WO2024011052A2 - Méthodes et dispositifs pour évaluer et modifier un état physiologique via l'espace interstitiel - Google Patents

Méthodes et dispositifs pour évaluer et modifier un état physiologique via l'espace interstitiel Download PDF

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WO2024011052A2
WO2024011052A2 PCT/US2023/069308 US2023069308W WO2024011052A2 WO 2024011052 A2 WO2024011052 A2 WO 2024011052A2 US 2023069308 W US2023069308 W US 2023069308W WO 2024011052 A2 WO2024011052 A2 WO 2024011052A2
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pressure
patient
interstitial
fluid
implantable device
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PCT/US2023/069308
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WO2024011052A3 (fr
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Joseph Passman
Robert S. Schwartz
Glen Rabito
Stanton J. Rowe
Abubaker KHALIFA
Alexander ROTHMAN
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Nxt Biomedical, Llc
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Publication of WO2024011052A2 publication Critical patent/WO2024011052A2/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/03—Detecting, measuring or recording fluid pressure within the body other than blood pressure, e.g. cerebral pressure; Measuring pressure in body tissues or organs
    • A61B5/036—Detecting, measuring or recording fluid pressure within the body other than blood pressure, e.g. cerebral pressure; Measuring pressure in body tissues or organs by means introduced into body tracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/02—Details of sensors specially adapted for in-vivo measurements
    • A61B2562/0247—Pressure sensors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/01—Measuring temperature of body parts ; Diagnostic temperature sensing, e.g. for malignant or inflamed tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/0205—Simultaneously evaluating both cardiovascular conditions and different types of body conditions, e.g. heart and respiratory condition
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/024—Detecting, measuring or recording pulse rate or heart rate
    • A61B5/0245—Detecting, measuring or recording pulse rate or heart rate by using sensing means generating electric signals, i.e. ECG signals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/103—Detecting, measuring or recording devices for testing the shape, pattern, colour, size or movement of the body or parts thereof, for diagnostic purposes
    • A61B5/11—Measuring movement of the entire body or parts thereof, e.g. head or hand tremor, mobility of a limb
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/103—Detecting, measuring or recording devices for testing the shape, pattern, colour, size or movement of the body or parts thereof, for diagnostic purposes
    • A61B5/11—Measuring movement of the entire body or parts thereof, e.g. head or hand tremor, mobility of a limb
    • A61B5/1116—Determining posture transitions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
    • A61B5/1451—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/316—Modalities, i.e. specific diagnostic methods
    • A61B5/318—Heart-related electrical modalities, e.g. electrocardiography [ECG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4806—Sleep evaluation
    • A61B5/4809—Sleep detection, i.e. determining whether a subject is asleep or not

Definitions

  • the human body is mostly composed of water and dissolved solutes. Fluid is distributed between the intracellular (within cells) compartments and extracellular (within tissue but not in cells) compartments. Additionally, fluid can be “third-spaced” which is accumulations within body cavities such as the peritoneum and pleural cavities. Some of this solution is located within cells and can be termed intracellular fluid. Some of this solution is located outside cells and can be termed extracellular fluid. Extracellular fluid is further segmented into intravascular, interstitial, and lymphatic fluid. Typically, about 2/3 of total body water is intracellular fluid and 1/3 is extracellular fluid. A quarter of the extracellular fluid is in the intravascular space. 1 The proportionately dominant remainder of the extracellular fluid is comprised of the interstitial space and the lymphatic circulation.
  • Extracellular fluid is dispersed in the intravascular, interstitial, and lymphatic spaces.
  • the circulatory system of a human mainly consists of the cardiovascular system and the lymphatic system.
  • the cardiovascular system is a closed, high- pressure circulatory system with the heart acting as a central pump.
  • the lymphatic system is an open, low-pressure circulatory system with no central pump.
  • the interstitial compartment acts as an intermediary between the cardiovascular compartment and the lymphatic circulation. 2 ' 3
  • a visualization of the interactional between the microvascular bed, the interstitial space, and the lymphatics is shown in Fig. 1 where the lymphatics L collect fluid from the interstitial space. Fluid, solutes, proteins, lipids, etc. exchange between the microvascular circulation and the interstitial space.
  • the Figure is from Titze, Kidney International 2013, 4 which is hereby incorporated by reference.
  • Extracellular fluid transport generally works as follows: (1 ) Several liters of fluids are filtered via the semi-permeable membrane of the capillaries into the interstitial space every day, governed by the Starling equation as known to those of skill in the art; and, (2) The lymphatic system collects the filtered fluid that accumulates in the interstitial space (mainly water, salts, plasma proteins) and returns it to the central venous component of the cardiovascular circulation.
  • the interstitial compartment has at times been considered a static and relatively uninteresting space from a pathophysiologic perspective. Recent research has revealed that the interstitial space plays an important role in volume regulation (e.g., pathogenesis of congestion); is key mediator in the pathogenesis of inflammation and shock; 5 regulates immune function; and can play a role in cancer metastasis/therapy. 6
  • T o illustrate utility of the methods and devices in this application, a synopsis of various disease states will be discussed with attention paid to the contributions of the interstitial space towards each pathology:
  • Heart failure is traditionally associated with venous congestion. 8 Increased central venous pressure (CVP) is the largest determinant of adverse clinical outcomes (e.g., impaired renal function) and is an independent predictor of mortality in patients with heart failure. 9 Additionally, most heart failure hospitalizations are related to manifestations of venous congestion rather than low cardiac output. 10 11
  • congestion can promulgate further pathology.
  • the vascular endothelial cells sense biomechanical forces, and increased hydrostatic pressure can cause the vascular endothelial cells to switch from a dormant state to an activated state, which is marked by inflammation, vasoconstriction, and an increase in the oxidative stress. 12 Therefore, a chronic state of venous congestion can lead to organ damage, such as pulmonary vascular remodeling, hepatic injury, and renal injury.
  • the mechanism behind interstitial fluid accumulation in heart failure may be postulated as follows: a) Increased capillary hydrostatic pressure drives increased filtrate to flow into the interstitial spaces via Starling-governed mechanics as known to those skilled in the art. b) Increased central venous pressure impedes lymphatic return via the thoracic duct via Hagen-Poiseuille mechanics 14 and possibly restrictive pathology at the lympho-venous junction(s). 15 c) Increases in vascular permeability, irrespective of the underlying etiology (e.g., sepsis, heart failure, cancer) can cause large proteins and other solutes, such as sodium, to leak into the extravascular space.
  • etiology e.g., sepsis, heart failure, cancer
  • Diuretics are the most common method used to manage volume overload in the setting of heart failure. 20 A few things make the titration of diuretic therapy for heart failure patients difficult in practice. These are listed below: 21 a) Determination of euvolemic status is difficult, with many patients being discharged with residual clinical congestion (e.g., 15% of patients discharged with clinical congestion in the DOSE-AHF study 22 ). b) Routine measures of congestion can only be done in the clinic, limiting the amount of touch points to titrate therapy. c) Many patients exhibit resistance to loop diuretics (e.g., 35% of patients in the PRAISE study displayed resistance to daily furosemide dose > 80mg). 23
  • CardioMEMS technology which is commercially offered by the cardiovascular division of Abbott is an implantable hemodynamic monitor that can be used to assess a surrogate of clinically accepted measures of congestion.
  • CHAMPION trial of CardioMEMS heart failure hospitalizations were statistically reduced compared to controls. This may have been due to practitioners receiving enabling information that resulted in diuretic changes occurring twice as often in the treatment group.
  • 26 While effective, CardioMEMS is a costly, invasive implant that carries risks including bleeding, pulmonary embolism, device embolization, and arrythmias, among others.
  • Other systems are being developed to non-invasively monitor volume status.
  • One example is the ReDS technology created by Sensible Medical Innovations, Ltd.
  • This technology comprises a vest that can be used to assess a surrogate of fluid in the lungs.
  • a study of N 50 patients showed a reduction in heart failure readmissions. 28
  • the ReDS technology provides a surrogate index that lacks a true physiologic correlate.
  • a hallmark of septic shock is an inflammation-mediated increase in microvascular permeability (e.g., capillary leakage), intravascular hypovolemia, and increased cardiac output 29
  • Fluid resuscitation is required to treat hypotension and systemic inflammatory response.
  • inflammation- mediated increases in capillary permeability cause extravasation of fluid into the interstitial space.
  • Fluid therapy (resuscitation) and pressor administration is a therapeutic used to treat hypotension. This often results in fluid overload - which is correlated to increased mortality. 31 See Osterman, Crit. Care. 2015.30
  • fluid administration is part of a positive feedback cycle where fluid overload is an iatrogenic consequence of this fluid therapy (e.g., 86% of patients in a retrospective study of 245 patients with sepsis had positive fluid balance during their treatment 32 ).
  • fluid overload is an iatrogenic consequence of this fluid therapy (e.g., 86% of patients in a retrospective study of 245 patients with sepsis had positive fluid balance during their treatment 32 ).
  • determining euvolemia is difficult, as mentioned above. This results in many patients being discharged with fluid overload (e.g. 35% of patients in a retrospective study of 245 patients with sepsis had fluid overload at ICU discharge 32 ).
  • An important consequence of fluid overload in septic patients is an increase in mortality 31 .
  • a tool to more reliably, easily, and minimally invasively or non-invasively determine physiologic euvolemia in septic patients would be useful to guide fluid administration as well as fluid off-loading via medical therapies such as hemodialysis and diuretics.
  • Fluid is administered intravenously to maintain adequate blood pressure and consequently, end organ perfusion.
  • inflammation-mediated increases in capillary permeability cause extravasation of fluid into the interstitial space.
  • a study comparing septic patients to non-septic patients found higher volumes of extracellular water in septic patients. 34
  • researchers have hypothesized that the interstitial space may provide signals to guide the management of sepsis more adequately.
  • interstitial pressure in septic and non-septic patients NCT03818269. It is possible that probing the interstitial space may prove useful in guiding the management of sepsis.
  • Kidney disease is the 9 th -ranked cause of death in the United States accounting for 13% of age-adjusted deaths, as of 2017. 35 Declining kidney function is stratified across five stages of chronic kidney disease (CKD) by estimated glomerular filtration rate (eGFR). End-stage renal disease (ESRD) is nomenclature for Stage 5 CKD, defined 36 as an eGFR ⁇ 15 mL/min/1 ,73m 2 . As of 2015, there are 700,000 prevalent patients with ESRD in the U.S. This U.S. ESRD population is growing at about 2, 128 cases per million population per year (approximately 700,000 patients per year). 37 Renal replacement therapy (RRT) is used to manage ESRD patients.
  • RRT Renal replacement therapy
  • RRT comprises either kidney transplant, peritoneal dialysis (RD), hemodialysis (HD), or a combination thereof.
  • RD peritoneal dialysis
  • HD hemodialysis
  • the estimation of dry weight is clinically derived, typically using metrics such as measures of increased preload (typically atrial natriuretic peptide levels, cyclic guanidine monophosphate levels, and vena diameter on ultrasound), surrogates of extracellular fluid levels (typically bioimpedance), and blood volume monitoring.
  • measures of increased preload typically atrial natriuretic peptide levels, cyclic guanidine monophosphate levels, and vena diameter on ultrasound
  • surrogates of extracellular fluid levels typically bioimpedance
  • Other common methods include looking for normal blood pressure, clinical edema, jugular vein distention, absence of rales on auscultation, no dyspnea, and a normal size heart shadow on x-ray. 43
  • T umor cells exist in the interstitial space 48
  • Tumors have long been known to have elevated interstitial pressure. 52 This elevated interstitial pressure in the tumor microvascular environment has been hypothesized as a barrier to delivery of cancer therapies. Elevated interstitial pressure in tumors has been found in a range of carcinomas. Furthermore, the interstitial pressure increases as a function of tumor size. 53 It may then be inferred that late-stage cancers with larger tumors may have even higher barriers for drug delivery.
  • Liver cirrhosis is defined by the scarring of liver tissue leading to various pathophysiological abnormalities including volume overload. Fluid accumulates proximal to the liver leading to fluid accumulation in the abdomen (ascites) and fluid accumulates in the lower limbs leading to peripheral edema. The fluid accumulation occurs due to the increased pressure in the liver and the decreased production of albumin. This accumulation of the fluid is also driven by the increased stimulation of renin-angiotensin-aldosterone axis leading to preferential accumulation of total sodium and water in potential spaces. This fluid accumulation is seen in the interstitial space leading to potential increase in the interstitial pressure. Considering liver cirrhosis- associated fluid overload is a chronic condition treated by titration of diuretics, there are likely fluctuations in the interstitial pressure that would guide diuretic treatment planning.
