P0026312.01 PATENT

SENSOR FOR IMPLANTABLE MEDICAL DEVICE

CROSS-REFERENCE [0001] This application claims priority to U.S. Provisional Application Serial No.

60/825,493, filed September 21 , 2006, the disclosure of which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

[0002] The present invention relates to medical devices and, more particularly, to ion sensors on implantable medical leads.

BACKGROUND

[0003] Implantable medical devices (IMDs) detect and deliver therapy for a variety of medical conditions in patients. IMDs include implantable pulse generators (IPGs) or implantable cardioverter-defibrillators (ICDs) that deliver electrical stimuli to tissue of a patient. ICDs typically comprise, inter alia, a control module, a capacitor, and a battery that are housed in a hermetically sealed container. When therapy is required by a patient, the control module signals the battery to charge the capacitor, which in turn discharges electrical stimuli to tissue of a patient through a medical electrical lead.

[0004] Leads deliver pacing, cardioversion or defibrillation pulses via electrodes disposed on the leads, e.g., typically near distal ends of the leads. In that case, the leads may position the electrodes with respect to various cardiac locations so that the pacemaker can deliver pulses to the appropriate locations. Leads are also used for sensing purposes and/or delivery of an agent (e.g. drug, gene etc.).

BRIEF DESCRIPTION OF DRAWINGS

[0005] Aspects and features of the present invention will be appreciated as the same becomes better understood by reference to the following detailed description of the embodiments of the invention when considered in connection with the accompanying drawings, wherein:

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[0006] FIG. 1 is a schematic view of a medical device system;

[0007] FIG. 2 is a schematic view of a medical electrical lead that includes ion- selective electrodes;

[0008] FIG. 3 is a schematic view of a medical electrical lead that includes ion- selective electrodes;

[0009] FIG. 4 is a schematic view of a sensor structure;

[0010] FIG. 5 depicts a chemical reaction for synthesis of a representative fluorinated bis-crown ether-based sodium ionophore;

[0011] FIG. 6 depicts a chemical reaction for synthesis of a representative fluorinated bis-crown ether potassium ionophore; and

[0012] FIG. 7 depicts chemical reactions for synthesis of three representative fluorinated crown ether-based potassium ionophores.

DETAILED DESCRIPTION

[0013] The following description of the preferred embodiments is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses. For purposes of clarity, similar reference numbers are used in the drawings to identify similar elements.

[0014] The present invention is directed to ion sensors on implantable medical leads.

Ion sensors include ion-selective electrodes (ISEs) such as a working electrode and a reference electrode. Each electrode includes an ion-sensing membrane component. The ion-sensing membrane component comprises organic compounds (e.g. polymers such as polyurethane, silicone rubber, ionophores, additives etc.) that are partially, not fully, fluorinated. An organic compound is fully fluorinated when all the hydrogens on the carbon are replaced by fluorine (e.g., - ionophores, additives R- CF ₂ CF ₂ CF ₂ CF ₂ CF ₂ CF ₃ ). In contrast, a partially fluorinated organic compound exists when only a portion of the hydrogens on an organic compound are replaced by fluorine (e.g., R-CH ₂ CH ₂ CH ₂ CF ₂ CF ₂ CF ₃ ).

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[0015] Partial fluorination of one or more organic compounds occurs through fluorination of about less than 5% by weight of the polymer. In another embodiment, organic compounds undergo fluorination by about 1 % to about 5% by weight of the polymer. Partially fluorinated organic compounds in an ion-sensing membrane component increases the fluorophilic interaction in sensor chemistry. Increased fluorophilic interaction (i.e. hydrophobic interaction and fluorophilic interaction) prevents leaching of any sensing components from a sensor membrane, which enhances biostability and extends the useful life of an ISE.

[0016] FIG. 1 depicts a medical device system 100. A medical device system

100 includes a medical device housing 102 having a connector module 104 that electrically couples various internal electrical components of medical device housing 102 to a proximal end 105 of a medical lead 106. A medical device system 100 may include any of a wide variety of medical devices that include one or more medical lead(s) 106 and circuitry coupled to the medical lead(s) 106. By way of example, medical device system 100 may take the form of an implantable cardiac pacemaker that provides therapeutic stimulation to the heart. Alternatively, medical device system 100 may take the form of an implantable cardioverter, an implantable defibrillator, or an implantable cardiac pacemaker-cardioverter-defibrillator (PCD). Medical device system 100 may deliver electrical stimuli to a patient via electrodes 108 disposed on distal ends 107 of one or more lead(s) 106.

