthetic Nerve Conduits
Schlosshauer et al., 2006.
NeuraGen. Integra Neuroscience (collagen).
Neurolac.
(PL-caprolactone)
Neurotube.Synovis Micro (polyglocolide)
• Limited to the repair of short digital sensory nerve gaps (≤3cm) in humans.
• No luminar fillers or growth factors
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Biomimetic Nerve Implant: BNI
Biodegradable conduit
Agarose
Collagen +
Agarose
Collagen + growth factors
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7Tansey et al., 2011
BNI Short Nerve Gap Repair (10 mm)
Tansey et al., 2011
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BNI: EM Morphometry and Behavioral Recovery
Tansey et al., 2011Tansey et al., 2011
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Long Gap Nerve Repair ( >30 mm)
Luminar saline Luminar ECM Muliluminal ECM Multiluminar ECM with growth facors
Complexity/Efficacy
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CTR
GDNF
BSA GDNF_MP
PLGA Microparticle Growth Factor Release
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Synergetic effects of pleiotrophic and neurotrophic factors on axonal growth in vitro.
Control
Combination A
Combination B
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12Romero et al., Unpublished
Biodegradable conduit
Agarose
Collagen +
Agarose
Collagen
Growth Factor MP
Combination A
Control
GF-MP BNI: 30 mm Rabbit Peroneal Nerve
Romero et al., In preparation
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Normalside
Injured side: No regeneration
Normalside
Injured side: Regeneration
4 weeks 6 weeks
GF-MP BNI: 30 mm Motor Recovery
Romero et al., In preparation
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14Romero et al., Unpublished
Biodegradable conduit
Agarose
Collagen +
Agarose
Collagen
Growth Factor MP
GF-MP BNI: 30 mm Rabbit Peroneal Nerve
Alsmadi et al., submitted
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Deployment of GF Coiled Microfibers in Microchannels
Alsmadi et al., Submitted
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Deployment of GF Coiled Microfibers in Microchannels
Alsmadi et al., Submitted
Cheng-Jen Choung
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Deployment of GF Coiled Microfibers in Microchannels
Alsmadi et al., Submitted
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Bidirectional Molecular Guidance
Alsmadi et al., Submitted
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More than 1.6 million Americans are amputees, and 185,000 more are expected to loss their limbs each year.
Ziegler-Graham et al., 2008
Modular Prosthetic Limb: JHAPL
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Neural Control of Robotic Prosthesis
Kuiken et al., 2007
http://armdynamics.com/pages/tmr
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Cortical Neuro-Electrode Interfaces
BMI- 3D Neural Control of Robotic ProsthesisCollinger, Andrew Schwartz, Univ Pittsburgh 2013
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Current Challenges in PNS Neurointerfacing
- Tissue damage/Inflammation– limited functionality (weeks to months)
due to continued signal deterioration
- Current injection– Tissue damage due to metal dissolution
or water electrolysis.
- Motor decoding/Sensory encoding capability. – Sensitive neural recording from low
voltage (µV) signals.
– Accurate and efficient stimulation of specific neuron subtypes Luke Skywalker's Bionic Arm, "The Empire
Strikes Back (1980)
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TMR(Targeted Muscle Reinnervation)-Prothese. Foto: Otto Bock/Michael Appelt
SynTouch BioTacG. Loeb, USC
Kinea Tactor: Johns Hopkins APL
Advanced Limb Prosthetics: Sensory Feedback
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Selective Function and Neural Encoding
Motor Axon
20 distinct sensory modalities
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Flat ElectrodeD. Durand, D. Tyler; CWRU
TIME ElectrodeS Micera; EPFL
Four weeks recording and efficacy of sensory stimulation decayed after 10 days” Rossini et al., 2010
Pierpaolo Petruzziello, 2010
K. Horch, 2004
K. Warnick, 2004
Motor Decoding/Sensory encoding
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15 d 30 d 60 d
Regenerative Multielectrode Interface: REMI
Garde et al., 2009
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Recording/Stimulation Free-Moving Animals
Garde et al., 2009
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Kinematic Analysis during Bipedal Locomotion
Gait
Cineplex
Rats are also video tracked using Cineplex software (Plexon Inc.) to track angle between the joints.
Rats are trained on a robot treadmill (Robomedica, Inc.) for gait analysis to monitor recovery after peripheral nerve injury.
