HK1207012B

HK1207012B - System for monitoring and controlling organ blood perfusion

Info

Publication number: HK1207012B
Application number: HK15107565.3A
Authority: HK
Inventors: Joop FIERENS; Jason Kevin NACKARD; Eric Thierry Jean MARCOUX; Emmanuel J. BARTHOLOME
Original assignee: 医疗设备工程公司
Priority date: 2012-03-01
Filing date: 2013-03-01
Publication date: 2018-06-01

Description

System for monitoring and controlling organ blood perfusion

Technical Field

The present invention generally relates to the field of medical systems. More particularly, the present invention relates to systems, devices and methods for monitoring and controlling perfusion of an organ of a subject.

Background

Currently, the most common modes of treating primary and secondary cancers of the organ include surgical resection, radiation therapy, and/or systemic chemotherapy. The side effects of cytotoxic agents associated with systemic chemotherapy are well known. Some common toxicities are: myelosuppression, leading to neutropenia, anemia, and thrombocytopenia; damage to hair follicle cells, leading to alopecia; induces apoptosis of gastrointestinal crypt cells, resulting in diarrhea and canker sores. In addition, different drug classes can cause other toxicities, including cardiac injury, peripheral nerve injury, resulting in sensorimotor neuropathy, kidney damage, and pulmonary fibrosis.

For cancer in many organs, the only effective treatment is surgical resection. However, surgical resection is not always an option. Typically, the cancer is not detected until it is in a state of progression and has metastasized to the entire organ, and thus cannot be resected. Under these circumstances, systemic chemotherapy moderately increases patient survival, but has disappointing response rates. The dose of chemotherapy is often limited by toxic side effects from other organs. Therefore, it is desirable to apply chemotherapy only to the organ to be treated. Treating isolated organs can potentially use higher doses because the drug will concentrate on the target organ and significantly reduce or eliminate systemic toxicity. Furthermore, ex vivo organ perfusion allows multiple treatments to be performed in a relatively short period of time, as the human body does not need to recover from the long-lasting effects of systemic toxicity.

Ex vivo organ perfusion has been performed using general surgical and interventional techniques. Organ perfusion with ex vivo surgery on the liver has encouraging results. However, trauma from surgery to isolate the organ prevents multiple applications of chemotherapy. Moreover, even by stopping the inflow and outflow of the main blood, the organ cannot be completely separated from the systemic blood flow; the organ will communicate with the systemic circulation through collateral connections or blood vessels. For example, for the liver, the portal vein and the vena cava have collateral blood vessels that communicate with the systemic blood circulation, in addition to the major blood vessels that are hepatic arteries. The perfusion therapeutic will be delivered at least partially to the non-target organs of the patient by systemic blood flow. This is disadvantageous to the patient (i) it results in dilution of the dose of the perfusing therapeutic agent, which inhibits the effect on the target organ, (ii) it limits the maximum dose that can be perfused to the target organ to the maximum dose that leaks out of the organ that can be received by other non-target organs of the patient's body.

In addition, in response to certain diseases, such as tumors, that make organ blood flow difficult, blood may attempt to bypass the tumor by creating and/or connecting to other tissues and/or organs. In this case, the doctor is unaware of the newly developed connection. The connection increases the leakage rate of the therapeutic agent or chemotherapeutic agent from the perfused organ to the systemic blood flow. This leads to higher blood loss or systemic toxicity during intervention, which in some cases is dangerous for the subject being treated and for the subject's systemic function.

Up to now, local perfusion requires a large panel of clinical experts to perform the whole process: interventional radiologists, anesthesiologists, nuclear specialists, perfusionists, oncologists, nurses. Furthermore, due to the full manual control, the process may take more than four hours to complete. Local perfusion needs to be performed 2 to 5 times per patient. All of these factors result in expensive treatments. Thus, for economic reasons, not all patients are able to receive the treatment.

It is an object of the present invention to provide a solution to at least some of the above problems. The present invention provides systems, devices and methods for monitoring and controlling organ perfusion in a subject. The method of the present invention overcomes the above-mentioned problems because it provides a safer and less expensive treatment for the patient.

Disclosure of Invention

In a first aspect, the present invention provides a system for monitoring and control of organ perfusion of a subject. The system comprises:

-optionally, at least one therapeutic agent,

-at least one first retrievable medical device for simultaneous or separate perfusion and occlusion of an organ flowing into a blood vessel, comprising: a body having a distal end, a proximal end, at least one lumen extending between the proximal and distal ends, at least one opening in fluid communication with the lumen for delivering fluid to the vessel, and at least one inflatable balloon coupled with the body of the device,

-at least one second retrievable medical device for isolating and collecting organ outflow, said device having a distal end and a proximal end; the second medical device comprises a catheter adapted to deploy an expansion member; the proximal end of the expansion member is attached to the distal end of the catheter,

-a fluid storage reservoir having at least one inlet adapted to be connected to the proximal end of the second retrievable medical device and at least one outlet adapted to be connected to the proximal end of the first retrievable medical device,

at least one pump for withdrawing fluid from an organ and directing the fluid to a fluid storage reservoir through an inlet of the fluid storage reservoir,

at least one pump for withdrawing fluid from the fluid storage reservoir at a determined flow rate and directing the fluid to the organ inflow,

optionally, at least one marker for monitoring in real time the leak rate from the organ to the systemic blood circulation,

-at least one marker detector located upstream of the inlet of the fluid storage reservoir,

at least one marker detector located in at least one blood vessel of the systemic blood circulation,

at least one volume sensor located in the fluid storage reservoir,

-at least one pressure detector for measuring the fluid pressure inside the organ to be perfused, and

-at least one interface for receiving and presenting output system data and for controlling and/or adjusting the input system data, wherein the output system data comprises data collected by the pressure detector and the marker detector; and the input system data includes a fluid flow rate retrieved from the fluid storage reservoir directed to the organ inflow. The output system data further includes a volume of fluid present in the fluid storage reservoir.

In a second aspect, the present invention provides a method for monitoring and control of organ perfusion of a subject, comprising the steps of:

(a) introducing a first retrievable medical device into an organ inflow vessel for simultaneous or separate perfusion and occlusion of the inflow vessel, the first medical device comprising: a body having a distal end, a proximal end, at least one lumen extending between the proximal and distal ends, at least one opening in fluid communication with the lumen for delivering fluid to the blood vessel; and at least one inflatable balloon coupled to the body of the device,

(b) introducing a second retrievable medical device for isolating and collecting outflow from the organ, the second medical device having a distal end and a proximal end and comprising a catheter adapted to deploy an expansion member; the proximal end of the expansion member is attached to the distal end of the catheter; the expansion member comprising a carrier and a liquid impermeable liner bonded to the carrier over at least a portion of the length of the carrier,

(c) connecting a first retrievable medical device and a second retrievable medical device to a fluid storage reservoir having an inlet and an outlet, wherein the proximal end of the second retrievable medical device is connected to the inlet of the fluid storage reservoir and the proximal end of the first retrievable medical device is connected to the outlet of the fluid storage reservoir,

(d) measuring fluid pressure within the organ using at least one pressure detector,

(e) withdrawing fluid from the organ and directing the fluid to the fluid storage reservoir through an inlet of the fluid storage reservoir,

(f) withdrawing fluid from the fluid storage reservoir and directing the fluid to an organ inflow,

(g) adjusting the fluid withdrawal rate of steps (d) and (e) such that the fluid pressure within the organ is less than the systemic blood pressure,

(h) adding at least one marker and/or at least one therapeutic agent to fluid retrieved from the fluid storage reservoir and directed to the inflow of the organ,

(i) monitoring a leak rate from the organ to the systemic blood flow with a marker detector, wherein at least one marker detector is located upstream of the inlet of the fluid storage reservoir and at least one marker detector is located in at least one blood vessel of the systemic blood circulation, and

(j) withdrawing the medical device of steps (a) and (b) from the organ inflow vessel and the organ outflow vessel, respectively.

In a third aspect, the invention provides a computer implemented method for monitoring and controlling an organ perfusion system of a subject, the system comprising: at least one pressure detector for measuring fluid pressure within the organ; an outflow tube for retrieving fluid from the organ; and an inflow tube for delivering fluid to the organ, wherein the method comprises the steps of:

-receiving output system data from the system, wherein the output system data comprises: fluid pressure within the organ, fluid flow rate at which fluid is withdrawn from the organ, amount of marker present in fluid flowing in the outflow conduit, amount of marker present in the subject's systemic blood flow,

-processing the received output system data, and

-transmitting input system data, wherein the data comprises a determined fluid flow rate at which fluid is delivered to the organ through an inflow tube of the system.

In a fourth aspect, the present invention provides the use of the above system for monitoring and controlling organ perfusion in a subject.

In a fifth aspect, the present invention provides the use of the above method for monitoring and controlling organ perfusion in a subject.

In a sixth aspect, the present invention provides the use of a computer implemented as described above for monitoring and controlling organ perfusion in a subject.

The present invention allows monitoring and controlling perfusion of a subject's organ and provides tools for real-time assessment, measurement, control and monitoring of the rate of leakage of therapeutic agent from the perfused organ to the systemic blood flow and other organs of the subject's body, and therefore has several advantages. The present invention allows for identifying collateral flow and the direction of the flow; thus, whether the perfusion organ is communicated with the whole body blood or not and whether the whole body blood is communicated with the perfusion organ or not are known in real time. The present invention also allows the physician to respond immediately when the therapeutic agent is highly diluted or near the systemic toxic level of the therapeutic agent is reached. Real-time measurements of leak rates will drive perfusion parameters to minimize collateral flow and should ensure that proper action is taken when certain limits are exceeded. The limit is, for example, the amount or concentration of therapeutic agent that may be present in the systemic blood stream. Thus, the present invention provides improved organ perfusion results and ensures patient safety when organs are treated locally with high doses of therapeutic agents. Delivery of such high doses may also be made possible by use of the present invention, rather than being provided by other systems and/or methods of the prior art.

Furthermore, the present invention provides a non-invasive method for organ perfusion, which allows for repeated treatments of the organ. Furthermore, with the present invention, a small number of physicians are required to perform organ perfusion. Thus, perfusion is less expensive for the subject.

Drawings

Further features, advantages and objects of the present invention will become apparent to those skilled in the art when reading the following detailed description of embodiments of the invention in conjunction with the accompanying drawings.

Fig. 1 shows an embodiment of a second medical device of the invention comprising a tubular member (dumbbell shape) attached to a catheter in an expanded state. Fig. 1A shows a cross-section through a catheter, wherein the pusher device is a push rod. Fig. 1B shows a cross-section through a catheter, wherein the pusher device is formed by the wall of the inner tube.

Fig. 1C shows another embodiment of a second medical device of the invention in an expanded state comprising a tubular member (dumbbell shape) attached to a catheter. The liner is attached to the inner wall of the tubular member.

Fig. 1D shows a side view of another embodiment of a second medical device of the invention, wherein the distal end of the inner tube has the shape of a cup or spoon. FIG. 1E shows a top view of the same embodiment. FIG. 1F shows a cross-sectional view along A-A shown in FIG. 1D.

Fig. 1G illustrates another embodiment of a second medical device of the present invention in an expanded state, wherein the device has a bell shape.

Fig. 2A shows an embodiment of the second medical device of fig. 1, wherein the tubular member is in its collapsed compressed state and has a closed tip.

Fig. 2B shows another embodiment of the second medical device of fig. 1, wherein the tubular member is in its collapsed compressed state and has a conically shaped closed tip.

Fig. 3 shows a second medical device of the invention having been placed in situ, wherein: a shows the lining of the exterior of the carrier and B shows the lining of the interior of the carrier.

