Wireless and non-invasive epidermal electronics

Abstract

Conformable devices and related methods for measuring subcutaneous fluid flow are provided. A soft, stretchable and flexible substrate supports a thermal actuator and various specially positioned temperature sensors. A microprocessor in electronic communication with the sensors calculates the subcutaneous fluid flow based on the measured upstream and downstream temperatures and various application-related parameters. The devices and methods provided herein are particularly suitable for measuring cerebrospinal fluid in a ventricular shunt placed to treat hydrocephalus.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 650,826, filed on March 30, 2018, and U.S. Provisional Patent Application No. 62 / 791,390, filed on January 11, 2019, each of which is expressly incorporated by reference in its entirety to the extent consistent with this application.

[0003] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0004] not applicable. Background Art

[0005] Hydrocephalus and shunt-related expenses cost the U.S. system more than $2 billion per year, with 125,000 shunt surgeries performed annually and an estimated 50-60% mortality rate without treatment. Existing diagnostics are expensive, inaccurate, and often harmful or invasive and may result in unnecessary hospital admissions, further testing, or unwanted surgery. To address these issues, a noninvasive thermal biosensor capable of diagnosing ventricular shunt malfunction is provided.

[0006] Hydrocephalus is a common and expensive condition caused by the accumulation of cerebrospinal fluid in the brain. In the United States, hydrocephalus occurs in 1-5 cases per 1000 live births, and more than 70,000 patients are admitted and diagnosed each year. Cerebrospinal fluid (CSF) is produced in the ventricles of the brain and is responsible for its nutrition and protection, but dysfunction of its drainage or reabsorption may cause devastating neurological complications. Symptoms may include headache, lethargy, seizures, coma or death, and the mortality rate of untreated hydrocephalus is estimated to be 50-60%. Hydrocephalus in children accounts for 38% of patients, and related surgery is the most common neurosurgery performed in children. Adult hydrocephalus can be regarded as a sequela of many conditions (such as tumors, trauma and infection) or is seen in normal pressure hydrocephalus (NPH), which is a condition with an increasing number of confirmed cases currently affecting 375,000 patients in the United States. Dementia is often underdiagnosed or misdiagnosed, and 25% of those diagnosed receive a shunt, representing a growing segment of care associated with hydrocephalus. The mainstay of treatment for hydrocephalus involves the diversion of CSF using a device called a ventricular shunt. These surgically implanted devices consist of a cannula that drains from the ventricles to a distant site such as the peritoneum, pleural cavity, or right atrium of the heart and is regulated by a valve. Unfortunately, shunt failure rates are extremely high; most children undergo 2-3 surgical revisions before adulthood, and an estimated 30% undergo at least 1 revision surgery in the first year, with rates approaching 98% by year 10 in some studies.

[0007] The need for shunt monitoring has been addressed using an ice pack-based thermal cooling system connected to a Windows PC DAQ. However, the technique is cumbersome and time consuming. The cumbersome multi-step method of the device, unclear or negative previous clinical studies, and the need for ice pack cooling have limited its acceptance. In addition, patient discomfort due to long-term skin cooling (which is detrimental to pediatric diagnosis) and lack of long-term monitoring further limit its diagnostic relevance. Therefore, there is a need for a wireless, non-invasive shunt diagnostic device that can conform to the skin and has epidermal-like mechanical properties. Summary of the invention

[0008] The device presented herein provides a platform for measuring flow in subcutaneous catheters and is advantageously non-invasive and rapid while maintaining a high level of accuracy. The device can be conformable to the skin and is wireless, without the need for hard-wired connections to bulky external components such as controllers, digital monitors, and power supplies). In this way, the device is painless and unobtrusive to the patient, similar to wearing an adhesive bandage.

[0009] One particular application of any of the devices and methods described herein is the detection of shunt failures, particularly ventricular shunts. Long-term use can capture hidden failures, similar to a holter monitor for cerebrospinal fluid.

[0010] Provided herein is a soft, wireless, non-invasive, non-surgical skin-mounted device for continuous measurement of fluid flow in a subcutaneous catheter, such as shunt-based CSF flow. The epidermal device utilizes precise measurements of thermal transport to characterize CSF flow in an underlying shunt. The device platform is ultrathin (<100 μm), soft (70 kPa), and flexible, making the device mechanically invisible to the wearer and continuously wearable. The size is similar to The device is composed primarily of a soft silicone rubber (no hard edges) for an adhesive bandage and transmits recorded data wirelessly via Bluetooth to a companion mobile application. Patient data and in vitro testing confirmed the efficacy of the device in generating clinical quality data suitable for shunt fault diagnosis. To aid in handling durability and device placement, a carrier substrate can be provided around the active sensor area where close conformal contact is desired, the carrier substrate having an open channel through a central portion of the carrier substrate. The carrier substrate can have relatively larger mechanical parameters than the substrate supporting the sensor, such as being less flexible, elastic, and / or soft, so that the device can be handled in a manner similar to an adhesive bandage (e.g., without tearing during application and use), but without sacrificing conformability and patient comfort.

[0011] The devices and methods described herein provide a basic platform for measuring flow in a wide range of artificial and natural flow conduits. Examples include, but are not limited to, catheters, stents, and blood vessels.

[0012] The claims appended hereto are expressly incorporated herein by reference and form a part of this application.

[0013] Provided herein are various conformable devices for measuring subcutaneous fluid flow reliably, accurately and continuously, including subcutaneous fluid flow in a catheter. Various active ingredients are supported by a substrate, such as a substrate characterized by softness, stretchability and flexibility. A thermal actuator, an upstream temperature sensor and a downstream temperature sensor are supported by the substrate. A microprocessor communicates electronically with the temperature sensor and other related components such as an actuator to calculate the subcutaneous fluid flow based on the measured upstream and downstream temperatures. This configuration maximizes patient comfort during use, thereby facilitating long-term monitoring of fluid flow. Any device can be wireless, thereby further facilitating low patient impact monitoring, including without hard-wired connections. In this way, the patient can even go home without adversely affecting monitoring.

[0014] To further improve the accuracy and reliability of fluid flow measurements, any of the devices described herein may have additional temperature sensors. The positioning of these sensors may be described relative to a conceptual line (e.g., an imaginary line) formed by drawing lines over spatially aligned upstream sensors, actuators, and downstream sensors. The additional sensors serve as reference sensors and aid in determining various skin properties and related convective properties, for example, which may be used to determine fluid flow rate and flow-independent actuator effects. Preferably, at least one sensor is positioned so that a temperature reading is obtained that is independent of whether the thermal actuator is actuated.

[0015] Also provided is a method for determining fluid flow in a subcutaneous catheter by any of the devices described herein. For example, the device is conformably mounted to the skin covering the subcutaneous catheter. A thermal actuator is actuated to heat the underlying skin and subcutaneous catheter. The temperature upstream and downstream of the thermal actuator is measured, wherein the sensor measuring the temperature is spatially aligned with the catheter. A microprocessor processes the measured temperature to determine the flow rate in the subcutaneous catheter. The determined flow rate is transmitted to a display on a handheld device or a computer. Preferably, the method is wireless, and the data generated from the conformable device is wirelessly provided to the handheld device or computer for real-time monitoring.

[0016] Further, resistive heating thermal actuators utilizing arrays of resistor assemblies are described herein, which provide heating when an electric current or potential is applied. These thermal actuators can utilize various resistors known in the art, which are arranged in arrays (e.g., circular, square, linear) in some cases to accurately provide thermal energy, thereby allowing various measurements provided herein.

[0017] In addition, various methods for improving the signal-to-noise ratio of thermal measurements are provided. For example, additional layers that partially or completely encapsulate and insulate various components can enhance the ability to isolate the thermal energy provided by various actuation devices and improve the accuracy and reliability of sensing. Conductive layers can also be provided to improve the efficacy of thermal actuation and thermal sensing by providing conduits for directing thermal energy to the skin or receiving thermal energy from the skin. Various discontinuous thermally conductive layers can further improve the signal-to-noise ratio of various measurements, including thermal sensing.

[0018] Non-electronic methods for thermal sensing are also described herein. For example, instead of electronic thermal sensors, optical measurements made by thermal imaging systems or thermochromic dyes can be used to determine tissue properties or parameters, including subcutaneous fluid flow.

[0019] Without wishing to be bound by any particular theory, there may be a discussion herein of the beliefs or understandings of the underlying principles associated with the devices and methods disclosed herein. It should be recognized that regardless of the ultimate correctness of any mechanical explanation or hypothesis, embodiments of the invention may still be operable and useful. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figures 1A-1E .A soft, skin-mounted wearable device for noninvasive, continuous or intermittent measurement of flow through a cerebrospinal shunt to assess shunt function. Figure 1A .100 - Exploded view illustration of a sensor device incorporating a central thermal actuator placed above the skin with an underlying shunt cannula ("catheter"). PI = Polyimide. Figure 1B An optical micrograph of the device showing the sensor, which contains multiple individual resistive sensors arranged in an array, and the central thermal actuator. A close-up showing the stretchable serpentine interconnects used to facilitate conformability and individual resistive temperature sensors. Figure 1C Infrared (IR) temperature logger showing addressing of individual sensors (left) and the power from actuation at 1.8 mW / mm 2 Thermal actuation of the center heater. Figure 1D .Optical images of the device on the neck, above the diverter location, in different deformation modes. Figure 1E IR temperature logger with color and contrast enhancement, showing thermal isotropy in the absence of flow (top) and anisotropy in the presence of flow (bottom), with the flow heading toward the right of the page.

[0021] Figure 2A-2E .Flow visualization and measurements from the ESA (Epidermal Square Array). Figure 2A .100 Spatially accurate schematic diagram of the sensor arrangement showing the pipe positioning coverage and upstream (Tu ) and downstream (T d )temperature. Figure 2B .like Figure 2A The color coding shows the baseline-subtracted temperature differences of the four sensor pairs. Figure 2C .Selected T u Biplot of principal component analysis (PCA) of baseline-subtracted differences between sensors (two sensors, each indicated in a subplot) and each Td sensor (PCA 1 and 2). Clustering occurs in the following cases: no flow and no actuation; at 1.8 mW / mm 2 No flow when actuated; at 1.8mW mm -2 The actuation was carried out at 0.02 mL min -1 flow under 1.8mW / mm 2 Actuation at 2 mL min -1 Flow under the . Vectors correspond to selected Td sensors that are positively (red) and negatively (blue) correlated with the flow. Figure 2D .The flow chart details the process of converting raw ESA sensor data into spatially accurate temperature maps. Figure 2E . In the absence (left) of flow and in the presence (right) of 1.8mW / mm 2 Actuation 0.02mL min -1 Temperature recorder from IR imaging (top) and ESA-generated temperature map (bottom) in the case of flow (flow from right to left).

[0022] Figures 3A-3L .System characterization of the effects of geometry, thermal properties, and flow rate. Figure 3A Optical image of the epidermal linear array (ELA), an illustration overlaid with a diagram of cannulation and blood vessels (top), and a schematic illustration of the benchtop system showing key features including a skin phantom, blood flow (Q 血液 ), CSF flow (Q 流 ) and skin thickness (h 皮肤 )'s thermal properties. Figure 3B .In Q 流 4 values ​​of 0mL min -1 (No shaded area), 0.05ml min -1 (blue shaded area), 0.1 mL min -1 (grey shaded area) and 0.5 ml min -1 Raw transient temperature data after heating of the actuator (blue curve), downstream sensor (black curve), and upstream sensor (red curve) (red shaded area). Figure 3C .0.01ml min -1T values ​​of the upstream (red) and downstream (black) sensors for flow rates ranging from 0.1 mL / min to 0.1 mL / min 传感器 / T 致动器 . Figure 3D For h 皮肤 The three anatomically relevant values ​​of 1.1 mm (black curve), 1.7 mm (red curve) and 2.1 mm (blue curve) in Q 流 The range of ΔT was 0.01 ml min to 0.1 ml min 传感器 / T 致动器 =(T 下游 -T 上游 ) / T 致动器 . Figure 3E .Targeted at Figure 3D Same Q 流 and h 皮肤 value, Figure 3F . The sampling frequency of 5 Hz is 5 Hz within a sampling window of 60 seconds for Q 流 =0.1mLminMeasured signal (ΔT 传感器 / T 致动器 ) to the noise (standard deviation σ), as h 皮肤 Function of normalized actuator power for three different values ​​of 1.1 mm (black curve), 1.7 mm (red curve) and 2.1 mm (blue curve). Figure 3G and 3E .For h 皮肤 Two values ​​of 1.1 mm (black curve) and 2.1 mm (blue curve) measured in the presence of phantom blood flowing through adjacent tubes in co-current (+x) and counter-current (-x) configurations (ΔT 传感器 / T 致动器 )( Figure 3G ) and (T 下游 +T 上游 ) / 2T 致动器 ( Figure 3E ). Figure 3H is a plot of the ratio of sensor to actuator temperature as a function of blood flow. Fig. 3I Two different skin phantoms Sylgard 184 (black curve) and Sylgard 170 (grey curve) for simulating and measuring skin thermal properties at Q 流 = 0 as a function of time T 致动器 Experimental data (solid line) and analytical fit (dashed line). Figures 3J-3K .Measured for two skin phantom materials (ΔT 传感器 / T 致动器 )( Figure 3J ) and (T 下游+T 上游 ) / 2T 致动器 ( Figure 3K ). Figure 3L h 皮肤 (1.1, 1.7, 2.1 and 6.0 mm at four flow rates) and Q 流 ΔT of 0 ml / min (black curve), 0.05 ml / min (red curve), 0.1 ml / min (blue curve) and 0.5 ml / min (purple curve) 传感器 / T 致动器 In vitro experimental measurements.

[0023] Figures 4A-4H .A wireless device including Bluetooth for communicating with a portable device. Figure 4B is an image of a fully assembled integrated wireless ELA showing the soft conformable sensing / actuating components, the flexible PCB (Cu / PI / Cu), and the surface mounted electronics, including the battery and wireless communication components. PDMS, polydimethylsiloxane. Figure 4C is an image of the device bent, showing flexibility. Figure 4D is an image of a device mounted on the skin using a medical grade acrylate-based pressure sensitive adhesive. Figure 4E .Raw sensor readings in measurement bits from the 8-bit ADC during actuation and flow. Figure 4F IR-measured temperature rise due to 3.6-mW actuation on the phantom shunt assembly. Figure 4G Calibration curve used to measure the raw 8-bit, 3-V ADC value (left) and the associated voltage (right) versus temperature through calibration. Figure 4H T acquired wirelessly as a function of time for two different flows Q = 0.05 mL / min and Q = 0.13 mL / min 上游 and T 下游 All data were collected on a skin phantom.

[0024] Figures 5A-5J .Patient trials. Figure 5A . Exploded view illustration of an ELA used in a hospital setting, the ELA having an elastomeric treated frame and adhesive. Figure 5B Illustration (left) and image (right) of shunt-on and shunt-off ELA positioning on a patient and a representative Doppler ultrasound image of the catheter under the skin at the shunt-on site (inset). Figure 5C IR images with shunt on (top) and shunt off (bottom) indicating the total local temperature rise due to the actuator and the characteristic teardrop-shaped thermal distribution caused by the presence of flow. Figure 5D .Representative transient T at shunt open position致动器 Measurements and transient plane source (TPS) curve fitting were used to generate skin thermal properties. Figure 5E-5F .k for each patient 皮肤 ( Figure 5E ) and α 皮肤 ( Fig. 5F ) is the calculated value of . Figure 5G-5H . No anisotropic shunt disconnection position ( Figure 5G ) and the shunt switch position with significant anisotropy ( Figure 5H )'s representative T 致动器 (blue curve), T 上游 (black curve) and T 下游 (red curve). Fig.5I .ΔT measured for each patient in the shunt-off position and the shunt-on position 传感器 / T 致动器 , where error bars represent SD across 100-sample windows. Figure 5J is the ΔT of the clinically or surgically confirmed flow pair n = 5 patients in the shunt-off position and the shunt-on position 传感器 / ΔT 致动器 Plot of the calculated means of , where the error bars represent SD. Statistical analysis was performed using paired t-tests (n=5) for confirmed flow in the shunt-on position and the shunt-off position. Individual patient-level data are summarized as patient # (ΔT at shunt on) 传感器 / T 致动器 and ΔT when the shunt is disconnected 传感器 / T 致动器 : Patient 1 (0.209339 and 0.00205); Patient 2 (0.0518 and 0.0084); Patient 3 (0.09503 and -0.00597); Patient 4 (0.100991 and 0.0061); Patient 5 (0.1392 and 0.000963).