  • COPD Chronic Respiratory Illness
  • COPD Chronic Obstructive Pulmonary Disease
  • Pulmonary fibrosis has a multitude of subtypes impacting the lung parenchyma and lung interstitial space. The direct inflammatory impact of these disease processes on the interstitial space is likely translated into changes in the interstitial space pressure. As these disease processes have treatment options that are titratable, the accurate and early measurement of the interstitial pressure would have direct impact not just on defining disease prognosis but also in informing treatment decisions.
  • the present disclosure is generally directed to procedures and devices for monitoring and treating a physiologic condition of a patient based on the status of an interstitial space of a patient and particularly the level of the interstitial fluid pressure (e.g., IFP) or total tissue pressure (TTP) or both, of the interstitial space of a patient.
  • IFP interstitial fluid pressure
  • TTP total tissue pressure
  • a method to treat a physiologic condition of a patient whereby IFP is measured and it is determined whether IFP is in a normal range, the normal range being typically between -8 and -1 mmHg. If the SCIP is outside a normal range, a therapy is conducted on the patient. The IFP is monitored and the therapy is discontinued when the IFP is in a normal range.
  • a device for measuring interstitial fluid pressure includes a capsule with perforations.
  • a pressure conduit is insertable into the capsule and a pressure sensor is connected to the pressure conduit.
  • a device for measuring interstitial fluid pressure includes a capsule with perforations; and a pressure sensor placed inside the capsule.
  • a device for measuring interstitial fluid pressure includes a capsule with perforations and a pressure conduit insertable into the capsule. It also includes an amplifier connected to the pressure conduit and a pressure sensor connected to the pressure conduit.
  • a device for measuring interstitial fluid pressure includes a housing and a printed circuit board and microprocessor and battery disposed in the housing.
  • a pressure sensor is associated with the housing and the microprocessor.
  • a fluid column is associated with the pressure sensor and a flush port connected to the fluid column.
  • an implantable device for measuring interstitial fluid pressure includes a housing and a printed circuit board and microprocessor and battery disposed in the housing.
  • a pressure sensor is associated with the housing and the microprocessor.
  • a device for measuring interstitial fluid pressure includes a housing and a column extending from the housing.
  • a perforated capsule is disposed at a distal end of the column for placement in an interstitial space.
  • the following items may be disposed in the housing: an atmospheric chamber; a pressure sensor; a flush fluid reservoir for supplying flush fluid to the interstitial space surrounding the perforated capsule; a flush fluid connection for refilling the flush fluid reservoir; a pressure fluid reservoir connected to the pressure sensor for communicating pressure from the perforated capsule via a fluid the pressure sensor; a pressure fluid connection for refilling the pressure fluid reservoir; and a micropump for pumping flush fluid to the interstitial space around the perforated capsule.
  • the techniques described herein relate to an implantable device for measuring interstitial pressure, including: a housing including a first cavity with a plurality of perforations; a filter membrane at least partially defining a second cavity within the first cavity; wherein the filter membrane is configured to allow passage of fluid therethrough and limit tissue ingrowth into the second cavity; and, a first pressure sensor in communication with the second cavity.
  • the techniques described herein relate to an implantable device, wherein the filter membrane includes a plurality of pores within an inclusive range of about 0.1 - 20 micrometers.
  • the techniques described herein relate to an implantable device, wherein the filter membrane includes a first layer having a first plurality of pores with a first pore size, and a second layer having a second plurality of pores with a second pore size.
  • the techniques described herein relate to an implantable device, wherein the second cavity is connected to the first pressure sensor via a conduit.
  • the techniques described herein relate to an implantable device, wherein the first pressure sensor is located in or near the second cavity.
  • the techniques described herein relate to an implantable device, further including a second pressure sensor in communication with a space outside of the device to provide an atmospheric pressure measurement.
  • the techniques described herein relate to an implantable device, wherein the second pressure sensor is connected to a conduit having a membrane exposed on an outer surface of the housing so as to communicate a pressure outside of the device to a lumen within the conduit.
  • the techniques described herein relate to an implantable device, wherein the device is configured to determine interstitial pressure within a patient from sensor data of the first pressure sensor and the second pressure sensor.
  • the techniques described herein relate to an implantable device, wherein the device is configured to determine interstitial pressure within a patient from sensor data of the first pressure sensor and an atmospheric pressure received from a cell phone or electronic device external to the patient.
  • the techniques described herein relate to an implantable device, further including electrodes exposed on an external surface of the housing and configured to sense ECG.
  • the techniques described herein relate to an implantable device, wherein the device further includes an accelerometer configured to record movement of a patient.
  • the techniques described herein relate to an implantable device, wherein the device is configured to quantify data from the accelerometer into patient activity levels or types of activity.
  • the techniques described herein relate to an implantable device, wherein the device is configured to determine a sleep incline of a patient.
  • the techniques described herein relate to an implantable device, further including a magnetic sensor.
  • the techniques described herein relate to an implantable device, wherein the device is configured to sense interstitial fluid pressure and one or more of the following: heartrate, an electrocardiogram, movement of a patient, a sleep incline of the patient, impedance, orthostatic position, fluid pressure within the patient, atmospheric pressure, glucose, temperature, and magnetic fields.
  • the techniques described herein relate to an implantable device, further including a protein-resisting coating that is coated on the filter membrane.
  • the techniques described herein relate to an implantable device, wherein the protein-resisting coating includes one or more of albumin, PEG, steroids, PEG200MA, dimethyl aminoethyl methacrylate, acrylic acid and hydrophilic coatings.
  • the techniques described herein relate to an implantable device, further including a back pulsing system configured to flush proteins from the filter membrane.
  • the techniques described herein relate to an implantable device for measuring interstitial pressure, including: a housing including a first cavity with a plurality of perforations; a balloon defining a second cavity within the first cavity; and, a first pressure sensor in communication with the second cavity.
  • the techniques described herein relate to an implantable device, wherein the second cavity is connected to the first pressure sensor via a conduit.
  • the techniques described herein relate to an implantable device, further including a second pressure sensor in communication with a space outside of the device to provide an atmospheric pressure measurement.
  • the techniques described herein relate to an implantable device, wherein the second pressure sensor is connected to a conduit having a membrane exposed on an outer surface of the housing so as to communicate a pressure outside of the device to a lumen within the conduit.
  • the techniques described herein relate to an implantable device, wherein the device is configured to determine interstitial pressure within a patient from sensor data of the first pressure sensor and the second pressure sensor.
  • the techniques described herein relate to an implantable device, wherein the device is configured to determine interstitial pressure within a patient from sensor data of the first pressure sensor and an atmospheric pressure received from a cell phone or electronic device external to the patient.
  • the techniques described herein relate to an implantable device, further including electrodes exposed on an external surface of the housing and configured to sense ECG.
  • the techniques described herein relate to an implantable device, wherein the device further includes an accelerometer configured to record movement of a patient. [0070] In some aspects, the techniques described herein relate to an implantable device, wherein the device is configured to quantify data from the accelerometer into patient activity levels or types of activity.
  • the techniques described herein relate to an implantable device, wherein the device is configured to determine a sleep incline of a patient.
  • the techniques described herein relate to an implantable device, further including a magnetic sensor.
  • the techniques described herein relate to an implantable device, wherein the device is configured to sense interstitial fluid pressure and one or more of the following: heartrate, an electrocardiogram, movement of a patient, a sleep incline angle of the patient, impedance, orthostatic position, atmospheric pressure, glucose, temperature, and magnetic fields.
  • the techniques described herein relate to an implantable device for measuring interstitial pressure, including: a housing including a first cavity with a plurality of perforations; a first pressure sensor configured to measure pressure within the first cavity such that the device measure an interstitial pressure when implanted within a patient; and, a plurality of electrodes exposed on an outer surface of the housing and configured to measure ECG of the patient when the device is implanted within the patient.
  • the techniques described herein relate to an implantable device, wherein the device is configured to sense one or more of the following: movement of a patient, a sleep incline angle of the patient, impedance, orthostatic position, fluid pressure within the patient, atmospheric pressure, glucose, temperature, and magnetic fields.
  • the techniques described herein relate to an implantable device for measuring interstitial pressure, including: a housing including a first cavity with a plurality of perforations; a first pressure sensor configured to measure pressure within the first cavity such that the device measure an interstitial pressure when implanted within a patient; and, an accelerometer configured to determine an activity level of a patient, a sleep incline angle of a patient, or both.
  • the techniques described herein relate to a wearable device for measuring interstitial pressure, including: a housing; an adhesive positioned on a surface of the housing to adhere the housing to a patient's skin; a probe extending from the housing and configured for placement within tissue of a patient; wherein the probe is configured to measure a pressure within interstitial tissue of a patient; and, a plurality of electrodes exposed on an external surface of the housing and configured to measure an ECG of the patient.
  • the techniques described herein relate to a device for measuring interstitial pressure, including: a housing; an adhesive positioned on a surface of the housing to adhere the housing to a patient's skin; and, a probe extending from the housing and configured for placement within tissue of a patient; wherein the probe is configured to measure a pressure within interstitial tissue of a patient; and wherein the probe further includes an outer needle and a balloon catheter positioned within the needle.
  • the techniques described herein relate to a device for measuring interstitial pressure, including: a housing; an adhesive positioned on a surface of the housing to adhere the housing to a patient's skin; and, a probe extending from the housing and configured for placement within tissue of a patient; wherein the probe is configured to measure a pressure within interstitial tissue of a patient; and wherein the probe further includes 1 ) an outer tube having a lumen and one or a plurality of openings, 2) a wick positioned near the one or a plurality of openings, 3) a diaphragm positioned across the lumen to seal a distal portion of the lumen from a proximal portion of a lumen, and 4) a first pressure sensor in communication with the proximal portion of the lumen.
  • the techniques described herein relate to a method, including: monitoring and storing interstitial pressure data from within interstitial tissue of a patient; monitoring and storing sensor data for one or more of the following: heartrate, an electrocardiogram, movement of the user, sleep incline, fluid pressure within the patient, atmospheric pressure, a sleep incline angle of the patient, impedance, orthostatic position, glucose, temperature, and magnetic fields; optionally processing the interstitial pressure data and the sensor data; sending the interstitial pressure data and the sensor data to an external electronic device; and, determining a disease state based on the interstitial pressure data and the sensor data.
  • the techniques described herein relate to a method of establishing a baseline interstitial pressure value, including: implanting a device within the patient; monitoring interstitial pressure from the device for a first predetermined period of time; and determining the baseline interstitial pressure value based on interstitial pressure based on interstitial pressure at low activity levels and over a low activity level and over a second predetermined period of time.
  • the techniques described herein relate to a method of determining an error state of an interstitial pressure measurement device, including: receiving periodic interstitial pressure measurements with a cell phone or electronic device; if the periodic interstitial pressure measurements are trending upward or downward at low activity levels within a predetermined pressure range, providing a user survey within a cell phone app requesting information to assess patient symptoms, and if the patient reports no new or worsening symptoms within the app, signaling with the app that the interstitial pressure measurement may be in an error state.
  • the techniques described herein relate to a method of determining thresholds for indicating fluid overload within a patient, including: monitoring an interstitial pressure within a patient for a negative to positive pressure transition; and determining a fluid overload condition within a patient based on the negative to positive pressure transition.
  • the techniques described herein relate to a method of determining thresholds for indicating fluid overload within a patient, including: monitoring an interstitial pressure within a patient; determining about a 5mmHg positive pressure trend from an established interstitial pressure baseline value; storing self-assessed symptoms of congestion from a survey within the patient's cell phone; and determining a fluid overload condition in the patient based on the positive trend and the self-assessed symptoms.
  • the techniques described herein relate to a method of determining thresholds for indicating fluid overload within a patient, including: monitoring an interstitial pressure within a patient; determining an interstitial pressure delta of > 5mmHg, confirmed over repeated body movements of the patient; and determining that an interstitial space of the patient is losing compliance and becoming loaded with fluid.
