(W1430-01-04) Innovative Device for Concomitant Therapeutic Compound Delivery into the Brain and Neural Recordings - Feasibility Bench and In Vivo Studies

Purpose: Convection enhanced delivery (CED) of therapeutic compounds (e.g. drug, gene or stem cells) into the brain has been increasingly used in clinical trials for a variety of neurological conditions, including Parkinson’s disease, epilepsy and others ^1,2. The existing CED devices consist of cannulas able to deliver infusate, but unable to record neural activity. This severely limits the ability to evaluate compound effects both in acute settings (e.g. impact of delivery on physiological cell activity, compound screening) and long-term settings (e.g. evaluation of therapy efficacy for therapies intended to alter neural activity). We have developed a new device that CED combines delivery with on-site recordings, by taking advantage of the existing stereoelectroencephalography (sEEG) electrodes. These electrodes are FDA cleared for stereotactic implantation in desired brain regions and indicated for temporary ( < 30 days) monitoring, recording and stimulation of neural activity. We modified the sEEG electrodes to incorporate a unique accessory cannula that can be connected to a syringe infusion pump. Here we present design optimization and feasibility data from bench studies and in vivo animal testing.

Methods: Prototypes of sEEG with the added cannula were designed with or without the cannula step and with various step lengths. Bench testing was conducted to evaluate infusion rates, reflux and infusion/diffusion volume relationship. Experiments were performed in 0.6 % agarose gel, an accepted surrogate model for drug delivery into the brain³, using 1% Methylene Blue. In vivo studies were conducted to evaluate feasibility of neural recordings pre- and post- drug delivery. Experiments were performed in urethane anesthetized rat model. The modified sEEG electrode was implanted into the hippocampus using stereotactic atlas coordinates. Baseline neural activity was recorded for ~30 min, after which penicillin (5000 units/µl; 5 µl), an agent known to elicit seizure-like neural activity⁴, was infused at rate of 0.5 µl/min. Tissue was collected in 10% neutral buffer formalin, trimmed and processed for histology. Sections (4 µm) were cut parallel and as close as possible to the sEEG track and stained with hematoxylin and eosin.

Results: The sEEG with the accessory drug delivery cannula was optimized for CED using a step design to prevent backflow.  Agarose gel studies showed that CED was achieved for infusion rates from 0.5 to 15 µl/min and infused volumes from 100-1000 µl. The in vivo experiments showed that penicillin elicited seizure-like episodes consisting of large amplitude bursts of coordinated activity interspaced by quiet periods. Histological examination of the brain tissue showed an ellipsoidal shape diffusion volume centered around the infusion site.

Conclusion: These experiments provide proof of concept that the prototype device is able to perform the desired functions, monitor neural activity and deliver therapeutic compounds.  The availability of drug delivery capability in an sEEG electrode can potentially have significant impact on the screening, safety and efficacy of the pharmacological treatments. In acute settings, real time monitoring of the effect of a drug or therapy on cellular activity can be used as a screening and/or safety indication (e.g. does the compound and/or delivery impact neuronal activity, does it have negative impact on the cells). In long term settings, it can be used to directly assess the onset, mechanism of action and efficacy of therapeutic compounds, especially for therapies intended to alter neural activity (e.g. for epilepsy).

References: 1. Meyer AH, Feldsien TM, Mezler M, Untucht C, Venugopalan R, Lefebvre DR. Novel Developments to Enable Treatment of CNS Diseases with Targeted Drug Delivery. Pharmaceutics. 2023 Mar 29;15(4):1100. doi: 10.3390/pharmaceutics15041100. PMID: 37111587; PMCID: PMC10145602.
2. Richardson RM, Bankiewicz KS, Christine CW, Van Laar AD, Gross RE, Lonser R, Factor SA, Kostyk SK, Kells AP, Ravina B, Larson PS. Data-driven evolution of neurosurgical gene therapy delivery in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2020 Nov;91(11):1210-1218. doi: 10.1136/jnnp-2020-322904. Epub 2020 Jul 30. PMID: 32732384; PMCID: PMC7569395.
3. Chen ZJ, Gillies GT, Broaddus WC, Prabhu SS, Fillmore H, Mitchell RM, Corwin FD, Fatouros PP. A realistic brain tissue phantom for intraparenchymal infusion studies. J Neurosurg. 2004 Aug;101(2):314-22. doi: 10.3171/jns.2004.101.2.0314. PMID: 15309925.
4. Fisher RS. Animal models of the epilepsies. Brain Res Brain Res Rev. 1989 Jul-Sep;14(3):245-78. doi: 10.1016/0165-0173(89)90003-9. PMID: 2679941.

Acknowledgements: This study was funded by NeuroOne Medical Technologies Corporation. Authors AK, MPC, AC, MM, MV, CDB, DD are employees of NeuroOne Medical Technologies Corporation. The funding did not influence the design, execution, and data interpretation.