SBIR-STTR Award

Paradromics is developing high data rate brain computer interface technologies as a platform for medical device applications. In our Phase I SBIR, we designed, built, and tested a neural recording system based on massively parallel microwire electrode arrays bonded to CMOS readout electronics. That system supports up to 65,536 active electrode channels sampled simultaneously at over 32,000 Hz. We used this system to record action potentials from arrays of up to 1200 microelectrodes in rats (penetrating, 1mm depth) and local field potentials from >30,000 microelectrodes in sheep (surface). This serves as a demonstration of the microwire- to-CMOS bonding architecture that will form the core of our next device, a medical implant. For this new implantable medical device, we have developed a new and substantially improved method of electrode array fabrication. This method produces more ordered, regular arrays through Electrical Discharge Machining (EDM), thus improving on the stochastic connections of the bundle architecture from Phase I with the ability to be produced under GMP. A new, custom CMOS sensor, also developed following the NIH SBIR Phase I effort, performs compressive sensing of neural data to reduce power and data requirements in the future device. As we prepare to build this implantable medical device and take it to market, it is critical to extensively test the insertion reliability of different arrays designs in order to produce a device best optimized for insertion and recording. Here we propose to use passive arrays of 400-1600 electrodes, smaller than our Phase I approach, to find the optimal electrode array design for clinical translation. We will test array designs that can reliably insert into the sheep cortex, validate the insertion of that array in human tissue intraoperatively (under IRB), and evaluate the tissue response to the array over a period of up to 6 months, implanted chronically in sheep. The overall goal for the future array is to ensure that we can reliably insert the array with the smallest shank width to mitigate the chronic foreign body response at an appropriate pitch (100 - 400 μm) and length (i.e. 1 mm) suitable for the human cortex. Moreover, this data will also be critical for designing certified GLP studies, and for planning conversations with the FDA for pre-IDE meetings, where we will need a finalized array design and testing plan in place. The aims of this Direct to Phase II study are as follows: Specific Aim (SA) 1: Determine optimal microelectrode array design and validate implantation in sheep and human cortical tissue intraoperatively with passive arrays of 400-1600 electrodes. We aim to better understand how the geometric parameters of high density microwire electrode arrays impact insertion reliability into cortical tissue in vivo in an ovine (sheep) model (SA 1.1), with refined geometries implanted intraoperatively into human cortex (SA 1.2). Specific Aim 2: Determine long-term viability of implanted, passive arrays in sheep. . We will determine the long-term viability of our high-density array by chronically implanting the passive arrays in sheep. Animals will be implanted over 4, 8, 12, and 24 weeks. The degree of glial scarring and neuron loss will be compared around electrodes between high-density and commercial arrays over these timepoints.

Public Health Relevance Statement:
PROJECT NARRATIVE Given that decoding ability from neural recordings increases with the number of recording electrodes, new innovations are being developed with high-channel neural recordings in animal models, though translation to humans is currently limited to only 100 channels. Here we propose preclinical and clinical studies to optimize our high-channel count, microwire arrays for safe and reliable insertions and determine chronic viability of the arrays, focusing on translation towards a medical device. This could revolutionize brain-computer interfaces by increasing the degrees of freedom to decode neural activity, potentially enabling people with locked-in-syndrome new tools to interact with the world.

Project Terms:
Action Potentials; Animals; Architecture; Engineering / Architecture; Cells; Cell Body; Cicatrix; Scars; Clinical Research; Clinical Study; Clinical Trials; Electrodes; Electronics; electronic device; Epilepsy; Epileptic Seizures; Epileptics; Seizure Disorder; epilepsia; epileptiform; epileptogenic; Feedback; Foreign Bodies; Freedom; Liberty; Future; Goals; Histology; Human; Modern Man; Implantation procedure; implant placement; implant procedure; Locked-In Syndrome; Medical Device; Methods; Microelectrodes; Miniaturized Electrodes; United States National Institutes of Health; NIH; National Institutes of Health; Patients; Rattus; Common Rat Strains; Rat; Rats Mammals; Sheep; Ovine; Ovis; Technology; Testing; Time; Tissues; Body Tissues; Translations; Custom; base; density; sensor; improved; Surface; Chronic; Phase; Series; Ensure; Evaluation; Recovery; tool; Investigation; human tissue; System; Width; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; Operative Surgical Procedures; meetings; nerve cell death; nerve cell loss; neuron cell death; neuron cell loss; neuron death; neuronal cell death; neuronal cell loss; neuronal death; neuronal loss; neuron loss; cohort; Animal Models and Related Studies; model of animal; model organism; Animal Model; neural; relating to nervous system; novel; Devices; Abscission; Extirpation; Removal; Surgical Removal; resection; Excision; Social Support System; Support System; Modeling; Sampling; response; Diameter; Caliber; Length; Data; in vivo; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Monitor; Process; Development; developmental; safety study; preclinical study; pre-clinical study; medical implant; design; designing; brain computer interface; innovation; innovate; innovative; clinical application; clinical applicability; Implant; implantation; good laboratory practice; phase 2 study; phase II study; Institutional Review Boards; IRB; IRBs; Geometry; translation to humans; clinical translation; sheep model; ovine animal model; ovine model