Fig. 3C and D illustrate the delivery of a therapeutic agent to the right and left lungs, respectively, using a second medical device. Fig. 3E and F illustrate the delivery of a therapeutic agent to the right and left lungs, respectively, using a second medical device having a bell shape.

Fig. 4 illustrates an embodiment of a kit in which a first medical device, a second medical device, and a separation device are used to deliver a therapeutic agent and remove excess therapeutic agent from the liver.

Fig. 5 shows a second medical device introduced in a vena cava.

Fig. 6 illustrates an embodiment showing the position of the separation device within the second medical device.

Fig. 7 shows another embodiment illustrating the position of the separation device within the second medical device.

Fig. 8 is a detailed schematic view of a first medical device.

Fig. 9 is a detailed schematic view of an embodiment of a third medical device.

Fig. 10 is a detailed schematic view of another embodiment of a third medical device.

Fig. 11A and 11B illustrate an embodiment of a first medical device.

Fig. 11C, 11D, and 11E illustrate embodiments of a first medical device in which each opening that allows a lumen to be in fluid communication with the interior of the balloon is provided with a valve.

Fig. 12A and 12B are longitudinal cross-sectional views of a first medical device.

Fig. 13 illustrates an embodiment of a third medical device.

Fig. 14 is a schematic diagram of a system that may be used to perfuse a medical drug through an organ. The system may be controlled by a processing unit.

FIG. 15 is an algorithmic flow chart that may be used to control the processing unit of the perfusion system of FIG. 14.

Fig. 16A shows a blood vessel with a lesion. Fig. 16B shows a second retrievable medical device introduced into a vessel having a lesion.

Detailed Description

Unless otherwise defined, all terms used in the disclosure of the present invention, including technical terms and scientific terms, have the meanings commonly understood by one of ordinary skill in the art to which the present invention belongs. By way of further guidance, definitions of terms are included to better understand the teachings of the present invention.

As used herein, the following terms have the following meanings:

as used herein, the terms "a" and "an" refer to a single or multiple of an object, unless the context clearly dictates otherwise. For example, "a compartment" refers to one or more than one compartment.

As used herein, "about" meaning a measurable value such as a parameter, amount, time period, etc., is meant to encompass variations of +/-20% or less, preferably +/-10% or less, more preferably +/-5% or less, more preferably +/-1% or less, and more preferably +/-0.1% or less of the particular value, variation values within this range being suitable for practicing the disclosed invention. However, it is to be understood that the value modified by "about" is also expressly disclosed by itself.

As used herein, "comprising," "consisting of" … … is synonymous with "including" or "containing," and is an inclusive or open-ended term that specifies the presence of the following items, such as components, but does not exclude or preclude the presence of additional components, features, elements, components, steps, etc. known in the art or otherwise disclosed herein.

The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within that range and the recited endpoint.

Unless otherwise defined, the expression "% by weight" (percent by weight), here and throughout the specification, refers to the relative weight of the components based on the total weight of the formulation.

The term "therapeutic agent" as used herein refers to a therapeutic fluid or particle that is delivered to an organ of a patient.

The terms "particle," "microsphere," and "bead" are used synonymously herein to refer to an object that is substantially spherical in shape and has a diameter of less than 1 millimeter.

The terms "lateral" and "side branch" are used herein synonymously. The terms "control unit" and "processing unit" are used herein as synonyms.

The term "glass" refers to a hard, brittle, amorphous, inorganic substance that is generally transparent; glasses are typically made by fusing silicates and soda, as described by Webster's New World dictionary.

The terms "inflow" and "outflow" herein refer to the inflow of blood into an organ and the outflow of blood out of an organ, respectively.

The systems, devices and methods of the present invention are further described for treating the liver and/or lungs. However, any other organ may be treated using the systems, devices and methods of the present invention.

In a first aspect, the present invention provides a system for monitoring and controlling organ perfusion in a subject. A preferred embodiment of the system is shown in fig. 14. The system optionally includes at least one therapeutic agent.

The system further comprises at least one first retrievable medical device for simultaneous or separate perfusion and occlusion of an organ flowing into the vessel, comprising: a body having a distal end, a proximal end, at least one lumen extending between the proximal and distal ends, at least one opening in fluid communication with the lumen for delivering fluid to the vessel, and at least one inflatable balloon coupled with the body of the device.

The system further comprises at least one second retrievable medical device for isolating and collecting outflow from the organ, the device having a distal end and a proximal end; the second medical device comprises a catheter adapted to deploy an expansion member; the proximal end of the expansion member is attached to the distal end of the catheter.

The system further comprises a fluid storage reservoir 107 having at least one inlet adapted to be connected to the proximal end of the second retrievable medical device and at least one outlet adapted to be connected to the proximal end of the first retrievable medical device. The fluid storage reservoir is used for storage of fluid that is retrieved from a perfused organ via an organ outflow or organ outflow vessel and is to be delivered to the organ via an organ inflow or organ inflow vessel. The fluid may be blood, blood supplemented with a marker, blood supplemented with a therapeutic agent, blood supplemented with a marker and a therapeutic agent, a physiological solution, or any combination thereof. In a preferred embodiment, 0-5 litres, preferably 0.5-4 litres, more preferably 0.5-3 litres of fluid may be stored in the fluid storage reservoir. In a preferred embodiment, the total fluid volume flowing through the system is at least 10cc, preferably at least 20cc, more preferably at least 40cc, most preferably at least 50 cc. The maximum volume flowing through the system is at most 1000cc, preferably at most 800cc, more preferably at most 600cc, more preferably at most 500cc, most preferably at most 300 cc.

In a preferred embodiment, the inlet of the fluid storage reservoir is adapted to be connected to the proximal end of the second retrievable medical device using an outflow tube 102, and the outlet of the fluid storage reservoir 107 is adapted to be connected to the proximal end of the first retrievable medical device using an inflow tube 103. In a preferred embodiment, the tube is preferably made of silicon or any silicon-like material known to those skilled in the art.

The system further comprises at least one pump 104,105 for withdrawing fluid from the organ 101 at a determined flow rate and directing said fluid to the fluid storage reservoir 107 through an inlet of said fluid storage reservoir 107. At least one pump 108 is used to withdraw fluid from the fluid storage reservoir 107 at a determined flow rate and direct the fluid into the organ 101. The pumps may be of similar type or of different type. The number and type of pumps required depends on the organ to be treated. Blood can be drawn from a plurality of different blood vessels with a single pump as desired by the physician.

These pumps may be of any type and selected from the group comprising roller pumps, centrifugal pumps, syringe pumps or any other pump known to the person skilled in the art. Preferably, the pumps are of the same type. More preferably, the pump is a centrifugal pump. Those skilled in the art will appreciate that the flow rate of the withdrawn fluid from the organ and the flow rate of the withdrawn fluid from the fluid storage reservoir 107 are adapted depending on the type of pump used. If a roller pump is used, it is preferable to reduce the flow rate by using, for example, a damping system.

The system optionally includes at least one marker for monitoring in real time the leak rate from the organ 101 to the systemic blood circulation.

The system further includes at least one marker detector 119 located upstream of the inlet of the fluid storage reservoir 107. At least one marker detector 120 located in and/or near at least one blood vessel of the systemic blood circulation, and/or above a region of high blood flow in the subject's body, is sufficiently distant from the organ being treated.

The system further comprises at least one pressure detector 123 for measuring the fluid pressure inside the organ 101 to be perfused. The pressure detector is located inside or connected to the organ to be perfused. The detector may be of any type known to those skilled in the art.

The system further comprises at least one volume sensor located in the fluid storage reservoir 107. The detector is used to provide the physician with a continuous monitoring of the volume of fluid inside the fluid storage reservoir. By monitoring the volume, the physician may react if the volume of fluid inside the reservoir must be adjusted to reach a predetermined upper and/or lower limit.

The system may also include at least one flow meter. The flow meters 115, 116 may be used to determine the flow rate at which fluid is withdrawn from the organ. Another flow meter 113, 114 may be used to determine the flow rate of fluid withdrawn from the organ into the fluid storage reservoir. Another flow meter may be used to determine the flow rate at which fluid is withdrawn from the fluid storage reservoir. Additional flow meters may be used to determine the flow rate of fluid into the organ. The sensor may also be used to measure the temperature of the fluid entering and/or exiting the organ and/or the fluid storage reservoir. Other sensors may be used to measure the oxygen level of the fluid entering and/or exiting the organ and/or the fluid storage reservoir.

The system further comprises at least one interface for receiving and presenting output system data and for controlling and/or adjusting input system data.

Outputting the system data includes: data collected by the pressure detector 123, including fluid flow pressure inside the organ; data collected by the different flow meters, the data comprising a flow rate of fluid exiting the organ and/or exiting the fluid storage reservoir, and/or a flow rate of fluid entering the organ and/or entering the fluid storage reservoir; data collected by sensors for measuring the temperature of fluid entering the organ and/or fluid exiting the organ and/or fluid entering the fluid storage reservoir and/or fluid exiting the fluid storage reservoir; an oxygen level in fluid entering the organ and/or fluid exiting the organ and/or fluid entering the fluid storage reservoir and/or fluid exiting the fluid storage reservoir; and/or any other data collected by any sensors and/or detectors and/or gauges used in the system of the present invention. The output system data also includes data collected by the marker detectors 104,105, including the amount of marker present in the fluid retrieved from the organ and the amount of marker present in the systemic blood circulation. The detected amount of marker in the systemic blood flow provides the physician with an assessment of the rate of fluid leakage from the organ into the systemic blood flow. Thus, physicians may react and intervene whenever the leak rate is considered high and/or there is a risk of poisoning the subject. The output system data further includes a volume of fluid present in the fluid storage reservoir.

The input system data includes the fluid flow rate retrieved from the fluid storage reservoir 107 that is directed to the organ inflow. The input system may further include: data collected by the different flow meters, the data including a flow rate of fluid into the organ; data collected by sensors for measuring the temperature of fluid entering the organ and/or fluid exiting the fluid storage reservoir and/or data collected by sensors measuring the volume of fluid in the fluid storage reservoir 107; an oxygen level in the fluid entering the organ and/or the fluid exiting the fluid storage reservoir. In a preferred embodiment, the input system data is at least partially manually adjusted by the physician. For example, when a high rate of fluid leakage into the systemic blood circulation is observed, the physician may manually reduce the flow rate of fluid withdrawn from the fluid storage reservoir, thereby reducing the flow rate of fluid into the perfused organ.

In a preferred embodiment, the system further comprises a processing unit 112i for adjusting the flow rate of the fluid to be withdrawn from the fluid storage reservoir and directed to the inflow of the organ. The processing unit 112i is implemented by means of a method for receiving and processing output system data and sending signals to a pump comprising input system data. This allows automation of the perfusion, thereby significantly reducing the number of physicians required during perfusion. In a preferred embodiment, the method comprises an algorithm.

In a preferred embodiment, the output system data received by processing unit 112i includes: fluid pressure inside the organ; a fluid flow rate for withdrawing fluid from the organ; an amount of the marker measured by a detector located upstream of an inlet of the fluid storage reservoir and an amount of the marker measured by a detector located in at least one blood vessel of the systemic blood circulation. The output system data also includes the volume of fluid present in the fluid storage container. Furthermore, the output system data received by the processing unit 112i may also include all of the above data.

In a preferred embodiment, the input system data includes a determined fluid flow rate retrieved from the fluid storage reservoir and directed to the organ inflow. Furthermore, the input system data received by the processing unit 112i may also include all of the above data.

In a preferred embodiment, the determined fluid withdrawal flow rate from the fluid storage reservoir is determined to maintain a fluid pressure inside the organ below a pressure of systemic blood flow.

