# US 10,368,791 B2 · Devices and associated methods for monitoring of neuromodulation using biomarkers

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- Number: US 10,368,791 B2
- Document ID: US10368791B2
- Status: Granted
- Kind: B2
- Application number: 15/296,925
- Filed: 2016-10-18
- Published: 2017-05-11
- Granted: 2019-08-06
- Earliest claimed: 2012-03-08
- Assignees: Medtronic Adrian Luxembourg S.a.r.l.
- Applicants: Medtronic Ardian Luxembourg S.a.r.l.
- Inventors: Ayala Hezi-Yamit; Rudy Beasley; Susan Thornton Edwards; Lori Garcia; Michele Lee Silver; Christopher W. Storment; Carol M. Sullivan; Joseph A. Traina; Stefan Stoyanov Tunev
- Web page: https://patentgrep.com/patent/US10368791B2

## CPC

- A61N 1/3606: {adapted for a particular treatment}
- A61B 5/14503: {invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors (A61B5/1459, A61B5/1464, A61B5/1473, A61B5/1482, A61B5/14865 take precedence)}
- A61B 5/14546: {for measuring analytes not otherwise provided for, e.g. ions, cytochromes}
- A61B 5/15003: {for venous or arterial blood}
- A61B 5/201: {Assessing renal or kidney functions}
- A61B 5/6852: {Catheters}
- A61B 5/6853: {with a balloon}
- A61B 18/1492: {having a flexible, catheter-like structure, e.g. for heart ablation (A61B18/1477 takes precedence)}
- A61N 1/36121: {Production of neurotransmitters; Modulation of genes expression}
- A61B 5/1405: {Devices for taking blood samples (devices for taking samples of other body liquids A61B10/0045)}
- A61B 5/15: Devices for taking samples of blood
- A61B 5/150229: {Pumps for assisting the blood sampling}
- A61B 5/150992: {Blood sampling from a fluid line external to a patient, such as a catheter line, combined with an infusion line; Blood sampling from indwelling needle sets, e.g. sealable ports, luer couplings or valves}
- A61B 5/157: {Devices} characterised by integrated means for measuring characteristics of blood
- A61B 5/20: for measuring urological functions {restricted to the evaluation of the urinary system (A61B5/4375 takes precedence)}
- A61B 5/4035: {Evaluating the autonomic nervous system}
- A61B 5/4836: {Diagnosis combined with treatment in closed-loop systems or methods (A61B5/0036 takes precedence)}
- A61B 5/4848: {Monitoring or testing the effects of treatment, e.g. of medication}
- A61B 5/6858: {with a distal basket, e.g. expandable basket}
- A61B 10/0045: {Devices for taking samples of body liquids}
- A61B 10/007: {for taking urine samples (measuring urological functions A61B5/20; genital receptacles A61F5/451; urinals for bed-ridden persons A61G9/006)}
- A61B 2018/00166: {Multiple lumina}
- A61B 2018/00214: {Expandable means emitting energy, e.g. by elements carried thereon}
- A61B 2018/00232: {having an irregular shape}
- A61B 2018/00279: {deployable}
- A61B 2018/00345: {Vascular system}
- A61B 2018/00404: {Blood vessels other than those in or around the heart}
- A61B 2018/00434: {Neural system}
- A61B 2018/00511: {Kidney}
- A61B 2018/00577: {Ablation}
- A61B 2018/00642: {with feedback, i.e. closed loop control}
- A61B 2018/0212: {using an instrument inserted into a body lumen, e.g. catheter}
- A61N 1/05: for implantation or insertion into the body, e.g. heart electrode (A61N1/06 takes precedence)
- A61N 1/0551: {Spinal or peripheral nerve electrodes}
- A61N 1/32: alternating or intermittent currents {(applying electric fields by inductive or capacitive coupling A61N1/40; microwave apparatus A61N5/02)}
- A61N 1/3605: {Implantable neurostimulators for stimulating central or peripheral nerve system}
- A61N 1/36135: {using physiological parameters}
- G01N 2800/347: Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Provided herein are methods, devices, compositions, and kits for monitoring neuromodulation efficacy based on changes in the level or activity of one or more target biomarkers.

## Claims

### Claim 1

A catheter for determining biomarker activity in a human patient during a neuromodulation procedure, the catheter comprising:
an elongated shaft including a distal portion configured for transluminal delivery to a target blood vessel of a human patient;
an energy delivery element at the distal portion of the shaft and configured to, during an ablation procedure, deliver energy sufficient to at least partially ablate target neural fibers adjacent to the target blood vessel of the patient;
a capture compartment configured to intravascularly obtain a volume of at least one type of biomarker from the patient, wherein the at least one type of biomarker is secreted as a result of the ablation procedure; and
an analyzer operably coupled to the shaft, wherein the analyzer is configured to receive at least a portion of the volume and detect a concentration of one or more types of biomarkers from the portion of the volume, and wherein the concentration corresponds, at least in part, to a degree of ablation of the target neural fibers.

