WO2020148577A1 - Continuous equilibrium-based diagnostic and therapeutic system - Google Patents

Abstract

System and methods for detecting the presence and/or concentration of an analyte in blood and/or a bodily fluid and/or tissue and/or an organ. A system comprises a perfusate container with a perfusate disposed there within, wherein the perfusate is hyper-osmolar, iso-osmolar or hypo-osmolar relative to the blood and/or bodily fluid and/or tissue and/or organ, perfusate circulating means, a catheter in fluid communication with the perfusate and operably coupled to the perfusate circulating means, and a detector configured to detect in the perfusate the presence of analyte originating from the blood and/or bodily fluid and/or tissue and/or organ following a predetermined equilibration period of the catheter being in contact with the blood and/or bodily fluid and/or tissue and/or organ, wherein the predetermined equilibration period is sufficient to indicate the presence and/or concentration of the analyte.

Description

CONTINUOUS EQUILIBRIUM-BASED DIAGNOSTIC AND THERAPEUTIC SYSTEM

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority from US Provisional Patent Applications No. 62/641,563 filed March 12, 2018 and 62/794,001 filed January 18, 2019, both of which are incorporated herein by reference in their entirety.

FIELD

Embodiments disclosed herein relate in general to diagnostic and therapeutic systems and in particular to systems and methods for isolation, detection, exchange and analysis of analytes, gases or fluids of interest from blood, tissue and/or organ and/or interstitial fluid or other bodily fluids.

BACKGROUND

Microdialysis is a method of e amination in which a probe is inserted into tissue in vivo, such that one side of a semi-permeable membrane is in contact with tissue and extra cellular liquid and the other side is circulated with a perfusate which takes-up substances and/or fluids from the extra cellular liquid through the membrane. In this method, the perfusate is perfused continuously or intermittently through a probe, and a gas, a drug, a metabolic substance, or another material of interest, passively or actively diffuses into or out from the perfusate from or into the surrounding tissue. The perfusate is collected and analyzed for analyte content (e.g. a drug, neurotransmitters etc.), and the concentration of the analyte of interest in the surrounding medium is then estimated from that information. For example, measuring the level of drugs in the tissue is typically done by measuring the drug concentration in the blood and inferring the concentration in the tissue from the concentration in the blood. Disadvantageously, designs of current microdialysis probes have low surface area, low exchange rate, yield variable (and non-reliable) results and therefore are clinically inapplicable.

Positive pressure mechanical ventilation, in which air (or another gas mix) is pushed into the lungs through the airways, is a commonly used method for treating patients with respiratory problems. It is also indicated as prophylaxis for imminent collapse of other physiologic functions, or ineffective gas exchange in the lungs. Because mechanical ventilation serves only to provide assistance for breathing and does not cure a disease, the patient's underlying condition should be treated over time. In addition, other factors must be taken into consideration because mechanical ventilation is not without its complications. These include ventilator associated lung injury, pressure wounds, pneumothorax due to barotrauma, inability to eliminate excretions, airway injury, alveolar damage, and ventilator-associated pneumonia (commonly with drug-resistant bacteria). Moreover, ventilation of a diseased lung will result in poor gas exchange that will result in insufficient blood oxygenation and increased systemic C02 levels. The latter is also associated with altered level of consciences.

The following disclosure addresses these shortcomings.

SUMMARY

Disclosed, in various embodiments, are systems and methods for isolation, detection, exchange and analysis of analytes, gases or fluids of interest from blood, tissue and/or organ and/or interstitial fluid or other bodily fluids by reaching an equilibrium or sub-equilibrium state using perfusates that are iso-osmolar, hypo-osmolar or hyper-osmolar relative to the blood, tissue and/or organ interstitial fluid. Also, some of the disclosed systems enable the exchange of gases (02, C02, N2, CO, etc.) either free or dissolved within a fluid. The analysis of derived perfusates may be done in real-time. Some applications include sampling of blood, interstitial, and other biological bodily fluids for the purpose of detecting the presence and concentration of an analyte. Other applications include changing the blood or tissue content of specific analytes or gases of interest for therapeutic purposes. Yet other applications include early diagnosis of infections associated with indwelling catheters and/or objects by an adjacent sensor (that examines the perfusate) and/or monitoring drug levels.