In a preferred embodiment, the label is selected from the group comprising a radioactive label, a dye such as indocyanine green, a therapeutic agent itself, a therapeutic agent derivative, alkaline phosphatase (ALP), 5' nucleotidase, Gamma Glutamyl Transpeptidase (GGT), alanine aminotransferase (ALT, also known as SGPT), glutamic oxaloacetic aminotransferase (AST, also known as SGOT), Prothrombin Time (PT) and coagulation by INR test, albumin, bilirubin.

In a preferred embodiment, the marker detectors 119, 120 allow indirect measurement of the amount of marker. The detector allows collection of a fluid sample. The fluid sample is analyzed to determine the amount of the marker. Preferably, the sample is analyzed immediately to ensure continuous assessment and control of the leak rate of fluid from the organ to the systemic blood circulation.

In a preferred embodiment, the marker detectors 119, 120 allow direct measurement of the amount of marker. The marker is adapted to detect the amount of the marker in the fluid withdrawn from the organ and in the systemic blood flow. The different labels and the corresponding suitable detectors are listed in table 1. It is to be understood that the markers listed here are suitable for liver perfusion, and that any other suitable marker suitable for liver perfusion or any other organ, as well as corresponding marker detectors known to the person skilled in the art, may be used in the system of the present invention.

Table 1: marker and suitable marker detector

Marker substance	Marker detection	Methods or techniques of use
				Direct measurement	Scintillation counter using NaI crystals
Dyes such as indocyanine green	Direct measurement	Use indicator detector
			The therapeutic agent itself	Indirect measurement	Dependent on the drug
Therapeutic agent derivatives	Indirect measurement	Dependent on the drug
			Alkaline phosphatase	Direct measurement	Serum alkaline phosphatase levels
Gamma Glutamyl Transpeptidase (GGT)	Direct measurement	Clinical biochemistry
			ALT	Direct measurement	Clinical biochemistry
AST	Direct measurement	Clinical biochemistry
			PT	Direct measurement	Clinical biochemistry
INR	Direct measurement	Clinical biochemistry
			Albumin	Direct measurement	Clinical biochemistry
Bilirubin	Direct measurement	Clinical biochemistry

Alanine aminotransferase (ALT, also known as SGPT). This enzyme acts to process proteins. When the liver is damaged or inflamed, the level of ALT in the blood is usually elevated.

-aspartate aminotransferase (AST, also known as SGOT). This enzyme can be found in a variety of body tissues, including the liver. Like ALT, AST also functions to process proteins. If the liver is damaged, the body releases AST into the bloodstream.

Alkaline phosphatase (ALP). This enzyme can be found in a variety of body tissues, including the liver. Because of skeletal growth, ALP levels are generally higher in children and adolescents than in adults. However, higher than normal levels of ALP may be evidence of liver disease or bile duct occlusion.

-total bilirubin and direct bilirubin. Bilirubin is a by-product of the normal breakdown of red blood cells. It usually passes through the liver and is cleared from the body. However, if this is not the case due to liver disease, the bilirubin level in the blood may rise and the skin may appear yellow, known as jaundice. The bilirubin assay may be total (measuring the level of all bilirubin in the blood) or direct (measuring only bilirubin that has been processed by the liver and attached to other chemicals).

Albumin and total protein. Liver function tests involve measuring albumin (the major blood protein produced by the liver), as well as the total amount of all proteins in the blood. When there is a liver problem, the amount of albumin and other proteins it produces may change.

Prothrombin time and INR. Prothrombin time (also known as "prothrombin time" or PT) and INR are assays used to assess coagulation. Coagulation factors are proteins produced by the liver. When the liver is significantly damaged, these proteins are not normally produced. PT and INR are also useful liver function tests because there is a good correlation between the coagulation abnormalities measured by these tests and the degree of liver dysfunction. The value of PT is usually expressed in seconds and compared to the control patient's blood (control at normal +/-2 seconds).

In a preferred embodiment, the system further comprises at least one oxygenator 110 (fig. 14) located downstream of the outlet of the fluid storage reservoir 107. In a preferred embodiment, the system further comprises at least one heat exchanger 109 located downstream of the outlet of the fluid storage reservoir 107. The heat exchanger 109 may be located downstream of the oxygenator 110 (fig. 14).

In a preferred embodiment, the system further comprises at least one filter 106 (fig. 14) located upstream of the inlet of the fluid storage reservoir 107. The filter is used to filter the fluid retrieved from the organ, thereby removing any air bubbles or microemboli that may be present in the fluid. This is advantageous as it reduces the risk of having emboli in the systemic blood flow of the subject. In a preferred embodiment, the filter is provided with a reservoir as a buffer for the fluid storage reservoir.

In a preferred embodiment, the system further comprises one or more third retrievable medical devices for occlusion of a vessel of an organ, the devices having a proximal end, a distal end, a lumen extending between the proximal end and the distal end, at least one inflatable balloon for occlusion of the vessel, and a lumen. A perfused organ may have more than one major blood vessel; the blood vessel is preferably occluded to better isolate the organ. For example, the liver is connected to the systemic blood flow by the following blood vessels: vena cava, hepatic artery, and portal vein.

In a preferred embodiment, the first medical device and/or the second medical device and/or the third medical device is introduced percutaneously into a different organ vessel; this is a non-invasive introduction, allowing for repeated perfusion of the organ.

In a preferred embodiment, the system further comprises at least one container 122 containing a physiological solution that is selectively delivered to the organ 101 before the start of perfusion and/or when said perfusion is completed, for washing said organ. The container may be connected to a pump 108 for withdrawing the physiological solution at a determined flow rate. The pump is adapted to be connected to an organ inflow. The container 122 may be connected to the inflow tube 103 and/or to a processing unit 122i which sends a signal to actuate the valve 121. The valve 121 is located between the reservoir 122 and the pump 108 and is used to allow or prevent the withdrawal of physiological solution from the reservoir 122. The valve may also be manually actuated by the physician.

In a preferred embodiment, the system further comprises at least one injection manifold 111 for adding a marker and/or therapeutic agent to the fluid withdrawn from the fluid storage reservoir and directed to the inflow of the organ. The marker and/or therapeutic agent may be added directly to the fluid storage reservoir. The amount and/or concentration of the marker and/or therapeutic agent is determined by the physician according to different parameters, such as the organ to be perfused and the disease to be treated.

In a preferred embodiment, the system further comprises at least one bubble trap 112. The system is adapted to connect other sensors and/or actuators and/or pumps and/or detectors as required and depending on the organ to be perfused. The sensors and/or actuators and/or pumps and/or detectors may be used to perform in-process assays to determine drug concentrations or for blood analysis as desired.

In a preferred embodiment, the system further comprises at least one blood source 117 connected to the fluid storage reservoir 107 for adding blood to said reservoir if required. The person skilled in the art will understand that the blood added is of the same blood type as the blood of the subject.

In a second aspect, the present invention provides a method of delivering a therapeutic agent to an organ's blood stream and removing excess of the therapeutic agent from the organ's blood stream. The method comprises the following steps: (a) introducing a first medical device (26, fig. 4) into the organ inflow vessel; (b) introducing a second medical device into the organ outflow vessel without obstructing systemic blood flow; (c) controlling the infusion and/or perfusion flow so as to optimize the setting for maximum local therapeutic effect with minimal collateral damage; (d) injecting a therapeutic agent into the organ inflow using a first medical device; (e) collecting organ blood outflow using a second medical device; (f) circulating the drug-loaded lavage fluid to optimize the treatment outcome by adjusting physical parameters, and adding or removing therapeutic additives; and (g) isolating excess therapeutic agent from the collected organ vein using an isolation device. The method further comprises the steps of: (h) in the case of extracorporeal blood filtration, the filtered blood is redirected into the organ blood stream.

In a preferred embodiment, once the organ has been isolated from the systemic circulation, the method utilizes the blood pressure within the organ and the leak rate to the systemic circulation to be monitored and used by the system in the processing unit to control the perfusion kinetics of the therapeutic agent perfusion, i.e. the pump speed and/or pressure, flow balance and metering and possibly drug administration.

In a preferred embodiment, the present invention provides a method for monitoring and controlling organ perfusion in a subject. The method comprises the following steps:

(a) introducing a first retrievable medical device in an organ inflow vessel for simultaneous or separate perfusion and occlusion of the inflow vessel, the first medical device comprising: a body having a distal end, a proximal end, at least one lumen extending between the proximal and distal ends, at least one opening in fluid communication with the lumen for delivering fluid to the blood vessel; and at least one inflatable balloon coupled to the body of the device,

(c) the first and second retrievable medical devices are connected to a fluid storage reservoir 107 having an inlet and an outlet, wherein the proximal end of the second retrievable medical device is connected to the inlet of the fluid storage reservoir 107 and the proximal end of the first retrievable medical device is connected to the outlet of said fluid storage reservoir 107. The fluid storage reservoir is as described above for the system of the present invention. The connection of the fluid storage reservoir to the first medical device and the second medical device is also as described above for the system of the present invention.

(d) The fluid pressure within the organ 101 is measured using at least one pressure detector 123. The pressure detector is located inside or connected to the organ to be perfused. The detector may be of any type known to those skilled in the art.

(e) Withdrawing fluid from the organ 101 and directing the fluid to the fluid storage reservoir 107 through an inlet of the fluid storage reservoir 107. The flow rate at which the fluid is withdrawn from the organ and directed to the fluid storage reservoir is continuously measured by at least one flow meter 115, 116.

(f) Withdraw fluid from fluid storage reservoir 107 and direct the fluid into organ 101. The flow rate at which the fluid is withdrawn from the fluid storage reservoir and directed to the organ is continuously measured by at least one flow meter 113, 114.

(g) Adjusting the fluid withdrawal rate of steps (d) and (e) such that the fluid pressure within the organ is lower than the systemic blood pressure.

(h) At least one marker and/or at least one therapeutic agent is added to the fluid retrieved from the fluid storage reservoir and directed to the inflow of the organ. The at least one marker and/or at least one therapeutic agent may be added to fluid storage reservoir 107.

(i) The leak rate from the organ 101 to the systemic blood flow is monitored with a marker detector, whereby at least one marker detector 119 is located upstream of the inlet of the fluid storage reservoir 107 and at least one marker detector 120 is located in at least one blood vessel of the systemic blood circulation. Labels and label detectors are as described above for the system of the invention.

In a preferred embodiment, the physician is able to control the perfusion method through at least one interface for receiving and presenting output system data and for controlling and/or adjusting input system data.

The input system data includes the fluid flow rate retrieved from the fluid storage reservoir 107 that is directed to the organ inflow. The input system may further include: data collected by the different flow meters, the data including a flow rate of fluid into the organ; data collected by a sensor for measuring the temperature of fluid entering the organ and/or fluid exiting the fluid storage reservoir; an oxygen level in the fluid entering the organ and/or the fluid exiting the fluid storage reservoir. In a preferred embodiment, the input system data is at least partially manually adjusted by the physician. For example, when a high rate of fluid leakage into the systemic blood circulation is observed, the physician may manually reduce the flow rate of fluid withdrawn from the fluid storage reservoir, thereby reducing the flow rate of fluid into the perfused organ.

In a preferred embodiment, a processing unit 112i is used to regulate the flow rate of fluid retrieved from fluid storage reservoir 107 and directed into organ 101, said processing unit 112i being implemented by means of a method for receiving and processing output system data and sending signals to pump 108 including input system data. This allows automation of the perfusion, thereby significantly reducing the number of physicians required during perfusion. In a preferred embodiment, the method comprises an algorithm.

