U.S. patent application number 17/568791 was filed with the patent office on 2022-04-28 for wireless and noninvasive epidermal electronics.
The applicant listed for this patent is NORTHWESTERN UNIVERSITY. Invention is credited to Amit B. Ayer, Philipp Gutruf, Siddharth Krishnan, Kun Hyuck Lee, Tyler R. Ray, Jonathan T. Reeder, John A. Rogers, Chun-Ju Su.
Application Number | 20220125390 17/568791 |
Document ID | / |
Family ID | 1000006075594 |
Filed Date | 2022-04-28 |
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United States Patent
Application |
20220125390 |
Kind Code |
A1 |
Rogers; John A. ; et
al. |
April 28, 2022 |
WIRELESS AND NONINVASIVE EPIDERMAL ELECTRONICS
Abstract
Provided are conformable devices to measure subdermal fluid flow
and related methods. A soft, stretchable and flexible substrate
supports a thermal actuator and various specially positioned
temperature sensors. A microprocessor in electronic communication
with sensors calculates subdermal fluid flow from the measured
upstream and downstream temperatures, as well as various
application-dependent parameters. Devices and methods provided
herein are particularly useful for measuring cerebral spinal fluid
in a ventricular shunt placed for treatment of hydrocephalus.
Inventors: |
Rogers; John A.; (Wilmette,
IL) ; Krishnan; Siddharth; (Evanston, IL) ;
Ray; Tyler R.; (Evanston, IL) ; Ayer; Amit B.;
(Evanston, IL) ; Gutruf; Philipp; (Evanston,
IL) ; Reeder; Jonathan T.; (Evanston, IL) ;
Lee; Kun Hyuck; (Morton Grove, IL) ; Su; Chun-Ju;
(Evanston, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NORTHWESTERN UNIVERSITY |
Evanston |
IL |
US |
|
|
Family ID: |
1000006075594 |
Appl. No.: |
17/568791 |
Filed: |
January 5, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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17043111 |
Sep 29, 2020 |
11259754 |
|
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PCT/US2019/025009 |
Mar 29, 2019 |
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17568791 |
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62791390 |
Jan 11, 2019 |
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62650826 |
Mar 30, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/7278 20130101;
A61B 2562/18 20130101; A61B 2562/0271 20130101; A61B 5/01 20130101;
A61B 2562/164 20130101 |
International
Class: |
A61B 5/00 20060101
A61B005/00; A61B 5/01 20060101 A61B005/01 |
Claims
1. A device to measure a subdermal tissue parameter comprising: a
substrate; a thermal actuator supported by the substrate; at least
one temperature sensor supported by the substrate; and an
insulating layer supported by the substrate, wherein the insulating
layer thermally insulates the thermal actuator and the temperature
sensor; wherein the insulating layer is characterized by a thermal
conductivity less than or equal to 0.1 W/m*K.
2. The device of claim 1, wherein the insulating layer is
characterized by a thermal conductivity selected from the range of
0.01 W/m*K to 0.1 W/m*K
3. The device of claim 1, wherein the insulating layer at least
partially encapsulates said the thermal actuator and the
temperature sensor.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S. patent
application Ser. No. 17/043,111, filed Sep. 29, 2020, now allowed,
which is a national stage entry of PCT Patent Application Serial
No. PCT/US2019/025009, filed Mar. 29, 2019, which itself claims the
benefit of and priority to U.S. Provisional Patent Application No.
62/650,826 filed Mar. 30, 2018, and U.S. Provisional Patent
Application No. 62/791,390, filed Jan. 11, 2019, each of which is
specifically incorporated by reference in its entirety to the
extent not inconsistent herewith.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not applicable.
BACKGROUND OF INVENTION
[0003] Hydrocephalus and shunt-related expenditures cost the US
system over $2 billion dollars in annual expenses, with 125,000
shunt surgeries per year and an untreated mortality rate estimated
at 50-60%. Existing diagnostics are expensive, inaccurate, and
often harmful or invasive, and can lead to unnecessary admissions,
further testing, or needless surgery. To address these issues,
provided herein is a noninvasive, thermal biosensor capable of
diagnosing ventricular shunt malfunction.
[0004] Hydrocephalus is a common and costly condition caused by the
accumulation of cerebrospinal fluid in the brain. It occurs in 1-5
of every 1000 live births, and over 70,000 patients are admitted
and diagnosed yearly in the United States. Cerebrospinal fluid
(CSF) is produced within the ventricles of the brain and is
responsible for its nourishment and protection, but dysfunction in
its drainage or reabsorption can lead to devastating neurological
complications. Symptoms may include headache, lethargy, seizures,
coma, or death, and untreated hydrocephalus has a mortality rate
estimated at 50-60%. Pediatric hydrocephalus accounts for 38% of
patients, and related surgeries are the most common neurosurgical
procedures performed in children. Adult hydrocephalus can be seen
as the sequelae to many conditions (such as tumors, trauma and
infection) or in normal pressure hydrocephalus (NPH), an
increasingly diagnosed condition which currently affects 375,000
patients in the United States. Often underdiagnosed or misdiagnosed
for dementia and with 25% of those diagnosed shunted, this
represents a growing segment of hydrocephalus related care. The
mainstay of treatment for hydrocephalus involves the use of CSF
diversion accomplished through devices known as ventricular shunts.
These surgically implanted devices consist of a catheter draining
from the ventricle to a distal site (such as the peritoneum,
pleural cavity, or right atrium of the heart) and regulated by a
valve. Unfortunately, shunts have extremely high failure rates;
most children undergo 2-3 surgical revisions before adulthood and
30% are expected to have at least 1 revision operation in the first
year, with rates approaching 98% by 10 years in some studies.
[0005] ShuntCheck.RTM. utilizes an ice-pack based thermal cooling
system connected to a Windows PC DAQ to address a need for shunt
monitoring. That technology, however, is cumbersome and
time-consuming. The device's cumbersome, multi-step protocol;
equivocal or negative past clinical studies; and need for ice-pack
cooling have limited its acceptance. Additionally, patient
discomfort due to prolonged skin cooling (detrimental for pediatric
diagnostics) and absence of chronic monitoring further limits its
diagnostic relevance. Accordingly, there is a need for a wireless
noninvasive shunt diagnostic, that is conformable to skin and has
epidermal-like mechanical properties.
SUMMARY OF THE INVENTION
[0006] The devices presented herein provide a platform for
measuring flow in subdermal conduits and are advantageously
non-invasive and rapid, while preserving a high level of accuracy.
The devices may be conformal to skin and wireless without a need
for hard-wire connection to bulky external components, such as
controllers, digital monitors and power supplies. In this manner,
the device is painless and non-obtrusive to a patient, akin to
wearing an adhesive bandage.
[0007] One particular application for any of the devices and
methods described herein is detection of shunt malfunction,
specifically ventricular shunts. Extended use can capture occult
malfunction, akin to a holter monitor for cerebrospinal fluid.
[0008] Provided herein is a soft, wireless, noninvasive,
non-surgical, skin-mounted device for the continuous measurement of
fluid flow in a subdermal conduit, such as shunt-based CSF flow.
The epidermal device exploits the precise measurement of thermal
transport to characterize CSF flow in underlaid shunts. The device
platform is ultrathin (<100 .mu.m), soft (70 kPa), flexible
resulting in a continuously wearable device mechanically invisible
to the wearer. Similar in size to a Band-Aid.RTM. adhesive bandage,
the device is composed primarily of soft, silicone rubber (no hard
edges) and transmits recorded data wirelessly via Bluetooth to a
companion mobile app. Patient data and in vitro tests confirm
device efficacy in producing clinical-quality data suitable for
shunt malfunction diagnostics. To assist in handling durability and
device placement, a carrier substrate having an open passage
through a central portion of the carrier substrate, may be provided
around the active sensors region, where intimate conformal contact
is desired. The carrier substrate may have a relatively larger
mechanical parameter compared to the substrate that supports the
sensors, 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., does not tear during application and use) but
without sacrificing conformability and patient comfort.
[0009] The devices and methods described herein provide a
fundamental 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.
[0010] The claims appended herein are specifically incorporated by
reference herein and form part of the application.
[0011] Provided herein are various conformable devices capable of
reliably, accurately, and continuously measuring subdermal fluid
flow, including in a conduit. Various active components are
supported by a substrate, such as a substrate that is characterized
as soft, stretchable and flexible. A thermal actuator, an upstream
temperature sensor and a downstream temperature sensor is supported
by the substrate. A microprocessor is in electronic communication
with the temperature sensors and other relevant components, such as
the actuator, to calculate subdermal fluid flow from the measured
upstream and downstream temperatures. Such a configuration
maximizes patient comfort during use, facilitating long-term
monitoring of fluid flow. Any of the devices may be wireless,
further facilitating low patient impact monitoring, including
without a need for hard-wire connections. In this manner, the
patient may even return to home, without adversely impacting
monitoring.
[0012] To further increase the accuracy and reliability of fluid
flow measurement, any of the devices described herein may have
additional temperature sensors. The position of those sensors may
be described relative to a notional line (e.g., imaginary) line
that is formed by drawing a line over spatially aligned upstream
sensor, actuator, and downstream sensor. The additional sensors
function as reference sensors and assist with determining various
skin properties and related convection-type properties, for
example, useful in determining fluid flow rate and the effect of
the actuator independent of flow. Preferably, at least one sensor
is positioned so that a temperature reading is obtained that is
independent of whether or not the thermal actuator is actuated.
[0013] Also provided is a method of determining fluid flow in a
sub-dermal conduit by any of the devices described herein. For
example, a device is conformally mounted to skin that overlays the
sub-dermal conduit. The thermal actuator is actuated to heat the
underlying skin and sub-dermal conduit. Temperature upstream and
downstream of the thermal actuator is measured wherein the sensors
measuring the temperature are spatially aligned with the conduit.
The microprocessor processes the measured temperatures to determine
a flow-rate in the sub-dermal conduit. The determined flow-rate is
transmitted to a display on a handheld device or computer.
Preferably the method is wireless and data generated from the
conformal device is wirelessly provided to the handheld device or
computer for real-time monitoring.
[0014] Further, described herein are resistive heating thermal
actuators utilizing an array of resistor components that provide
heating upon application of an electrical current or potential.
These thermal actuators may utilize various resistors known in the
art, in some cases arranged in an array (e.g. circular, square,
linear) to precisely provide thermal energy to allow for various
measurements provided herein.