[0025] Figures 6A-6D .Case study of a patient with shunt malfunction. Fig. 6A .X-ray and radionuclide tracer showing kinking and occlusion of the catheter. Figure 6B .Optical image of the patient's peritoneal cavity immediately after surgery, showing flow in the repaired shunt. Figure 6C .X-ray and radionuclide tracing confirmed that the repaired shunt worked. Fig.6D .ΔT measured by ELA before and after renovation at locations above the shunt (on) and adjacent to the shunt (off) 传感器 / T 致动器 , confirming the results from X-rays and radionuclide tracers before and after the renovation.

[0026] Figures 7A-7D .Calculation of flow rate. Fig. 7A .For ΔT 传感器 / T 致动器 A series of FEA calculated curves for different skin thicknesses are overlaid with the in vivo measured data from each patient. Figure 7B .For different skin thickness Calculation curve of . Figure 7C By iteratively The calculated flow rates are solved, where the error bars represent the average difference between the values ​​produced by the two curves. Fig.7D .Use the value h 皮肤 = 1.5 mm (obtained from CT imaging) and k obtained from the patient as previously shown 皮肤 =0.29W m -1 K -1 and α 皮肤 =0.091mm 2 s -1 The obtained ΔT 传感器 / ΔT 致动器 and T 传感器 / T 致动器 The FEA calculated values ​​of , which were overlaid on the experimental measurement points on the same patient, yielding a flow rate of 0.1 mL / min.

[0027] Figures 8A-8B .The current path through the resistor array. Fig. 8A .IR image (top) and ESA simulation of single sensor addressing, showing the current through the same input (row) and output (column) lines. Figure 8B .and Fig. 8A Same, but for a non-square array (16x6), showing the larger power dissipation (spoke-like) through non-addressed sensors in the same output line.

[0028] Fig. 9 .100Schematic illustration of the data acquisition and control system of the sensor array.

[0029] Fig.10 . Heat map, where each pixel corresponds to the meas The residuals (R) calculated for each element in the 10x10 array obtained by linear fitting to temperature for calibration 2 )value.

[0030] Fig.11 . Illustration of the steps used to convert measured current values ​​into a heat map, where the steps correspond to Figure 2DFlow visualization and measurements from an ESA. Top: Example of raw (resistance) ESA data. Second: Conversion of raw ESA data to calibrated temperatures via a calibration matrix specific to each ESA. Third: Temperature differences resulting from removal of isotropic heat transfer effects from the thermal actuator via baseline subtraction. Bottom: ESA temperature map obtained from the temperature difference map of the previous figure by grid bicubic interpolation.

[0031] Figures 12A-12C .Flow visualization and measurements from ESA. Fig. 12A : Spatially accurate schematic diagram of a 100 sensor arrangement showing tube positioning coverage and upstream (U) and downstream (D) temperatures. Fig. 12B : Principal component analysis (PCA) biplot of baseline-subtracted differences between selected U sensors (two sensors, each indicated in the subplot) and each D sensor (PCA 1 and 2). Clustering occurs in the following cases: no flow and no actuation; at 1.8 mW / mm 2 No flow when actuated; at 1.8mWmm -2 The actuation was carried out at 0.02 mL min -1 The flow below. Fig. 12C .Five (1-5) sensors (in Fig. 12A Figure 2. PCA biplot of the sensor data (identified in Figure 2) showing the identification of sensors aligned with the flow direction regardless of the selected sensor (red vector). When the PCA model is applied to the aligned data (used to generate the temperature map), PC1 is associated with the presence / absence of flow and PC2 corresponds to the thermal actuation state (on / off).

[0032] Figures 13A-13C .Benchtop flow system. Fig.13A .Optical image of a benchtop fluidic phantom with an embedded flow diverter. Fig. 13B . Shows the cannulation geometry and h 皮肤 Optical micrographs of cross-sectional and isometric views. Fig. 13C .Sensors laminated to the free surface of the assembly.

[0033] Fig.14 . Finite element simulations of dimensionless scaling parameters showing the temporal evolution of heat through the skin as a measure of penetration depth overlay systematic experimentally measured figures.

[0034] Fig.15 .For Q 流 =0.13 mL min -1 Three different h 皮肤 Value of ΔT 传感器 / T 致动器Experimental and simulated transient responses of , as a demonstration of an alternative method for quantifying skin thickness, the data show the time constant (τ = time required to reach 63.7% of the steady-state value) vs. h 皮肤 (Illustration) The relationship between them.

[0035] Fig.16 .In Q 流 =0.13 mL min -1 T on the Sylgard 184 skin phantom 致动器 / T 传感器 Varies with power level.

[0036] Fig.17 . Graphical representation of covered and uncovered (encapsulated) actuator measurements (left) used to generate the fitted H conv The transient rising curve of the value of (right figure).

[0037] Figures 18A-18C . Fig.18A .Graphs and experimental data show that ( Fig.18B ) rotation and ( Fig. 18C ) Translational misalignment ΔT 传感器 / T 致动器 (black curve) and (red curve) shows the influence of the measured value.

[0038] Figures 19A-19F .DC noise sources. Fig.19A .Simplified schematic diagram of the ELA data acquisition system. Fig.19B . Variation of the standard deviation with the sampling window for the resistance measured by ELA (black), the resistance measured by a commercial sensor connected by an ACF cable (blue), and the resistance measured by a commercial resistor connected by soldered leads (red). Fig.19C . Standard deviation of actuator output power versus sampling window. Fig.19D .When covered by the case (black) and uncovered (red), on a desktop system in Q 流 =0.13 mL min -1 When the measured ΔT 传感器 / T 致动器 The standard deviation of varies with the sampling window. Fig.19E . High frequency noise. Figure A. Schematic representation of the experimental system. Figure B. Fourier transform of the resistance measured at 20 kHz. Figure C. S / N calculated as the average of 5 consecutive resistance measurements divided by its standard deviation as a function of the number of samples (N) and the sampling window (time, seconds). Figure 5. Experimental data and linear fit of S / N as a function of N. Fig.19FNoise in vivo. A. Optical images showing no deformation (left) and extreme deformation of the sensor on the skin (right). BD. Temperature fluctuations on a stationary subject as a function of time (B), frequency (C) and measured as normalized power spectral density (D). EG on a subject that was moving vigorously, same as BD.

[0039] Fig. 20 .Optical image of an elastomeric adhesive with a tape frame on a wrist, demonstrating conformal contact during extreme deformation.

[0040] Figures 21A-21B . Above the shunt switch-on position with low anisotropy ( Fig.21A ) and after stimulating flow by pressing the regulating valve ( Fig.21B ) 致动器 (blue curve), T 上游 (black curve) and T 下游 (Red curve) Measurements as a function of time.

[0041] Fig. 22 T of external ventricular drainage when flow is changed by increasing the height of the reservoir bag (not shown) thereby changing the pressure differential 致动器 Measurement.

[0042] Fig.23 Representative CT images of skin thickness above the superficial cannulation site above the clavicle.

[0043] Fig.24 . Schematic illustration of relevant parameters.

[0044] Fig.25 . Flowchart summarizing flow rate determinations performed using any of the devices described herein.

[0045] Fig.26 . Illustration of the carrier and handle layer, with the device flipped over and peeled away from the rigid glass handle layer.

[0046] Fig. 27 .Skin-safe silicone adhesive wherein the active sensing portion of the device is able to maintain conformal contact with the skin, with delamination limited to the edge treatment substrate surrounding the active sensing portion.

[0047] Fig.28 Another illustration of a handle substrate having an opening in which an active sensing portion of a device may be positioned is shown.

[0048] Fig.29 . Provides an overview of the sensing platform technology, including hardware and software.

[0049] Fig.30. shows an example sensor design for a commercially available surface mount temperature sensor.

[0050] Fig.31 An example of a flexible printed circuit board (PCT) based flow sensor incorporating thermal actuation via an array of resistive elements is provided.

[0051] Fig.32 . Provides a simulation design of the circuit described in this article.

[0052] Fig.33 . The use of thermochromic dyes arranged in an array for determining subcutaneous fluid flow is demonstrated.

[0053] Fig.34 . Provides examples of thermal imaging methods and currently available inexpensive thermal imaging devices.

[0054] Fig.35 An example of in vitro testing of a surface mount device as described herein without foam insulation is provided.

[0055] Fig.36 An example of in vitro testing of a surface mount device as described herein with a foam insulation layer is provided, demonstrating the increase in signal-to-noise ratio provided by the insulation.

[0056] Fig.37 In vitro testing of surface mounted devices with foam insulation across flow rates and relevant skin thicknesses is provided, containing a discontinuous thermally conductive layer positioned proximate to the thermal actuator and sensor.

[0057] Fig.38 .Example sensors integrated with packaging and encapsulation for thermal insulation are provided.

[0058] Fig.39 . An example device is shown with packaging removed to expose and demonstrate various components as described herein.

[0059] Fig.40 . Both benchtop sensing results and on-body sensing results of the example device are provided.

[0060] Fig.41 .The ability of the sensing device to measure temperature changes when positioned over a shunt is demonstrated as an in vivo example.

[0061] Fig.42 .The use of a device with multiple sensors is demonstrated and an example circuit diagram is provided.

[0062] Fig.43 . shows the increase in rotational tolerance for a setup with 4 sensors.

[0063] Fig.44 . Demonstrates the increase in translation tolerance for a 4-sensor setup.

[0064] Fig.45 .Example hardware for wireless inductive power coupling for recharging and BLE wake-up is provided.

[0065] Fig.46 .A sample software interface is provided.

[0066] Fig.47 . A summary of clinical results is provided.

[0067] Fig.48 .Examples of clinical protocols that can be used to ensure accurate application of the devices described herein are provided.

[0068] Fig.49 .Examples of clinical checklists that may be used to ensure accurate application of the devices described herein are provided.

[0069] Fig.50 .Example schematics of devices as described herein that utilize resistor arrays to provide thermal actuation are provided.

[0070] Fig.51 Example cross-sectional schematics of devices incorporating insulating layers and discontinuous thermally conductive layers are provided.

[0071] Figures 52A-52C The effect of varying the inter-sensor distance (L) is shown. Fig.52A is a schematic illustration showing the positioning of the actuator and the upstream and downstream temperature sensors relative to the underlying conduit. Fig.52B is in h 皮肤 = 0.5mm, 1.0mm, 1.5mm, 2.0mm ΔT 传感器 / T 致动器 FEA simulation as a function of L, where the effect of 15% strain results in a change in the inter-sensor positioning uncertainty of ±0.375 mm, as shown by the rectangular bars. Fig.52C is in h 皮肤 =0.5mm, 1.0mm, 1.5mm, 2.0mm FEA simulation as a function of L, where the effect of 15% strain results in a change in the inter-sensor positioning uncertainty of ±0.375 mm, as shown by the rectangular bars.

[0072] Figures 53A-53D .Miniaturized and soft wireless flow sensor based on commercial components. Fig.53A .Schematic diagram of the breakdown of the key device layers. Fig.53B .Packaging of encapsulated devices distorts and bends the optical image. Fig.53C.Optical image of the device mounted on the patient's neck. Fig.53D .Screen shot of the software application on a tablet computer showing data readout, pairing and on-demand thermal actuation options.

[0073] Figures 54A-54F .Benchtop flow characterization using the platform. Fig.54A . Exploded schematic of the sensor and actuator, with the foam layer covering the shunt embedded in the silicone skin phantom. Fig.54B .Actuator heat dissipation power is 1.2mW / mm 2 Infrared (IR) temperature recorder. Fig.54C . Upstream (grey) and downstream (red) temperature readings after actuation and during flow, respectively, showing the divergence of the traces after flow starts (ΔT) and the decreasing overall average temperature (T avg ). Fig.54D .ΔT as a function of time before and after the start of flow. Fig.54E .ΔT as a function of flow rate over the physiologically relevant skin thickness range of 0.7 mm to 4 mm. Fig.54F .T as a function of flow rate over a range of physiologically relevant skin thicknesses avg .

[0074] Figures 55A-55B .Studies in adult patients. Fig.55A .Optical image of wireless sensor on shunt of representative patient, without smartphone reading. Fig.55B .ΔT for cases with confirmed flow, no flow / irregular flow, and splitter disconnect position, where error bars represent SD.

[0075] Fig.56 .Spatial and temporal accuracy of negative temperature coefficient (NTC) temperature sensors.

[0076] Fig.57 .Temperature sensor stability, where the measured temperature from two temperature sensors is plotted as a function of time.

[0077] Fig.58 .The layout of the unpackaged circuit provides the various electronic components on the device board, including circuit systems for power supply, wireless communication, and control and measurement.

[0078] Fig.59 .Analog front end and wireless temperature sensing accuracy. The temperature sensor shows high linearity over the biologically relevant skin temperature range.

[0079] Figures 60A-60D .Power saving switch feature.

[0080] Fig.61.The molding and packaging processes that can be used to manufacture any device of the present invention.

[0081] Fig.62 . The device is configured to have rotational tolerance by means of a 4 sensor device. The drawings relate to the aligned device and various rotations of 22.5, 45 and 90 degrees.

[0082] Fig.63 . Device configured to have translational tolerance through a device with 4 sensors. Plots relate to the aligned device and various translational offsets of 2mm, 5mm and completely misaligned.

[0083] Fig.64 .The effect of foam insulation on temperature sensors.

[0084] Fig.65 .Suitability for blood vessels, where the left picture is for a device not on a blood vessel and the right picture is for a device on a vein.

[0085] Fig.66 .Representative clinical images of the device positioned with the shunt on and off.

[0086] Fig.67 .Schematic representation of the device. DETAILED DESCRIPTION

[0087] In general, the terms and phrases used herein have their art-recognized meanings, which can be evidenced by reference to standard texts, journal references, and context known to those skilled in the art. The following definitions are provided to clarify their specific use in the context of the present invention.

[0088] By "soft" is meant a material that can be comfortably positioned against the skin without causing discomfort or irritation to the underlying skin due to deformation of the material itself to conform to the skin, and without excessively exerting force on the underlying skin under corresponding device-generated skin deformation. Softness / hardness can optionally be quantified, such as with a durometer or the material's resistance to deformation. For example, a substrate can be characterized by a Shore 00 hardness scale, such as a Shore 00 of less than 80. Softness can also be characterized by a modulus, such as a Young's modulus of less than or equal to 100 kPa.

[0089] "Stretchable" refers to the ability of a material to undergo reversible deformation under applied strain. This ability can be characterized by Young's modulus (stress / strain). Bulk or effective Young's modulus refers to the composite being formed from materials with different Young's moduli, such that the bulk or effective Young's modulus is affected by each of the different materials and provides an overall device-level modulus.

[0090] "Flexibility" refers to the ability of a material to undergo bending without breaking or permanently deforming and can be described by the flexural modulus.

[0091] Any device may be described herein as being "mechanically matched" to the skin, particularly the skin on which the device rests. This matching of the device to the skin refers to a conformable interface that can be used, for example, to establish conformable contact with a tissue surface. The devices and methods may incorporate a mechanically functional substrate comprising, for example, a soft material exhibiting flexibility and / or stretchability, such as a polymer and / or elastomeric material. The modulus of the mechanically matched substrate may be less than or equal to 100 MPa, less than or equal to 10 MPa, less than or equal to 1 MPa. The thickness of the mechanically matched substrate may be less than or equal to 0.5 mm, and optionally for some embodiments, less than or equal to 1 cm, and optionally for some embodiments, less than or equal to 3 mm. The bending stiffness of the mechanically matched substrate may be less than or equal to 1 nN m, optionally less than or equal to 0.5 nN m.

[0092] Mechanically matched devices and more specifically substrates are characterized by one or more mechanical properties and / or physical properties that are within a specified factor of the same parameter of the epidermal layer of the skin, such as a factor of 10 or a factor of 2. For example, the Young's modulus or thickness of the substrate may be within a factor of 20 of the tissue at the interface with the device of the present invention, such as the epidermal layer of the skin, or optionally within a factor of 10 for some applications, or optionally within a factor of 2 for some applications. The mass or modulus of the mechanically matched substrate may be equal to or lower than the mass or modulus of the skin.

[0093] "Encapsulated" refers to the orientation of a structure so that it is at least partially, and in some cases completely, surrounded by one or more other structures such as a substrate, an adhesive layer, or an encapsulation layer. "Partially encapsulated" refers to the orientation of a structure so that it is partially surrounded by one or more other structures, for example, where 30% or optionally 50% or optionally 90% of the outer surface of the structure is surrounded by one or more structures. "Fully encapsulated" refers to the orientation of a structure so that it is completely surrounded by one or more other structures.