The term“interstitial fluid” or“interstitial liquid”, as used herein, refers to the clear fluid that occupies the space between the cells in the organ and or tissue analyzed. Likewise,“bodily fluid” refers to a naturally occurring fluid from an animal, such as blood, saliva, sputum, serum, plasma, urine, mucus, gastric juices, pancreatic juices, semen, products of lactation or menstruation, tears, or lymph. The term“hyper-osmolar” refers to any solution or composition of solute above about 295 mOsm/L, and "iso-osmolar" refers to any solution or composition of solute in the range of 285- 295 mOsm/L. Suitable solutes include, but are not limited to electrolytes, such as sodium, potassium, chloride, calcium, magnesium and citrate; natural or synthetic amino acids known by those skilled in the art; saccharides, such as mannitol, sucrose, mannose, dextrose, glucose, dextran, starch, naturally occurring or synthetic polymers, glycoproteins, hemoglobin, fluorocarbon fluid, perfluorocarbon, perfluoropentane, or other oxygen/gas carrying molecules and the like. Hyper osmolar solutions may be for example, solutions having 295 to 2000 mOsm/L. Other hyper osmolar solutions can be, for example, 0.9-3% electrolyte solutions, or 0.25-1M saccharide solutions, or, for example 2-3% NaCl, 0.25-1M mannitol. An exemplary iso-osmolar solution may be 295mOsm (0.9% NaCl, 5% Glucose). An exemplary hypo-osmolar may be <295mOsm (0.45% NaCl).

The pressure in a system disclosed herein may be similar to that of the fluid or tissue the catheter is placed in, or alternatively be higher or lower than that pressure. Therefore, the pressure may be positive or negative. Pressures may be continuously monitored and modified.

A system disclosed herein can be used to insert or extract fluids into the tissue or bodily fluids. Positive relative intra-catheter pressures (compared with the catheter surroundings) and hypo-osmolar fluids will favor fluid and gas movement from the catheter to the tissue of bodily fluid. Negative or neutral relative (or absolute) intra-catheter pressure and hyper-osmolar fluids will favor the movement of fluids, analyte or gas from the tissue or bodily fluid into the catheter. In some embodiments, the inserted or extracted fluids may contain fluids, solvents or gases, thus amplifying the insertion or elimination of specific materials from the tissue or bodily fluids. Possible applications include also controlled fluid infusion or extraction from specific tissues or bodily fluids. For instance, specific elimination of fluids from the blood or interstitial tissue as a treatment for fluid overload, either due to heart failure, decreased venous return due to pulmonary hypertension, cor-pulmonale, other reasons, hypothyroidism, hypoalbominemiam, and other occasions.

In addition, systems and methods provided herein can provide early indication of infection resulting from catheter implantation in the body, by, for example, detecting a decrease in pH and/or other changes in the tissue. An infection can be detected, for example, by isolating and detecting specific bacterial antigens, or a specific known and reactive immune mediator such as an antigen specific for plastic-adherent S. Epidermidis, Staph. Aureus, Pseudomonas and the like. A method for diagnosis of infections associated with catheters or foreign objects disclosed herein may use a sensor integrated within the catheter or implanted objects to identify changes in pH, decrease in biochemical properties within the surroundings, etc. Alternatively, changes can be detected in the exchangeable fluids extracted from the tissue or bodily fluids where the catheter is positioned.

V ascular catheters disclosed herein may be used to continuously monitor pH and atrial blood gas (e.g., ABG, 02, pC02), to, inter-alia, eliminate the need for recurrent blood extractions.

In various exemplary embodiments there are provided systems for obtaining a tissue and/or organ analyte comprising a perfusate container with a perfusate disposed there within, the perfusate being hyper-osmolar, iso-osmolar or hypo-osmolar relative to blood and/or tissue and/or organ interstitia; perfusate circulating means; a catheter in fluid communication with the perfusate and operably coupled to the perfusate circulating means; and a detector, configured to detect in the perfusate the presence of analyte originating from the blood and/or a bodily fluid and/or tissue and/or an organ following a predetermined equilibration period of the catheter being in contact with at least one of the tissue and an organ, the predetermined equilibration period sufficiently indicative of the analyte presence and/or concentration in the tissue, organ or bodily fluid in contact with the catheter.

As used herein, the term“sufficiently indicative” means in a manner sufficient to detect the presence of an analyte and sufficient in order to indicate the levels of the analyte in the investigated tissue. For example, any detectable amount of toxin that does not spontaneously produce in the body (e.g. tetrodotoxin) or of a foreign molecule (e.g. bacterial antigens) will be considered sufficiently indicative of intoxication or infection, respectively. A normal blood sodium level is between 135 and 145 milliequivalents per liter (mEq/L). One can assume that extraction of, for example, 13.5-14.5 mEq/L after certain minutes of equilibrium with the blood reflects normal serum sodium levels, and that lower values or higher values may reflect a determinable degree of hyponatremia (<135 mEq/L) or hypernatremia (> 145 mEq/L), respectively.

In an exemplary embodiment, the perfusate circulating means is at least one of a peristaltic pump, a positive displacement pump, or a reciprocating plunger pump.

