WO2007081741A2

WO2007081741A2 - Implantable wireless fluid flow monitoring system

Info

Publication number: WO2007081741A2
Application number: PCT/US2007/000162
Authority: WO
Inventors: Richard J. Cohen; Baruch Schori; Peter Nathan Madras
Original assignee: Massachusetts Institute Of Technology
Priority date: 2006-01-04
Filing date: 2007-01-03
Publication date: 2007-07-19
Also published as: WO2007081741A3

Abstract

Fluid flow monitoring system. Structure for implantation in association with vascular tissue is provided. Fluid flow monitoring apparatus is supported on the structure to generate a signal related to fluid flow. A wireless transmitter supported on the structure transmits the signal outside the body. A reader external to the body is provided for wirelessly energizing the monitoring apparatus and transmitter and for receiving the transmitted signal. The external reader also displays fluid flow velocity and/or rate.

Description

Implantable Wireless Fluid Flow Monitoring System

This application claims priority to Provisional Application Serial No. 60/756,006 filed January 4, 2006 entitled, "Method and Device for Arterial Blood Flow Measure," the contents of which are incorporated herein by reference.

Background of the Invention

This invention relates to fluid flow monitoring apparatus and more particularly to an implantable, wireless system for body fluids flow measurement. 1. Arterial Blood Flow in Bypass Grafts and Stents

Coronary artery disease affects approximately seven million Americans, causing 1.5M myocardial infarctions and over half a million deaths per year at an estimated cost exceeding $100B.⁶ Peripheral artery disease affects a similar number of patients. Superscript numbers refer to the attached references, the contents of which are incorporated herein by reference. Coronary artery disease and peripheral artery disease are the result of a complex, years-long process called atherosclerosis, in which cellular intimal and mineral additives, fatty and clotting debris accumulate and deposit in the arterial vessel walls, forming a plaque comprised of cells, lipids (fats or cholesterol) and fibrous tissue (mostly collagen). This process may lead to a narrowing of the vessel lumen (stenosis), and reduction of blood flow (ischemia). Symptoms include angina pectoris (chest pain), and myocardial infarction (heart attack) in the case of coronary artery disease, and intermittent claudication (leg and foot pain) in the case of peripheral artery disease. In addition, the formed plaque is susceptible to rupture, resulting in an inflammatory process culminating in thrombus (clot) formation and acute cessation of blood flow to the heart, and leading to acute coronary syndrome, myocardial infarction, limb loss, stroke or sudden death.⁷ Nearly a million new angioplasty constructions followed by implantation of a coronary stent - a mechanical device designed to keep the artery open - are performed every year in the United States in order to treat and overcome arterial stenosis related to blood vessel diseases⁶'⁷. The use of peripheral stents for similar reasons is rapidly growing as well.

Although such procedures are relatively common and have been proven to save hundreds of thousands of lives every year, they do not eliminate the underlying pathophysiology that initially led to arterial stenosis, and pose additional challenges. Post surgery patients implanted by bare-metal stents are still at a relatively high risk for vessel stenosis and occlusion at the site of the stent, and in 20-30% of the cases, stenosis persists and leads to narrowing and reblocking of the stented artery (stent restenosis) over time (typically at six-months).^1"5 This stent restenosis occurs due to the body's response to the "controlled injury" of angioplasty which is characterized by vascular smooth muscle cells migration into the lumen of the stent and proliferation, thus forming scar tissue which encroaches on the lumen and either forces the stent to close or accumulates within the stent and restricts blood flow in the arteries. Drug-eluting stents - coated with a thin polymer that slowly releases an antiproliferative drug - were recently approved for use. While clinical trials assessing the efficacy of drug-eluting stents after 1 year of patient follow-up have shown encouraging results - reducing the frequency of vessel retreatment to less than 5%^8"18 - it remains unclear whether the drug-eluting stents are inhibiting or simply delaying restenosis. Ongoing clinical trials of two dominant drug-coated stents - Johnson & Johnson's Cypher stent¹⁹'²⁰ and Boston Scientific Corp.'s Taxus stent²¹ - presented new evidence of longer-term blood clots, raising concerns that there is an increase in potentially deadly blood clots in patients' arteries that have been implanted with drug-coated stents.²²'²³

Stenosis and blood clotting at the site of the stent may eventually lead to clinical symptoms such as myocardial infarction, stroke or limb loss, and if overlooked might lead to death, which raises two major questions - which stent will fail, and how to monitor the entire post surgery population in a cost effective manner. Nevertheless, the progress of restenosis as well as the formation of blood clots in these patients is nearly impossible to monitor with current imaging technologies (see Table 2), consisting of extremely invasive, costly and risky methods such as Catheter Angiography (CA), or non-invasive, but extremely expensive tests such as Magnetic Resonance Imaging (MRI) scan and specifically Coronary Magnetic Resonance Angiography (MRA). For instance, MRA fails to provide imaging of vessels containing a stent and often shows signal void at the location of a metallic implant, rendering evaluation of the lumen impossible.²⁴'²⁵

The gold standard treatment therefore remains the indirect stress test of symptomatic patients only, which if positive, is followed by diagnostic CA.²⁶'²⁷ These techniques, being used selectively and periodically, and being conducted in a stationary setup, result in a very late diagnosis, if at all, only when the stent is over seventy percent occluded. Such a high percentage of occlusion coupled with late diagnosis places the patient at very high risk and leads to expensive inefficiencies - all treated patients are administered extensive, long-lasting anti-clotting medications as a preventive means, and a significant portion of patients needs a repeat procedure or further treatment to reduce blockage and restore perfusion. These inefficiencies result in extensive burdens, both financial and clinical, on the health system, such as surveillance direct costs, repeat intervention risks and caregiver expenses.

For coronary and peripheral stents current surgical interventions are palliative and do not cure the underlying disease, leaving the patients highly susceptible to vessel restenosis and occlusion. Invasive and non-invasive methodologies with improved specificity and sensitivity are therefore critical for vessel surveillance and subsequent treatment of vessel stenosis and occlusion. 2. Blood Flow in Dialysis Grafts

Over 600,000 hemodialysis procedures, and approximately 100,000 new dialysis graft constructions are performed every year in the United States in order to treat patients suffering from an end stage renal disease and other renal diseases (see Table 1 for procedure breakdown). While such surgeries are very common and facilitate dialysis in hundreds of thousands of patients every year, they do not eliminate the underlying mechanisms that led initially to renal failure in the patient, and are susceptible to additional factors, leading to graft narrowing and occlusion. Graft occlusion reduces dialysis effectiveness which may eventually lead to clinical symptoms and if overlooked might lead to death. Within five years of surgery, a significant portion of patients require additional surgical intervention.

3. Cerebrospinal Fluid in CSF Shunts

Hydrocephalus is a condition in which the primary characteristic is excessive accumulation of cerebrospinal fluid (CSF) in the brain. The excessive accumulation of CSF results in an abnormal dilation of the spaces in the brain called ventricles. This dilation causes potentially harmful pressure on the tissues of the brain. Hydrocephalus may result from genetic inheritance (aqueductal stenosis) or developmental disorders such as those associated with neural tube defects including spina bifida and encephalocele. In infants, symptoms of hydrocephalus include the rapid increase in head circumference or an unusually large head size, as well as vomiting, sleepiness, irritability, downward deviation of the eyes (also called "sunsetting"), and seizures. In older children and adults symptoms may include headache followed by vomiting, nausea, blurred vision, sunsetting of the eyes, poor coordination, balance and gait disturbance, urinary incontinence, and developmental impairment^54'56. The reported incidence of infantile hydrocephalus is approximately 2 to 4 per 1000 live births. It ranks as the second most common congenital neurological malformation in North America, after spina bifida. However, this is probably a gross underestimate of the overall incidence, since many cases of hydrocephalus are associated with other conditions and are not diagnosed until later in life⁵⁴.

Based on the 1988 United States National Health Interview Survey, it has been estimated that there are 70,000 discharges a year from hospitals in the United States with a diagnosis of hydrocephalus, and 25,000 shunt operations are performed each year in the United States. Approximately 40% of shunts experience mechanical failure in the first year that requires re- operation⁵⁵.

CSF shunting procedures account for almost $100 million dollars of national health care expenditures in the United States, with nearly half of these dollars are spent on shunt revisions⁵⁵.

Table 1- Statistics on surgeries performed in order to treat and overcome arterial stenosis related to blood vessel diseases, dialysis access related to renal failure, and CSF shunt placement related to hydrocephalus

Current surveillance methodologies include broad categories to assess vessel patency.²⁶ In general, these methodologies can be separated into two categories - direct flow observation by using radiological techniques, that are dangerous, uncomfortable and invasive; and indirect flow measurements, such as scans, stress tests, etc. that infer flow characteristics by watching the reaction of the heart or relevant vessels, that are less specific and less sensitive.

The current most common direct method of blood flow assessment, catheter angiography (CA), often called arteriography - which involves skin and arterial puncture with vessel catheterization by insertion of a thin plastic tube (catheter) into an artery in the arm or leg, advancement into the coronary arteries or other target arteries, and injection of a dye visible by X-ray into the bloodstream - is highly invasive, with associated long-term risk of renal failure, bleeding, and stroke.

Computed tomography angiography (CTA) is a less invasive procedure and uses a small peripheral vein instead of an artery for dye injection, but the technology can not reliably image small, twisted arteries or vessels in rapidly moving organs such as the heart, and therefore is not readily a substitute for CA.

Nuclear imaging tests such as radionuclide ventriculography or multiple-gated acquisition scanning (MUGA), positron emission tomography (PET) or thallium stress test all involve injecting a radioactive dye into a vein, then using tomographic imaging to take pictures of the heart as it pumps blood. These tests suffer from rapid dissolution of dye, require expensive gamma imaging cameras and are able to give a positive result only above 70% vessel occlusion.

Another invasive technique, referred to as "intravascular ultrasound", in which a miniature ultrasound transducer in inserted by a catheter into a vessel to monitor blood vessel acoustic impedance has yet to prove its efficacy.

Indirect methods include diagnostic ultrasound or echocardiography - a safe, painless test that generates a sound wave that bounces off the heart or target vessel, creating images of the hearts' chambers and valves or the vessel lumen, allowing examination of its structure and motion. This technique has gained popularity in assessing non-coronary flow velocities but remains insensitive in general to coronary vessels and cannot detect an occlusion that is less than 50% of the vessel lumen.

Magnetic resonance imaging (MRI), another indirect method, and specifically magnetic resonance angiography (MRA) produces images of flowing blood and has become the modality of choice for angiography due to its non-invasiveness. It suffers from low spatial resolution, however, and is not adequate for diagnosis and treatment planning for small vessels (3 to 4 mm in diameter) and, in particular, for the coronary arteries due not only to their size, but also to their tortuous and complex pathway, the abundant signal from surrounding epicardial fat, and the significant motion associated with both respiration²⁸'²⁹ and cardiac motion. In addition, a major obstacle for coronary MRA imaging is the use of intracoronary stents. Although not a contraindication for MRA³ , local signal voids or artifact associated with implanted metallic objects such as intravascular stents preclude assessment of the stented portion of the vessel.³¹

A stress test, sometimes called a treadmill test or exercise test, gradually increases heart demand for oxygen thus requiring the heart to pump more blood and thereby reveals coronary insufficiencies. The stress test remains the gold standard to assess heart performance, but is limited in nature for some patients and can subject patients with a dysfunctional heart to exercise loads that pose additional risk.

Table 2 - Current Diagnostic Methods

Currently employed methodologies are unable to screen the asymptomatic, general population of post-surgery patients for vessel occlusion. Traditional testing methods are time consuming, often invasive, expensive and associated with risk to patients. Large groups of post-surgical patients are therefore at risk for clinically silent vessel occlusion leading to myocardial infarction, loss of limb, stroke and sudden death. In addition, currently available methodologies are not specialized for frequent blood flow determinations during the convalescent period. By ignoring the changing physiology of coronary arteries and peripheral arteries' blood flow, data from current techniques provide static anatomical measurements and misinterpret physiological, hemodynamic changes seen in these vessels. A better methodology would be capable of monitoring hemodynamic conditions over extended periods of time to allow dynamic assessment of such changes.

Besides the blood flow measurement mechanism used, other aspects of modern vessel surveillance and care are non-optimal. Currently employed techniques require outpatient hospitalization, critical operator expertise and have traditionally been restricted to cardiac catheterization laboratories and intensive care units (ICUs). Such measurements cannot be made easily in ambulatory settings, or under conditions of cardiac loading, such as exercise, and therefore result in inconsistent information. A better technique would permit simplified, rapid and real-time vessel interrogation.

A preferred arterial flow measurement approach would include: (1) non-invasive technique, (2) easy deployment of the measuring element, (3) efficacy for all types of coronary and peripheral stents and bypass grafts, and (4) optimal post-surgical assessment and care of the vessel. Prior art systems and devices for measuring coronary artery flow rate and arterial blood velocity will now be discussed. Ohlsson et al³² describe implantation of a pressure sensor and an oxygen sensor, the IHM-I, Model 10040 (Medtronic, Inc.)- However, in this study, 12 out of 21 oxygen sensors failed within the first 6 months of implantation, probably because sensors were being coated by fibrous tissue. In addition, surgical implantation of this pacemaker-style device requires a 2-3 hour procedure in the operating room, which is more costly than a catheterization procedure to insert a pressure sensor. Data from this study, however, points to the importance of long-term, continuous pressure monitoring, as opposed to one-time measurements using standard cardiac catheterization techniques.

In U.S. Pat. No. 6,053,873: Pressure-sensing stent issued Apr. 25, 2000 to Govari, Assaf et al, a method of monitoring flow rates within a stent is described. In particular, the use of ultrasonic sensors to monitor blood flow rates is described. However, due to the change in composition and thickness of the biological material present on the sensor surface, the boundary conditions at the sensor may change over time. Initially, the sensor surface, which may be calibrated against blood, may become covered with a layer of thrombus over time. Subsequently, the thrombus will transform into fibrous tissue, affecting the absorption of the ultrasound signal. Blood may have an ultrasound absorption level similar to water, of around 0.002 dB/MHz cm, while the fibrous tissue layer may have an absorption level similar to muscle, of around 2 dB/MHz cm. Thus, such a sensor may require periodic re-calibration. Unfortunately, the re-calibration process requires an invasive cardiac catheterization procedure, in which flow rates are determined using ultrasound, thermodilution, or the Fick method. In order to avoid additional interventional procedures, a fouling-resistant approach may be valuable.

Another approach to the use of pressure sensors to quantify pulsatile flow in vessel is disclosed in U.S. Pat. No. 6,237,398: System and method for monitoring pressure, flow and constriction parameters of plumbing and blood vessels, issued May 29, 2001 to Porat, Yariv, et al. In this patent, two spaced pressure sensors are attached to the inner walls of a blood vessel for recording pressure records on the basis of which pulsatile flow is quantified. It has been shown that variations in intraluminal pressure are being compensated for by the body by means of a change in flow rate, preventing obtaining a measurable, significant pressure drop only until approximately 70 percent of the vessel is occluded.⁵⁰ Therefore, measuring pressure might not be the best approach to monitor subtle changes in vessel patency to fine tune a post procedure treatment regimen.

Another method of ultrasonic Doppler monitoring of blood flow in a blood vessel is disclosed in U.S. Pat. No. 5,289,821: Method of ultrasonic Doppler monitoring of blood flow in a blood vessel issued Mar. 1, 1994 to Swartz, William M., wherein an ultrasonic transducer-conducer wire assembly is removably attached to a non-removable cuff around a vessel, to monitor blood flow within the blood vessel. After completion of monitoring the ultrasonic transducer-wire assembly, but not the cuff, is removed from the patient. This method is clearly highly invasive and allows monitoring of blood flow only during the procedure.

In U.S. Pat. No. 6,729,336: In-stent restenosis detection, issued May 4, 2004 to Da Silva, Luiz B., et al., an apparatus is described that can be used to detect stent restenosis using an acoustic sensor to detect stent acoustic oscillations. In U.S. Pat. No. 6,308,715: Ultrasonic detection of restenosis in stents, issued Oct. 30, 2001 to Weissman, Eric M., et al., a diagnosing method is described which utilizes a similar concept of exciting the stent structure to produce an acoustic signal indicative of the diagnosis. The acoustic signal is then analyzed to predict the degree of restenosis experienced by the stent. In both methods disclosed, ultrasonic waves are used to assess indirectly the level of stenosis within the stent, by predicting material composition and the thickness of the wall around the stent rather than to assess blood flow velocity. Such an indirect approach can only estimate the vessel patency and is not complete - material composition, as well as wall thickness, might present asymmetric patterns which make it nearly impossible to accurately assess patency. In addition, exciting an intraluminal acoustic vibration at a site of potential stenosis might pose an additional risk of plaque rupture and thrombosis.

In U.S. Pat. No. 6,309,350: Pressure/temperature/monitor device for heart implantation, issued Oct. 30, 2001 to VanTassel, Robert A., et al, a sensor is described which is anchored in the wall of the heart, or in a blood vessel. However, no mention is made of the problem of sensor fouling due to thrombus formation, or how to compensate for such fouling. Pressure sensors require recalibration as a softer thrombus transforms into neointimal tissue, or as the thickness of the encapsulating tissue layer changes. While the device could be initially calibrated during implantation, it would need to be recalibrated over time. Because recalibration requires an invasive cardiac catheterization procedure, it would be desirable to avoid this if at all possible.

In addition, VanTassel et al. suggest the use of standard therm odilution methods to determine flow rates. Thermodilution is normally performed by injection of either room temperature or iced saline through a catheter. However, it is desirable to avoid re- interventions if possible. Therefore, standard thermodilution methods are less desirable. In addition, it is impractical to use the sensor in the standard method, i.e., by locally cooling the blood, because chilling units are impractically large for implantation as a sensor. Further, thermodilution methods would be inaccurate if a relatively thick layer of cells covered a thermocouple or other sensing element. Such inaccuracy would be especially true if only a small temperature rise were introduced into a large volume of flowing blood, such as in the pulmonary artery. Larger temperature rises (>2.5 degree C) would cause local tissue damage.

Another approach of thermodilution is disclosed in U.S. Pat. No. 5,598,847: Implantable flow sensor apparatus and method, issued Feb. 4, 1997 to Renger, Herman L., in which a pyroelectric sensor in a rigid cylindrical tube is implanted intraluminally to measure the resultant temperature change of blood, produced by a heater, to indicate the blood flow rate through the blood vessel or artery. By using a rigid tube this approach suffers several drawbacks - a rigid tube may limit the device usage, by constraining its deliverability by a catheter, limiting the treated arteries to ones with a relatively larger diameter. A rigid structure may compromise vessel elasticity and induce friction or irritation of surrounding tissues, such as the vessel endothelium, the epicardium, and the visceral layer of the pericardium. It may also increase the long-term risk of thrombosis along the tube. In addition, the amount of energy required to significantly increase the blood volume that flows through the tube to a measurable level is higher so as to allow an external reading of physiological conditions.

In U.S. Pat. No. 5,271,408: Hydrodynamic system for blood flow measurement, issued Dec. 21, 1993 to Breyer, Branko, et al., a hydrodynamic system for blood flow measurement is disclosed. Two spaced passive transducers are mounted at the exterior surface of a catheter implanted within the vascular vessel, the first with a protrusion in the form of a hydrofoil profile, and the other with a flat surface at the exterior of the catheter. The transducer having the hydrofoil profile generates a signal due to the quasi-static pressure acting on the transducer as well as due to the drag force acting on the transducer caused by the blood flow. The other transducer generates a signal solely due to the quasi-static pressure. Their respective signals are subtracted in a differential amplifier, so that a signal proportional to the axial flow velocity is obtained. The insertion of the catheter into the vessel lumen for a long period, as well as the transducers' required interaction with the blood flow, poses a significant risk of thrombosis formation on the catheter's or transducers' surfaces, and makes its long-term functionality questionable after the transducers' surface is coated by endothelium or restenosis. Notwithstanding the extensive efforts in the prior art, however, there remains a need for an implantable blood velocity/flow sensor, which can provide useful flow measurements for an extended period of time, without material interference from thrombus formation, embolization, or other foreign body response. Preferably, such a sensor is capable of continuous or near continuous monitoring, making data available to the patient or medical personnel. Summary of the Invention

In one aspect, the invention is a fluid flow monitoring system including structure for implantation in association with vascular tissue. Fluid flow monitoring apparatus is supported on the structure to generate a signal related to fluid flow. A wireless transmitter is supported on the structure for transmitting the signal outside the body. A reader external to the body wirelessly energizes the monitoring apparatus and transmitter, receives the transmitted signal, and displays fluid flow rate. In a preferred embodiment, the structure is a stent implanted within the vascular tissue. The fluid flow monitoring apparatus may include at least one electrically conducting coil. In this embodiment, the wireless transmitter includes an RFID tag that receives a signal from the coil. In this embodiment, the reader energizes the monitoring apparatus through electromagnetic induction. Alternatively, the fluid flow monitoring apparatus may be a thermodilution system sensing a temporal temperature gradient. The thermodilution system may include means for locally heating or cooling blood. The thermodilution system may also include a thermocouple or thermistor for measuring temperature. In a preferred embodiment, the vascular tissue is a coronary artery and the stent is a coronary stent.

In another aspect, the structure is a sheath integrated into vascular tissue such as a dialysis access graft. In this aspect, the fluid flow monitoring apparatus may be a thermodϊlution system or an anemometry system. It is preferred that the sheath be coated with silicon.

In another aspect, the structure is a sheath integrated into a tubular device such as a CSF shunt.

The invention allows blood flow to be monitored so as to detect conditions such as restenosis or to monitor occlusion in vessel grafts. Brief Description of the Drawing

Fig. 1 is a perspective view of an embodiment of the invention in conjunction with a coronary stent.

Fig. 2 is a cross-sectional view of the device illustrated in Fig. 1.

Fig. 3 is a perspective view of an embodiment of the invention installed in association with a coronary artery and also showing an external reader.

Fig. 4 is a schematic illustration of a flow circuit in an experimental embodiment of the invention.

Fig. 5 is a perspective view of another embodiment of the invention in association with a dialysis access graft.

Fig. 6 is a cross-sectional, perspective view of the flow sensor of Fig. 5. . Description of the Preferred Embodiment

There are several techniques well known for use in flow meters that can be used for non-invasive monitoring of vessel patency. Velocity sensor techniques may be based on electromagnetic, ultrasonic and thermodilution designs. Two preferred velocity sensor technologies for use in the present invention are electromagnetic flow meters and thermodilution systems. The operation of electromagnetic flow meters derives from Faraday's law of electromagnetic induction in which a voltage will be induced when a conductor moves through a magnetic field. Because blood is an electrically conductive liquid, it can serve as a conductor. When blood passes through a magnetic field generated by energized coils, the motion will generate a voltage across coil electrodes. In particular, the amount of voltage (E) developed across the electrodes will be proportional to the diameter of the vessel (D), the magnetic field density (B) generated by the coils, and the velocity (V) of blood flow related by the following equation E=VxBxD. If B and D are known the blood flow velocity V can be easily deduced by measuring E. Electromagnetic flow meters have an expected inaccuracy of 0.2-1% of the velocity.

Thermodilution measurement systems sense a temperature gradient of blood for a specific time period. An initial blood temperature change is produced either by injection of iced saline through a catheter to cool locally the blood, or by a heater to heat locally the blood. A thermocouple, thermistor or other sensing element responds to the resulting temperature change of the blood which is indicative of blood flow rate through the blood vessel or artery.

Those of ordinary skill in the art will recognize that other flow meter methodologies may be utilized in the present invention such as ultrasonic flow meters.

The device of the invention is an implantable, wireless sensor able to measure flow rate and communicate its measured data to an external source. In a preferred embodiment, the implantable, wireless sensor will be incorporated on or within a stent in order to measure blood flow velocity and/or rate in the stent post angioplasty and stenting surgery. The device may be adhered to the stent wire mesh in a way that its layout will not extend beyond the stent footprint thereby allowing for vascular spontaneous contraction and dilation while insuring mechanical flexibility and fixation to the stent. It is preferred that the device of the invention be attached to the stent as part of the stent's manufacturing process and delivered to the patient's vascular system together with the stent. With reference to Figs. 1 and 2, blood monitoring apparatus 10 includes a coronary stent 12 and coils 14. This embodiment also includes an RFID tag 16. As shown in Fig. 3 the blood flow monitoring system 10 is associated with a coronary artery 18. As shown in Fig. 3 the RFID tag 16 wirelessly communicates with an external reader 20. Any other wireless technology may be used.

In operation, the external reader 20 will impress an external electromagnetic field on the coils 14. The external reader 20 will also deliver radio frequency energy to the RFID tag 16 to activate its microprocessor. Because blood is a conductor, its flow will induce a voltage across coil leads in the presence of the externally generated magnetic field. This voltage is transmitted by the RFID tag 16 to the external reader 20. The external reader 20 then displays blood flow velocity which is proportional to the voltage detected across the leads of the coil as discussed above.

An alternative technique for measuring blood flow is a thermodilution system. In one embodiment, a constant heating thermistor adhered to stent wire mesh, induced by an external electromagnetic field, will be altered by blood flow that facilitates rapid dissipation of heat from the thermistor into the blood stream. Flow characteristics are deduced by measuring, after a time shift from initial heating, the thermistor resistance which is proportional to the thermistor temperature. The thermistor temperature is in turn proportional to blood flow rate through the stent.

In these embodiments, the disclosed devices are passive in the sense that they will measure blood flow only upon a temporary activation from outside the body. It is contemplated, however, that other embodiments can allow data storage for blood flow requiring an internal electrical power source and might incorporate bi-directional data transfer to allow control, initiation and calibration of the device and the signaling of flow measurements to the external reader. The chip on which the coil and RFID tag is mounted is silicon coated and may be made of unalloyed, grade 2 titanium (ASTM B-338-95, Tico Titanium Inc., Farmington Hills, MI). The coils 14 are made of a conductive, biocompatible metal. Suitable materials are tungsten and gold. In this embodiment, analog measurement of voltage across coil leads is converted to digital signals by using an a/d converter located on a chip. The RFID tag 16 includes an integrated circuit to encode and hold information. The RFID tag 16 may include its own antenna or could use the stent 12 wire mesh as an antenna. A suitable RFID tag operates on low frequency radio waves in the range of 125-134 KHz. A suitable RFID tag 16 is available from VeriChip Corporation, a subsidiary of Applied Digital Solutions Inc.

An in vitro experiment was performed to demonstrate a proof of concept relating to this invention. A simplified planar model of a coronary artery was fabricated from a paper straw with diameter of 4mm (Chenille-Kraft-Company, IL, USA). This value represents the diameter of a normal non-diseased Left Main (LM) coronary artery, which is 4.5 ± 0.5 mm in men and 3.9 ± 0.4 mm in women.⁴⁹ The angulations and tortuosity of the coronary artery segment were not reproduced.

The stent used was a commercial coronary stent (ACS Multi-Link RX Tristar 3.O x 18mm Coronary Stent System, Guidant, Advanced Cardiovascular Systems, Inc., CA, USA). A metal spring substituted for the actual stent in the experiments conducted.

During intravascular deployment, the stent (of diameter 3 mm when fully expanded) is located inside the paper straw. To allow flow rate measurements and data retrieval the straw was penetrated by a thin wire. As in clinical practice, the device was deployed by a delivery system pressurized in 2 ATM increments until the stent is completely expanded.

The flow apparatus served the functions of partially mimicking the coronary artery blood flow, by providing a constant flow rate of 13.6 cc/min, which translates into flow velocity of 1.15 cm/sec which is comparable to flow rate within coronary arteries.⁵⁰ Pulsatile flow rate was not generated in this setup. This apparatus provided a controlled setup for measuring flow rate within a stent.

The experimental flow apparatus is shown in Figure 4. The inlet section into the SCA model was a straight PVC pipe (silicone tube) of inner diameter 5mm and length 0.3m which incorporated a temperature-controlled reservoir, a large volume infusion pump (Deltec® 3000, Graseby Medical, Watford, UK ), and an ultrasonic cannulating flow probe (24N, Transonic System Inc., Ithaca, NY, USA). After the SCA model fluids were collected in a fluid container.

Flow rate was generated by an infusion pump which produced a pre-defined steady flow rate. The actual mean flow rates were determined by measuring the volume of fluid collected in the container over a known time interval. The flow probe served as control to provide an additional indication of the flow rate trough the SCA model.

For flow rate measurement with the EM prototype, the fluid was a 10% sucrose and sodium chloride solution with conductivity comparable to that of human blood.⁵¹

For the EM prototype measurements, a constant, linear electromagnetic field was induced at the stented site, by placing two magnets (S 1030 Square magnet, N38 Nickel, 4mm thick) at opposite locations around the SCA model at a distance of 13mm. The electromagnetic field density, measured using a Gauss meter, was 0.192 Tesla.

To measure blood flow through the stent, one of three different prototypes was adhered to the stent, and measurements were made in the following three ways:

The EM prototype - two electrodes were attached to the stent at opposite locations along its longitudinal axis. The voltage gradient induced at these electrodes by the local electromagnetic field generated by two magnets was measured at a fixed interval of 30 seconds after setting a specific flow rate. Faraday's Law implies that this voltage gradient is proportional to the fluid velocity. Additional details are disclosed in "Market Application of a Novel Stent-Based Patency Monitor to the Management of Ischemic Vascular Disease," Baruch Schori, MIT Masters Thesis, June 2006, the contents of which are incorporated herein by reference.

Another embodiment of the present invention is shown in Figs. 5 and 6. This embodiment has particular applicability for monitoring arterial blood flow in dialysis grafts. A dialysis graft 30 includes a sheet sensor 32 embedded in the wall of the graft 30. The sheet sensor 32 includes a chip 34 that includes thermistors 36. The embodiment shown in Figs. 5 and 6 utilize thermodilution to measure blood flow as discussed above in conjunction with the earlier embodiment. In this embodiment, an upstream ring 38 measures blood temperature and serves as a control. A downstream ring 40 measures blood temperature post- heating. A middle ring 42 hosts a heating element. Alternatively, a single ring may be utilized in anemometry architecture. In this case, the single ring serves to monitor the temperature difference under a constant amount of energy being delivered into the blood stream. The temperature difference across the ring under known heating parameters enables deducing the flow rate within the graft 30.

The embodiment shown in Figs. 5 and 6 for monitoring arterial blood flow in dialysis grafts will allow understanding of the flow fluctuations and underlying physiological changes within the graft during and after surgery by providing a non-invasive, on-demand, and dynamic information about blood flow rate along the graft. In addition to blood flow monitoring and graft patency assessment, the information will allow an early diagnosis and intervention in case of graft narrowing and occlusion. As will be appreciated, this device should be able to deal with pulsatile flow with no synchronization with heart beats and so it is preferred that the device average several flow readings during a defined time. Measurement accuracy should be within 5 % of the actual flow rate in order truly to reflect blood rate changes over time and correlate with graft patency. It is also preferred that the device have a selected elasticity to allow vascular spontaneous contraction and dilation to avoid graft kinking and occlusion due to device stiffness. The device shown in Figs. 5 and 6 should also be biocompatible and not induce any unnatural responses or remodeling of surrounding organs, tissues, and cells. The device will not induce any toxicity to surrounding organs, tissues, and cells because it is made of materials with no short term irritation or sensitization, no cytotoxicity, no acute systemic toxicity and no chronic toxicity. Outer layers of the device must be hemocompatible.

The device is intended to be a long-term internal device contacting tissue and tissue fluids. A suitable material is polyethylene terephthalate which is a polyester widely used in the human body as fibers in the fabrication of artificial vascular grafts with little or no immune response.

Those skilled in the art will recognized that the technologies disclosed herein can also be used with cerebrospinal fluid shunts, transjugular intrahepatic portosystemic shunts, bypass grafts and stents.

Modifications and variations of the invention disclosed herein will be apparent to those of ordinary skill in the art and all such modifications and variations are included within the scope of the appended claims.

References

1. Kuntz RE, Gibson CM, Nobuyoshi M, et al. Generalized model of restenosis after conventional balloon angioplasty, stenting and directional atherectomy. / Am Coll CardioL 1993;21:15-25.

2. Cutlip DE, Chauhan MS, Baim DS, et al. Clinical restenosis after coronary stenting: perspectives from multicenter clinical trials. J Am Coll CardioL 2002 ;40:2082— 2089.