### Claim 2 (depends on 1)

The catheter of claim 1, further comprising a distal filter at a distal end of the capture compartment, wherein the distal filter is configured to allow passage of the volume of the at least one type of biomarker through the distal filter into the capture compartment while preventing passage of volumes of other biomolecules through the distal filter into the capture compartment.

### Claim 3 (depends on 1)

The catheter of claim 1, further comprising a proximal filter at a proximal end of the capture compartment, wherein the proximal filter is configured to prevent passage of the volume of the at least one type of biomarker out of the capture compartment through the proximal filter while allowing blood to flow through the proximal filter and out of the capture compartment.

### Claim 4 (depends on 1)

The catheter of claim 1 wherein the capture compartment comprises one or more filters positioned to concentrate biomarkers of the one or more types of biomarkers within the capture compartment.

### Claim 5 (depends on 1)

The catheter of claim 1 wherein the analyzer is configured to detect the concentration within 1 minute of energy delivery from the energy delivery element sufficient to at least partially ablate the target neural fibers.

### Claim 6 (depends on 1)

The catheter of claim 1 wherein the analyzer is configured to detect the concentration within 5 minutes of energy delivery from the energy delivery element sufficient to at least partially ablate the target neural fibers.

### Claim 7 (depends on 1)

The catheter of claim 1 wherein the analyzer is configured to detect the concentration within 15 minutes of energy delivery from the energy delivery element sufficient to at least partially ablate the target neural fibers.

### Claim 8 (depends on 1)

The catheter of claim 1 wherein the analyzer is configured to detect the concentration within 30 minutes of energy delivery from the energy delivery element sufficient to at least partially ablate the target neural fibers.

### Claim 9 (depends on 1)

The catheter of claim 1 wherein the energy delivery element comprises an electrode.

### Claim 10 (depends on 1)

The catheter of claim 1 wherein the energy delivery element comprises a radio frequency (RF) electrode.

### Claim 11 (depends on 1)

The catheter of claim 1 wherein the energy delivery element comprises a RF transducer.

### Claim 12 (depends on 1)

The catheter of claim 1 wherein the energy delivery element comprises a cryotherapeutic cooling assembly.

### Claim 13 (depends on 1)

The catheter of claim 1 wherein the energy delivery element is one of a plurality of energy delivery elements.

### Claim 14 (depends on 1)

The catheter of claim 1 wherein:
the energy delivery element is one of a plurality of energy delivery elements at the distal portion of the shaft; and
the energy delivery elements are carried by a neuromodulation element transformable between a low-profile delivery state and a deployed state tending to assume a spiral or helical shape, and wherein, in the deployed state, the neuromodulation element is sized and shaped to position the energy delivery elements in apposition with one or more treatment positions along the inner wall of the target blood vessel.

### Claim 15 (depends on 1)

The catheter of claim 1 wherein the capture compartment is adjacent to the energy delivery element and adapted to be located within the patient while obtaining the volume of the at least one type of biomarker.

### Claim 16 (depends on 1)

The catheter of claim 1 wherein the capture compartment is located external to the patient while obtaining the volume of the at least one type of biomarker.

### Claim 17 (depends on 1)

The catheter of claim 1 wherein the at least one type of biomarker comprises BDNF.

### Claim 18 (depends on 1)

The catheter of claim 1 wherein the at least one type of biomarker is selected from the group consisting of ADRA2b, ATP1A1, BDNF, BMP7, BNP, BTG2, CALCB, CD40L, CDKN1B, CDKN2B/p15, CLU, DNAJA4, DNAJB1, EDN3, ETB, FASLG, FOS, HMOX-1, HSPA5, HSPA14, HSPB1, HSPD1, HSPH1, IL-10, ITGAM, KLKB1, LIF, MC2R, NTF3, P2RY12, SELE, SLC2A5/GLUT5, SOD2, TLR3, TLR4, TLR7, and TNFRSF1B.

### Claim 19 (depends on 1)

The catheter of claim 1 wherein the at least one type of biomarker is selected from the group consisting of CASP10, CCL13, CCND1, CD70, CRYAB, CPS1, DNAJB1, DNAJB11, HSPA1A, HSPA1B, HSPB6, IL-10, KIT, LTA, MYLK3, NODAL, NPY1R, POU1F1, and TCP1.

### Claim 20 (depends on 1)

The catheter of claim 1 wherein the at least one type of biomarker is selected from the group consisting of ACTA2, CACY/2A9, CFL1, CTAG1A1/CTAG21, LDHA, MGC141/TMEM141, NAA20/NAT5, NM23B, PAHX/PHYH1, PFDN1, PLK-2, TUBA1B, and VIM.

### Claim 21 (depends on 1)

The catheter of claim 1 wherein the at least one type of biomarker is selected from the group consisting of SNCA, BDNF, CNTF, FGF2, GDNF, NGF2, NTF3, PF4, EDN2, ACE2, IFN-γ, ARTN, LIF, CBLN1, NRG1, NRG2, NRG4, PSPN, NTF4, and TGFA.

### Claim 22 (depends on 1)

The catheter of claim 1 wherein the at least one type of biomarker is selected from the group consisting of NE, CFL1, NPY, DBN, Ca2+, renin, DBH, AGT, endothelin 1, 2, and 3, NTS, and APP.