Liquid Biopsy Following BBB Disruption Using Barrier Disrupting Fields in Patients Undergoing Spine Surgery (BDF002)

Liquid Biopsy Following Blood-Brain Barrier Disruption Using Barrier Disrupting Fields in Patients Undergoing Spine Surgery

Objective: To identify new central nervous system (CNS) biomarkers to be used for blood-derived liquid biopsy once the blood-brain barrier (BBB), specifically the blood-arachnoid barrier (BAB), has been transiently disrupted by BDF in patients undergoing spine surgery.

Design: Single center (Sheba Medical Center), prospective, controlled. Phase: Feasibility study

Endpoints:

Efficacy The primary endpoint of the study is the elevation in blood concentration of CNS biomarkers following the study procedure compared to biomarkers detected in cerebrospinal fluid (CSF) of the same subject.

Safety The primary safety endpoint will be the overall incidence of BDF procedure-related AEs and SAEs, with severity graded according to CTCAE v5.0 criteria.

Study population:

The study population will include up to 20 patients undergoing spine surgery.

Study period:

24 months.

Inclusion criteria:

1. Adult subjects over the age of 18
2. Able to sign informed consent
3. Candidates for intradural tumor resection spinal surgery with intraoperative neuromonitoring.

Exclusion criteria:

1. Pacemakers, or other implanted electric medical devices
2. Pregnant or lactating females
3. Major medical, neurologic or psychiatric condition who are judged as unable to fully comply with the study
4. History of skull fractures or previous brain surgery
5. American Society of Anesthesiologists grade >2
6. Anticoagulants treatment
7. Damage to the dura resulting in CSF leak
8. Patients with seizures/epilepsy

Study procedure:

1. Candidates for intradural tumor resection spinal surgery with intraoperative neuromonitoring will be enrolled in the study prior to surgery.
2. The patient will undergo preparation for surgery according to the standard care.
3. Once anesthetized and intubated, electrodes will be attached to the patient's head.
4. After placing the electrodes, when the patient is under anesthesia, a blood sample will be taken prior to BDF. This sample will be used as baseline for BDF.
5. The patient will then undergo a BDF procedure.
6. Additional blood samples will be taken for identification of CNS biomarkers.
7. Surgery will then proceed according to the standard of care.
8. Once the dura is opened, a CSF sample will be taken, in order to compare the blood biomarkers of the specific subject with the CSF biomarkers.
9. The surgery will continue according to the standard of care.

Study Overview

• Status: Recruiting
• Conditions: Spinal Tumors
• Intervention / Treatment: Procedure: spinal surgery; Device: BDF

Detailed Description

Barrier-disrupting fields (BDF), based on low pulsed electric fields, offer a non-invasive and transient method for selectively opening CNS barriers. We have previously shown that BDF can be applied for efficient delivery of systemically administered drugs into the CNS in rodents. We further demonstrated the application of BDF to enable blood-based detection of brain-derived proteins in rats and mice.

The primary endpoint of the study is the elevation in blood concentration of CNS biomarkers following the study procedure compared to biomarkers detected in CSF of the same subject. The concentration of the biomarkers is expected to be elevated in the blood after the BDF procedure. These include specific CSF proteins such as Protein S100A, S100B and prostaglandin D2 isomerase and include additional proteins identified by us in preclinical experiments in rats, and other CNS-derived molecules that were not identified in our preliminary studies.

Candidates for intradural tumor resection spinal surgery with intraoperative neuromonitoring will be enrolled in the study prior to surgery.

BDF treatment parameters are planned using a simulation package. The distributions of electric fields on the BAB are calculated using a finite elements model, to reach desired electric fields on the BAB needed for inducing BAB disruption. This is done using a simulation package, based on brain MRI after tissue segmentation. Different locations, sizes and distances between the electrodes are modeled in order to reach the optimal setup for obtaining optimal BAB disruption with no BBB disruption.

The patient will undergo preparation for surgery according to the standard care. Once anesthetized and intubated, electrodes will be attached to the patient's head. After placing the electrodes, when the patient is under anesthesia, a blood sample will be taken prior to BDF. This sample will be used as baseline for BDF. The patient will then undergo a BDF procedure. Additional blood samples will be taken post BDF for identification of CNS biomarkers. Surgery will then proceed according to the standard of care. Once the dura is opened, a CSF sample will be taken. The surgery will continue according to the standard of care. Adverse Events will be recorded according to CTCAE V 5.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yael Mardor, PhD; Phone Number: +97235302993; Email: yael.mardor@sheba.health.gov.il, yael.mardor@gmail.com
• Study Contact Backup: Name: Ran Harel, MD; Phone Number: +97235302440; Email: ran.harel@sheba.health.gov.il

Study Locations

• Israel
  • Ramat Gan, Israel, 52621
    • Recruiting
    • Sheba Medical Center
    • Sub-Investigator: Yael Mardor, PhD
    • Contact: Yael Mardor, PhD; Phone Number: +97235302993; Email: yael.mardor@sheba.health.gov.il, yael.mardor@gmail.com
    • Contact: Ran Harel, MD; Phone Number: +97235302440; Email: ran.harel@sheba.health.gov.il
    • Principal Investigator: Ran Harel, MD
    • Sub-Investigator: Itzik Cooper, PhD
    • Sub-Investigator: Maya Nulman, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult subjects over the age of 18
• Able to sign informed consent
• Candidates for intradural tumor resection spinal surgery with intraoperative neuromonitoring.