[0094] "Polymer" refers to a macromolecule consisting of a polymerized product of repeating structural units or one or more monomers connected by covalent chemical bonds, which is generally characterized by a high molecular weight. The term polymer includes homopolymers or polymers consisting essentially of a single repeating monomer subunit. The term polymer also includes copolymers or polymers consisting essentially of two or more monomer subunits, such as random copolymers, block copolymers, alternating copolymers, multi-block copolymers, graft copolymers, tapered copolymers, and other copolymers. Useful polymers include organic polymers or inorganic polymers that can be in an amorphous, semi-amorphous, crystalline, or partially crystalline state. Cross-linked polymers with connected monomer chains are particularly useful for some applications. Polymers that can be used in the disclosed methods, devices, and components include, but are not limited to, plastics, elastomers, thermoplastic elastomers, elastoplastic plastics, thermoplastics, and acrylates. Exemplary polymers include, but are not limited to, acetal polymers, biodegradable polymers, cellulosic polymers, fluoropolymers, nylons, polyacrylonitrile polymers, polyamide-imide polymers, polyimides, polyarylates, polybenzimidazoles, polybutenes, polycarbonates, polyesters, polyetherimides, polyethylene, polyethylene copolymers and modified polyethylenes, polyketones, poly(methyl methacrylate), polymethylpentene, polyphenylene oxide and polyphenylene sulfide, polyphthalamide, polypropylene, polyurethane, styrenic resins, sulfone-based resins, vinyl-based resins, rubbers (including natural rubber, styrene-butadiene, polybutadiene, chloroprene, ethylene-propylene, butyl, nitrile, silicone), acrylics, nylons, polycarbonates, polyesters, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyolefins, or any combination of these.

[0095] "Elastomer" refers to a polymer material that can be stretched or deformed and restored to its original shape without substantial permanent deformation. Elastomers are generally subjected to substantial elastic deformation. Useful elastomers include those elastomers comprising a polymer, a copolymer, a composite material or a mixture of a polymer and a copolymer. An elastomer layer refers to a layer comprising at least one elastomer. The elastomer layer may also include dopants and other non-elastomeric materials. Useful elastomers include but are not limited to thermoplastic elastomers, styrene materials, olefin materials, polyolefins, polyurethane thermoplastic elastomers, polyamides, synthetic rubbers, PDMS, polybutadiene, polyisobutylene, poly(styrene-butadiene-styrene), polyurethanes, polychloroprene and silicones. Exemplary elastomers include, but are not limited to, silicon-containing polymers such as polysiloxanes, including poly(dimethylsiloxane) (i.e., PDMS and h-PDMS), poly(methylsiloxane), partially alkylated poly(methylsiloxane), poly(alkylmethylsiloxane), and poly(phenylmethylsiloxane), silicon-modified elastomers, thermoplastic elastomers, styrenic materials, olefinic materials, polyolefins, polyurethane thermoplastic elastomers, polyamides, synthetic rubbers, polyisobutylene, poly(styrene-butadiene-styrene), polyurethanes, polychloroprene, and silicones. In an embodiment, the polymer is an elastomer.

[0096] "Conformable" refers to a device, material or substrate having a sufficiently low bending stiffness to allow the device, material or substrate to adopt any desired contour, such as a contour that allows conformal contact with a surface having a pattern of embossed features. In some embodiments, the desired contour is the contour of the skin.

[0097] "Conformal contact" refers to the contact established between the device and the receiving surface, specifically the skin. On the one hand, conformal contact involves the macroscopic adaptation of one or more surfaces of the device, such as the contact surface, to the overall shape of the surface. On the other hand, conformal contact involves the microscopic adaptation of one or more surfaces of the device, such as the contact surface, to the surface, thereby producing a close contact with essentially no gaps. In an embodiment, conformal contact involves the adaptation of one or more contact surfaces of the device to one or more receiving surfaces, so that close contact is achieved, for example, wherein less than 20% of the surface area of ​​the contact surface of the device is not in physical contact with the receiving surface, or optionally, less than 10% of the contact surface of the device is not in physical contact with the receiving surface, or optionally, less than 5% of the contact surface of the device is not in physical contact with the receiving surface. Devices in certain aspects are capable of establishing conformal contact with internal and external tissues. Devices in certain aspects are capable of establishing conformal contact with tissue surfaces characterized by a range of surface morphologies, including planar surfaces, curved surfaces, wavy surfaces, macro-feature surfaces, and micro-feature surfaces, as well as any combination of these. Devices in certain aspects are capable of establishing conformal contact with tissue surfaces corresponding to tissues undergoing movement.

[0098] "Young's modulus" is a mechanical property of a material, device, or layer, which refers to the ratio of stress to strain for a given substance. Young's modulus can be given by the following expression:

[0099]

[0100] Where E is Young's modulus, L0 is the equilibrium length, ΔL is the change in length under applied stress, F is the applied force, and A is the area over which the force is applied. Young's modulus can also be expressed in terms of the Lame constant using the following equation:

[0101]

[0102] where λ and μ are the Lame constants.

[0103] "Low modulus" refers to materials having a Young's modulus less than or equal to 10 MPa, less than or equal to 5 MPa, or less than or equal to 1 MPa.

[0104] "Bending stiffness" is a mechanical property of a material, device, or layer that describes the resistance of the material, device, or layer to an applied bending moment. Typically, bending stiffness is defined as the product of the modulus and the area moment of inertia of the material, device, or layer. Materials with non-uniform bending stiffness can optionally be described in terms of an "overall" or "average" bending stiffness for the entire layer of material.

[0105] "Thermal actuation state" refers to a thermal actuator being in an off state or an on state. In this context, "substantially independent" means that the reference sensor is positioned sufficiently separate from the actuator so that the reference sensor output is independent of whether the thermal actuator is on or off. Of course, the systems and methods presented herein are compatible with a relatively small effect of the actuator on the reference sensor when the actuator is in the on state compared to when the actuator is in the off state, such as within 5%, within 1%, or within 0.1% of the reference temperature. Depending on the specific device and tissue characteristics, this distance can be between about 10 mm and 20 mm, such as about 15 mm.

[0106] Referring to the figures provided herein, a conformable device 10 for measuring subcutaneous fluid flow contained in a conduit 75 such as a shunt or a blood vessel may include a substrate 20 supporting an upstream temperature sensor 30 and a downstream temperature sensor 40. Upstream and downstream are described relative to the flow direction in the fluid conduit. The temperature sensor may be a substrate 20 including a flow sensor 30 and a downstream temperature sensor 40. Figure 1A-1BA portion of a temperature sensor array of a high density array 300 is shown. Any number of reference sensors (including actuator reference sensors 60 and / or environmental reference sensors 80) for assessing one or more baseline skin properties are located within the array. As explained herein, the reference sensor location can be determined as a location that is independent of thermal actuation conditions (e.g., environmental reference sensors) or a location that is independent of flow conditions in the conduit (e.g., actuator reference sensors). The reference sensor location can be characterized by the spacing distance (65 85) from the conceptual line 70 to the reference sensor (60 80) ( Fig.67 ), the conceptual line is a straight line connection between the upstream temperature sensor and the downstream temperature sensor and the thermal actuator.

[0107] Microprocessor 160 (in Fig.67 The device 10 may be wirelessly connected to the temperature sensor via one or more wireless communication components 310 and / or connect the device 10 to a microcontroller 320 shown as being within a handheld or computer 330 remote device. As desired, the power supply 150 (also shown as being within the device 10) may be wirelessly connected to the temperature sensor via one or more wireless communication components 310 and / or connect the device 10 to a microcontroller 320 shown as being within a handheld or computer 330 remote device. Figure 4B The power source may correspond to a wireless charging component. The wireless communication component 5810 may also be connected to a board of the device 10. Optionally, the power source may correspond to a wireless charging component. Fig.58 Shown in (see also Figure 4B antenna).

[0108] If necessary, the encapsulation layer 1700 ( Fig.17 ) covering means, the encapsulation layer comprising an encapsulation layer (also referred to herein as a cover - see e.g. Fig.53A ) on top of the packaging layer or an additional partial layer formed of foam. Since the foam layer has been shown to improve device performance, any of the devices provided herein may include a foam layer positioned above the packaging layer, wherein the foam layer may cover the entire packaging layer or a portion thereof, the portion corresponding to the temperature sensor and the actuator in a vertical geometric configuration to minimize thermal noise and improve device performance and sensitivity.

[0109] The devices and methods provided herein can be easily implemented and managed, including by health care providers. For example, Fig.46 The device is shown operably integrated or connected to a computer implemented program or application 4600 with on-demand actuation 4610 on a handheld device. In this way, individual sensor control, device actuation, and data monitoring are easily, conveniently, and reliably available to a medical professional who may be located remotely from the patient wearing the device.

[0110] Example 1: Epidermal electronic device for noninvasive, wireless, quantitative assessment of intraventricular shunt function

[0111] Ventricular shunts represent an essential component of the clinical treatment of hydrocephalus, a common and debilitating neurological condition caused by excessive production and / or impaired reabsorption of cerebrospinal fluid (CSF) produced by the brain's ventricular system [Rachel]. Hydrocephalus is caused by a variety of causes, including but not limited to cancer, hemorrhage, trauma, and congenital malformations. In the United States alone, this condition affects an estimated 750,000 patients and accounts for approximately 3.1% of all pediatric acute care costs [Lam, Patwardhan, Shannon, Stone]. In the United States, 125,000 pediatric hydrocephalus patients spend 400,000 days in the hospital each year [Simon]. The shunt assembly typically involves two silicone cannulas connected upstream and downstream of a regulating valve to drain excess CSF from the ventricles to a distal absorption site, typically the peritoneum, pleura, or right atrium of the heart. Although shunts are effective in diverting CSF and preventing the sequelae of hydrocephalus, including seizures, coma, neurologic impairment, and death, shunts are highly susceptible to failure [Tervonen] due to fibrin catheter ingrowth, kinking, interruption, overdrainage, distal malabsorption, and infection [Garton, Yuh]. An estimated 84.5% of shunt recipients require revision surgery [Cochrane, Shah, Stone, Piatt]. The clinical symptoms of shunt failure are often nonspecific, such as headache, nausea, and lethargy, making it challenging to diagnose [Kirkpatrick, Piatt, Garton]. Because the consequences of misdiagnosis can include significant morbidity and mortality, the location and cause of shunt failure are critical to the appropriate care of patients with hydrocephalus.

[0112] Diagnostic tests to assess shunt function include computed tomography (CT), plain radiographs (X-rays), magnetic resonance imaging (MRI), radionuclide shunt patency studies (RSPS, or "shunt-o-gram"), and the ShuntCheck system [Boyle, Wallace, Madsen]. However, each method has several disadvantages, including high cost, poor reliability, slow speed, susceptibility to interference, and patient discomfort, including the potential for harm. CT scans and X-rays expose a vulnerable pediatric population to harmful radiation (1.57 ± 0.6 mSv and 1.87 ± 0.45 mSv, respectively). Shunt patients undergo an average of two CT scans per year, which, over the patient's lifetime, result in dangerous levels of radiation exposure that have been associated with the onset of neurologic and hematologic malignancies [Koral, Krishnamurthy]. MRI methods cost $3000 per study, measurements may interfere with the magnetic shunt valve, availability is limited, and wait times are often long. Invasive testing (in the form of RSPS or simple aspiration) is painful, time-consuming, and often inaccurate [Brendel, Ouellette, Uliel, Vernet]. Recent diagnostic additions attempt to address these shortcomings but are limited by cumbersome multi-step protocols that in some cases include ice-mediated cooling, and previous clinical data that are unclear or negative [Madsen, Recinos, Boyle, Frim]. Each hospital admission can cost more than $10,000 for observation alone, with prolonged hospital stays also exacerbating frustration for patients, caregivers, and families [Boyle, Yue]. Ultimately, surgical intervention is required to evaluate and revise the shunt in many patients. The total cost of surgery approaches $67,000 per patient, with the risk of intraoperative complications, anesthetic exposure [Aqueduct neurosciences. Hydro association]. Since a large proportion of these surgeries reveal shunt devices with adequate flow distribution, these unnecessary surgeries place a significant burden on the healthcare system.

[0113] This example presents a simple, noninvasive sensor platform that provides a low-cost, comfortable device for quantitatively assessing flow through cerebrospinal fluid shunts. The platform exploits advances in materials, mechanics, and manufacturing protocols to achieve ultrathin (<100 μm), soft (Young's modulus, E is approximately 70 kPa), lightweight (areal mass density, <10 mg / cm 2) and skin-like (which is a physical property), where the resulting bending stiffness is nine orders of magnitude lower than traditional rigid sensors. Such "epidermal" electronic systems support a wide range of measurement capabilities that provide clinical-grade accuracy in capturing body kinematics [1], electrophysiological signals [2,3], soft tissue mechanical properties [4], chemical markers in sweat [5,6], and many other aspects. Due to the exceptionally low thermal mass of these platforms (<10 mJ cm -2 K -1 ), fast response time (about 10 milliseconds) and exceptional accuracy of temperature measurement (about 20 mK) and their ability to controllably transfer thermal power to underlying tissues [7-11], multimodal thermal characterization is also possible. Specific embodiments allow high-resolution skin thermography and precise measurement of the thermal conductivity and thermal diffusivity of the skin. Recent studies

[12] have also demonstrated the possibility of quantifying large vessel blood flow based on measurements of spatial anisotropy in thermal transport. Here, these concepts are extended to enable a soft, skin-interfaced sensor that can accurately measure flow through a cerebrospinal shunt in real time in a noninvasive, quantitative and wireless manner. The results represent a breakthrough in the diagnosis of hydrocephalus that is equally accessible to physicians and patients, where flow can be visualized in a simple, user-friendly manner. Systematic benchtop evaluation of thermal transport physics, thermal imaging and finite element analysis (FEA) revealed the effects of skin thermal properties and thickness as well as device and cannulation geometry. The results establish design considerations under a range of realistic operating conditions. An integrated wireless system allows data recording and transmission to standard consumer devices such as smartphones and tablet computers. Trials in five adult shunt recipients with various etiologies and comparisons with CT, MRI, and radionuclide tracking validated the in vivo functionality of the device and the advanced processing algorithm used to quantify flow velocity.

[0114] Dense arrays for flow visualization: The feasibility of using arrays of epidermal temperature sensors and thermal actuators to quantify anisotropy in thermal transport through the skin induced by large vessel blood flow has been demonstrated [10,12]. The device architecture and fabrication scheme presented here increases the number of sensors by almost tenfold relative to such previous studies and increases the density of these elements by fourfold using clusters distributed around a central thermal actuator to provide the levels of precision and spatial resolution necessary to characterize flow through a flow diverter. A schematic illustration of this platform (epidermal sensing array, ESA) is shown in Figure 1A Optical micrographs of key features are shown in Figure 1BThe device presented here comprises a circular (R = 2.5 mm) thin-film metal (Cr / Au 10 / 50 nm) actuating element surrounded by 100 circular (R = 0.25 mm) thin-film metal (Cr / Au 10 / 50 nm) temperature sensors. Two layers of metal traces (Ti / Cu / Ti / Au 20 / 600 / 20 / 25 nm) patterned in a serpentine geometry define the interconnections between the sensing and actuating elements, with polyimide (PI) as the interlayer dielectric. A PI film (9 μm total thickness) patterned and aligned to the metal features is used as an encapsulation layer. A soft (70 kPa) substrate such as an elastomeric substrate (Ecoflex, 100 μm) is used as a support. The rows (to supply the sensing voltage Vsup) and columns (to measure the resulting current I meas ) enables the Figure 2C Each element in the array is individually addressed. The operation of the thermal actuator (e.g. Figure 2C The IR thermograph (seen in Figure 1) produces a temperature time-space pattern that can be captured by high-speed, automated interrogation of the sensors in the array. A diagram of the data acquisition system is shown in Fig. 9 Arrays with square geometry (10 × 10 for the case presented here) with equal numbers of input and output lines mitigate the effects of parasitic current paths. (For a theoretical and experimental comparison of current distribution in square and non-square arrays, see Figures 8A-8B . ) The fabrication simplicity and operational robustness of metal resistor sensor elements make them an attractive choice compared to semiconductor devices, composite organic thermistors, and other devices. Figure 2E The series of images in demonstrate the mechanical compliance and physical robustness of these systems.