  • the techniques described herein relate to a method of determining thresholds for indicating fluid overload within a patient, including: performing a clinical study to assess medication changes, hospitalizations, and mortality alongside multiparameter data including interstitial fluid pressure; applying the multiparameter data to a predictive algorithm looking at different combinations of this multiparameter data, and developing a risk index for each outcome with the predictive algorithm.
  • the techniques described herein relate to a method of comparing different data to improve a signal to noise ratio, including: monitoring an interstitial pressure within a patient; comparing the interstitial pressure with noninterstitial pressure data, and filtering the interstitial pressure data for data produced during specific physiologic variables.
  • Fig. 1 is a schematic visualization of the interactional between the microvascular bed, the interstitial space, and the lymphatics;
  • Fig. 2 is a schematic representation of the positive feedback cycle of congestion leading to decompensation
  • FIG. 3 is a flow chart representing inflammation-mediated increases in capillary permeability which cause extravasation of fluid into the interstitial space;
  • Fig. 4 is representation of an interstitial space and different historic technologies that measure different pressure constituents in the interstitial space;
  • Fig. 5 is an embodiment of measuring interstitial pressure in accordance with the present disclosure.
  • Fig. 6 is a graphical representation of subcutaneous interstitial pressure readings correlated with invasive cardiovascular metrics in accordance with the present disclosure
  • Fig. 7 is an embodiment of measuring interstitial pressure in accordance with the present disclosure.
  • Fig. 8 is an embodiment of measuring interstitial pressure in accordance with the present disclosure.
  • FIGs. 9A-9B are embodiments of measuring interstitial pressure in accordance with the present disclosure.
  • FIG. 10 is a schematic representation of measuring interstitial pressure in accordance with the present disclosure.
  • Fig. 11 is an embodiment of measuring interstitial pressure in accordance with the present disclosure.
  • Fig. 12 is an embodiment of measuring interstitial pressure in accordance with the present disclosure.
  • Fig. 13 is an embodiment of measuring interstitial pressure in accordance with the present disclosure.
  • Fig. 14 is an embodiment of measuring interstitial pressure in accordance with the present disclosure.
  • Figs. 15A-15B are embodiments of measuring interstitial pressure in accordance with the present disclosure
  • Figs. 16A-16B are embodiments of measuring interstitial pressure in accordance with the present disclosure
  • Fig. 17 is an embodiment of measuring interstitial pressure in accordance with the present disclosure.
  • Fig. 18 is an embodiment of measuring interstitial pressure in accordance with the present disclosure.
  • Fig. 19 is an embodiment of measuring interstitial pressure in accordance with the present disclosure.
  • Fig. 20 is an embodiment of measuring interstitial pressure in accordance with the present disclosure.
  • FIG. 21 is a perspective view of an interstitial pressure measuring device in accordance with the present disclosure.
  • Fig. 22 is a perspective view of the interstitial pressure measuring device of Fig. 21 in accordance with the present disclosure
  • FIG. 23 is a perspective view of the interstitial pressure measuring device of Fig. 21 in accordance with the present disclosure.
  • FIG. 24 is a perspective view of the interstitial pressure measuring device of Fig. 21 with a transparent housing in accordance with the present disclosure
  • Fig. 25 is a perspective view of the interstitial pressure measuring device of Fig. 21 with a transparent housing in accordance with the present disclosure
  • Fig. 26 is a cross-sectional view of the interstitial pressure measuring device of Fig. 21 in accordance with the present disclosure
  • Fig. 27 is a cross-sectional view of the interstitial pressure measuring device of Fig. 21 in accordance with the present disclosure
  • Fig. 28 is a cross-sectional view of the interstitial pressure measuring device of Fig. 21 in accordance with the present disclosure
  • Fig. 29 is a cross-sectional view of the interstitial pressure measuring device of Fig. 21 in accordance with the present disclosure
  • Fig. 30 is a cross-sectional view of the interstitial pressure measuring device of Fig. 21 in accordance with the present disclosure
  • Fig. 31 is a cross-sectional view of the interstitial pressure measuring device of Fig. 21 in accordance with the present disclosure
  • Fig. 32 is a view of internal components of the interstitial pressure measuring device of Fig. 21 in accordance with the present disclosure
  • Fig. 33 is a view of internal components of the interstitial pressure measuring device of Fig. 21 in accordance with the present disclosure.
  • Fig. 34 is a view of internal components of the interstitial pressure measuring device of Fig. 21 in accordance with the present disclosure
  • Fig. 35 is a view of internal components of the interstitial pressure measuring device of Fig. 21 in accordance with the present disclosure.
  • Fig. 36 is a perspective view of an interstitial pressure measuring device in accordance with the present disclosure.
  • Fig. 37 is a perspective view of the interstitial pressure measuring device of Fig. 36 in accordance with the present disclosure.
  • Fig. 38 is a perspective view of the interstitial pressure measuring device of Fig. 36 in accordance with the present disclosure
  • Fig. 39 is a perspective view of the interstitial pressure measuring device of Fig. 36 with a transparent housing in accordance with the present disclosure
  • Fig. 40 is a cross-sectional view of the interstitial pressure measuring device of Fig. 36 in accordance with the present disclosure
  • Fig. 41 is a cross-sectional view of the interstitial pressure measuring device of Fig. 36 in accordance with the present disclosure
  • Fig. 42 is a cross-sectional view of the interstitial pressure measuring device of Fig. 36 in accordance with the present disclosure
  • Fig. 43 is a cross-sectional view of the interstitial pressure measuring device of Fig. 36 in accordance with the present disclosure
  • Fig. 44 is a view of a balloon of the interstitial pressure measuring device of Fig. 36 in accordance with the present disclosure
  • Fig. 45 is a view of tool for implanting an interstitial pressure measuring device in accordance with the present disclosure.
  • Fig. 46 is a view of tool for implanting an interstitial pressure measuring device in accordance with the present disclosure.
  • FIG. 47 is a view of an interstitial pressure measuring device in accordance with the present disclosure.
  • Fig. 48 is a view of the interstitial pressure measuring device of Fig. 47 in accordance with the present disclosure.
  • Fig. 49 is a view of the interstitial pressure measuring device of Fig. 47 with a transparent housing in accordance with the present disclosure
  • Fig. 50 is a view of the interstitial pressure measuring device of Fig. 47 with a transparent housing in accordance with the present disclosure
  • Fig. 51 is a view of a transcutaneous probe in accordance with the present disclosure.
  • Fig. 52 is a view of a transcutaneous probe in accordance with the present disclosure.
  • Fig. 53 is a graph of experimental data in accordance with the present invention.
  • Fig. 54 is a graph of experimental data in accordance with the present invention.
  • Fig. 55 is an image of an experimental outcome in accordance with the present invention.
  • Fig. 56 is an image of an experimental outcome in accordance with the present invention.
  • Fig. 57 is an image of an experimental outcome in accordance with the present invention.
  • Fig. 58 is an image of an experimental outcome in accordance with the present invention.
  • Fig. 59 is an image of an experimental outcome in accordance with the present invention.
  • Fig. 60 is an image of an experimental outcome in accordance with the present invention.
  • Fig. 61 is an image of an experimental outcome in accordance with the present invention.
  • Fig. 62 is an image of an experimental outcome in accordance with the present invention.
  • Fig. 63 is a graph of experimental data in accordance with the present invention.
  • Fig. 64 is a graph of experimental data in accordance with the present invention.
  • Fig. 65 is a graph of experimental data in accordance with the present invention.
  • Fig. 66 is a graph of experimental data in accordance with the present invention.
  • Fig. 67 is a graph of experimental data in accordance with the present invention
  • Fig. 68 is a graph of experimental data in accordance with the present invention.
  • Fig. 69 is an image of an example software interface for an electronic device in accordance with the present invention.
  • capsule or perforated capsule are used throughout this specification, it should be understood to also mean a perforated cavity, lumen, or hollow space.
  • the present specification includes many different embodiments according to the present invention. It is specifically contemplated by the inventors that aspects of any or all of these embodiments may be interchangeable with each other. In other words, aspects of one embodiment should be understood to be usable with or incorporated with another embodiment.
  • device 1000 discussed elsewhere in this specification discusses the inclusion of a plurality of different types of sensors. These non-IFP sensors may be used with other embodiments. Additionally, any of the methods discussed for one embodiment may be similarly used with other embodiments. Hence, the specification should not be strictly limited to only the specific feature combinations described below.
  • the interstitial space typically exists in a gel state. As such, it will have pressure resulting from the presence of solid tissue (e.g., Types I and III collagen fibers, elastic fibers, microfibrils, and glycosaminoglycans) known as Solid Stress (SS) pressure as well as pressure resulting from the presence of fluid, known generally as Interstitial Fluid Pressure (IFP) or Subcutaneous Interstitial Pressure (SCIP) which is a more specific measurement of IFP.
  • SS Solid Stress
  • IFP Interstitial Fluid Pressure
  • SCIP Subcutaneous Interstitial Pressure
  • fluid pressure in the interstitial space of subcutaneous tissue shall now be referred to as SCIP or IFP. While the term “interstitial pressure” is used in this specification, it should be understood to mean interstitial fluid pressure.
  • IFP is a primary indicator of interstitial fluid accumulation which accumulation is driven by the Starling relationship mentioned above.
  • An equation defining the Starling relationship is set forth below where J(F) is the net flow rate at the microvascular level, L(p)A is the filtration coefficient, Pv is the pressure in the capillary bed, Pi is IFP, a is the aggregate reflection coefficient, n v is the oncotic pressure in the plasma, and is the oncotic pressure in the interstitial space.
  • J(F) is the net flow rate at the microvascular level
  • L(p)A is the filtration coefficient
  • Pv is the pressure in the capillary bed
  • Pi is IFP
  • a is the aggregate reflection coefficient
  • n v is the oncotic pressure in the plasma
  • is the oncotic pressure in the interstitial space A positive J(F) indicates that a net flux of fluid will move towards the interstitial space and could lead to edema in certain conditions.
  • J F L p A[ p v - Pi ) - ⁇ J(TT V - 7Ti)]
  • Total Tissue Pressure is the sum of the SS pressure and IFP.
  • Method A Measuring IFP, referred to herein as Method A, and measuring TTP, referred herein as Method B, may each be used to achieve the therapeutic improvements according to the present disclosure.
  • Method A typically involves the use of indirect methodologies such as wicking or a perforated capsule (discussed below) to measure the amount of fluid accumulation, independent of the presence of SS.
  • Method B typically involves the use of an in-situ sensor such as piezoresistive or fiber optic sensor. These sensors are placed directly in the tissue, outside of the vascular space and are not mechanically shielded from the tissue. Such a sensor is sensitive to solid stress indicators resulting from such things as muscular contractions and tissue-to-tissue variations not otherwise measured with the methodologies of Method A. The measurement of such solid stress indicators is useful for evaluating fluid accumulation as well as indicating the status of the interstitial space, such as compartment syndrome.
  • an in-situ sensor such as piezoresistive or fiber optic sensor.
  • both SCIP and TTP are measured, SCIP by an indirect methodology such as a perforated capsule disclosed herein and TTP by a direct methodology such as an in situ sensor disclosed herein.
  • the measurement of both SCIP and TTP provide useful information indicating the state of the interstitial space of a patient and thus the physiologic condition of a patient as will be appreciated by one of skill in the art.
  • IFP may be measured using a perforated capsule constructed from a biocompatible polymer, such as polyurethane.
  • the capsule 500 has a diameter in the range of 1 .4-2.0cm and is perforated with holes 501.
  • the holes 501 may be sized in a range of ,2-3mm.
  • the capsule 500 may be formulated of a bio-inert polymer.
  • a pressure sensor 503 for use with a fluid fillable needle 504.
  • the perforated capsule 500 is implanted subcutaneously in, for example, a thorax, of a patient for a period of time. In one embodiment, the period may be 1-5 weeks.
  • a conduit, such as a fluid fillable needle 504 is connected to the pressure sensor 503 and the sensor is leveled or calibrated to match the level of the capsule 500.
  • the fluid fillable needle 504 is inserted through one of the holes 501 of the capsule 500 into the free fluid pocket 502.
  • the pressure sensor then provides signals that represent the SCIP.
  • the time of implantation may be chosen based on the diameter of the capsule 500.
  • a smaller diameter capsule 500 may have a reduced implantation time compared to a larger diameter capsule 500.