[0017] Referring to FIG. 2, lead 106 includes a lead shaft 132 that has a symmetric sensor pair carrying a primary ISE 138 (i.e. the working electrode) for measuring an ion (e.g. potassium (K ⁺ ) ion etc.) and a secondary ISE 134 (i.e. the reference electrode) for measuring an ion (e.g. sodium (Na ⁺ ) ion). An ion has a charge due to gaining (i.e. negatively charged) or losing (positively charged) one or more electrons. An ion is a conductive element that electrically becomes either positive or negative due to its surrounding conductive system. In the heart, the conductive system is the electrolyte of the blood and the heart tissue. Ionic charge is simply a measurement of a voltage or difference in potential. For a cardiac lead, the voltage difference that is measured is between the relatively neutral charge of the blood electrolyte and the charge created within the heart's electrical system traveling down the

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interventricular septum (i.e. center wall of the heart between the right and left ventricles). Conductors 136 and 140 carry the differential electrical signal from shaft 132 to be measured as indicated at 142.

[0018] FIG. 3 illustrates another symmetric ISE pair 150 including a first planar ISE

152 for measuring K ⁺ and a second ISE 154 for measuring Na+. The ISE pair 150 is coupled through conductors 156 and 158 to have the differential electrical potential measured as indicated at 160. ISEs are typically used for blood electrolyte analysis. ISEs include a polymeric sensing membrane that is configured with several functional layers. The sensing membrane is in direct contact with physiological fluid of the body (e.g., blood, subcutaneous (subQ fluid) etc.). Typically, the membrane includes one or more layers of hydrogel, lipophilic ionophore and additive, working electrolyte etc.) and one or more layers of ionophore/additive incorporated polymer. Hydrogel is a network of polymer chains that are water-soluble, sometimes found as a colloidal gel in which water is the dispersion medium. Hydrogels are natural and/or synthetic polymers that are superabsorbent (i.e. may contain over 99% water) and possess a degree of flexibility very similar to natural tissue, due to their significant water content. Exemplary hydrogels include silicone hydrogels, polyacrylamides, cross linked polymers (polyethylene oxide, polyAMPS polyvinylpyrrolidone, polyHEMA) and other suitable compounds. The hydrogel layer that is in direct contact with a solid-state Ag/AgCI electrode contains a fixed amount of electrolytes (e.g. NaCI and KCI, etc.) to fix the electrochemical potentials on the Ag/AgCI electrode surface and at the interface between the hydrogel and polymer layer containing ionophore/additive. Electrolytes (NaCI and KCI, both of which contain a common ion, Cl ^" , that Ag/AgCI has) in the hydrogel can also be completely replaced by fluoride-containing inorganic salts such as AgPF ₆ , and eliminate the need of a hydrogel layer, with the electrode being Ag instead of AgCI. This can potentially increase the mobility as well as the compatibility of the electrolytes within the fluorinated hydrogel.

[0019] Hydrophobic polymers (e.g. polyurethane, silicone etc.) are typically used as the ionophore/additive layer matrix. A matrix is the bulk part of the membrane, film, coating that contain all the additives/ingredients. Within such a matrix, ionophores (ion- selectors) and additives (e.g. tetraphenylborate-type of salts as ion exchangers etc.)

P0026312.01 PATENT

work synergistically to selectively bind the target ions (i.e. ions that are being selectively measured) at the interface between the ion-sensing membrane and body fluid. Electrochemical potential generated at this interface is related to the target ion's concentration in the body fluid. Ion-sensor membrane component(s) such as polymers, ionophore and lipophilic additives are structurally modified by attaching a fluorinated aliphatic side chain or a fluorinated aromatic functional group onto available functional groups of molecules. Exemplary functional groups include carbon-carbon double bond (alkenes), carbon-carbon triple bond (alkynes), halogens, hydroxyl (-OH), carbonyl (C=O), ketones, amino, amides, and nitro. Exemplary partially fluorinated ionophores/additives are presented below:

benzo (15-crown-5) benzo (18-crown-6)

(Rf is a fluorinated side chain) (Rf is a fluorinated side chain)

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calixarene tetraphenylborate, potassium salt

(Rf is a fluorinated side chain) (Rf is a fluorinated side chain)

Skilled artisans understand that the position of a fluoride atom may affect the function of an ionophore; consequently, spacing or placement of a fluoride atom is a possible criteria to be considered when designing a fluorinated ionophore. The degree of fluorination can be adjusted during the molecular design and synthesis of fluorinated organic compounds. Fluorinated side chains with various degrees or percentages of fluorination can be used or attached to the parent ionophore structure by varying the number of fluorinated groups attached or by tuning the fluoride content of the attached group for different purposes. An exemplary partially fluorinated fluorosilicones, as depicted below, are selected as matrices for partial flourination of the above fluorinated lipophilic molecules.