In a preferred embodiment, the output system data received by processing unit 112i includes: fluid pressure inside the organ; a fluid flow rate for withdrawing fluid from the organ; an amount of the marker measured by a detector located upstream of an inlet of the fluid storage reservoir and an amount of the marker measured by a detector located in at least one blood vessel of the systemic blood circulation. Furthermore, the output system data received by the processing unit 112i may also include all of the above data. In a preferred embodiment, the input system data comprises a determined fluid flow rate of fluid retrieved from the fluid storage reservoir and directed to the organ inflow. The output system data also includes the volume of fluid present in the fluid storage container. Furthermore, the output system data received by the processing unit 112i may also include all of the above data.

In a preferred embodiment, withdrawing fluid from the organ 101 and directing the fluid to the fluid storage reservoir 107 and withdrawing fluid from the fluid storage reservoir 107 and directing the fluid to the organ inflow 101 are performed continuously. In a preferred embodiment, the fluid pressure within the organ is measured continuously.

In a preferred embodiment, the label is selected from the group comprising a radioactive label, a dye such as indocyanine green, a therapeutic agent itself, a therapeutic agent derivative, alkaline phosphatase, 5' nucleotidase, gamma glutamyl transpeptidase, ALT, AST, PT, INR, albumin, bilirubin.

In a preferred embodiment, the method further comprises an optional flushing step, wherein the organ 101 is perfused with a physiological solution, wherein said solution is stored in at least one container 122. The flushing step may be performed prior to perfusion with the therapeutic agent or at the completion of perfusion of the organ with the therapeutic agent. The container may be connected to a pump 108 for withdrawing physiological solution at a determined flow rate. The pump is adapted to be connected to an organ inflow. The container 122 may be connected to the inflow tube 103 and/or to a processing unit 122i which sends a signal to actuate the valve 121. The valve 121 is located between the reservoir 122 and the pump 108 and is used to allow or prevent the withdrawal of physiological solution from the reservoir 122. The valve may also be manually actuated by the physician.

In a preferred embodiment, the fluid flowing in the inflow tube 103 is selectively passed through at least one oxygenator 110 located downstream of the outlet of the fluid storage reservoir 107.

In a preferred embodiment, the fluid flowing in the inflow pipe 103 is selectively passed through at least one heat exchanger 109 located downstream of the outlet of the fluid storage reservoir 107.

In a preferred embodiment, fluid flowing in the outflow pipe 103 selectively passes through at least one filter 106 located upstream of the inlet of the fluid storage reservoir 107.

It will be appreciated that fluid entering and/or exiting the organ selectively passes through all of the elements of the system described above, such as the filter 106 located upstream of the inlet of the fluid storage reservoir 107, the injection manifold 111 for adding markers and/or therapeutic agents to the fluid retrieved from the fluid storage reservoir and directed into the organ inflow, and the bubble trap 112.

In a preferred embodiment, one or more third retrievable medical devices are introduced for occluding the organ vessel, wherein the first and/or second medical devices are not introduced. Said means are as described above for the system according to the invention.

In a preferred embodiment, the fluid storage reservoir 107 is connected to at least one blood source 117 for adding blood to the reservoir if needed. The person skilled in the art will understand that the blood added is of the same blood type as the blood of the subject.

In a preferred embodiment, the present invention allows for perfusion of isolated organs with therapeutic agents, wherein perfusion parameters, such as flow, pressure, duration, etc., are automatically adjusted. According to the invention, there is no need for a team comprising at least perfusionists, anesthesiologists and nuclear radiologists to monitor and control perfusion. The present invention reduces the number of people required and simplifies extremely complex medical procedures by using the processing unit 122i and a computer implementing a method for adjusting the machine used, to minimize the leakage rate of the infused therapeutic agent into the systemic circulation and to automate various procedures of the infusion.

The present invention is novel in that no real-time leak testing and leak control methods and/or devices and/or systems currently exist. Now, to ensure the lowest level of safety, the patient needs to be injected with a radioactive load, and the technologist will continuously measure the radioactive load in the perfused organ and in the systemic blood flow, assessing the possibility of drug and isotope laden perfusate leaking to the patient system. The technologist verbally warns the responsible physician. The physician in charge assigns the perfusionist to adjust the set parameters to regain control of the situation or decides to immediately start flushing the perfusate to end the procedure. The present invention provides a quick and proper corrective action that ensures patient safety.

In addition to fluid leak monitoring and correction, the present invention allows for continuous measurement of perfused organ liver parameters such as flow rate, pressure, drug status, additives, etc. The present invention allows for an optimized process in which real-time measurements are taken to allow the physician to react immediately.

In the method of the invention, blood flows into and out of the isolated organ. The method includes the step of determining all major blood sources entering and leaving the organ. Before the process starts, the perfusion path must be determined. Perfusion may be performed anterograde or retrograde. If desired, only some of the vessels may be occluded without using them. The perfusion path depends on the organ to be treated and must be determined prior to clinical use. The method of the invention may also be used for open or partially open procedures, especially when percutaneous access to organs is not possible. For percutaneous access, the vessel is accessed with a guidewire using ultrasound localization and using the Seldinger technique. Once the vessel has been accessed, an introducer sheath may be placed. Normal blood flow may then be controlled using an occlusion balloon or stent-like device having a central lumen for perfusion to separate the organ's blood flow from the systemic blood flow. If the blood flow is occluded, blood from the systemic side is shunted back into the systemic circulation to minimize the possibility of thrombosis. Effective isolation of the container can be confirmed by contrast methods if possible. Once organ isolation has been confirmed, perfusion may begin.

The method of the present invention comprises the step of connecting the perfusion apparatus to a perfusion system and a processing unit. The perfusion system is filled with blood or physiological solution as needed to prevent any air from entering the perfusion circuit. The perfusion system comprises at least one roller or centrifugal pump to draw blood from the organ to be treated. The blood is collected in a storage reservoir. The perfusate is pumped out of the reservoir and back into the organ. Optionally, the perfusate may be pumped through a heat exchanger to make it warmer or colder, and/or through an oxygenator before being returned to the organ, as desired.

In the method of the invention, the intra-organ pressure may be measured by any static chamber in direct contact with the perfused blood circuit. The pressure data is transmitted to the processing unit as system output data. The pumps for withdrawing fluid from the organ and for withdrawing fluid from the fluid storage reservoir are adjusted such that there is a negative equilibrium, i.e. outflow from the organ is higher than inflow to the organ. Through in vivo testing in animal models, the inventors observed that leakage from the perfusion circuit or from the organ to the systemic blood flow can be reduced or eliminated if the pressure in the organ can be reduced below the systemic pressure. The processing unit regulates the flow until a desired intra-organ pressure is obtained. Once the desired intra-organ pressure is obtained, leak monitoring can begin.

The isolation of the organ in the method of the invention can be continuously monitored in several ways. First, a radioactive label, e.g.^99mTc, are bound to larger molecules such as albumin or red blood cells to prevent migration through the cell wall that could show false leaks.The radioactive label can be detected using a sodium iodide (NaI) crystal scintillation counter or the like. One method of detection is to use a single NaI detector placed on a body region with high blood flow, but with perfused organs far enough to prevent background noise (e.g., the groin region in the case of processing the liver). A small amount of radioisotope is first injected into the systemic circulation for calibration purposes. A larger amount of radioisotope, e.g., 10 times the calibration dose, is then injected into the isolated organ. The NaI detector is continuously monitored by the processing unit and any leakage into the systemic circulation is minimized by adjusting the perfusion kinetics.

Another method of nuclear detection is to use two NaI scintillation counters placed in line. The detector is housed in a lead shield to prevent the possibility of any background noise from the perfused organ. One detector is placed in line on the perfusion circuit and a second detector is placed in line on any extracorporeal system shunt, such as an extracorporeal venous shunt, if present. A small amount of radioisotope is injected into the systemic circulation prior to use for calibration purposes. Leakage into the systemic circulation can be detected by detectors on the systemic shunt and confirmed by detectors on the perfusion apparatus. The advantage of this system is that there is substantially no measurement from the background in the systemic circulation of the perfused organ. Furthermore, a second detector on the perfusion circuit will verify that there is a leak to the system, and the count will be reduced on the perfusion detector, and vice versa on the system detector. A variation of this arrangement is that no system shunting is done. In this case, the system detector may be placed on a body region with high fluidity in the first method as described above. The output of the detector is monitored by a processing unit and any leakage into the systemic circulation is minimized by adjusting the perfusion kinetics.

In a preferred embodiment, the therapeutic agent is administered into the perfusion circuit once the leak rate to the systemic circulation has stabilized at an acceptably low value. This can also be performed automatically as part of the processing unit signal. In a preferred embodiment, the absorption of the therapeutic agent may be monitored by the processing unit, and the perfusion parameters adjusted to obtain the correct pharmacokinetic response.

The method of the invention allows for perfusion for a specific period of time and monitors perfusion for a specific period of time. At the end of this period, the processing unit may begin a flushing process to remove any therapeutic agent in the perfusate. Depending on the application, this can be done by specifying the time and/or volume for cleaning the blood or physiological solution instead of the lavage solution or by methods known to those skilled in the art. After the therapeutic agent has been removed from the perfusate, the perfusion apparatus is disconnected from the isolated medical apparatus. The device is then withdrawn and normal blood flow is restored to the patient. All access points are closed and the process is complete.

Fig. 14 illustrates an example of perfusing an organ 101 using a system and/or method and/or computer-implemented method according to the present invention. Once the organ has been isolated using percutaneous interventional techniques, isolation catheters are attached to the outflow 102 and inflow 103 tubes of the system. Isolation of the organ has been confirmed by contrast methods before the device is connected to the system. Before use, blood or physiological solution is perfused, as desired.

Blood is pumped from the organ with pumps 104 and 105. The number and type of pumps required depends on the organ to be treated. These pumps may be flow-controlled roller pumps or pressure-controlled centrifugal pumps. The purpose of the pumps 104 and 105 is to draw blood from the organ or to generate suction from the organ. Blood may also be drawn from a plurality of different blood vessels with a single pump as desired by the clinician. Blood drawn from the organ may then pass through a blood filter 106, if desired. This filter serves to remove any air bubbles or microemboli that may be present in the blood. In a preferred embodiment, the filter is provided with a reservoir that serves as a perfusate buffer for the fluid storage reservoir 107. The filtered blood is then collected in fluid storage reservoir 107. Blood from reservoir 107 is pumped into optional heat exchanger 109 and oxygenator 110. The need for low or high heat oxygenated blood is based on medical and application requirements and may not always be necessary. Similar to the evacuation pump, more than one pump 108 may be used to return blood to the organ as desired. The pump is preferably a roller pump, but centrifugal pumps may be preferred for some applications. From the oxygenator, the blood then flows through an injection manifold 111 and a bubble trap 112. The injection manifold may be connected to an injection pump as needed to administer the at least one marker and the at least one therapeutic agent, such as chemotherapy or heparin as needed. The syringe pump connected to manifold 111 may be controlled by processing unit 112i to administer a therapeutic agent at a predetermined point or as a result of continuous blood monitoring. From there, the blood is returned to the organ.

The method of the present invention also allows for various sensors, valves, metering pumps or flow meters 113, 114, 115, 116 to be placed on the outflow and/or inflow pipes. This allows fluid flow to be monitored and controlled as required by the processing unit. The fluid level in the reservoir 107 is also monitored by the processing unit. If the level becomes too low, fluid may be added from the blood source 117. If desired, an overflow outlet 118 is present on the reservoir, e.g., excess lavage fluid can be collected during the rinsing step.

