Systems and methods for optimizing accuracy of diagnostic and therapeutic processes

Abstract

The invention discloses a system and a method for optimizing diagnostic and therapeutic effects, and includes a diagnostic intravascular invasive device and a controller, the diagnostic intravascular invasive device has a sensing device and is designated to be close to a target tissue in order to monitor and provide valuable data regarding in vivo biochemical and / or physiological conditions of the target tissue, and the controller is designated to process the data received from the sensor in order to generate medical advice and / or conclusions.

Description

Field of the Invention

[0001] The present disclosure relates to measures for optimizing treatment effectiveness, and particularly, but not exclusively, to systems and methods for optimizing treatment effectiveness, patient safety, treatment costs, or any combination thereof, of a treatment regimen by utilizing a catheter-based diagnostic device. Background of the Invention

[0003] Cancer remains a leading cause of suffering and death worldwide. Systemic treatment options for cancer include traditional cytotoxic chemotherapy, targeted small molecules, and biologic therapies (including immunotherapy), among others. Patients with malignancies will typically undergo multiple sequential lines of treatment over several years, and there are few guidelines to inform the choice or duration of treatment with any of the multiple potential systemic options. The breadth of treatment options grows each year with the introduction of new drugs, new drug classes, and new combinations of existing drugs.

[0004] Matching a drug to a patient often starts with a biopsy. A biopsy is most commonly a sample of tissue or cells taken from the diseased site and is evaluated on several levels. At its most basic, basic histology is evaluated. For example, a biopsy taken from a cancerous site and its surroundings often provides information about, for example, the origin of the cell, how quickly the cell proliferates, and whether the cell has expanded into lymphatic / neural / vascular structures. By sequencing the genomic signature of the cell, specific mutations can be identified that can be correlated with prognostic information or predict treatment response to a given treatment. Surface cell staining can indicate what proteins are actually produced and expressed at the diseased site. The information extracted from a biopsy has some value in predicting which of various courses of treatment are likely to be effective.

[0005] The limitations of biopsy or other monitoring techniques in the prior art described above do not currently allow for reliable assessment of treatment efficacy and safety.

[0006] US7787937B2 discloses measures for monitoring the progression of neoplastic disease and assessing treatment response by using in vivo sensors to detect radiation and wirelessly transmit information about the location of radiolabeled compounds injected into the tumor.

[0007] US20210207223A1 discloses a method configured to genetically monitor tumors through blood monitoring of cell-free DNA. US7949474B2 discloses a method capable of performing in vivo microscopy to detect cellular changes indicative of cancer-related mutations or responses to drugs. US9789241B2 discloses a system for monitoring blood perfusion into an organ to facilitate cancer treatment.

[0008] In addition to tools for tumor analysis and assays for monitoring disease progression and response, the art also presents publications disclosing in vivo measurements covering pH sensing, such as in US8062234B2, CN109289112B; publications disclosing spectral measurements, such as in US20150157405A1, US8571640B2; and publications disclosing biosensing and assays, such as in US9119533B2, US9510780B2.

[0009] However, none of the above publications discloses a intravenous diagnostic intravascular device configured to monitor a target tissue such as a tumor and provide valuable data regarding the in vivo biochemical and / or physiological state of the target tissue, wherein the configuration also prevents the biochemical signal from being attenuated or weakened in the bloodstream before being detected.

[0010] Furthermore, none of the above publications discloses a complex system that combines the described intravenous diagnostic intravascular device with an intravenous diagnostic intravascular device to achieve real-time therapeutic and diagnostic feedback, as will be extensively disclosed below.

[0011] Companion diagnostic techniques are known to aim to bridge the gap between the increasing number of treatment options on the one hand and the increasingly complex tumor and patient subclassifications on the other. However, prediction of treatment efficacy has been severely limited to date. Tumor characterization is prone to sampling errors due to spatial tissue heterogeneity. In addition, tumor samples have been disconnected from relevant interactions with the host (e.g., immune system and microbiota) and its immediate microenvironment. The complication of spatial heterogeneity constraints leads to a high degree of temporal variability, in other words, rapid tumor changes, as mutagenesis itself is affected by therapeutic interventions.

[0012] Even reliable diagnostic tests cannot inform the appropriate dose or duration of treatment. Indications of treatment response and decisions to change drugs are often based on imaging features (e.g., CT / PET / MRI) acquired at three to six month intervals. If a new drug is introduced, it is often selected based on the same diagnostic data available from the start of treatment. In essence, despite the dynamic nature of the disease, many cancer treatments are based on long-term continuous treatment with few discrete feedback points.

[0013] However, like any physiological tissue, cancer provides continuous molecular feedback in response to stimulation, including stimulation from treatment. Incoming stimulation always travels to the tissue in the arteries, and the resulting molecular feedback is released from the tissue into the venous drainage. The molecular products are most highly concentrated in the veins closest to the cells that release them.

[0014] As venous blood travels distally, attenuation occurs at each venous confluence. In addition to the effects of steric attenuation, molecules undergo enzymatic degradation within a short period of time once they enter the bloodstream. This physiological principle is the basis for the use of selective venous sampling to localize the source of abnormal tissue, such as in cases of hyperparathyroidism, adrenal adenomas, or neuroendocrine tumors. SUMMARY OF THE INVENTION

[0016] The invention herein is a system and method for data collection as part of a medical procedure prescribed to allow better insight into the response of a tumor or other disease to treatment.

[0017] Biopsies are routinely and repeatedly performed in some patients for diagnosis, severity or malignancy assessment, or treatment customization. Pathologists can analyze them by microscopic observation of cell size, shape, tissue behavior, or compound analysis. However, practical time constraints limit the direct use of biopsies during medical procedures. In addition, due to the nature of biopsies, they only show limited information representing a point in time and space, and cannot reflect overall relevant information, such as the patient's microbiome or the tumor's microbiome. The same is true for the malignant cells of the tumor, whose microenvironment is also heterogeneous and only partially sampled in the biopsy. In addition, within the tumor, physiological and biochemical characteristics often change significantly at different times in response to treatment.

[0018] According to some embodiments of the invention, at least one catheter-based diagnostic device is designated to be positioned in a draining vein near a tumor or other tissue undergoing treatment. According to some embodiments, the catheter-based diagnostic device is introduced simultaneously with an arterial catheter capable of selectively infusing the tumor / target tissue of interest.

[0019] According to some embodiments, as the therapeutic catheter introduces the active material, at least one diagnostic catheter monitors the biological response and reports the physiological results and observations to the medical practitioner. By utilizing and implementing such insights, treatment efficacy can be improved and safety issues can be better addressed.

[0020] According to some embodiments, the invention disclosed herein provides for the use in close proximity to a tumor, and the use of diagnostic tools in parallel with therapeutic effects, thereby allowing the acquisition of data that would otherwise be indistinguishable above background physiological noise levels.

[0021] The present invention also illustrates a variety of measurement systems and techniques that achieve similar goals in the context of a diagnostic catheter.

[0022] According to one aspect, a medical system is provided, comprising: (i) at least one diagnostic intravascular invasive device designated for insertion into venous vasculature, (ii) at least one sensor integrated with the at least one diagnostic intravascular invasive device and configured to detect biochemical or physiological changes in a bodily fluid, and (iii) a controller designated to receive data derived from the at least one sensor, wherein the at least one diagnostic intravascular invasive device is designated to be proximate to a target tissue, and wherein the controller is designated to process the received data to generate a medical recommendation and / or conclusion.

[0023] According to some embodiments, the target tissue is a tumor, and wherein the diagnostic intravascular invasive device is designated to monitor biochemical or physiological changes in blood flow originating from the tumor.

[0024] According to some embodiments, a diagnostic intravascular invasive device comprises at least two lumens, wherein a first lumen comprises at least one sensor and a second lumen comprises an operating device.

[0025] According to some embodiments, the second lumen comprises an opening configured to infuse a designated substance having an effect on the fluid surrounding the at least one sensor in the first lumen.

[0026] According to some embodiments, the infused substance is designed to prevent blood clots from approaching the at least one sensor.

[0027] According to some embodiments, the infused substance is designated to enhance the sensing capabilities of at least one sensor.

[0028] According to some embodiments, the system further comprises visual internal control means, which are designed to provide a spectral control reference to at least one sensor.

[0029] According to some embodiments, at least two sensors are positioned at a specific distance from each other along the diagnostic intravascular invasive device.

[0030] According to some embodiments, at least two sensors are geometrically arranged in a staggered manner and are configured to infer spatial and spatiotemporal information about biochemical or physiological signals found in the vicinity of a diagnostic intravascular invasive device.