  • the size of the capsule 500 and time of implantation is, in part, derived based on the speed of ingrowth of the interstitial tissue, etc. A period of time allowing too much ingrowth may diminish the formation of a free fluid pocket 502, as is discussed in greater detail later in this specification.
  • other embodiments discussed later in this specification may include features (e.g., filter membranes or balloons) that limit or prevent complete ingrowth of interstitial tissue and keep the free fluid pocket 502 open for long periods of time.
  • the time of implantation may be chosen with little or less consideration for interstitial tissue ingrowth (e.g., several years within a patient).
  • the perforated capsule has a diameter of 2.0cm and is implanted for a period of 2-3 weeks and yields a free fluid pocket 502 suitable for receiving the fluid fillable needle 504 and thus for measuring SCIP with the pressure sensor 503.
  • a thoracic SCIP reading was made alongside two cardiovascular metrics of congestion - left ventricular end diastolic pressure (LVEDP) and central venous pressure (CVP) - in an animal model of fluid-overloaded heart failure.
  • the heart failure model was created using a cardio-selective beta-blocker and acute fluid loading with saline. After fluid loading, congestion was alleviated via ultrafiltration of the plasma. In this manner, both fluid onloading and fluid offloading are simulated.
  • the SCIP reading was made using an implanted perforated capsule similar to the perforated capsule embodiments disclosed herein. Furthermore, acute changes in filling pressures were made using orthostatic maneuvers (e.g., table tilting to change the position of the dependent anatomy relative to the heart). The objective of the experiment was to determine how SCIP changed relative to standard, more invasive metrics of congestion.
  • SCIP can be used to track cardiovascular metrics of congestion, and by corollary, to other physiologic metrics of congestion, such as impedance-based interstitial volume measurements, pitting edema, jugular venous pressure palpation, inferior vena cava diameter, etc.
  • this measurement can be obtained non-invasively, i.e., by methods disclosed herein.
  • physicians may have a window into cardiovascular physiology (and other physiological conditions such as acute kidney injury, cancer, sepsis, and chronic kidney disease) on a more deployable scale and be able to sense physiologic changes with more granularity in the area of disproportionate fluid accumulation in, for example, the vicious cycle of heart failure.
  • the movements of a patient could be tracked to sense SCIP changes during an at-home orthostatic maneuver, such as getting out of bed in the morning. This may be deduced from the data suggestion that the changes of SCIP induced by orthostatic maneuvers correspond to fluid status. This could be used to check for noise in data, to filter data, or to make treatment decisions.
  • a IFP sensing system in accordance with this disclosure is attached the patient.
  • the IFP sensing system sends continuous IFP data to a database.
  • the patient is asked to perform orthostatic maneuvers, for example, a passive leg raise. If IFP is elevated beyond a normal range, the physician uses physiologic knowledge to move IFP towards a normal range using one or more fluid offloading therapies known to those of skill in the art. Therapy is stopped when IFP reaches a normal range.
  • a heart failure team or physician assesses that a patient is at high risk of recurrent hospital admission due to patient history, demographics, or some other clinical assessment.
  • the heart failure physician prescribes a SCIP sensing system in accordance with this disclosure to the patient.
  • the IFP system is attached to the patient.
  • the physician prescribes a patient a diuretic dosage appropriate for the patient.
  • the IFP sensing system sends continuous SCIP data to a database.
  • the heart failure team observes the data and notes any abnormalities in IFP. Several orthostatic changes naturally occur during the observation window.
  • IFP e.g., elevation in SCIP
  • changes in medical therapy e.g., diuretic dosage
  • diuretic dosage e.g., diuretic dosage
  • the recommended changes will be reported to the patient. Changes in the medication prescription are logged, and the impact on IFP is observed. Treatment changes are determined to be adequate when IFP moves towards a normal range.
  • an intervention that can be used to prevent hospitalization due to fluid overload and associated dyspnea.
  • Sepsis is associated with rapid onset interstitial fluid loading due to increased capillary permeability.
  • One therapy is to administer fluid to counteract the massive loss of intravascular fluid to the interstitial compartment.
  • a main guiding signal is arterial blood pressure (ABP). It is of importance to the intensivist that the ABP does not drop. Therefore, it is not uncommon that an intensivist will over-administer fluid and induce iatrogenic fluid overload. Iatrogenic fluid overload in sepsis is associated with increased mortality.
  • the IFP sensing system in accordance with this disclosure is placed on a patient upon admission for sepsis.
  • the IFP signal is monitored alongside the ABP signal to obtain a quantitative understanding of the fluid distribution, answering how the vascular and interstitial compartments are accumulating fluid relative to one another. In one embodiment, this information is used by the intensivist to determine when to stop fluid loading. In one embodiment, the IFP signal is used to guide active deresuscitation via ultrafiltration, continuous renal replacement therapy, etc. In one embodiment, the physician uses the IFP signal to determine the rate at which to offload fluid and to determine the total volume to remove. In one embodiment, the IFP signal is used by the clinician through understanding normal physiologic ranges or by a predictive analytic algorithm trained on preventing morbid events in sepsis.
  • Kidney disease is a prevalent condition with fluid overload that occurs between every dialysis session.
  • a principal goal of dialysis is moving a patient safely to dry weight. To do this, a nephrologist must determine how much fluid to remove and the rate of fluid removal. If the dialysis machine removes the fluid too quickly, the vascular space may be depleted and cause intradialytic hypotension.
  • an IFP sensing system in accordance with this disclosure is used to inform the rate of fluid removal.
  • an IFP sensing system in accordance with this disclosure is attached to a patient.
  • Arterial Blood Pressure is monitored. If Arterial Blood Pressure, ABP, is dropping but the IFP is not changing, it is possible the ultrafiltration rate is too high.
  • ultrafiltration fluid offload
  • dry weight determination can be difficult.
  • the IFP sensing system provides the fluid overload information and a physician can adjust the treatment/therapy accordingly.
  • Cancer cells are typically located in the interstitial space. In other words, they sit “outside” normal cells. The growth of cancer cells crowds the interstitial compartment and increases interstitial fluid pressure. Low interstitial fluid pressure is essential to drive chemicals such as cancer treatment therapies into the interstitial space, as governed by Starling dynamics and importantly, the difference between capillary pressure and interstitial fluid pressure. In cancer, capillary pressures can be normal and interstitial fluid pressure elevated. This acts as a hydrodynamic barrier to therapeutic secretion of cancer treatment into the interstitial space. The flux of therapeutic to the cancer cells, through the interstitial space, is critical to increasing the bioavailability of therapeutic to the cancer cell.
  • a IFP sensing system in accordance with this disclosure is placed on a patient.
  • a physician prescribes a therapeutic, such as a vasodilator or an agent that increases vascular permeability or an agent that increases net flux from the interstitial space to the vascular compartment, to lower IFP.
  • a therapeutic such as a vasodilator or an agent that increases vascular permeability or an agent that increases net flux from the interstitial space to the vascular compartment.
  • the cancer therapeutic is administered. This increases the efficacy of cancer therapeutics.
  • Liver cirrhosis is a chronic condition whose pathophysiological abnormalities include volume overload.
  • the fluid accumulation occurs due to the increased pressure in the liver and the decreased production of albumin.
  • the treatment regimen for liver cirrhosis-associated fluid overload includes the titration of diuretics.
  • an IFP sensing system in accordance with this disclosure is used to inform the titration of diuretics by monitoring changes in interstitial fluid pressure to support treatment plans accordingly.
  • COPD Chronic Respiratory Illness
  • COPD Chronic Obstructive Pulmonary Disease
  • Pulmonary fibrosis has a multitude of subtypes impacting the lung parenchyma and lung interstitial space. The direct inflammatory impact of these disease processes on the interstitial space is likely translated into changes in the interstitial space pressure.
  • an IFP sensing system in accordance with this disclosure can be used to support both the definition of disease prognosis and to inform treatment decisions. As these disease processes have treatment options that are titratable, the accurate and early measurement of the interstitial fluid pressure could be used to support the appropriate titration.
  • a perforated capsule 500 as described above with reference to Fig. 6 is shown.
  • the perforated capsule includes a foam matrix
  • the foam matrix 505 causes the ingrowth of the interstitial tissue and capillaries to occur in a uniform and predictable manner and ensures the formation of the free fluid pocket 502. Usage of the perforated capsule with the foam matrix 505 may follow the same protocol as set forth with respect to the perforated capsule of Fig. 6.
  • the measured pressure is the IFP.
  • a perforated capsule 500 with a foam matrix 505 as described above with reference to Fig. 7 is shown.
  • the perforated capsule 500 includes a balloon lining 507 adjacent the foam matrix 505.
  • the balloon lining 507 serves as a barrier to the ingrowth of the interstitial tissue 510 and capillary beds
  • a conduit such as a fluid column 508 is either added to the balloon lining 507 or an integral part of the balloon lining 507 (molded or extruded) and is attached to the pressure sensor 503. Usage of the perforated capsule with the foam matrix 505 and the balloon lining 507 may be similar to the protocol discussed above with respect to the perforated capsule of Fig. 6. However, instead of a conduit in the form of a needle, a conduit in the form of the fluid-filled column 508 serves as the conduit of pressure to the pressure sensor 503. The measured pressure is the IFP.
  • a perforated capsule 500 with a foam matrix 505 and a balloon lining 507 as described above with reference to Fig. 8 is shown.
  • the perforated capsule 500 includes a balloon lining 507 with small pores 509.
  • the balloon lining 507 serves as a barrier to the ingrowth of the interstitial tissue and capillaries and ensures the stable formation of the free fluid pocket 502.
  • the small pores 509 of the balloon lining 507 allow free fluid transfer of the interstitial fluid into the free fluid pocket 502.
  • the small pores are sized in an inclusive range of 0.5-20 microns.
  • a fluid column 508 is either added to the balloon lining 507 or an integral part of the balloon lining 507 (molded or extruded) and is attached to the pressure sensor 503. Usage of the perforated capsule 500 with the foam matrix 505 and the balloon lining 507 with small pores 509 may be similar to the protocol discussed above with respect to the perforated capsule of Fig. 6. However, instead of a needle, the fluid-filled column 508 serves as the conduit of pressure to the pressure sensor 503. The measured pressure is the IFP.
  • a perforated capsule 500 (with a different shape than shown in Fig. 9A) with a foam matrix 505 and a lining 512 (e.g., polymer) is shown.
  • the lining 512 with small pores 513.
  • the lining 512 serves as a barrier to the ingrowth of the interstitial tissue 510 and capillary beds 506 and ensures the formation of the free fluid pocket 502.
  • the small pores 513 of the lining 512 allow free fluid transfer of the interstitial fluid into the free fluid pocket 502. In one embodiment the small pores are sized in a range of 0.5-20 microns.
  • a pressure sensor 503 is located in situ, meaning in the free fluid pocket 502.
  • the pressure sensor 503 has a connection 514 to electronics as is known to those of skill in the art. Usage of the perforated capsule 500 with the foam matrix 505 and the lining 512 with small pores 513 may be similar to the protocol discussed above with respect to the perforated capsule of Fig. 6. However, the pressure sensor 503 is located in situ. The measured pressure is the IFP.
  • a typical SCIP is in the range of -5 to -3 mmHg.
  • SCIP increases to approximately +2mmHg.
  • a pressure amplification method is shown.
  • a pressure sensor 503 is calibrated to read SCIP within a physiologic range of -3 mmHG (normal fluid state) and +5 mmHG (fluid overloaded state).
  • a mechanical pressure amplification/intensifier is integrated with the pressure sensor and thus leads to an amplified SCIP range of -10 mmHG (normal fluid state) to +20 mmHG (fluid overloaded state).
  • the intensifying of the physiologic pressure changes in this manner could exist for the purposes of improving the signal to noise ratio or increase the true positive rate of detecting fluid overload.
  • a perforated capsule 500 is shown.
  • the capsule has a width in a range of 0.5 - 2.0 cm and a length in a range of 0.5 - 3.0 cm.
  • the capsule 500 is lined with a foam matrix 505 and a lining 512 (e.g., polymer) is located on an inner portion of the foam matrix 505.
  • the lining 512 has small pores 513.
  • the small pores 513 are 0.5-20 microns in diameter.
  • the lining 512 serves as a barrier to the ingrowth of the interstitial tissue 510 and capillary beds 506.
  • the small pores 513 of the lining 512 allow free fluid transfer of the interstitial fluid into the first fluid filled chamber 520.