Detectors 119 and 120 may be placed on the perfusion circuit and system cycle. It is desirable that the two detectors are housed in a lead shield with an irrigation line to avoid any background interference. This is only possible in the systemic circulation if an extracorporeal shunt, such as an extracorporeal venous shunt, is made. If there is no shunting, the detector 120 is located on a body region where high blood flow is far enough away from the organ being treated to prevent interference. The processing unit may control the administration of the radioisotope and perform all leak rate calculations.

The method is implemented in a control unit, 112i, also referred to as processing unit. The method includes a programming algorithm. The processing unit has a graphical user interface. To control the method of the present invention, the user is required to enter key information. Such information may be: target perfusion flow rate, acceptable flow range, and maximum leak rate and perfusion time. The processing unit may use a feedback loop to control the speed of the pump to achieve the desired intra-organ pressure and leak rate. Furthermore, the processing unit automates the step of priming as follows: the flow rates into and out of the organ are first increased until the target flow rate is achieved. During this process, the flow meters 113, 114, 115, and 116 may be read to ensure that the inflow and/or outflow tubes do not collapse or compromise flow. In vivo animal testing, monitoring the perfusion tube to ensure adequate flow takes a significant amount of time. If there is a problem with the flow, the physician is notified so that the problem can be corrected. Once the flow is acceptable, the processing unit will begin the process of reducing the pressure in the organ to a target value. This is done by adjusting the negative balance of the infusion pump. This may be done using a feedback controller, such as a PID controller. During this time, the patency of all perfusion lumens was confirmed by the flow meter. The processing unit may then initiate leak monitoring by administering the marker and controlling the leak rate as previously described. At the end of the perfusion period, the processing unit may actuate the valve 121 and flush the organ with clean blood and/or physiological solution 122. The present invention also allows for the connection of other sensors, actuators or pumps 124 as desired. Such sensors may be used to perform in-process assays to determine drug concentrations or for blood analysis as desired.

The first, second and third medical devices may be used to isolate and perfuse an organ as described above. However, in order to control a local, isolated, perfusion or infusion process, a specific vasculature, collateral connection of the patient must be addressed to control communication between the perfusion or infusion fluid and the patient system.

In a third aspect, the present invention provides a computer-implemented method for monitoring and controlling an organ perfusion system of a subject, the system comprising: at least one pressure detector for measuring fluid pressure within the organ; an outflow tube for retrieving fluid from the organ; and an inflow tube for delivering fluid to the organ, wherein the method comprises the steps of:

-processing the received output system data, and

Fig. 15 shows an exemplary flowchart of a method and/or algorithm that may be computer-implemented and used to control perfusion of a liver using a system and/or method according to the present invention. The flow chart describes the different steps of the method that have to be performed after isolating the liver using the first, second and third medical devices as described above. N and Y in the figure represent "no" and "yes", respectively.

It should be understood that all values in fig. 15 are exemplary values and may be modified depending on the organ to be perfused and the disease to be treated. In fig. 15, asterisks indicate that the values given here are exemplary values. At the beginning of retrograde perfusion, the fluid flow rate to the liver was set to 0. The fluid flow rate withdrawn from the liver is set at a value of from 200 to 1000cc/min, preferably from 300 to 800cc/min, more preferably from 400 to 700cc/min, most preferably about 500 cc/min. The retrieval is maintained for a period of time from 20 seconds to 5 minutes, preferably from 30 seconds to 3 minutes, more preferably from 40 seconds to 2 minutes, most preferably about 1 minute.

Thereafter, the fluid flow rate to the liver is set at a value of from 20 to 200cc/min, preferably from 50 to 150cc/min, more preferably from 70 to 140cc/min, even more preferably from 80 to 120cc/min, most preferably about 100 cc/min. The fluid flow rate withdrawn from the liver is set at a value of from 100 to 250cc/min, preferably 120 to 220cc/min, more preferably 150 to 200cc/min, most preferably about 170 cc/min.

In a preferred embodiment, the blood loss according to the method of the invention does not exceed 2 litres, preferably does not exceed 1 litre. The blood loss is at most 300cc, preferably at most 250cc, more preferably at most 200cc, even more preferably at most 150cc, preferably at most 100 cc. In a further preferred embodiment, the blood loss is at most 50cc, preferably at most 40cc, more preferably at most 30cc, even more preferably at most 10cc, most preferably no blood loss when using the method according to the invention. By "blood loss" is meant the volume of blood containing the therapeutic agent and/or any derivative of the therapeutic agent that is not returned to the systemic blood flow at the end of the perfusion process and prior to withdrawal of the introduced medical device.

The present invention provides an automatically controlled optimal perfusion flow, wherein the local treatment is optimized in terms of organ isolation and controlled automatic stopping when the measured or calculated leakage is higher than a preset value. This preset value may be, for example, a percentage of the maximum systemically allowable dose. The total leakage should be limited to ensure that in the event of such a leakage the maximum allowable systemic dose remains below a defined maximum, preferably < 40%, more preferably < 10% of the systemic allowable maximum.

In a fourth aspect, the present invention provides the use of a system as described above for monitoring and controlling organ perfusion in a subject.

In a fifth aspect, the present invention provides the use of a method as described above for monitoring and controlling organ perfusion in a subject.

In a sixth aspect, the present invention provides the use of a computer-implemented method as described above for monitoring and controlling organ perfusion in a subject.

Therapeutic agents

The therapeutic agent of the kit according to the invention may be a treatment fluid or a particle or bead containing said treatment. Particles are known to the person skilled in the art and are described, for example, in US2004/197264, the content of which is incorporated herein by reference. The particles comprise: a material selected from the group consisting of glass, polymer, and resin; emitting a first radioisotope to treat the beta-particle; and a second radioisotope that emits diagnostic gamma radiation; wherein the atomic number of the first radioisotope is different from the atomic number of the second radioisotope. In a preferred embodiment of the invention, the particles are beads, preferably polymer or glass beads, comprising the radioactive element.

The granule can be used for treating organ tumor. The particles are delivered into the organ's blood stream through the arteries of the organ to be treated. The radioactive particles are selectively implanted into the microvascular supply of the tumor, where they are trapped. These particles emit beta radiation for a period of time to kill the tumor.

The particles can be used for treating, for example, liver cancer. Patients with primary or metastatic tumors can be treated by radio embolization via a catheter placed in the hepatic artery at its leading end. The beads can also be injected directly into the tumor using a needle. The spheres eventually lodge in the microvasculature of the liver and tumor, remaining until complete decay of the radioisotope.

The particles have a diameter in the range of about 1 to 500 microns, preferably 2 to 400 microns, more preferably 4 to 300 microns, and most preferably 5 to 200 microns. The diameter of the particles may be any value included in the above range.

In another preferred embodiment, the particles are between 10 and 300 microns in size, preferably between 15 and 200 microns, more preferably between 20 and 60 microns, and most preferably the particle size is about 30 microns.

Preferably, the particles have a diameter of between 50 and 70 microns, more preferably between 40 and 60 microns, and most preferably about 30 microns.

First retrievable medical device

The first medical device is used for simultaneous or separate perfusion and occlusion of an organ flowing into a blood vessel. The device comprises: a body having a distal end, a proximal end, at least one lumen extending between the proximal and distal ends, at least one opening in fluid communication with the lumen for delivering fluid to the vessel, and at least one inflatable balloon coupled with the body of the device.

The first retrievable medical device (26, fig. 4) is preferably a catheter. For treatment of liver tumors, the catheter will be introduced into the Hepatic Artery (HA). Insertion of the catheter enters the common hepatic artery via the right interfemoral artery.

In a preferred embodiment, the first medical device (26, fig. 4) allows for a shunt revenue of 10-500cc/min, allowing for a slow supply of a medicament with undesirable tissue reactions such as spasticity, and allowing for higher flow rates for bolus treatments.

In a preferred embodiment, the first medical device has a small size and is a flexible device, which may be positioned, for example, along a tortuous path. The diameter of the device is between 5F (about 1.67 mm) and 7F (about 2.3 mm). The length of the device is about 800 mm. The latter allows the device to be positioned close to or in an organ. The device provides control of blood flow through the target organ and provides unlimited infusion/perfusion revenue.

The device is shown in fig. 11A, including a gripping area 67, a single lumen 66, and at least one balloon 65. Inflation of the balloon is induced and controlled by the infusion/perfusion fluid. The device may at least partially and/or temporarily occlude a blood vessel to control blood flow and inject a therapeutic agent into the organ at a flow rate of at least 20 ml/min. In a preferred embodiment, the balloon of the first medical device has an interior in fluid communication with the inflation lumen through at least one opening in the body of the device. During delivery of the therapeutic agent to the blood vessel, an infusion/perfusion fluid containing the therapeutic agent flows in lumen 66 and inflates balloon 65 by flowing through openings 68 and 69 (fig. 11A). Fig. 11B shows another embodiment of the catheter in which an opening 70' allows the flow of infusion/perfusion fluid to cause inflation of the balloon 70.

The device may also have a plurality of valves 71, as shown in FIGS. 11C, 11D and 11E. The valve 71 is located on the surface of the opening. When the perfusion fluid is injected, pressure is generated in the lumen of the device. The liquid causes the valve 71 to open and accumulate in the balloon 70, thereby inflating the balloon 70, as shown by the arrows in fig. 11C. When the infusion of the perfusion fluid is terminated, the valve 71 is closed and the balloon remains inflated (fig. 11D). When the device is to be withdrawn at the end of the treatment, a negative pressure is created within the lumen of the device, which causes the valve 71 within the lumen to open and the balloon 70 to deflate (fig. 11E). The valve is made of any suitable flexible material, such as, but not limited to, silicon. A draw cord may be provided in the device to control the opening and closing of the valve.

Fig. 12A shows the catheter of the first medical device when the balloon 81 is not in the inflated state. The diameter of the lumen 80 decreases at one end 82 of the catheter. The narrowed end may have a tapered tip. The decrease in diameter at one end of the catheter results in an increase in pressure during infusion and/or delivery of the therapeutic agent. The latter accelerates the inflation of the balloon. The reduction in diameter ensures that the balloon segments are inflated at a minimum defined flow rate. The diameter at the end 82 of the catheter is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or any value in between these values compared to the diameter of the lumen to ensure inflation of the balloon during perfusion. Fig. 12B shows the catheter with balloon 81 in an inflated state due to the flow of infusion/perfusion fluid in lumen 80. The infusion/perfusion fluid creates pressure within the lumen due to the reduced diameter of the catheter tip. The fluid and fluid pressure cause inflation of balloon 81.

The catheter of the first medical device is made of biocompatible materials that are generally suitable for short-term (<120 minutes) endovascular procedures. Balloon 81 may be the most flexible portion of the catheter, such as by having a smaller wall thickness, or made of other materials bonded to the catheter. The catheter of the first medical device according to the invention is a transcutaneous device with a minimum amount of material to ensure vessel occlusion, increase flexibility and maximize infusion/perfusion flow.

Fig. 8 shows a catheter with a guidewire 52 and a lumen 51. The balloon is substantially spherical and is located at the distal end X of the device. The length c of the balloon after inflation is about 10 mm. The catheter includes a tube 44 having a lumen. The diameter j of the tube 44 is about 2.5 mm. The diameter e of the distal X portion of the first retrievable medical device is about 2 mm. Said portion extends over a length g of about 150 mm. The length h of the catheter is about 900 mm. Tube 44 is disposed at proximal end Y and has a female luer adapter 49. At the distal end X, the tube 44 has a balloon that expands when the user pushes against the inflated balloon 47. The inflation bladder 47 has an inflation check valve 46 and a male luer adapter 48. The inflatable balloon 47 is connected to the catheter via a female luer adapter 49 and a connector tube 50.