[0015] Additionally, various methods for increasing the signal to
noise ratio of thermal measurements are also provided. For example,
additional layers that partially or fully encapsulate and insulate
various components may enhance the ability to isolate thermal
energy provided by the various actuation means and increase the
accuracy and reliability of sensing. Conductive layers may also be
provided to increase the efficacy of thermal actuation and thermal
sensing by providing a conduit for thermal energy to be directed to
or received from the skin. Various discontinuous thermal conductive
layers may further increase the signal to noise ratio for a variety
of measurements, including thermal sensing.
[0016] Also described herein are non-electronic methods for thermal
sensing. For example, optical measurements via a thermal imaging
system or thermochromatic dyes may be utilized in place of
electronic thermal sensors to determine tissue characteristic or
parameters, including subdermal fluid flow.
[0017] Without wishing to be bound by any particular theory, there
may be discussion herein of beliefs or understandings of underlying
principles relating to the devices and methods disclosed herein. It
is recognized that regardless of the ultimate correctness of any
mechanistic explanation or hypothesis, an embodiment of the
invention can nonetheless be operative and useful.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIGS. 1A-1E. Soft, skin-mounted wearable device for
noninvasive, continuous, or intermittent measurement of flow
through cerebrospinal shunts for evaluation of shunt functioning.
FIG. 1A. Exploded view illustration of 100-sensor device that
incorporates a central thermal actuator, placed over skin with an
underlying shunt catheter ("conduit"). PI=polyimide FIG. 1B.
Optical micrograph of device, illustrating sensors, including a
plurality a plurality of individual resistive sensors arranged in
an array, and central thermal actuator. The close up panels
illustrate the stretchable, serpentine interconnects to facilitate
conformability and individual resistive temperature sensors. FIG.
1C. Infrared (IR) thermographs illustrating addressing of an
individual sensor (left), and thermal actuation from central heater
with 1.8 mW/mm.sup.2 actuation power. FIG. 1D. Optical images of
device on neck, over location of shunt, under different deformation
modes. FIG. 1E. IR thermographs with color and contrast enhancement
showing thermal isotropy in the absence of flow (top) and
anisotropy in the presence of flow (bottom), with flow going
towards the right of the page.
[0019] FIGS. 2A-2E. Flow visualization and measurement from ESA
(epidermal square array). FIG. 2A. Spatially precise schematic map
of 100 sensor device with tube position overlay and upstream
(T.sub.u) and downstream (T.sub.d) temperatures shown. FIG. 2B.
Baseline-subtracted temperature differentials of 4 sensor pairs as
shown by the color coding in FIG. 2A. FIG. 2C. Principal components
analysis (PCA) biplot (principle component 1 and 2) of
baseline-subtracted differentials between a selected T.sub.u sensor
(two sensors, each indicated in subfigure) and each T.sub.d sensor.
Clustering occurs for the following cases: no flow and no
actuation; no flow with actuation at 1.8 mW/mm.sup.-2, Actuation at
1.8 mW mm.sup.-2 and flow at 0.02 mL min.sup.-1, Actuation at 1.8
mW/mm.sup.2 and flow at 2 mL min.sup.-1. Vectors correspond to
selected T.sub.d sensors correlated positively (red) and negatively
(blue) with flow. FIG. 2D. Flow chart detailing the process of
transforming raw ESA sensor data to spatially precise temperature
maps. FIG. 2E. Thermographs from IR imaging (top) and ESA-generated
temperature maps (bottom), in the absence (left) and presence
(right) of 0.02 mL min.sup.-1 flow (flow from right to left) with
actuation at 1.8 mW/mm.sup.-2.
[0020] FIGS. 3A-3L. Systemic characterization of effects of
geometry, thermal properties, flow rates. FIG. 3A. Optical image of
epidermal linear array (ELA) overlaid with illustration of catheter
and blood vessel (top) and schematic illustration of benchtop
system illustrating key features, including thermal properties of
skin phantom, blood flow (Q.sub.blood), CSF flow (Q.sub.flow) and
skin thickness (h.sub.skin). FIG. 3B. Raw transient temperature
data after the onset of heating for actuator (blue curve),
downstream sensor (black curve) and upstream sensor (red curve)
under 4 values of Q.sub.flow --0 mL min.sup.-1 (unshaded region),
0.05 ml min.sup.-1 (blue shaded region), 0.1 mL min.sup.-1 (gray
shaded region) and 0.5 ml min.sup.-1 (red shaded region). FIG. 3C.
T.sub.sensors/T.sub.actuator for upstream (red) and downstream
(black) sensors across a range of flow rates from 0.01 ml
min.sup.-1 to 0.1 mL min.sup.-1. FIG. 3D.
.DELTA.T.sub.sensors/T.sub.actuator=(T.sub.downstream-T.sub.upstream)/T.s-
ub.actuator for a range of Q.sub.flow from 0.01 ml min to 0.1 ml
min for three anatomically relevant values of h.sub.skin, 1.1 mm
(black curve), 1.7 mm (red curve) and 2.1 mm (blue curve). FIG. 3E.
T.sub.sensors=(T.sub.downstream+T.sub.upstream)/2T.sub.actuator for
the same Q.sub.flow and h.sub.skin values as FIG. 3D. FIG. 3F.
Ratio between signal (.DELTA.T.sub.sensors/T.sub.actuator) and
noise (standard deviation, .sigma.) measured for Q.sub.flow=0.1 mL
min over a 60 s sampling window, at a sampling frequency of 5 Hz,
as a function of normalized actuator power for three different
values of h.sub.skin, 1.1 mm (black curve), 1.7 mm (red curve) and
2.1 mm (blue curve). FIGS. 3G and 3E.
(.DELTA.T.sub.sensors/T.sub.actuator) (FIG. 3G) and
(T.sub.downstream+T.sub.upstream)/2T.sub.actuator (FIG. 3E)
measured in the presence of phantom blood flowing through adjacent
tubes in co-flow (+x) and counter-flow (-x) configurations, for two
values of h.sub.skin, 1.1 mm (black curve) and 2.1 mm (blue curve).
FIG. 3H is a plot of the ratio of sensor to actuator temperature as
a function of blood flow. FIG. 3I. Experimental data (solid lines)
and analytical fits (dashed lines) for T.sub.actuator as a function
of time for Q.sub.flow=0 for two different skin phantoms, Sylgard
184 (black curve) and Syl 170 (gray curve) to simulate and measure
skin thermal properties.
[0021] FIGS. 3J-3K. .DELTA.T.sub.sensors/T.sub.actuator) (FIG. 3J)
and (T.sub.downstream+T.sub.upstream)/2T.sub.actuator (FIG. 3K)
measured for the two skin phantom materials. FIG. 3L In vitro
experimental measurements of .DELTA.T.sub.sensors/T.sub.actuator
for h.sub.skin (1.1, 1.7, 2.1, and 6.0 mm for four flowrates) and
for Q.sub.flow (0 ml/min (black curve), 0.05 ml/min (red curve),
0.1 ml/min (blue curve), and 0.5 ml/min (purple curve)).
[0022] FIG. 4A-4H. Wireless device, including Bluetooth
communication with a portable device. FIG. 4B is an image of a
fully assembled, integrated wireless ELA showing soft, conformal
sensing/actuating components, flex-PCB (Cu/PI/Cu), and
surface-mounted electronic components, including battery and
wireless communication components. PDMS, polydimethylsiloxane. FIG.
4C is an image of device bending, showing flexibility. FIG. 4D is
an image of a device mounted on the skin using medical-grade,
acrylate-based pressure-sensitive adhesive. FIG. 4E. Raw sensor
readout in measured bits from an 8-bit ADC during actuation and
flow. FIG. 4F. IR-measured temperature rise due to 3.6-mW actuation
on the phantom shunt assembly. FIG. 4G Calibration curve to measure
raw 8-bit, 3-V ADC values (left) and associated voltages (right) to
temperatures via calibration. FIG. 4H. Difference in T.sub.upstream
and T.sub.downstream acquired wirelessly as a function of time for
two different flows, Q=0.05 mL/min and Q=0.13 mL/min. All data are
collected on a skin phantom.
[0023] FIG. 5A-5J. Patient trials. FIG. 5A. Exploded view
illustration of ELA used in hospital setting, with elastomeric
handling frame and adhesive. FIG. 5B. Illustration (left) and image
(right) of on-shunt and off shunt ELA positioning on patient, with
representative Doppler ultrasound image (inset) of catheter under
skin at on-shunt location. FIG. 5C. IR images at on-shunt (top) and
off shunt (bottom) indicating total local temperature rise due to
actuator, and characteristic tear-drop shaped heat distribution
caused by presence of flow. FIG. 5D. Representative transient
T.sub.actuator measurement on off-shunt location, and transient
plane source (TPS) curve fit to yield skin thermal properties.
FIGS. 5E-5F. Computed values of k.sub.skin (FIG. 5E) and
.alpha..sub.skin (FIG. 5F) for each patient. FIGS. 5G-5H.
Representative T.sub.actuator (blue curve), T.sub.upstream (black
curve) and T.sub.downstream (red curve) for off-shunt location with
no anisotropy (FIG. 5G) and on-shunt location with significant
anisotropy (FIG. 5H). FIG. 5I. .DELTA.T.sub.sensors/T.sub.actuator
measured for each patient, at off-shunt and on-shunt locations,
with error bars representing SDs across a 100-sample window. FIG.
5J is a plot of the computed mean of
.DELTA.T.sub.sensors/.DELTA.T.sub.actuator on n=5 patients with
clinically or surgically confirmed flow on off-shunt and on-shunt
locations, with error bars representing SD. Statistical analysis
was performed using a paired t test (n=5) for cases with confirmed
flow over on-shunt and off-shunt locations. Individual
patient-level data are summarized as Patient #
(.DELTA.T.sub.sensors/T.sub.actuator On Shunt and
.DELTA.T.sub.sensors/T.sub.actuator Off Shunt): 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).
[0024] FIGS. 6A-6D. Case study of patient with shunt malfunction.
FIG. 6A. X-Ray and radionuclide tracer showing kinking and
occlusion of catheter. FIG. 6B. Optical image of patient's
peritoneal cavity immediately after surgery showing flow in
repaired shunt. FIG. 6C. X-ray and radionuclide tracer confirming
working of repaired shunt. FIG. 6D.
.DELTA.T.sub.sensors/T.sub.actuator measured by ELA before and
after revision, at locations over (on) and adjacent to (off) shunt,
before and after revision, confirming results from X-Ray and
Radionuclide tracer.
[0025] FIGS. 7A-7D. Computation of flow rates. FIG. 7A.