In an exemplary embodiment, the hyper-osmolar perfusate is plasma, saline, or distilled water containing solutes resulting in hyper-osmolarity. In an exemplary embodiment, the catheter comprises a triple lumen tube with a proximal end operably coupled to the perfusate container and in liquid communication with the perfusate and a distal end configured to contact the tissue.

In an exemplary embodiment, the distal end comprises a balloon.

In an exemplary embodiment, the balloon is a semi-permeable membrane having a cut-off molecular weight permeability specific for at least one of the tissue analyte that needs to be extracted and measured from the bodily fluid, tissue or organ.

In an exemplary embodiment, the triple lumen tube includes an inflow lumen coupled to the perfusate circulating means through an inflow tube at the catheter proximal end and an outflow lumen coupled to the perfusate circulating means through an outflow tube at the catheter proximal end and wherein each the inflow tube includes an inflow check-valve and the outflow tube includes an ouflow check-valve.

In an exemplary embodiment, the inflow check-valve is configured to maintain unidirectional flow from at least one of the tissue and the organ to the perfusate container, and wherein the outflow check-valve is configured to maintain unidirectional flow from the perfusate container to at least one of the tissue and the organ.

In an exemplary embodiment, the balloon is made of a semi-permeable membrane having cut-off molecular weight permeability specific for at least one of the analyte, the tissue and the organ.

In an exemplary embodiment, the detector is at least one of a pH detector, a spectrophotometer, a pressure sensor, an enzyme-linked immunosorbent assay (ELISA) capillary immunosensor, a flame-ionization detector (FID), a conductivity detector, an ion-specific probe, for example a probe specific for Na⁺, K⁺, Ca⁺², Cl , uSm, etc., a gas level detector, an analytes detector, a Fourier Transfer Infrared (FTIR) detector, a light detector, a refractive index detector or a HPLC detector.

In various exemplary embodiments, there are provided methods of determining at least one of the presence and concentration of an analyte in at least one of a tissue and an organ, comprising providing a catheter in fluid communication with a perfusate container having a perfusate disposed therewithin, the perfusate being hyper-osmolar, iso-osmolar or hypo-osmolar relative to blood and/or tissue and/or organ interstitial, the catheter operably coupled to perfusate circulating means; contacting at least one of the tissue or the organ with a catheter; circulating the perfusate; and upon the analyte reaching a sufficiently indicative concentration in the perfusate, detecting at least one of the presence or the concentration of the analyte.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting examples of embodiments disclosed herein are described below with reference to figures attached hereto that are listed following this paragraph. Identical structures, elements or parts that appear in more than one figure are generally labeled with a same numeral in all the figures in which they appear. The drawings and descriptions are meant to illuminate and clarify embodiments disclosed herein and should not be considered limiting in any way. In the drawings:

FIG. 1A illustrates a schematic representation of a system disclosed herein;

FIG. IB illustrates an enlargement of the catheter in the system of FIG. 1A, with the catheter head inserted into the inferior vena cava;

FIG. 2 illustrates an exemplary embodiment of a catheter used in the system of FIG. 1A;

FIG. 3 illustrates four additional exemplary embodiments of a catheter used in the system of FIGS. 1, with details of radial cross sections;

FIG. 4 illustrates yet another exemplary embodiment of a catheter used in the system of FIG. 1A;

FIG. 5 illustrates yet another exemplary embodiment of a catheter in the system of FIG. 1A.

DETAIFED DESCRIPTION

FIG. 1 A illustrates an embodiment of a system disclosed herein and numbered 100. In an example, system 100 may be used for isolation, detection and analysis of analytes of interest from interstitial fluid (e.g. subcutaneous area, peritoneal or pleural fluid), or blood in a tissue or organ 102 (either in blood or lymphatic vessels that construct the organ or dense tissue that contain interstitial fluid, e.g. heart, brain, liver, etc.) of a patient 104, by reaching an equilibrium or sub equilibrium state using a iso-osmolar, hypo-osmolar or hyper-osmolar perfusate relative to the tissue and/or organ interstitial fluid. Notably, the use of iso-osmolar or hyper-osmolar perfusates will facilitate such equilibrium. In another example, system 100 may be used to increase the oxygen concentration in blood, interstitial fluid, or in tissue or organ 102 using a hyper-, iso-, or hypo-osmolar perfusate relative to the blood, tissue and/or organ interstitial fluid. In yet another example, system 100 may be used for extracting fluids tissue using an iso-osmolar or hyper osmolar perfusate relative to the blood, interstitial fluid, or other bodily fluid.