[0031] According to some embodiments, the system further comprises a therapeutic intravascular invasive device designated to be inserted into the arterial vasculature and to administer a substance designated to affect at least one sensor of the diagnostic intravascular invasive device placed within the venous vasculature.

[0032] According to some embodiments, the designated substance is configured to facilitate detection of cell death.

[0033] According to some embodiments, drug administration is designated to be optimized based on a therapeutic effect of the drug administration detected by at least one sensor of the diagnostic intravascular invasive device.

[0034] According to some embodiments, the designated substance may be detected by an external sensor, such as an ultrasonic sensor or magnetic detection equipment.

[0035] According to some embodiments, at least one sensor is a chemical sensor configured to detect inorganic or organic ions, such as potassium, phosphate, sodium, calcium, copper, hydronium, lactate, or the like.

[0036] According to some embodiments, the sensor is based on an ion specific field effect transistor (ISFET) / is an electrochemical cell having at least 2 electrodes made of at least one material / configured to detect the ionic strength of blood.

[0037] According to some embodiments, at least one sensor is an optical sensor configured to detect cellular remnants characteristic of cell death, such as membrane vesicles, nucleic acids, DNA or RNA fragments, exosomes, nucleic acid fragments, structural proteins, mitochondrial proteins or other cellular debris, biochemical signals or others.

[0038] According to some embodiments, the sensor is of optical type, such as a UV-VIS spectrometer, a NIR spectrometer, a FTIR spectrometer, etc. / configured to detect the second harmonic generation signature of collagen.

[0039] According to some embodiments, at least one sensor is a biosensor configured to detect cell remnants characteristic of cell death and / or based on immunosorbent assays / fluorescent labeling.

[0040] According to a second aspect, a medical method is provided, the method comprising the steps of: (i) inserting at least one diagnostic intravascular invasive device comprising at least one sensor into the venous vasculature, (ii) utilizing the at least one sensor to detect biochemical or physiological changes in a body fluid, (iii) analyzing data captured by the at least one sensor using a controller, wherein the at least one diagnostic intravascular invasive device is designated to be proximate to a target tissue, and wherein the controller is designated to process the received data to generate a medical recommendation and / or conclusion.

[0041] According to some embodiments, the method further comprises the steps of inserting the therapeutic intravascular invasive device into the arterial vasculature and administering a designated substance in order to affect at least one sensor of the diagnostic intravascular invasive device placed in the venous vasculature. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Some embodiments of the present invention are described herein with reference to the accompanying drawings. The description in conjunction with the accompanying drawings makes it apparent to a person of ordinary skill in the art how some embodiments may be practiced. The accompanying drawings are for illustrative purposes and are not intended to show structural details of the embodiments in more detail than is necessary for a basic understanding of the present invention.

[0044] In the attached picture:

[0045] Figure 1 is a schematic perspective view of a typical needle biopsy of a solid tumor.

[0046] Figure 2 is a schematic perspective view of a tumor located in the liver.

[0047] Figure 3 is a schematic perspective view of typical vascular flow through tissue.

[0048] Figure 4 is a schematic perspective view of a diagnostic and therapeutic system associated with an abnormal mass, according to some embodiments of the present invention.

[0049] Figure 5 is a schematic perspective view of a tip of a catheter-based diagnostic device associated with an abnormal mass, according to some embodiments of the present invention.

[0050] Figure 6 is a schematic perspective view of a proximal catheter hub / connector forming part of a diagnostic and therapeutic system according to some embodiments of the present invention.

[0051] Fig. 7A is a schematic perspective view of the relationship between a distal sensor tip and a more proximal sensor tip of a dual tip catheter based diagnostic device forming part of a diagnostic and therapeutic system according to some embodiments of the present invention.

[0052] Figure 7B is a schematic perspective view of a compact structure of a catheter-based diagnostic device having a two-lumen or telescoping lumen structure according to some embodiments of the present invention.

[0053] Figure 7C is a schematic perspective view of an optical internal contrast forming part of a catheter-based diagnostic device according to some embodiments of the present invention.

[0054] FIG. 8A to FIG. 8B is a schematic perspective view of a side-by-side dual lumen and a "telescopic" single lumen forming part of a catheter-based diagnostic device according to some embodiments of the present invention.

[0055] 9A to 9C is a schematic perspective view of the location and function of staggered side and tip sensors embedded in a catheter-based diagnostic device forming part of a diagnostic and therapeutic system according to some embodiments of the present invention.

[0056] Fig. 10A Some embodiments according to the present invention graphically show results for varying levels of phosphate ion concentration in a physiological fluid.

[0057] FIG. 10B to FIG. 10C Some embodiments according to the present invention show experimental results of phosphate concentration measurement using a gold working electrode and a platinum counter electrode and experimental results of phosphate concentration measurement using a gold working electrode and a platinum counter electrode, respectively.

[0058] Detailed Description of Some Embodiments

[0059] In the following detailed description, many specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be appreciated by those skilled in the art that the present invention can be practiced without these specific details. In other examples, known methods, procedures, and components, modules, units, and / or circuits are not described in detail to avoid blurring the present invention. Some features or elements described about an embodiment may be combined with features or elements described about other embodiments. For the sake of clarity, the same or similar features or elements may not be discussed repeatedly.

[0060] Although embodiments of the invention are not limited in this regard, discussions using terms such as "control," "processing," "computing," "calculating," "determining," "establishing," "analyzing," "checking," "setting," "receiving," and the like may refer to the operations and / or processes of a controller, computer, computing platform, computing system, or other electronic computing device that manipulates and / or transforms data represented as physical (e.g., electronic) quantities within a computer's registers and / or memory to other data similarly represented as physical quantities within a computer's registers and / or memory or other information non-transitory storage media that may store instructions for performing the operations and / or processes.

[0061] Unless explicitly stated, the method embodiments described herein are not limited to a particular order or sequence.In addition, some of the described method embodiments or some of their elements may occur or be performed synchronously, at the same point in time, or simultaneously.

[0062] It should be understood that certain features of the present disclosure described in the context of separate embodiments for the sake of clarity may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure described in the context of a single embodiment for the sake of brevity may also be provided individually or in any suitable sub-combination, or be considered suitable for any other described embodiment of the present disclosure.

[0063] Throughout this application, the various embodiments described may be presented in a range format. It should be understood that the description of the range format is only for convenience and brevity, and should not be interpreted as a rigid limitation on the scope of the present disclosure. Therefore, the description of the scope should be considered to have all possible sub-ranges disclosed specifically and each numerical value within the range. For example, a description such as a scope from 1 to 6 should be considered to have a sub-range such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc. disclosed specifically, and each numeral within the range, such as 1, 2, 3, 4, 5 and 6. Regardless of the breadth of the scope, this applies.

[0064]

[00136] Various embodiments and aspects of the present disclosure as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.

[0065] The terms "comprises," "comprising," "includes," "including," "having" and variations thereof mean "including but not limited to."

[0066] As used herein, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. For example, the term "compound" or "at least one compound" may include a plurality of compounds, including a mixture of a plurality of compounds.

[0067] As used herein, the term "treatment" refers to therapeutic intervention, such as ameliorating the signs or symptoms of a disease or pathological condition, inhibiting the progression of a disease or pathological condition, slowing the worsening of a disease or pathological condition, and even preventing the development of a disease or pathological condition altogether. As used herein, the term "treatment regimen" refers to a precise and detailed plan for the management and / or treatment of a disease or condition.

[0068] As used herein, the term "administration" is for therapeutic purposes or diagnostic purposes, by the selected approach to provide or introduce one or more active agents (such as medicine) to the subject. Systemic administration is the route of administration that medicine, nutrition and / or other substances enter the circulatory system so that the whole body is affected. Systemic administration can be carried out by enteral administration (drugs are absorbed by the gastrointestinal tract) or parenteral administration (for example, injection, infusion or implantation). Systemic administration routes include, for example, oral administration, nasal administration, rectal administration, skin administration, intravenous injection, intracardiac administration, intramuscular injection, peritoneal injection, intranasal administration, oral administration, sublingual administration and / or surface (topical) administration. Local administration (Local administration) is to deliver one or more active agents in the site of action or directly or almost directly to the site of action, and the site of action can be, for example, lesions, tumors, organs, transplants, etc. In local drug administration, the risk of systemic side effects is reduced. Local administration is such as topical administration and / or injection or infusion in vivo.