  • the small pores are sized in a range of 0.5-20 microns.
  • first fluid chamber 520 and a second fluid chamber 524 in the perforated capsule 505 formed by a lubricious polymer body 526 positioned in the perforated capsule 505.
  • the first fluid chamber 520 and second fluid chamber 524 are pre-filled with a non-compressible liquid (e.g., silicone oil, saline, etc.)
  • the lining 512 may be composed of a hydrophilic polymer or it may contain a hydrophilic coating. This would prevent the silicone oil from leaving the fluid chamber 520.
  • a pressure sensor 503 is fluidly connected to the second fluid chamber 524 via a fluid column. In one embodiment, an in-situ pressure sensor is located within the second fluid chamber 524.
  • the first fluid chamber 520 and second fluid chamber 524 are connected to each other via a piston system that comprises a first pressure disc 516 and a second pressure disc 518.
  • the surface area of the first pressure disc 516 is larger than the surface area of the second pressure disc 518. Accordingly, in operation, changes to IFP as applied to the first fluid chamber 520 induce a force against the first pressure disc 516.
  • the piston system is allowed to translate because of a sealed air pocket 522.
  • a lubricious polymer body 526 exists as a seal for the pocket and also allows the pistons to translate, if needed, along the air pocket chamber 522 with minimal friction.
  • the piston system thus exerts a pressure change into the second fluid chamber via the second pressure disc 518.
  • the pressure change exerted into the second fluid chamber is amplified (i.e. , is larger than the pressure change in the first fluid chamber) because the surface area of the first pressure disc 516 is larger than the surface area of the second pressure disc 518.
  • 512 with small pores 513 as set forth in Fig. 1 1 may be similar to the protocol discussed above with respect to the perforated capsule of Fig. 6. However, the pressure readings have a higher signal-to-noise ratio given the amplification of the pressure reading provided by the piston system and fluid chambers.
  • a tube 600 contains an in-situ pressure sensor 503 surrounded by a foam matrix 505.
  • the foam matrix may also include a lining 602 between the foam matrix 505 and the pressure sensor 503 and has small pores 603.
  • the lining is a polymer lining and the small pores 603 have a size ranging from 0.5-20 microns.
  • the in-situ pressure sensor can be a fiber optic transducer, a piezoresistive transducer or a strain-gage transducer.
  • the capillary bed 506 and in the interstitial tissue 510 grows into the foam matrix.
  • the small pores 604 inhibit tissue and capillary growth into a space around the pressure sensor 503 for creating a free fluid pocket.
  • Electronics 604 connect the pressure sensor 503 to a pressure reading device as know to those of skill in the art.
  • the tube 600 can be a needle or a polymer tube.
  • the tube 600 has a pre-filled fluid chamber (e g., with silicone oil or water, etc.) instead of a foam matrix 505.
  • the foam matrix 505 may be initially filed with non- compressible fluid and de-aired. This means that the foam matrix 505 may replace the function of a traditional wick-in-needle (WIN) method of measuring IFP.
  • the WIN method may encounter clogging induced by ingrowth or mechanical compaction of interstitial tissue.
  • Using a bioinert foam matrix can reduce these problems.
  • Usage of the tube 600 to measure IFP may be similar to the protocols discussed above.
  • One product may be a wearable device 700 that can be applied to a user’s arm or other location on the skin as shown in Fig. 13.
  • a wearable device 700 could be periodically replaced, e.g., every 14 days; can be applied by a user (e.g., a patient); can be controlled and/or monitored remotely, e.g., through a mobile phone; and can also integrate other physiologic measurements such as heart rate, ECG, bioimpedance, PPG, blood pressure, etc.
  • Another such product may be a subcutaneous implant 800 that can be implanted beneath a patient’s skin, e.g., in a patient’s chest, as shown in Fig. 14.
  • Such an implant 800 could have an extended life, e.g., 5 years and could also integrate other physiologic measurements such as heart rate, ECG, bioimpedance, activity level, sleep incline, orthostatic position, glucose, PPG, blood pressure, etc.
  • a wearable device 700A having a housing 701 which houses components known in the art to process signals such as a pressure sensor signal and to wireless communicate information to a user.
  • components include a printed circuit board (PCB) 710, a battery 712, an A/D converter and microcontroller unit (MCU) 714, a Bluetooth device 718.
  • PCB printed circuit board
  • MCU microcontroller unit
  • Bluetooth device 718 Also in the housing is a fluid column 703 and a flush port 716.
  • An electronics extension 705 extends outside of the housing 701 and is attached to a pressure sensor 702.
  • the housing is adhered to a user’s skin with an adhesive 708 and, in doing so, the sensor 702 is located either in the epidermis 704 or the deep epidermis 706 of the user or in a range between the two. I n this fashion the sensor 702 is then deemed an in situ sensor. As such, the sensor 702 is positioned to read TTP as pressure is measured directly and not indirectly through, for example, a perforated capsule.
  • the wearable device can have both an in-situ sensor as described as well as a sensor housed in, for example, a perforated capsule for measuring IFF.
  • the device then is capable of measuring both TTP and IFP, which, in one embodiment provides further useful information as to the physiologic condition of a patient as will be appreciated by one of skill in the art.
  • a syringe 720 or other plunger mechanism is attached to the flush port 716 and saline or other suitable fluid is urged into the fluid column 703 to flush the area in the epidermis 704, 706 around the sensor 702.
  • the flush ensures a space around the sensor 702 to allow accurate pressure readings.
  • the pressure sensor 702 communicates signals representative of IFP to the A/D converter and MCU 714.
  • An algorithm as is known to those of skill in the art is used by the MCU to process the pressure into pressure signals that are then communicated via the Bluetooth device 718 to a receiving device such as a mobile phone.
  • the wearable device 700A is a patch.
  • a wearable device 700B having a housing 701 which houses components known in the art to process signals such as a pressure sensor signal and to wirelessly communicate information to a user.
  • components include a printed circuit board (PCB) 710, a battery 712, an A/D converter and microcontroller unit (MCU) 714, a Bluetooth device 718.
  • PCB printed circuit board
  • MCU microcontroller unit
  • Bluetooth device 718 Also in the housing is a fluid column 703 and a flush port 716.
  • a pressure column 709 connects the fluid column 703 to a pressure sensor 702.
  • the fluid column 703 extends outside of the housing 701 and is attached to a perforated capsule 707.
  • the perforated capsule 707 can be a perforated capsule as discussed above with respect to other embodiments. In one embodiment the perforated capsule 707 may be a Guyton capsule as is known to those of skill in the art.
  • the housing is adhered to a user’s skin with an adhesive 708 and, in doing so, the perforated capsule 707 is located either in the epidermis 704 or the deep epidermis 706 of the user or in a range between the two.
  • a syringe 720 or other plunger mechanism is attached to the flush port 716 and saline or other suitable fluid is urged into the fluid column 703 to flush the perforated capsule 707 and the surrounding area in the epidermis 704, 706.
  • the flush ensures a space within and around the sensor perforated capsule 707 to allow accurate pressure to be communicated from a free fluid pocket of the perforated capsule 707 through the fluid column 703 to the pressure column 709 connected to the pressure sensor 702.
  • the pressure sensor 702 communicates signals representative of IFF to the A/D converter and MCU 714.
  • An algorithm as is known to those of skill in the art is used by the MCU to process the pressure into pressure signals that are then communicated via the Bluetooth device 718 to a receiving device such as a mobile phone.
  • the wearable device 700B is a patch.
  • an implantable device 800A having a housing 801 which houses a printed circuit board (PCB) 810, a battery 812, an A/D converter and microcontroller (MCU) 814, a Bluetooth device 818.
  • PCB printed circuit board
  • MCU microcontroller
  • the housing 801 is implanted either in the epidermis 804 or the deep epidermis 806 or in a range including the two. In one embodiment, the housing is above the fascia 822. In doing so, the sensor 802 is located either in the epidermis
  • the implantable device can have both an in-situ sensor as described as well as a sensor housed in, for example, a perforated capsule for measuring IFP.
  • the device then is capable of measuring both TTP and IFF, which, in one embodiment provides further useful information as to the physiologic condition of a patient as will be appreciated by one of skill in the art.
  • the pressure sensor 802 communicates signals representative of IFP to the A/D converter and MCU 714.
  • An algorithm as is known to those of skill in the art is used by the MCU to process the pressure into pressure signals that are then communicated via the Bluetooth device 718 to a receiving device such as a mobile phone.
  • the system of Fig. 17 measures total tissue pressure (e.g., the summation of solid stress and IFP).
  • an implantable device 800B having a housing 801 which houses components known in the art to process signals such as a pressure sensor signal and to wirelessly communicate information to a user.
  • components include a printed circuit board (PCB) 810, a battery 812, an A/D converter and microcontroller unit (MCU) 814 and a Bluetooth device 818.
  • An electronics connection 803 extends outside of the housing 801 and is attached to a pressure sensor 802. Also attached to the housing is a perforated capsule 807.
  • the perforated capsule 807 can be a perforated capsule as discussed above with respect to other embodiments. In one embodiment the perforated capsule 807 may be a Guyton capsule as is known to those of skill in the art.
  • the housing 801 is implanted either in the epidermis 804 or the deep epidermis 806 or in a range including the two. In one embodiment, the housing is above the fascia 822. In doing so, the perforated capsule 807 is located either in the epidermis 804 or the deep epidermis 806 of the user or in a range between the two.
  • a pressure sensor 802 is located inside the perforated capsule 807 and is connected to the MCU 814 via an electronics connection.
  • a pressure sensor 802 is located inside the housing 801 and a pressure column extends from the pressure sensor 802 to a free fluid compartment inside the perforated capsule 807. [00232] In operation, the pressure sensor 802 communicates signals representative of IFP to the A/D converter and MCU 714. An algorithm as is known to those of skill in the art is used by the MCU to process the pressure into pressure signals that are then communicated via the Bluetooth device 818 to a receiving device such as a mobile phone.
  • the system of Fig. 18 measures IFP.
  • a device attachable or wearable by a user 900 having a housing 902 which houses a printed circuit board (PCB) 903; a battery 908, a processing unit 910 having, for example, a Bluetooth mechanism, an MCU, storage mechanism, etc.
  • PCB printed circuit board
  • processing unit 910 having, for example, a Bluetooth mechanism, an MCU, storage mechanism, etc.
  • Extending from the housing 902 and into a subcutaneous space is a column containing a perforated capsule 962 and its distal end.
  • the perforated capsule 962 can be one of any perforated capsules previously described herein.
  • the housing 902 also houses an atmospheric chamber 904 which has holes to the atmosphere allowing the chamber to be maintained at an atmospheric pressure; a flush fluid reservoir 912 for supplying flush fluid (e.g., saline) to an interstitial space surrounding the perforated capsule 962; a flush fluid connection 916 for refilling the flush fluid reservoir 912; a pressure fluid reservoir 914 connected to a pressure sensor 922 for communicating pressure from said perforated capsule 962 via a fluid, e.g., silicone to the pressure sensor 922; a pressure fluid connection 916 for refilling the pressure fluid reservoir; and a micropump 920 for pumping flush fluid to the interstitial space around the perforated capsule 962.
  • flush fluid e.g., saline
  • a pressure fluid reservoir 914 connected to a pressure sensor 922 for communicating pressure from said perforated capsule 962 via a fluid, e.g., silicone to the pressure sensor 922
  • a pressure fluid connection 916 for refilling the pressure fluid reservoir
  • the pressure sensor 922 is a dual port sensor with one port exposed to atmosphere in the atmospheric chamber 904 and a second port connected to the pressure fluid reservoir 914
  • the column extending from the housing 902 may be constituted by a braided cover 950 having the perforated capsule 952 connected or coextensive therewith.
  • the perforated capsule 962 has small pores 960.
  • the shaft 950 is a polymer. In another embodiment, the shaft 950 is a braided material.
  • the column further is constituted by a balloon shaft 954 and a coextensive balloon 956 contained within the braided cover 950.
  • the flush fluid space 952 is connected to the flush fluid reservoir 912.
  • the balloon shaft 954/balloon 956 is in fluid communication with the pressure fluid reservoir 914, which, in turn, is in fluid communication with one of the ports of the pressure sensor 922.
  • a wick mechanism 960 Integrated into the perforated capsule 962 is a wick mechanism 960 to provide a wicking action around the perforated capsule 952.