System 100 comprises an exchange fluid circulating means 106 and a perfusate container 108 with a perfusate 110 disposed therewithin. Exchange fluid circulating means 106 can be, for example a peristaltic or pulsatile pump, which delivers liquid product in aliquot portions respective to a pulsed action, a positive displacement pump, which forces a fluid to move by displacing a trapped volume of the fluid from a chamber, or a positive displacement reciprocating plunger pump, such as a duplex pump or a triplex pump. Additionally or alternatively, the circulating means can include a vacuum pump forming a vacuum in the lumen draining the catheter. Perfusate 110 may be hyper-osmolar, iso-osmolar or hypo-osmolar relative to the blood, interstitial fluid or the tissue or organ. The perfusate may include artificial oxygen carriers such as hemoglobin or other natural or synthetic molecule. The fluid or gas content can be pumped with high or low/negative pressure compared with the reference tissue the catheter is placed in. Pressure may be continuously monitored and relative differences between the two may be maintained. System 100 further comprises a catheter 112 in liquid communication with perfusate 110 via a tube portion 114. Tube portion 114 is configured to let exchange perfusate 110 flow out of perfusate container 108 through perfusate circulating means 106 and through an intermediate tube portion 116 equipped with a first unidirectional check-valve 118 and a sensor 144 able to monitor various parameters such as pressure, temperature, and/or content of the delivered fluid/gas. Sensor 138 is coupled functionally to an appropriate system or apparatus in which data detected by detector 138 is processed. Such system/apparatus is not shown. Catheter 112 has a catheter shaft 126 with membranes that enable exchange of gas, fluids and analytes with the surroundings. In an example shown in FIG. IB, shaft 126 is shown inserted into inferior vena cava 128. System 100 further comprises an outflow tube 122 in fluid communication through a second check-valve 124 with the catheter and with exchange fluid container 108, thus closing a circulating loop of the catheter.

System 100 further includes an apparatus 130 for oxygen perfusion and distribution, a power source 132 for sonication to increase the oxygen saturation in the perfusate 110 by mechanical breaking of the non-dissolved gas bubbles into microbubbles, and a source 134 of surface acoustic waves or other vibration or energy transfer means to vibrate the catheter to prevent thrombosis, enhance flow of fluid in the catheter, enhance gas solubility, and enhance gas exchange across the membranes. The surface acoustic waves and/or other vibrations may be coupled to the catheter at a point or area 136.

System 100 further comprises a detector 138 configured to detect the presence of analyte or gas in the perfusate following a predetermined equilibration period of catheter 112 being in contact with at least one of the tissue or organ or bodily fluid. Detector 138 may be for example a pH detector, a spectrophotometer, a pressure sensor, an ELISA capillary immunosensor, a flame- ionization detector, a conductivity detector, an ion-specific probe, for example a probe specific for Na⁺, K⁺, Ca⁺², Cl , uSm, etc., a gas level detector, an analytes detector, a FTIR detector, a light detector, a refractive index detector or a HPLC detector. Detector 138 is coupled functionally to an appropriate system/apparatus (e.g. ELISA, FTIR, HPLC) in which data detected by detector 138 is processed. Such system/apparatus is not shown.

System 100 may further comprise a central processing module (CPM) 140 in communication with a display 142, circulating means 106 and detector 138, the CPM including a processor and having a memory with a set of executable instructions thereon that, when executed, cause the processor to initiate the circulation of the perfusate by the circulating means, to use the detector to continuously determine the concentration of the analyte in the circulating perfusate and, if after a predetermined time the concentration of the analyte remains zero, to provide an indication to the display of no presence of the analyte in the at least one of the tissue and the organ. Else, the CPM may be used to calculate the rate of increase in concentration of the analyte over time, and when the rate of increase is zero, to provide an indication to the display of the concentration of the analyte at the time corresponding to the zero rate of increase. The system may yield notifications according to predetermined thresholds.

In some embodiments, the catheter may comprise compressible membranes that allow changes in the three-dimensional (3D) shape of the catheter to increase the catheter surface area and increase the exchange rate of analytes, fluids or gases between the catheter and the blood surrounding the catheter (that will proceed its movement to the lungs). The conformational change will facilitate unidirectional blood flow and replacement of "untreated" or "non-equilibrized" blood or bodily fluid around the catheter, thus facilitating further exchange of gas, fluid or analyte.

FIG. 2 illustrates in (a) one exemplary embodiment of a catheter numbered 212 and in (b) an enlargement of a catheter distal end (head) 226. Catheter 212 includes a central lumen 202, an inflow lumen 204 and an outflow lumen 206 which are inserted through a section 208 into shaft 126. A groove 208 enables suturing of the catheter to skin. Groove 208 may be coupled to a plastic member 214 having suturing holes 216.