[0069] As used herein, the term "controller" refers to any type of computing platform or component that may be equipped with a central processing unit (CPU) or a microprocessor and may be equipped with a number of input / output (I / O) ports, for example, a general-purpose computer such as a personal computer, a laptop, a tablet computer, a mobile cellular phone, a controller chip, a SoC, or a cloud computing system.

[0070] Many tumors are diagnosed at a stage where they are not suitable for surgical resection. In such cases, systemic treatment is usually used. Systemic treatment is taking medication or administering medication intravenously. In some cases, the drug can be delivered via the tumor's arterial supply, such as in chemoembolization or selective arterial infusion.

[0071] According to some embodiments, a diagnostic catheter is provided that is designated as a minimally invasive device that provides for placement of multiple sensors or mechanisms in a selective vein. According to some embodiments, the diagnostic catheter may be any known device for accessing the vascular system, such as a needle, implant, port, and the like.

[0072] According to some embodiments, the present invention includes systems and methods configured to monitor the response of a target tissue undergoing treatment. Tissue physiological and chemical responses are monitored by a diagnostic device, which may be a minimally invasive catheter, and the collected information is typically transmitted to a control unit where quantitative analysis is performed and the information and conclusions are configured to be presented to medical personnel.

[0073] According to some embodiments, the use of a local diagnostic catheter allows existing limitations in other known sensing technologies to be overcome, as its placement in a vein draining the target tissue prevents the biochemical signal from being attenuated or weakened in the bloodstream before being detected.

[0074] According to some embodiments, placing a sensor-enabled catheter in the vein draining the target tissue allows for detection of relevant signals at the most relevant time and location and with the highest signal-to-noise potential ratios. In addition, the invention herein can be used in conjunction with the use of selective arterial infusion, whereby an arterial catheter is positioned in the arterial inflow of the tumor / target tissue.

[0075] According to some embodiments, the combination of selective arterial infusion and the sensor-enabled intravenous catheter described hereinbefore can be used to assess the effects of an infused therapeutic agent on a target tissue in near real time. Thus, the selection of therapeutic agents, tissue modulators, and other infusible compounds is made based on dynamic and observed results. According to some embodiments, the claimed invention can be used to obtain observed / experimentally based drug-specific diagnostic information, and by optimizing infusion therapy based on feedback, the claimed invention can be used not only for diagnostic purposes, but also for therapeutic intent.

[0076] According to some embodiments, the claimed invention includes at least one sensor integrated on a diagnostic catheter and configured to collect data, transmit data to a control unit, or perform analysis in situ. The data may relate to biochemical signals of the type described herein. According to some embodiments, potential chemical information, biochemical information, biological information, or physiological information may also be obtained by the diagnostic catheter.

[0077] According to some embodiments, the diagnostic catheter includes at least one chemical sensor configured to detect an increase in ion concentration in the bloodstream. It is known that in many tumors, a detectable increase in ion concentration is present throughout most or all of the tumor growth.

[0078] For example, increases or decreases in ions (eg, sodium, potassium, chloride, etc.) as well as pH and lactate from within tumor-draining veins indicate changing physiology and often cell death.

[0079] According to some embodiments, detection of one or more ion species may be performed by sensors integrated on the diagnostic catheter. For example, an ion specific field effect transistor (ISFET) may be integrated on the catheter in such a configuration to detect any of the above ions or other ions. Ionic species such as an ISFET with a SiO2 or SiN3 ion sensitive membrane may be used to detect changes in pH, an ISFET with a hafnium oxide membrane may be used to detect changes in potassium or sodium ion concentration, etc.

[0080] According to some embodiments, multiple ISFETs can be integrated on a single catheter for multiple ion sensing purposes and the ability to correct for interference between measurements (e.g., a single sensing membrane is electrically responsive to more than one ion concentration). Additionally, in some embodiments, multiple similar ISFETs are placed at different locations or orientations on the catheter to allow analysis of time domain responses, such as advection velocity in blood flow.

[0081] According to some embodiments, the signal of the sensor can be electrically analyzed at the tip of the catheter, multiplexed at the tip, or drawn to the external (proximal) portion of the catheter via an electrical current and electrotherapy is performed outside the patient's body. According to some embodiments, an extended gate ion specific field effect transistor (EGISFET) is used to transmit the ion signal on the sensitive membrane to an external field effect transistor at a more distal, more proximal location (such as an external device) through a galvanic connection in the catheter. In yet another embodiment, the use of ISFETs can be enhanced by using dual gate ISFETs (DGISFETs) to obtain better sensitivity.

[0082] According to some embodiments, in addition to or in lieu of ion or material sensing, the diagnostic catheter is integrated with sensors to detect general properties of blood as an analyte. For example, the ionic strength of a liquid can be measured by integrating a sensor such as a crystal colloid array (CCA sensor), which generally responds to ionic strength rather than specific ion species. Such a sensor can be used to correct or bias other measurements, as well as corrections obtained through internal or external temperature sensing and flow rate sensing, which can be integrated into the system for calibration, correction, or verification.

[0083] Reference Figure 1 , Figure 1 Schematically shown is a representation of a typical needle biopsy of a solid tumor 3 within an organ 1. As shown, the tumor 3 is composed of a heterogeneous cellular component, undergoing a biopsy using a needle 2. According to some embodiments, the needle 2 has an inner diameter of 0.8 mm to 1.0 mm, so that even if several biopsies are taken of a single tumor, there is ample opportunity for misrepresentation or accurate representation of various cells within the tumor.

[0084] Tumor heterogeneity can exist in several important ways: Cells within a single tumor can differ from each other in their specific genetic mutations. Over time, cancer cells accumulate mutations in their DNA, which can cause different cells within a tumor to have different mutations. As tumor cells proliferate, the result can be a heterogeneous patchwork of tumor subtypes within a mass. In addition to genetic differences, epigenetic variations, such as differences in DNA methylation, can also be seen within tumors such as glioblastoma.

[0085] Within a single solid tumor, further heterogeneity can be observed regarding the tumor microenvironment, including variations in the types of stromal cells (e.g., fibroblasts), immune cells (e.g., macrophages and lymphocytes), and blood vessels immediately adjacent to tumor cells. This heterogeneity can lead to areas of increased or decreased pH, oxygenation, necrosis, and interstitial pressure within the tumor.

[0086] This heterogeneity can lead to differences in how parts of a tumor respond to treatment. In this dynamic scenario of tumor treatment, a given treatment can also induce or accelerate the rate of change in a subpopulation of the treated tumor. Systemic treatment may lead to the activation of adaptive feedback mechanisms such as BRAF / EGFR. Systemic treatment may also cause tumors to change in a more direct way: tumor cells with mutations in genes targeted by the therapy may evolve to be more advantageous. In addition, tumor cells can adapt by increasing the expression of tumor efflux pumps.

[0087] Reference now Figure 2 , Figure 2 A tumor 4 located in a liver 5 is schematically shown, and the venous blood of the tumor 4 is drained through the lower branch of the middle hepatic artery 6. As shown in the figure, the tumor-specific venous blood is marked by a color gradient, which is gradually diluted by the blood flow marked by the dotted line, which is draining to the normal non-tumor area of ​​the liver. For example, the concentration of tumor-specific venous blood immediately near the tumor is 100%, while the concentration after a certain distance is 50%, etc.

[0088] It is important to note that Figure 2 The pathologies described in this paper can occur in any other organ or tissue. The venous gradient of tumor-specific products is a feature that can be exploited to locate tumors that are too small or otherwise difficult to detect using traditional medical imaging.

[0089] Reference now Figure 3 , Figure 3 The vascular flow through the tissue is schematically shown. As shown, branching arteries 7, divide into smaller arteries and capillaries 8 and accumulate into branching veins, which combine at each confluence to form a larger vein.

[0090] According to some embodiments, the selective arterial supply 9 of the tumor 12 and its venous drainage 11 are visible in the lower part of the tissue. According to some embodiments, the diagnostic catheter of the claimed invention is designed to be positioned in the selective tumor venous outflow, and the arterial catheter / microcatheter is designed to be positioned in the selective arterial supply of the tumor, which is further disclosed below. It should be noted that for the purpose of achieving local therapeutic delivery, a percutaneous or otherwise placed needle into the target tissue would be equivalent to arterial access or any known access technique.

[0091] Reference now Figure 4 , Figure 4 The diagnostic and therapeutic system 10 is schematically shown in relation to an abnormal mass 103. As shown, the abnormal mass 103 is within the patient's body, as typically presented in a physiological scenario. The abnormal mass 103 typically draws on the vascular system to sustain its growth, and has at least one artery 107 leading to the abnormal mass 103 and at least one vein 105 leading from the abnormal mass 103.

