Measurement of tissue properties using pressure modes

Abstract

A method of measuring tissue characteristics using a fluid line in fluid communication with subcutaneous tissue includes: applying a pressure distribution or a flow distribution to subcutaneous tissue via the fluid line, wherein the fluid line is isolated from atmospheric pressure; in response to the applied pressure distribution or the applied flow distribution, measuring a pressure value or a flow rate value over time; and calculating, using the at least one processor, at least one of: a time constant of pressure decay; fluid resistance of the tissue; permeability of tissues; mechanical compliance of the tissue; osmotic pressure of tissue interstitial fluid; capillary pressure in subcutaneous tissue; and the ionic strength of the interstitial fluid.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to European patent application number 22197737.4, filed on September 26, 2022, and entitled “Measurement of Tissue Properties Using Pressure Pattern”, the entire disclosure of which is incorporated herein by reference in its entirety. Background of the Invention Technical Field

[0004] The present disclosure relates to methods of measuring tissue properties using pressure patterns. Background Art

[0005] An advantage of a wearable medical device (e.g., an auto-injector) is that it provides treatment to a patient at a location remote from a clinical facility and / or when worn discretely under the patient's clothing. The wearable medical device can be applied to the patient's skin, and the wearable medical device can be configured to automatically deliver a dose of a pharmaceutical composition within a predetermined time period (e.g., after a delay of 27 hours) after the wearable medical device is applied to the patient's skin. After the device delivers the pharmaceutical composition to the patient, the patient can then remove and dispose of the device.

[0006] In some cases, the flow of fluid out of the device may be impeded by the medium in which the fluid is injected, which may cause pressure to build up in the fluid lines of the device. When the pressure rises above a certain threshold, the integrity of the fluid path may be compromised, resulting in leaks within the device and failure to deliver the full dose of the drug. Fluid leaks within the device may also lead to device damage and subsequent system failure, as well as potential contamination issues due to contact between the fluid and the device.

[0007] Human subcutaneous tissue is composed of various cell types, extracellular matrix (ECM) components, microstructures, and macroscopic arrangements of cells and ECM. These elements contribute to the mechanical properties of the tissue. The tissue may also include a lymphatic system, blood vessels, and have inherent fluid absorption and retention properties. These characteristics vary from individual to individual, from location in the body, and over time, these characteristics may create varying degrees of resistance to fluid infusion at the injection site. When the fluid resistance of the tissue is too high or the absorption rate is too low for a given delivery flow rate from the device, pressure may accumulate and reach a value above the threshold, in which case fluid lines and other components may be damaged. Summary of the invention

[0008] In one aspect or embodiment, a method for measuring tissue properties using a fluid line in fluid communication with subcutaneous tissue includes: applying a pressure profile or flow profile to the subcutaneous tissue via the fluid line, wherein the fluid line is isolated from atmospheric pressure; measuring pressure values ​​or flow rate values ​​over time in response to the applied pressure profile or the applied flow profile; and using at least one processor to calculate at least one of the following: a time constant for negative pressure to decay back to tissue resting pressure; a time constant for positive pressure to decay back to tissue resting pressure; fluid resistance of the tissue; permeability of the tissue; mechanical compliance of the tissue; osmotic pressure of interstitial fluid of the tissue; capillary pressure in the subcutaneous tissue; and ionic strength of the interstitial fluid. A negative pressure profile is applied to the subcutaneous tissue, and the negative pressure profile is below atmospheric pressure.

[0009] The tissue resting pressure may be about atmospheric pressure. The tissue resting pressure may be positive relative to atmospheric pressure, with a pressure difference of 0 Pa to 500 Pa. The tissue resting pressure may be negative relative to atmospheric pressure, with a pressure difference of 0 Pa to 500 Pa.