The enlargement in FIG. 2(b) shows details of catheter distal end 226 in a longitudinal cross section. Inflow lumen 204 is in fluid or gas communication with one or more inflow sections or channels 204’ and outflow lumen 206 is in fluid or gas communication with one or more outflow sections or channels 206’. The inflow and outflow channels are separated in some embodiments by a permeable, semi-permeable or non-permeable barrier 220. In other embodiments, channels 206' are in close or direct proximity to inflow channels 204', lacking any barrier between the two directional currents. Outflow channel(s) 206’ are surrounded by, and separated from the tissue by a selective or non-selective semi-permeable membrane 222 that enabled gas, fluid or analyte transfer between the perfusate and tissue or bodily fluid. In this and all following embodiments, the inflow lumen (and inflow channels) is configured to maintain unidirectional flow from the perfusate container to the tissue or organ, and the outflow lumen (and outflow channels) is configured to maintain unidirectional flow from the tissue or organ to the perfusate container. Membrane 222 may be configured to have a molecular weight cut-off (MWCO) permeability specific for at least one of the analytes or gas found in the tissue and/or the organ and/or the bodily fluid. Specific membranes may be used, with the molecular weight of a specific substance of interest having a sieving coefficient (S) of 0.01 in water. The sieving coefficient, S, is calculated according to S=(2C_F)/(C_Bin+C_Bout), where CF IS the concentration of a solute in the filtrate, C_Bin is the concentration of a solute at the inlet side of the catheter under test, and C_BOUI is the concentration of a solute at the outlet side of the catheter. In another embodiment, the term“molecular weight cut-off’ (MWCO) refers to the lowest molecular weight solute (in daltons) in which 90% of the solute is retained by the membrane, or to the molecular weight of the molecule (e.g. globular protein) that is 90% retained by the membrane.

A cover 230 enables fluid communication between the inflow and outflow channels as catheter distal end 226. Central lumen 202 enables drawing blood following intravascular deployment and insertion of the catheter in the first place (using e.g. the Seldinger technique or direct vascular cannulation) and ends at a catheter tip 232.

The inflow and outflow channels and the semi -permeable membrane (envelope) between the outflow channel and surrounding tissue may have different structures, positions and shapes, as shown in FIG. 3. FIG. 3 illustrates another exemplary embodiment of a catheter like catheter 212, numbered 312, with (a), (b), (c) and (d) showing different structures at two radial cross sections along the catheter, A-A and B-B. The specific details at A-A and B-B relate mainly to different embodiments of membrane 222 and to the inflow and outflow lumens. Thus in an example shown in FIG. 3(a), at A-A the catheter shaft 126 includes central lumen 202, inflow lumen 204 and outflow lumen 206, while at B-B shows the shaft including central lumen 202 and inflow lumen 204. Outflow lumen 206 is connected to a space or channel 206' located beneath membrane 222. In an example shown in FIG. 3(b), the lumens are arranged in a concentric arrangement, with central lumen 202 surrounded by inflow lumen 204 which in turn is surrounded by outflow lumen 206. The catheter is surrounded (covered) by membrane 222. In an example shown in FIG. 3(c), the lumens are arranged at cross section A-A as in (a) while along the catheter outflow lumen 206 is coupled to a plurality of circumferential outflow channels 322 (at B-B) designed to increase the surface area of the membrane and to facilitate rapid exchange of gas, fluids and analytes. In an example shown in FIG. 3(d), the lumens are arranged at cross section A-A as in (a), while along the catheter inflow lumen 204 is switched to be concentric around central lumen 202 with outflow lumen 206 coupled to a larger plurality of circumferential outflow channels 206’ (at B-B).

The membranes used in various embodiments disclosed herein may have high structural complexity manifesting in high fractal dimension to increase their surface area. The membranes may be modified to include or to be covered with drugs (e.g. Hepain) or substances (e.g. Phosphorylcholine) that prevent platelet adhesion, fibrin attachment, and/or coagulation .

FIG. 4 illustrates another exemplary embodiment of a catheter like catheter 212, numbered 412, with (a), (b) and (c) showing different configurations of the flow channels along the catheter. Like element numbers indicate the same elements as in other figures and therefore need no explanation. The different configurations may affect fluid/gas/analyte transport time through the catheter and catheter effectiveness. The different configurations also create interchange spaces at various levels that may affect blood that was already partly treated, which is important in diagnostics.

In (a), membrane 222 is supported by a radial spiral support 402, while 410 indicates a continuous spiral outflow fluid path. The spiral architecture comprises one or more parallel channels. Due to the spiral path, the perfusate or gas travels along one or more long paths, using the entire surface area of the catheter. This configuration enables a countercurrent path with a large distance/surface area, and may therefore be effective for viscous fluids that flow at a non-rapid rate but require long time to equilibrate.

