Chaitanya Kolluru, a collaborator from Dave Wilson's lab published his first author paper describing 3D MUSE of peripheral nerve.
Kolluru, C., Todd, A., Upadhye, A.R. et al. Imaging peripheral nerve micro-anatomy with MUSE, 2D and 3D approaches. Sci Rep 12, 10205 (2022). https://doi.org/10.1038/s41598-022-14166-1
Understanding peripheral nerve micro-anatomy can assist in the development of safe and effective neuromodulation devices. However, current approaches for imaging nerve morphology at the fiber level are either cumbersome, require substantial instrumentation, have a limited volume of view, or are limited in resolution/contrast. We present alternative methods based on MUSE (Microscopy with Ultraviolet Surface Excitation) imaging to investigate peripheral nerve morphology, both in 2D and 3D. For 2D imaging, fixed samples are imaged on a conventional MUSE system either label free (via auto-fluorescence) or after staining with fluorescent dyes. This method provides a simple and rapid technique to visualize myelinated nerve fibers at specific locations along the length of the nerve and perform measurements of fiber morphology (e.g., axon diameter and g-ratio). For 3D imaging, a whole-mount staining and MUSE block-face imaging method is developed that can be used to characterize peripheral nerve micro-anatomy and improve the accuracy of computational models in neuromodulation. Images of rat sciatic and human cadaver tibial nerves are presented, illustrating the applicability of the method in different preclinical models.
Successful NANS January 2023 Meeting
Congrats to Aniruddha on his first national meeting presentation and to Danny for his multiple posters related to his Abbott internship
Upadhye, A., Chin, J., M. Settell, C. Kolluru, A. Deshmukh, B. Knudsen, M. Laluzerne, O. Buyukcelik, et al. “Imaging the Neural Micro-Anatomy of the Swine Spinal Cord.” Session presented at the NANS Annual Meeting, Las Vegas, January 2023.
Lam, D., S. Kang, N. Verma, B. Romanauski, Y. Nishiyama, J. Hao, K. Ludwig, H. Park, E. Ross, I. Lavrov, M. Zhang. "Changes in Evoked Responsesl During Epidual Spinal Cord Stimulation Generated by Minimal Movement of Leads." Presented at the NANS 2023, Las Vegas, NV, 2023.
National Institutes of Health awards $15.75M to research team led by Case Western Reserve University (Shoffstall) and Duke University (Pelot) to map vagus nerve—body’s ‘super highway’ for controlling major organ functions
Mapping the Autonomic Pathways in 100 Human Vagus Nerves in a Demographically Representative Sample (MAP-100VN): NIH SPARC 75N98022
Mapping the Vagus Nerve, Autonomic Nervous System
“’National Institutes of Health awards $15.75M to research team led by Case Western Reserve University and Duke University to map vagus nerve—body’s ‘super highway’ for controlling major organ functions”
Ozge Buyukcelik graduated with her M.S. in BME
Ozge's MS project focused on the
Aniruddha's first author paper on vagus nerve fascicle splitting and merging, using microCT images, was published in JNE
Upadhye, Aniruddha R., Chaitanya Kolluru, Lindsey Druschel, Luna Al Lababidi, Sami S. Ahmad, Dhariyat M. Menendez, Ozge N. Buyukcelik, et al. “Fascicles Split or Merge Every ∼560 Microns within the Human Cervical Vagus Nerve.” Journal of Neural Engineering 19, no. 5 (November 2022): 054001. https://doi.org/10.1088/1741-2552/ac9643.