  • the wick mechanism 962 is constituted by a bioinert polymer.
  • the attachable device 900 is secured to a user by urging the perforated capsule 962 into a subcutaneous space of the user and the housing is adhered to the user with an adhesive or adhesive-lined flexible polymer 906.
  • Flush fluid e.g., saline
  • the wick mechanism 958 serves to enhance coupling to the interstitial space. It could also ensure immediate coupling to the interstitial space without the need for an implantation period. A coupled wick and capsule as shown may ensure that the device works immediately so as to avoid an implantation period.
  • the wick 946 is optional.
  • the MCU then processes the signal from the pressure sensor 922 to represent IFP and communicates the IFP via Bluetooth to a device such as a mobile phone.
  • the data may be processed via simple time series and trending analysis as known to those of skill in the art.
  • artificial intelligence models e.g., neural networks
  • IFP data may be processed using IFP data versus hospitalizations or other abnormalities to inform a predictive model to define when to intervene.
  • a threshold algorithm may be employed using physiologic pressure-volume curves relevant to the specific region of anatomy the IFP measurement is being performed in. For example, the nominal IFP value (euvolemic state) is negative. Transitions to positive pressures, relative to atmosphere, are associated with massive increases in interstitial volume. Thus, a threshold of OmmHg may be an important indicator of acute onset of edema and an important way of determining true physiologic dry weight.
  • a clinician could use this transition point as an indicator that fluid offloading via, for example, diuretic up-titration should be attempted. It is possible that other areas of the body may be more sensitive to early fluid accumulation than others. Different pressure-volume curves in different organs could lead to earlier or organ specific identification of the degree of fluid overload or edema. Other example areas to place a device to measure interstitial pressure may include the heart, lungs, spleen, the mesentery and kidneys.
  • Figs. 21 -35 illustrate various views of a device 1000 that is configured to be implanted within a patient, such as in the epidermis, the deep epidermis, or similar locations to measure interstitial fluid pressure (e.g., SCIP).
  • the device may optionally further include one or more sensors to sense heart characteristics (e.g., heartrate, an electrocardiogram, etc.), movement of the user, sleep incline, impedance, orthostatic position, fluid pressure within the patient, atmospheric pressure, temperature, glucose, and magnetic fields. While the pressure data alone may be helpful for monitoring a patient, additional data from these sensors may provide a more accurate or nuanced condition of the patient and therefore better improved patient treatment can be provided.
  • the device 1000 may include an outer housing 1002 comprising a variety of different shapes, such as rectangular cuboid, egg-shaped, cube-shaped, or cylindrical shaped.
  • the present example housing 1002 has a generally rectangular shape that seals an interior cavity from fluid.
  • the housing 1002 may include a perforated chamber or capsule 1004 (e.g., a Guyton capsule).
  • the perforated capsule 1004 is located at one end of the housing 1002 and has a similar shape (e.g., the end of a rectangular cuboid).
  • the perforated capsule 1004 may have a larger shape/profile or a smaller shape/profile than the housing 1002.
  • the perforated capsule 1004 may have features that connect it to the housing 1002, such as arms 1004A with raised feature that engages with a depression or hole in the housing 1002 (e.g., a detent-like mechanism).
  • the perforated capsule 1004 may be generally similar to those previously described in this application.
  • it may be composed of a rigid biocompatible material (e.g., a biocompatible polymer, metal, ceramic, etc.) and may form a cavity or lumen with a plurality of apertures opening into the cavity.
  • the apertures may be similar in number and size as described for other embodiments such that they allow a neovascular capillary network to grow into the apertures (e.g., an inclusive range of 1 cm to 3 cm, though other sizes larger and smaller are likely to function sufficiently).
  • the perforated capsule 1004 may have a thickness that provides sufficient strength for forces experience during and after implantation, such as an inclusive range of 0.75 mm to 1.5 mm, though thicknesses larger and smaller are also believed to function adequately for their intended purposes.
  • the apertures may be within an inclusive range of about 0.5 mm to 3 mm in diameter (e.g., 1 .25 mm), between about 50-500 apertures total, and may be spaced from each other at a distance within an inclusive range of about 0.25 - 2.5 mm.
  • a free space, secondary cavity, or secondary lumen that is at least partially defined by a microporous filter membrane 1010 which prevents or limits tissue from growing into or through the filter membrane 1010.
  • the free space or secondary cavity may remain free from tissue to allow the pressure of fluid within it to be accurately measured and interstitial pressure within the patient to be determined (e.g., IFF).
  • the filter membrane 1010 may be arranged in a variety of different shapes within the cavity of the perforated capsule 1004, such as in a cylindrical shape, a spherical shape, a cubic shape, a rectangular cuboid shape, or similar shapes. Additionally, the filter membrane 1010 may be connected to or fixed to an underlying support structure or framework.
  • the filter membrane 1010 may have a cylindrical shape and may generally extend between an end of the filter membrane 1010 closest to the housing 1002 and an end farthest away from the housing 1002.
  • a support structure may also be included to support the cylindrical filter membrane 1010, comprising an outer end cap 1014, an inner end cap member 1016, and a plurality of struts 1012 that connected to both caps 1014, 1016.
  • the caps 1014, 1016 form a generally cylindrical-shaped framework which allows the filter membrane 1010 to be disposed around.
  • the caps 1014, 1016 block the ends of the cylindrical/tube shape of the filter membrane 1010 and thereby close of the free space or secondary cavity from other areas within the main cavity of the perforated capsule 1004. Hence, fluid may enter but tissue is unable to grow into the free space or secondary cavity. This may help allow the device 1000 to measure interstitial fluid pressure for longer periods of time, particularly as compared with traditional Guyton capsules.
  • the filter membrane 1010 may be composed of a filter material having a plurality of micropores.
  • the material may have pores within an inclusive range of about 0.1 - 20 micrometers in diameter (e.g., about 10 micrometers in diameter).
  • the filter membrane 1010 may be composed of PFA, EPTFE, PTFE, PVDF, porous hydrophilic polymer, or similar materials or combinations of materials.
  • the filter membrane 1010 may have a thickness within an inclusive range of about 0.45 mm and 2 mm, though thicker and thinner filter membranes are believed to also function sufficiently. It may also be desirable for the filter membrane 1010 to be composed of layers of different materials and/or different pore sizes.
  • the filter membrane 1010 may have a first layer with about 0.5 micrometer sized pores and a second adjacent layer with 10 micrometer sized pores.
  • the filter membrane 1010 may have pore sizes of several different diameters (e.g., within an inclusive range of 0.1 to 20 micrometers in diameter).
  • the free space or secondary cavity defined and within the filter membrane 1010 is connected to and in fluid communication with a conduit or passage 1018 that opens through the cap 1016 and extends into the main cavity of the housing 1002 (best seen in Figs. 26-30).
  • the passage 1018 further connects to a first pressure sensor 1020 connected on a printed circuit board 1024.
  • the first pressure sensor 1020 may perform constant or periodic pressure measurements of the fluid within the passage 1018 and secondary cavity of the filter membrane 1010.
  • the measured pressure from the first pressure sensor 1020 may be subtracted from the current atmospheric pressure to achieve a subcutaneous interstitial fluid pressure (e.g., SCIP).
  • SCIP subcutaneous interstitial fluid pressure
  • the atmospheric pressure reading may be obtained from one or both of an onboard atmospheric pressure sensor and/or atmospheric pressure data sensed from a user’s phone (or similar portable electronic device) that is wirelessly connected to the device 1000 or via web-based data collected via public atmospheric pressure readings and location matched to the device using GPS or simulation location tracking.
  • discrete interstitial pressure readings may be obtained by simply subtracting a measured pressure of the first pressure sensor 1020 (capsule cavity pressure) from an atmospheric pressure value, it may also be possible to create rolling averages for each value (e.g., 5 minute rolling averages of the capsule cavity pressure and atmospheric pressure) and then subtract those two values, which may help improve the overall accuracy of the determined interstitial pressure calculation.
  • Figs. 24, 25, and 31 best show one example of an onboard atmospheric pressure sensor.
  • a second pressure sensor 1022 is connected to the printed circuit board 1024 and is in communication with conduit or passage 1006A, which terminates with an outer membrane 106 that is located at an opening through the housing 1002.
  • conduit or passage 1006A which terminates with an outer membrane 106 that is located at an opening through the housing 1002.
  • pressure changes outside the membrane 1006 may be communicated to the air/gas or liquid within the passage 1006A, allowing the second pressure sensor 1022 to constantly or periodically obtain pressure sensor data.
  • the membrane 1006 may be a microporous membrane that may be composed of PVDF, PTFE, or similar material and may have a pore size within an inclusive range of 0.5-10 micrometers in diameter.
  • the device 1000 may obtain atmospheric pressure readings from a cell phone or similar portable electronic device that is in wireless communication with the device 1000 (e.g., via a Bluetooth connection).
  • the second sensor 1022 may not be needed and the atmospheric sensor on the cell phone may be relied upon, or data from both sources can be used.
  • the cell phone atmospheric data may be used when available and the data from the second pressure sensor can be used when the cell phone is unavailable, the data from the two sources may be averaged, or the cell phone atmospheric pressure data may be used to check the accuracy of the data from the second pressure sensor.
  • the atmospheric pressure data from the cell phone may be periodically wirelessly sent to the device 1000 and/or the atmospheric pressure data (and optionally the data from the first pressure sensor 1020) may be periodically wirelessly sent to the cell phone.
  • the interstitial pressure may be calculated by the device 1000 and/or by software on the cell phone. If atmospheric data from a public data source (e.g., accessible via a phone’s internet connection) is used, the location of the cell phone may be used to obtain the atmospheric data from or near the cell phone’s location.
  • the device 1000 may also be configured to sense heart activity characteristics, such as heart rate and ECG.
  • heart activity characteristics such as heart rate and ECG.
  • two (or optionally three or more) electrodes 1008 may be located on an outer surface of the housing 1002, such that when the device 1000 is implanted under the skin of a patient, the electrodes 1008 make electrical contact so as to sense electrical characteristics of the patient’s heart (e.g., ECG).
  • the printed circuit board 1024 may include a biopotential circuit 1026 to sense these electrical characteristics.
  • additional electrodes may be included on the outside of the housing 1002 or may be connected to the device 1000 via wire and placed at other locations within the patient’s body (e.g., intravascular, intramuscular, or subcutaneous locations) to obtain additional ECG vectors (e.g., two lead ECG vs. 6 lead ECG).
  • additional information may be determined from the ECG and used in connection with other data to enhance a diagnosis and/or to improve treatment for a patient. Additional information may include: Heart rate (afib), heart rate variability (autonomic I nervous system activity), P wave dispersion (afib risk and atrial remodeling), ST elevation (myocardial infarction).
  • QRS width ventricular abnormalities
  • amplitude cardiac contractility
  • biphasic P wave interference in atrial conduction
  • respiration rate dispnea
  • T wave analysis early risk of myocardial infarction or hyperkalemia
  • PR interval abnormalities pathologic AV conduction, atrial-ventricular desynchrony
  • QT interval ventricular tachycardia
  • the device 1000 may also include an accelerometer 1028 (Fig. 33) which is configured to monitor and record movement of the patient. As discussed in greater detail later in this specification, the movement can be compared or aligned with interstitial pressure readings, heartrate/ECG readings, and/or other sensor data to provide better context and accuracy for what the interstitial pressure readings may mean for the patient’s health. For example, interstitial pressure readings during periods of higher activity may result in increased interstitial pressure.
  • This accelerometer data may be further analyzed and quantified into discrete periods of time that are characterized by the patient’s activity, such as “high activity” and “low activity.”
  • Fig. 53 illustrates example accelerometer sensor data and lengths of time that may be determined to be “high activity” 1028A or “low activity” 1028B based on that data.
  • One example technique for characterizing raw accelerometer data to activity types and/or activity counts can be found in the journal article Brondeel, R. (2021 ) Converting Raw Accelerometer Data to Activity Counts Using Open-Source Code: Implementing a MATLAB Code in Python and R, and Comparing the Results to ActiLife.
  • activity characterizations or counts may be used for a variety of different purposes.
  • the activity characterization may be used to assess patient function (e.g., if they are exercising more so they must feel okay or if they are moving/exercising less, they may feel worse).
  • the activity characterization may be used to segment other data based on activity level.
  • cardiovascular variables are intimately related to level of patient activity.