In (b), membrane 222 is supported by longitudinal supports 404, while 412 indicates a plurality of longitudinal outflow fluid paths. Many longitudinal parallel paths also use the entire surface area, but due to their parallel flow nature, offer little resistance to the flow of perfusate or gas.

In (c), membrane 222 is supported by separate horizontal supports 406, while 414 indicates a horizontal fluid path connecting the inflow to the outflow channel. Notably, in (c) fluids or gas move from inflow channels 204’ to outflow channels 206’ on both sides of the shaft. Horizontal paths provide the shortest path configuration for perfusate and gas flow and cause more rapid fluid exchange at the catheter proximal end compared with the distal end.

FIG. 5 illustrates another exemplary embodiment of a catheter like catheter 212, numbered 512. Catheter 512 has exemplarily the shape of a balloon, with outflow channels 206’ deployable into a balloon outer surface, shaped to increase the surface area for exchange of fluid/gases with surrounding tissue, and exchanging blood flow around the catheter. In other embodiments, the conformational change of the catheter is caused by balloon-unrelated elongation of the fibers that result in a balloon-like structure of the membranes that are no longer in close proximity to the catheter shaft. The balloon may be a semi-permeable membrane having a cut-off molecular weight permeability specific for the analyte.

Catheter 512 is shown in three states: (a) a“sheathed” state, in which catheter 512 is housed in a sheath 502 prior to deployment; (b) a closed state, in which catheter 512 is pulled out partially from the sheath by e.g. pulling on a string 504 attached to its tip; and (c) an open,“active” state in which the catheter can be used for any of the applications mentioned above or below. The arrows indicate the actions of moving between the different states.

Methods of use

Example 1:

In a first method embodiment, a system disclosed herein may be used for real-time sampling and analysis of blood, interstitial fluid or other biological bodily fluids in an examined tissue or organ. An iso-osmolar, hyper-osmolar or hypo-osmolar perfusate is circulated inside the catheter under positive or negative pressure relative to the venous blood pressure, or to the pressure in the tissue (where the catheter is implanted), the interstitial fluid or other biological bodily fluids. The concentration of analyte (pH, pC02, HC03, lactate, electrolytes, troponin, creatinine, hepatic enzymes, etc), in the circulating perfusate may be continuously determined using the detector. If after a predetermined time period the concentration of the analyte remains zero, an indication may be provided to the display of no presence of the analyte in the at examined tissue and the organ. Otherwise, the rate of increase in concentration of the analyte may be followed over time, and when the rate of increase is unchanged, an indication can be provided of the concentration of the analyte at that time.

Example 2:

In a second method embodiment, a system disclosed herein may be used for monitoring drug levels in blood, interstitium or other bodily fluids. The general procedure is as in Example 1, but using a specialized sensor for drug levels, for example: a) Protease Inhibitors. Indinavir, Ritonavir, Lopinavir, Saquinavir, Atazanavir, Nelfinavir; b) Antibiotics. Aminoglycosides (Gentamicin, Tobramycin, Amikacin) Vancomycin, Chloramphenicol, Cubicin, Zyvox; c) digoxin ; d) Antiepileptics: Phenobarbital, phenytoin, valproic acid, carbamazepine, ethosuximide, sometimes gabapentin, lamotrigine, levetiracetam, topiramate, zonisamide, eslicarbazepine acetate, felbamate, lacosamide, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, vigabatrin; e) Bronchodilators: Theophylline; f) Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, azathioprine; g) Anti-cancer drugs: Methotrexate, all cytotoxic agents; and h) Psychiatric drugs: Lithium, valproic acid, some antidepressants (imipramine, amitriptyline, nortriptyline, doxepin and desipramine.

Example 3:

In a third method embodiment, a system disclosed herein may be used for identification of systemic and localized infection. The general procedure is as in Example 1, with the method used to identify high lactate, low pH, inflammatory markers, chemokines and or cytokines, and specific materials extracted from bacteria, viruses, fungi or immune cells. Example 4:

In a fourth method embodiment, a system disclosed herein may be used for providing a localized drug, chemotherapy or treatment. The general procedure may be as in Example 1 , using hypo-osmotic or iso-osmotic fluids, positive intra-catheter pressure, and high content of metabolite, toxin, chemotherapeutic agent or drug, for example: a) Antibiotics. Aminoglycosides (Gentamicin, Tobramycin, Amikacin) Vancomycin, Chloramphenicol, Cubicin, Zyvox; b) Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, azathioprine; and c) Anti-cancer drugs: Methotrexate, all cytotoxic agents..