FEA-computed family of curves for different skin thicknesses of
.DELTA.T.sub.sensors/T.sub.actuator with data measured in-vivo from
each patient overlaid. FIG. 7B. Computed curves for
T.sub.sensors/T.sub.actuator for different skin thicknesses. FIG.
7C. Computed flow rates from iteratively solving for both
.DELTA.T.sub.sensors/.DELTA.T.sub.actuator and
T.sub.sensors/T.sub.actuator with error bars representing average
differences in the individual values yielded by the two curves.
FIG. 7D. FEA-computed values of
.DELTA.T.sub.sensors/.DELTA.T.sub.actuator and
T.sub.sensors/T.sub.actuator using values of h.sub.skin=1.5 mm
(acquired from CT imaging) and k.sub.skin=0.29 W m.sup.-1 K.sup.-1
and .alpha..sub.skin=0.091 mm.sup.2 s.sup.-1 acquired in vivo from
a patient as shown previously, overlaid with experimentally
measured points from the same patient, yielding a flow rate of 0.1
mL/min.
[0026] FIGS. 8A-8B. Current pathways through resistive arrays. FIG.
8A. IR image (top) and simulations of ESA with single sensor
addressed, showing currents through same input line (row) and
output line (column). FIG. 8B. Same as FIG. 8A, but for a
non-square array (16.times.6), showing large power dissipation
through non-addressed sensors in same output line (spoke).
[0027] FIG. 9. Schematic illustration of data acquisition and
control system for 100 sensor array.
[0028] FIG. 10. Heat map with each pixel corresponding to a
residual (R.sup.2) value computed for each element in 10.times.10
array from linearly fitting I.sub.meas to temperature for
calibration.
[0029] FIG. 11. Illustration of steps to convert measured current
values to heat map, with steps corresponding to the images of FIG.
2D. Flow visualization and measurement from ESA. Top panel: Example
of raw (resistance) ESA data. Second panel: Transformation of raw
ESA data to calibrated temperatures via a calibration matrix
specific to each ESA. Third panel: temperature differentials
resulting from the removal of isotropic heat transfer effects from
the thermal actuator via baseline subtraction. Bottom panel: ESA
temperature map obtained from temperature differential map of
preceding panel by meshed bicubic interpolation.
[0030] FIGS. 12A-12C. Flow visualization and measurement from ESA.
FIG. 12A: Spatially precise schematic map of 100 sensor device with
tube position overlay and upstream (U) and downstream (D)
temperatures shown. FIG. 12B: Principal components analysis (PCA)
biplot (principle component 1 and 2) of baseline-subtracted
differentials between a selected U sensor (two sensors, each
indicated in subfigure) and each D sensor. Clustering occurs for
the following cases: no flow and no actuation; no flow with
actuation at 1.8 mW/mm.sup.-2, Actuation at 1.8 mWmm.sup.-2 and
flow at 0.02 mL min.sup.-1. FIG. 12C. PCA biplots for five (1-5)
sensors (identified in FIG. 12A) illustrating the identification of
the sensors aligned with the flow direction regardless of selected
sensor (red vector). When a PCA model is applied to the aligned
data (used to generate temperature maps), PC1 correlates to
presence/absence of flow and PC2 corresponds to thermal actuation
state (on/off).
[0031] FIGS. 13A-13C. Benchtop flow system. FIG. 13A. Optical image
of benchtop flow phantom with embedded shunt. FIG. 13B. Optical
micrograph of cross section and isometric views showing catheter
geometry and h.sub.skin. FIG. 13C. Sensor laminated onto the free
surface of the assembly.
[0032] FIG. 14. Finite element simulations of dimensionless scaling
parameters illustrating time evolution of heat through skin, as a
measure of depth penetration, with experimentally measured numbers
from the system overlaid.
[0033] FIG. 15. Experimental and simulated transient responses of
.DELTA.T.sub.sensors/T.sub.actuator for three different values of
h.sub.skin for Q.sub.flow=0.13 mL min.sup.-1 as a demonstration of
an alternative method to quantify skin thickness, with data showing
relationship between the time constant (.tau.=time taken to reach
63.7% of steady-state value) and h.sub.skin (inset).
[0034] FIG. 16. T.sub.actuator and T.sub.sensors as a function of
power level for Q.sub.flow=0.13 mL min.sup.-1 on Sylgard 184 skin
phantom.
[0035] FIG. 17. Illustration of covered and uncovered
(encapsulated) actuator measurements (left) to yield transient rise
curves for fitting the value of H.sub.conv (right).
[0036] FIGS. 18A-18C. FIG. 18A. Illustration and experimental data
showing the effect of (FIG. 18B) rotational and (FIG. 18C)
translational mispositioning on measured values of
.DELTA.T.sub.sensors/T.sub.actuator (black curve) and
T.sub.sensors/T.sub.actuator (red curve).
[0037] FIGS. 19A-19F. DC Noise sources. FIG. 19A. Simplified
schematic of data acquisition system for ELA. FIG. 19B. Standard
deviations as a function of sampling window for resistances
measured by ELA (black), a commercial sensor connected via ACF
cable (blue) and a commercial resistor connected via soldered lead
wires (red). FIG. 19C. Standard deviation as a function of sampling
window for actuator output power. FIG. 19D. Standard deviation for
measured .DELTA.T.sub.sensors/T.sub.actuator as a function of
sampling window for Q.sub.flow=0.13 mL min.sup.-1 on benchtop
system, when covered by an enclosure (black) and uncovered (red).
FIG. 19E. High Frequency Noise. Panel A. Schematic illustration of
experimental system. Panel B. Fourier transform of resistance
measured at 20 kHz. Panel C. S/N, computed as the average of 5
successive resistance measurements divided by their standard
deviation as a function of number of samples (N) and sampling
window (time, ns). Panel D. Experimental data and linear fit for
S/N as a function of N. FIG. 19F. S15. In-vivo noise A. Optical
images illustrating no deformation (left) and extreme deformation
(right) of sensor on skin. B-D. Temperature fluctuations measured
as a function of time (B), frequency (C) and as a normalized power
spectral density (D) on a stationary subject. E-G Same as B-D on a
vigorously moving subject.
[0038] FIG. 20. Optical images of elastomeric adhesive with tape
frame on wrist illustrating conformal contact during extreme
deformation.
[0039] FIGS. 21A-21B. In-vivo T.sub.actuator (blue curve),
T.sub.upstream (black curve) and T.sub.downstream (red curve)
measurements as a function of time over on-shunt locations with low
anisotropy (FIG. 21A) and after stimulating flow by pressing the
regulating valve (FIG. 21B).
[0040] FIG. 22. T.sub.actuator measurements on external ventricular
drain as flow is varied by raising height of reservoir bag (not
shown), thereby changing differential pressure.
[0041] FIG. 23. Representative CT image of skin thickness over
superficial catheter location over clavicle.
[0042] FIG. 24. Schematic illustration of relevant parameters.
[0043] FIG. 25. Flow-chart summary of flow rate determination using
any of the devices described herein.
[0044] FIG. 26. Illustration of carrier and handling layer, with
the device peeled back and away from the rigid handling layer of
glass.
[0045] FIG. 27. Skin-safe, silicone adhesive, with active sensing
portion of device able to maintain conformal contact with skin,
with delamination confined to edge handling substrate that
surrounds the active sensing portion.
[0046] FIG. 28. Another illustration showing the handling substrate
with an opening where the active sensing portion of device may be
positioned.
[0047] FIG. 29. provides an overview of the sensing platform
technology, including hardware and software.
[0048] FIG. 30. illustrates an example sensor design for
commercial, surface mounted temperature sensors.
[0049] FIG. 31. provides an example of a flexible printed circuit
board (PCT) based flow sensor including thermal actuation by an
array of resistive elements.
[0050] FIG. 32. provides an analog design of circuits described
herein.
[0051] FIG. 33. illustrates the use of thermochromatic dyes
arranged in an array to determine subdermal fluid flow.
[0052] FIG. 34. provides an example of a thermal imaging approach
and currently available inexpensive thermal imaging devices.
[0053] FIG. 35. provides an example of in vitro testing of a
surface-mount device ad described herein without foam
insulation.
[0054] FIG. 36. provides an example of in vitro testing of a
surface-mount device ad described herein with a foam insulation
layer, illustrating the increase in signal to noise ratio provided
by insulation.
[0055] FIG. 37. provides in vitro testing of a surface-mount device
with foam insulation across flow rates and relevant skin
thicknesses, including a discontinuous thermally conductive layer
positioned proximate to the thermal actuator and sensors.
[0056] FIG. 38. provides an example sensor integrated with
packaging and encapsulation for thermal insulation.
[0057] FIG. 39. shows an example device with encapsulation removed
to expose and illustrate the various components as described
herein.
[0058] FIG. 40. provides both benchtop and on-body sensing results
of an example device.
[0059] FIG. 41. illustrates the ability of a sensing device to
measure change in temperature when positioned over a shunt as an in
vivo example.
[0060] FIG. 42. illustrates the use of a device with multiple
sensors and provides an example circuit diagram.
[0061] FIG. 43. illustrates the increase in rotational tolerance
for 4-sensor device.
[0062] FIG. 44. illustrates the increase in translational tolerance
for 4-sensor device.
[0063] FIG. 45. provides example hardware for wireless, inductive
power coupling for recharging and BLE wake-up.
[0064] FIG. 46. provides an example software interface.
[0065] FIG. 47. provides a summary of clinical results.
[0066] FIG. 48. provides an example of a clinical protocol that may
be useful to ensure accurate application of the devices described
herein.
[0067] FIG. 49. provides an example of a clinical checklist that
may be useful to ensure accurate application of the devices
described herein.
[0068] FIG. 50. provides an example schematic of a device as
described herein utilizing an array of resistors to provide thermal
actuation.
[0069] FIG. 5I provides an example cross-sectional schematic of a
device incorporating an insulating layer and a discontinuous
thermally conductive layer.
[0070] FIGS. 52A-52C illustrate the effect of altered intersensor
distances (L). FIG. 52A is a schematic illustration showing
positions of actuator and upstream and downstream temperature
sensors relative to underlying catheter. FIG. 52B FEA simulation of
.DELTA.Tsensors/Tactuator as a function of L, for h.sub.skin=0.5
mm, 1.0 mm, 1.5 mm, 2.0 mm, with the effect of 15% strain resulting
in an altered inter-sensor positional uncertainty of .+-.0.375 mm,
as shown by the rectangular bar. FIG. 52C FEA simulation of
T.sup.-.sub.sensors/T.sub.actuator as a function of L, for
h.sub.skin=0.5 mm, 1.0 mm, 1.5 mm, 2.0 mm, with the effect of 15%
strain resulting in an altered inter-sensor positional uncertainty
of .+-.0.375 mm, as shown by the rectangular bar.