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Flourosilicone

It will be appreciated that fluorosilicone is not only limited to the chemical structure presented above.

[0017] Partially fluorinated fluorosilicones provide silicones that are used to prepare ion sensors due to its desired hydrophobicity, flexibility, processibility and excellent biocompatibility characteristics. Additionally, matrices with fluoropolymers (e.g. polytetrafluorethylene (PTFE) etc.) are widely used in the biomedical device area due to its excellent biocompatibility.

[0018] A partially fluorinated hydrogel replaces conventional non-fluorinated hydrogel

(i.e., polyvinyl alcohol (PVA), polyhydroxyethyl methacrylate (pHEMA), etc.) and operates more compatibly with the above fluorosilicone layer to minimize phase separation or delamination between the hydrogel layer and the hydrophobic polymer layer. Fluorophilic interaction created by a partially fluorinated hydrogel eliminates or minimizes phase separation between the hydrogel layer and the hydrophobic polymer layer. Fluorinated groups of the adjacent layers can actually migrate and/or penetrate to each other therefore anchor/bridge the two layers together at the interfaces, like using glue. The fluorinated PVA can be made, for example, by the reaction of regular PVA with perfluorooctanoyl chloride. The degree of modification can be modulated by the amount of perfluorooctanoyl chloride used. Such modification is not limited to only such fluorinated agent, a large variety of similar agent can be chosen to tailor the hydrogel's property. For example, a bifunctional, fluorinated crosslinker can be used to crosslink PVA chains. Such new hydrogels may exhibit other desired, tunable properties for sensor applications (such as small volume change before/after soaking thereby minimizing sensor drifting).

P0026312.01 PATENT

[0019] Referring to FIG. 4, to simplify, a two-layer sensor structure is reduced to a single-layer sensor structure by completely eliminating a hydrogel layer. The single- layer sensor structure comprises a hydrophobic silver ionophore with a fluorinated side- chain or a fluoro- functional group can be added together with partially fluorinated ionophore in the fluorosilicone, and deposit this sensing material directly on the AgCI substrate. A representative silver ionophore is depicted below.

[0021] Lipophilic silver salt and silver ionophore fixes the AgCI electrochemical potential. This approach simplifies sensor fabrication and avoids the lengthy sensor in situ conditioning period before sensor normal function. Partially fluorinated silver ionophore enhances its stability and hence sensor use-life as a whole.

[0021] A fluorophilic interaction is utilized to prevent leaching of any key sensing components from the sensor membrane therefore to enhance biostability and use-life of implantable biochemical sensors. The claimed invention uses partially fluorinated approach to add a stronger fluorophilic interaction on the existing hydrophobic interaction in the sensor chemistry.

[0022] Table 1 presents exemplary partially fluorinated ionophores, plasticizers and fluorinated polymers used in combination with ionophores. Table 1 includes a chemical class in the first column; the chemical structure of a generic fluorinated ionophore in the second column; an exemplary commercially available chemical structure of a generic fluorinated ionophore in the third column; and in the fourth column, notes related to chemical structures for that particular row.

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Table 1 : List of exemplary fluorinated ionophores, plasticizers and fluorinated polymers used in combination with ionophores

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[0023] Referring to FIGs. 5-7, exemplary chemical reactions are depicted for formation of partially fluorinated organic compounds. FIG. 5 depicts a chemical reaction for synthesis of a representative fluorinated bis-crown ether-based sodium ionophore. Synthesis of a representative fluorinated bis-crown ether-based sodium ionophore includes the following operations:

[0024] (1 ) 2-Hydroxymethyl-12-crown-4 is first reacted with malonyl chloride in tetrahydrofuran (THF) in the presence of triethyl amine as a base.

[0025] (2) The resulting bis-12-crown-4 is deprontonated with sodium methoxide and

[0026] (3) is then reacted with 1 ,1 ,1 ,2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10-

Henicosafluoro-12-iodododecane to form the final fluorinated bis-crown ether as sodium ionophore.

[0027] FIG. 6 depicts a chemical reaction for synthesis of a representative fluorinated bis-crown ether potassium ionophore. Synthesis of a representative fluorinated bis- crown ether potassium ionophore includes the following operations:

P0026312.01 PATENT

[0028] Excess of pentaerythritol is first protected with acetone in acid condition for its two hydroxyl groups. The resulting compound is then reacted with 1 ,1 ,1 ,2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10-Henicosafluoro-12-iod ododecane. Deprotection is then done in basic condition while heating and the resulting compound is then reacted with isocyanate functionalized 15-crown-5 to form the final fluorinated bis-15-crown-5 potassium ionophore.

[0029] Referring to FIG. 7, depicts a chemical reaction for synthesis of three representative fluorinated crown ether-based potassium ionophores. Synthesis of three representative fluorinated crown ether-based potassium ionophores. includes the following operations:

[0030] 4'-Aminobenzo-18-crown-6 is reacted with

1 ,1 ,1 ,2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10-Henicosafluoro-12-iod ododecane to form a fluorinated final compound using an amine linkage. 4'-Aminobenzo-18-crown-6 is reacted with heptadecafluorononanoyl chloride to form a fluorinated final compound with an amide linkage. 4'-Aminobenzo-18-crown-6 is reacted with

2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-heptadecafluorononyl)ox irane to form a mixture of two fluorinated final compounds.

[0031] Another embodiment of the invention involves an optical sensor. An optical chemical sensor is typically made by depositing a very thin polymer layer (1 -5 micrometer) on an optical waveguide or on the tip of a optical fiber, or in some cases, by using a micro to nanopolymer bead capable of optical chemical sensing. To detect specific chemicals, one or two sensing chemicals are incorporated inside the polymer membrane, i.e., to detect the interest analyte and to transducer this detection event into an optical signal.

[0032] By introducing fluorinated side chains to both the sensing polymer and the sensing chemicals incorporated in the polymer, leaching of optical chemical sensing chemicals from the polymer will be slowed down and sensor use longevity and performance stability will be enhanced.

[0033] In another embodiment, an optical sensing polymer formulation, related to potassium sensing is described below. For the carboxylated PVC based potassium selective optode membrane mixture, 1.4wt% of partially fluorinated potassium ion-

P0026312.01 PATENT

selective ionophore F-BM E44, 0.4 wt% partially fluorinated hydrogen selective chromoionophore F-ETH 5350, 65wt% of partially fluorinated bis(2-ethylhexyl)apidic acid (F-DOA) plasticizer, and 33wt% of partially fluorinated polymer (F-pursil), with a total mass of 200 mg dissolved in 1.5 ml freshly distilled tetrahydrofuran. The chemical structures of these compounds are presented below:

F-BM E44

F-DOA

F-Pursil

[0041] To make a fiber optical potassium sensor, 4 micro-liter of the above prepared mixture will be coated on a tapered optical fiber tip. Alternatively, to make a planar optical sensor, 20 micro-liter of the above prepared mixture can be spin coated on a

P0026312.01 PATENT

plastic planar. Still yet another embodiment relates to depositing the mixture inside a flow-through optical cell.

[0042] Micro-bead based micro or nano optical sensor can be prepared by dispensing this mixture directly into an aqueous saline solution and be used in flow-cytometry or other suitable operations.

[0043] It is understood that the present invention is not limited for use in pacemakers, cardioverters of defibrillators. Other uses of the leads described herein may include uses in patient monitoring devices, or devices that integrate monitoring and stimulation features. In those cases, the leads may include sensors disposed on distal ends of the respective lead for sensing patient conditions.

[0044] The leads described herein may be used with a neurological device such as a deep-brain stimulation device or a spinal cord stimulation device. In those cases, the leads may be stereotactically probed into the brain to position electrodes for deep brain stimulation, or into the spine for spinal stimulation. In other applications, the leads described herein may provide muscular stimulation therapy, gastric system stimulation, nerve stimulation, lower colon stimulation, drug or beneficial agent dispensing, recording or monitoring, gene therapy, or the like. In short, the leads described herein may find useful applications in a wide variety of medical devices that implement leads and circuitry coupled to the leads.

[0045] The present invention applies to a wide range of medical uses. For example, the sensor applies to all types of ISEs. An exemplary optical sensor may be seen with respect to U.S. Patent No. 6,165,796 issued December 26, 2000, to Bell et al., the disclosure of which is incorporated by reference in its entirety herein.

[0046] Various embodiments of the invention have been described. These and other embodiments are within the scope of the following claims. Additionally, skilled artisans appreciate that other values may be used for the mechanical and electrical elements described herein.