[0115] During operation, the current I through the sensor for a given applied potential meas defines a resistance that can be converted to temperature via a linear calibration factor whose goodness of fit is shown in Fig.10 2F . The effect of directional flow through a small diameter tube located below the device can be seen in the IR temperature recorder of FIG. 2F . Here, as discussed subsequently, heat transfer occurs most efficiently along the flow direction, thereby producing significant anisotropy in the temperature distribution at a magnitude that can be quantitatively related to the volume flow rate. For situations related to flow through a subcutaneous shunt of typical size, the layout of the sensing elements allows accurate measurement of this anisotropy. Compared to previously reported platforms for sensing blood flow, the high-density platform introduced here (1) eliminates the need for perfect alignment with the underlying ventricular shunt, (2) facilitates the use of image processing techniques to visualize the flow field, and (3) allows interpretation of the flow by statistical methods due to the density of the information.

[0116] Figure 2A The schematic diagram in FIG. 1 identifies a set of 50 upstream (T 上游 ) and downstream (T 下游 ) sensors. For each physically matched segment sensor pair (given by Figure 2A Paired color indication in T 下游 Subtract T 上游 This produces a temperature difference (ΔT) that measures the degree of thermal anisotropy caused by the fluid flow. 传感器 ).like Figure 2B As shown, the ΔT of the sensor pairs A and B directly covered on the catheter 传感器 Two different flow conditions within the established range of CSF flow (0.02 mL min -1 、0.2mL min -1 ) exhibit strong thermal anisotropy

[13] . Sensor location B shows higher flow sensitivity than location A due to the reduced effect of direct heat conduction from the actuator relative to the anisotropic heat transfer caused by the fluid flow. ΔT measurements of the distal sensor pair orthogonal to the flow direction show weak anisotropy (C), while the distal pair parallel to the flow direction (D) shows no flow-induced thermal anisotropy. Due to the ESA sensor density and cardinality symmetry, this orientation dependence eliminates the requirement for precise alignment of the sensor with the pipe direction.

[0117] A principal component analysis (PCA) model (generated using R) was provided for assessing cannula positioning relative to the ESA coordinate system and for confirming the presence or absence of flow (e.g. Figure 2C The PCA model constructed from time series ESA measurements uses ΔT PCA The principal component (PC) is calculated using the ΔT PCA =T 下游 -T 上游,i , where T 下游 is the temperature matrix of all downstream sensors (1-50), and T 上游,i is the temperature of the single (i) upstream sensor. The first two components (PC1, PC2) describe approximately 92% of the overall variability in the data (70.5% PC1, 22.1% PC2), with the remainder (8% across PC3:PC50) being noise related. PCA biplot ( Figure 2C ) shows the ESA time series (with Figure 2B Same) in each measurement, the two selected T 上游,i Each ΔT of the sensor (upper image – orthogonal remote sensors, red; lower image – collinear remote sensors, red) PCA Projection. Figure 2CThe data clusters (95% confidence ellipses) corresponding to the following three experimental conditions are revealed: for different flow regimes (0.02 mL min -1 、0.2mL min -1 ), there is no fluid flow without thermal actuation (flow off / thermal off); there is no flow with thermal actuation (flow off / thermal on); and there is fluid flow with thermal actuation with separate clusters. As shown, these clusters are independent of the selected Tui sensor ( Figures 12A-12B ). Comparison of the data clusters to the principal components shows that PC1 is primarily related to the degree of thermal actuation, while PC2 is related to the presence or absence of flow. Mapping the variables to the PCA biplot indicates the correlation of the sensor to the fluid flow. Figure 2C In Figure 1, the superposition of four variable factors corresponding to known Td sensors at the proximal (red) and distal (blue) ends of the fluid flow is shown for orthogonal and collinear T 上游,i The strategy provided by PCA is used to identify the T that produces the largest separation between the no-flow / flow data clusters (along the PC2 axis). 上游,i Sensors are used to mitigate the effects of ESA misalignment. Figure 2C As observed in the orthogonal T 上游,i Sensor compared to the collinear T 上游,i The sensor strongly separates these clusters. In this way, for scenes without a priori orientation, PCA provides a direct means for estimating T 上游,i Correlation with flow conditions and thus assessment of the orientation of the catheter relative to the ESA.

[0118] The ESA density enables spatial mapping of the temperature anisotropy produced by fluid flow. These maps result from processing of the ESA raw measurements, such as Figure 2D First, by converting the original ESA measurement value (I meas ) is converted to resistance and then to temperature by linear calibration (a curve established a priori for each sensor of the ESA, the process is Fig. 9 ), the temperature values ​​can be mapped to an array of analog square "pixels" that are larger than the ESA (grid: 17mm×17mm, 10px mm -1 ), resulting in a 170×170×N matrix of time series measurements for N frames. The background temperature T is subtracted from each frame. 背景 Get to T 归一化 The temperature map is obtained by bicubic interpolation via a grid (from the boundary conditions T of the IR temperature recorder 归一化 = 0) Fit the surface to the measured T in each frame归一化 The value is obtained from the T 归一化 The actuator temperature is subtracted from the resulting isotropic heat transfer temperature (T 致动器 ) enhances the visualization of flow-induced anisotropic heat transport. Figure 2D In the absence of flow (left) and the presence of flow (0.02 mL min -1 )(right), the ESA temperature map is compared to an IR temperature recorder (same scale). As can be seen from the sensor overlay in each image, the high density of the ESA allows for good fidelity in visualizing thermal anisotropies above the embedded catheter. Although patient experiments do not typically allow for direct measurements of flow and no-flow conditions, theoretically derived or a priori measured “calibrated” T 致动器 Helps with the type of analysis described here.

[0119] Quantitative analysis of flow and comparison with model: The complete mapping results obtained using high-density ESA show a means to simplify the sensor for fast measurements in a low-cost platform that consists at its core of only an actuator and a pair of sensors positioned upstream of the actuator (T 上游 ) and downstream (T 下游 )1.5mm, known as the epidermal linear array (ELA). In this system, the actuator also acts as a temperature sensor, and the measured temperature T 致动器 A useful normalization factor is generated that facilitates data analysis independent of the actuation power. Using this system together with a benchtop model allows for a controlled exploration of the effects of flow, thermal, and geometric parameters. A schematic illustration of the apparatus and evaluation setup is shown in Figure 3A , where the optical images of representative systems are shown in Figures 13A-13C At controlled low power (1.35mW / mm 2 ) level, the actuator will generate heat, which is determined by the thermal diffusivity of this material (α 皮肤 ) diffuses through a silicone skin phantom (Silicone) at a rate controlled by the thermal field. A graphical representation of the scaling law of the depth of penetration of this thermal field into the phantom is shown in Fig.14 Here, the phantom can be considered as a semi-infinite solid

[14] , which approaches quasi-steady-state equilibrium for a relatively long time (about 400 seconds), corresponding to a penetration depth of about 5 mm. Typical ventricular catheters are implanted subcutaneously at a depth of 1-2 mm

[15] , which is well within the detectability range. The original transient sensor in this system and the transient state of the sensor after actuation and at different flow rates (Q CSF ) during the actuator response (ΔT 传感器 =T 传感器 (t)-T 传感器 (t 致动 ), ΔT 致动器 =T致动器 (t)-T 致动器 (t 致动 ))See Figure 3B In the absence of flow (Q CSF = 0), the heat transfer from the actuator is and -z directions, so that ΔT 上游 and ΔT 下游 This scheme is shown in Figure 3B The presence of flow will affect ΔT 上游 and ΔT 下游 At low flow rates (0 mL min _1 CSF <0.05mL min -1 ), the fluid is used to transfer heat from the actuator preferentially to the downstream sensor and away from the upstream sensor, thereby measuring ΔT 下游 Increase and ΔT 上游 Reduce, as in Figure 3B As seen in the blue shaded area. At higher flow rates (0.05 mL min -1 CSF <1mL min -1 ), the convection effect of the fluid dominates, causing a net cooling effect on the two sensors, but at different rates, where ΔT 上游 Below ΔT 下游 The value of Figure 3B The actuator is convectively cooled by the fluid at a rate controlled by the magnitude of the flow, so that ΔT 致动器 In the presence of Figure 3B The blue curve in the figure shows the flow. Figure 3C Middle Q CSF The full range of physiologically relevant values ​​is shown for the normalized quantity T 上游 / T 致动器 and T 上游 / T 致动器 When considering the sensor (ΔT 传感器 / T 致动器 ) and its average value The difference between the two is that for different skin thicknesses (h 皮肤 ), the non-monotonic effects of the flow will increase and decrease, e.g. Figure 3D-3E Here, ΔT 传感器 / T 致动器 and are measures of thermal anisotropy and flow value, respectively. Together, these quantities allow the flow velocity to be determined and can be used to distinguish Figure 3D Degenerate points on either side of the peak shown.​​

[0120] Skin thickness (h 皮肤 ) represents important geometric parameters. Figure 3D-3E As shown, due to the limited penetration depth of the thermal field, increasing h 皮肤 As discussed later, although transient techniques can be used to determine h from thermal measurements, 皮肤 ,like Fig.15 As shown, in practice, h 皮肤 It can be measured directly using CT and Doppler ultrasound.

[0121] Actuator (P 致动器 ) represents an important design consideration. Increasing P 致动器 The signal-to-noise ratio (S / N) of the measurement is improved, but biological considerations set an upper limit for noninvasive use. 致动器 Impact on S / N Figure 3F , where the signal is ΔT 传感器 / T 致动器 At 0.13 mL min -1 The noise is the standard deviation calculated to three significant figures (σ 60秒 ). When P 致动器 The value of P is high enough 致动器 >1mW / mm 2 ), the advantage of the increased actuation power diminishes and the noise stabilizes at 2% of the measured signal. Fig.16 As shown, on PDMS (Sylgard 184), the local temperature increase was 6.01 K (mW mm -2 ) -1 The rate of P 致动器 Changes linearly.

[0122] like Figure 3G-3H As shown in the benchtop model in , for two skin thicknesses and in the following two configurations, a possible confounding effect of the measurement comes from blood flow through the superficial veins: flow aligned with the flow of CSF flow (+x, co-current flow) and flow opposite to the flow of CSF flow (-x, counter-current flow) for rates at the upper end of the range typically encountered in veins located near the skin surface of the neck. In practice, co-current flow represents the most realistic case, as venous blood flow typically travels from the brain toward the heart. Arterial flow can be neglected because the depth at which it occurs (>1 cm) is below the detectable limit of the sensors reported here. In the experiments, as an extreme case, the flow through the cannula was 0.13 mL min -1 , and the phantom blood vessels (R 血管 =1mm) at (d 血液) is 5 mm from the central axis of the sensor and 2.5 mm from the edge of the actuator. In this system, the h of both the catheter and the blood vessel 皮肤 are the same. The reverse flow condition will make ΔT 传感器 / T 致动器 and Both were reduced by 20%, while the co-current case measured a reduction of <5%.

[0123] Thermal conductivity of skin (k 皮肤 ) and diffusion rate (α 皮肤 ) also represents an unknown number, where the range of human skin is 0.2Wm -1 K -1 <k 皮肤 <0.45W m -1 K -1 and 0.9mm 2 s -1 <α 皮肤 <0.17mm 2 s -1

[11] Phantom skin with properties defining this range can be made from silicone materials of two different formulations (Sylgard 170 and Sylgard 184, Dow Corning). The measured values ​​of the thermal properties of these materials ( Fig. 3I ) matches the literature value: and: For both cases, ΔT 传感器 / T 致动器 The measured values ​​are almost the same, such as Figure 3J In contrast, the increased heat transfer rate associated with Sylgard 170 increases the cooling effect of the fluid, thereby reducing the Figure 3K As shown in The result is an increase in the sensitivity of the sensor.

[0124] The ventricular catheter was constructed from standard medical grade silicone and its thermal properties were assumed to be known a priori (k 置管 =0.22Wm -1 K -1 , α 置管 =0.12mm 2 s -1 )

[16] .

[0125] Another experiment will be the convective heat transfer coefficient (H conv =20W m -2 K -1 , Fig.17 ), positioning tolerance( Fig.18B30° rotation tolerance, Fig. 18C The approximately 1 mm translation tolerance) and the noise introduced by the data acquisition system are quantified as a function of the sampling window ( Figures 19A-19D ).

[0126] The system provided herein is compatible with wireless data acquisition (including wireless data acquisition via Bluetooth). This represents an important patient care aspect, as the patient does not need to be hardwired to any instrument. In this way, monitoring can continue without restricting the patient's position or movement.

[0127] Human studies for the assessment of intraventricular shunt function:

[0128] Experiments on five shunt recipients with different pathologies demonstrated the utility of these measurement platforms. The device design addresses three requirements: (1) ease of handling by the surgeon to ensure flexible placement and removal; (2) patient comfort during application, manipulation, and removal; and (3) strong mechanical and thermal coupling to the skin. A schematic illustration of the resulting embodiment is shown in Figure 5A , which shows an ELA and an ultrathin elastomeric substrate (100 μm, Ecoflex+MG7 1010 adhesive) supported by an elastomeric frame (2 mm, Sylgard 170). Figures 19A-19D As shown, these platforms adhere securely and non-invasively to the skin solely through van der Waals interactions, without the need for a separate adhesive layer, wherein the device maintains conformal contact with the skin even under extreme deformations. Continuous measurements involve placement on the skin above the distal cannula ("shunt on") and at a location adjacent to the distal cannula ("shunt off"). The shunt off measurement has two key uses: (1) it serves as a control for comparison with the shunt on measurement; and (2) it allows the thermal properties of the skin to be measured without being affected by flow. Figure 5B The locations of the shunt on and shunt off are schematically shown. The cannula is easily positioned under the skin by touch and can be precisely positioned using Doppler ultrasound (Sonosite Inc., Bellevue WA). Representative Doppler images of the cannula are shown in Figure 5B (Inset). Linear markings on the device ( Figure 5B Although the shunt is not visible under the skin, its ends can be easily aligned with the markings on the device by touch. Figure 5C As confirmed by the IR images in 2 ) ensured that the maximum temperature rise was <5°C. Based on the IRB-approved protocol, these values ​​were well below the sensory threshold. Figure 5B Marking in Figure 5CThe results show a characteristic teardrop distribution with temperature consistent with the flow.

[0129] T 致动器 Transient shunt disconnection measurements define the thermal transfer properties of the patient's skin. Representative responses before, during, and after actuation are shown in Figure 5D The k extracted from these data 皮肤 and α 皮肤 The value of Figure 5E-5F ; the values ​​are comparable to those expected for the skin

[11] . The data from the flow sensor are Figure 5G-5H , where the red, black, and blue curves represent the temperatures measured from the upstream sensor, downstream sensor, and actuator, respectively. The location adjacent to the shunt without near-surface vessels has no sources of thermal anisotropy and can therefore be used as a control measurement. The results for a representative case are shown in Figure 5G where the upstream and downstream responses are almost identical. The anisotropy caused by the flow through the splitter is shown in Figure 5H In a simple binary sense, simply by observing the presence or absence of thermal anisotropy, one can immediately determine whether flow is present, corresponding to shunt function or failure. ΔT for shunt-on and shunt-off positions for all five patients 传感器 / T 致动器 The measured values ​​are shown in Fig.5I For all working shunts, anisotropy is evident. The error bars correspond to the standard deviation calculated on 100 samples. The raw data for the other two cases are given in Fig. 20 Details of the etiology and outcome for each patient are given in Figures 21A-21B .

[0130] Studies performed with X-ray, MRI, and CT imaging validated the measurements. Fig. 6A This corresponds to a patient with shunt failure (F, 36), which was suspected to be due to kinking of the distal catheter and was subsequently confirmed by X-ray and radionuclide tracer (RT) images. Surgical intervention relieved the kink, resulting in a dramatic, visible increase in flow, as shown in Figure 3. Figure 6B As shown in the optical image. Figure 6C As shown, continued flow was further confirmed by postoperative X-ray and RT, which revealed a clear trace of distal cannulation and the other side of the valve. Placement of ELA in the shunt-on and shunt-off positions revealed no flow before revision, which was consistent with X-ray and RT imaging. Fig.6D As shown, the postoperative shunt-off measurements showed no significant change, whereas the shunt-on measurements showed significant flow.