[0010] A negative pressure distribution can be applied to the subcutaneous tissue, wherein the negative pressure distribution is lower than atmospheric pressure. A positive pressure distribution can be applied to the subcutaneous tissue, wherein the positive pressure distribution is higher than atmospheric pressure. The negative pressure distribution can be applied to the subcutaneous tissue by inserting a needle and a catheter into the subcutaneous tissue using an insertion mechanism and then retracting the needle from the subcutaneous tissue while maintaining fluid communication with the subcutaneous tissue, wherein the catheter is in fluid communication with a fluid line. The pressure value or flow rate value can be measured using a pressure sensor that measures the pressure in the fluid line. The pressure distribution or flow rate distribution can be applied by pumping a fluid through a fluid line. The method can also include delivering fluid to the subcutaneous tissue at a predetermined flow rate based on the calculated permeability of the tissue.

[0011] In another aspect or embodiment, a drug delivery device includes: a power source; a reservoir configured to contain a fluid; a fluid line connected to the reservoir fluid; a pump configured to deliver fluid from the reservoir to the fluid line; and a microcontroller including at least one processor, the at least one processor being programmed or configured to cause the device to: apply a pressure distribution or a flow distribution to subcutaneous tissue via the fluid line, the fluid line being isolated from atmospheric pressure; measure pressure values ​​or flow rate values ​​over time in response to the applied pressure distribution or the applied flow distribution; and calculate at least one of the following: a time constant for a negative pressure to decay back to a tissue resting pressure; a time constant for a positive pressure to decay back to a tissue resting pressure; fluid resistance of the tissue; permeability of the tissue; mechanical compliance of the tissue; osmotic pressure of interstitial fluid of the tissue; capillary pressure in the subcutaneous tissue; and ionic strength of the interstitial fluid. The drug delivery device may further include an insertion mechanism comprising a catheter and a needle, wherein the microcontroller is configured to apply a negative pressure distribution to the subcutaneous tissue by inserting the needle and the catheter into the subcutaneous tissue using the insertion mechanism and then retracting the needle from the subcutaneous tissue while maintaining fluid communication between the catheter and the subcutaneous tissue, and wherein the catheter is fluidly connected to the fluid line.

[0012] The device may also include an insertion mechanism including a catheter and a needle, wherein the microcontroller is configured to apply a negative pressure distribution to the subcutaneous tissue by inserting the needle and catheter into the subcutaneous tissue using the insertion mechanism and then retracting the needle from the subcutaneous tissue while maintaining fluid communication between the catheter and the subcutaneous tissue. The catheter is in fluid communication with the fluid line. The device may also include a pressure sensor, wherein the pressure value or flow rate value is measured using a pressure sensor that measures the pressure in the fluid line. The microcontroller may be configured to apply a pressure distribution or a flow distribution by pumping the fluid through the fluid line using a pump. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The above and other features and advantages of the present disclosure and the manner of achieving them will become more apparent, and the present disclosure itself will be better understood by referring to the following description of the embodiments of the present disclosure in conjunction with the accompanying drawings.

[0014] Figure 1 It is a perspective view of a drug delivery device according to one aspect or embodiment of the present application.

[0015] Figure 2 for Figure 1 A perspective view of a drug delivery device with the top cover removed.

[0016] Figure 3 for Figure 1 Schematic diagram of a drug delivery device.

[0017] Figure 4 The present invention is a flowchart of a method for measuring tissue characteristics according to one aspect or embodiment of the present application.

[0018] Corresponding reference numerals indicate corresponding parts throughout the several views.The exemplifications set out herein illustrate exemplary embodiments of the disclosure, and these exemplifications should not be construed as limiting the scope of the disclosure in any way. DETAILED DESCRIPTION

[0019] Spatial or directional terms such as "left," "right," "inner," "outer," "upper," and "lower" should not be considered limiting as the invention can assume various alternative orientations.

[0020] All numbers used in the specification and claims are to be understood as being modified in all cases by the term "about". "About" means a range of plus or minus ten percent of the stated value. As used in the specification and claims, the singular forms "a", "an", and "the" include plural references unless the context clearly indicates otherwise. The terms "first", "second", etc. are not intended to refer to any particular order or sequence, but rather to different conditions, characteristics, or elements. "At least" means "greater than or equal to".

[0021] As used herein, "at least one of" is synonymous with "one or more of." For example, the phrase "at least one of A, B, and C" refers to any one of A, B, or C, or any combination of any two or more of A, B, or C. For example, "at least one of A, B, and C" includes one or more A alone; or one or more B alone; or one or more C alone; or one or more A and one or more B; or one or more A and one or more C; or one or more B and one or more C; or one or more A, B, and C.