Exclusion Criteria:

• Pacemakers, or other implanted electric medical devices
• Pregnant or lactating females
• Major medical, neurologic or psychiatric condition who are judged as unable to fully comply with the study
• History of skull fractures or previous brain surgery
• American Society of Anesthesiologists grade >2
• Anticoagulants treatment
• Damage to the dura resulting in CSF leak
• Patients with seizures/epilepsy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: BDF are applied following anaesthesia, blood/CSF samples acquired; Following anaesthesia a blood sample will be acquired, followed by BDF, following by additional blood samples acquisition and finally a CSF sample when opening the dura

Procedure: spinal surgery; Candidates for intradural tumor resection spinal surgery with intraoperative neuromonitoring will be enrolled in the study prior to surgery. The patient will undergo preparation for surgery according to the standard care. Once anesthetized and intubated, electrodes will be attached to the patient's head. After placing the electrodes, when the patient is under anesthesia, a blood sample will be taken prior to BDF. This sample will be used as baseline for BDF. The patient will then undergo a BDF procedure. Additional blood samples will be taken for identification of CNS biomarkers. Surgery will then proceed according to the standard of care. Once the dura is opened, a CSF sample will be taken. The surgery will continue according to the standard of care; Other Names: Barrier disrupting fields; Acquire blood samples; Acquire CSF sample; Device: BDF; electrodes couples (voltage and ground) will be placed on the patient head and will be connected to a pulse generator. 2 electrodes couples will be activated in parallel, up to 8 electrodes couples total. EEG will be acquired after each series of pulses for a few sec.; Other Names: pulsed electric fields

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Elevation in blood concentration of CNS biomarkers following BDF compared to biomarkers detected in CSF of the same subject. The overall incidence of BDF procedure-related AEs and SAEs, with severity graded according to CTCAE v5.0 criteria.	Efficacy We will quantify potential biomarkers in pre- and post- BDF blood samples and expect to see an increase in the blood concentration in the post-BDF samples. The primary endpoint of the study is the elevation in blood concentration of CNS biomarkers including fatty acid or other lipid levels, and/or barrier opening biomarkers and/or unique vascular and cytokines-related proteins and metabolites, following BDF, compared to biomarkers detected in cerebrospinal fluid (CSF) of the same subject. Safety The primary safety endpoint will be the overall incidence of BDF procedure-related AEs and SAEs, with severity graded according to CTCAE v5.0 criteria.	Blood samples will be acquired before and 5 and 10 min post BDF. Another blood sample will be taken before opening the dura. CSF sample will be taken at the time of opening the dura.

Collaborators and Investigators

• Sponsor: Sheba Medical Center
• Investigators: Principal Investigator: Ran Harel, MD, Sheba Medical Center; Study Chair: Yael Mardor, PhD, Sheba Medical Center

Publications and helpful links

General Publications

• Sharabi S, Last D, Daniels D, Fabian ID, Atrakchi D, Bresler Y, Liraz-Zaltsman S, Cooper I, Mardor Y. Non-Invasive Low Pulsed Electrical Fields for Inducing BBB Disruption in Mice-Feasibility Demonstration. Pharmaceutics. 2021 Jan 27;13(2):169. doi: 10.3390/pharmaceutics13020169.
• Sharabi S, Bresler Y, Ravid O, Shemesh C, Atrakchi D, Schnaider-Beeri M, Gosselet F, Dehouck L, Last D, Guez D, Daniels D, Mardor Y, Cooper I. Transient blood-brain barrier disruption is induced by low pulsed electrical fields in vitro: an analysis of permeability and trans-endothelial electric resistivity. Drug Deliv. 2019 Dec;26(1):459-469. doi: 10.1080/10717544.2019.1571123.

Helpful Links

• Israeli ministry of health list of clinical trials

Study record dates

Study Major Dates

• Study Start (Actual): October 16, 2025
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: November 3, 2025
• First Submitted That Met QC Criteria: November 3, 2025
• First Posted (Estimated): November 4, 2025

Study Record Updates

• Last Update Posted (Estimated): November 4, 2025
• Last Update Submitted That Met QC Criteria: November 3, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: liquid biopsy; blood-brain barrier opening; spinal tumors; Barrier disrupting fields; pulse electrical fields; blood-arachnoid barrier opening
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Nervous System Neoplasms; Central Nervous System Neoplasms; Spinal Cord Diseases; Spinal Cord Neoplasms
• Other Study ID Numbers: SHEBA - 25 - 2323 - RH - CTIL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data that underlie the results reported in a published article (text, tables, figures, and appendices) will be available to qualified researchers upon reasonable request.
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal will receive the de-identified individual participant data that underlie the results reported in a published article (text, tables, figures, and appendices) by mail upon providing a methodologically sound proposal
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes