(12) Patent Application Publication (10) Pub. No.: US 2009/0124875 A1 Bentsen Et Al
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US 200901.24875A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0124875 A1 Bentsen et al. (43) Pub. Date: May 14, 2009 (54) IMPLANTABLE CREATININE SENSOR AND Related U.S. Application Data RELATED METHODS (60) Provisional application No. 60/987.942, filed on Nov. 14, 2007. (75) Inventors: James Gregory Bentsen, North St. Publication Classification Paul, MN (US); Misty L. Noble, (51) Int. Cl. Bothell, WA (US) A6B 5/459 (2006.01) (52) U.S. Cl. .............................. 600/341; 600/322; 607/4 Correspondence Address: PAULY, DEVRIES SMITH & DEFFNER, L.L.C. (57) ABSTRACT PLAZA VII- SUITE 3000, 45 SOUTH SEVENTH Embodiments of the invention are related to implantable crea STREET tinine sensors and related methods, amongst other things. In MINNEAPOLIS, MN 55402-1630 (US) an embodiment, the invention includes an implantable crea tinine sensor including a sensing element. The sensing ele ment can include a creatinine deiminase enzyme covalently (73) Assignee: CARDIAC PACEMAKERS, bound to a Substrate and a pH-indicating compound in ionic INC., St. Paul, MN (US) communication with the creatinine deiminase enzyme. The implantable creatinine sensor can also include an optical excitation assembly configured to illuminate the sensing ele (21) Appl. No.: 12/269,510 ment and an optical detection assembly configured to receive light from the sensing element. Other embodiments are also (22) Filed: Nov. 12, 2008 included herein. 5 OO Patent Application Publication May 14, 2009 Sheet 1 of 13 US 2009/O124875 A1 O2 OO OA XXXXXXXXXXXXXXXXX) XXX.X\ XXXXX /N /C O 6 FG O8 2O2 p1 XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 22 XYYYYOYCYYx 2O6 FG 2 2O8 Patent Application Publication May 14, 2009 Sheet 3 of 13 US 2009/O124875 A1 566 56 A. 358 X XC CXXX arXXXX 8 ZY A/Y (XX(X 8XXXXXX) 562 357 F.G. 5 Patent Application Publication May 14, 2009 Sheet 4 of 13 US 2009/O124875 A1 37 9 58 A. 378 5%8% Patent Application Publication May 14, 2009 Sheet 5 of 13 US 2009/O124875 A1 Patent Application Publication May 14, 2009 Sheet 6 of 13 US 2009/O124875 A1 82O/PROGRAMVER 800 a N 8 O2 C REATININE SENSOR 8 OA 8 O 6 OPTICAL EXCITATIONASSEMBLY 8 O8 OPTICAL DETECTIONASSEMBLY Patent Application Publication May 14, 2009 Sheet 7 of 13 US 2009/O124875 A1 92 O-PROGRAMMER CREATININE SENSOR 9 OA SENSINC EEMENT 9 O6 OPTICAL EXCITATIONASSEMBLY 9 O8 OPICAL DETECTIONASSEMBLY FIG. O Patent Application Publication May 14, 2009 Sheet 8 of 13 US 2009/O124875 A1 OOO Patent Application Publication May 14, 2009 Sheet 9 of 13 US 2009/O124875 A1 2 OO 22 FIG 3 Patent Application Publication May 14, 2009 Sheet 10 of 13 US 2009/O124875 A1 3 OO FG. A. Patent Application Publication May 14, 2009 Sheet 11 of 13 US 2009/O124875 A1 Creatinine Deiminase Activity Assay O 2OO 400 6OO 800 1 OOO Concentration (in uglmL) F.G. 5 Patent Application Publication May 14, 2009 Sheet 12 of 13 US 2009/O124875 A1 HPTSAbsorbance in 5 mM Creatinine with Bound CD O.8 ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 50 min O.7 - 41 Post-CreaAddition 0.6 Pre-CreaAddition h 10 min. Post-Crea O.5 Addition O2 O.1 300 350 400 450 500 550 Wavelength (in nm) FIG. 6 Patent Application Publication May 14, 2009 Sheet 13 of 13 US 2009/O124875 A1 HPTSAbsorbance in Creatinine Solutions with unbound CD 0.8 cc, a0 mM Crea H0.1 mM Crea O.7 -0.5 mM Crea - 10 mMCrea -5.0 mMCrea O6 0.5 O4 - 0.5 mM O3 O2 0.1 1-Z OnM O O 2 4 6 8 10 12 14 Time (in min) FIG. 7 US 2009/O124875 A1 May 14, 2009 IMPLANTABLE CREATININE SENSOR AND wound healing phenomena and the host response to the RELATED METHODS implant contributes to the observed signal drift. SUMMARY OF THE INVENTION 0001. This application claims the benefit of U.S. Provi sional Application No. 60/987,942, filed Nov. 14, 2007, the 0007 Embodiments of the invention are related to content of which is herein incorporated by reference in its implantable creatinine sensors and related methods, amongst entirety. other things. In an embodiment, the invention includes a chronically implantable creatinine sensor. The sensor can TECHNICAL FIELD include a sensing element comprising a creatinine deiminase enzyme covalently bound to a Substrate and a pH-indicating 0002 This disclosure relates generally to implantable sen compound in ionic communication with the creatinine deimi sors and, more particularly, to implantable sensors for detect nase enzyme. The sensing element can be configured to ing creatinine, amongst other things. change optical properties in response to changes in creatinine concentrations in vivo. The sensor can include an optical BACKGROUND OF THE INVENTION excitation assembly configured to illuminate the sensing ele 0003 Creatinine is a normal breakdown product of muscle ment and an optical detection assembly configured to receive metabolism and is excreted from the body through the kid light from the sensing element. neys. It is considered to be a clinical marker of renal function. 0008. In an embodiment, the invention includes an Normal serum creatinine concentrations are between 0.6 and implantable medical device. The medical device can include 1.3 mg/dL of blood. When renal function declines, less crea a pulse generator and a chemical sensor in communication tinine is excreted from the body and serum concentrations of with the pulse generator. The chemical sensor can be config creatinine rise. A serum creatinine concentration higher than ured to detect creatinine concentration in a bodily fluid. The 3.0 mg/dL is generally believed to be an indicator of renal chemical sensor can include system failure. 0009 a sensing element comprising creatinine deiminase 0004 Creatinine is an important clinical analyte for vari covalently bound to a Substrate and a pH-indicating com ous heart conditions because of the dependence of proper pound in ionic communication with the creatinine deiminase. renal function on adequate cardiac output. Specifically, crea 0010. In an embodiment, the invention can include a medi tinine is an important clinical analyte for monitoring heart cal system. The medical system can include an external moni failure patients. Heart failure refers to a clinical syndrome in toring device and a chemical sensor in communication with which an abnormality of cardiac function causes a below the external monitoring device. The chemical sensor can be normal cardiac output that can fall below a level adequate to configured to detect creatinine concentrationina bodily fluid. meet the metabolic demand of peripheral tissues. Reduced The chemical sensor can include a sensing element compris cardiac output has a depressing effect on renal function due to ing creatinine deiminase covalently bound to a substrate and decreased renal perfusion, which causes a reduction in Salt a pH-indicating compound in ionic communication with the and water excretion by the pressure natriuresis mechanism creatinine deiminase. and results in increased fluid retention. Chronic reduced car 0011. In an embodiment, the invention can include an diac output can also lead to renal failure and a resulting implantable creatinine sensor. The sensor can include a sens increase in serum creatinine concentrations. Creatinine is ing element comprising an enzyme with creatinine deiminase also an important clinical analyte for monitoring heart failure activity covalently bonded to a Substrate and a pH-indicating patients because the pharmacological therapy prescribed in compound in ionic communication with the creatinine deimi heart failure can accentuate electrolyte imbalance and renal nase. The sensor can also include an optical excitation assem insufficiency. bly configured to illuminate the sensing element and an opti 0005 Typically, clinicians caring for heart failure patients cal detection assembly configured to receive light from the evaluate serum creatinine concentration by drawing blood sensing element. and then using in vitro assays. Such tests can accurately 0012. This summary is an overview of some of the teach determine the serum creatinine concentration of the patient at ings of the present application and is not intended to be an the time of the blood draw. Unfortunately, the use of in vitro exclusive or exhaustive treatment of the present Subject mat assays generally requires that the patient visita care facility to ter. Further details are found in the detailed description and have their blood drawn. As such, when using in vitro assays, appended claims. Other aspects will be apparent to persons there are practical limits to the frequency with which serum skilled in the art upon reading and understanding the follow creatinine concentrations can be assessed. In addition, co ing detailed description and viewing the drawings that form a morbidities commonly associated with renal disease and/or part thereof, each of which is not to be taken in a limiting heart disease, such as diabetes, can make frequent blood sense. The scope of the present invention is defined by the draws risky in some patient populations. appended claims and their legal equivalents. 0006 Significant efforts have been focused on developing implantable sensors. For example, attempts have been made to develop implantable glucose sensors because of the need to BRIEF DESCRIPTION OF THE DRAWINGS frequently monitor glucose levels in the serum of diabetics. However, many implantable glucose sensors have suffered 0013 The invention may be more completely understood from various problems including Substantial signal drift over in connection with the following drawings, in which: time making them generally not suitable for chronic use in the 0014 FIG. 1 is a schematic cross-sectional view of an in vivo environment. It has been postulated that the formation implantable creatinine sensor in accordance with various of a fibrous capsule around the implanted sensor as a result of embodiments of the invention.