[0131] Quantitative extraction of flow rate from such data can be achieved by fitting to a FEA model that uses k 皮肤 and α皮肤 , ΔT 传感器 / T 致动器 and The measurement results and the inner and outer diameters of the tube and its thermal properties k 置管 and α 置管 Placing the most superficial sensor determined by touch at the distal catheter location maximizes measurement accuracy. Figure 5B and Fig.23 Analysis of the CT and Doppler ultrasound images shown will show that the h 皮肤 Limited to FEA showed 0.01 ml min -1 CScsF <1ml min -1 T 传感器 / T 致动器 and ΔT 传感器 / T 致动器 In this way, T 传感器 / T 致动器 The measured value of defines the flow rate scheme, that is, high flow (Q>0.05mL min -1 ) or low flow (Q<0.05mL min -1 ). Specifically, Figure 7B As shown, for all skin thicknesses, T 传感器 / T 致动器 A value > 0.29 indicates low flow, and T 传感器 / T 致动器 <0.29 indicates high flow. Then T 传感器 / T 致动器 and ΔT 传感器 / T 致动器 After this process, the measured data will produce a quantitative flow value.

[0132] This procedure is described with respect to use in human subjects. Figures 6A-6D The evaluation of patient 1 in the study showed shunt failure, which was consistent with the ELA measurements. Measurements after revision surgery revealed a flow rate of Patients 2 and 3 were not suspected of shunt malfunction and had flow rates of and well within the established range of healthy CSF flow

[13] . Patient 4 was initially measured as having occluded flow ​This patient had been experiencing severe and prolonged constipation over the past week and had clinical deterioration due to possible pseudo-obstruction. Prolonged constipation may reduce the reabsorptive capacity of the peritoneum due to increased intra-abdominal pressure and decreased pressure gradient from the ventricles to the peritoneum.

[17] After the administration of a strict bowel regimen, the patient's mental status improved, and subsequent measurements revealed ambulatory health. Patient 5 was suspected of having shunt malfunction, and thermal measurements revealed a high degree of flow occlusion that was subsequently confirmed surgically (For these studies, no clinical measurements were made using the sensor.) In patients 4 (pre-bowel exam) and 5 (pre-operative), the measurements were masked to the physician's assessment. These results are shown in Figure 7C .

[0133] Error, Noise, and Uncertainty: Data analysis requires converting the measured resistance of the two sensors and one actuator first to temperature and then to flow rate. A simplified schematic of this process is shown in Figure 18A. The first conversion relies on precise, high-resolution (10 mil) resistance measurements performed with a digital multimeter at a 5 Hz sampling rate. The inherent noise in the resistance measurement is 4.8 ppm over a 20 minute sampling window, as measured with a commercial 1 kΩ resistor and as Fig.18B As shown in Figure 2. Adding a conductive anisotropic film (ACF) cable increases the noise to 12.5ppm. Introducing a soft temperature sensing element and a second ACF connection further increases the noise to 93.9ppm. Conversion to temperature relies on a linear calibration where R 2 >0.999, corresponding to a temperature resolution of 15mK. Actuation involves a high-performance constant current source that operates very stably, with a deviation of 1.73ppm within a 20-minute sampling window, such as Fig. 18C As shown. With the influence of skin thickness and in-plane heat dissipation, ΔT 传感器 / T 致动器 The total noise of the measured values ​​is about 2%, as shown in Figure 18D. In practice, the mechanical mismatch induced by patient motion, the strain on the ACF cable and the soft pad are the main noise sources, which are averaged in vivo for all patients (in the shunt-on position) as ΔT 传感器 / T 致动器 9-10% of the signal. Eliminating the ACF cable through wireless implementations or through thin soldered connections represents a straightforward way to mitigate these effects.

[0134] Comparison with State of the Art: A commercially available sensor (ShuntCheck) offers an alternative to imaging-based diagnostic tools [18-21]. The system consists of a cooling pack held against the skin above a distal cannula, with a conventional bulky temperature sensor attached to the skin downstream in the direction of the cannula. The pack cools the flowing CSF, thereby reducing the temperature of the downstream sensor. Although this system has high specificity (approximately 100%)

[20] and sensitivity (80%), it suffers from key limitations. First, the embodiment is bulky and has poor coupling at the sensor-skin interface, which requires the use of a large pack (2.5 cm × 2.5 cm) and significant cooling. This requirement, coupled with conventional large-scale data acquisition (DAQ) systems, reduces the usability of the system and prevents continuous, long-term measurements. Second, the measurements are semi-quantitative and fail to account for key factors such as skin thickness, skin thermal properties, and device layout. Together, these factors can lead to overall patient discomfort and prevent straightforward interpretation of the data

[20] . For a comparison of existing diagnostic techniques, see Fig.16 .

[0135] Outcomes for Hydrocephalus Treatment: The skin-like precision sensor systems introduced here have the potential to represent a paradigm shift in the clinical diagnosis of shunt malfunction. These platforms offer unique advantages over radiographic imaging, invasive sampling, and ice pack cooling in terms of integration of precision soft thermal sensors with wireless transmission capabilities. By leveraging advanced concepts in thermal anisotropy measurements and skin-conformable epidermal electronics, these devices may offer further quantitative modes of use beyond the opportunities provided by the embodiments studied here.

[0136] Clinically, individuals with shunts are subject to prolonged and expensive hospital observation, toxic radiation exposure, painful surgical interventions, and socioeconomic disparities in care. The current standard of care is a disservice to this vulnerable population, and better diagnostic methods are invaluable in the management of patients with hydrocephalus. The technology introduced here will introduce the power of personalized medicine into the field of hydrocephalus, which is currently only reflected in current treatments through the type and setting of generalized valve systems. By quantitatively assessing CSF flow rates, baseline flow rates can be established for individual patients after initial surgery and at follow-up, providing new insights into the patient's hydrodynamic physiology. With a large amount of previous literature describing neurosurgical exploration and witnessing intraoperative flow, such results can reveal the flow level required to produce symptoms in vivo. Further, wireless capabilities allow for telemetric monitoring of ventricular shunts, with mobile application development to assist treating physicians in clinical assessment. As value-based care reforms the healthcare environment, precise measurements and seamless wireless transmission will provide clinicians with cost-effective, clinically effective tools. In addition, the psychological burden of nonspecific symptoms creates tremendous anxiety for patients, families, and caregivers. After careful validation, sensor platforms of the type introduced here could be used for home diagnostics with reduced uncertainty.

[0137] Research Application: Many poorly understood pathologies stem from neurohydraulic dysfunction, including normal pressure hydrocephalus (NPH), idiopathic intracranial hypertension (IIH), and slit-ventricle syndrome. These pathologies cause great distress to affected patients. NPH, characterized by a triad of neuropsychiatric changes, urinary incontinence, and gait imbalance, may affect up to 20 million (usually elderly) individuals each year. The associated pathophysiology may be related to choroidal villous malabsorption, and excessive drainage in these individuals may lead to venous rupture and subdural hematoma, often requiring neurosurgical intervention [Kameda, Lesniak]. IIH predominantly affects young female patients and is associated with abnormal vitamin A metabolism and intracranial venous stenosis. The relatively small ventricular system possessed by these patients results in a high risk of shunt failure from ventricular collapse, complicating revision surgery attempts and making hospitalization painful and prolonged [McGirt, Karsy, Liu]. Similarly, patients with slit-ventricle syndrome experience poor ventricular wall compliance, where failure is largely undetectable on radiographic studies [Drake]. By understanding the individual flow rates in each of these pathologies, new and improved treatments may be developed for their care. Ultimately, personalized, better-designed shunt systems with integrated flow monitoring systems will provide the ability to appropriately compensate for these physiological flow patterns, offering hope to a population with significant need.

[0138] Fabrication of the sensor system: For the sensors presented here, fabrication started with spin casting of a sacrificial layer of poly(methyl methacrylate) (700 nm) onto a 4” undoped Si wafer. A dielectric layer of polyimide (PI, 3 μm) was then spin coated on top. For the epidermal linear array (ELA), a single bilayer film of Cr / Au 10 / 100 nm deposited onto the wafer by electron beam evaporation and patterned by photolithography and etching formed the sensors and serpentine interconnects according to the design rules in stretchable electronic devices [22-25]. For the epidermal square array (ESA), the Cr / Au was photolithographically defined. A 10 / 100nm bilayer film was used to form 100 resistive temperature sensing elements arranged in a 10×10 array around a central resistive thermal actuator. Evaporated and photolithographically defined Ti / Cu / Ti / Au 20 / 600 / 20 / 25nm multilayer films produced the first layer of rows of serpentine interconnects used to address each row of sensors. Photolithography and reactive ion etching (RIE) defined vias in the second spin-cast layer of PI (3μm). Ti / Cu / Ti / Au formed using the same method as the first multilayer film A second multilayer film of 20 / 600 / 20 / 25nm defines columnar serpentine interconnects for addressing each column. For both ELA and ESA designs, spin casting defines the last layer of the PI layer (3μm), which is also patterned with the geometry of the metal traces. A final RIE step isolates the outline of the device and opens vias for wired connections to external data acquisition electronics. Immersion in an acetone bath weakens the sacrificial PMMA layer, allowing release and transfer via water-soluble tape. The device is then transferred to a thin double-layer silicone film (Ecoflex, 20μm, Dow Corning, MG 7 1010 Skin Adhesive, 20μm) and spin-cast onto a glass slide. Immersion in warm water dissolves the tape, and the spin-cast silicone top layer (Ecoflex, 50μm) completes the device. A thin (100μm) double-sided sheet adhesive (JMS 1400, Label Innovations, Ontario, Canada (Label Innovations, Ontario, Canada) is laser structured to form an outline around the device. This sheet is bonded to silicone and a processing frame, which can be in the form of a printed circuit board containing wireless transmission electronics or a simple, thick elastomeric frame for facilitating processing of wired electronics. An isotropic conductive film (ACF) makes the connection to the wired data acquisition electronics. The sensor resistance is then calibrated by the temperature measured by IR imaging.

[0139] Fabrication of flexible printed circuit boards: Fabrication starts with a commercially available dense three-layer Cu / PI / Cu laminate (Pyralux, 6535, DuPont, 18 μm / 75 μm / 18 μm). Conductive traces and bonding pads are patterned by laser structuring (LPKF U4, LPKF Systems, Germany) with a resolution of 50 pm. In addition to the soft electronic components, commercially available SMD resistors, capacitors, as well as a Bluetooth microcontroller (NRF 52, Nordic Semiconductor) and a battery are bonded to the PCB by reflow soldering.

[0140] Data acquisition system: Data from the ELA resistor element is recorded by a digital multimeter (DMM) (NI, USB 4065, National Instruments). Actuation power is supplied with a constant current source (Keithley 6220, Tektronix). ESA needs to sequentially actuate the voltage output module (NI 9264, National Instruments) of each of the ten input channels at 3V and requires a single-channel DMM to measure the current. The red LED connected in series with each channel is used as a visual indicator of the state of multiplexing and each addressing channel. Time-division multiplexing measurements are performed on each of the ten channels using a mechanical reed (REED) relay module (J-Works 2418, J-Works Inc.). All data were recorded using custom software designed and programmed in LabView (National Instruments) and processed using custom algorithms in Matlab (Mathworks Inc., Natick, MA).

[0141] Thermomechanical Modeling and Finite Element Analysis

[0142] Benchtop Experiments: A phantom skin assembly was constructed for in vitro evaluation. A distal shunt cannula (Medtronic, Minneapolis, MN) was embedded in a PDMS matrix (Sylgard 184, Dow Corning) supported by a 3D printed mold containing struts to prevent the cannula from sagging. Optical images of this assembly are shown in Figures 13A-13C The depth of the tube under the PDMS is 1.1 mm. Fig. 13B As shown, and the sensor is laminated to the free surface of the assembly, as Fig. 13C The cannula is connected to a syringe pump through which the flow rate is varied to produce Figures 3A-3KExperimental data shown. Water was chosen as the test fluid for these experiments. The observed flow rates were 33% higher than the values ​​displayed on the pump, which were corrected by a simple linear calibration in which the true flow value was measured with accurate weight measurements on an analytical balance at fixed time intervals. The syringe pump was allowed to reach steady state at the flow rate for 180 seconds before the measurements were made. Each measurement consisted of a 60 second "off" period, Q 致动器 <0.001mW / mm 2 ; followed by a 600-second actuation ("on") period, Q 致动器 =1.45mW / mm 2 ; followed by a 180 second off period to allow the sensor to return to its pre-actuation baseline temperature value. Simultaneously, the temperature logger was recorded with an IR camera (FUR Systems, a6255sc) with a high magnification lens. Different skin thicknesses were achieved by casting PDMS onto a 3D printed mold with a negative relief structure of defined height and laminating the resulting sheet onto the above fluid assembly.

[0143] Human study design: Patients were recruited from the existing ICU population. Inclusion criteria were any patient with an implanted ventricular shunt, regardless of whether the patient was suspected of having a shunt malfunction. Patient 1 (36, F) presented with pseudotumor cerebri and suspected shunt malfunction, which was subsequently corrected surgically. Patient 2 (F, 53) presented with Chiari type I malformation and no suspected shunt malfunction. Patient 3 (M, 32) presented with glioblastoma multiforme, without suspected malfunction; and patient 4 (F, 58) presented with glioblastoma multiforme, with suspected pseudo-obstruction due to acute and prolonged constipation, which resolved with rigorous bowel examination. Patient 5 (F, 30) presented with suspected malfunction due to obstruction, with severely reduced but non-zero flow, which was confirmed during surgery. Depending on the patient's clinical condition, the patient was asked to sit at 45° or lie completely supine. A single measurement consists of placing the sensor on the skin and waiting 60 seconds for the sensor to reach equilibrium with the skin. Then a low-power thermal actuation (1.6 mW / mm 2 ) for 240 seconds and then paused for the next 120 seconds while continuous temperature measurements were taken of both the sensor and the actuator. All data recording was done at 5 Hz and processing used a neighboring average filter and a 10 point sampling window. Two consecutive measurements were taken, one on the skin overlying the shunt just above and one at a skin location adjacent to the shunt. The shunt was easy to locate and alignment marks on the device facilitated alignment. An elastomeric housing around the device facilitated handling of the device.

[0144] Table 1. Table summarizing the etiology and measurements performed for each patient.

[0145]

[0146] Table 2. Table summarizing existing shunt diagnostic tools and techniques.

[0147]

[0148] References

[0149] 1. Xu, S. et al., Soft microfluidic assemblies of sensors, circuits, and radios for the skin. Science, 2014. 344(6179): 70–74.

[0150] 2. Norton, JJ, et al. Soft, curved electrode systems capable of integration on the auricle as a persistent brain-computer interface. Proceedings of the National Academy of Sciences, 2015. 112(13): 3920–3925.

[0151] 3. Kim, J. et al., Epidermal electronics with advanced capabilities in near-field communication, Small, 2015.11(8): 906–912.

[0152] 4. Dagdeviren, C., et al., Conformal piezoelectric systems for clinical and experimental characterization of soft tissue biomechanics. Nature Materials, 2015. 14(7): 728–736.

[0153] 5. Choi, J. et al., Thin, Soft, SkinnMounted Microfluidic Networks with Capillary Bursting Valves for ChrononSampling of Sweat. Advanced healthcare materials, 2017. 6(5).

[0154] 6. Koh, A. et al. A soft, wearable microfluidic device for the capture, storage, and colorimetric sensing of sweat. Science translational medicine, 2016. 8(366): 366ra165-366ra165.

[0155] 7. Tian, ​​L. et al., Flexible and Stretchable 3ω Sensors for Thermal Characterization of Human Skin. Advanced Healthcare Materials, 2017.

[0156] 8. Krishnan, S. et al., Multimodal epidermal devices for hydration monitoring. Microsystems & Nanoengineering, 2017.3: 17014.

[0157] 9. Zhang, Y. et al., Theoretical and Experimental Studies of Epidermal Heat Flux Sensors for Measurements of Core Body Temperature, Advanced Healthcare Materials, 2016.5(1): 119-127.

[0158] 10. Webb, RC, S. Krishnan, and JA Rogers, Ultrathin, Skin-Like Devices for Precise, Continuous Thermal Property Mapping of Human Skin and Soft Tissues, Stretchable Bioelectronics for Medical Devices and Systems, Springer, 2016, pp. 117-132.

[0159] 11. Webb, RC, et al. Thermal transport characteristics of human skin measured invivo using ultrathin conformal arrays of thermal sensors and actuators. PLoS One, 2015. 10(2): e0118131.

[0160] 12. Webb, RC, et al. Epidermal devices for noninvasive, precise, and continuous mapping of macrovascular and microvascular blood flow. Sci Adv, 2015.1(9): e1500701.

[0161] 13. Hidaka, M. et al. Dynamic measurement of the flow rate in cerebrospinal fluid shunts in hydrocephalic patients. European Journal of Nuclear Medicine, 2001. 28(7): 888-893.

[0162] 14. Carslaw, HS and JC Jaeger, Conduction of heat insolids. Oxford: Clarendon Press, 1959, 2nd ed., 1959.