Second retrievable medical device

The second retrievable medical device is used to isolate and collect the organ outflow. The device has a distal end and a proximal end; the second medical device comprises a catheter adapted to deploy an expansion member; the proximal end of the expansion member is attached to the distal end of the catheter. In a preferred embodiment, the expansion member of the second retrievable medical device comprises a carrier and an impermeable liner bonded to at least a portion of the length of the carrier. In a further preferred embodiment, the expansion member of the second medical device has a tubular shape. In another preferred embodiment, the expansion member of the second medical device has a bell shape.

In a preferred embodiment of the invention, the expansion member of the second medical device comprises a liquid permeable carrier configured to assume a substantially cylindrical state when compressed and to expand radially to form a central portion flanked by two annular ridges.

Fig. 1 shows an embodiment of a second medical device according to the invention. The device comprises a radially self-expandable tubular member 9, shown in an expanded state attached to a delivery catheter 10. Fig. 1A shows a cross-section of a catheter. The expandable tubular member 9 may be a self-expandable tubular member 9.

The second medical device has a distal end 21 and a proximal end 20, comprising a hollow self-expanding tubular member 9 and a catheter 10 adapted to deploy the self-expanding tubular member 9, wherein:

the tubular member 9 is configured to expand radially to form a central portion 11 flanked by two annular ridges,

a distal annular ridge 12 and a proximal annular ridge 13,

the tubular member 9 comprises a liquid-impermeable area defined at least by the area flanked by the annular ridges 12, 13,

the tubular member 9 comprises two liquid permeable areas, one distal to the distal annular ridge 12 and one proximal to the proximal annular ridge 13, thereby forming a passage 14 between the distal 21 and proximal 20 ends of the tubular member 9 for the flow of vascular fluid,

the proximal end 20 of the tubular member 9 is attached to the distal end 21 of the delivery catheter 10,

the liquid impermeable area is provided with one or more fluid ports 15 for the passage of blood.

The self-expandable tubular member 9, herein known as "tubular member", is typically an elastic tube which self-expands after being compacted. Exemplary examples of self-expandable tubular members are disclosed in the following documents, which are incorporated herein by reference in their entirety: US5,876,445, US5,366,504, US5,234,457, US5,061,275; watkinson et al: the roll of self-expanding metals in esophageal structures, "sensines in Interactive radio", 13(1):17-26 (3.1996). In another preferred embodiment the carrier is made of a woven wire mesh. The annular ridge is adapted to be in contact with a blood vessel of the organ, thereby applying a sealing pressure to the blood vessel wall.

In a preferred embodiment, the tubular member 9 comprises, in the expanded state, a central portion 11 flanked on both sides by two annular ridges, a proximal annular ridge 13 and a distal annular ridge 12. The central portion 11 expands radially to a lesser extent than the annular ridges 12, 13. The expanded central portion 11 has a generally cylindrical shape, while the annular ridges 12, 13 are at least partially conical, thereby forming a funnel-like structure in the expanded state. By so designing the device, it is partially formed into an hourglass or dumbbell when inflated. When deployed in a body vessel, the central portion 11 forms an annular cavity 18 sealed by the annular ridges 12, 13 for collecting blood delivered to the body vessel by other vessels, such as side branch vessels.

Those skilled in the art will appreciate that in the expanded state the diameter of the tubular member 9 at the annular ridges 12, 13 and the central portion 11 may be adapted to the diameter of the blood vessel in the deployed position. The diameter of the central portion 11 should be wide enough to avoid obstructing blood flow, but not so wide that the flow reaches a high level, which would affect the leakage resistance and disturb laminar flow. The diameter of the annular ridges 12, 13 should be chosen such as to provide a perfect seal against the inner wall of the blood vessel when the tubular member 9 is in the expanded state. The seal is ensured by: the pressure exerted by the carrier 2 on the vessel wall; and the annular ridges 12, 13 are in contact with the inner vessel over a distance of between 15-100mm, preferably between 16-80mm, more preferably between 17-60mm, most preferably between 18-40 mm.

In another preferred embodiment, in the expanded state, the central portion of the tubular member and the annular ridge are designed to expand radially to the same extent. The expanded tubular member is then cylindrical in shape with an at least partially conical end (fig. 1C), forming a funnel-like structure in the expanded state. The cylindrical shape is obtained by expansion of the carrier 2. A liner 1 having a hour glass or dumbbell shape is at least partially attached to the inner wall of the carrier 2 as shown in fig. 1C. When deployed in a body vessel, the liner 1 forms an annular cavity 18 for collecting blood delivered to the body vessel by other vessels, such as side branch vessels. The straight carrier 2 is made of a flexible material, such as a woven wire mesh. It is therefore able to follow the vessel curvature and ensure reliable isolation between systemic blood flow and fluid flowing in through both the inner tube 5 and the annular cavity 18. The continuous cylindrical carrier ensures optimal opening of the blood vessel during organ treatment.

In another preferred embodiment, in the expanded state, the central portion of the tubular member and the annular ridge are designed to expand radially to the same extent. The expanded tubular member is then cylindrical in shape with an at least partially conical end (fig. 1D and 1E), forming a funnel-like structure in the expanded state. The cylindrical shape is obtained by expansion of the carrier 2. The distal end 21 of the inner tube 5 is formed as a cup or scoop 1' attached to the carrier 2 in at least two positions to form an annular cavity 18, as shown in fig. 1D. The cup or scoop 1' of the device is adapted to be in fluid connection with several veins. For example, the cup or scoop 1' is adapted to be in fluid connection with several bronchial branches when the device is placed in a thoracic duct arch. Fig. 1F shows a cross-sectional view along a-a shown in fig. 1D, and fig. 1E shows a top view of a second medical device according to the present embodiment. The straight carrier 2 is made of a flexible material, such as a woven wire mesh. It is therefore able to follow the vessel curvature and ensure reliable isolation between systemic blood flow and fluid flowing in through both the inner tube 5 and the annular cavity 18. The continuous cylindrical carrier ensures optimal opening of the blood vessel during organ treatment.

In another preferred embodiment, the second medical device in the expanded state has a bell-shaped member 9', as shown in fig. 1G. The bell member 9' may be a self-expanding bell member. The apparatus comprises a carrier 2 and a liner 1 disposed on an outer wall of the carrier 2. The liner 1 is in this embodiment provided over the full length of the device shown in figure 1G. The device is primarily used for delivering therapeutic agents to organs. The therapeutic agent flows through the inner tube 5.

It should be understood that all of the embodiments of the second medical device described above may be used to deliver and/or retrieve a therapeutic agent to and/or from an organ. Delivery and/or retrieval of the therapeutic agent is performed while maintaining systemic blood flow in the patient. The organ to be treated is for example the liver or the lung.

For liver treatment, the second medical device is located in the vena cava with the proximal end just above the renal vein inflow. The proximal portion of the device occludes the collateral inflow form of the renal vein up to the annular space 18 around the hepatic vein. This isolation is ensured by the rounded-end annular ridge, thereby preventing possible damage to the right atrium portal even when placed deep into the right atrium.

The annular chamber 18 around the hepatic vein is about 15-20mm long. Physicians do not encounter difficulty in positioning the device in front of the hepatic vein. In addition to the annular cavity 18, the vena cava is in contact with a second medical device: from the renal vein to the right atrium.

The minimum diameter of the central portion 11 in the expanded state may be 45, 50, 55, 60, 65, 70, 76, 80, 85, 90 or 95% of the inner diameter of the vena cava, or a value between any two of the above values. Preferably, the minimum diameter of the central portion 11 in the expanded state is at least 50% of the internal diameter of the vena cava. According to one aspect of the invention, the minimum diameter of the central portion 11 in the expanded state is a value in the range between 6, 8, 10, 12, 14, 16, 18, 20, 22mm or between any two of the above values, preferably 8-18mm diameter.

The maximum diameter of the annular ridges 12, 13 in the expanded state may be 5, 10, 15, 20, 25, 30, or 35% greater than the inner diameter of the vena cava, or a value between any two of the foregoing values. Preferably, the maximum diameter of the annular ridges 12, 13 in the expanded state is between 10, 15, 20, 25, 30% larger than the inner diameter of the vena cava. According to one aspect of the invention, the maximum diameter of the annular ridges 12, 13 in the expanded state is a value between 20, 25, 30, 35, 40, 45mm or in a range between any two of the above values, preferably 20, 26, 33 or 43mm diameter.

According to an aspect of the invention, the difference between the largest diameter of the annular ridges 12, 13 and the smallest diameter of the central portion 11 in the expanded state may be 2, 3, 4, 5 or 6mm or a value in the range between any two of the above mentioned values, preferably a diameter of 4-5 mm.

The area flanked by the annular ridges 12, 13 defines a liquid-impermeable area. Those skilled in the art will appreciate the adaptation of the tubular member 9 required to define the liquid impermeable area to provide a sealed annular cavity 18 in the deployed state. Generally, the liquid impermeable area extends between the annular ridges 12, 13 from the area of maximum diameter of the proximal annular ridge 13 to the area of maximum diameter of the distal annular ridge 12. For example, it is within the practice of those skilled in the art to determine smaller or larger areas based on the patency of the vessel wall.

Between the distal end 21 and the proximal end 20 of the tubular member 9, the passage 14 extends through the interior of the tubular member; blood can flow therebetween. The tubular member 9 comprises two liquid permeable areas, one distal to the distal annular ridge 12 and one proximal to the proximal annular ridge 13, so that blood can flow through the channels from the distal 21 and proximal 20 ends and vice versa. Preferably, the liquid permeable area of the distal end 21 of the tubular member 9 comprises the open area, while the liquid permeable area of the proximal end 20 comprises the area 16 without the liquid impermeable lining. According to one aspect of the invention, the tubular member 9 comprises a carrier 2 and a liquid impermeable liner 1. The carrier portion 2 is typically, although not always, the outermost portion of the device and is in contact with the vessel wall in the deployed state. The carrier 2 is inflated in the manner described above. The carrier 2 is preferably collapsible, which means that it generally takes the shape of an hourglass or dumbbell as described above; when retracted into the cylindrical sheath, the carrier may be compressed to assume a generally cylindrical state, suitable for introduction into a blood vessel and free positioning within the blood vessel. The carrier 2 may be described as being self-expanding. The carrier is attached to the catheter, to which the pusher device 23 element is attached, as described below. Preferably, the proximal end 20 of the carrier 2 is circumferentially attached to the distal end 21 of the pusher device 23, thus giving the proximal end 20 of the tubular member 9 a conical shape 16.

The tubular member 9 or carrier 2 is attached to the catheter 10 or pusher device 23. It is configured to remain attached when the tubular member 9 or carrier 2 is in the collapsed and expanded positions. According to one aspect of the invention, it is non-releasably attached, meaning that the tubular member 9 or carrier 2 cannot be released from the catheter 10 or pusher device 23 in situ. In other words, the device may be devoid of a mechanism for releasing the tubular member in situ. This feature allows the tubular member to be withdrawn simultaneously with the catheter 10 without the possibility of the tubular member remaining in the vessel. The non-releasable attachment may still allow the member 9 or carrier 2 to be detached from the catheter 10 or pusher device 23 from outside the body, for example using a screw fit, a clip, a push fit or any other reliable coupling. The non-releasable attachment also includes the possibility of the member 9 or carrier 2 being permanently attached to the catheter 10 or pusher device 23.

In the inflated state, the carrier 2 is able to maintain its shape without the need for an additional pressure source, e.g. from a balloon catheter. The load carrier 2 may or may not maintain a substantially constant axial length in the compressed state as compared to the expanded state.