[0022] refer to Figures 1 to 3 , the drug delivery device 10 includes a reservoir 12, a power source 14, an insertion mechanism 16, control electronics 18, a cover 20, and a base 22. In one aspect or embodiment, the drug delivery device 10 is a wearable automatic injector, such as an insulin or bone marrow stimulant delivery device. The drug delivery device 10 can be mounted on the patient's skin and triggered to inject the drug composition from the reservoir 12 into the patient's body. The drug delivery device 10 can be pre-filled with the drug composition, or the drug delivery device 10 can be filled with the drug composition by the patient or a medical professional before being used.

[0023] The drug delivery device 10 is configured to deliver a dose of a drug composition (e.g., any desired medicament) to a patient via subcutaneous injection at a slow, controlled injection rate. An exemplary duration of delivery achieved by the drug delivery device 10 may be in the range of about 5 minutes to about 60 minutes, but is not limited to this exemplary range. An exemplary volume of the drug composition delivered by the drug delivery device 10 may be in the range of about 0.1 milliliters to about 10 milliliters, but is not limited to this exemplary range. The volume of the drug composition delivered to the patient may be adjusted.

[0024] Reference again Figures 1 to 3 In one aspect or embodiment, the power source 14 is a direct current (DC) power source that includes one or more batteries. The control electronics 18 includes a microcontroller 24 that controls actuation of the drug delivery device 10, a sensing electronics 26, a pump and valve controller 28, a sensing electronics 30, and a deployment electronics 32. The drug delivery device 10 includes a fluid subsystem that includes a reservoir 12, a volume sensor 34 for the reservoir 12, a reservoir fill port 36, and a metering system 38 that includes a pump and valve actuator 40 and a pump and valve mechanism 42. The fluid subsystem may also include an occlusion sensor 44, a deployment actuator 46, a cannula 48 for insertion into the patient's skin, and a fluid line 50 in fluid communication with the reservoir 12 and the cannula 48. The cannula 48 may include a needle and / or a catheter. In one aspect or embodiment, the insertion mechanism 16 is configured to move the cannula 48 from a retracted position that is completely within the device 10 to an extended position in which the cannula 48 extends outside the device 10. The drug delivery device 10 may be operated in the same manner as discussed in US Pat. No. 10,449,292 to Pizzochero et al.

[0025] refer to Figure 4In one aspect or embodiment, a method 100 for measuring tissue properties using a fluid line 50 connected to a subcutaneous tissue fluid includes: applying a pressure distribution or a flow distribution 102 to the subcutaneous tissue via the fluid line 50, wherein the fluid line 50 is isolated from atmospheric pressure; measuring a pressure value or a flow rate value over time 104 in response to the applied pressure distribution or the applied flow distribution; and calculating 106 using at least one processor at least one of the following: a time constant for a negative pressure to decay back to atmospheric pressure; a time constant for a positive pressure to decay back to atmospheric pressure; fluid resistance of the tissue; permeability of the tissue; mechanical compliance of the tissue; osmotic pressure of interstitial fluid of the tissue; capillary pressure in the subcutaneous tissue; and ionic strength of the interstitial fluid. In one aspect or embodiment, one or more of the above-mentioned multiple characteristics are calculated using at least one of the following: the amplitude of the pressure peak (negative or positive); the initial slope of the decay obtained by linear interpolation of any combination of two or more consecutive pressure measurements; a curve fit of a first-order exponential decay equation Y=A*(x^-t / tau)+B, where A can be positive or negative; and a curve fit of a higher-order or lower-order exponential decay equation Y=A*(x^-t / tau)^Z+B, where Z can be between 0 and infinity.

[0026] In one aspect or embodiment, the method 100 is performed using the drug delivery device 10 discussed above, but the method 100 can be performed using other suitable devices and arrangements. For example, the method 100 can be performed using an infusion pump system or device instead of a wearable drug delivery device.