[0092] According to some embodiments, the vascular system disclosed above can provide a caregiver with access to the vicinity of the abnormal mass 103 for treatment, and in particular for introducing a catheter-based diagnostic device 101 to introduce different types of therapeutic payloads. According to some embodiments, the arterial catheter 102 can have at least one lumen designated for the flow of at least one active ingredient (such as a chemotherapy payload, etc.). According to some embodiments, the catheter-based diagnostic device 101 can have at least one lumen designated for receiving and analyzing at least one diagnosable substance secreted or discharged from the abnormal mass 103. According to some embodiments, the arterial catheter 102 can be designated for insertion into an artery 107 that supplies blood to the abnormal mass 103, and the catheter-based diagnostic device 101 can be designated for positioning in a vein 105 that drains the abnormal mass 103.

[0093] Reference now Figure 5 , Figure 5 The tip of a catheter-based diagnostic device 101 is schematically shown in relation to an abnormal mass 103 (not shown). As shown, the catheter tip 200 includes multiple ISFET sensors integrated at different locations and allows for the detection of multiple substances. According to some embodiments, FET-based sensors are disclosed as a general type of sensor for representing some of the multiple embodiments described herein.

[0094] According to some embodiments, at least one sensor 201 may be configured and positioned to be exposed to the venous blood flow to interact with the outflowing biochemical substances. For example, the sensor 201 may be located on the side of the catheter, at the tip of the catheter, etc.

[0095] According to some embodiments, the sensor 201 can be controlled and read by a connector 202 (which can be a galvanic connector) through which voltage and current are supplied or measured, respectively. In addition to direct chemical sensing, spectrally related sensing is shown as a potential prospect, such as optical fiber 203, which can provide excitation and reflection measurement, and potentially utilize other light sources 204 such as local LEDs.

[0096] According to some embodiments, the catheter-based diagnostic device 101 includes mechanical components, such as a guidewire receiving port 205 configured to provide mechanical steering and connectivity, and at least two lumens 206 / 207, wherein one lumen is configured to house a sensor 201 for real-time measurements and another lumen is configured to draw blood for periodic external analysis or for infusion, which is described below.

[0097] According to some embodiments, the sensor 201 may be at least one electrochemical sensor, meaning at least two electrodes between which some voltage is applied and a current is measured, or vice versa, a current is applied and a voltage is measured. The information collected based on the relationship between voltage and current may be referred to as electrochemical impedance spectroscopy (EIS) in general, or voltammetry in the specialized case of low frequency scanning, and has the potential to discriminate between different materials in an analyte.

[0098] According to some embodiments, at least two inert and biocompatible electrodes can be made of one or more materials (such as platinum, gold, palladium, titanium), or some biocompatible alloys (such as magnesium alloy, stainless steel, etc.) can be incorporated as sensors. Electrical reactions can occur between the electrodes and on the electrode surfaces. The collected data can be used to detect and quantify the above-mentioned characteristic inorganic ions or organic ions.

[0099] According to some embodiments, one example of using the structure uses two platinum electrodes, one platinum electrode as a working electrode (WE) and one platinum electrode as a counter electrode (CE), and performs a linear sweep of the voltage while measuring the resulting current to infer when a reduction or oxidation reaction occurs. Such information is related to the ion species present in the bloodstream and their quantification.

[0100] Reference now Figure 6 , Figure 6 There is schematically shown a proximal catheter head / connector forming part of the diagnostic and therapeutic system 10. As shown, the proximal section of the catheter may include a designated guidewire 302 and an infusion lumen / port 304 with a Luer lock compatible head 306.

[0101] In accordance with some embodiments, the interfaces between the various sensor fibers and the light source embedded within the catheter-based diagnostic device 101 are optionally bundled into one or more heads 306 for connection to a controller (not shown), such as a computing consul designated to process and analyze data received from the catheter-based diagnostic device 101 and to provide power and light.

[0102] According to some embodiments, the catheter-based diagnostic device 101 is designed to be connected to a controller (not shown) via a wired or wireless connection to enable data transfer and analysis.

[0103] Reference now Fig. 7A , Fig. 7A The relationship between the distal sensor tip and the more proximal sensor tip of a dual tip catheter-based diagnostic device 101 forming part of a diagnostic and therapeutic system 10 is schematically illustrated. As shown, the distal tip 403 of the catheter-based diagnostic device 101 has a dual lumen structure or a telescoping lumen structure further disclosed below including lumens 400 and 402. According to some embodiments, the proximal catheter lumen 402 is occupied by a sensor and a distal catheter suitable for evaluating blood components in vivo as further described herein.

[0104] According to some embodiments, the distal tip of lumen 400 is configured to allow to use a guide wire during intravenous navigation. In case the diagnostic device 101 based on catheter has arrived at the position for vein sensing, a guide wire (not shown) can be removed. At this moment, distal catheter tip 403 is designated as a point for carrying out fluid infusion and / or blood aspiration by being positioned at a specified opening 408 on wall 404 as described below.

[0105] According to some embodiments, there is at least one sensing side hole E and / or F on wall 405 between the distal lumen and the proximal sensing tip 406, which are positioned so that the infusate is directed to the space between the incoming venous blood and the sensor at the proximal catheter tip 406.

[0106] According to some embodiments, this configuration enables continuous maintenance and inspection of sensors located in the proximal catheter lumen 402 by, for example, providing a continuous flow of blood diluent from the opening 408 to prevent blood clots from forming on the proximal catheter tip 406 and the sensing side holes E and / or F. In another example, continuous infusion of a specific substance from the opening 408 can provide a reference for the sensitivity of various sensors located in the catheter lumen 402.

[0107] Reference now Figure 7B , Figure 7BA compact structure of a catheter-based diagnostic device 101 having lumens 400 and 402 or a telescoping lumen structure as further disclosed below is schematically shown. As shown, various sensors are incorporated along the circumference of the catheter-based diagnostic device 101 and terminate proximally to the distal lumen. In this configuration, at least one side hole is retained in the distal lumen between the distal tip and the proximal sensor.

[0108] According to some embodiments, distal infusions from end port 403 and side ports 410 / 412 may be used to promote and maintain optimal conditions for operation of catheter-based diagnostic device 101. For example, low-dose infusions of anticoagulants or other pharmacology may be used to inhibit protein adhesion and / or clot formation around an indwelling sensor embedded within catheter lumen 402.

[0109] According to some embodiments, the end hole 403 and the side holes 410 / 412 can also be used to infuse agents into the draining venous blood to optimize the detection of specific molecules / substances of interest. For example, fluorescent probes or other agents can be locally infused to interact with and recognize specific molecules. Similarly, the distal infusion opening 408 (e.g., Fig. 7A ) can be used to optimize local conditions for detection, including changes such as temperature and pH.

[0110] According to some embodiments, catheter end port 403 and side port 410 may be used for procedures such as aspirating venous blood, which may then be subjected to further laboratory analysis, such as advanced genomics and proteomics.

[0111] Reference now Figure 7C , Figure 7C An optical internal control forming part of a catheter-based diagnostic device 101 is schematically shown. As shown, the catheter-based diagnostic device 101 may include an internal sensor control 414. For example (particularly if the spectral control can be positioned on the outer circumference of the catheter lumen 402), in close proximity, a Siri optical sensor can be mounted. Another example of such an internal control is composed of a material having the same spectral characteristics as a molecule of interest (e.g., free DNA). According to some embodiments, the internal control is configured to ensure the accuracy and reliability of the sensor and potentially alert an operator to a technical failure or other contamination.

[0112] Reference Fig. 8A and Figure 8B , Fig. 8A and Figure 8B Schematically illustrated are side-by-side dual lumens and a "telescopic" single lumen forming part of a catheter-based diagnostic device 101. As shown, Fig. 9A A diagnostic device 101 based on a side-by-side dual lumen structure catheter is depicted.

[0113] According to some embodiments, the catheter lumen 504 can accommodate a guidewire or vascular snare (not shown) for intravascular navigation. Another lumen 502 is occupied by a combination of a sensor and an optional microinfusion channel. According to some embodiments, if the sensor needs to be maintained, the double lumen 500 including the sensor lumen 502 can be replaced with a sensor of a different configuration, or temporarily removed and replaced in advance. Optionally, other embodiments will include additional sensor lumen configurations.

[0114] According to some embodiments and Figure 8B As shown, the sensor 506 is incorporated into a telescoping lumen structure 501 having a peripheral / tubular structure forming part of the catheter-based diagnostic device 101. The configuration includes a single through lumen 508 extending centrally therethrough and reaching distally to the location of the sensor 506.