[0163] 15. Sandby-Moller, J., T. Poulsen and HC Wuf. Epidermal thickness at different body sites: relationship to age, gender, pigmentation, blood content, skin type and smoking habits. Acta Dermato Venereologica, 2003. 83(6): 410-413.

[0164] 16. Braley, S., The chemistry and properties of the medical-grade silicones, Journal of Macromolecular Science-Chemistry, 1970. 4(3): 529-544.

[0165] 17. Martínez-Lage, JF, et al. Severe constipation: an under-appreciated cause of VP shunt malfunction: a case-based update. Child's Nervous System, 2008. 24(4): 431-435.

[0166] 18. Ragavan, VV. Evaluation of shunt flow through a hydrocephalic shunt: a controlled model for evaluation of the performance using Shuntcheck. 2017: 1–4.

[0167] 19. Boyle, TM, J; Neuman, M; Tamber, M; Hickey, RW; Heuer, G; Leonard, J; Leonard, JC; Keating, R; Chamberlain, J; Frim, D; Zakrzewski, P; Klinge, P; Merck, L; Platt, J; Bennett, J; Sandberg, D; Boop, F; Zorc, J. ShuntCheck versus Neuroimaging for Diagnosing Ventricular Shunt Malfunction in the Emergency Department. American Association of Pediatrics, 2017: 1–2.

[0168] 20. Madsen, JR, et al. Evaluation of the ShuntCheck Noninvasive Thermal Technique for Shunt Flow Detection in Hydrocephalic Patients. Neurosurgery, 2011. 68(1): 198-205.

[0169] 21. Recinos, VA, E; Carson, B; Jallo, G. Shuntcheck, A Non-invasive Device To Assess Ventricular Shunt Flow: One Institution's Early Experience. American Association of Neurological Surgeons, 2009. Abstract: pp. 1-1.

[0170] 22. Zhang, Y., Y. Huang and JA Rogers, Mechanics of stretchable batteries and supercapacitors. Current Opinion in Solid State and Materials Science, 2015. 19(3): 190-199.

[0171] 23. Zhang, Y. H. et al., Experimental and Theoretical Studies of Serpentine Microstructures Bonded To Prestrained Elastomers for Stretchable Electronics. Advanced Healthcare Materials, 2014. 24(14): 2028-2037.

[0172] 24. Zhang, Y. et al., Mechanics of ultra-stretchable self-similar serpentine interconnects. Acta Materialia, 2013. 61(20): 7816-7827.

[0173] 25. Zhang, Y. et al. Buckling in serpentine microstructures and applications in elastomer-supported ultra-stretchable electronics with high areal coverage. Soft Matter, 2013. 9(33): 8062-8070.

[0174] Example 2: System characterization and use.

[0175] Figure 24-28 Various features of the devices and methods described herein are presented. Fig.24 The device and temperature sensor positioning are shown as well as the calculation of the subcutaneous catheter (in Fig.24 The unknowns include skin-related parameters such as the depth of the catheter from the skin surface (h 皮肤 ) and the thermal conductivity (k) and diffusivity (α) of the skin. The known parameters include the thermal conductivity (k) and diffusivity (α) of the catheter and the fluid in the catheter, the outer and inner diameters of the catheter, the upstream and downstream distances between the sensor and the actuator (labeled "heater"), and the temperature measured by the sensor and applied by the heater. Under controlled conditions, the flow rate (Q) of the fluid in the catheter can be known. Based on these parameters, the flow rate can be determined, such as Fig.25 The flow chart is summarized in the figure.

[0176] The active sensing portion of the device is very thin and therefore relatively difficult to handle. To aid in handling, any device described herein may have a handling layer, including, for example, Fig.26 A rigid layer such as a glass slide can support any of the devices described herein, including using adhesive layers and encapsulation layers. The device can be peeled from the treatment layer and prepared for conformal contact with the skin.

[0177] Figure 27-28 A carrier substrate is presented having an open channel through a central portion of the carrier substrate, wherein a conformable device is positioned in the open channel to provide improved handling characteristics during application and durability during use. Fig. 27 The carrier substrate is circular, and Fig.28 The carrier substrate in is rectangular. Any number of shapes can be used, including depending on the application and location of interest.

[0178] The sensors described herein have many potential applications in a wide range of applications including the medical field. For example, bypass vascular grafts and heart stent flows can be evaluated after surgery. This involves placing the sensor over the applicable area with an appropriate depth and quantifying the flow parameters. Similarly, sensors applied over large blood vessels can be used to help detect microemboli associated with the management of diseases such as carotid atherosclerotic disease. Finally, appropriate pressure readings can be invaluable in providing non-invasive arterial pressure measurements in the operating room or angiography suite, thereby eliminating the need for invasive arterial line placement.

[0179] Example 3: Soft tissue mounted flow sensor.

[0180] summary

[0181] Hydrocephalus and shunt-related expenses cost the U.S. system more than $2 billion annually, with 125,000 shunt surgeries performed annually and an estimated 50-60% mortality rate without treatment. Existing diagnostics are expensive, inaccurate, and often harmful or invasive and may result in unnecessary hospital admissions, further testing, or unwanted surgeries. Northwestern materials engineers, led by Dr. John Rogers, in a collaborative effort with neurosurgeons at Northwestern Memorial Hospital and Lurie Children's Hospital, have developed and validated a noninvasive thermal biosensor capable of diagnosing ventricular shunt malfunction.

[0182] application

[0183] Non-invasive, rapid and accurate detection of shunt failure

[0184] Conformable and painless sensor technology with wireless capabilities

[0185] Long-term use can catch hidden faults, similar to the Holter monitor used for cerebrospinal fluid

[0186] advantage

[0187] It is the smallest device with similar functions on the market.

[0188] Current analogs (i.e. Shuntcheck) require the use of ice, cumbersome techniques, and refills

[0189] Provides sensitive and rapid flow detection of minimal flow through silicone rubber tubing

[0190] Components and manufacturing processes that are compatible with existing scalable ISO:13485 compliance methods

[0191] Brief technical summary

[0192] Provided herein is a device that allows sensing of fluid flow through near-surface catheters (natural and implanted). Examples of these catheters include near-surface blood vessels such as veins and arteries and implanted silicone shunt catheters for draining excess cerebrospinal fluid in patients with hydrocephalus. Since near-surface flow affects heat transfer, heat from a local heat source preferentially flows in the direction of flow, so the sensor relies on the measurement of heat transfer through the skin. Earlier disclosures covered concepts related to hydrocephalus diagnosis. The present disclosure describes technologies that are also advanced clinical deployment, manufacturability, and usability for patients and physicians. The feature of the technology described below is that it is directly related to clinical deployment. Specifically, the components and technologies described below are compatible with scalable ISO:13485 compliant manufacturing methods, and the key features described are known through patient trials. These advances are important for any related technology that seeks regulatory approval from the Federal Food and Drug Administration, for example, in the form of pre-market approval (PMA) or 510 (k).

[0193] Technical Description

[0194] Fig.29 An overview of various aspects of the new platform technology and the systems and methods described herein is provided.

[0195] Sensing / actuation hardware

[0196] As an example, the sensing hardware involves a collection of thermal actuators (e.g., heating elements) and temperature sensors with a layout and form factor that allows them to map heat flow across the skin to reveal near-surface flow and its magnitude at depths up to 8 mm. The form factor of the thermal actuators and temperature sensors also allows them to be tightly coupled to the skin with low thermal mass and interface resistance. Three different technologies to achieve this are described:

[0197] Thin Film Electronic Actuators / Sensors: These describe any technology that is specifically able to respond to temperature changes with changes in its electronic properties or is able to induce local temperature changes on demand, with a total thickness of <10μm. Examples of sensing mechanisms include piezoresistive sensors made of metal or semiconductor materials that can exhibit positive or negative correlation with changes in temperature and diodes that exhibit temperature-dependent turn-on voltage. Examples of actuating elements include metal heating coils composed of metals or their alloys that exhibit Joule heating when current is applied.

[0198] Commercial Surface Mount Technologies: These describe miniaturized commercial components for temperature sensing and thermal actuation. Examples of temperature sensing technologies include positive temperature coefficient (PTC) and negative temperature coefficient (NTC) temperature sensors, typically in a surface mounted, lightweight form factor, which enable low thermal mass sensing and can be easily integrated with flexible circuit boards via reflow soldering or commercial pick and place techniques. These sensors are composed of metals, metal oxides, and polymers in some cases and are commercially available for a range of sensing applications from the automotive industry to manufacturing. Typical sizes for these sensors are 1200μm×600μm×600μm or less. These sensors exhibit temperature response times of <100 ms and are accurate to 50mK temperature changes or better. These results are characterized in Fig.30 Similarly, when wired together in series on a flexible circuit board, commercially available surface mount resistors act as thermal actuators when a voltage is applied. The spacing and layout of these components determines the local heat transport into the underlying tissue layers. Fig.31 The infrared and optical images shown demonstrate these concepts. The flexible circuit material can be composed of metals (e.g., copper, Al, nickel, chromium, or alloys / combinations thereof) or polymers (e.g., polyimide, polyetheretherketone, polyester, polyethylene terephthalate) with a combined thickness of <1 mm. Figure 35-37 Exemplary performance of these devices is shown in .

[0199] For both methods 1) and 2), a custom analog conditioning circuit is used to convert the change in piezoresistance or other electronic properties into an accurate, measurable change in voltage or current. This voltage or current is then digitized by an analog-to-digital converter (ADC), making the signal suitable for wired or wireless data transmission. This circuit can consist of a Wheatstone bridge, a voltage divider, an amplifier, and a combination of these. Fig.32 An analog circuit consisting of an NTC temperature sensor, a Wheatstone bridge and an operational amplifier and an example of circuit simulation are shown in FIG. 1 and are capable of performing temperature measurements with an accuracy of <5mK across an ADC range of 2-5V.

[0200] Optical methods: In addition to or independently of the above methods, this covers a group of techniques designed to optically measure flow through near-surface conduits such as flow splitters by thermal transport measurements. Broadly speaking, these methods can be divided into two techniques:

[0201] Colorimetric methods: The arrangement of thermochromic dyes around an actuating element as described by Gao et al. [1] allows quantitative imaging of heat flow through biological tissue. Images can be recorded with a commercial camera or with a camera built into a commercial smartphone and using image processing algorithms that can convert subtle color changes into thermal maps with a temperature resolution of <100 mK. Fig.33is an example of such a construction.

[0202] Infrared / thermal imaging: Low-cost, commercially available infrared imaging technologies allow imaging of heat transfer directly through thermal imaging cameras, many of which can be seamlessly integrated with smartphone cameras. Examples of such commercially available imagers are available at Fig.34 , there are representative examples of infrared images with flow (top) and without flow (bottom) in a benchtop system.

[0203] Both of the above optical methods require thermal actuation, which can be carried out by the method described in points 1-2 or by wireless inductive power coupling to an on-board receiver coil as described by Gao et al. [1].

[0204] Packaging and packaging

[0205] A packaging and encapsulation strategy was developed with the following objectives:

[0206] Insulation from thermal noise: The introduction of thermal foam or gel eliminates ambient convective noise. The effect of this foam is shown in Figure 35-37 In this study, the introduction of foam improved the signal-to-noise performance by an order of magnitude.

[0207] Soft, flexible, user-friendly: Adding elastomeric substrates, covers, and shells makes the appearance easy to adjust and has a soft finish. These features can be achieved by casting or molding, such as Fig.38 shown.

[0208] Strong, non-irritating adhesion to human skin: This is achieved using tailor-made silicone- or acrylate-based adhesives with adhesion energies <1000 N / m.

[0209] Easy alignment to the shunt, achieved using alignment marks.

[0210] Miniaturized form factor, alignment marks in Fig.39 As can be seen in FIG. 4 , where measurements made by the platform can clearly distinguish between the presence and absence of flow, respectively, in a patient with an implanted shunt. Fig.40 Additional examples on the palmar wrist vein and clavicle of a patient are shown in , as well as in vitro data on a temperature-controlled hot plate and representative data in the presence (venous) and absence (clavicular) of flow-induced anisotropy, respectively, demonstrating the stability of the temperature sensor. Fig.41 The sensor is shown operating in a patient with a shunt in an IRB-approved study.

[0211] Electronic Devices

[0212] The present disclosure relates to the following advanced electronic device features, particularly in the context of wearable wireless flow sensors, where there is a near-term opportunity to monitor flow through shunts in hydrocephalus patients.

[0213] Multiple temperature sensors (>2) are interfaced and multiplexed through multiple ADCs on the board of the Bluetooth chip. These temperature sensors can be addressed directly to the ADC pins or quickly addressed through a miniaturized multiplexing unit. Adding multiple sensors provides redundancy in the measurement and also ensures a larger tolerance for positioning uncertainty. Schematic diagrams and bench data from an embodiment with 4 sensors are shown in Figure 42-44 middle.

[0214] A coiled wire is included to wirelessly inductively couple power into the circuit for powering, wireless recharging, or for operating the Bluetooth chip, such as waking it from deep sleep mode. Fig.45 A schematic diagram of such a system is shown in .

[0215] Contains associated power management components such as regulators, DC-DC converters, and rectification circuit elements such as diodes and capacitors to form a full-wave or half-wave rectifier.

[0216] Power transfer is performed using a frequency compatible with the near field communication protocol (eg, 13.56 MHz).

[0217] A gate actuation scheme is used to switch the large load to an actuator with a low current output from the Bluetooth chip.

[0218] Each of the above features contributes to system-level usability, as demonstrated in multiple patient trials.

[0219] software

[0220] 1. Create a firmware embedded application (hereafter referred to as an “application”) that can operate on a Nordic Semiconductor NRF52 development board or System-on-Chip (SoC).

[0221] 2. The application will be able to read from the four temperature sensors attached to the development board at a rate of 3 samples per second or higher.

[0222] 3. The app transmits the temperature reading to the Bluetooth 4.0 stream where the data can then be received by a paired Bluetooth 4.0 enabled device.

[0223] 4. The app will have a time indicator for each temperature sample obtained. This will also be transmitted over the Bluetooth 4.0 data stream.

[0224] 5. The app will be able to activate a heating element or collection of heating elements via a button or option on the app screen.

[0225] 6. Create Windows / Android / iOS applications (hereinafter referred to as "applications") that can be operated in Windows 10 Home OS, Android or iPhone environment respectively.

[0226] 7. The app will require that the device on which the app operates supports Bluetooth 4.0 through the operating system.

[0227] application.

[0228] 8. The application will be able to read the data stream from the application.

[0229] 9. The application will be able to graph the 4 temperature readings as well as other related quantities on the same plot or on different plots.

[0230] 10. The app will be able to update the graph when new data is sent from the app.

[0231] 11. The application will be able to perform the mathematical operations associated with converting the thermal signal into a quantitative flow rate.

[0232] Additional features include but are not limited to:

[0233] Text reminders to users for regular checks.

[0234] Instructions for use, integrated directly into the app as a step-by-step guide with comics and more.

[0235] Quick link interface with hospital and / or attending physician

[0236] Fig.46 Examples of such applications are provided in .

[0237] Clinical program:

[0238] Contains clinical protocols and checklists developed with the sensor to reduce inter-operator variability and increase patient and physician use. Figures 47-48 Among them, Fig.47 Clinical data validate these regimens.

[0239] Although established shunt diagnostics are an alternative to this new technology, a competitor has developed a device based on a similar thermal principle. ShuntCheck, developed by the late Dr. Samuel Neff in 2005, utilizes an ice-pack-based thermal cooling system connected to a Windows PC DAQ. Although ShuntCheck itself has been established for 12 years, has 11 manuscripts or abstracts, has a large number of positive studies proving its value, and has more than $3 million in NIH funding, it is cumbersome and time-consuming. Until this year, there were few marketing efforts and publicity efforts. Although NeuroDX's Phase III trial is ongoing and may ultimately prove equivalent to clinical measurements, the device's cumbersome multi-step protocol, unclear or negative previous clinical studies, and the need for ice pack cooling limit its acceptance. In addition, patient discomfort due to long-term skin cooling (harmful to pediatric diagnosis) and lack of chronic monitoring further limits its diagnostic relevance.

[0240] To the best of our knowledge, there are no other comparable wireless noninvasive shunt diagnostics, either biometric or epidermal in nature, in the research literature or in the commercial arena.

[0241] References related to Example 3

[0242] 1. Gao, L. et al., Epidermal photonic devices for quantitative imaging of temperature and thermal transport characteristics of the skin. Nature Communications, 5(2014): 4938.

