Electrophoretic drug delivery for seizure control

An implantable microfluidic ion pump prevents seizures in a mice by delivery of inhibitory neurotransmitters to the seizure source. The persistence of intractable neurological disorders necessitates novel therapeutic solutions. We demonstrate the utility of direct in situ electrophoretic drug delivery to treat neurological disorders. We present a neural probe incorporating a microfluidic ion pump (μFIP) for on-demand drug delivery and electrodes for recording local neural activity. The μFIP works by electrophoretically pumping ions across an ion exchange membrane and thereby delivers only the drug of interest and not the solvent. This “dry” delivery enables precise drug release into the brain region with negligible local pressure increase. The therapeutic potential of the μFIP probe is tested in a rodent model of epilepsy. The μFIP probe can detect pathological activity and then intervene to stop seizures by delivering inhibitory neurotransmitters directly to the seizure source. We anticipate that further tailored engineering of the μFIP platform will enable additional applications in neural interfacing and the treatment of neurological disorders.

[1]  Ivan Soltesz,et al.  Closed-loop optogenetic intervention in mice , 2013, Nature Protocols.

[2]  Felice T. Sun,et al.  Responsive cortical stimulation for the treatment of epilepsy , 2011, Neurotherapeutics.

[3]  A. Baranyi,et al.  Mechanism of aminopyridine-induced ictal seizure activity in the cat neocortex , 1987, Brain Research.

[4]  D. Kullmann,et al.  Gene therapy in epilepsy—is it time for clinical trials? , 2014, Nature Reviews Neurology.

[5]  C. Elger,et al.  Clinical Relevance of Quantified Intracranial Interictal Spike Activity in Presurgical Evaluation of Epilepsy , 2000, Epilepsia.

[6]  Raghu Raghavan,et al.  Convection-enhanced delivery of therapeutics for brain disease, and its optimization. , 2006, Neurosurgical focus.

[7]  Thomas J. Davidson,et al.  Closed-loop optogenetic control of thalamus as a new tool to interrupt seizures after cortical injury , 2012, Nature Neuroscience.

[8]  E. Yuliwati,et al.  A Review , 2019, Current Trends and Future Developments on (Bio-) Membranes.

[9]  Jean-Pierre Daurès,et al.  The prevalence of epilepsy and pharmacoresistant epilepsy in adults: A population‐based study in a Western European country , 2008, Epilepsia.

[10]  C. Nicholson,et al.  Diffusion in brain extracellular space. , 2008, Physiological reviews.

[11]  R. Nicoll,et al.  Local and diffuse synaptic actions of GABA in the hippocampus , 1993, Neuron.

[12]  J. L. Stringer,et al.  Epileptiform discharges induced by altering extracellular potassium and calcium in the rat hippocampal slice , 1988, Experimental Neurology.

[13]  B. Bean,et al.  Potassium Currents during the Action Potential of Hippocampal CA3 Neurons , 2002, The Journal of Neuroscience.

[14]  Christophe Bernard,et al.  Bioelectronic neural pixel: Chemical stimulation and electrical sensing at the same site , 2016, Proceedings of the National Academy of Sciences.

[15]  George G. Malliaras,et al.  A Microfluidic Ion Pump for In Vivo Drug Delivery , 2017, Advanced materials.

[16]  K. Woodhouse,et al.  Understanding the biodegradation of polyurethanes: from classical implants to tissue engineering materials. , 2005, Biomaterials.

[17]  D. Johnston,et al.  Epileptiform activity induced by changes in extracellular potassium in hippocampus. , 1985, Journal of neurophysiology.

[18]  R. N. Adams,et al.  Diffusion coefficients of neurotransmitters and their metabolites in brain extracellular fluid space , 1985, Neuroscience.

[19]  M. Bialer,et al.  Key factors in the discovery and development of new antiepileptic drugs , 2010, Nature Reviews Drug Discovery.

[20]  J. Cavazos,et al.  Electromyography‐based seizure detector: Preliminary results comparing a generalized tonic–clonic seizure detection algorithm to video‐EEG recordings , 2015, Epilepsia.