[0115] Reference now 9A to 9C , 9A to 9C The location and function of staggered side sensors 602 , 604 and tip sensor 606 embedded in a catheter-based diagnostic device 101 forming part of a diagnostic and therapeutic system 10 are schematically illustrated.

[0116] According to some embodiments, and as described above, during venous navigation of the catheter-based diagnostic device 101, there is a detectable signal gradient within the target tumor, which is caused by a gradient of substances secreted by the tumor. The signal is weakened at each venous confluence. Figure 4 A to Figure 4 As shown in C, a gradual increase in the signal indicates travel toward the source (eg, a tumor).

[0117] According to some embodiments, in the event of a wrong turn, which would direct the catheter tip away from the tumor 603, the sensor 606 at the catheter tip would register a smaller signal (e.g., Figure 4 B). In this case, the catheter can be withdrawn and directed in an alternate direction (as in Figure 4 C).

[0118] According to some embodiments, staggered side sensors 602 and 604 are positioned along the sides of the catheter and are used to assess the attenuation gradient relative to the more proximal staggered side sensors 602 and 603 based on the signal detected at the catheter tip sensor 606. For example, the staggered side sensors 602 and 604 can assist in intravenous catheter navigation, as well as optimize and standardize the final placement of the catheter for continuous long-term analysis.

[0119] According to some embodiments and as described above, the detected signal may be generated endogenously by the target tissue / tumor, or alternatively, may be released from an arterial catheter, selectively perfusing the target tissue. Alternatively, the signal may be injected into the target tissue via a needle, allowing the signal to travel through the tissue and into the draining vein.

[0120] Reference now Fig. 10A , Fig. 10A The results of varying levels of phosphate ion concentration in a physiological fluid are graphically shown. As shown, an electrochemical impedance scan, which is commonly used to characterize the physiological and chemical properties of biological fluids, was performed by cyclic voltammetry (CV) using phosphate buffered saline (PBS).

[0121] According to some embodiments, a test result graph of two curves of CV performed on PBS and on PBS with a phosphate concentration 5 mM higher than the baseline. The current change by the linear voltage sweep is obvious in the graph, and in particular, the cathode current at -0.2V (negative voltage in the figure) is known to be characteristic of the reaction and is similar to such knowledge in the art.

[0122] According to some embodiments, in addition to the two electrodes (WE, CE) mentioned above and depicted in the graph, a reference electrode (RE) can be used to act as a constant or near-constant known voltage, as is common in many electrochemical measurements. An example of a RE is the use of a pseudo-reference electrode (PRE), which is typically one of the at least two electrodes mentioned above, or an additional electrode of similar or different conductors, and may have different sizes to increase stability, and with or without additional components such as glass frits or salt bridges for separation.

[0123] According to some embodiments, the above description relates to direct current cyclic voltammetry, but is also applicable to square wave, pulse, AC voltammetry, vibrating electrodes, etc. According to some embodiments, EIS can also be used to analyze analytes qualitatively and quantitatively. According to some embodiments, arrays of electrodes or microelectrodes can be used to tomographic results with spatial components or weights.

[0124] Reference now FIG. 10B to FIG. 10C , FIG. 10B to FIG. 10C The experimental results of phosphate concentration measurement using a gold working electrode and a platinum counter electrode and the experimental results of phosphate concentration measurement using a gold working electrode and a platinum counter electrode are graphically shown, respectively.

[0125] According to some embodiments, Fig. 10B Depicts the results of experiments verifying the quantitative analysis of phosphate ions in physiologically representative fluids. Fig. 10AWhen the cyclic voltammetry shown is applied in parallel with square wave voltammetry, different results are obtained. Fig. 10B The results shown in show a relatively clear response at relatively low phosphate concentrations above physiological conditions. Fig. 10C Also depicted are the results obtained in the same manner for different ion species found in the blood and that may represent abnormal masses.

[0126] According to some embodiments, the diagnostic and therapeutic system 10 may also include other types of sensors and sensing capabilities to detect potential residues that serve as proxy measurements of the effects of cell death due to apoptosis, necrosis, or other means. Such processes typically produce membrane-bound bodies such as microsomes or vesicles with cytoplasmic residues, cell-free nucleic acids, DNA or RNA fragments, and other biological materials. Such substances and cellular components typically have certain spectral characteristics in one of the relevant parts of the spectrum (including UV, visible light, or IR) and in the absorbance or reflectance of the incident wave.

[0127] According to some embodiments, the diagnostic and therapeutic system 10 includes components for spectrometry, such as optical fibers, light sources, and gratings and sensors typically used for analysis. In one embodiment, the present invention includes an illumination fiber and a sensing fiber, the illumination fiber typically transmitting light from a light source external to the patient, and the sensing fiber typically having a sensing element external to the patient. The optical device is typically configured to detect such spectral features, such as spectral features of RNA or DNA fragments around 260nm, or alternatively, Fourier transform infrared spectroscopy (FTIR) bands (such as 1741 1 / cm representing phospholipid membranes, etc.), or other wider spectral portions representing one or more substances in the bloodstream. In other embodiments, other spectrometric tools are used, such as fluorescence spectroscopy or Raman spectroscopy. For example, it is suggested to use Raman spectroscopy in vivo, and Raman spectroscopy is shown to be able to detect components as extracellular matrix (ECM). In the context of the present invention herein, the use of Raman spectroscopy can therefore be used in embodiments to detect ECM components released from target tissues into the drainage venous vasculature.

[0128] According to some embodiments, nonlinear optical effects are used to analyze and quantify components using diagnostic catheters. One such example is the detection of second harmonic generation components from a monochromatic source such as a laser. Since collagen comprises a large portion of the tumor extracellular matrix (ECM), it is likely that release of collagen degradation-related products can be detected in the venous effluent of the tumor in response to administration of an ECM-altering agent (such as collagenase). Therefore, second harmonic generation (SHG) IR, optical or UV detection can be used by pulsing a laser source (usually with a duration in the femtosecond range) into the blood and measuring the reflected or transmitted light through a narrowband filter designed to double the frequency of the light source. In this configuration, at least one of the optical fibers described above is connected to a photomultiplier typically located outside the patient's body. Therefore, the light emission of the counted relevant frequency can be associated with the amount of collagen in the bloodstream. As an example, the use of a near-IR excitation laser can be used to provide a relatively transparent portion of the spectrum in the blood and measure IR or optical emissions.

[0129] According to some embodiments, high order frequency generation, such as third harmonic generation (THG), can be used to quantify components such as lipids, phospholipid membranes, etc. To this end, optical filters as well as polarization filters can be applied on the transmitting or receiving optics.

[0130] According to some embodiments, other analytical chemistry techniques may be applied, such as nuclear magnetic resonance (NMR or MRI) combined with external magnetic manipulation, electron paramagnetic resonance (EPR) for detecting free radicals leaving the tumor due to the therapeutic payload, etc.

[0131] According to some embodiments, the analytical chemistry techniques can be applied under the action of an external strong magnetic field and in the case of excitation and emission in the radio frequency range. In addition, optical methods for chirality studies, such as circular dichroism (CD) or other optical methods using light polarization, can be applied. Other applicable techniques include Raman spectroscopy, tip enhanced Raman spectroscopy, anti-Stokes Raman spectroscopy, X-ray fluorescence (usually using an external source), etc.

[0132] In accordance with some embodiments, the use of multiple light sources and potentially multiple readout points can be used for multispectral or hyperspectral imaging, typically referring to multiple spatial pixels, where each point contains various spectral information about: the illumination used for excitation and potential absorbance, transmittance, or reflectance with nonlinear effects (such as fluorescence or harmonic generation).

[0133] According to some embodiments, chemical and physiological reactions are by definition involved in a variety of biological mechanisms, and therefore biochemical and biological detection tools can be included in the described diagnostic catheters. Such tools may include, for example, enzyme-linked immunosorbent assays (ELISAs), which can be used to detect specific types of proteins, and in particular proteins associated with cell death in apoptosis or necrosis. For example, similar to commercial assays commonly referred to as M30 or M65, the application of surfaces with affinity for proteins such as caspase-cleaved Keratin 18 (ccK18) can allow detection of apoptotic protein residues in the blood. For example, by using optical fibers as described above, detection can be color-based.

[0134] According to some embodiments, blood flow is used or additional flow is induced to analyze the sample volume by cytometry, which means introducing some external excitation and detection, such as fluorescence, on the flowing fluid and the biological components therein. In such embodiments, the implementation of flow cytometry (FC) may include equipment such as fluorescence-based sorting (FACS), or cytometry channels and sensors configured to detect specific proteins, protein activity, total DNA amount, total RNA amount, etc.