[0071] FIGS. 53A-53D. Miniaturized, soft wireless flow sensor based
on commercial components. FIG. 53A. Exploded view schematic of key
device layers. FIG. 53B. Optical images of packaged, encapsulated
device twisting and bending. FIG. 53C. Optical image of device
mounted on neck of patient. FIG. 53D. Screenshot of software
application on tablet computer showing data readout, pairing and
options for on-demand thermal actuation.
[0072] FIGS. 54A-54F. Benchtop flow characterization using
platform. FIG. 54A. Exploded view schematic of sensors and
actuators with overlaid foam layer over shunt embedded in silicone
skin phantom. FIG. 54B. Infrared (IR) thermograph of actuator
dissipating thermal power at 1.2 mW/mm.sup.2. FIG. 54C. Upstream
(gray) and downstream (red) temperature readout after actuation,
and after during flow respectively, showing the bifurcation of the
traces (AT) and the reduced overall average temperature
(T.sub.avg), respectively, after the onset of flow. FIG. 54D. AT as
a function of time before and after the onset of flow. FIG. 54E. AT
as a function of flow rate for a range of physiologically relevant
skin thicknesses, from 0.7 mm to 4 mm. FIG. 54F. T.sub.avg as a
function of flow rate for a range of physiologically relevant skin
thicknesses.
[0073] FIGS. 55A-55B. Patient studies on adults. FIG. 55A. Optical
image of wireless sensor over shunt on representative patient,
without smartphone readout. FIG. 55B. AT for cases with confirmed
flow, no flow/irregular flow and off shunt locations, with error
bars representing S.D.
[0074] FIG. 56. Spatial and Temporal Precision of negative
temperature coefficient temperature sensors (NTCs).
[0075] FIG. 57. Stability of temperature sensors, with measured
temperature from two temperature sensors as a function of time.
[0076] FIG. 58. Unpackaged circuit layout providing various
electronic components on-board the device, including for power,
wireless communication and circuitry to control and measure.
[0077] FIG. 59. Analog front end and wireless temperature sensing
precision. The temperature sensors show high linearity over a range
of biologically-relevant skin temperatures.
[0078] FIGS. 60A-60D. Power-saving switch feature.
[0079] FIG. 61. Molding and packaging process that can be used to
make any of the devices of the instant invention.
[0080] FIG. 62. Device configured to have rotational tolerance by a
4-sensor device. The plots are for a device aligned and for various
rotations of 22.5, 45 and 90 degree rotation.
[0081] FIG. 63. Device configured to have translational tolerance
by a 4-sensor device. The plots are for a device aligned and for
various translational offsets of 2 mm, 5 mm and complete
misalignment.
[0082] FIG. 64. Effect of foam insulation on temperature
sensors.
[0083] FIG. 65. Applicability to blood vessels, with the left
panels for a device that is not over a blood vessel and the right
panels for a device over a vein.
[0084] FIG. 66. Representative clinical images of a device
positioned on and off shunt.
[0085] FIG. 67. Schematic illustration of a device.
DETAILED DESCRIPTION OF THE INVENTION
[0086] In general, the terms and phrases used herein have their
art-recognized meaning, which can be found by reference to standard
texts, journal references and contexts known to those skilled in
the art. The following definitions are provided to clarify their
specific use in the context of the invention.
[0087] "Soft" refers to a material that may be comfortably
positioned against the skin without discomfort or irritation to the
underlying skin by the material itself deforming to conform to the
skin without unduly exerting force on the underlying skin with
corresponding device-generated skin deformation. Softness/hardness
may be optionally quantified, such as in terms of durometer, or a
material's resistance to deformation. For example, the substrate
may be characterized in terms of a Shore 00 hardness scale, such as
a Shore 00 that is less than 80. Soft may also be characterized in
terms of a modulus, such as a Young's modulus that is less than or
equal to 100 kPa.
[0088] "Stretchable" refers to a material's ability to undergo
reversible deformation under an applied strain. This may be
characterized by a Young's modulus (stress/strain). A bulk or
effective Young's modulus refers to a composite material formed
from materials having different Young's modulus, so that the bulk
or effective Young's modulus is influenced by each of the different
materials and provides an overall device-level modulus.
[0089] "Flexible" refers to a material's ability to undergo a
bending with fracture or permanent deformation, and may be
described in terms of a bending modulus.
[0090] Any of the devices may be described herein as being
"mechanically matched" to skin, specifically the skin over which
the device will rest. This matching of device to skin refers to a
conformable interface, for example, useful for establishing
conformal contact with the surface of the tissue. Devices and
methods may incorporate mechanically functional substrates
comprising soft materials, for example exhibiting flexibility
and/or stretchability, such as polymeric and/or elastomeric
materials. A mechanically matched substrate may have a modulus less
than or equal to 100 MPa, less than or equal to 10 MPa, less than
or equal to 1 MPa. A mechanically matched substrate may have a
thickness 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. A mechanically matched
substrate may have a bending stiffness less than or equal to 1 nN
m, optionally less than or equal to 0.5 nN m.
[0091] A mechanically matched device, and more particularly a
substrate is characterized by one or more mechanical properties
and/or physical properties that are within a specified factor of
the same parameter for an epidermal layer of the skin, such as a
factor of 10 or a factor of 2. For example, a substrate may have a
Young's Modulus or thickness that is within a factor of 20, or
optionally for some applications within a factor of 10, or
optionally for some applications within a factor of 2, of a tissue,
such as an epidermal layer of the skin, at the interface with a
device of the present invention. A mechanically matched substrate
may have a mass or modulus that is equal to or lower than that of
skin.
[0092] "Encapsulate" refers to the orientation of one structure
such that it is at least partially, and in some cases completely,
surrounded by one or more other structures, such as a substrate,
adhesive layer or encapsulating layer. "Partially encapsulated"
refers to the orientation of one structure such that it is
partially surrounded by one or more other structures, for example,
wherein 30%, or optionally 50%, or optionally 90% of the external
surface of the structure is surrounded by one or more structures.
"Completely encapsulated" refers to the orientation of one
structure such that it is completely surrounded by one or more
other structures.
[0093] "Polymer" refers to a macromolecule composed of repeating
structural units connected by covalent chemical bonds or the
polymerization product of one or more monomers, often 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, block, alternating, segmented, grafted, tapered and other
copolymers. Useful polymers include organic polymers or inorganic
polymers that may be in amorphous, semi-amorphous, crystalline or
partially crystalline states. Crosslinked polymers having linked
monomer chains are particularly useful for some applications.
Polymers useable in the methods, devices and components disclosed
include, but are not limited to, plastics, elastomers,
thermoplastic elastomers, elastoplastics, 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, polybenzimidazole,
polybutylene, polycarbonate, polyesters, polyetherimide,
polyethylene, polyethylene copolymers and modified polyethylenes,
polyketones, poly(methyl methacrylate), polymethylpentene,
polyphenylene oxides and polyphenylene sulfides, polyphthalamide,
polypropylene, polyurethanes, styrenic resins, sulfone-based
resins, vinyl-based resins, rubber (including natural rubber,
styrene-butadiene, polybutadiene, neoprene, ethylene-propylene,
butyl, nitrile, silicones), acrylic, nylon, polycarbonate,
polyester, polyethylene, polypropylene, polystyrene, polyvinyl
chloride, polyolefin or any combinations of these.
[0094] "Elastomer" refers to a polymeric material which can be
stretched or deformed and returned to its original shape without
substantial permanent deformation. Elastomers commonly undergo
substantially elastic deformations. Useful elastomers include those
comprising polymers, copolymers, composite materials or mixtures of
polymers and copolymers. Elastomeric layer refers to a layer
comprising at least one elastomer. Elastomeric layers may also
include dopants and other non-elastomeric materials. Useful
elastomers include, but are not limited to, thermoplastic
elastomers, styrenic materials, olefinic materials, polyolefin,
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(dimethyl siloxane) (i.e. PDMS and h-PDMS), poly(methyl
siloxane), partially alkylated poly(methyl siloxane), poly(alkyl
methyl siloxane) and poly(phenyl methyl siloxane), silicon modified
elastomers, thermoplastic elastomers, styrenic materials, olefinic
materials, polyolefin, polyurethane thermoplastic elastomers,
polyamides, synthetic rubbers, polyisobutylene,
poly(styrene-butadiene-styrene), polyurethanes, polychloroprene and
silicones. In an embodiment, a polymer is an elastomer.
[0095] "Conformable" refers to a device, material or substrate
which has a bending stiffness that is sufficiently low to allow the
device, material or substrate to adopt any desired contour profile,
for example a contour profile allowing for conformal contact with a
surface having a pattern of relief features. In certain
embodiments, a desired contour profile is that of skin.
[0096] "Conformal contact" refers to contact established between a
device and a receiving surface, specifically skin. In one aspect,
conformal contact involves a macroscopic adaptation of one or more
surfaces (e.g., contact surfaces) of a device to the overall shape
of a surface. In another aspect, conformal contact involves a
microscopic adaptation of one or more surfaces (e.g., contact
surfaces) of a device to a surface resulting in an intimate contact
substantially free of voids. In an embodiment, conformal contact
involves adaptation of a contact surface(s) of the device to a
receiving surface(s) such that intimate contact is achieved, for
example, wherein less than 20% of the surface area of a contact
surface of the device does not physically contact the receiving
surface, or optionally less than 10% of a contact surface of the
device does not physically contact the receiving surface, or
optionally less than 5% of a contact surface of the device does not
physically contact the receiving surface. Devices of certain
aspects are capable of establishing conformal contact with internal
and external tissue. Devices of certain aspects are capable of
establishing conformal contact with tissue surfaces characterized
by a range of surface morphologies including planar, curved,
contoured, macro-featured and micro-featured surfaces and any
combination of these. Devices of certain aspects are capable of
establishing conformal contact with tissue surfaces corresponding
to tissue undergoing movement.
[0097] "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 may be provided by the
expression:
E = ( stress ) ( strain ) = ( L 0 .DELTA. .times. L ) .times. ( F A
) , ( I ) ##EQU00001##
where E is Young's modulus, L.sub.0 is the equilibrium length,
.DELTA.L is the length change under the applied stress, F is the
force applied, and A is the area over which the force is applied.