[0243] Example 4 - Exemplary Schematic Diagram

[0244] Fig.50 An example of a thermal sensing device 100 using an array of resistors 142 as a thermal actuator 140 is provided. The thermal actuator 140 is positioned between an upstream temperature sensor 120 and a downstream temperature sensor 130 along a possible fluid flow path, such as an artery, vein, or shunt. The temperature sensors 120, 130 and the thermal actuator 140 are all supported by a substrate 110. The upstream temperature sensor 120, the downstream temperature sensor 130, or both may be an array of temperature sensors or a plurality of temperature sensors.

[0245] In some embodiments, the device 100 may further include a power source 150 (e.g., a rechargeable battery) supported by the substrate 110 and operably connected to the temperature sensors 120, 130 and / or the thermal actuator 140. In addition, a microprocessor 160 may also be provided, which is in operative communication with the temperature sensors 120, 130 and / or the thermal actuator 140.

[0246] Fig.51 An exemplary cross-sectional schematic diagram of a thermal sensing device 100 including an insulating layer 200 and a discontinuous thermally conductive layer 210 is provided. Again, a thermal actuator 140 is positioned between an upstream temperature sensor 120 and a downstream temperature sensor 130 along a possible fluid flow path, such as an artery, a vein, or a shunt. The temperature sensors 120, 130 and the thermal actuator 140 are all supported by a substrate 110.

[0247] The temperature sensors 120, 130 and the thermal actuator 140 are encapsulated by an insulating layer 200, such as a foam that reduces external temperature interference and increases the thermal signal-to-noise ratio captured by the temperature sensors 120, 130. In some embodiments, the insulating layer 200 is further encapsulated by a cover 202. A discontinuous thermally conductive layer 210 may be included proximate the temperature sensors 120, 130, the thermal actuator 140, or both. Additionally, an adhesive layer 220 may be included for establishing and maintaining contact with the tissue of a subject or patient.

[0248] Example 5: Long-term continuous measurement of CSF hydrodynamics in vivo.

[0249] Hydrocephalus is a common and debilitating condition that causes cerebrospinal fluid to accumulate in the ventricles of the brain. This condition affects more than 1,000,000 people in the United States, including more than 350,000 children. The current standard of care for hydrocephalus is surgical implantation of a ventricular shunt assembly to drain excess fluid from the brain and into a distal absorption site, such as the peritoneal cavity. Unfortunately, the failure rate of shunts is extremely high (50% in the first two years and about 10% per year thereafter), and accurate diagnosis of shunt failure is a major clinical challenge due to ambiguous symptoms such as headaches and nausea. In addition, real-time in vivo CSF ​​hydrodynamics remain poorly understood, which has hindered the development of advanced shunt technology. For example, shunt intermittency is a well-known phenomenon, but the frequency and amplitude vary from patient to patient. Therefore, a working but intermittent shunt may be mistaken for shunt failure when tested with a shunt tap or other well-known diagnostic techniques (such as ice pack-mediated cooling). Introducing a wearable sensor based on thermal transport that relies on anisotropic thermal transport to accurately measure shunt flow rates. In this example, building on these platforms to provide a clinically focused device built entirely from commercially available components and using technology consistent with large-scale manufacturing. The resulting fully wireless, miniaturized embodiment has a set of properties that represent significant improvements in accuracy, precision, size, weight, and cost. Importantly, the size and construction of the platform allows it to be worn continuously over an extended period of time, thereby enabling the first long-term continuous measurement of CSF hydrodynamics in vivo.

[0250] Fully integrated flow sensing using commercially available components:

[0251] manufacture Fig.53AAn exploded view of the sensor is shown in . The platform utilizes commercially mature flexible circuit board (flex PCB) structuring technology and relies entirely on commercial off-the-shelf (COTS) components for operation. A commercial UV laser constructs conductive traces and bonding pads on a dense three-layer laminate of copper-polyimide-copper (18μm-75μm-18μm). Reflow soldering using low-temperature solder paste allows miniaturized surface mount device (SMD) components to be accurately and quickly placed on the circuit board. Separately, a thin silicone sheet (Silbione, Bluestar Silicone 100μm) is spin-cast onto a smooth glass slide, the surface of which is treated to be hydrophobic. Importantly, the silicone sheet is semi-cured to enhance its adhesion. Rapid curing of the entire assembly at 100°C for 120 seconds ensures a firm adhesion between the silicone and the device. The top silicone layer is then drop-molded and cured at 70°C for 60 minutes to form a 300μm cover. UV-ozone treatment of the top surface rendered it hydrophilic, and an in-situ curing of a soft, flat (3 mm) polyurethane foam layer (FlexFoam, Smooth-On Inc.) over the sensing and actuation components ensured robust isolation from ambient thermal noise. Separately, a thin (<2 mm) silicone (Silbione) shell was formed by casting a liquid precursor into a pair of custom male and female fittings ( Fig.61 ), milled from commercially available aluminum in a 3-axis CNC milling machine and cured at 100°C for 15 minutes. The cover layers on the device and housing were UV-ozone treated to form a hydrophilic interface, and the two surfaces were bonded together by curing at 70°C for 6 hours. The sensor outline was laser cut and a commercially available skin-safe laser cut adhesive was installed to complete the fabrication.

[0252] Working Principle: The sensing platform relies on the measurement of heat transfer generated by a combination of thermal sensors and actuators that are tightly thermomechanically coupled to the underlying skin using the soft, flexible construction of the device to ensure a tight thermomechanical coupling to the underlying skin. The sensing platform includes thermal actuators and a set of coplanar temperature sensors ( Fig.54A ). The actuator is constructed from a series of fixed surface mount resistors (230um x 300um x 600um) electrically connected in series and laid out in a circular densely stacked array. The packing density of the resistors represents a compromise between yield (high density exceeding the capabilities of commercial and placement technologies) and thermal transport considerations. <40Ω / mm 2 The packing density of 1.7 mW / mm2 results in uneven heat transfer and significant in-plane heat dissipation. Applying a fixed controlled voltage results in 1.7 mW / mm2 2 The local thermal actuation causes the local temperature to rise by about 5K ( Fig.54B As reported above, the presence of flow under the actuator leads to anisotropic heat transfer ( Fig.54C Commercially available negative temperature coefficient (NTC) temperature sensors composed of metal oxides form high accuracy (2 mK) low hysteresis temperature sensors whose resistance varies approximately linearly in biologically relevant regimes ( Fig.56 The low thermal mass of these elements results in an equilibrium time with the underlying tissue of approximately 60 seconds. Positioning these elements upstream and downstream of the actuator along the flow splitter direction captures the effects of flow as well as downstream and upstream temperature measurements (T 下游 , T 上游 )Fork( Figures 54D-54C ). The resulting temperature difference T = (T 下游 -T 上游 ) fits a nonmonotonic but well-understood relationship with the range of flow rates associated with CSF flow through the shunt that has been extensively described in previous reports ( Fig.54E ). By capturing the net temperature drop caused by the convection effect of the high-rate downstream flow, the average temperature of the two sensors, T 平均值 =(T 下游 +T 上游 ) / 2 to distinguish high flow values ​​from low flow values ​​with the same thermal anisotropy level ( Fig.54E ). Skin thickness plays a key role in regulating heat transfer to the underlying shunt, and increased skin thickness will result in a reduced signal-to-noise ratio, with 6 mm representing the outer limit of reliable measurements.

[0253] Positioning uncertainty and ambient thermal noise represent two key potential sources of error. Positioning uncertainty is reduced by the following steps: 1) Adding two additional temperature sensors (one each upstream and downstream) provides increased positioning and rotational tolerance. Figure 61-62 These effects are shown in , where the sensor can accommodate up to 5 mm of positioning uncertainty and about 23° of rotational uncertainty. 2) Adding alignment marks along the centerline of the sensor / actuator axis (see Fig.53B ) allows the physician / practitioner to align the device immediately after palpating the shunt. 3) If Fig.64 As shown, adding an insulating layer (such as a foam layer) above the sensing / actuating element significantly reduces the ambient thermal noise. Therefore, the apparatus and method provided herein can be described as having rotational and / or translational positioning tolerances, including accommodating up to 23 degrees of rotational misalignment and / or up to 5 mm of translational misalignment without significantly affecting performance. This is a significant improvement because in use, the actual challenge is to achieve precise alignment with the flow conduit below.

[0254] Wireless Electronics and Signal Conditioning:

[0255] Converting the temperature-induced resistance change on the NTC into a voltage that can be digitized relies on a Wheatstone bridge ( Fig.59 ). The voltage difference across the two arms of the bridge (sensing and non-sensing arms) is fed into the inverting and non-inverting inputs of an operational amplifier whose gain is tuned by a feedback resistor. The amplified signal is digitized by a 12-bit analog-to-digital converter (ADC) built into the Bluetooth Low Energy (BLE) system-on-chip (SoC), with a full sensing range of 3.3V. The resulting sensor operates linearly over a temperature range between 28°C and 40°C with an accuracy of 3.5mK. Controlled thermal actuation is produced by supplying a controlled voltage directly to the resistor array in a manner that can be controlled via a metal oxide semiconductor field effect transistor (MOSFET), the gate of which is switched by a general purpose input / output (GPIO) pin on the BLE SoC. The actuation power can be tuned by pulsing the MOSFET with a programmable duty cycle.

[0256] When not in use, the device platform operates in a low energy deep "sleep" mode consuming approximately 30nA of current. Operation of the momentary switch turns the device on, followed by a programmable advertising period. If pairing does not occur, the device reverts to deep sleep mode, and pairing results in normal operation. Figures 60A-60D This approach is shown in .

[0257] Data acquisition relies on a graphical interface on a tablet PC that can record and display temperature values ​​from 4 ADCs, while also providing means for controlling thermal actuation ( Fig.53D ).

[0258] Notice Regarding Incorporation by Reference and Modifications

[0259] Throughout this application, all references, such as patent documents, including issued or issued patents or their equivalents, patent application publications, and non-patent literature documents or other sources of material are incorporated herein by reference in their entirety, as if individually incorporated by reference, to the extent each reference is at least partially not inconsistent with the disclosure in this application (e.g., a partially inconsistent reference is incorporated herein by reference except for the partially inconsistent portion of the reference).

[0260] The terms and expressions that have been adopted herein are used as descriptive rather than limiting terms, and it is not intended that any equivalents of the features shown and described or parts thereof be excluded by the use of such terms and expressions, but it should be recognized that various modifications are possible within the scope of the claimed invention. Therefore, it should be understood that although the present invention has been specifically disclosed through preferred embodiments, exemplary embodiments and optional features, those skilled in the art may make modifications and changes to the concepts disclosed herein, and such modifications and changes are considered to be within the scope of the invention as defined by the appended claims. The specific embodiments provided herein are examples of useful embodiments of the present invention, and it will be apparent to those skilled in the art that a large number of changes in the devices, device components, and method steps set forth in this specification can be used to implement the present invention. As will be apparent to those skilled in the art, the methods and devices that can be used for the methods of the present invention may include a large number of optional components and processing elements and steps.

[0261] When a group of substitutes is disclosed herein, it should be understood that all individual members and all subgroups of the group are disclosed separately. When Markush groups or other groupings are used herein, all individual members of the group and all combinations and subcombinations possible of the group are intended to be individually included in the disclosure.

[0262] Unless otherwise stated, every formulation or combination of components described or exemplified herein can be used to practice the present invention.

[0263] Whenever a range is given in this specification, such as a numerical range, thickness range, modulus range, temperature range, time range, or thermal conductivity range, it is intended that all intermediate ranges and subranges, as well as all individual values ​​contained within the given range, are included in the disclosure. It should be understood that any subrange or individual value contained within a range or subrange in the description herein may be excluded from the claims herein.

[0264] All patents and publications mentioned in this specification indicate the technical level of the technical personnel in the field to which the present invention belongs. The references cited herein are incorporated herein by reference in their entirety to indicate the state of the art as of their disclosure or filing date, and it is intended that this information can be adopted herein when necessary to exclude specific embodiments in the prior art. For example, when claiming the composition of a substance, it should be understood that compounds known and available in the art before the applicant's invention (including compounds that enable disclosure provided in the references cited herein) are not intended to be included in the composition of the substance claim herein.

[0265] As used herein, "comprising" is synonymous with "including", "containing" or "characterized by" and is inclusive or open and does not exclude additional, unlisted elements or method steps. As used herein, "consisting of" excludes any element, step or ingredient not specified in the claim element. As used herein, "consisting essentially of" does not exclude materials or steps that do not substantially affect the basic and novel characteristics of the claim. In each case herein, any of the terms "comprising", "consisting essentially of" and "consisting of" can be replaced with any of the other two terms. The present invention, which is appropriately illustratively described herein, can be practiced in the absence of any one or more elements, one or more limitations not explicitly disclosed herein.

[0266] It will be appreciated by those of ordinary skill in the art that starting materials, biological materials, reagents, synthetic methods, purification methods, analytical methods, assay methods, and biological methods other than those specifically exemplified may be employed in the practice of the present invention without undue experimentation. All functional equivalents known in the art for any such materials and methods are intended to be included in the present invention. The terms and expressions that have been adopted are used as illustrative rather than limiting terms, and it is not intended to exclude any equivalents of the features shown and described or parts thereof using such terms and expressions, but it will be appreciated that various modifications are possible within the scope of the claimed invention. Therefore, it will be appreciated that, although the present invention has been specifically disclosed by preferred embodiments and optional features, those skilled in the art may modify and alter the concepts disclosed herein, and such modifications and alterations are considered to be within the scope of the present invention as defined by the appended claims.

[0267] surface

[0268] Table 3: Calorimetric and geometric quantities required to quantitatively measure flow rate.

[0269] quantity unit Range / Value Measurement <![CDATA[k 皮肤 ]]> <![CDATA[Wm -1 K]]> 0.30-0.50 In vivo, using epidermal transient planar sources <![CDATA[α 皮肤 ]]> <![CDATA[ 2-1 ]]> 0.07-0.15 In vivo, using epidermal transient planar sources <![CDATA[H 对流 ]]> <![CDATA[Wm -2 K]]> 6-25 In vitro, fitting with the model <![CDATA[k CSF ]]> <![CDATA[Wm -1 K]]> 0.5-0.6 A priori known <![CDATA[α CSF ]]> <![CDATA[ 2-1 ]]> 0.13-0.16 A priori known <![CDATA[k 置管 ]]> <![CDATA[Wm -1 K]]> 0.22 A priori known <![CDATA[α 置管 ]]> <![CDATA[ 2-1 ]]> 0.12 A priori known <![CDATA[h 皮肤 ]]> mm 1.5 Radiological and acoustic imaging, transient thermal measurements <![CDATA[ID 置管 ]]> mm 1.0 A priori known <![CDATA[OD 置管 ]]> mm 1.5 A priori known

[0270] Table 4: Summary of etiology and measurements performed for each patient.

[0271]

[0272] 1. The patient had a visualized kink in the neck area on x-ray after the initial surgery and clinically deteriorated the morning after the initial shunt placement. Radionuclide shunt studies showed distal flow abnormalities.

[0273] 2. The patient deteriorated post-operatively and had a significant stool burden on abdominal CT. With the administration of a bowel regimen, the patient improved clinically and the sensor readings verified resolution of the pseudo-obstruction.

[0274] 3. During final testing, the device was accidentally destroyed and no postoperative readings could be obtained. Due to concomitant distal and partial proximal obstruction, the patient was noted to have a change in flow pattern during inspiration and expiration, corresponding to the low drainage rates seen in the OR.

[0275] 4. CT scan demonstrated septal ventriculomegaly; radionuclide studies demonstrated abnormal flow pattern; X-ray and abdominal CT demonstrated that the catheter was mispositioned extraperitoneally near the liver with adjacent fluid accumulation (probably CSF).

[0276] Table 5: Raw data measured for each patient

[0277]

[0278] Table 6: Summary of technical difficulties and solutions during patient experiments.

[0279]

[0280]

Claims

1. A conformable device for measuring subcutaneous fluid flow, comprising: a substrate, wherein the substrate is soft, stretchable and flexible; a thermal actuator supported by the substrate; an upstream temperature sensor supported by the substrate; a downstream temperature sensor supported by the substrate, wherein the upstream temperature sensor and the downstream temperature sensor are relatively positionable relative to the thermal actuator to measure an upstream temperature of the thermal actuator with the upstream temperature sensor and to measure a downstream temperature of the thermal actuator with the downstream temperature sensor; an actuator reference sensor supported by the substrate, wherein the actuator reference sensor is spaced a reference sensor spacing distance from a notional line connecting the upstream temperature sensor and the downstream temperature sensor to measure an effect of the actuator independent of flow in a conduit beneath the conformable device during use; an environmental reference sensor supported by the substrate, wherein the environmental reference sensor is spaced from the notional line connecting the upstream temperature sensor and the downstream temperature sensor by an environmental reference sensor spacing distance that is sufficiently large so that an environmental reference sensor reading is substantially independent of a thermally actuated condition; A microprocessor is in electronic communication with the actuator reference sensor, the environmental reference sensor, the downstream temperature sensor, and the upstream temperature sensor, the microprocessor being configured to calculate subcutaneous fluid flow in the catheter based on the measured upstream and downstream temperatures.