[0135] According to some embodiments, other biological tools can be used to detect specific proteins, lipid concentrations, or organelles. Technologies from the field of "lab-on-a-chip" or "micro-total-analytic-solutions" (uTAS) can be integrated on the diagnostic catheter to provide capabilities such as PCR, isothermal amplification, gel electrophoresis, liquid chromatography (LC), or others.

[0136] According to some embodiments, in other embodiments, substances in the blood can be further characterized using a photoacoustic (PAS) component that is integrated to optically excite tissue or blood volume and measure the acoustic and ultrasonic response thereto. Such PAS techniques can be used independently or in combination with other laser excitation techniques as described above, and in particular in combination with harmonic generation measurements (SHG, THG, etc.). Furthermore, for example in an optical coherence tomography system (OCT), tomographically high-resolution measurements can be performed based on the phase information of the reflected light.

[0137] According to some embodiments, the above-mentioned analytical techniques can also be used to detect signals directly related to therapeutic payloads rather than biological effects. Specifically, the detection of therapeutic agents can be performed directly as the measurement of their effective chemical spectral signals. For example, the commonly used chemotherapy agent doxorubicin is fluorescent, with excitation of about 500nm and emission of about 600nm. In addition, doxorubicin fluorescence depends on the medium in which it is located, and more specifically, the emission spectrum can be affected by the surrounding pH value or by reactions with quenching forms of other molecules. These all allow information to be collected through diagnostic catheters and used as examples of additional data that can be used for treatment monitoring and optimization.

[0138] According to some embodiments, the therapeutic payload can therefore be detected to infer whether it reached the tumor, interacted with it, or passed through ineffectively. To this end, direct detection with dedicated sensors or indirect inference using some spectroscopic methods can be used.

[0139] According to some embodiments, in addition to the therapeutic payload itself, additional materials may be added through the therapeutic catheter for detection and analysis purposes. Such materials may be intended to be detected by any of the above-mentioned analytical techniques or by additional techniques.

[0140] According to some embodiments, superparamagnetic iron oxide nanoparticles (SPIONs) are added to the therapeutic payload. SPIONs can be detected by non-invasive and minimally invasive means, such as MRI scans or magnetic particle imaging (MPI) scans and magnetic particle spectrometer (MPS) measurements (as shown in the review document

[16] ). In such embodiments, nanoparticles can be added to track the therapeutic payload entering the artery or leaving the vein. These can also be used in conjunction with biomolecules or components to react with materials found locally. For example, nanoparticles linked to antibodies can be used to detect and spatially resolve the location of such proteins (such as cCK18 described above), or alternatively, the location of proteins of the Bcl-2 family, indicating and potentially quantifying the prevalence of induced apoptosis. This technology can also be used to non-invasively monitor the movement of extracellular matrix materials or lipid remnants (such as broken membrane vesicles).

[0141] According to some embodiments, the added material is a contrast agent that is configured to be visible in an x-ray imaging modality or an ultrasound imaging modality. For example, a typical x-ray contrast agent such as iodine or barium is used to react with the intended output material as described above when used in conjunction with a therapeutic payload or some adhesion mechanism for a biological component. In another embodiment, gas bubbles, gas-filled silica beads, or other embodiments of non-miscible gases that can be safely introduced are used for the purpose of being used as ultrasound imaging contrast agents.

[0142] According to some embodiments, the added substance or therapeutic payload further responds to incoming external radiation, such as x-rays or ultrasound, by mechanisms such as scintillation, fluorescence, sonoluminescence, or others.

[0143] It is also noted that some of the above techniques can benefit from concepts in quantum metrology, such as, but not limited to, photon entanglement in the excitation light in measurements such as fluorescence sensing, which can benefit from measurements at low photon numbers, working around bleaching or exceeding photon shot noise.

[0144] The information collected by the diagnostic and therapeutic system 10 described above may refer to a signal and include a series of quantitative values ​​collected in the time domain or the frequency domain. The signal may be analyzed by various measures including some analog preprocessing or filtering, digital acquisition, digital filtering, etc. The signal may be analyzed using one or more mathematical techniques to perform dimensionality reduction, classification, anomaly detection, or heuristic algorithms, such as thresholding, peak detection, frequency domain analysis, Laplace transform analysis, etc. For these purposes, such common techniques as singular value decomposition (SVD), support vector machine (SVM), clustering, Gaussian mixture models, regression, artificial neural network (ANN), etc. may be applied.

[0145] According to some embodiments, the diagnostic and therapeutic system 10 may be applied in a variety of medical fields, such as treating human patients, veterinary applications, and research fields.

[0146] However, it is worth noting that continuous monitoring of the physiological and chemical effects of the therapeutic payload can allow for the adjustment of many parameters including, but not limited to: specific materials introduced as part of the payload, local temperature, local pH, additional materials used to dissolve specific materials (such as enzymes), the rate at which the payload is introduced, the dose of the payload introduced, and the like.

[0147] According to some embodiments, the diagnostic and therapeutic system 10 can be considered a tool for medical diagnosis, information acquisition, and treatment optimization, which can be used before, during, or close in time to the use of certain medical treatments. Therefore, the main role played by the diagnostic catheter is referred to herein as "dynamic vascular biopsy."

[0148] According to some embodiments, the diagnostic and therapeutic system 10 includes an intravascular system, which generally includes a catheter that can be selectively positioned in an artery supplying a (suspected) diseased target tissue and a second diagnostic catheter that can be positioned in a vein draining the target tissue (e.g., by utilizing an arterial catheter 102). The purpose of the arterial catheter is to provide controlled regional delivery of drugs and other agents to change the environment of the tissue. The purpose of the venous sampling catheter is to analyze or collect blood samples from the tissue in real time. The proximity of the blood sample to the target tissue increases and potentially maximizes the concentration of soluble compounds originating from within the target tissue, the concentration of which indicates processes such as cell death (apoptosis or necrosis) or cell replication (mitosis) that are ongoing in the selected tissue of interest.

[0149] According to some embodiments, the proximity can also provide a means of assessing the presence of cell types within the target tissue and the activity of those cells: for example, the presence of lymphocytes or secreted cytokines. Selective proximity to tumor venous blood can also be used to collect high concentrations of circulating tumor cells, DNA, RNA, and other soluble factors, including tumor secreted proteins and hormones, for further analysis.

[0150] According to some embodiments, blood can be analyzed in vivo, in real time or near real time, while in some embodiments, blood is collected to be analyzed externally using classical analytical equipment. The present invention also shows their combination to allow the collection of layered information during surgery, later (e.g., a few minutes) during surgery, or afterwards when the patient recovers. It should also be mentioned that in some embodiments, blood samples can be analyzed externally and circulated back into the patient to prevent blood loss. This is especially true in the case of analytical assays that require large amounts of blood.

[0151] According to some embodiments, the detection and characterization of biomarkers and other entities present in a venous blood sample can be achieved, for example, using an in vitro portable laboratory console, where the fluid sample is analyzed. The analysis of some entities can be achieved in near real time within a few seconds to a few minutes. For the characterization of other entities, such as DNA sequencing, the sample can be evaluated using, for example, known techniques. In real-time evaluation, the resulting data can be used to inform which agents and / or which concentrations are delivered to the diseased target tissue using, for example, an arterial catheter.

[0152] For example, a target tissue can be exposed sequentially to one or more potentially therapeutic agents while evidence of their effects is recorded in near real time, such as detecting evidence of tumor cell death.

[0153] According to some embodiments, the diagnostic and therapeutic system 10 provides diagnostic and therapeutic benefits because once a given treatment modality is evaluated as effective, it can be delivered locally to the target tissue to treat the disease, rather than just evaluating its effect. Similarly, once the sensed effect signal decreases, the infused material can be switched.

[0154] According to some embodiments, particularly in cancer treatment and given the heterogeneity and clonal variation within a tumor, the disclosed dynamic biopsy system is able to evaluate the effects of multiple lines of treatment on a heterogeneous cell population in relatively short intervals (minutes to hours) rather than what is typically performed in standard systemic chemotherapy or local chemotherapy or immunoarterial drug delivery, whereby the effects of therapeutic agents are typically evaluated by imaging features every 3 to 6 months.