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Firing Pattern of Single Unit Spikes recorded from Tibial Nerve
• Robot assisted standing on hind limbs – No Rhythmic Walking
Single Unit on Ch 2
45 Days Post Implant
Tonic Unit seen only on Ch 2, while Ch1 and 3 did not have Single Unit activity
Ch 1
Ch 2
Ch 3
Ch 2
Raster Plot
50 sec interval
1400 μsec
148 μV
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Tonic to Bursting during Walking
• Robot assisted Bipedal Locomotion – Rhythmic Walking
Bursting Units elicited while walking as seen on Ch1, 2, 3
Channel 1 Channel 2 Channel 3
Ch 1
Ch 2
Ch 3
50 sec interval
1400 μsec
184 μV
1400 μsec
828 μV
1400 μsec
296 μV
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Sensory Specific Evoked Neural Activity
Perievent Histogram bin = 500ms
Freq
uenc
y (s
pike
s/se
c)
Ch
ann
el
AC
han
ne
l B
0- 55 CFr
eque
ncy
(spi
kes/
sec)
Ch
ann
el
AC
han
ne
l B
0-50 gr
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REMI: Mix Modality Interfacing
The rat sciatic nerve consist of 3 fascicles containing about 8,100 motor axons and 17,000 unmylinated axons (Castro et al., 2008)
Motor and SensoryModalities
ChAT
Badia et al. 2009
Badia et al. 2009
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Axon Composition in PNS
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Targeting Sensory Type Regeneration In Vivo
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Directed Axonal Growth by NGF and NT-3
Unmyelinated Fibers
Myelinated Fibers
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Both DRGs and ventral motor neurons grow towards A/B targets
Surrogate Targets
Muscle
Skin
Nerve
Nerve
Single Growth Factors
Multiple Growth Factors
BDNF/GDNFNT-3
PTN
BSA
BSA
BSA
NGF
NT-3
BDNF/GDNF
BDNF/GDNF
NT-3/NGF
BDNF/GDNF
BDNF/GDNF
BDNF/GDNF
PTN/NGF/NT-3
PTN/NGF
BSA
PTN
Anand et al., In Preparation
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Painful Neuromas Occur in up to 80% of limb amputations
Sehirlioglu et al., 2009Healthy Nerve Neuroma
Granja et al., In Preparation
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BNI- Nerve Block: Discouraging Nerve Growth
BNI
BNI-NB
Granja et al., In Preparation
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BNI-NBBNI
BNI- Nerve Block: Discouraging Nerve Growth
Granja et al., In Preparation
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Healthy Nerve
Guided Inhibition
r= .175mmX3channelsA= 0.29 sq.mm
r= 4.5 mmA= 25.4 sq.mm
Healthy Nerve
Uncontrolled Regeneration
Hollow tube
r= 4.5 mmA= 25.4 sq.mm
r= 9 mmA= 254 sq.mm
Simple Tubularization vs BNI-Nerve Block
Granja et al., In Preparation
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BNI-NB Prevents Mechanoceptive Pain
Granja et al., In Preparation
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Grow-No Grow Strategies
Increasing Gap Length • Contact guidance: Agarose microchannels filled with collagen
• Growth Factors: Linear GFR Promote neuronal and functional recovery in 3 cm gaps
• Longer Gaps might be repair with GF-Gradient Multi-luminal implants.
Growth: Long Gap Repair
No Growth: Neuroma
• Amputated nerves: Differential growth of modality-specific axons
• Axon growth can be GF-directed separate Y-shaped compartments
Conditional Growth: Interfaces
• Surgical placement: Bone, Muscle
• Capped Tubularization: Silicon tubes, epineurium cap.
• BNI-NB can be used to prevent neuroma
Interfacing Amputated Nerves
Block Growth
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Bioelectronic Medicines
Nano-scale devices connect to groups of individual nerve fibres and change patterns of electrical signals to restore health to organs and biological functions
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Soft, Conformal Electrodes for Small Nerves and Inoperable Plexi
Walter Voit
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UTARI Michrochannel Multielectrode Array
Muthu Wijesundara Young-tae Kim
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UTARI MMEA: Fabrication
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UTARI MMEA: Recording/Stimulation
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AcknowledgmentsUTA Students
Sanjay Anand
Nesreen Alsmadi
Benjamin Johnston
Vidhi Desai
Rafael Granja, MD
Aswini Kanneganti
Parisa Lotfi
Lokesh Patil
Srikanth Vasudevan
UTA/UTSW facultyYoung-tae KimJonathan ChengCheng-Jen ChuongJennifer Seifert
Plexon Inc.Edward KeeferHarvey Wiggins
Grant Sources:NIH NINDS Scottish Rite Hospital for ChildrenTexas Higher Education Coordinating BoardCrowley-Carter FoundationTexas Star Plus FundTissue Gen CorporationDefense Advanced Research Projects Agency (DARPA)
Microsystems Technology Office (MTO), Naval Warfare Systems Command (SPAWAR) Systems Center (SSC) Pacific grants No. N66001-11-1-4408 and No. N66001-11-C-4168.
UoW AustraliaGordon Wallace
UTARIMuthu WijesundarCaleb NothnagleEileen ClementsRet. Gral. Rick Lynch