[21]  M. Berggren,et al.  Organic electronics for precise delivery of neurotransmitters to modulate mammalian sensory function. , 2009, Nature materials.

[22]  M. Berggren,et al.  Electronic control of Ca2+ signalling in neuronal cells using an organic electronic ion pump. , 2007, Nature materials.

[23]  Sandipan Pati,et al.  Pharmacoresistant epilepsy: From pathogenesis to current and emerging therapies , 2010, Cleveland Clinic Journal of Medicine.

[24]  Shuyun Dong,et al.  Directed molecular evolution of DREADDs: a generic approach to creating next-generation RASSLs , 2010, Nature Protocols.

[25]  Ivan Osorio,et al.  Performance Reassessment of a Real‐time Seizure‐detection Algorithm on Long ECoG Series , 2002, Epilepsia.

[26]  Tobias Loddenkemper,et al.  Seizure detection, seizure prediction, and closed-loop warning systems in epilepsy , 2014, Epilepsy & Behavior.

[27]  William C. Stacey,et al.  Seizure Prediction Is Possible–Now Let's Make It Practical , 2018, EBioMedicine.

[28]  A. Baranyi,et al.  Convulsive effects of 3-aminopyridine on cortical neurones. , 1979, Electroencephalography and clinical neurophysiology.

[29]  P. Kwan,et al.  Drug-resistant epilepsy. , 2011, The New England journal of medicine.

[30]  H. Knapp,et al.  Solid on liquid deposition , 2010 .

[31]  Magnus Berggren,et al.  Regulating plant physiology with organic electronics , 2017, Proceedings of the National Academy of Sciences.

[32]  Michael A Vogelbaum,et al.  Convection-enhanced delivery for the treatment of glioblastoma. , 2015, Neuro-oncology.

[33]  Fotios Papadimitrakopoulos,et al.  Biomaterials/Tissue Interactions: Possible Solutions to Overcome Foreign Body Response , 2010, The AAPS Journal.

[34]  George G. Malliaras,et al.  The Rise of Organic Bioelectronics , 2014 .

[35]  M. E. Arzate,et al.  Effect of taurine on seizures induced by 4‐aminopyridine , 1981, Journal of neuroscience research.

[36]  I. Soltesz,et al.  On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy , 2013, Nature Communications.

[37]  M. Berggren,et al.  Correction for Jonsson et al., Bioelectronic neural pixel: Chemical stimulation and electrical sensing at the same site , 2016, Proceedings of the National Academy of Sciences.

[38]  Christian Bergaud,et al.  A review on mechanical considerations for chronically-implanted neural probes , 2018, Journal of neural engineering.

[39]  Dieter Schmidt,et al.  New avenues for anti-epileptic drug discovery and development , 2013, Nature Reviews Drug Discovery.

[40]  Max Woolley,et al.  Chronic, intermittent convection-enhanced delivery devices , 2016, Journal of Neuroscience Methods.

[41]  S. Ramakrishna,et al.  Biomedical applications of polymer-composite materials: a review , 2001 .

[42]  M. Szente,et al.  Comparative study of aminopyridine-induced seizure activities in primary and mirror foci of cat's cortex. , 1981, Electroencephalography and clinical neurophysiology.

[43]  David Nilsson,et al.  Therapy using implanted organic bioelectronics , 2015, Science Advances.

[44]  Magnus Berggren,et al.  Chemical delivery array with millisecond neurotransmitter release , 2016, Science Advances.

[45]  S. Haber,et al.  Closed-Loop Deep Brain Stimulation Is Superior in Ameliorating Parkinsonism , 2011, Neuron.

[46]  Christophe Bernard,et al.  Controlling Epileptiform Activity with Organic Electronic Ion Pumps , 2015, Advanced materials.

[47]  Ivan Soltesz,et al.  Dentate gyrus mossy cells control spontaneous convulsive seizures and spatial memory , 2018, Science.

[48]  C. Nicholson.  Interaction between diffusion and Michaelis-Menten uptake of dopamine after iontophoresis in striatum. , 1995, Biophysical journal.