Delivery of Low-Intensity Pulsed Ultrasound in the Cortex to Improve Longevity and Performance of Neural Interfaces
NN TIRKO, AS ALSUBHI, JK GREASER, RS CLEMENT, KA SNOOK, RB BAGWELL, ML MULVIHILL
Actuated Medical, Inc., Bellefonte, PA
Chronic neural implants hold great potential for illuminating features of neural function, treating neurological disorders, and enabling the next generation of neuroprosthetics. Penetrating electrode arrays provide direct access to neural signals across the central and peripheral nervous system with high temporospatial resolution. However, a consistent point of failure for chronically implanted microelectrode arrays is poor longevity and variability in functionality of these devices. The foreign body response (FBR) can cause glial scarring and neural cell loss near the electrode sites. The FBR begins with electrode insertion, when damage to the blood brain barrier activates astrocytes and microglia and continues throughout the lifetime of the implant due to the persistent presence of the foreign material in the tissue. Significant efforts have been made to reduce the FBR, both at the outset of implantation by limiting initial insertion damage and over the long-term by reducing the mechanical mismatch between brain and implant, or long-term use of exogenous chemicals to suppress the FBR.
Rather than relying on temporary interventions to limit the FBR, we proposed a method to harness endogenous cortical function to improve the long-term neural interface microenvironment. Low-intensity pulsed ultrasound (LIPUS) has recently been shown to have protective and healing effects in models of cerebral disease and injury, through promotion of brain-derived neurotrophic factor (BDNF) and other neurotrophic factors that affect the anti-inflammatory response of microglia and other cells. Here, we investigate the use of sub-threshold LIPUS focused directly at the neural electrode interface to improve tissue health and increase the quality and longevity of neural recordings. A study was undertaken in which silicon shank electrodes (A4x4-5mm-100-125-703-CM16LP, NeuroNexus, Inc.) oriented at 45º from horizontal, were chronically implanted into cortical layers II/III of the motor or somatosensory cortex of rats (N=8). The effects of LIPUS on neural recording quality over 6 weeks post-implant were studied (n=4) with respect to Sham treatment (n=4). Nominal conditions used were based on the prior LIPUS research on disease and injury; stimulation (0.5 W/cm2 intensity, 1.1 MHz, 15 min. total treatment at 4% duty cycle) was administered daily Week 1, and twice weekly for Weeks 2-6 and coupled with electrophysiology recording sessions (SmartBox Pro Allego, NeuroNexus). Single unit analysis of electrophysiological data reveals strong trends in signal quality improvements in the LIPUS-treated group. More than double the electrode channels remained active throughout the 6 weeks in subjects in the LIPUS stimulation group as compared to Sham (p<0.01). Also, the channels that remained active maintained an average 4 dB higher signal-to-noise ratio (SNR) over the same time period (p<0.01). Our studies demonstrate that periodic application of localized LIPUS to tissue at the neural interface has potential to improve electrophysiology signal quality. Implications for future studies will be discussed.
Microelectrode Arrays Insertion System Using Ultrasonic Vibration to Improve Insertion Mechanics and Reduce Tissue Dimpling and Trauma in the Cortex
NN TIRKO, RS CLEMENT, JK GREASER, AS ALSUBHI, EM STEFFAN, RB BAGWELL, ML MULVIHILL
Actuated Med. Inc., Bellefonte, PA
S LEE, HJ KIM, MF AGHA
University of North Carolina, Chapel Hill, NC
Intracortical Electrode Arrays (IEAs) provide direct access to extracellular neural signals in the brain with high temporal and spatial resolution. Unfortunately, chronically implanted IEAs have limited functional lifespans that impede significant clinical translation. The host tissue reaction is a major contributor to neural interface failure, causing formation of glial scars and loss of neurons at electrode sites. Studies suggest that the initial insertion trauma alone is responsible for significant damage. The forces applied to the cortical tissue during insertion can deform tissue, causing strain and membrane disruptions in underlying neurons and vasculature. While insertion is a technical hurdle common to all IEA types, high-density multi-shank arrays have uniquely significant insertion challenges. Following insertion, the IEA chronic interface can be degraded due to mechanical mismatch between the IEA and the cortical tissue. Superior tissue response and device longevity has been demonstrated with ultra-fine microwire (<15 µm diameter) and flexible (e.g., polyimide) arrays. However, given their tendency to buckle/break during insertion they struggle to penetrate meningeal layers and temporary support structures, shuttles, or dissolvable stiffeners are often necessary for mechanical reinforcement during insertion. This increases the complexity and time of the surgery and insertion process, and may limit reliable electrode performance and adaptation of these arrays.