Young's modulus may also be expressed in terms of Lame constants
via the equation:
E = .mu. .function. ( 3 .times. .lamda. + 2 .times. .mu. ) .lamda.
+ .mu. , ( II ) ##EQU00002##
where .lamda. and .mu. are Lame constants.
[0098] "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.
[0099] "Bending stiffness" is a mechanical property of a material,
device or layer describing the resistance of the material, device
or layer to an applied bending moment. Generally, bending stiffness
is defined as the product of the modulus and area moment of inertia
of the material, device or layer. A material having an
inhomogeneous bending stiffness may optionally be described in
terms of a "bulk" or "average" bending stiffness for the entire
layer of material.
[0100] "Thermal actuation state" refers to the thermal actuator
that is on an off-state or an on-state. In this context,
"substantially independent" refers to a position of the reference
sensor that is sufficiently separated from the actuator 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 relatively minor effects of the actuator
on the reference sensor, such as within 5%, within 1% or within
0.1% of a reference temperature when the actuator is in the on
state compared to when the actuator is in the off state. Depending
on specific device and tissue characteristics, this distance may be
between about 10 mm and 20 mm, such as about 15 mm.
[0101] Referring to the figures provided herein, a conformable
device 10 to measure subdermal fluid flow, including in a conduit
75 such as a shunt or a blood vessel, may comprise a substrate 20
that supports upstream 30 and downstream 40 temperature sensors.
Upstream and downstream are described relative to flow direction in
the fluid conduit. The temperature sensors may be part of an array
of temperature sensors, including a high density array 300 as shown
in FIG. 1A-1B. Within that array, are any number of reference
sensors used to assess one or more baseline skin properties,
including an actuator reference sensor 60 and/or ambient reference
sensor 80. As explained herein, the reference sensor locations may
be determined to be those that are independent of thermal actuation
status (e.g., ambient reference sensor) or of flow status in the
conduit (e.g., actuator reference sensor). The reference sensor
locations may be characterized in terms of a separation distance
(65 85) from notional line 70 that is a straight line connection
between the upstream and downstream temperature sensors and the
thermal actuator to the reference sensors (60 80) (FIG. 67).
[0102] A microprocessor 160 (illustrated as on-board device 10 in
FIG. 67, but may be positioned remotely), may be wirelessly
connected via one or more wireless communication components 310 to
the temperature sensors and/or to connect the device 10 to a
microcontroller 320 illustrated as within a hand-held or computer
330 remote device. As desired, a power source 150 (also illustrated
as 350 in FIG. 4B) may be connected on-board device 10. Optionally,
the power source may correspond to wirelessly charging components.
Wireless communication components 5810 are also illustrated in FIG.
58 (see also antenna of FIG. 4B).
[0103] As desired, the device may be covered with an encapsulation
layer 1700 (FIG. 17), including a foam layer or an additional
partial layer formed of foam on top of the encapsulating layer
(also referred herein as a superstrate--see, e.g., FIG. 53A)
positioned to vertically cover the temperature actuator and
sensors. As the foam layer is demonstrated to improve device
performance, any of the devices provided herein may comprise a foam
layer positioned over an encapsulation layer, wherein the foam
layer may cover the entire encapsulation layer or a portion thereof
that corresponds, in a vertical geometrical configuration, to the
temperature sensors and actuator to minimize thermal noise and
improve device performance and sensitivity.
[0104] The devices and methods provided herein are conveniently
implementable and manageable, including to a health care provider.
For example, FIG. 46 illustrates a device operably integrated or
connected to a computer-implemented program or application 4600
having an on-demand actuation 4610 on a handheld. In this manner,
individual sensor control, device actuation, and date monitoring is
readily, conveniently and reliably available to a medical
professional who may be remotely located from a patient who is
wearing the device.
Example 1: Epidermal Electronics for the Noninvasive, Wireless,
Quantitative Assessment of Ventricular Shunt Function
[0105] Ventricular shunts represent an essential component of
clinical treatment for hydrocephalus, a common and debilitating
neurological disorder that results from the overproduction and/or
impaired reabsorption of cerebrospinal fluid (CSF) produced in the
ventricular system of the brain [Rachel]. Hydrocephalus arises from
a number of causes, including but not limited to cancer,
hemorrhage, trauma, and congenital malformations. This condition
affects an estimated 750,000 patients in the United States alone,
and it is responsible for .about.3.1% of all pediatric acute care
costs [Lam, Patwardhan, Shannon, Stone]. 125,000 pediatric
hydrocephalus patients in the US account for 400,000 days spent in
the hospital each year [Simon]. Shunts assemblies typically involve
two silicone catheters, connected upstream and downstream of a
regulating valve, to drain excess CSF from the ventricle to a
distal absorptive site, usually the peritoneum, pleura, or right
atrium of the heart. While effective in CSF diversion and
prevention of the sequelae of hydrocephalus, including seizures,
coma, neurological injury and death, shunts are highly prone to
failure [Tervonen] due to fibrinous catheter ingrowth, kinking,
discontinuity, over-drainage, distal malabsorption and infection
[Garton, Yuh]. An estimated 84.5% shunt recipients require revision
operations [Cochrane, Shah, Stone, Piatt]. Clinical symptoms of
shunt malfunction tend to be non-specific, such as headache, nausea
and somnolence, thereby creating challenges in clinical diagnosis
[Kirkpatrick, Piatt, Garton]. Because ramifications of misdiagnosis
can include severe morbidity and mortality, isolating the location
and cause of failure is critical in the appropriate care of
hydrocephalic patients.
[0106] Diagnostic tests to assess shunt function include
computerized tomography (CT), plain films (X-Ray), magnetic
resonance imaging (MRI), radionuclide shunt patency studies (RSPS,
or `shunt-o-gram`), shunt aspiration, and flow monitoring systems
(ShuntCheck) [Boyle, Wallace, Madsen]. Each method, however,
suffers from some combination of disadvantages, including excessive
cost, poor reliability, low speeds, susceptibility to interference
and patient discomfort, including potential for harm. CT scans and
X-rays expose a vulnerable pediatric population to harmful
radiation (1.57.+-.0.6 mSv & 1.87.+-.0.45 mSv, respectively).
Shunted patients undergo an average of two CT scans annually that,
over the course of the patient's lifetime, result in dangerous
levels of radiation exposure that have been linked to the onset of
neurological and hematological malignancies [Korai, Krishnamurthy].
The MRI approach costs $3000 per study, the measurement can
interfere with magnetic shunt valves, the availability is limited,
and the wait-times are typically long. Invasive testing, in form of
RSPS or simple aspiration, is painful, time-consuming and often
inaccurate [Brendel, Ouellette, Uliel, Vernet]. Recent diagnostic
entrants attempt to address these drawbacks, but are limited by
cumbersome, multi-step protocols, in some cases including ice
mediated cooling, with equivocal or negative past clinical data
[Madsen, Recinos, Boyle, Frim]. Observation alone can cost over
$10,000 per admission, with prolonged hospital stays that compound
the frustrations of patients, caregivers, and families alike
[Boyle, Yue]. Ultimately, surgical intervention is required to
assess and revise shunts in many patients. With risk of
intraoperative complications, anesthetic exposure, gross procedural
expenditures approach $67,000 per patient [Aqueduct neurosciences.
Hydro association]. Because a significant proportion of such
surgeries reveal shunt apparatuses with proper flow profiles, these
unnecessary procedures represent a tremendous burden to the health
care system.
[0107] This example presents a simple, non-invasive sensor platform
that provides a low-cost, comfortable means for quantitatively
assessing flow through cerebrospinal shunts. The platform exploits
advances in materials, mechanics and fabrication schemes that serve
as the foundations for a class of electronics that is ultrathin
(<100 .mu.m), soft (Young's modulus, E .about.70 kPa),
lightweight (area mass density, <10 mg/cm.sup.2) and skin-like
it is physical properties, with resulting flexural rigidities that
are nine orders of magnitude lower than those of traditional, rigid
sensors. Such `epidermal` electronic systems support broad classes
of measurement capabilities that offer 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 others. Multimodal thermal characterization is also
possible, owing to the exceptionally low thermal masses (<10 mJ
cm.sup.-2K.sup.-1), fast response times (.about.10 ms), and
exceptional precision in temperature measurements (.about.20 mK) of
these platforms and to their ability for controlled delivery of
thermal power to underlying tissue [7-11]. Specific embodiments
allow for high resolution skin thermography and for precise
measurements of the thermal conductivity and the thermal
diffusivity of the skin. Recent work [12] also illustrates the
possibility of quantifying macrovascular blood flow based on
measurements of spatial anisotropies in thermal transport. Here, we
extend these concepts to realize a soft, skin-interfaced sensor
that can accurately measure flow through cerebrospinal shuts in
real-time, in a noninvasive, quantitative and wireless manner. The
results represent a breakthrough in hydrocephalus diagnostics, with
ability to visualize flow in a simple, user-friendly mode,
accessible to the physician and patient alike. Systematic benchtop
evaluations, thermographic imaging and finite element analysis
(FEA) of the physics of heat transport reveal the effects of skin
thermal properties and thickness, as well as device and catheter
geometries. The results establish considerations in design for a
range of practical operating conditions. An integrated wireless
system allows for recording and transmission of data to standard
consumer devices such as smartphones and tablet computers. Trials
on five adult shunt recipients with a diverse range of etiologies,
and comparisons with CT, MRI and radionuclide tracing validate
device function in-vivo, and advanced processing algorithms for
quantitative determination of flow rates.
[0108] Dense arrays for flow visualization: The feasibility of
using arrays of epidermal temperature sensors and thermal actuators
to quantify anisotropies in thermal transport through the skin
induced by macrovascular blood flow has been demonstrated [10,12].
The device architectures and fabrication schemes shown here
increase the number of sensors by nearly a factor of ten relative
to this past work, and the density of these elements by a factor of
four, using clusters distributed around a central thermal actuator,
to provide levels of precision and spatial resolution necessary for
characterizing flow through shunts. A schematic illustration of
this platform (epidermal sensing array, ESA) appears in FIG. 1A.
