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Molecular Bioelectronics for Neural Interfacing and Repair Mario I. Romero-Ortega

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. Peripheral Nerve Injury. Axonotmesis. Neurotmesis. Neurapaxia. Amputation.

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Molecular Bioelectronics for Neural Interfacing and Repair Mario I. Romero-Ortega

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  1. 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

  2. Peripheral Nerve Injury Axonotmesis Neurotmesis Neurapaxia Amputation Aba and Cavalli, 2008

  3. The Grow/No Grow Dilemma in PNI GROW NO-GROW DIRECTED GROWTH . Foto: Otto Bock/Michael Appelt • Neuroma • Excruciating pain • Responsive to thermal, barometric, and other stimuli. • Can lead to phantom limb perception • Transection Nerve Injury: • Paralysis • Anesthesia • Allodynia • Can be permanent • Peripheral Neural Interfaces • Control growth to MEAs • Modality specificity • Avoid pain or aesthesias • Prevent neuromas

  4. 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

  5. FDA Approved Biosynthetic Nerve Conduits Neurolac. (PL-caprolactone) • Limited to the repair of short digital sensory nerve gaps (≤3cm) in humans. • No luminar fillers or growth factors Neurotube. Synovis Micro (polyglocolide) NeuraGen. Integra Neuroscience (collagen). Schlosshauer et al., 2006.

  6. Biomimetic Nerve Implant: BNI Biodegradable conduit Agarose Agarose Collagen + Collagen + growth factors

  7. BNI Short Nerve Gap Repair (10 mm) Tansey et al., 2011 Tansey et al., 2011

  8. BNI: EM Morphometry and Behavioral Recovery Tansey et al., 2011 Tansey et al., 2011

  9. Long Gap Nerve Repair ( >30 mm) Complexity/Efficacy Luminar saline Muliluminal ECM Luminar ECM Multiluminar ECM with growth facors

  10. PLGA Microparticle Growth Factor Release GDNF CTR BSA GDNF_MP

  11. Synergetic effects of pleiotrophic and neurotrophic factors on axonal growth in vitro. Control Combination A Combination B

  12. GF-MP BNI: 30 mm Rabbit Peroneal Nerve Biodegradable conduit Agarose Agarose Collagen + Collagen Control Growth Factor MP Combination A Romero et al., In preparation Romero et al., Unpublished

  13. GF-MP BNI: 30 mm Motor Recovery Normal side Injured side: No regeneration Normal side Injured side: Regeneration 4 weeks 6 weeks Romero et al., In preparation

  14. GF-MP BNI: 30 mm Rabbit Peroneal Nerve Biodegradable conduit Agarose Agarose Collagen + Collagen Growth Factor MP Alsmadi et al., submitted Romero et al., Unpublished

  15. Deployment of GF Coiled Microfibers in Microchannels Alsmadi et al., Submitted A) A)

  16. Deployment of GF Coiled Microfibers in Microchannels Cheng-Jen Choung Alsmadi et al., Submitted A) A)

  17. Deployment of GF Coiled Microfibers in Microchannels Alsmadi et al., Submitted A) A)

  18. Bidirectional Molecular Guidance Alsmadi et al., Submitted A) A)

  19. Modular Prosthetic Limb: JHAPL 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

  20. Neural Control of Robotic Prosthesis http://armdynamics.com/pages/tmr Kuiken et al., 2007

  21. Cortical Neuro-Electrode Interfaces BMI- 3D Neural Control of Robotic Prosthesis Collinger, Andrew Schwartz, Univ Pittsburgh 2013

  22. 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)

  23. Advanced Limb Prosthetics: Sensory Feedback SynTouch BioTac G. Loeb, USC TMR(Targeted Muscle Reinnervation)-Prothese. Foto: Otto Bock/Michael Appelt Kinea Tactor: Johns Hopkins APL

  24. Selective Function and Neural Encoding Motor Axon 20 distinct sensory modalities

  25. Motor Decoding/Sensory encoding Flat Electrode D. Durand, D. Tyler; CWRU K. Horch, 2004 Four weeks recording and efficacy of sensory stimulation decayed after 10 days” Rossini et al., 2010 TIME Electrode S Micera; EPFL Pierpaolo Petruzziello, 2010 K. Warnick, 2004

  26. Regenerative Multielectrode Interface: REMI 60 d 15 d 30 d Garde et al., 2009

  27. Recording/Stimulation Free-Moving Animals Garde et al., 2009

  28. Kinematic Analysis during Bipedal Locomotion Gait Rats are trained on a robot treadmill (Robomedica, Inc.) for gait analysis to monitor recovery after peripheral nerve injury. Cineplex Rats are also video tracked using Cineplex software (Plexon Inc.) to track angle between the joints.

  29. Firing Pattern of Single Unit Spikes recorded from Tibial Nerve • Robot assisted standing on hind limbs – No Rhythmic Walking Ch 1 Ch 2 Ch 3 Tonic Unit seen only on Ch 2, while Ch1 and 3 did not have Single Unit activity Raster Plot Ch 2 Single Unit on Ch 2 148 μV 1400 μsec 45 Days Post Implant 50 sec interval

  30. Tonic to Bursting during Walking • Robot assisted Bipedal Locomotion – Rhythmic Walking Ch 1 Ch 2 Ch 3 Bursting Units elicited while walking as seen on Ch1, 2, 3 828 μV 296 μV 184 μV 1400 μsec 1400 μsec Channel 1 1400 μsec Channel 3 Channel 2 50 sec interval

  31. Sensory Specific Evoked Neural Activity Perievent Histogram bin = 500ms 0-50 gr 0- 55 C Channel A Channel A Frequency (spikes/sec) Frequency (spikes/sec) Channel B Channel B

  32. REMI: Mix Modality Interfacing ChAT Badia et al. 2009 Badia et al. 2009 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

  33. Axon Composition in PNS

  34. Targeting Sensory Type Regeneration In Vivo

  35. Directed Axonal Growth by NGF and NT-3 Unmyelinated Fibers Myelinated Fibers

  36. Both DRGs and ventral motor neurons grow towards A/B targets Multiple Growth Factors Single Growth Factors Surrogate Targets PTN BDNF/GDNF Muscle BDNF/GDNF BSA Skin BDNF/GDNF NT-3 PTN/NGF Nerve BDNF/GDNF BSA NGF Nerve BDNF/GDNF NT-3/NGF BSA BDNF/GDNF PTN/NGF/NT-3 NT-3 PTN BSA Anand et al., In Preparation

  37. Painful Neuromas Occur in up to 80% of limb amputations Neuroma Healthy Nerve Sehirlioglu et al., 2009 Granja et al., In Preparation A) A)

  38. BNI- Nerve Block: Discouraging Nerve Growth BNI BNI-NB Granja et al., In Preparation A) A)

  39. BNI- Nerve Block: Discouraging Nerve Growth BNI BNI-NB Granja et al., In Preparation A) A)

  40. Simple Tubularization vs BNI-Nerve Block r= 9 mm A= 254 sq.mm Uncontrolled Regeneration Hollow tube r= 4.5 mm A= 25.4 sq.mm Healthy Nerve Guided Inhibition r= .175mm X3channels A= 0.29 sq.mm r= 4.5 mm A= 25.4 sq.mm Healthy Nerve Granja et al., In Preparation A) A)

  41. BNI-NB Prevents Mechanoceptive Pain Granja et al., In Preparation A) A)

  42. Grow-No Grow Strategies Growth: Long Gap Repair 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. Interfacing Amputated Nerves Conditional Growth: Interfaces • Amputated nerves: Differential growth of modality-specific axons • Axon growth can be GF-directed separate Y-shaped compartments Block Growth No Growth: Neuroma • Surgical placement: Bone, Muscle • Capped Tubularization: Silicon tubes, epineurium cap. • BNI-NB can be used to prevent neuroma

  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

  44. Soft, Conformal Electrodes for Small Nerves and Inoperable Plexi Walter Voit

  45. UTARI Michrochannel Multielectrode Array Muthu Wijesundara Young-tae Kim

  46. UTARI MMEA: Fabrication

  47. UTARI MMEA: Recording/Stimulation

  48. 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 UoW Australia Gordon Wallace UTARI Muthu Wijesundar Caleb Nothnagle Eileen Clements Ret. Gral. Rick Lynch 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.

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