Ultrasonic vibration of IEAs represents a promising approach to reduce frictional and penetration forces associated with insertion. We have demonstrated that this approach has implantation capability of both rigid, multi-shank arrays and mechanically soft microwire or polymer-based arrays. In the case of rigid arrays (i.e. silicon shanks from NeuroNexus, Blackrock and microwires from MicroProbes, Tucker Davis Technologies) vibration-assisted insertion reduces insertion force 61-82% relative to standard insertion via stereotaxic equipment when using an agar model (0.5% base, 1.5% top layer). In vivo studies demonstrated a significant (p<0.01) reduction in cortical surface dimpling/compression with vibration during insertion of silicon arrays (NeuroNexus H-series) into rat cortex, as well as successful insertion through the dura. Electrodes inserted with vibration have no detriment to electrophysiology signal quality.
In the case of flexible arrays, vibration-assisted insertion both reduces insertion force and improves insertion trajectory. Polyimide thin-film single-shanks probes were inserted in rat nucleus accumbens without vibration (n=6), with vibration through pia (n=10) and with vibration through dura (n=5). Using T2-weighted MRI, insertion accuracy was measured; targeting success was improved with vibration (through pia: 70%, through dura: 83%) as compared to Control (50%; p>0.05 due to limited sample size). Ten days after surgery, neuromodulation outcomes (evoked response patterns, as measured through fMRI) were increased with the vibration-inserted electrodes (through pia: 100%, through dura: 80%) versus Control (66%). Additionally, histological evaluation of the implantation site (4 weeks post-op) revealed that the intensity of glial scaring (visualized via glial fibrillary acidic protein immunohistochemistry) was significantly reduced when electrodes were inserted with vibration (p<0.05) relative to Control. Together, these benchtop insertion studies in agar and ex vivo tissue models, as well as in vivo insertion studies support the potential of vibrated insertion for improved outcomes for studies using IEAs, specifically for flexible electrodes.
A startup needed a Faceshield that would integrate with their reusable N95 respirator design.
Actuated Medical’s engineers worked with the startup to understand their N95 respirator design. Using our rapid prototyping facility, our engineers developed a design using 3D printed components. The face shield’s 3D printed parts enable the face shield to be moved in and out from the face and also to be flipped up. The design also enabled face shields to be quickly removed and changed. Due to the cost of 3D printed parts, Actuated Medical conducted cost analysis and time studies between 3D vs injection molded parts to streamline and reduce manufacturing costs.
Actuated has manufactured the first lot of face shields.
“Throughout our working relationship, we have been extremely impressed with their engineering quality, knowledge of the prototyping and manufacturing space, and ability to move quickly from innovation through small-scale manufacturing.”
-Doug Clift, COO
Two physicians came to us with a robotic medical device. They described that their needle was having a targeting issue that they believed our intelligent tissue deformation expertise may be able to solve.
We began working with the startup team to design and optimize a motor that would meet their product specifications. We optimized the frequency, voltage, and displacement to improve their device’s targeting precision. We are currently running reliability testing on the motors to ensure that they maintain product specifications over the lifetime of the device.
Currently pending a motor manufacturing contract.
“The Actuated Medical team worked with our engineering team to develop a motor with optimized drive conditions for our robotic system. They worked efficiently and quickly to meet our product development timeline.” – Russ Seiber, CEO, Obvius Robotics
A ER physician came to Actuated with a patent for a device. The physician had a full-time job, and no time to develop his device. He said to us, “Can you take this product from concept to FDA submission?”
Actuated Medical’s engineering team reviewed the patent. They investigated the design (Stage 1) and built some feasibility prototypes using Actuated Medical’s rapid prototyping facility (Stage 2). After refining the design, a design review was held with the physician and the design was frozen (Stage 3). Verification and Validation (V&V) Protocols were written, testing performed and test reports completed (Stages 4 & 5). Included in V&V was usability testing with 30 participants. The device passed V&V. Actuated Medical’s Director QA/RA and the engineering team are currently writing the 510(k) application.
Currently, pending FDA clearance.
“I took my patent to Actuated Medical, and they completed all the V&V testing, are writing the 510(k) and submitted it to the FDA. Because of Actuated my patent is a medical device.”
– Brian Shippert, DO, Emergency Physician, Shippert Tech, LLC