Molecular Bioelectronics for Neural Interfacing and Repair Mario I. Romero-Ortega Bioengineering, University of Texas in Arlington and U.T. Southwestern.

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<ul><li> Slide 1 </li> <li> 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 </li> <li> Slide 2 </li> <li> 2 Peripheral Nerve Injury Neurapaxia Axonotmesis Neurotmesis Amputation Aba and Cavalli, 2008 </li> <li> Slide 3 </li> <li> 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 GROWNO-GROW. Foto: Otto Bock/Michael Appelt DIRECTED GROWTH Peripheral Neural Interfaces -Control growth to MEAs -Modality specificity -Avoid pain or aesthesias -Prevent neuromas </li> <li> Slide 4 </li> <li> 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 </li> <li> Slide 5 </li> <li> 5 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 </li> <li> Slide 6 </li> <li> Biomimetic Nerve Implant: BNI Biodegradable conduit Agarose Collagen + Agarose Collagen + growth factors </li> <li> Slide 7 </li> <li> 7 Tansey et al., 2011 BNI Short Nerve Gap Repair (10 mm) Tansey et al., 2011 </li> <li> Slide 8 </li> <li> 8 BNI: EM Morphometry and Behavioral Recovery Tansey et al., 2011 </li> <li> Slide 9 </li> <li> Long Gap Nerve Repair ( &gt;30 mm) Luminar saline Luminar ECM Muliluminal ECM Multiluminar ECM with growth facors Complexity/Efficacy </li> <li> Slide 10 </li> <li> CTR GDNF BSAGDNF_MP PLGA Microparticle Growth Factor Release </li> <li> Slide 11 </li> <li> Synergetic effects of pleiotrophic and neurotrophic factors on axonal growth in vitro. Control Combination A Combination B </li> <li> Slide 12 </li> <li> 12 Romero 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 </li> <li> Slide 13 </li> <li> Normal side Injured side: No regeneration Normal side Injured side: Regeneration 4 weeks6 weeks GF-MP BNI: 30 mm Motor Recovery Romero et al., In preparation </li> <li> Slide 14 </li> <li> 14 Romero et al., Unpublished Biodegradable conduit Agarose Collagen + Agarose Collagen Growth Factor MP GF-MP BNI: 30 mm Rabbit Peroneal Nerve Alsmadi et al., submitted </li> <li> Slide 15 </li> <li> A) Deployment of GF Coiled Microfibers in Microchannels Alsmadi et al., Submitted </li> <li> Slide 16 </li> <li> A) Deployment of GF Coiled Microfibers in Microchannels Alsmadi et al., Submitted Cheng-Jen Choung </li> <li> Slide 17 </li> <li> A) Deployment of GF Coiled Microfibers in Microchannels Alsmadi et al., Submitted </li> <li> Slide 18 </li> <li> A) Bidirectional Molecular Guidance Alsmadi et al., Submitted </li> <li> Slide 19 </li> <li> 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 </li> <li> Slide 20 </li> <li> Neural Control of Robotic Prosthesis Kuiken et al., 2007 http://armdynamics.com/pages/tmr </li> <li> Slide 21 </li> <li> Cortical Neuro-Electrode Interfaces BMI- 3D Neural Control of Robotic Prosthesis Collinger, Andrew Schwartz, Univ Pittsburgh 2013 </li> <li> Slide 22 </li> <li> 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 (V) signals. Accurate and efficient stimulation of specific neuron subtypes Luke Skywalker's Bionic Arm, "The Empire Strikes Back (1980) </li> <li> Slide 23 </li> <li> TMR(Targeted Muscle Reinnervation)-Prothese. Foto: Otto Bock/Michael Appelt SynTouch BioTac G. Loeb, USC Kinea Tactor: Johns Hopkins APL Advanced Limb Prosthetics: Sensory Feedback </li> <li> Slide 24 </li> <li> Selective Function and Neural Encoding Motor Axon 20 distinct sensory modalities </li> <li> Slide 25 </li> <li> Flat Electrode