2. The conformable device of claim 1, comprising a high-density array of temperature sensors supported by a soft and flexible substrate surrounding the thermal actuator.

3. The conformable device of claim 1 or 2, wherein the temperature sensor comprises one or more thin film temperature sensors or thermistors.

4. The conformable device of claim 1 or 2, wherein the temperature sensor is one or more of: a diode temperature sensor, a positive temperature coefficient of resistance sensor, a negative temperature coefficient of resistance sensor, or a colorimetric temperature sensor.

5. The conformable device of claim 2, wherein the high density array of temperature sensors comprises at least 100 sensors to provide a thermal spatial resolution of at least nearly 500 μm and a flow rate accuracy of ±20%.

6. The conformable device of claim 1, 2 or 5, further comprising a wireless communication component for wirelessly connecting the microprocessor to the temperature sensor.

7. The conformable device of claim 1, 2 or 5, further comprising a wireless communication component for wirelessly connecting the device to a microcontroller, wherein the microcontroller provides on-demand actuation of the thermal actuator.

8. The conformable device of claim 7, wherein the microcontroller and the microprocessor are located in a portable device, the portable device comprising a handheld device, a laptop computer, or a workstation.

9. The conformable device of claim 8, further comprising a computer-implemented application on the portable device or workstation for controlling and monitoring the conformable device.

10. The conformable device of claim 1, 2 or 5, wherein the microprocessor is configured to signal an out-of-tolerance flow condition where a fluid flow rate in the conduit is below a user-specified flow rate.

11. The conformable device of claim 7, wherein the microcontroller is operably connected to a flow control assembly to adjust the flow rate in the conduit.

12. The conformable device of claim 1, 2 or 5, further comprising one or both of a battery and an NFC component for wireless rechargeable circuitry to power the actuator and the microprocessor.

13. The conformable device of claim 1, 2 or 5, wherein the microprocessor is configured to calculate subcutaneous fluid flow based on a plurality of flow calculation parameters selected from one or more of the following: Skin thermal conductivity, Skin thermal diffusivity; Heat transfer coefficient, Thermal conductivity of the fluid in the subcutaneous catheter, thermal diffusivity of the fluid contained in the conduit; the thermal conductivity of the subcutaneous catheter in which the fluid flows, thermal diffusivity of the subcutaneous catheter; the depth of the subcutaneous fluid flow, The inner and outer diameters of the subcutaneous catheter and Actuator temperature.

14. The conformable device of claim 1, 2 or 5, wherein the microprocessor is located: on a plate of a substrate supporting the actuator sensor and thermal sensor; or The substrate supporting the actuator sensor and the thermal sensor is off-board; wherein the microprocessor is in wireless communication with the thermal sensor.

15. The conformable device of claim 1, 2 or 5 having a total thickness less than 100 μm and an effective device Young's modulus less than 5 MPa and an effective substrate Young's modulus less than 100 kPa.

16. The conformable device of claim 1, 2 or 5, having a mass density of less than 100 mg / cm 2 .

17. The conformable device of claim 1, 2 or 5, wherein the flexibility is characterized by a bending stiffness that provides conformability to an underlying skin surface, wherein the bending stiffness is less than or equal to 1 mN m.

18. The conformable device of claim 1, 2 or 5, having a thickness between 1 cm and 1 cm that can be attached to the skin surface. 2 With 25cm 2 The total occupied area between.

19. The conformable device of claim 1, 2 or 5, wherein device stretchability, flexibility and bending parameters are matched to corresponding parameters of underlying skin during use.

20. The conformable device of claim 1, 2 or 5, further comprising a carrier substrate having an open channel through a central portion of the carrier substrate, wherein the conformable device is positioned in the open channel to provide improved handling characteristics during application and durability during use.

21. The conformable device of claim 20, wherein the thickness (t sub ) is greater than the conformable device thickness (t dev ).

22. The conformable device of claim 19, wherein the effective Young's modulus of the substrate is higher than the effective Young's modulus of a soft and flexible substrate supporting the thermal actuator and the upstream and downstream temperature sensors.

23. The conformable device of claim 1, 2 or 5, configured to operate continuously for an operating life greater than or equal to 72 hours or an operating life at least corresponding to the length of time of a hospital stay.

24. The conformable device of claim 1, 2 or 5, further comprising an adhesive layer in adhesive contact with the skin-facing surface of the soft and flexible substrate.

25. The conformable device of claim 1, 2 or 5, further comprising an encapsulation layer for encapsulating electronically active components supported by the soft and flexible substrate.

26. The conformable device of claim 1, 2 or 5, further comprising a power source for powering the sensor, the actuator and the microprocessor, wherein the device has a maximum thickness corresponding to the positioning of the power source and a minimum thickness corresponding to the positioning of the temperature sensor.

27. The conformable device of claim 1, 2 or 5, wherein the catheter is a cannula positioned subcutaneously between 0.5 mm and 4 mm from the skin surface.

28. The conformable device of claim 26, wherein the catheter corresponds to a ventricular shunt.

29. The conformable device of claim 28, wherein the ventricular shunt is part of a cerebrospinal shunt for treating hydrocephalus and contains a flow of cerebrospinal fluid (CSF).

30. The conformable device of claim 1, 2 or 5, configured to provide real-time quantitative flow rate in a non-invasive and wireless manner.

31. A method of determining fluid flow in a subcutaneous catheter, the method comprising the steps of: conformably mounting the substrate of any one of the conformable devices according to claims 1 to 30 onto the skin covering the subcutaneous catheter; actuating a thermal actuator to heat underlying skin and the subcutaneous catheter; measuring a temperature upstream and downstream of the thermal actuator and spatially aligned with the conduit using an upstream temperature sensor and a downstream temperature sensor; processing the measured temperature with a microprocessor to determine a flow rate in the subcutaneous catheter; and Wherein the measured temperature or the flow rate is provided wirelessly to a handheld device or computer for real-time monitoring, and optionally, the determined flow rate is provided to a display on the handheld device or computer.

32. The method of claim 31, wherein the subcutaneous catheter corresponds to a blood vessel.

33. The method of claim 31, wherein the subcutaneous catheter corresponds to a manually placed shunt.

34. The method of claim 33, wherein the shunt is a ventricular shunt placed to treat hydrocephalus.

35. The method of claim 34, further comprising the step of generating an alert to the handheld device or computer for out of range flow conditions.

36. The method of claim 34 or 35, further comprising the step of actuating a flow valve to control the flow rate of fluid in the diverter.

37. The method of claim 31, 32, 33, 34 or 35 having a power of between 0.5 and 5 mW / mm 2 to increase the signal-to-noise ratio of the temperature measurements.

38. The method of claim 31, 32, 33, 34 or 35, wherein data from the conformable device is acquired wirelessly.

39. The method of claim 31, 32, 33, 34 or 35, further comprising the steps of: The device is personalized for the individual patient.

40. The method of claim 39, wherein the step of personalizing comprises: Flow rates in the catheters were quantitatively assessed immediately after surgery and at initial follow-up assessments thereafter to establish baseline flow rates.

41. The method of claim 31, 32, 33, 34 or 35, further comprising the step of telemetrically interacting with the conformable device on a patient at a distance from a clinical setting.

42. An apparatus for measuring a subcutaneous fluid flow parameter, comprising: substrate; at least one upstream temperature sensor, the at least one upstream temperature sensor being supported by the substrate; at least one downstream temperature sensor, the at least one downstream temperature sensor being supported by the substrate; as well as a thermal actuator supported by the substrate and positioned between the upstream temperature sensor and the downstream temperature sensor; wherein the thermal actuator comprises a resistor array having a cumulative resistivity sufficient to provide thermal actuation such that the upstream temperature sensor measures an upstream temperature and the downstream temperature sensor measures a downstream temperature to allow determination of the subcutaneous fluid flow parameters; and wherein the resistor array of the thermal actuator provides a fill factor selected from the range of 10% to 60% of the area between the upstream temperature sensor and the downstream temperature sensor.

43. The apparatus of claim 42, further comprising a microprocessor in electronic communication with the downstream temperature sensor and the upstream temperature sensor to calculate a subcutaneous fluid flow parameter based on the measured upstream and downstream temperatures.

44. The device of claim 42 or 43, wherein the area between the upstream temperature sensor and the downstream temperature sensor is 5%-60% of the total printed circuit board footprint of the device.

45. The device of claim 42 or 43, wherein the thermal actuator comprises 10 to 30 resistors operably connected to a power source.

46. ​​The device of claim 42 or 43, wherein each of the resistors independently has a resistance selected from the range of 15 ohms to 40 ohms.

47. A device according to claim 42 or 43, wherein each of the resistors in the array is independently separated from an adjacent resistor by less than 1.5 mm.

48. A device as claimed in claim 42 or 43, wherein adjacent resistors in the array are characterized by an average separation distance selected in the range of 0.5 mm to 3 mm.

49. The device of claim 42 or 43, wherein the resistor array is characterized by being sufficient to provide a current at 0.5 mW / mm 2 Up to 3mW / mm 2 The spacing and cumulative resistance per unit area are selected within the range of thermal power.

50. The device of claim 42 or 43, wherein the resistors are arranged in one or more of a circular array, a concentric circular array, a square array, a series of concentric square arrays, a linear array, or any combination.

51. The device of claim 42 or 43, wherein the subcutaneous fluid flow parameter is selected from the group consisting of fluid flow rate, volume of fluid flow, presence or absence of fluid flow, presence or absence of occlusion, thermal conductivity, heat capacity, time-dynamic flow rate variation, or any combination of these.

52. The apparatus of claim 42 or 43, further comprising 2 to 8 upstream temperature sensors.

53. The apparatus of claim 42 or 43, further comprising 2 to 8 downstream temperature sensors.

54. A device for measuring subcutaneous tissue parameters, comprising: substrate; a thermal actuator supported by the substrate; at least one temperature sensor, the at least one temperature sensor being supported by the substrate; as well as A discontinuous thermally conductive layer is positioned between the substrate and the at least one temperature sensor, the thermal actuator, or both, wherein the thermally conductive layer is characterized by a thermal conductivity greater than or equal to 20 W / m*K.

55. The device of claim 54, wherein the thermally conductive layer is characterized by a thermal conductivity selected from the range of 20 W / m*K to 2000 W / m*K.

56. The apparatus of claim 54 or 55, wherein the thermally conductive layer comprises a metal, a carbon-based material, a silicone-based polymer composite, or any combination of these.

57. The device of claim 54 or 55, wherein the thermally conductive layer comprises copper, aluminum, constantan, nickel, gold, silver, or any combination thereof.

58. The device of claim 54 or 55, wherein the thermally conductive layer is diamond or graphite.

59. The device of claim 54 or 55, wherein the thermally conductive layer is a silicone elastomer matrix loaded with thermally conductive particles or tubes.

60. The device of claim 54 or 55, wherein the thermally conductive layer covers 5% to 30% of the inwardly facing interface area of ​​the substrate.

61. The device of claim 54 or 55, wherein the thermally conductive layer covers 15% to 30% of the total printed circuit board footprint of the device.

62. The device of claim 54 or 55, wherein the thermally conductive layer has a thickness selected from the range of 5 μm to 100 μm.

63. The device of claim 54 or 55, further comprising an insulating layer supported by the substrate, wherein the insulating layer thermally insulates the thermal actuator and the temperature sensor.

64. The apparatus of claim 54 or 55, wherein the at least one temperature sensor comprises an upstream temperature sensor and a downstream temperature sensor.

65. The device of claim 54 or 55, further comprising a microprocessor in electronic communication with the temperature sensor to calculate subcutaneous fluid flow based on the measured upstream and downstream temperatures.

66. A device according to claim 54 or 55, wherein the subcutaneous tissue parameter is selected from the group consisting of: fluid flow rate, volume of fluid flow, presence or absence of fluid flow, presence or absence of occlusion, hydration status, thermal conductivity, tissue composition, tissue density, onset of disease conditions, susceptibility to disease conditions, effectiveness of treatment, or any combination of these.

67. The device of claim 42, 43, 54 or 55, further comprising an adhesive layer connected to the substrate.

68. The device of claim 67, wherein the adhesive layer is positioned proximate to the substrate and adheres to the skin or tissue of a subject during use.

69. The device of claim 67, wherein the adhesive layer provides an adhesion energy selected from the range of 100 N / m to 500 N / m.

70. The device of claim 67, wherein the adhesive layer comprises a silicone-based polymer or gel, an acrylate-based polymer or gel, a cyanoacrylate-based polymer or gel, an acrylamide-based polymer or gel, or any combination thereof.

71. The device of claim 24, wherein the adhesive layer comprises a hydrogel.

72. The device of claim 42, 43, 54 or 55, wherein the device is a wearable device.

73. The device of claim 42, 43, 54 or 55, wherein the device is a tissue mounting device.

74. The device of claim 42, 43, 54 or 55, wherein the device is a skin-mounted device.

75. The device of claim 74, wherein the interface of the device with the skin is characterized by an adhesion energy selected from the range of 100 N / m to 500 N / m.

76. The device of claim 42, 43, 54 or 55, wherein the device is an internal tissue mounting device.

77. The device of claim 42, 43, 54 or 55, wherein the device is a conformable device.

78. The device of claim 42, 43, 54 or 55, wherein the device is encapsulated in an encapsulation layer.

79. The device of claim 78, wherein the device is completely encapsulated in an encapsulation layer.

80. The device of claim 78, wherein the encapsulation layer comprises a substrate, a cover, or both.

81. The device of claim 42, 43, 54 or 55, wherein the device further comprises a rechargeable battery supported by the substrate for providing power.

82. The device of claim 81, wherein the rechargeable battery is configured to be charged wirelessly.

83. The apparatus of claim 42, 43, 54 or 55, further comprising an energy harvester configured to be powered wirelessly.

84. The device of claim 42, 43, 54 or 55, wherein the device has a Young's modulus less than or equal to 1000 MPa.

85. The device of claim 42, 43, 54 or 55, wherein the device has a net bending stiffness less than or equal to 10 mN m.

86. The device of claim 42, 43, 54 or 55, wherein the device has a thickness less than or equal to 10 cm.

87. The device of claim 42, 43, 54 or 55, wherein the substrate has a Young's modulus less than or equal to 100 MPa.

88. The device of claim 42, 43, 54 or 55, wherein the Young's modulus of the substrate is less than or equal to the Young's modulus of epidermal tissue.

89. The device of claim 42, 43, 54 or 55, wherein the substrate has a net bending stiffness less than or equal to 1 mN m.

90. The apparatus of claim 42, 43, 54 or 55, wherein the substrate has a thickness less than or equal to 100 mm.

91. The device of claim 42, 43, 54 or 55, wherein the substrate has a Shore 00 hardness less than or equal to 80.

92. The device of claim 42, 43, 54 or 55, wherein the device has a diameter selected from 1 cm 2 Up to 25cm 2 The occupied area of ​​the range.

93. The device of claim 42, 43, 54 or 55, wherein the thermal actuator provides a power selected from 0.5 mW / mm 2 and 5mW / mm 2 range of energy.

94. The device of claim 42, 43, 54 or 55, wherein the device provides a feedback signal to a user at a threshold value of the subcutaneous fluid flow parameter.

95. The apparatus of claim 94, wherein the threshold is personalized for the user.

96. The apparatus of claim 42, 43, 54 or 55, further comprising a wireless communication system.

97. The apparatus of claim 96, wherein the wireless communication system is a two-way wireless communication system.

98. The device of claim 96, wherein the wireless communication system is used to send an outgoing signal from the device to an external device.

99. An apparatus as claimed in claim 42, 43, 54 or 55, which continuously monitors and generates real-time metrics.

100. The apparatus of claim 96, wherein the wireless communication system provides real-time metrics to a clinician or caregiver.

101. The apparatus of claim 99, wherein said real-time metric corresponds to flow through a blood vessel, shunt, catheter, or stent.

102. The apparatus of claim 99, wherein said real-time metric corresponds to flow through a ventricular shunt for treating hydrocephalus.

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