Paradromics is developing high data rate brain computer interface technologies as a platform for medical device applications. In our Phase I SBIR, we designed, built, and tested a neural recording system based on massively parallel microwire electrode arrays bonded to CMOS readout electronics. That system supports up to 65,536 active electrode channels sampled simultaneously at over 32,000 Hz. We used this system to record action potentials from arrays of up to 1200 microelectrodes in rats (penetrating, 1mm depth) and local field potentials from >30,000 microelectrodes in sheep (surface). This serves as a demonstration of the microwire- to-CMOS bonding architecture that will form the core of our next device, a medical implant. For this new implantable medical device, we have developed a new and substantially improved method of electrode array fabrication. This method produces more ordered, regular arrays through Electrical Discharge Machining (EDM), thus improving on the stochastic connections of the bundle architecture from Phase I with the ability to be produced under GMP. A new, custom CMOS sensor, also developed following the NIH SBIR Phase I effort, performs compressive sensing of neural data to reduce power and data requirements in the future device. As we prepare to build this implantable medical device and take it to market, it is critical to extensively test the insertion reliability of different arrays designs in order to produce a device best optimized for insertion and recording. Here we propose to use passive arrays of 400-1600 electrodes, smaller than our Phase I approach, to find the optimal electrode array design for clinical translation. We will test array designs that can reliably insert into the sheep cortex, validate the insertion of that array in human tissue intraoperatively (under IRB), and evaluate the tissue response to the array over a period of up to 6 months, implanted chronically in sheep. The overall goal for the future array is to ensure that we can reliably insert the array with the smallest shank width to mitigate the chronic foreign body response at an appropriate pitch (100 - 400 μm) and length (i.e. 1 mm) suitable for the human cortex. Moreover, this data will also be critical for designing certified GLP studies, and for planning conversations with the FDA for pre-IDE meetings, where we will need a finalized array design and testing plan in place. The aims of this Direct to Phase II study are as follows: Specific Aim (SA) 1: Determine optimal microelectrode array design and validate implantation in sheep and human cortical tissue intraoperatively with passive arrays of 400-1600 electrodes. We aim to better understand how the geometric parameters of high density microwire electrode arrays impact insertion reliability into cortical tissue in vivo in an ovine (sheep) model (SA 1.1), with refined geometries implanted intraoperatively into human cortex (SA 1.2). Specific Aim 2: Determine long-term viability of implanted, passive arrays in sheep. . We will determine the long-term viability of our high-density array by chronically implanting the passive arrays in sheep. Animals will be implanted over 4, 8, 12, and 24 weeks. The degree of glial scarring and neuron loss will be compared around electrodes between high-density and commercial arrays over these timepoints.

Public Health Relevance Statement:
PROJECT NARRATIVE Given that decoding ability from neural recordings increases with the number of recording electrodes, new innovations are being developed with high-channel neural recordings in animal models, though translation to humans is currently limited to only 100 channels. Here we propose preclinical and clinical studies to optimize our high-channel count, microwire arrays for safe and reliable insertions and determine chronic viability of the arrays, focusing on translation towards a medical device. This could revolutionize brain-computer interfaces by increasing the degrees of freedom to decode neural activity, potentially enabling people with locked-in-syndrome new tools to interact with the world.

Project Terms:
Action Potentials; Animals; Architecture; Engineering / Architecture; Cells; Cell Body; Cicatrix; Scars; Clinical Research; Clinical Study; Clinical Trials; Electrodes; Electronics; electronic device; Epilepsy; Epileptic Seizures; Epileptics; Seizure Disorder; epilepsia; epileptiform; epileptogenic; Feedback; Foreign Bodies; Freedom; Liberty; Future; Goals; Histology; Human; Modern Man; Implantation procedure; implant placement; implant procedure; Locked-In Syndrome; Medical Device; Methods; Microelectrodes; Miniaturized Electrodes; Persons; NIH; National Institutes of Health; United States National Institutes of Health; Patients; Common Rat Strains; Rat; Rats Mammals; Rattus; Ovine; Ovis; Sheep; Technology; Testing; Time; Tissues; Body Tissues; Translations; Custom; base; density; sensor; improved; Surface; Chronic; Phase; Series; Ensure; Evaluation; Recovery; tool; Investigation; human tissue; System; Width; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; Operative Surgical Procedures; meetings; nerve cell death; nerve cell loss; neuron cell death; neuron cell loss; neuron death; neuronal cell death; neuronal cell loss; neuronal death; neuronal loss; neuron loss; cohort; Animal Models and Related Studies; model of animal; model organism; Animal Model; neural; relating to nervous system; novel; Devices; Abscission; Extirpation; Removal; Surgical Removal; resection; Excision; Social Support System; Support System; Modeling; Sampling; response; Diameter; Caliber; Length; Data; in vivo; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Monitor; Process; Development; developmental; safety study; preclinical study; pre-clinical study; medical implant; design; designing; brain computer interface; innovation; innovate; innovative; clinical application; clinical applicability; Implant; implantation; good laboratory practice; phase 2 study; phase II study; Institutional Review Boards; IRB; IRBs; Geometry; translation to humans; clinical translation; sheep model; ovine animal model; ovine model