Objective. Vagus nerve stimulation (VNS) is Food and Drug Administration-approved for epilepsy, depression, and obesity, and stroke rehabilitation; however, the morphological anatomy of the vagus nerve targeted by stimulatation is poorly understood. Here, we used microCT to quantify the fascicular structure and neuroanatomy of human cervical vagus nerves (cVNs). Approach. We collected eight mid-cVN specimens from five fixed cadavers (three left nerves, five right nerves). Analysis focused on the 'surgical window': 5 cm of length, centered around the VNS implant location. Tissue was stained with osmium tetroxide, embedded in paraffin, and imaged on a microCT scanner. We visualized and quantified the merging and splitting of fascicles, and report a morphometric analysis of fascicles: count, diameter, and area. Main results. In our sample of human cVNs, a fascicle split or merge event was observed every ∼560 µm (17.8 ± 6.1 events cm−1). Mean morphological outcomes included: fascicle count (6.6 ± 2.8 fascicles; range 1–15), fascicle diameter (514 ± 142 µm; range 147–1360 µm), and total cross-sectional fascicular area (1.32 ± 0.41 mm2; range 0.58–2.27 mm). Significance. The high degree of fascicular splitting and merging, along with wide range in key fascicular morphological parameters across humans may help to explain the clinical heterogeneity in patient responses to VNS. These data will enable modeling and experimental efforts to determine the clinical effect size of such variation. These data will also enable efforts to design improved VNS electrodes.
Derrick's EMBC conference paper was published - Glasgow 2022
Liu, Derrick X., Danny V. Lam, Yingyi Gao, Rachel C. LeBlanc, Alyssa A. Usab, Elizabeth S. Fielding, Charlotte L. Brunkalla, Kevin Yang, and Andrew J. Shoffstall. “Characterization of a Temporary Peripheral Nerve Stimulation Electrode Utilizing a Bioabsorbable Suture Substrate.” In 2022 44th Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC), 5094–98, 2022. https://doi.org/10.1109/EMBC48229.2022.9871604.
Electrical stimulation after peripheral nerve injury (PNI) has the potential to promote more rapid and complete recovery of damaged fiber tracts. While permanently implanted devices are commonly used to treat chronic or persistent conditions, they are not ideal solutions for transient medical therapies due to high costs, increased risk of surgical injury, irritation, infection, and persistent inflammation at the site of the implant. Furthermore, removal of temporary leads placed on or around peripheral nerves may have unacceptable risk for nerve injury, which is counterproductive in developing therapies for PNI treatment. Transient devices which provide effective clinical stimulation while being capable of harmless bioabsorption may overcome key challenges in these areas. However, current bioabsorbable devices are limited in their robustness and require complex fabrication strategies and novel materials which may complicate their clinical translation pathway. In this study, we present a simple bioabsorbable / biodegradable electrode fabricated by modifying standard absorbable sutures, and we present data characterizing our prototype's stability in vitro and in vivo.
Our students represented the lab well at BMES October 2022!
Congrats to Danny, Aniruddha, Anna, Dhariyat, Longshun, Elizabeth and Ozge on a job well done!
Buyukcelik, O., and A. Shoffstall. “Deep Learning Based Segmentation of Fascicles in MicroCT Images of the Vagus Nerve.” Presented at the BMES 2022, San Antonio, TX, 2022.
Jitendran, E., D. Menendez, L. Li, and A. Shoffstall. “Evaluating the Route of Systemic Administration for Platelet Inspired Nanoparticles for Targeting Brain-Implanted Microelectrodes.” Presented at the BMES 2022, San Antonio, TX, 2022.
Lam, D., and A. Shoffstall. “Characterizing Feasibility and Performance of Injectable Gold Microwires for Neural Interfacing.” Presented at the BMES 2022, San Antonio, TX, 2022.
Menendez, D., L. Li, and A. Shoffstall. “Platelet Inspired Drug Delivery Vehicle Targets Brain Implanted Microelectrodes.” Presented at the BMES 2022, San Antonio, TX, 2022.
Upadhye, A., and A. Shoffstall. “Imaging Vagus Nerve Micro-Anatomy Using MicroCT.” Presented at the BMES 2022, San Antonio, TX, 2022.
Notice of Award: We are excited to be a part of a collaboration with Dr. Ludwig and Dr. Grill's lab on "A Rational Engineering Design Approach to Minimizing the Off-Target Effects of Baroreceptor Activation Therapy". Our lab will be using microCT techniques to investigate the anatomy of the carotid sinus nerve.
