Methods for blood-brain barrier disruption using electrical energy

• US 10,272,178 B2
• Filed: 02/03/2017
• Issued: 04/30/2019
• Est. Priority Date: 04/29/2008
• Status: Active Grant

• Current Assignee: Virginia Tech Intellectual Properties, Inc. (Virginia Polytechnic Institute and State University)
• Original Assignee: Virginia Tech Intellectual Properties, Inc. (Virginia Polytechnic Institute and State University)
• Inventors: Davalos, Rafael V., Garcia, Paulo A., Rossmeisl, John H.
• Primary Examiner(s): Kim, Taeyoon
• Application Number:
  US15/424,335
• Publication Number:
  US 20170189579A1
• Time in Patent Office: 816 Days
• CPC Class Codes: A61K 35/12 Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells vaccines or medicinal preparations containing antigens or antibodies A61K39/00
• CPC Class Codes: A61L 27/3633 Extracellular matrix [ECM]
• CPC Class Codes: A61L 27/3683 subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
• CPC Class Codes: A61L 27/3691 characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
• CPC Class Codes: C12N 13/00 Treatment of microorganisms or enzymes with electrical or wave energy, e.g. magnetism, sonic waves
• CPC Class Codes: C12N 2533/90 Substrates of biological origin, e.g. extracellular matrix, decellularised tissue
• CPC Class Codes: C12N 5/0068 General culture methods using substrates for specific animal cell type C12N5/06

Abstract

The present invention provides engineered tissue scaffolds, engineered tissues, and methods of using them. The scaffolds and tissues are derived from natural tissues and are created using non-thermal irreversible electroporation (IRE). Use of IRE allows for ablation of cells of the tissue to be treated, but allows vascular and neural structures to remain essentially unharmed. Use of IRE thus permits preparation of thick tissue scaffolds and tissues due to the presence of vasculature within the scaffolds. The engineered tissues can be used in methods of treating subjects, such as those in need of tissue replacement or augmentation.

Claims

1. A method for delivering an agent to a brain tissue of a subject, the method comprising:

placing first and second electrodes in the brain tissue of the subject;

applying a plurality of electrical pulses through the first and second electrodes, which pulses are capable of;

creating an irreversible electroporation (IRE) decellularization zone, and

causing a disruption of the blood-brain-barrier peripheral to the IRE decellularization zone; and

allowing the agent to be transferred to the brain tissue through the disrupted blood-brain-barrier.

2. The method of claim 1, wherein the agent is incapable of permeating an intact blood-brain-barrier into the brain tissue.

3. The method of claim 2, wherein the agent is administered to the subject prior to the applying of the plurality of electrical pulses.

4. The method of claim 2, wherein the agent is a chemotherapeutic agent.

5. The method of claim 1, after applying the plurality of electrical pulses, further comprising detecting the IRE decellularization zone and the disrupted blood-brain-barrier.

6. The method of claim 1, wherein the applying includes applying pulses having a pulse duration of at least 5 microseconds.

7. The method of claim 1, wherein the applying includes applying pulses having a pulse duration of between 5 and 100 microseconds.

8. The method of claim 1, wherein the applying includes applying the plurality of pulses in a manner to cause non-thermal IRE of the brain tissue.

9. The method of claim 2, wherein the agent is administered to the subject after the applying of the plurality of electrical pulses.

10. The method of claim 2, wherein the agent is administered to the subject during the applying of the plurality of electrical pulses.

11. The method of claim 1, wherein the plurality of electrical pulses does not cause IRE in the brain tissue that is peripheral to the IRE decellularization zone.

12. The method of claim 1, wherein the agent is administered systemically to the subject.

13. The method of claim 1, wherein the brain tissue is malignant tissue.