  • hemodynamic pressures increase as a response to exercise.
  • trending data as function of activity level may be used to more appropriately understand how congestion is changing by controlling for activity.
  • the activity characterization may be used to estimate a walk distance (e.g., a 6 minute walk distance). This is a clinical outcome used to assess how a patient is improving in response to therapy. This estimation may be calculated by counting steps and integrating acceleration twice to obtain distance traveled over a period of time and therefore project an estimated 6 minute walk distance.
  • a walk distance e.g., a 6 minute walk distance
  • the accelerometer data may be used to calculate a patient’s sleep incline angle.
  • the accelerometer data may help determine when a patient is asleep and then also determine what angle the patient is oriented at during sleep.
  • Sleep incline is known to increase as a patient feels short of breath. Patients tend to elevate their heart above their lower limbs to relieve shortness of breath. Physiologically, this elevation is known to reduce cardiac filling pressures. Increases in sleep incline are indicative of deteriorating cardiac physiology based on latent symptoms.
  • These data could be incorporated in algorithms that tie physiological absolute values, like IFP, with symptomatic data. This information could be used to titrate medical therapy if the sleep incline, in concert with IFP, indicates deteriorating physiology.
  • the device 1000 may also include a magnetic sensor (e.g., connected to the printed circuit board 1024).
  • This magnetic sensor may be used in combination with the accelerometer to increase the accuracy of the sleep incline data and integrate position measurements, known as dead reckoning.
  • the magnetic sensor may be used to give a gravity vector to orient acceleration.
  • a gyroscope may be added to correct for additional errors to allow for sub centimeter accuracy for positional dead reckoning.
  • the device 1000 may also include a glucose sensor that is configured to sense a glucose level within the patient.
  • the glucose sensor may be an electrochemical glucose sensor or a fiber optic or optical sensor.
  • one or more electrodes e.g., 3 electrodes
  • the electrode(s) may be electrically connected to sensor circuitry on the circuit board.
  • the device 1000 may also include a temperature sensor (e.g., a thermocouple). This can be used to record body temperature of the patient. Additionally, the temperature may be used the temperature is used to compensated for changes in the pressure sensor reading. There may be multivariable calibrations stored at different temperatures. These calibrations may be used to adjust for changes in skin temperature to maintain an accurate pressure reading. Typical skin temperatures vary from 27-33 degrees C, and the temperature sensor may help provide more accurate pressure readings in that temperature range.
  • a temperature sensor e.g., a thermocouple
  • a method of assessing device functionality by performing glucose readings to verify the functionality of the permeable membrane structure may include 1 ) performing glucose readings with a glucose sensor, 2) analyzing for a predetermined glucose range or glucose fluctuation within a predetermined range over a predetermined time, and 3) if the range or fluctuation does not occur, triggering an alert.
  • the range or fluctuation may be about 50 - 200 mg/dL glucose throughout a time period of about a day (e.g., 12 hours, 18 hours, 24 hours, etc.).
  • the filter membrane and therefore the device 1000 is functional (e.g., interstitial tissue has not completely grown into the cavity of the filter membrane), because normal interstitial glucose levels are expected to fluctuate by this amount after eating and being fasted. If such daily fluctuations greater than ⁇ 50mg/dL daily do not occur, it is likely the filter and interstitial pressure sensor is no longer functional.
  • the printed circuit board 1024 of the device 1000 may also include a processor or microcontroller that is configured to execute software and related algorithms, memory for storing both software and sensor data, a battery 1030 for powering the device 1000, and a wireless transceiver and antenna (e.g., Bluetooth) configured to communicate with one or more devices outside the patient (e.g., a cell phone and/or other electronic devices).
  • a cell phone, tablet, or similar electronic device may include an app or software for communicating with the device 1000, as well as uploading data to a cloud server, contacting a physician, and displaying a battery charge level of the device 1000, as seen in Fig. 69.
  • the filter membrane 1010 may be coated with a proteinresisting coating to prevent against the risk of protein adhesion to the membrane.
  • a proteinresisting coating may include one or more of albumin, PEG, steroids, PEG200MA, dimethyl aminoethyl methacrylate, acrylic acid and/or hydrophilic coatings.
  • the filter membrane 1010 may be surrounded with another membrane that filters out proteins that may pose a risk to the long-term porosity of the filter membrane 1010. In both these examples, these features could be considered to ensure a long-term porous membrane to facilitate unimpeded movement of capillary filtrate directly to the interstitial fluid pressure sensor.
  • passage 1018 may include epoxy at or around its joints with other components, such as the first pressure sensor 1020. Additionally, the electronic components may be surrounded with a potting material to further prevent fluid from reaching sensitive components.
  • the device 1000 may include a metal conduit with an interior passage that connects between an interior of cavity created by the filter membrane 1010 and that is directly welded (or brazed if ceramic).
  • the first pressure sensor 1020 may be located at or near the interior cavity formed by the filter membrane 1010, with an electrical cable or connection extending to the circuit board 1024 or a passthrough similar to that used for pacemakers.
  • the first pressure sensors 1024 may be piezoelectric, capacitive, standard Wheatstone bridge, or fiber optic.
  • An example method of the present specification includes 1 ) monitoring and storing data of a sensed pressure within interstitial tissue of a patient, 2) monitoring and storing data for one or more of heart characteristics (e.g., heartrate, an electrocardiogram, etc.), movement of the user, sleep incline, fluid pressure within the patient, atmospheric pressure, a sleep incline angle of the patient, impedance, orthostatic position, glucose, temperature, and magnetic fields, 3) optionally processing that data, 4) sending that data to an external device (e.g., cell phone), 5) determining a disease state, and 6) treating the disease state based on the data.
  • heart characteristics e.g., heartrate, an electrocardiogram, etc.
  • movement of the user sleep incline
  • sleep incline fluid pressure within the patient
  • atmospheric pressure e.g., an electrocardiogram, etc.
  • a sleep incline angle of the patient e.g., impedance, orthostatic position, glucose, temperature, and magnetic fields
  • impedance e
  • Another method of the present specification includes establishing a baseline IFP value by 1 ) starting with a patient in inpatient setting, 2) titrating medications to achieve euvolemia, 3) implanting a device 1000, 4) discharging the patient, 5) monitoring data from the device for a predetermined period of time (e.g., allowing about two weeks for interstitial tissue ingrowth), 6) providing continuous symptomatic reports of data from the device 1000 regularly (e.g., once week) from a phone app that has received data from the device 1000, 7) Accepting IFP readings at a low activity level as an IFP baseline when they are stable (e.g., measurement standard deviation less than 1 mmHg for about 3 days).
  • Another method of the present specification includes a method of determining an error state of the device 1000 by 1 ) receiving periodic (e.g., weekly) IFP measurements with a cell phone or electronic device, 2) if the periodic IFP measurements are trending upward or downward at low activity levels (e.g., within a predetermined range > 5 mmHg) a user survey is triggered within a cell phone app requesting information to assess patient symptoms, and 3) if the patient reports no new or worsening symptoms within the app, the app may signal (e.g. , send a message to a remote server and/or a physician) that the device 1000 may be in an error state (e.g., due to drifting or erroneous sensor readings).
  • periodic e.g., weekly
  • low activity levels e.g., within a predetermined range > 5 mmHg
  • the app may signal (e.g. , send a message to a remote server and/or a physician) that the device 1000 may be in an error state (e
  • Another method of the present specification includes a method of determining thresholds for indicating fluid overload by 1 ) monitoring an interstitial pressure within a patient with the device 1000 for a negative to positive pressure transition, and 2) determining a fluid overload condition within a patient.
  • this method may further include alerting a physician or patient to a possible fluid overload condition, as well as further testing for a fluid overload condition and/or heart congestion in the patient.
  • Another method of the present specification includes a method of determining thresholds for indicating fluid overload by 1 ) monitoring an interstitial pressure within a patient with the device 1000, 2) determining about a 5mmHg positive pressure trend from an established IFP baseline, 3) storing self-assessed symptoms of congestion from a survey within the patient’s cell phone, and 4) determining a fluid overload condition in the patient based on the positive trend and self-assessed symptoms.
  • Another method of the present specification includes a method of determining thresholds for indicating fluid overload by determining high changes in IFP with changes in orthostatic position, by 1 ) monitoring an interstitial pressure within a patient with the device 1000, 2) determining an IFP pressure delta of > 5mmHg, confirmed over repeated body movements of the patient (for example, three to five lying down to standing maneuvers), and 3) determining that the interstitial space of the patient is losing compliance and becoming loaded with fluid.
  • Another method of the present specification includes a method of determining thresholds for indicating fluid overload based on machined learned / predictive analytics by 1 ) performing a clinical study to assess interventions (medication changes) and events (hospitalizations, mortality) alongside the multiparameter data, including interstitial fluid pressure; 2) applying this data to a predictive algorithm looking at different combinations of this multiparameter data, and 3) developing a risk index for each outcome with the predictive algorithm.
  • This method may further include allowing the algorithm to provide recommendations based on the risk index.
  • the algorithm may employ neural networks, K clustering, Z scores, linear regression, polynomial regression, logistic regression, correlation, decision tree, support vector tree, single variable decomposition, naive Bayes, etc.
  • Another method of the present specification includes a method of comparing different data to improve a signal to noise ratio by 1) monitoring an interstitial pressure within a patient with the device 1000, 2) comparing the interstitial pressure with noninterstitial pressure data (e.g., other sensor data described for device 1000), and 3) filtering the interstitial pressure data for data during specific physiologic variables.
  • Monitoring activity levels and orthostatic are the dominant driver for changed physiologic variables like interstitial fluid pressure and ECG derived metrics, and therefore the physiologic variables may include orthostatic pressure and ECG derived metrics.
  • Figs. 36-44 illustrate various views of a device 1050 that is otherwise similar or the same as the previously described device 1000, including one or more sensors to sense heart characteristics (e.g., heartrate, an electrocardiogram, etc.), movement of the user, fluid pressure within the patient, sleep incline, activity, orthostatic position, atmospheric pressure, glucose, temperature, and magnetic fields.
  • heart characteristics e.g., heartrate, an electrocardiogram, etc.
  • movement of the user e.g., movement of the user
  • fluid pressure within the patient e.g., sleep incline, activity, orthostatic position, atmospheric pressure, glucose, temperature, and magnetic fields.
  • the pressure within a balloon 1052 is instead measured.
  • the balloon 1052 may be positioned within the cavity of the perforated capsule 1004.
  • An outer end cap 1054 may be connected to the balloon 1052 (and optionally plug an outer passage if the balloon 1052 has one), as well as may connect to the perforated capsule 1004 to provide support to the balloon.
  • the inner end of the balloon 1052 may include an opening that is disposed on the end of a tube 1056 that connects to and is in communication with the first pressure sensor 1020.
  • the balloon 1052 may be filled with a gas (e.g., air), a fluid(e.g., silicone oil or saline), or a gel (e.g., hydrogel, xerogel, gelatin, or flowable rubber).
  • the pressure in the fluid in the cavity of the perforated capsule 1004 changes, those changes also change the pressure exerted on the balloon 1052.
  • the pressure on the balloon 1052 communicates pressure to the gas or liquid in the inner tube 1056, which is then measured by the first pressure sensor 1020.
  • the pressure from the first pressure sensor 1020 may be referenced relative to the atmospheric pressure sensed by either the second pressure sensor 1022, an atmospheric pressure sensor in a wirelessly connected cell phone, or a combination of both.
  • the pressure readings from the balloon 1052 may require an adjustment factor to determine interstitial pressure since the material of the balloon 1052 may provide a mechanical element to the pressure reading.
  • any tissue that grows into the perforated capsule 1004 may press/pull on the balloon 1052 physically. This may lend to sensing the capillary and tissue more mechanically than the prior “filter” embodiment of device 1000 and may possibly represent at least some components of total tissue pressure (TTP). This may be a different variable than the sum of I FP and solid stress.
  • TTP total tissue pressure
  • the balloon may sense different physiology than device 1000 for potentially differentiated diagnoses.
  • the balloon may indicate more sensitively how quickly the patient could decompensate because total tissue pressure could estimate the turgor of the interstitial space. If the interstitial space is more turgid (less compliant), small changes in hemodynamic pressures could case the patient to decompensate quickly, simply because the interstitial space can no longer serve as a pressure relief system for an overloaded hemodynamic system.