[0155] According to some embodiments, a further application of the diagnostic and therapeutic system 10 is to improve or optimize the conditions for therapeutic effect within a defined anatomical region, such as improving or optimizing the local pH, temperature and other modulator levels, so as to reduce interstitial tumor pressure and / or change the extracellular matrix, such as by administering collagenase, thereby increasing the effect of the therapeutic agent. Such improvement or optimization of the tumor microenvironment for treatment may require multiple simultaneous or sequential administrations, which will only be possible through the selective vascular access (approach) disclosed herein.

[0156] Methods for optimizing treatment precision

[0157] According to some embodiments, at least two clinical needs that are prevalent in the management of chronic, long-term patients (e.g., cancer patients) are addressed by utilizing the diagnostic and therapeutic system 10. The first is the ability to select the most effective and appropriate treatment and / or combination of treatments while optimizing the conditions for therapeutic efficacy. The second involves reducing the (systemic) toxicity and morbidity associated with the treatment itself while maintaining its therapeutic efficacy.

[0158] According to some embodiments, the diagnostic and therapeutic system 10 may provide a method for evaluating the effect of a treatment in a target tissue of a subject undergoing a treatment regimen. The method comprises at least the following steps:

[0159] (i) introducing an intravascular intravenous catheter supporting the sensor function into a vein, the catheter collecting blood directly drained from the target tissue;

[0160] (ii) subjecting a venous blood sample collected from the venous implant to an external and / or internal analysis module operable to identify and / or quantify one or more predetermined components in the venous blood; and

[0161] (iii) determining the effectiveness of the treatment in the target tissue based on the presence, and optionally the amount, of one or more predetermined components in the drained venous blood.

[0162] According to some embodiments, the disclosed method for evaluating the therapeutic effect of a given treatment regimen at a target tissue may be expanded and utilized to improve and / or optimize the treatment accuracy by further comprising the following steps:

[0163] (iv) if the therapeutic effect in the target tissue determined in step (iii) above is less than the desired predetermined effect, changing one or more components of the treatment regimen; and

[0164] (v) Repeating steps (iii) and (iv) one or more times until the desired optimized effect is achieved in the target tissue.

[0165] According to some embodiments, the effectiveness of a given treatment regimen according to the embodiments described herein can be determined in near real time or even in real time, thereby enabling treatment of target tissue within a relatively short period of time, such as within 1 hour, 3 hours, 5 hours, 10 hours, 15 hours, 24 hours, 30 hours, 36 hours, 48 ​​hours, or 72 hours.

[0166] According to some embodiments, the treatment regimen comprises systemically administering at least one active agent to the subject.

[0167] According to some embodiments, the treatment regimen includes local administration (eg, intra-arterial administration) of at least one active agent to a target tissue. According to some embodiments, the invention includes combining systemic and local administration of one or more active agents.

[0168] According to some embodiments, the anticipated dynamic biopsy enabled by the diagnostic and therapeutic system 10 enables the design or customization of a treatment regimen that will precisely provide the desired therapeutic effect at the target tissue of the subject. Such a treatment regimen may be patient-specific or personalized, specifically tailored to meet the unique needs and requirements of the subject being treated.

[0169] According to some embodiments, the diagnostic and therapeutic system 10 discloses and refers to a method for designing and providing an improved or optimized treatment regimen for a target tissue in a subject, the method comprising the steps of:

[0170] (i) introducing an intravascular arterial device into an artery that directly supplies blood to the target tissue;

[0171] (ii) introducing into the vein a sensor-enabled intravascular intravenous device that collects or monitors blood draining directly from the target tissue;

[0172] (iii) subjecting the target tissue to a localized therapeutic regimen delivered via an intravascular arterial device;

[0173] (iv) collecting venous blood data from the venous device and subjecting it to an external and / or internal analysis module / controller operable to identify and / or quantify one or more predetermined components in the venous blood;

[0174] (v) determining the effectiveness of the treatment in the target tissue based on the presence of one or more predetermined components in the drained venous blood and optionally based on the amount of the one or more predetermined components;

[0175] (vi) if the effect of the treatment in the target tissue determined in (v) is less than a predetermined, desired (e.g., optimal) effect, changing one or more components of the treatment regimen; and

[0176] (vii) repeating steps (iii) to (vi) one or more times until improved or optimized treatment precision is achieved and maintained in the target tissue.

[0177] According to some embodiments, the diagnostic and therapeutic system 10 can be designed to operate as a system that delivers a specific local treatment regimen via a drug delivery module, while monitoring the local effect of the treatment and transmitting an effect assessment reading to the drug delivery module. Based on the treatment effect readings received, one or more parameters in the treatment regimen can be adjusted, changed, and / or altered, and the modified treatment can be optionally delivered via the drug delivery module, or the treatment can be stopped entirely for safety or other reasons.

[0178] According to some embodiments, the diagnostic and therapeutic system 10 includes two main elements operable to work in conjunction:

[0179] According to some embodiments, the first element in the diagnostic and therapeutic system 10 is an intravascular intravenous sensor device, which includes a venous device connected to a sensor, which is operable to identify and quantify molecules or biological entities that are discharged from tissues by a venous device that collects blood samples. Such molecules can indicate ongoing physiological properties and / or metabolic properties in the drained tissue. For example, detection of evidence such as cell division, genomic phenotypic changes and / or cell death can be achieved and quantified in near real time. Optionally, the introduced sensor has the ability to transmit the recorded signal to a remote device (referred to herein as a "remote port"). Optionally, the sensor device is introduced intravascularly (venously).

[0180] According to some embodiments, the second element in the diagnostic and therapeutic system 10 is an optional port that includes one or more reservoirs containing therapeutic and / or diagnostic materials, collectively referred to herein as a "drug delivery module." The reservoir communicates with the vasculature systemically, intravenously, or via a communication tip selectively positioned within the arterial supply of the treatment area of ​​interest, also referred to herein as an "intravascular arterial device."

[0181] According to some embodiments, the sensor is an analysis module connected to a venous device, and is operable to continuously or repeatedly, in real time or near real time analyze venous blood samples, and communicate with the port by providing corresponding feedback. Therefore, the two elements have the ability to connect and collaborate with each other. In this collaborative system, the information or feedback provided by the first element is transmitted to the port, and is used to adjust, change and / or otherwise modify the treatment strategy by, for example, changing or completely replacing the treatment type, changing the specific parameters in the treatment regimen (such as the timing and / or dosage of administration of one or more active agents, the replacement of one or more active agents, etc.), so as to improve or optimize the treatment accuracy.

[0182] Example

[0183] Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non-limiting fashion.

[0184] Generally, the nomenclature used herein and the laboratory procedures utilized in the present disclosure include molecular, chemical, biochemical and / or microbiological, as well as clinical procedures. These techniques are fully explained in the literature.

[0185] Example 1

[0186] Monitoring the effects of local anti-tumor therapy in near real time

[0187] In order to evaluate the therapeutic effect in the cancerous tissue of the subject who experienced the two-step systemic sequential treatment regimen including infusion of chemotherapeutic agent A (e.g., Oxaliplatin), followed by infusion of chemotherapeutic agent B (e.g., Irinotecan), the effect of treatment on the level of secreted apoptosis markers was evaluated according to time. To this end, one or more intravenous microcatheters are placed in the vein to collect blood directly discharged from the target tumor. Blood samples collected every 30 to 60 minutes are analyzed by, for example, a portable laboratory console to detect evidence of tumor cell death caused by the systemic treatment provided. It is expected that apoptosis is recorded to rise sharply after infusion of chemotherapeutic agent A, followed by a decline and additional rise at a time of, for example, 2 hours as the switch to a different chemotherapeutic agent B occurs.

[0188] Example 2

[0189] Optimizing local treatment options

[0190] Based on the change of the apoptosis marker level detected and quantified in the above-mentioned example 1 with the treatment time, the effectiveness of systemic treatment at the site of the diseased tissue is determined. If the treatment presents a result consistent with the expected result at the target tumor, the systemic treatment scheme is replaced by a local treatment strategy. For this reason, one or more arterial microcatheters are introduced into the artery, and fresh blood is directly delivered to the tumor site of the subject. The one or more arterial microcatheters are connected to a drug delivery module, and the drug delivery module includes two or more reservoirs, each of which contains chemotherapeutic agents A, B, etc. One or more venous microcatheters are kept in place for continuous drainage and collection of blood samples from the tumor site, which are analyzed in near real time. The blood analysis results are processed and compared with the predetermined treatment results. Based on this comparison, the desired treatment scheme is designed and customized to meet the unique needs of a specific tumor and its surrounding tissues, and it is delivered to the drug delivery module so that the drug delivery module can be programmed to deliver a specifically designed treatment scheme. Therefore, drugs A, B and more drugs are released from each reservoir at the precise time and concentration specified according to the designed treatment scheme. In a local regimen, drug doses are relatively low, but their local concentrations are very high and can range from 10 to 500 times the concentrations provided by systemic delivery.