D. Durand, D. Tyler; CWRU TIME Electrode S 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 </li> <li> Slide 26 </li> <li> 15 d 30 d 60 d Regenerative Multielectrode Interface: REMI Garde et al., 2009 </li> <li> Slide 27 </li> <li> Recording/Stimulation Free-Moving Animals Garde et al., 2009 </li> <li> Slide 28 </li> <li> 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. </li> <li> Slide 29 </li> <li> 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 sec 148 V </li> <li> Slide 30 </li> <li> 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 sec 184 V 1400 sec 828 V 1400 sec 296 V </li> <li> Slide 31 </li> <li> Sensory Specific Evoked Neural Activity Perievent Histogram bin = 500ms Frequency (spikes/sec) Channel A Channel B 0- 55 C Frequency (spikes/sec) Channel A Channel B 0-50 gr </li> <li> Slide 32 </li> <li> 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 Sensory Modalities ChAT Badia et al. 2009 </li> <li> Slide 33 </li> <li> Axon Composition in PNS </li> <li> Slide 34 </li> <li> Targeting Sensory Type Regeneration In Vivo </li> <li> Slide 35 </li> <li> Directed Axonal Growth by NGF and NT-3 Unmyelinated Fibers Myelinated Fibers </li> <li> Slide 36 </li> <li> Both DRGs and ventral motor neurons grow towards A/B targets Surrogate Targets Muscle Skin Nerve Single Growth Factors Multiple Growth Factors BDNF/GDNF NT-3 PTN BSA NGF NT-3 BDNF/GDNF NT-3/NGF BDNF/GDNF PTN/NGF/NT-3 PTN/NGF BSA PTN Anand et al., In Preparation </li> <li> Slide 37 </li> <li> Painful Neuromas Occur in up to 80% of limb amputations A) Sehirlioglu et al., 2009 Healthy Nerve Neuroma Granja et al., In Preparation </li> <li> Slide 38 </li> <li> BNI- Nerve Block: Discouraging Nerve Growth A) BNI BNI-NB Granja et al., In Preparation </li> <li> Slide 39 </li> <li> A) BNI-NB BNI BNI- Nerve Block: Discouraging Nerve Growth Granja et al., In Preparation </li> <li> Slide 40 </li> <li> A) Healthy Nerve Guided Inhibition r=.175mm X3channels A= 0.29 sq.mm r= 4.5 mm A= 25.4 sq.mm Healthy Nerve Uncontrolled Regeneration Hollow tube r= 4.5 mm A= 25.4 sq.mm r= 9 mm A= 254 sq.mm Simple Tubularization vs BNI-Nerve Block Granja et al., In Preparation </li> <li> Slide 41 </li> <li> BNI-NB Prevents Mechanoceptive Pain A) Granja et al., In Preparation </li> <li> Slide 42 </li> <li> 42 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 </li> <li> Slide 43 </li> <li> 43 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 </li> <li> Slide 44 </li> <li> 44 Soft, Conformal Electrodes for Small Nerves and Inoperable Plexi Walter Voit </li> <li> Slide 45 </li> <li> 45 UTARI Michrochannel Multielectrode Array Muthu WijesundaraYoung-tae Kim </li> <li> Slide 46 </li> <li> 46 UTARI MMEA: Fabrication </li> <li> Slide 47 </li> <li> 47 UTARI MMEA: Recording/Stimulation </li> <li> Slide 48 </li> <li> Acknowledgments UTA Students Sanjay Anand Nesreen Alsmadi Benjamin Johnston Vidhi Desai Rafael Granja, MD Aswini Kanneganti Parisa Lotfi Lokesh Patil Srikanth Vasudevan UTA/UTSW faculty Young-tae Kim Jonathan Cheng Cheng-Jen Chuong Jennifer Seifert Plexon Inc. Edward Keefer Harvey Wiggins Grant Sources: NIH NINDS Scottish Rite Hospital for Children Texas Higher Education Coordinating Board Crowley-Carter Foundation Texas Star Plus Fund Tissue Gen Corporation Defense 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 Australia Gordon Wallace UTARI Muthu Wijesundar Caleb Nothnagle Eileen Clements Ret. Gral. Rick Lynch </li> </ul>

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