[0027] In one aspect or embodiment, a negative pressure profile is applied to the subcutaneous tissue, wherein the negative pressure profile is below atmospheric pressure. The negative pressure profile can be applied to the subcutaneous tissue by inserting a needle and a catheter (cannula 48) into the subcutaneous tissue using the insertion mechanism 16 and then retracting the needle from the subcutaneous tissue while maintaining fluid communication between the catheter and the subcutaneous tissue. The catheter is in fluid communication with a fluid line 50.

[0028] In one aspect or embodiment, a positive pressure distribution is applied to the subcutaneous tissue, wherein the positive pressure distribution is higher than atmospheric pressure. In one aspect or embodiment, the tissue rest pressure is about atmospheric pressure. In one aspect or embodiment, the tissue rest pressure is positive relative to atmospheric pressure, and the pressure difference is 0Pa to 500Pa. In one aspect or embodiment, the tissue rest pressure is negative relative to atmospheric pressure, and the pressure difference is 0Pa to 500Pa.

[0029] The pressure value or flow rate value is measured using a pressure sensor that measures the pressure within the fluid line 50. The pressure sensor can be the occlusion sensor 44 or form a part of the occlusion sensor 44. In some aspects or embodiments, the pressure profile or flow profile is applied by pumping the fluid through the fluid line 50. The method can also include: delivering the fluid to the subcutaneous tissue at a predetermined flow rate based on the calculated permeability of the tissue. In other words, the injection or infusion profile can be adjusted based on the measured tissue properties to optimize the kinetics of drug absorption.

[0030] In one aspect or embodiment, the microcontroller 24 of the drug delivery device 10 includes at least one processor that is programmed or configured to cause the device to: apply a pressure distribution or a flow distribution to the subcutaneous tissue via the fluid line 50; measure pressure values ​​or flow rate values ​​over time in response to the applied pressure distribution or the applied flow distribution; and calculate at least one of the following: the time constant for the negative pressure to decay back to atmospheric pressure; the time constant for the positive pressure to decay back to atmospheric pressure; the fluid resistance of the tissue; the permeability of the tissue; the mechanical compliance of the tissue; the osmotic pressure of the interstitial fluid of the tissue; the capillary pressure in the subcutaneous tissue; and the ionic strength of the interstitial fluid.

[0031] In one aspect or embodiment, the microcontroller 24 is configured to apply a negative pressure profile to the subcutaneous tissue by inserting a needle and catheter (cannula 48) into the subcutaneous tissue using the insertion mechanism 16 and then retracting the needle from the subcutaneous tissue while maintaining fluid communication between the catheter and the subcutaneous tissue. The microcontroller 24 is configured to apply a pressure profile or a flow profile by pumping fluid through the fluid line 50 using a pump (e.g., the metering system 38).

[0032] Therefore, method 100 and / or drug delivery device 10 can measure tissue properties by analyzing pressure patterns (e.g., attenuation after a positive step or negative step of pressure applied in fluid line 50). Subcutaneous tissue is a medium that includes a variety of cell types arranged in various structures, as well as extracellular matrix and interstitial fluid. Different cell structures may include glomeruli, nerves, capillaries and blood vessels, lymphatic capillaries and blood vessels, and connective tissue. The permeability of the target site of subcutaneous tissue may vary greatly depending on the location and the patient. In some cases, the tissue may have a very low permeability, thereby affecting the delivery of fluid to the tissue and the absorption kinetics of the administered drug. In other cases, the tissue may show an abnormally high permeability, which may affect the absorption of the drug, resulting in faster absorption than that required for optimal treatment. Injection in tissues with low permeability may require adjustment of the flow rate to avoid high pressure that may cause leakage in the device 10. Tissues with very low permeability may cause drug release to be too slow, while tissues with very high permeability may cause drug release to be too fast. The ability to measure tissue permeability before, early in the course of, and / or during an injection allows for identification of injection sites that may affect the absorption and subsequent pharmacokinetics of the drug being delivered. In particular, the ability to detect problematic injection sites (e.g., sites with low permeability that may cause an occlusion alarm to be triggered during delivery) at or shortly after placement of the device provides advantages in improving patient safety by avoiding delayed notifications. The method 100 and drug delivery device 10 address these issues by providing a method for measuring tissue properties and, if necessary, adjusting the drug delivery profile to the patient.