The carrier part 2 is preferably made of a woven wire mesh, which is woven so as to be radially self-expanding. In an embodiment, the carrier is made of a surgical cable, preferably an alloy comprising cobalt, chromium, nickel, molybdenum and iron, more preferably a surgical cable according to the standard ASTM F1058. Alternatively, the carrier portion 2 may be a braided mesh of nitinol wire that is flexible in both radial and longitudinal axes. Alternatively, other materials, such as shape memory alloys or composite materials, may be used to produce the carrier. Alternatively, the carrier part 2 may be laser cut. The shape of the central portion 11 may be formed by crimping or heat treatment. The carrier may exhibit a high degree of flexibility and radial forces ensuring good contact with the vessel wall after positioning. The carrier part 2 is liquid-permeable, which means that blood can flow through it substantially unimpeded. This is achieved in the carrier in that it is formed of an open wire structure and may include open ends. The liquid-permeable area may comprise one or more openings, at least wide enough to prevent capillary action from occurring through the openings.

Since the carrier part 2 is preferably formed by an open mesh structure, it reliably comes into contact with the vessel wall in the expanded state due to the open structure creating a plurality of friction points. In the expanded state, the device is reliably anchored and provides a strong seal against the vessel wall. No additional pressure need be applied to the vessel wall, for example from a balloon.

Another component of the tubular member 9 is a liner 1, which liner 1 is made of a liquid impermeable material. This is typically partly attached to the wall of the carrier 2, either inside or outside the passage cavity 14 of the device. The lining 1 is arranged at least in the region of the annular chamber 18, so that in the deployed state the passage chamber 14 is liquid-tight with the annular chamber 18. Preferably, the liner 1 is arranged in an area defined at least by the areas flanking the annular ridges 12, 13.

The liner 1 may be made of a biocompatible material, preferably a medical grade expandable material, such as an elastomeric material that can expand simultaneously with the carrier 2. The liner may be made from a formulation of medical grade polycarbonate polyurethane. Alternatively, the liner may be made of polytetrafluoroethylene, polyurethane, silicon, or polyethylene terephthalate polymer. The most preferred materials are shown in table 2 below:

table 2: examples of preferred liner materials for use in the present invention. All trademark names are registered trademarks.

The liner 1 may be attached to the carrier 2 by chemical or thermal bonding. The liquid impermeable area formed by the liner 1 is provided with one or more fluid ports 15 for the passage of blood; this is described in more detail further below.

Between the distal end 21 and the proximal end 20 of the tubular member 9, a passage 41 extends through the interior of the tubular member 9; blood can flow therebetween. The tubular member 9 comprises at least two liquid permeable areas, one distal to the distal annular ridge 12 and one proximal to the proximal annular ridge 13, so that fluid can flow through the channel 14 from the distal end 21 and the proximal end 20 and vice versa. The flow is indicated by arrow "b" in fig. 1. Those skilled in the art will appreciate that the liquid-permeable region cannot extend into the liquid-impermeable region to break the seal of the annular cavity 18. Preferably, the distal end 21 of the tubular member is open, while the proximal end 20 is closed, but provided with a liquid permeable area 16, i.e. an area without the liner 1.

According to one aspect of the invention, the region 16 of the carrier facing the proximal end 20 of the proximal annular ridge 13 is free of the liner 1. According to another aspect of the invention, at least a portion of the carrier 2 between the distal end 21 of the catheter 10 and the proximal end 20 of the proximal annular ridge 13 is free of the liner 1. This creates a large liquid passage 14 within the tubular member 9 while the catheter 10 is still attached. This configuration has advantages over conventional designs that employ openings and lumens within the narrow confines of the catheter to maintain blood flow. Conventional lumens are narrow orifices and may cause an increase in pressure toward the proximal side of the occluding device. Thus, known devices require catheters with larger diameters to accommodate wider blood lumens, and these catheters may then be difficult to travel along a tortuous path, such as a blood vessel. Instead, the device is provided with a catheter blood lumen and maintains blood flow with a narrow diameter catheter using a wide bore passage in the expanded tubular member 9.

The portion of the catheter 10 of the device is used for introducing and guiding the tubular member 9 into the body vessel. The catheter 10 also serves to temporarily restrain the tubular member 9 in a compressed state to the distal end of the catheter. It also serves to withdraw liquid from the annular cavity 18. In use, the catheter is introduced into the body vessel at the desired location, unrestrained, allowing the tubular member 9 to expand by its own resilience and apply sealing pressure to the vessel wall using the annular ridges 12, 13.

Examples of delivery systems for expandable tubular members are described in the following US patents, which are incorporated herein by reference in their entirety: US5,484,444, US 4,990,151 and US 4,732,152.

According to one embodiment of the invention, the catheter 10 comprises an outer tube 3, a pusher device 23 for deploying the tubular member 9, and an inner tube 5 extending along the length of the catheter. The pusher device 23 may be a push rod (or lever) 4 (fig. 1A) disposed at least partially coaxially or concentrically around the inner tube 5. Alternatively, the pusher means 23 may be formed by the wall of the inner tube 5 (fig. 1B).

The outer tube 3 may be arranged coaxially or concentrically around the push rod 4. In case the pusher means 23 is formed by a wall of the inner tube 5, the outer tube 3 may be arranged coaxially or concentrically around the inner tube 5. The pusher device 23 is configured to translate axially along the length of the catheter relative to the outer tube 3.

Where the pusher device 23 is formed by a wall of the inner tube 5, the inner tube 5 may be configured to translate axially along the length of the catheter relative to the outer tube 3. Movement of the pusher device 23 may be achieved by operating a plunger 7 mechanically connected to the push rod 5 or inner tube 5 at the proximal end 20 of the catheter 10.

The position of the outer tube 3 can be maintained or adjusted by means of the grip region 6. The distal end 21 of the pusher device 23 is mechanically attached to the proximal end of the carrier 2.

According to one embodiment of the present invention, the catheter 10 comprises: (a) an inner tube 5; (b) an outer tube 3; (c) a pusher device 23. The outer tube 3 surrounds at least a portion of the length of the inner tube 5. The push rod 4 may be disposed between the inner tube 5 and the outer tube 3. Alternatively, the pusher means 23 may be formed by a wall of the inner tube 5, in which case the outer tube 3 surrounds at least a part of the length of said inner tube 5 (the wall of the inner tube 5 forming the pusher means 23). The push rod 4 is adapted to move axially relative to the outer tube. The tubular member 9 is attached to the distal end of the pusher device 23 and can be collapsed in the outer tube 3 in a compressed state.

Figure 2 shows a tubular member 9, comprising a liner 1 and a carrier 2, collapsed within an outer tube 3 of a catheter 10. In the compressed state, the tubular member 9 is held in compression by the inner surface of the outer tube 3 acting as a limiter. Fig. 2A shows an embodiment in which a closed tip 8 is provided to the device at the distal end 21. Fig. 2B shows an embodiment in which a tapered closed tip 8' is provided at the distal end 21 of the device. The tapered closed tip 8' acts as a dilator to help open and enlarge the blood vessel during introduction of the second medical device.

According to one aspect of the invention, the catheter 10 further comprises a restraining member disposed between the outer tube 3 and the tubular member 9, the restraining member being sized to maintain the tubular member 9 in a compressed state.

The restraining member described above may be a braided tube or any other type of tube surrounding the tubular member 9, the braided tube preferably being made of a strong flexible wire material having a low coefficient of friction. Examples of such materials may be fine polyester fibers or metal filaments. The braided tube may be formed directly on tubular member 9, preferably using an automatic braiding machine, or may be preformed and then inserted on tubular member 9. Where the braided tube is preformed and then inserted over the tubular member 9, the system preferably further comprises a braided retention sleeve secured to the inner tube 5, the braided retention sleeve being adapted to receive the proximal end of the braided tube. The distal end of the restraining member is preferably mechanically coupled to the distal end of the outer tube 3 such that contraction of the outer tube 3 causes the restraining member to contract from the tubular member 9, thereby allowing the tubular member 9 to self-expand. The catheter 10 and the tubular member 9 may be inserted in a blood vessel and deployed at their desired location, preferably with the aid of a guide wire. The guidewire may have a separate guidewire lumen. Alternatively, the inner tube 5 may be used as a guidewire lumen. The tubular member 9 may be deployed by axially moving the pusher device 23 in the distal direction while the outer tube 3 remains in a fixed position. Preferably, the tubular member 9 is deployed by axially collapsing the outer tube 3 in the proximal direction while the pusher device 23 is held in a fixed position. During deployment, the physician may position the tubular member appropriately to account for any foreshortening of the device. As the restriction of the outer tube is removed, the tubular member 9 self-expands. The catheter may optionally be closed with a tip 8.

As shown in fig. 1, the second medical device, comprising a liner 1 and a carrier 2, is expanded into the shape of a dumbbell or hour glass. The device is retrieved after treatment by retracting the tubular member 9 into the outer tube 3. This can be achieved by: the pusher device 23 is pulled towards the proximal end 20 while maintaining the position of the outer tube 3. Alternatively, the outer tube 3 is pushed towards the distal end 21 while maintaining the position of the push rod 4. Because the carrier 2 is connected to the pusher device 23, the tubular member 9 is forced to assume the unexpanded state again inside the outer tube 3. The device can then be carefully removed from the blood vessel.

The inner tube 5 of the catheter 10 is in fluid connection with one or more ports 15 present in the wall of the tubular member 9. Said port 15 is provided in the wall of the tubular member 9 in the region of the annular chamber 18. The ports 15 may be provided in the central portion 11 and/or in the portions of the annular ridges 12, 13 forming the annular cavity 18. The port 15 allows the lumen of the inner tube 5 to be in fluid contact with the annular cavity 18 so that liquid, such as blood, can be collected or withdrawn from the annular cavity 18 through the catheter 10. The port 15 may also serve as an entry/exit point for a guidewire.

Whether or not the second medical device is provided with one or more ports, the size of the port 15 and the diameter of the inner tube 5 should be selected such that when therapeutic agents are delivered in the particles they are not blocked by the particles. Preferably, the port is at least 1mm wide and the inner tube has a diameter of at least 5 mm.

The diameter of the inner tube is preferably >1mm to prevent build up of particles (which could occlude the device). Normal blood flow through the liver is about 1.5-18 liters/minute. The second retrievable medical device has a french code diameter of F18 (about 6mm), preferably a diameter below F16 (about 5.3mm), allowing up to 2 litres/minute of flow.

Those skilled in the art will appreciate that the connection between the inner tube 5 and the port 15 may be optimized such that expansion of the tubular member 9 does not result in axial stretching of the inner tube 5, or excessive relaxation along the inner tube 5. According to one embodiment of the invention, the inner tube 5 of the catheter 10 extends from the outer tube 3 and is fluidly connected with the annular cavity 18 via one or more ports 15. In other words, the inner tube 5 may extend from the outer tube 3 to connect with the port 15 as a continuous extension of the inner tube. According to another embodiment of the invention, the inner tube 5 of the catheter 10 is fluidly connected to the port 15 of the tubular member 9 using a bridging tube.

Figure 5 shows one configuration of the inner tube 5, using a rigid bridging tube 19 to fluidly connect the port 15 of the tubular member 9 to the inner tube 5 of the catheter 10. Figure 6 shows an alternative configuration of the inner tube 5 in which an axially expandable bridging tube 19' is used to fluidly connect the port 15 of the tubular member 9 to the inner tube 5 of the catheter 10. The latter bridge pipe 19 'is typically made of a flexible material which can be expanded by means of elastic properties and/or by means of concertina-like folding of the unexpanded bridge pipe 19'.