Example 5:

In a fifth method embodiment, a system disclosed herein may be used for in-vivo oxygenation of blood and removal of other gas such as C02, N2 and CO. Either free oxygen or a perfusate that carries oxygen and has low (negligible) levels of C02 may be circulated in the system with the catheter. If a perfusate is used as carrier, it may be iso-, hyper- or hypo-osmolar. The pressure of the exchange liquid or gas circulated inside the catheter may be either positive (higher) or negative (lower) relative to the pressure in the blood, interstitial fluid or other biological bodily fluids. If using a perfusate containing oxygen, the oxygen concentration in may be increased by sonification or other means of mechanical breakdown.

Use of artificial oxygen carriers may further increase oxygen delivery to and C02 extraction from the tissue.

Example 6:

In a sixth method embodiment, a system disclosed herein may be used to oxygenize hypoxic tissue (limb, brain, heart), increase tissue nutrients and eliminate waste.

Example 7 :

In a seventh method embodiment, a system disclosed herein may be used for fluid extraction from blood, bodily fluid, tissue and/or organ interstitial fluid. The general procedure is as in Example 1 , except that the perfusate is iso-osmolar or hyper-osmolar and the pressure used is negative. Example 8:

In an eighth method embodiment, a system disclosed herein may be used for selective extraction of analyte, electrolyte, toxin or drug from blood, bodily fluid, tissue and/or organ interstitial fluid for therapeutic purpose. The general procedure is as in Example 1, except that selective membranes and specific perfusate (deprived of the extractable substance) are used.

In conclusion, the continuous equilibrium-based diagnostic and therapeutic system disclosed herein and various associated methods for its use provide significant innovation in a number of areas: the combination of supersaturated fluids or gas and exchange membranes positioned inside the body enables direct oxygenation of the blood or other bodily tissue in a method that does not involves the lungs, and thus may be used to treat patients with respiratory insufficiency. The use of the described configuration enables the blood or tissue oxygenation without the generation of undesirable macro-bubbles (manifested as gas embolism or tissue damage). The system includes and uses catheters with novel structures and functionalities; the surface area or the position of the catheter in the central blood vessel (such as a major vein) may be continuously altered; catheter membranes may have fractal dimensions that increase surface area in order to facilitate gas and analyte transfer; fluid exchange performed inside the body may be used for fluid removal from tissue or blood; fluid and gas transfer in the catheter and through the membranes can be enhanced by application of surface acoustic waves or other modes of energy; artificial oxygen carriers divided from the tissue by exchange membranes may be used inside the body; and the system enables use of positive pressures in the body (thus facilitating the transfer of fluids/gases/analytes to the body), or negative pressures in the body (thus facilitating extraction of gas or fluids or analytes from the body).

The term "comprising" and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and/or steps. The foregoing also applies to words having similar meanings such as the terms, "including", "having" and their derivatives.

All ranges disclosed herein are inclusive of the endpoints, and the endpoints are independently combinable with each other.“Combination” is inclusive of blends, mixtures, alloys, reaction products, and the like. The terms“a”,“an” and“the” herein do not denote a limitation of quantity, and are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The suffix“(s)” as used herein is intended to include both the singular and the plural of the term that it modifies, thereby including one or more of that term (e.g., the fenestration(s) includes one or more fenestration). Reference throughout the specification to“one embodiment”,“another embodiment”,“an embodiment”, and so forth, when present, means that a particular element (e.g., feature, structure, and/or characteristic) described in connection with the embodiment is included in at least one embodiment described herein, and may or may not be present in other embodiments. In addition, it is to be understood that the described elements may be combined in any suitable manner in the various embodiments.

Furthermore, the terms“first,”“second,” and the like, herein do not denote any order, quantity, or importance, but rather are used to denote one element from another. Likewise, the term "about" means that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is "about" or "approximate" whether or not expressly stated to be such.

The above examples and description have of course been provided only for the purpose of illustration, and are not intended to limit the disclosed technology in any way. As will be appreciated by the skilled person, the disclosed technology can be carried out in a great variety of ways, employing more than one technique from those described above, all without exceeding the scope of the disclosure.

Claims

WHAT IS CLAIMED IS:

1. A system for detecting the presence and/or concentration of an analyte in blood and/or a bodily fluid and/or tissue and/or an organ, comprising:

a) a perfusate container with a perfusate disposed therewithin, wherein the perfusate is hyper osmolar, iso-osmolar or hypo-osmolar relative to the blood and/or bodily fluid and/or tissue and/or organ;

b) perfusate circulating means;

c) a catheter in fluid communication with the perfusate and operably coupled to the perfusate circulating means; and

d) a detector configured to detect in the perfusate the presence of analyte originating from the blood and/or bodily fluid and/or tissue and/or organ following a predetermined equilibration period of the catheter being in contact with the blood and/or bodily fluid and/or tissue and/or organ, wherein the predetermined equilibration period is sufficient to indicate the presence and/or concentration of the analyte.