3. Ho KKL, Senerchia C, Rodriguez O, et al. Predictors of angiographic restenosis after stenting: pooled analysis of 1197 patients with protocolmandated angiographic follow-up from 5 randomized stent trials. Circulation. 1998;98(suppl I):I-362. Abstract.

4. Hausleiter J, Kastrati A, Mehilli J, et al. Predictive factors for early cardiac events and angiographic restenosis after coronary stent placement in small coronary arteries. J Am Coll CardioL 2002,40:882-889.

5. de Feyter PJ, Vos J, Rensig BJ. Anti-restenosis trials. Curr Interv Cardiol Rep. 2000;2:326-331.

6. Hart Disease and Stroke Statistics - 2006 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2006;1 13:e85.

7. Heart and Stroke Facts, American Heart Association, http://www.americanheart.org/.

8. David RH, Jr, Martin BL, et al. Analysis of 1-Year clinical Outcomes in the SIRIUS Trial: A Randomized Trial of a Sirolimus-Eluting Stent Versus a Standard Stent in Patients at High Risk for Coronary Restenosis. Circulation 2004; 109:634-640.

9. Gregg WS, Stephen GE₃ David AC₃ et al. for the TAXUS-IV Investigators. One- Year Clinical Results With the Slow-Release, Polymer-Based, Paclitaxel-Eluting TAXUS Stent: The TAXUS-IV Trial. Circulation 2004; 109: 1942-1947.

10. Alexandra JL, Ricardo AC₃ Gary SM, et al. for the DELIVER Clinical Trial Investigators .Non— Polymer-Based Paclitaxel-Coated Coronary Stents for the Treatment of Patients With De Novo Coronary Lesions Angiographic: Folio w-Up of the DELIVER Clinical Trial. Circulation 2004; 109: 1948-1954.

11. Sousa JE, Costa MA, Abizaid A, et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation. 2001; 103: 192— 195.

12. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus- eluting stent with a standard stent for coronary revascularization. N Engl J Med. 2002,346: 1773-1780.

13. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003;349: 1315— 1323. 14. Rensing B, Vos J, Smits P, et al. Coronary restenosis elimination with a sirolimus-e luting stent: first European human experience with six month angiographic and intravascular ultrasonic follow up. Eur Heart J. 2001 ; 22:2125-2130.

15. Colombo A, Drzewiecki J, Banning A. Randomized study to assess the effectiveness of slow and moderate release polymer based paclitaxel-eluting stents for coronary artery lesions. Circulation. 2003;108:788-794.

16. Liistro F, Stenkovic G, Di Mario C, et al. First clinical experience with a paclitaxel derivative-eluting polymer stent system implantation for in-stent restenosis: immediate and long-term clinical and angiographic outcome. Circulation. 2002; 105: 1883— 1886.

17. Drug-Eluting Stents and multiple articles, Angioplasty. Org, http://www.angioplasty.org/.

18. Thomas M. Drug-Eluting Stents To Transform Cardiovascular Medicine. Managed Care Magazine July 2003.

19. Allen J, Brett S, Jonathan B₅ et al. Stent Thrombosis After Successful Sirolimus-Eluting Stent Implantation. Circulation 2004;109;1930-1932.

20. Unraveling the CypherTM: An Angioplasty.org Editorial on the FDA Warnings About Johnson Sc Johnson's Drug Eluting Stent, October 30, 2003, Angioplasty.org, http://www.angioplasty.org/

21. Patrick WS, Muzaffer D, Kengo T, et al; for the TAXUS II Study Group. Vascular Responses at Proximal and Distal Edges of Paclitaxel-Eluting Stents: Serial Intravascular Ultrasound Analysis from the TAXUS II Trial. Circulation 2004;109:627-633.

22. Sylvia PW. Some Doctors See Long-Term Clot Risk In Stent Patients. The Wall Street Journal, October 21, 2005.

23. David M, Jacqueline I. Stent Showdown. Wood Mackenzie Limited March 16th 2004.

24. Kent Y₃ Charles MA, Robert RE, et al. Magnetic Resonance Angiography: Update on Applications for Extracranial Arteries. Circulation 1999;100:2284-2301.

25. Lambertus WB, Henk FMS, Chris JGB, and Max AV. MR Imaging of Vascular Stents: Effects of Susceptibility, Flow, and Radiofrequency Eddy Currents. J Vase Interv Radiol 2001; 12:365-371.

26. Tests To Diagnose Heart Disease, American Heart Association, http://www.americanheart.org/.

27. Interviews with physicians at leading research hospitals (Boston Medical Center, Massachusetts General Hospital, Lahey Clinic).

28. Lambertus WB, Chris JGB, Jan LV, Max AV. Improved Lumen Visualization in Metallic Stents and Filters by Reduction of Susceptibility and RF Artifacts. Proc. Intl. Soc. Mag. Reson. Med 20Q\ ; 9: 305. 29. Wang Y, Riederer SJ, Ehman RL. Respiratory motion of the heart: kinematics and the implications for the spatial resolution in coronary imaging. Magn Reson Med. 1995;33:713— 719.

30. Scott NA, Pettigrew RI. Absence of movement of coronary stents after placement in a magnetic resonance imaging field. Am J Cardiol. 1994;73:900-901.

31. Duerinckx AJ, Atkinson D, Hurwitz R, Mintorovitch J, Whitney W. Coronary MR angiography after coronary stent placement. AJR Am J Roentgenol. 1995; 165:662— 664.

32. Ohlsson A, et al., Continuous ambulatory monitoring of absolute right ventricular pressure and mixed venous oxygen saturation in patients with heart failure using an implantable hemodynamic monitor: Results of a one year multicentre feasibility study. Eur Heart /2001; 22:942-954.

33. Fischman DL, Leon MB₅ Bairn D, et al, for the STRESS Trial Investigators. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N EnglJ Med. 1994;331:496-501.

34. Serruys PW, de Jaegere P, Kiemeneij F, et al, for the Benestent Study Group. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med. 1994;331 :489-495.

35. Paul ST. A Chicken in Every Pot and a Drug-Eluting Stent in Every Lesion. Circulation 2004;109:1906-1910.

36. John WH, JR., Robert LW. Drug-eluting stents are here - now what? Implications for clinical practice and health care costs. Cleveland Clinic Journal of Medicine 2004; 71.

37. Brenda G. Questions Are Raised About the Safety of a Major Heart Drug. The New York Times, March 13, 2006.

38. A Drug Is Found to Reduce Plaque in Arteries. Reuters March 14, 2006

39. OMEGA Complete Flow and Level Measurement Handbook and Encyclopedia®, OMEGA Press, 1995.

40. Miller RW, McGraw H. Flow Measurement Engineering Handbook, 1996.

41. Spitzer DW. Flow Measurement, Instrument Society of America, 1991.

42. Ginesi D. Flow Sensing: The Next Generation, Control Engineering, November 1997.

43. Siebes M, Verhoeff BJ, Meuwissen M, et al. Single- Wire Pressure and Flow Velocity Measurement to Quantify Coronary Stenosis Hemodynamics and Effects of Percutaneous Interventions. Circulation 2004;109;756-762.

44. Khazan AD. Transducers and Their Elements: Electromagnetic Flowmeter. Prentice Hall PTR, 1994. 45. Committee Report: Transit Time Ultrasonic Flowmeters. AWWA Subcommittee on Ultrasonic Devices, A WWA Journal, July 1997.

46. McGee, H.; Mclnerney, J.; and Harms, A. The Virtual Cook: Modeling Heat Transfer in the Kitchen. Physics Today 52, 30-36, Nov. 1999.

47. Peuster M, Kaese V, Wuensch G₅ et al. Composition and in vitro biocompatibility of corroding tungsten coils. J Biomed Mater Res B Appl Biomater. 2003 Apr 15;65(1):211- 216.

48. Lammers D. Micro medical devices could transform health care. EE Times June 2002.

49. Dodge JT Jr₅ Brown BG, Bolson EL, Dodge HT. Lumen diameter of normal human coronary arteries: influence of age, sex, anatomic variation, and left ventricular hypertrophy or dilation. Circulation 1992; 86: 232-246.

50. Chongl CK, How TV. Flow patterns in an endovascular stent-graft for abdominal aortic aneurysm repair. Journal of Biomechanics 2004; 37, 89-97.

51. Frederic GH, Texter EC, JR., Wood LA, et al. The Electrical Conductivity of Blood: Relationship to Erythrocyte Concentration. Blood. 1950 Nov;5(l 1): 1017-35.

52. Sperker W, Glogar D, Gyongyδsi M. Percutaneous Treatment of Left Main Coronary Artery Stenoses. Journal of Clinical and Basic Cardiology 2002; 5 (Issue 2), 163-169.

53. How To Invest in Cardiac Surgical Devices. Thomson Financial Inc.Venture Capital Journal, November 01, 2003.

54. Hydrocephalus Fact Sheet - National Institute of Neurological Disorders and Stroke

55. The Hydrocephalus Foundation, Inc.

56. HYDROCEPHALUS IN CHILDHOOD - a patient's guide , by Dr Abhaya Kulkarni - Neuorosurgeon.

Claims

CLAIMSWhat is claimed is:

1. Fluid flow monitoring system comprising: structure for implantation in association with vascular tissue; fluid flow monitoring apparatus supported on the structure to generate a signal related to fluid flow; a wireless transmitter supported on the structure for transmitting the signal outside a body; and a reader external to the body for wirelessly energizing the monitoring apparatus and transmitter, for receiving the transmitted signal, and for displaying fluid flow velocity and/or rate.

2. The monitoring system of Claim 1 wherein the structure is a stent implanted within the vascular tissue.

3. The monitoring system of Claim 2 wherein the fluid flow monitoring apparatus comprises at least one electrically conducting coil.

4. The monitoring system of Claim 3 wherein the wireless transmitter comprises an RFID tag receiving the signal from the coil.

5. The monitoring system of Claim 1 wherein the reader energizes the monitoring apparatus through electromagnetic induction.

6. The monitoring system of Claim 1 wherein the fluid flow monitoring apparatus is a thermodilution system sensing a temporal temperature gradient.

7. The monitoring system of Claim 6 wherein the thermodilution system includes means for locally heating or cooling blood.

8. The monitoring system of Claim 6 wherein the thermodilution system includes a thermocouple or thermistor for measuring temperature.

9. The monitoring system of Claim 2 wherein the vascular tissue is a coronary artery.

10. The monitoring system of Claim 1 wherein the structure is a sheath integrated into the vascular tissue.

1 1. The monitoring system of Claim 10 wherein the vascular tissue is a dialysis access graft.

12. The monitoring system of Claim 11 wherein fluid flow monitoring apparatus is a thermodilution system.

13. The monitoring system of Claim 11 wherein the fluid flow monitoring apparatus is an anemometry system.

14. The monitoring system of Claim 10 wherein the sheath is coated with silicon.

15. The monitoring system of Claim 2 wherein the stent is selected from the group consisting of peripheral stents, biliary stents and coronary stents.

16. The monitoring system of Claim 1 wherein the vascular tissue is a bypass graft.