George and Dhariyat's JoVE paper evaluating automated craniotomy drilling was accepted
Hoeferlin, George F., Dhariyat M. Menendez, Olivia K. Krebs, Jeffrey R. Capadona, and Andrew J. Shoffstall. “Assessment of Thermal Damage from Robot-Drilled Craniotomy for Cranial Window Surgery in Mice.” JoVE, no. 189 (November 11, 2022): e64188. https://doi.org/10.3791/64188.
Cranial window surgery allows for the imaging of brain tissue in live mice with the use of multiphoton or other intravital imaging techniques. However, when performing any craniotomy by hand, there is often thermal damage to brain tissue, which is inherently variable surgery-to-surgery and may be dependent on individual surgeon technique. Implementing a surgical robot can standardize surgery and lead to a decrease in thermal damage associated with surgery. In this study, three methods of robotic drilling were tested to evaluate thermal damage: horizontal, point-by-point, and pulsed point-by-point. Horizontal drilling utilizes a continuous drilling schematic, while point-by-point drills several holes encompassing the cranial window. Pulsed point-by-point adds a "2 s on, 2 s off" drilling scheme to allow for cooling in between drilling. Fluorescent imaging of Evans Blue (EB) dye injected intravenously measures damage to brain tissue, while a thermocouple placed under the drilling site measures thermal damage. Thermocouple results indicate a significant decrease in temperature change in the pulsed point-by-point (6.90 °C ± 1.35 °C) group compared to the horizontal (16.66 °C ± 2.08 °C) and point-by-point (18.69 °C ± 1.75 °C) groups. Similarly, the pulsed point-by-point group also showed significantly less EB presence after cranial window drilling compared to the horizontal method, indicating less damage to blood vessels in the brain. Thus, a pulsed point-by-point drilling method appears to be the optimal scheme for reducing thermal damage. A robotic drill is a useful tool to help minimize training, variability, and reduce thermal damage. With the expanding use of multiphoton imaging across research labs, it is important to improve the rigor and reproducibility of results. The methods addressed here will help inform others of how to better use these surgical robots to further advance the field.
Derrick Liu graduated with his M.S. in BME
Derrick's MS project focused on the development and evaluation of a novel resorbable stimulation electrode.
Maddie Lindemann graduated with her M.S. in MechE
Congratulations Maddie! Thesis: The Design and Development of a 3D Printed Hindlimb Stabilization Apparatus for the Measurement of Stimulation-Evoked Ankle Torque in the Rat.
Notice of Award: Collaboration with Dr. Grill and Dr. Ludwig on our NIH SPARC Project to visualize the vagus nerve using novel imaging techniques.
The Great Flood 2020! The lab is flooded and moves to the 5th floor
Global Pandemic; Lab Moves Virtual
Notice of Award: Danny received the prestigious NSF GRFP Fellowship. Congratulations Danny!
Book Chapter Accepted: Shoffstall and Capadona published a chapter on Bioelectronic Neural Implants in the new Biomaterials Science Textbook edited by Shelly Sakiyama-Elbert
Shoffstall, Andrew J., and Jeffrey R. Capadona. “2.5.7 - Bioelectronic Neural Implants.” In Biomaterials Science (Fourth Edition), edited by William R. Wagner, Shelly E. Sakiyama-Elbert, Guigen Zhang, and Michael J. Yaszemski, 1153–68. Academic Press, 2020. https://doi.org/10.1016/B978-0-12-816137-1.00073-8.
In this chapter, we discuss the fundamentals required for understanding the field of bioelectronics devices. We provide an overview of specific technologies, applications, and failure modes for existing and emerging approaches. Biomaterials-based strategies are a key to helping to solve some of the major problems in the field: chronic stability, biological tissue response and biocompatibility, and commercialization potential. The chapter is not intended to be a comprehensive and exhaustive list of all the latest technical developments as the field is rapidly changing. The intended reader is instead the new biomaterials-focused undergraduate or early graduate student interested in gaining an appreciation of the high level technical and physiological considerations in neural bioelectronic interfacing.