Optical micrographs of the key features are in FIG. 1B. The device
illustrated here comprises a circular (R=2.5 mm) thin-film metallic
(Cr/Au 10/50 nm) actuating element surrounded by 100 circular
(R=0.25 mm) thin-film metallic (Cr/Au 10/50 nm) temperature
sensors. Two layers of metallic traces (Ti/Cu/Ti/Au 20/600/20/25
nm) patterned in serpentine geometries define interconnects between
the sensing and actuating elements, with polyimide (PI) as an
interlayer dielectric. A film of PI (9 .mu.m total thickness)
patterned and aligned to the metal features serves as an
encapsulation layer. A soft (70 kPa) substrate, such as an
elastomeric substrate (Ecoflex, 100 .mu.m) serves as a support.
Connecting unique combinations of rows (to supply a sensing
voltage, V.sub.sup) and columns (to measure a resulting current,
I.sub.meas) enables individual addressing of each element in the
array, as in FIG. 2C. Operation of the thermal actuator, as seen in
the IR thermograph in FIG. 2C, results in a spatio-temporal pattern
of temperatures that can be captured by high-speed, automated
interrogation of the sensors in the array. An illustration of the
data acquisition system appears in FIG. 9. Arrays in square
geometries, with an equal number of input and output lines
(10.times.10 for the case illustrated here) mitigate effects of
parasitic current pathways. (Theoretical and experimental
comparisons of current distributions in square and non-square
arrays appear in FIGS. 8A-8B.) The ease of fabrication and
robustness of operation of metallic resistive sensor elements make
them attractive options compared to semiconductor devices,
composite organic thermistors and others. The series of images in
FIG. 2E illustrates the mechanical compliance and physical
robustness of these systems.
[0109] During operation, the current I.sub.meas that passes through
a sensor fora given applied potential defines a resistance that can
be converted to temperature via a linear calibration factor, whose
goodness of fit is illustrated in FIG. 10. The effects of
directional flow through a small diameter tube underlying the
device can be seen in the IR thermographs of FIG. 2F. Here, thermal
transport occurs most effectively along the direction of flow,
thereby creating a pronounced anisotropy in the temperature
distribution, with a magnitude that can be quantitatively related
to the volumetric flow rate, as discussed subsequently. The layout
of the sensing elements allows accurate measurements of this
anisotropy for cases relevant to flow through subcutaneous shunts
with typical dimensions. By comparison to previously reported
platforms for sensing of blood flow, the high-density platforms
introduced here (1) obviate the need for perfect alignment with the
underlying ventricular shunt, (2) facilitate the use of image
processing techniques to visualize flow fields, and (3) allow for
statistical approaches to interpreting flow due to the density of
information.
[0110] The schematic illustration in FIG. 2A identifies a set of 50
sensors upstream (T.sub.upstream) and downstream (T.sub.downstream)
of the thermal actuator. Subtracting T.sub.upstream from
T.sub.downstream for each physically-matched piecewise sensor pair
(indicated by the paired colors in FIG. 2A) yields temperature
differentials (.DELTA.T.sub.sensor) that measure the degree of
thermal anisotropy that results from fluid flow. As shown in FIG.
2B, .DELTA.T.sub.sensors for sensor pairs A and B that directly
overlay a catheter exhibit strong thermal anisotropy under two
different flow conditions (0.02 mL min.sup.-1, 0.2 mL min.sup.-1)
within an established range for CSF flow[13]. Sensor location B
displays a higher sensitivity to flow than location A due to the
reduced effect of direct thermal conduction from the actuator,
relative to anisotropic thermal transport due to fluid flow.
Measurements of .DELTA.T for distal sensor pairs orthogonal to the
flow direction show weak anisotropy (C) while distal pairs parallel
to flow direction (D) show an absence of flow-induced thermal
anisotropy. This orientation dependence obviates the requirement
for precise sensor alignment to tube direction due to the ESA
sensor density and cardinal symmetry.
[0111] A Principle Component Analysis (PCA) model (generated via R)
provides a facile method for assessing both catheter position with
respect to the ESA ordinate system and for confirming the presence
or absence of flow (shown in FIG. 2C). The PCA model, constructed
from a time-series ESA measurement, uses .DELTA.T.sub.PCA values to
calculate the principle components (PC).
.DELTA.T.sub.PCA=T.sub.downstream-T.sub.upstream,i, where
T.sub.downstream is the temperature matrix of all downstream
sensors (1-50) and T.sub.upstream,i is the temperature for a single
(i) upstream sensor. The first two components (PC1, PC2) describe
approximately 92% of the overall variability of the data (70.5%
PC1, 22.1% PC2) with the remainder (8% across PC3:PC50) associated
with noise. PCA biplots (FIG. 2C) show projections of each
.DELTA.T.sub.PCA for two selected T.sub.upstream,i sensors
(Top--orthogonal, distal sensor in red; Bottom--inline, distal
sensor in red) at each measurement in an ESA time-series (same as
FIG. 2B) in two dimensions using the first two principle
components. FIG. 2C reveals data clustering (95% confidence
ellipses) corresponding to three experimental conditions: absence
of fluid flow without thermal actuation (flow off/heat off),
absence of flow with thermal actuation (flow off/heat on), and
fluid flow with thermal actuation with separate clusters for
different flow regimes (0.02 mL min.sup.-1, 0.2 mL min.sup.-1). As
shown, these clusters are independent of the selected T.sub.Ui
sensor (additional biplots shown in FIGS. 12A-12B). A comparison of
the data clusters and principal components shows that PC1 primarily
relates to the degree of thermal actuation while PC2 relates to the
presence or absence of flow. Mapping the variables to the PCA
biplot indicates sensor correlation to fluid flow. In FIG. 2C, an
overlay of four variable factors corresponding to T.sub.D sensors
known to be proximal (red) and distal (blue) to fluid flow shows
the positive correlation for the proximal sensors and negative
correlation for the distal sensors to fluid flow for both
orthogonal and inline T.sub.upstream,i sensors. PCA offers a
strategy to mitigate effects of ESA misalignment by determining the
T.sub.upstream,i sensor that yields the maximal separation between
no flow/flow data clusters (along the PC2 axis). As observed in
FIG. 2C, the inline T.sub.upstream,i sensor strongly separates
these cluster groups as compared to the orthogonal T.sub.upstream,i
sensor. In this manner, for scenarios without a priori orientation,
PCA offers a straightforward means for evaluating correlations
between T.sub.upstream,i and flow state and, therefore, orientation
of the catheter relative to the ESA.
[0112] The density of the ESA enables spatial mapping of the
temperature anisotropy that results from fluid flow. These maps
result from the processing of raw measurements from the ESA as
outlined in FIG. 2D. First, by converting the raw ESA measurements
(I.sub.meas) resistance and then temperatures by linear calibration
(curve a priori established for each sensor of the ESA, process
described in detail in FIG. 9), the temperature values can be
mapped to the physical spatial coordinates of each sensor on a
simulated square "pixel" array larger than the ESA (grid: 17
mm.times.17 mm, 10 px mm.sup.-1) resulting in a
170.times.170.times.N matrix for a time-series measurement of N
frames. Conversion to T.sub.normalized results from the subtraction
of the background temperature T.sub.background from each frame. The
temperature map results from fitting a surface to the measured
T.sub.normalized values for each frame via meshed bicubic
interpolation (boundary conditions T.sub.normalized=0 from IR
thermograph). Subtracting the actuator temperature and resulting
isotropic heat transfer temperatures (T.sub.actuator) from
T.sub.normalized for every frame enhances visualization of
flow-induced anisotropic thermal transport. FIG. 2D compares the
ESA temperature maps with IR thermographs (same scale) in the
absence (left) and presence (right) of flow (0.02 mL min.sup.-1).
As seen via the sensor overlay in each image, the high density of
the ESA enables good fidelity in visualizing the thermal anisotropy
over the embedded catheter. Although experiments with patients do
not typically allow for direct measurements of the flow and no-flow
cases, theoretically derived or a priori measured "calibration"
T.sub.actuator facilitates the type of analysis described here.
[0113] Quantitative analysis of flow and comparison to models: The
full mapping results obtained with the high-density ESA suggest
means for simplifying the sensor to allow rapid measurements in a
low-cost platform that comprises at its core only of an actuator
and a pair of sensors, located 1.5 mm upstream (T.sub.upstream) and
downstream (T.sub.downstream) of the actuator respectively, which
we refer to as an epidermal linear array (ELA). In this system, the
actuator simultaneously serves as a temperature sensor, and the
measured temperature of the actuator, T.sub.actuator, yields a
useful normalizing factor that facilitates data analysis
independent of actuation power. Use of this system with a benchtop
model allows for the controlled exploration of the effects of flow,
thermal and geometric parameters. A schematic illustration of the
device and evaluation set-up appear in FIG. 3A, with optical images
of a representative system appearing in FIGS. 13A-13C. Operating
the actuator at a controlled, low-power (1.35 mW/mm.sup.2) level
creates heat that diffuses through the silicone skin phantom
(silicone) at a rate governed by the thermal diffusivity of this
material, .alpha..sub.skin. A scaling law that graphically
illustrates the depth of penetration of this thermal field into the
phantom appears in FIG. 14. Here, the phantom can be treated as a
semi-infinite solid[14], which approaches a quasi-steady state
equilibrium over relatively long (.about.400 s) times with a
corresponding penetration depth of .about.5 mm. Typical ventricular
catheters are implanted subdermally, at depths of 1-2 mm [15], well
within the range of detectability. The raw transient sensor and
actuator responses after actuation
(.DELTA.T.sub.sensors=T.sub.sensor(t)-T.sub.sensor(t.sub.actuat-
ion),
.DELTA.T.sub.actuator=T.sub.actuator(t)-T.sub.actuator(t.sub.actuati-
on)), and during different flows (Q.sub.CSF) in this system appear
in FIG. 3B. In the absence of flow (Q.sub.CSF=0) thermal transport
from the actuator occurs equally in the .-+.x, .-+.y and -z
directions, resulting in equal values for .DELTA.T.sub.upstream,
and .DELTA.T.sub.downstream. This regime appears in the unshaded
portion of FIG. 3B. The presence of flow leads to a non-monotonic
effect on .DELTA.T.sub.upstream, and .DELTA.T.sub.downstream. At
low flow rates (0 mL min.sup.-1<Q.sub.CSF<0.05 mL
min.sup.-1), the fluid serves to transport heat from the actuator
preferentially to the downstream sensor, and away from the upstream
sensor, resulting in a measured increase in
.DELTA.T.sub.downstream, and decrease in .DELTA.T.sub.upstream, as
seen in the blue shaded region in FIG. 3B. At higher flow rates
(0.05 mL min.sup.-1<Q.sub.CSF<1 mL min.sup.-1), the
convective effects of the fluid dominate, leading to a net cooling
effect on both sensors, but at different rates, with
.DELTA.T.sub.upstream equilibrating at a lower value than
.DELTA.T.sub.downstream as seen in the red and black shaded regions
in FIG. 3B. The actuator is convectively cooled by the fluid at a
rate governed by the magnitude of the flow, resulting in reductions
of .DELTA.T.sub.actuator, in the presence of flow as shown by the
blue curve in FIG. 3B. These effects appear in the normalized
quantities T.sub.upstream/T.sub.actuator and
T.sub.upstream/T.sub.actuator, shown for a complete range of
physiologically relevant values of Q.sub.CSF in FIG. 3C. The
non-monotonic effects of flow for different skin thicknesses
(h.sub.skin) increase and decrease when considering the difference
between the sensors (.DELTA.T.sub.sensors/T.sub.actuator) and their
average (T.sub.sensors/T.sub.actuator), respectively, as shown in
FIGS. 3D-3E. Here, .DELTA.T.sub.sensors/T.sub.actuator and
T.sub.sensors/T.sub.actuator are measures of thermal anisotropy and
flow magnitude, respectively. Taken together, these quantities
allow for determination of flow rate, and can be used to
distinguish degenerate points on either side of the peak values
shown in FIG. 3D.