Fig. 3A and 3B illustrate a system in which the tubular member 9 is deployed within a blood vessel 30. The proximal 13 and distal 12 annular ridges contact the wall of the blood vessel 30, the central portion 11 forming an annular cavity 18. Blood (indicated by arrow b) is able to flow freely through the unlined part of the tubular member 9. The annular cavity 18 may span the area of the branch vessels 31-37 where excess blood (represented by arrows a) of the therapeutic agent will flow. The blood with excess therapeutic agent (indicated by arrow a) then flows within the inner tube 5.

In fig. 3A, the liner 1 is attached to the carrier 2 such that the liner is located inside the carrier 2. Figure 3B shows an alternative configuration in which the liner 1 is located on the outside of the carrier 2.

The above-described device is particularly useful for minimally invasive and repeatable treatment of organs. After positioning, as mentioned, before the device is expanded to achieve its dumbbell or hourglass shape. The proximal 13 and distal 12 annular ridges (i.e., the ends of the device) expand until they press against the inner wall of the vessel, securing the device in the selected position and providing a fluid tight seal within the vessel. The central portion 11 of the device expands to a lesser extent, forming an annular cavity 18 between the device and the inner wall of the blood vessel. Inside the device is a passage chamber 14 for whole body blood to bypass the sealed area. In this way, the channel lumen 14 defines a new blood path that allows systemic blood flow to continue during perfusion. The fluid-tight sealing of the proximal annular ridge 13 and the distal annular ridge 12 against the blood vessel and the fluid-tight liner 1 of the device form a fluid-tight barrier separating systemic blood flowing through the channel 14 from blood present in the annular cavity 18. This blood can be collected from the annular cavity 18.

Depending on the type and location of the cells to be treated, the physician may decide in which vein the second medical device is to be introduced. During liver processing, a second medical device is introduced in the Vena Cava (VC) to isolate blood entering the VC through the HV.

Although the use of the system in a retrograde liver perfusion application is described below, this application is exemplary only. It will be clear to the skilled person that the system may also be used for treatment of other organs than the liver, either antegrade or retrograde.

In a preferred embodiment, for organs like liver and lung that can be perfused retrograde, a second medical device is used to deliver the therapeutic agent and remove excess therapeutic agent from the organ. The therapeutic agent may be delivered by outflow from the organ, loading it with retrograde flow, i.e., against systemic pressure, thereby ensuring that it stays in the organ. After a period of time, flow may again resume, which pushes the unbound therapeutic agent out of the organ and may be delivered by the VCD catheter.

Third retrievable medical device

The third retrievable medical device is for isolation and/or perfusion of a vein. The third retrievable medical device comprises: a distal end, a proximal end, a lumen, an inflation lumen, a balloon at the distal end of the device, and a plurality of outlets at the distal end of the balloon or at the proximal end of the balloon. A third medical device is used to occlude a blood vessel of an organ to be perfused to isolate the organ from systemic blood flow and may be used as a connection device for perfusion and/or shunt, e.g., extracorporeal venous shunt.

In, for example, the treatment of the liver, the main blood vessels connected to the liver are occluded: the method includes occluding the venous portal (PV, portal vein) with a third retrievable medical device, the Hepatic Artery (HA) with a first retrievable medical device, and the Hepatic Vein (HV) with a second retrievable medical device to achieve site specific blood isolation and collection. Isolation of the hepatic vasculature allows high local chemotherapeutic concentrations to be achieved.

The introduction of the third retrievable medical device and the first medical device may be effected by means of an introducer sheath. In a preferred embodiment, the third device incorporates a dilator and eliminates the need for a separate introducer sheath. A third retrievable medical device in PV has a bypass lumen, preferably an occlusion seal of a balloon, for example for extracorporeal venous shunt of the portal and a lumen for organ perfusion. The PV medical device may have an irrigation port and associated tubing. The seal is located upstream of the vein into which the PV branch enters. PV is difficult to access because it is located in a position between the liver and the intestinal part. Thus, PV may be accessed through the liver, as is commonly understood by those skilled in the art for performing transjugular intrahepatic portosystemic shunts.

A third retrievable medical device in the PV isolates abdominal blood flow from perfusion flow in the liver and is the junction of extracorporeal venous bypass for draining blood from the abdominal region. The device also represents a connection point for perfusion from the portal vein or from the organ side to the portal vein.

The third retrievable medical device of the invention is a single device adapted to isolate and perfuse the PV. Thus, the risk to the patient is reduced and the operation time is shortened.

This device is shown in fig. 13. It is a single device, has a small diameter, preferably < F12 (about 4mm), and is easy to place under ultrasound guidance. The device has at least one balloon occluding the PV. The device also serves as a perfusion and/or infusion catheter for the liver perfusate and may also facilitate extracorporeal venous diversion.

Fig. 9 and 10 show the third retrievable medical device in further detail. The third retrievable medical device comprises a tube having a lumen 58 and an inflation lumen 61. The diameter O of the cavity 58 is at least 2mm and the diameter P of the third retrievable medical device is about 3 mm. The diameter Q of the proximal end Y of the third retrievable medical device is about 4 mm. A lumen 58 is provided at the proximal end Y with the female luer adapter 50 and the four-way high flow stopcock 52. The device is provided with a marker band 60 and a balloon 59, the balloon 59 being inflated when the user presses on the inflated balloon 54. The inflation bladder 54 has an inflation check valve 53 and a male luer adapter 55. The inflatable balloon 54 is connected to the inflation lumen 61 via a female luer adapter 56 and a connector tube 57. In the embodiment shown in fig. 9, the outlet 62 allowing perfusion and/or exclusion is located at the distal end X of the balloon 59 of the device, and the distance J at the distal end X where the outlet 62 is distributed is comprised between 10-14 mm. In the embodiment shown in fig. 10, an outlet 64 allowing for perfusion and/or drainage is located at the proximal end Y of the balloon 59. The distance T over which the outlets 62 are distributed is comprised between 15-20mm and the distance S at the distal end X of the balloon is comprised between 4-6 mm. The balloon length L is comprised between 10-50mm, preferably between 15-40mm, more preferably between 20-30mm, most preferably about 24 mm. The extracorporeal venous flow of the device is preferably up to 800cc/min with a customary set point of about 400cc/min and the perfusion flow up to 400cc/min with a customary set point in the range of 100-200 cc/min. In a preferred embodiment, the third medical device is made of a biocompatible material that is generally suitable for short-term, <60 minutes, intravascular procedures.

Although the present invention has been described with reference to preferred embodiments thereof, many modifications and changes may be made by one of ordinary skill in the art without departing from the scope of the present invention, which is defined by the following claims.

Claims

1. A system for monitoring and control of organ perfusion of a subject, comprising:

-at least one therapeutic agent,

-at least one second retrievable medical device for isolating and collecting organ outflow, said second retrievable medical device having a distal end and a proximal end; the second medical device comprises a catheter adapted to deploy an expansion member; the proximal end of the expansion member is attached to the distal end of the catheter,

-a fluid storage reservoir (107) having at least one inlet adapted to be connected to the proximal end of the second retrievable medical device and at least one outlet adapted to be connected to the proximal end of the first retrievable medical device,

-at least one pump (104,105) for withdrawing fluid from an organ (101) and directing the fluid to a fluid storage reservoir (107) through an inlet of the fluid storage reservoir (107),

-at least one pump (108) for withdrawing fluid from a fluid storage reservoir (107) at a determined flow rate and directing the fluid to an organ (101) inflow,

-at least one marker for monitoring in real time the leak rate from the organ (101) to the systemic blood circulation,

-at least one marker detector (119) located upstream of an inlet of the fluid storage reservoir (107),

at least one marker detector (120) located in at least one blood vessel of the systemic blood circulation,

-at least one volume sensor located in a fluid storage reservoir (107),

-at least one pressure detector (123) for measuring the fluid pressure inside the organ (101) to be perfused, and

-at least one interface for receiving and presenting output system data and for controlling and/or adjusting the input system data, wherein the output system data comprises data collected by the pressure detector (123) and the marker detector (104, 105); and the input system data includes a fluid flow rate retrieved from a fluid storage reservoir (107) directed to the organ inflow.

2. The system of claim 1, further comprising: a processing unit (112i) for regulating the flow rate of a fluid to be withdrawn from the fluid storage reservoir (107) and directed into the organ (101), said processing unit (112i) being implemented by means of a method for receiving and processing output system data and sending a signal to a pump (108) comprising input system data for withdrawing a fluid from the fluid storage reservoir (107) at a determined flow rate and directing said fluid into the organ (101).

3. The system according to any one of the preceding claims, wherein the output system data received by the processing unit (112i) comprises: a fluid pressure inside the organ, a fluid flow rate at which fluid is withdrawn from the organ (101), an amount of the marker measured by a detector (119) located upstream of an inlet of the fluid storage reservoir (107), and an amount of the marker measured by a detector (120) located in at least one blood vessel of the systemic blood circulation.

4. The system according to claim 3, wherein the input system data comprises a determined fluid flow rate at which fluid is retrieved from the fluid storage reservoir (107) and directed to the organ inflow.

5. The system according to claim 2, wherein the determined fluid withdrawal flow rate from the fluid storage reservoir (107) is determined for keeping the fluid pressure inside the organ below the pressure of the systemic blood flow.

6. The system of claim 1, wherein the marker is selected from the group consisting of a radioactive marker, a dye, the therapeutic agent of claim 1, alkaline phosphatase, gamma glutamyl transpeptidase, ALT, AST, prothrombin time, albumin, bilirubin.

7. The system according to claim 2, wherein the inlet of the fluid storage reservoir is adapted to be connected to the proximal end of the second retrievable medical device using an outflow tube (102) and the outlet of the fluid storage reservoir (107) is adapted to be connected to the proximal end of the first retrievable medical device using an inflow tube (103).

8. The system of claim 2, further comprising at least one oxygenator (110) located downstream of the outlet of the fluid storage reservoir (107).

9. The system according to claim 2, further comprising at least one heat exchanger (109) located downstream of the outlet of the fluid storage reservoir (107).

10. The system according to claim 2, further comprising at least one filter (106) located upstream of the inlet of the fluid storage reservoir (107).

11. The system of claim 1, wherein the balloon of the first medical device has an interior in fluid communication with the inflation lumen through at least one opening in the body of the device.

12. System according to claim 11, wherein the opening is provided with at least one valve movable from a closed position preventing the lumen from being in fluid communication with the interior of the balloon to an open position in which the lumen is in fluid communication with the interior of the balloon.

13. The system according to claim 1, wherein the expansion member (9,9') of the second retrievable medical device comprises a carrier (2) and an impermeable liner (1) bonded to the carrier over at least a part of its length.

14. The system according to claim 1, further comprising one or more third retrievable medical devices for occlusion of a vessel of an organ, the devices having a proximal end, a distal end, a lumen extending between the proximal end and the distal end, at least one inflatable balloon for occlusion of a vessel, and a lumen.

15. The system according to claim 14, wherein the first medical device and/or the second medical device and/or the third medical device are percutaneously introduced into different organ vessels.

16. The system according to claim 6, wherein the therapeutic agent is a treatment fluid and/or particles comprising a radioactive element.

17. The system according to claim 1, further comprising at least one container (122) containing a physiological solution selectively delivered to the organ (101) before the start of perfusion and/or when said perfusion is completed, for washing said organ.

18. A computer implementing a method for monitoring and controlling an organ perfusion system of a subject, the system comprising: at least one pressure detector for measuring fluid pressure within the organ; an outflow tube for retrieving fluid from the organ; and an inflow tube for delivering fluid to the organ, wherein the method comprises the steps of:

-processing the received output system data, and

-transmitting input system data, wherein the input system data comprises a determined fluid flow rate at which fluid is delivered to the organ through an inflow tube of the system.