[0191] Cycles of sampling drained blood for apoptotic markers and delivering chemotherapy are repeated until there is no more evidence of ongoing cell death.

[0192] In a specific study evaluating optimization of local treatment of pancreatic tumors, each patient underwent treatment immediately after a PET CT scan and then underwent another PET CT scan one week later.

[0193] For each person, one or more arterial catheters are placed into the blood vessels supplying the tumor. One or more venous drainage catheters are positioned.

[0194] The patient underwent a pretreatment including administration of 10 mg of collagenase at a flow rate of 0.5 mg / min. Then, a combined infusion of paclitaxel, gemcitabine, and fluorouracil (a standard combination for this type of tumor) was administered. Each drug was infused over 1 hour, and apoptotic signals were recorded from the draining venous blood. The early effects of paclitaxel and fluorouracil on cell death were noted. Gemcitabine showed the highest signal of successful apoptosis, and it was the only drug that showed a sustained effect after 1 hour. Therefore, gemcitabine was then administered for another 45 minutes until the apoptotic signal reached zero. At this point, another round of pretreatment with collagenase was deployed. Liposomal irinotecan was infused within 1 hour, showing a moderate apoptotic signal that dropped to zero after 40 minutes.

[0195] The entire cycle was repeated one or more times, this time with no evidence of continued cell death. Tumor eradication was confirmed by PET-CT.

[0196] According to some embodiments, the experiments described in this example or other examples may also be applied to animal trials, referred to as preclinical trials. In such cases, at least one type of animal, such as pigs, mice, sheep, dogs, monkeys, or other animals, is subjected to a treatment regimen as a sample, wherein the animals have a spontaneous, induced, or implanted cancer model or another disease model.

[0197] According to some embodiments, the above methods and systems are collectively and interchangeably referred to herein as "dynamic intravascular biopsy technology" or simply "technology". In this case study, the application of dynamic intravascular biopsy technology has both diagnostic and therapeutic benefits, because once a given treatment is evaluated as effective, it can be designed as a local treatment plan and delivered locally to the target tissue to treat the disease, rather than just assessing its sensitivity to treatment.

[0198] Example 3

[0199] Conditions that optimize the effectiveness of local treatments

[0200] The disclosed intravascular dynamic biopsy technique is applied to optimize conditions for medical effects within a defined anatomical region, with high local concentration and effect.

[0201] In order to accurately determine the local conditions of the tumor site, in order to achieve an optimized effect in the local treatment of cancerous tissue, a small amount of glucose is first delivered to the tumor tissue via a microcatheter, followed by delivery of a mitogen that induces the mitotic phase in tumor cells and promotes DNA exposure. Then, (via a drug delivery module and one or more arterial microcatheters) a small dose of chemotherapeutic drugs is delivered with a high local concentration (e.g., 100 to 400 times the concentration for systemic treatment), which is mainly active in the mitotic phase, such as topoisomerase inhibitors, such as doxorubicin. Therefore, an optimized effect is obtained in the local treatment of cancerous tissue.

[0202] In such cases, side effects may be induced. For example, a response to tumor lysis syndrome (TLS) may be detected via intravascular dynamic biopsy, leading the practitioner to reduce the infusion rate, for example, by a factor of 1 / 5 to 1 / 100.

[0203] Similarly, other local conditions at the tumor site can be established with precision prior to delivering chemotherapy, e.g., adjusting local pH and / or temperature, inducing other modulators that reduce interstitial tumor pressure, and / or monitoring enzyme levels, such as collagenase, to optimize local therapeutic effects.

[0204] While it is plausible that this optimization will be unique for each given condition, it is nevertheless likely that for a given diagnosis, e.g., colon cancer, pancreatic cancer, etc., generalizable protocols will emerge.

[0205] Although the present invention has been described with reference to specific embodiments, the description is not meant to be interpreted in a limited sense. Various modifications of the disclosed embodiments and alternative embodiments of the present invention will become apparent to those skilled in the art after reference to the description of the present invention. Therefore, it is contemplated that the appended claims will cover such modifications that fall within the scope of the present invention.

Claims

1. A medical system, include: (i) at least one diagnostic intravascular invasive device intended for insertion into the venous vasculature, (ii) at least one sensor integrated with the at least one diagnostic intravascular invasive device and configured to detect biochemical or physiological changes in a body fluid, and (iii) a controller designated to receive data derived from the at least one sensor, wherein the at least one diagnostic intravascular invasive device is positioned proximate to a target tissue, and Therein, the controller is designated to process the received data in order to generate a medical recommendation and / or conclusion.

2. The system according to claim 1, in, The target tissue is a tumor, and wherein the diagnostic intravascular invasive device is designated to monitor biochemical or physiological changes in blood flow originating from the tumor.

3. The system according to claim 1, in, The diagnostic intravascular invasive device comprises at least two lumens, wherein a first lumen comprises at least one sensor and a second lumen comprises an operating device.

4. The system according to claim 3, in, The second lumen includes an opening configured to infuse a designated substance having an effect on the fluid surrounding the at least one sensor in the first lumen.

5. The system according to claim 4, in, The infused substance is designed to prevent blood clots from approaching the at least one sensor.

6. The system according to claim 4, in, The infused substance is designated to enhance the sensing capability of the at least one sensor.

7. The system of claim 1, further comprising an intra-visual control device designated to provide a spectral control reference to the at least one sensor.

8. The system according to claim 1, in, At least two sensors are positioned along the diagnostic intravascular invasive device at a specific distance from each other.

9. The system according to claim 8, in, At least two sensors are geometrically arranged in a staggered manner and are configured to infer spatial and spatiotemporal information about biochemical or physiological signals found in the vicinity of the diagnostic intravascular invasive device.

10. The system of claim 1 or 2, further comprising a therapeutic intravascular invasive device designated to be inserted into the arterial vasculature and to administer a designated substance so as to affect at least one sensor of the diagnostic intravascular invasive device placed within the venous vasculature.

11. The system according to claim 4, in, The designated substance is configured to facilitate detection of cell death.

12. The system according to claim 4, in, The drug administration is designated to be optimized based on a therapeutic effect of the drug administration detected by the at least one sensor of the diagnostic intravascular invasive device.

13. The system according to claim 4, in, The designated substance can be detected by an external sensor, such as an ultrasonic sensor or magnetic detection equipment.

14. The system according to claim 1, in, The at least one sensor is a chemical sensor configured to detect inorganic or organic ions, such as potassium, phosphate, sodium, calcium, copper, hydronium, lactate, or the like.

15. The system according to claim 14, in, The sensor is based on an ion specific field effect transistor (ISFET).

16. The system according to claim 14, in, The sensor is an electrochemical cell having at least two electrodes made of at least one material.

17. The system according to claim 14, in, The sensor is configured to detect the ionic strength of blood.

18. The system according to claim 1, in, The at least one sensor is an optical sensor configured to detect cellular remnants characteristic of cell death, such as membrane vesicles, nucleic acids, DNA or RNA fragments, exosomes, nucleic acid fragments, structural proteins, mitochondrial proteins or other cellular debris, biochemical signals or others.

19. The system according to claim 18, in, The sensor is of optical type, such as UV-VIS spectrometer, NIR spectrometer, FTIR spectrometer or the like.

20. The system according to claim 18, in, The sensor is configured to detect a second harmonic generation signature of collagen.

21. The system according to claim 1, in, The at least one sensor is a biosensor configured to detect cellular remnants characteristic of cell death.

22. The system according to claim 21, in, The sensor is based on an immunosorbent assay.

23. The system according to claim 21, in, The sensor is based on fluorescent markers.

24. A medical method, The following steps are involved: (i) inserting at least one diagnostic intravascular invasive device comprising at least one sensor into the venous vasculature, (ii) utilizing the at least one sensor to detect biochemical or physiological changes in a body fluid, and (iii) analyzing, using a controller, data captured by the at least one sensor, wherein the at least one diagnostic intravascular invasive device is positioned proximate to a target tissue, and Therein, the controller is designated to process the received data in order to generate a medical recommendation and / or conclusion.

25. The method according to claim 24, further comprising: The following steps are involved: A therapeutic intravascular invasive device is inserted into the arterial vasculature and a designated substance is administered to affect the at least one sensor of the diagnostic intravascular invasive device placed within the venous vasculature.

Images