Manuscript Accepted: Congratulations James! Trevathan et al., "A Truly Injectable Neural Stimulation Electrode Made from an In Body Curing Polymer/Metal Composite" Advanced Healthcare Materials
Trevathan, J. K., I. W. Baumgart, E. N. Nicolai, B. A. Gosink, A. J. Asp, M. L. Settell, S. R. Polaconda, et al. “An Injectable Neural Stimulation Electrode Made from an In-Body Curing Polymer/Metal Composite.” Adv Healthc Mater 8, no. 23 (December 2019): e1900892.
Implanted neural stimulation and recording devices hold vast potential to treat a variety of neurological conditions, but the invasiveness, complexity, and cost of the implantation procedure greatly reduce access to an otherwise promising therapeutic approach. To address this need, a novel electrode that begins as an uncured, flowable prepolymer that can be injected around a neuroanatomical target to minimize surgical manipulation is developed. Referred to as the Injectrode, the electrode conforms to target structures forming an electrically conductive interface which is orders of magnitude less stiff than conventional neuromodulation electrodes. To validate the Injectrode, detailed electrochemical and microscopy characterization of its material properties is performed and the feasibility of using it to stimulate the nervous system electrically in rats and swine is validated. The silicone-metal-particle composite performs very similarly to pure wire of the same metal (silver) in all measures, including exhibiting a favorable cathodic charge storage capacity (CSCC ) and charge injection limits compared to the clinical LivaNova stimulation electrode and silver wire electrodes. By virtue of its simplicity, the Injectrode has the potential to be less invasive, more robust, and more cost-effective than traditional electrode designs, which could increase the adoption of neuromodulation therapies for existing and new indications.
Notice of Award: Lab is awarded NIH U18; collaboration with Kip Ludwig, Doug Weber, Scott Lempka, Neuronoff Inc., to evaluate injectable electrode system for minimally invasive DRG stimulation
Notice of Award: Lab is awarded first VA Merit Review; collaboration with Anirban Sen Gupta, Haima Therapeutics to study platelet-inspired drug delivery to intracortical microelectrodes
First Ph D Students Join: Welcome to Danny Lam and Kevin Yang!!!
Case Western Reserve University
Neural Engineering Center
Misc Unsorted Grants
VA Merit I01RX003420
Active, Shoffstall / Capadona (PI), Role: PI
08/01/2020 - 01/31/2024
Optimizing Delivery of a Known Therapeutic Agent, Dexamethasone, to Improve Microelectrode Recording Performance
Abbott Neuromodulation Sponsored Contract
Active, Shoffstall (PI), Role: PI
11/01/2021 - 12/31/2023
Physiological / anatomical substrates of evoked compound action potentials during spinal cord stimulation
CVRx Sponsored Contrat
Active, Shoffstall (PI), Role: PI
12/01/2022 - 11/30/2023
Multiscale imaging of the carotid sinus nerve
Ohio Third Frontier Research Incentive
Active, Shoffstall (PI), Role: PI
11/01/2021 - 11/01/2023
Injectable multi-level sacral root neuromodulation interface for the treatment of SCI bladder dysfunction
VA ShEEP 1IS1BX005546-01
Completed, Shoffstall (PI), Role: PI
01/01/2021 - 01/01/2021
ShEEP Request for Ultra-High-Frequency Ultrasound VisualSonics Imaging System
Liva Nova Sponsored Contract UW#SPN00878
Completed, Ludwig (PI), Role: Co-I
05/16/2020 - 09/30/2020
Computational Modeling, Functional Validation of the Imthera Lead to Limit Off Target Effects of Cervical Vagus Stimulation
VA CDA-1 1IK1RX002492-01A2
Completed, Shoffstall (PI), Role: PI
05/01/2018 - 05/01/2020
VA RR&D Career Development Award -1: Dynamically Softening Microelectrodes to Improve Neural Recording Performance
DARPA Seedling N66001-17-2-4010, 801K356
Completed, Williams (PI), Role: Co-I
11/21/2017 - 11/21/2018
Development of an Adaptable Non-Invasive Neuromodulation Platform