[0033] Although the present invention has been described in detail based on what is currently considered to be the most practical and preferred embodiments for the purpose of illustration, it should be understood that such detail is only for this purpose and that the present invention is not limited to the disclosed embodiments, but on the contrary, the present invention is intended to cover modifications and equivalent arrangements within the spirit and scope of the appended claims. For example, it should be understood that the present invention contemplates that, to the extent possible, one or more features of any embodiment may be combined with one or more features of any other embodiment.

Claims

1. A method for measuring a tissue property using a fluid line in fluid communication with subcutaneous tissue, the method comprising: applying a pressure profile or a flow profile to the subcutaneous tissue via the fluid line, the fluid line being isolated from atmospheric pressure; measuring pressure values ​​or flow rate values ​​over time in response to the applied pressure profile or the applied flow profile; and Use at least one processor to calculate at least one of the following: a time constant for a negative pressure to decay back to a tissue resting pressure; a time constant for a positive pressure to decay back to a tissue resting pressure; fluid resistance of the tissue; permeability of the tissue; mechanical compliance of the tissue; osmotic pressure of interstitial fluid of the tissue; capillary pressure in subcutaneous tissue; and ionic strength of the interstitial fluid, wherein a negative pressure distribution is applied to the subcutaneous tissue, and the negative pressure distribution is less than atmospheric pressure.

2. The method according to claim 1, wherein: The tissue resting pressure is approximately atmospheric pressure.

3. The method according to claim 1, wherein: The tissue resting pressure is positive relative to the atmospheric pressure, and the pressure difference is 0Pa to 500Pa.

4. The method according to claim 1, wherein: The tissue static pressure is negative relative to the atmospheric pressure, and the pressure difference is 0Pa to 500Pa.

5. The method according to claim 1, wherein: The negative pressure profile is applied to the subcutaneous tissue by inserting a needle and a catheter into the subcutaneous tissue using an insertion mechanism and then retracting the needle from the subcutaneous tissue while maintaining fluid communication between the catheter and the subcutaneous tissue, and wherein the catheter is in fluid communication with the fluid line.

6. The method according to any one of claims 1 to 5, wherein: The pressure value or the flow rate value is measured using a pressure sensor that measures the pressure in the fluid line.

7. The method according to any one of claims 1 to 6, wherein: The pressure profile or the flow profile is applied by pumping a fluid through the fluid line.

8. The method according to any one of claims 1 to 7, further comprising: Fluid is delivered to the subcutaneous tissue at a predetermined flow rate based on the calculated permeability of the tissue.

9. A drug delivery device, comprising: power supply; a reservoir configured to contain a fluid; a fluid line in fluid communication with the reservoir; a pump configured to deliver the fluid from the reservoir to the fluid line; A microcontroller comprising at least one processor programmed or configured to cause the device to: applying a pressure profile or a flow profile to the subcutaneous tissue via the fluid line, the fluid line being isolated from atmospheric pressure; measuring pressure values ​​or flow rate values ​​over time in response to the applied pressure profile or the applied flow profile; and calculating at least one of the following: a time constant for the decay of negative pressure back to tissue resting pressure; a time constant for the decay of positive pressure back to tissue resting pressure; fluid resistance of tissue; permeability of tissue; mechanical compliance of tissue; osmotic pressure of interstitial fluid of tissue; capillary pressure in subcutaneous tissue; and ionic strength of interstitial fluid; as well as an insertion mechanism, the insertion mechanism comprising a catheter and a needle, wherein the microcontroller is configured to apply negative pressure distribution to the subcutaneous tissue by inserting the needle and the catheter into the subcutaneous tissue using the insertion mechanism and then retracting the needle from the subcutaneous tissue while maintaining fluid communication between the catheter and the subcutaneous tissue, and wherein the catheter is fluidically connected to the fluid line.

10. The apparatus according to claim 9, further comprising: A pressure sensor, wherein the pressure value or the flow rate value is measured using the pressure sensor that measures the pressure in the fluid line.

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