  • the balloon 1052 may be composed of a polymer that is either compliant or noncompliant.
  • the balloon 1052 may have a volume that occupies no more than about 20-60% of the interior cavity of the perforated capsule 1004 which may allow capillaries and tissues to grow in sufficient quantity to allow sensing.
  • the balloon 1052 may be only partially filled with gas or fluid or gel as previously noted to allow for expansion and contraction as pressure changes, particularly if a noncompliant balloon is used.
  • the balloon 1052 may be filled to its zero pressure volume. This is defined as the "nominal" volume of the balloon and may render the balloon incompressible while providing a 1 :1 pressure transduction system.
  • an interior surface of the cavity of the perforated capsule 1004 may include the previously described filter membrane which may help prevent tissue from growing against and constraining the balloon 1052.
  • no filter membrane may be present, allowing the interstitial tissue to grow into the cavity and around the balloon 1052.
  • Figs. 45 and 46 illustrate views of an insertion tool 1060 that may be used to insert any of the implantable devices, such as devices 1000, 1050, within or under the skin of a patient.
  • the insertion tool 1060 includes a body portion 1062 that includes a handle portion 1062A, a location or slot 1062C in the handle portion 1062A sized for placement of a device 1000, 1050, and a bayonet portion 1062.
  • An elongated plunger 1064 is positioned through an aperture in the handle portion 1062A so that it can slide into the slot 1062C. When the device 1000, 1050 is located within the slot 1062C, sliding the plunger 1064 towards the handle portion 1062 pushes the device 1000, 1050 out of the slot and across the bayonet portion 1062.
  • a physician may make an incision into a patient’s skin at the desired implantation location.
  • the bayonet portion 1062 is inserted into the incision and may be alternately turned over on its opposite side such that the bayonet portion 1062 helps create space within a pocket for the device 1000, 1050.
  • the plunger 1064 is moved toward the handle portion 1062A, pushing the device 1000, 1050 into the incision and under the skin of the patient.
  • the tool 1060 may be removed from the patient and the incision closed.
  • Figs. 47-50 illustrate an embodiment of an external, wearable device 1070 that is generally similar to other wearable devices described in this specification, such as device 700A or 700B.
  • the device 1070 may optionally further include one or more sensors to sense heart characteristics (e.g., heartrate, an electrocardiogram, etc.), movement of the user, sleep incline, impedance, orthostatic position, fluid pressure within the patient, atmospheric pressure, glucose, temperature, and magnetic fields.
  • the device 1070 generally includes similar components as the previously described devices 1000 and 1050 but is instead configured for placement on a user’s skin via adhesive 1074 and also includes a transcutaneous pressure measurement tube or probe 1076 that is placed within a user’s tissue layers.
  • the transcutaneous pressure measurement tube or probe 1076 may be similar to any of the previously described measurement arrangements, such as the pressure sensor 503 used with the fluid fillable needle 504, the fluid column 508 connected to the balloon 507, the pressure sensor 503 within the perforated capsule 500 with the connection 514, the electronics extension 705 with pressure sensor 702, balloon 707, sensor 802, or any other sensing arrangement described in this specification.
  • Fig. 51 illustrates one additional example of a transcutaneous pressure measurement tube or probe 1080 that may be used with the device 1070 or any other device described in this specification.
  • the transcutaneous pressure measurement tube or probe 1080 may comprise an outer needle 1082 and a balloon catheter 1084 sized and positioned to slide within a passage of the needle 1080.
  • the needle 1080 may first be inserted into a patient’s tissue and then the balloon catheter 1084 may be advanced out of a distal opening of the needle 1080.
  • a distal end of the balloon catheter 1084 may include a balloon 1086, which may then be used to measure fluid pressure within the tissue and allow interstitial pressure to be determined.
  • an interior of the balloon 1086 and a passage within the balloon catheter 1084 may be in communication with each other and with a pressure sensor within a device (e.g., device 1070).
  • a pressure sensor within a device (e.g., device 1070).
  • These interiors may contain either a gas (e.g., air) or liquid (e.g., saline) which communicates any pressure changes exerted on the balloon 1086 through the gas/liquid to the pressure sensor.
  • Fig. 52 illustrates an additional example of a transcutaneous pressure measurement tube or probe 1090 that may be used with the device 1070 or any other device described in this specification.
  • the tube or probe 1090 may include an outer probe 1092 with one or a plurality of openings 1092A that may be located on a sidewall of the probe 1092 or alternatively at the bottom end of the probe 1092.
  • An inner passage of the probe 1092 may include a wick 1094 positioned near the opening 1092A, as well as a diaphragm 1096 positioned across the passage of the probe 1092 so as to seal a distal portion of the passage with the opening 1092A from a proximal portion of the passage.
  • the probe 1092 may be inserted into tissue of a patient (e.g., may have a sharp or pointed end) such that interstitial fluid enters the one or more openings 1092A and soaks into the wick 1094. As the pressure of the interstitial fluid changes, it exerts different pressures on the diaphragm 1096. As the diaphragm moves, it communicates pressure changes to gas, liquid, or gel 1098 within the proximal portion of the passage of the probe 1092. Finally, a pressure sensor in communication with the proximal portion of the needle passage may measure pressure and thereby determine interstitial pressure (e.g., with additional data, such as atmospheric pressure).
  • additional data such as atmospheric pressure
  • Previously known Guyton capsules are typically known as a relatively small capsule having a plurality of openings or perforations into an interior cavity of the capsule. This capsule is implanted within or under the skin of a patient and allowed a period of time to “stabilize” or allow tissue growth around and at least partially into some of the openings.
  • Fig. 60 illustrates the neovasculature surrounding and entering into a traditional Guyton capsule taken via microCT scan by the inventors.
  • a pressure transducer may be located in the capsule or introduced later via needle to measure the pressure within, which is thought to represent the interstitial pressure.
  • Interstitial pressure is generally believed to be a negative pressure relative to the atmosphere and therefore once the pressure within the Guyton capsule reaches a negative value for a particular extent of time, it may be considered to reach its stabilization point and therefore the pressure readings are believed to represent a patient’s interstitial pressure.
  • Figs. 55 and 56 illustrate two sides of a prior art Guyton capsule 10 that has been removed from an animal model and cut in half at about three weeks post implantation. Tissue growth into the Guyton capsule 10 has resulted in much of the interior cavity being filled with tissue 12 and a small pocket 14 of fluid remaining.
  • Figs. 57 and 58 illustrate two sides of a similar prior art Guyton capsule 10 that has been removed from an animal model and cut in half at about six weeks post implantation. As can be seen, the tissue 12 has entirely filled the cavity of the Guyton capsule 10 such that it no longer has a pocket 14 within it and therefore is unable to allow for accurate pressure readings.
  • some of the embodiments described in this specification may allow for this fluid pocket within a capsule to be maintained for a much larger period of time.
  • some of the embodiments include a filter membrane, such as the filter membrane 1010 of device 1000, which acts as a barrier for tissue growth while allowing fluid to freely penetrate through.
  • Figures 61 and 62 illustrate a microCT scan of the example filter membrane 1010 in which neovascularization is located around the filter but has not penetrated through the filter.
  • Fig. 59 illustrates tissue scans of a traditional Guyton capsule (left) at about six weeks post implantation with the device 1000 including the filter membrane 1010 at about three months post implantation. Again, tissue has completely filled the traditional Guyton capsule while the space within the filter membrane 1010 of the device 1000 remains open and free of tissue, allowing for continued accurate pressure readings.
  • Fig. 54 illustrates pressure readings from the device 1000 in which stabilization occurs at about day 11 after implantation of the device 1000. In other words, the measured pressure becomes negative and relatively uniform, indicating accurate measurement of interstitial pressure within the patient.
  • one aspect of the present invention is to measure interstitial fluid pressure within a patient to help determine aspects or an extent of a disease state in a patient, and then treating the patient accordingly based on these measurements.
  • Figs. 63-63 illustrate charts of various experimental data taken by the inventors that demonstrate a correlation between interstitial pressure and aspects of heart failure (Figs. 63-66), focused on hemodynamic indicators of congestion.
  • Figs. 67-68 demonstrate the functional mechanism by which the capsulefilter system (e.g., device 1000) and interstitial fluid pocket and filter interact with the cardiovascular system. The relationship shown in Figs.
  • 63-66 between hemodynamic pressures and interstitial pressures demonstrates that the interstitial pressure signal has a timely, quantitative relationship with hemodynamic pressures. This relationship is useful because clinical practitioners can use this relationship to guide therapy across a host of diseases that present with congestion, particularly because hemodynamic signals are the standard of care for titrating therapies for congestion.
  • Fig. 63 illustrates data taken during a procedure in which an aortic balloon was inflated within the descending aorta of a test animal.
  • the blood pressure above the balloon and the central venous pressure of the patient became elevated.
  • the interstitial fluid pressure similarly became elevated.
  • Fig. 64 similarly shows a comparison and correlation between increased pressure in a pulmonary artery and interstitial fluid pressure.
  • Each animal was co-implanted with an implantable pulmonary artery pressure monitor and a remote interstitial pressure monitoring device.
  • the interstitial pressure monitoring devices were allowed to in-grow for fourteen days.
  • Pulmonary artery pressure elevated later than interstitial pressure in this animal model of heart failure. No significant change in either interstitial pressure or pulmonary pressure was observed in the control animals.
  • interstitial pressure could be an earlier indicator of congestion and decompensating physiology than pulmonary artery pressures, which are the standard of care. This early elevation and indication of congestion could be useful for chronic diseases that require slow fluid offloading to reach safe therapeutic effect, such as heart failure.
  • Figs. 65 and 66 illustrate the effects of ultrafiltration and fluid removal from a patient and its correlation with interstitial fluid pressure.
  • heart failure may often lead to increased fluid loads within a patient, resulting in edema and similar complications.
  • the inventors simulated such fluid loading in a patient by introducing fluid into the patient in the amount of about 10% of its body weight. Next, ultrafiltration and fluid removal were performed to return the patient to near a normal fluid loading level. As seen in both graphs in these figures, the interstitial fluid pressure tracks with measured invasive hemodynamic pressure.
  • Fig. 67 shows the simultaneous measurement of glucose in the interstitial fluid pocket of the capsule I filter device. Statistically larger concentrations of glucose were measured in the interstitial fluid pocket at 30 minutes. These concentrations were statistically lower than peak concentrations at 70 minutes.
  • the test results shown here by the inventors illustrate a clear correlation between interstitial fluid pressure levels and certain disease states (e.g., any of the diseases described in this specification).
  • the present invention includes a method of monitoring interstitial fluid pressures for characteristics of a disease state and treating the disease state. This method may further include performing additional monitoring to determine an efficacy of the disease treatment and performing further treatment procedures on the patient.

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Abstract

L'invention concerne une méthode et des dispositifs pour traiter l'état physiologique d'un patient à l'aide de mesures de pression d'un espace interstitiel d'un patient en tant qu'indicateur de thérapie requise.
PCT/US2023/069308 2022-07-06 2023-06-28 Méthodes et dispositifs pour évaluer et modifier un état physiologique via l'espace interstitiel WO2024011052A2 (fr)

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US6942633B2 (en) * 2002-03-22 2005-09-13 Twin Star Medical, Inc. System for treating tissue swelling
US7165682B1 (en) * 2003-07-16 2007-01-23 Accord Partner Limited Defect free composite membranes, method for producing said membranes and use of the same
WO2008086477A1 (fr) * 2007-01-10 2008-07-17 The Regents Of The University Of Michigan Membrane d'ultrafiltration, dispositif, organe bioartificiel et méthodes associées
US8684925B2 (en) * 2007-09-14 2014-04-01 Corventis, Inc. Injectable device for physiological monitoring
US9962084B2 (en) * 2013-06-15 2018-05-08 Purdue Research Foundation Wireless interstitial fluid pressure sensor
US10499822B2 (en) * 2014-05-09 2019-12-10 The Royal Institution For The Advancement Of Learning / Mcgill University Methods and systems relating to biological systems with embedded mems sensors
WO2018213564A1 (fr) * 2017-05-19 2018-11-22 Cardiac Pacemakers, Inc. Systèmes et procédés d'évaluation de l'état de santé d'un patient
NO20170927A1 (en) * 2017-06-07 2018-12-10 Lifecare As Interstitial fluid osmotic pressure measuring device system and method
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