[0114] The thickness of the skin (h.sub.skin) represents an
important geometric parameter. As shown in FIGS. 3D-3E, increasing
h.sub.skin decreases the effects of flow on the sensor responses,
simply due to the finite depth of penetration of the thermal field.
Although transient techniques can be used to determine h.sub.skin
from thermal measurements, as shown in FIG. 15, in practice,
h.sub.skin can be measured directly using CT and Doppler
ultrasound, as discussed subsequently.
[0115] The power/area of the actuator (P.sub.actuator) represents
an important design consideration. Increasing P.sub.actuator
improves the signal to noise ratio (S/N) of the measurements, but
biological considerations set an upper limit for non-invasive use.
The effects of P.sub.actuator on S/N appear in FIG. 3F, where the
signal is an averaged measurement over 60 s (measured at 5 Hz) of
.DELTA.T.sub.sensors/T.sub.actuator for a flow rate of 0.13 mL
min.sup.-1. The noise is the standard deviation (.sigma..sub.60s)
computed to three significant digits. At sufficiently high values
of P.sub.actuator (P.sub.actuator>1 mW/mm.sup.2) the advantages
of increased actuation power diminish, and the noise stabilizes at
2% of the measured signal. The increase in local temperature varies
linearly with P.sub.actuator at a rate of 6.01 K (mW
mm.sup.-2).sup.-1 on PDMS (Sylgard 184), as shown in FIG. 16.
[0116] A possible confounding effect for the measurement follows
from blood flow through superficial veins, as shown in a benchtop
model in FIGS. 3G-3H, for two skin thicknesses and in two
configurations: flow aligned with (+x, co-flow) and opposite to
(-x, counter-flow) flow of CSF flow, for rates at the upper end of
the range typically encountered in veins located near the surface
of the skin of the neck. In practice, co-flow represents the most
realistic case, as venous blood flow typically proceeds from the
brain towards the heart. Arterial flow can be neglected since its
depth (>1 cm) occurs below the limit of detectability for the
sensors reported here. In experiments, flow through the catheter is
0.13 mL min.sup.-1, and the phantom blood vessel (R.sub.vessel=1
mm) resides (d.sub.blood) 5 mm from the central axis of the sensor,
and 2.5 mm from the edge of the actuator, as an extreme case. In
this system, h.sub.skin is the same for both the catheter and the
blood vessels. The counter-flow cases result in a 20% reduction in
both .DELTA.T.sub.sensors/T.sub.actuator and
T.sub.sensors/T.sub.actuator, while the co-flow case results in a
measured reduction of <5%.
[0117] The thermal conductivity (k.sub.skin) and diffusivity
(.alpha..sub.skin) of skin also represent unknowns, with human skin
exhibiting a range of 0.2 W m.sup.-1K.sup.-1<k.sub.skin<0.45
W m.sup.-1K.sup.-1 and 0.9 mm.sup.2
s.sup.-1<.alpha..sub.skin<0.17 mm.sup.2 s.sup.-1 [11].
Phantom skins with properties that bound this range can be
constructed from silicone materials with two different formulations
(Sylgard 170 and Sylgard 184, Dow Corning, Inc.). Measurements of
the thermal properties of these materials (FIG. 3I) match
literature values: k.sub.184=0.18.-+.0.01 W m.sup.-1K.sup.-1,
.alpha..sub.184=0.11.+-.0.03 mm.sup.2 s.sup.-1 and:
k.sub.170=0.42.-+.0.01 W m.sup.-1K.sup.-1,
.alpha..sub.170=0.18.-+.0.01 mm.sup.2 s.sup.-1. The measured values
of .DELTA.T.sub.sensors/T.sub.actuator are nearly identical for
these two cases, as shown in FIG. 3J. By contrast, the increased
rates of thermal transport associated with Sylgard 170 increases
the cooling effect of the fluid, thereby reducing the values of
T.sub.sensors/T.sub.actuator as shown in FIG. 3K. The result
increases the sensitivity of the sensor.
[0118] Ventricular catheters are constructed from standard
medical-grade silicones, and their thermal properties are assumed
to be known a-priori (k.sub.catheter=0.22 W m.sup.-1K.sup.-1,
.alpha..sub.catheter=0.12 mm.sup.2 s.sup.-1) [16].
[0119] Additional experiments quantify the convective heat transfer
coefficient (H.sub.conv=20 W m.sup.-2K.sup.-1, FIG. 17), tolerance
in positioning (30.degree. rotational tolerance, FIG. 18B, .about.1
mm translational tolerance, FIG. 18C) and noise introduced by the
data acquisition system as a function of sampling window (FIGS.
19A-19D).
[0120] Systems provided herein are compatible with wireless data
acquisition, including via Bluetooth. This represents an important
patient care aspect, as the patient need not be hard-wired to any
instruments. In this manner, continued monitoring is possible
without confining patient location or motion.
[0121] Human studies for the evaluation of ventricular shunt
function: Experiments on five shunt recipients with varying
pathologies demonstrate the utility of these measurement platforms.
The device designs address three needs: (1) ease of handling for
the surgeon to ensure facile placement and removal, (2) comfort for
the patient during application, operation and removal, and (3)
robust mechanical and thermal coupling to the skin. A schematic
illustration of the resulting embodiment appears in FIG. 5A,
showing the ELA and ultrathin elastomer substrate (100 .mu.m,
Ecoflex+MG7 1010 Adhesive) supported by an elastomeric frame (2 mm,
Sylgard 170). These platforms adhere robustly and non-invasively to
the skin via van der Waals interactions alone, without the need for
separate adhesive layers, as illustrate in FIGS. 19A-19D, where a
device maintains conformal contact with the skin even under extreme
deformations. Successive measurements involve placement on the skin
over the distal catheter (`on-shunt`), and at a location adjacent
to the distal catheter (`off shunt`). The off-shunt measurement has
two key uses: (1) it serves as a control for comparison to the
on-shunt measurement and (2) it allows for the measurement of skin
thermal properties without the influence of flow. FIG. 5B
schematically illustrates the on-shunt and off-shunt location.
Locating the catheter under the skin via touch was facile, and
precise positioning was achieved with Doppler ultrasound (Sonosite
Inc., Bellevue Wash.). A representative Doppler image of the
catheter appears in FIG. 5B (inset). Linear markings on the device,
visible in FIG. 5B, allow for easily alignment of the central axis
of the actuator and sensors with the underlying shunt. Although the
shunt is not visible under the skin, its ends can be easily aligned
to the markings on the device via touch. Low-power actuation (1.3
mW/mm.sup.2) ensures maximum temperature increases of <5.degree.
C., as confirmed by IR images in FIG. 5C. These values are well
below the threshold for sensation, in accordance with IRB-approved
protocols. Markers in FIG. 5B identify mounting locations in FIG.
5C. The results show a characteristic tear-drop distribution of
temperature, consistent with flow.
[0122] Transient, off-shunt measurements of T.sub.actuator define
the thermal transport properties of the patient's skin. A
representative response before, during and after actuation appear
in FIG. 5D. Values of k.sub.skin and .alpha..sub.skin extracted
from these data appear in FIGS. 5E-5F; the magnitudes are
comparable to those expected for skin [11]. Data from the flow
sensor are in FIGS. 5G-5H, where the red, black and blue curves
represent the temperatures measured from the upstream sensor, the
downstream sensor, and the actuator, respectively. Locations
adjacent to the shunt that are free of near-surface blood vessels
present no sources of thermal anisotropy and, therefore, can serve
as control measurements. Results from a representative case are in
FIG. 5G, where the upstream and downstream responses are nearly
identical. Anisotropy that results from flow through a shunt
appears in FIG. 5H. In a simple binary sense, the presence or
absence of flow corresponding to shunt functioning or failure can
be immediately determined simply by observing the presence or
absence of thermal anisotropy. Measured values of
.DELTA.T.sub.sensors/T.sub.actuator appear in FIG. 5I for on-shunt
and off-shunt locations for all 5 patients. Anisotropy appears
clearly for all working shunts. Error bars correspond to standard
deviations computed over 100 samples. Raw data from two additional
cases appear in FIG. 20. Details of each patient's etiologies and
results are in FIGS. 21A-21B.
[0123] Studies by X-Ray, MRI and CT imaging validate the
measurements. FIG. 6A corresponds to a patient (F, 36) with a shunt
malfunction suspected to be due to a kink in the distal catheter,
and later confirmed by the X-Ray and Radionuclide Tracer (RT)
images. Surgical intervention relieved the kink, causing a
dramatic, visible increase in flow, as shown in the optical image
in FIG. 6B. The continuous presence of flow was further confirmed
via post-operative X-Ray and RT, revealing a straightened distal
catheter and a clear trace beyond the valve, as shown in FIG. 6C.
Placement of the ELA at on- and off-shunt locations respectively,
revealed no flow before the revision, consistent with X-Ray and RT
imaging. Post operatively, the off-shunt measurement showed no
appreciable changes, while the on-shunt measurement showed the
clear presence of flow, as shown in FIG. 6D.
[0124] The quantitative extraction of flow rates from such data can
be accomplished via fitting to FEA models that use measurements of
k.sub.skin and .alpha..sub.skin,
.DELTA.T.sub.sensors/T.sub.actuator and
T.sub.sensors/T.sub.actuator and a priori knowledge of the inner
and outer diameters of the catheter, and its thermal properties
k.sub.catheter and .alpha..sub.catheter. Placing the sensor at
distal catheter locations that are determined, via touch, to be the
most superficial maximizes the precision of the measurement.