2. The system of claim 1 , wherein the perfusate circulating means includes a pump selected from the group consisting of a peristaltic pump, a positive displacement pump, a reciprocating plunger pump and a triplex pump.

3. The system of claim 1, wherein the hyper-osmolar perfusate is selected from the group consisting of a plasma, a saline solution and distilled water containing solutes resulting in hyper- osmolarity.

4. The system of claim 1 , wherein the catheter comprises a triple lumen tube with a proximal end operably coupled to the perfusate container and in liquid communication with the perfusate, and a distal end configured to contact the blood and/or bodily fluid and/or tissue and/or organ.

5. The system of claim 4, wherein the distal end comprises a balloon.

6. The system of claim 5, wherein the balloon is a semi-permeable membrane having a cut off molecular weight permeability specific for the analyte.

7. The system of claim 4, wherein the triple lumen tube includes an inflow lumen coupled to the perfusate circulating means through an inflow tube having an inflow check-valve and positioned at the catheter proximal end, and an outflow lumen coupled to the perfusate circulating means through an outflow tube having an outflow check-valve and positioned at the catheter proximal end.

8. The system of claim 7, wherein the inflow check-valve is configured to maintain unidirectional flow from at least one of the blood and/or bodily fluid and/or tissue and/or organ to the perfusate container, and wherein the outflow check-valve is configured to maintain unidirectional flow from the perfusate container to at least one of the blood and/or bodily fluid and/or tissue and/or organ.

9. The system of any one of claims 1-8, wherein the detector is selected from the group consisting of a pH detector, a spectrophotometer, a pressure sensor, an enzyme-linked immunosorbent assay (ELISA) capillary immunosensor, a flame-ionization detector, a conductivity detector, an ion-specific probe, a gas level detector, a Fourier Transfer Infrared detector, a light detector, a refractive index detector and a HPLC detector.

10. A method for detecting the presence and/or concentration of an analyte in blood and/or a bodily fluid and/or tissue and/or an organ, comprising:

a) providing a catheter in fluid communication with a perfusate container having a perfusate disposed therewithin, wherein the perfusate is hyper-osmolar, iso-osmolar or hypo-osmolar relative to the blood and/or bodily fluid and/or tissue and/or organ;

b) contacting at least one of the blood and/or a bodily fluid and/or tissue and/or an organ with a catheter;

c) circulating the perfusate; and d) upon the analyte reaching a sufficiently indicative concentration in the perfusate, detecting the presence and/or concentration of the analyte.

11. The method of claim 10, wherein circulating the perfusate includes circulating the perfusate using a pump selected from the group consisting of a peristaltic pump, a positive displacement pump, a reciprocating plunger pump and a triplex pump.

12. The method of claim 10, wherein the hyper-osmolar perfusate is selected from the group consisting of a plasma, a saline solution and distilled water containing solutes resulting in hyper- osmolarity.

13. The method of claim 10, wherein the providing a catheter includes providing a catheter that comprises a triple lumen tube with a proximal end operably coupled to the perfusate container and in liquid communication with the perfusate, and a distal end configured to contact the blood and/or bodily fluid and/or tissue and/or organ.

14. The method of claim 13, wherein the distal end comprises a balloon.

15. The method of claim 14, wherein the balloon is a semi-permeable membrane having a cut off molecular weight permeability specific for the analyte.

16. The method of claim 13, wherein the triple lumen tube includes an inflow lumen coupled to the perfusate circulating means through an inflow tube having an inflow check-valve and positioned at the catheter proximal end, and an outflow lumen coupled to the perfusate circulating means through an outflow tube having an outflow check-valve and positioned at the catheter proximal end.

17. The method of claim 16, wherein the inflow check-valve is configured to maintain unidirectional flow from at least one of the blood and/or bodily fluid and/or tissue and/or organ to the perfusate container, and wherein the outflow check-valve is configured to maintain unidirectional flow from the perfusate container to at least one of the blood and/or bodily fluid and/or tissue and/or organ.

18. The method of any one of claims 10-17, wherein the detector is selected from the group consisting of a pH detector, a spectrophotometer, a pressure sensor, an enzyme-linked immunosorbent assay (ELISA) capillary immunosensor, a flame-ionization detector, a conductivity detector, an ion-specific probe, a gas level detector, a Fourier Transfer Infrared detector, a light detector, a refractive index detector and a HPLC detector.