Analysis of CT and Doppler ultrasound images, such as the ones
shown in FIG. 5B and FIG. 23 define h.sub.skin at these locations
to be 1.5 mm.-+.0.1 mm. FEA yields computed curves for
T.sub.sensors/T.sub.actuator and
.DELTA.T.sub.sensors/T.sub.actuator for a 0.01 ml
min.sup.-1<Q.sub.CSF<1 ml min.sup.-1. In this way, measured
values of T.sub.sensors/T.sub.actuator define regimes of flow, i.e.
high-flow (Q>0.05 mL min.sup.-1) or low-flow (Q<0.05 mL
min.sup.-1). Specifically, values of
T.sub.sensors/T.sub.actuator>0.29 represent low-flow, and
T.sub.sensors/T.sub.actuator<0.29 represent high-flow for all
skin thicknesses, as shown in FIG. 7B. Measured values of
T.sub.sensors/T.sub.actuator and
.DELTA.T.sub.sensors/T.sub.actuator are then iteratively fitted to
yield a unique flow rate. Following this process for our measured
data yields quantitative flow values.
[0125] Applications on human subjects illustrate this process.
Assessments of Patient 1 prior to corrective surgery, and as in
FIGS. 6A-6D, indicated a shunt malfunction, consistent with ELA
measurements (0.01.-+.0.01 mL min.sup.-1). Measurements after a
surgical revision revealed a flow rate of 0.06.-+.0.02 mL Patients
2 and 3 were not suspected of shunt malfunction and exhibited flow
rates of 0.36.-+.0.04 mL min.sup.-1 and 0.13.-+.0.02 mL min.sup.-1
respectively, well within established ranges for healthy CSF flow
[13]. Patient 4, was initially measured to have occluded flow
(0.013.-+.0.002 mL min.sup.-1). This patient had experienced severe
and prolonged constipation for the past week and clinically
deteriorated due to a likely pseudo-obstruction. Long term
constipation can decrease the resportive ability of the peritoneum
due to increased intraabdominal pressure and a decreased pressure
gradient from ventricle to peritoneum [17]. After administering a
rigorous bowel regimen, the patient's mental status improved, and a
subsequent measurement revealed healthy flow (0.16.-+.0.02 mL
min.sup.-1). Patient 5 was suspected to have shunt malfunction, and
thermal measurements revealed highly occluded flow (0.027.-+.0.005
mL min.sup.-1, which was later surgically confirmed. (For these
studies, the sensors were not used to make clinical
determinations). In patients 4 (pre-bowel examination) and 5
(pre-surgery), the results of the measurements were blinded to the
physician assessment. These results appear in FIG. 7C.
[0126] Error, Noise and Uncertainty: Data analysis requires
conversion of measured resistances from two sensors and one
actuator, first into temperature, and then into a flow rate. A
simplified schematic of this process appears in FIG. 18A. The first
conversion relies on a precise, high-resolution (10 m.OMEGA.)
measurement of resistance performed with a digital multimeter at a
sampling frequency of 5 Hz. The inherent noise in the resistance
measurement is 4.8 ppm over a 20-minute sampling window, as
measured with a commercial, 1 k.OMEGA. resistor and shown in FIG.
18B. The addition of a conducting anisotropic thin film (ACF) cable
increases the noise to 12.5 ppm. Introducing the soft temperature
sensing element and a second ACF connection further increases the
noise to 93.9 ppm. Conversion to temperature relies on a linear
calibration with R.sup.2>0.999, corresponding to a temperature
resolution of 15 mK. Actuation involves a high-performance constant
current source that exhibits remarkably stable operation, with
deviations of 1.73 ppm over a 20-minute sampling window, as shown
in FIG. 18C. Taken together with the effects of skin thickness and
in-plane heat dissipation, the total noise in measurements of
.DELTA.T.sub.sensors/T.sub.actuator are .about.2%, as shown in FIG.
18D. In practice, strains on the mechanically mismatched ACF cable
and soft bond pads induced by patient motion are the primary source
of noise, which we measure in vivo, on average, to be 9-10% of the
measured .DELTA.T.sub.sensors/T.sub.actuator signal for all
patients (on on-shunt locations). Elimination of ACF cable, either
through wireless embodiments or through thin, soldered connections
suggest straightforward ways of mitigating these effects.
[0127] Comparison to recent technologies: A commercially available
sensor (ShuntCheck) offers an alternative to imaging-based
diagnostic tools[18-21]. The system comprises a cooling pack that
is held against the skin over the distal catheter, with
conventional, bulk temperature sensors attached to the skin
downstream, along the direction of the catheter. The pack cools
flowing CSF, thereby decreasing the temperature of the downstream
sensor. Although this system has high specificity (.about.100%)[20]
and sensitivity (80%), it suffers from key limitations. First, the
embodiment is bulky and offers a poorly coupled sensor-skin
interface that demands the use of a large pack (2.5 cm.times.2.5
cm) and significant cooling. This requirement, together with a
conventional, large-scale data acquisition (DAQ) system, decreases
the usability of the system and prevents continuous, long-term
measurements. Second, the measurements are semi-quantitative,
without an ability to account for key factors such as skin
thickness, skin thermal properties and device layout. Taken
together, these factors lead to overall patient discomfort and
prevent straightforward interpretation of data[20]. A comparison of
existing diagnostic techniques is in FIG. 16.
[0128] Implications for the treatment of hydrocephalus: The
skin-like, precision sensor systems introduced here have the
potential to represent a paradigm shift in clinical diagnostics of
shunt malfunction. Compared to radiographic imaging, invasive
sampling, and ice-pack cooling, these platforms are unique in their
integration of precision, soft, thermal sensors with wireless
transmission capability. By exploiting advanced concepts in the
measurement of thermal anisotropy and skin-conformal epidermal
electronics, these devices can provide further quantitative modes
of use beyond opportunities afforded by the embodiments studied
here.
[0129] Clinically, shunted individuals suffer from prolonged and
costly hospital observations, exposure to toxic radiation, painful
procedural interventions and discrepancies in socioeconomic care.
The current standard of care is a disservice to this vulnerable
population, and a better method of diagnosis would be invaluable in
the management of hydrocephalic patients. The technology introduced
here will introduce capabilities in personalized medicine to the
hydrocephalus landscape, currently only embodied by types and
settings of generalized valve systems in current treatment. By
quantitatively assessing CSF flow rates, baseline flow rates can be
established for individual patients after initial surgeries and at
follow-up, thereby providing new insights into a patient's
hydrodynamic physiology. With an abundance of prior literature
describing neurosurgical exploration and witnessed intraoperative
flow, such results can shed insights into the levels of flow needed
to generate symptoms in vivo. Further, wireless capabilities allow
ventricular shunts to be monitored telemetrically, with mobile
application development aiding clinical assessment for treating
physicians. As value-based healthcare transforms medical
environments, precision measurements and seamless wireless
transmission will provide an economically practical, clinically
effective tool for the clinician. Additionally, the psychological
burden of non-specific symptoms creates significant anxiety for
patients, families and caregivers. With careful validation, a
sensor platform of the type introduced here can be employed in
at-home diagnostics, mitigating uncertainty.
[0130] Research Applications: Many poorly understood conditions
stem from neurological hydrodynamic dysfunction, including normal
pressure hydrocephalus (NPH), idiopathic intracranial hypertension
(IIH), and slit-ventricle syndrome. These conditions cause
tremendous suffering for affected patients. NPH, characterized by a
triad of neuropsychiatric changes, urinary incontinence, and gait
imbalance, may affect up to 20 million (typically elderly)
individuals annually. The associated pathophysiology may be related
to choroid villous malabsorption, and overdrainage in these
individuals may cause venous rupture and subdural hematoma, often
necessitating neurosurgical intervention [Kameda, Lesniak]. IIH
predominantly affects younger female patients and has been linked
to abnormal Vitamin A metabolism and intracranial venous stenosis.
The comparatively diminutive ventricular systems possessed by these
patients lead to high risks of shunt malfunction stemming from
ventricular collapse, complicating revision surgical attempts and
leading to extended, painful hospital stays [McGirt, Karsy, Liu].
Similarly, slit-ventricle syndrome patients experience poor
ventricular wall compliance, with malfunctions largely undetectable
in radiographic study [Drake]. By understanding individual flow
rates in each of these conditions, novel and improved treatment
approaches can be developed for their care. Ultimately,
personalized, better-designed shunt systems, with integrated flow
monitoring systems, will offer the ability to appropriately
compensate for these physiological flow patterns, providing hope to
a population with significant need.
[0131] Fabrication of the sensor system: For the sensors presented
here, fabrication began with spin-casting a sacrificial layer of
poly(methyl methacrylate) (700 nm) onto a 4'', undoped Si-wafer. A
dielectric layer, polyimide (PI, 3 .mu.m) is then spun on. For the
epidermal linear array (ELA), a single bilayer film of Cr/Au 10/100
nm deposited by electron-beam evaporation onto the wafer, and
patterned by photolithography and etching formed the sensors and
serpentine interconnects, in accordance with design rules in
stretchable electronics [22-25]. For the epidermal square array
(ESA), a bilayer film of Cr/Au 10/100 nm was photolithographically
defined to form 100 resistive temperature sensing elements,
arranged in a 10.times.10 array, around a central resistive thermal
actuator. A multilayer film of Ti/Cu/Ti/Au 20/600/20/25 nm
evaporated and photolithographically defined yielded a first layer
of rows of serpentine interconnects to address each row of sensors.
Photolithography and reactive ion etching (RIE defined via holes in
a second, spin-cast layer of PI (3 .mu.m). A second multilayer film
of Ti/Cu/Ti/Au 20/600/20/25 nm formed using the same methods as the
first, defined columnar serpentine interconnects to address each
column. For both the ELA and ESA designs, spin-casting defined a
final layer of PI layer (3 .mu.m) also patterned in the geometry of
the metal traces. A final RIE step isolated the outline of the
device and opened via holes for wired connections to external data
acquisition electronics. Immersion in an acetone bath undercuts the
sacrificial PMMA layer, allowing for release and transfer via water
soluble tape. The devices were then transferred to a thin, bi-layer
silicone membrane (Ecoflex, 20 .mu.m, Dow Corning, MG 7 1010 Skin
Adhesive, 20 .mu.m), spin-cast onto a glass slide. Immersion in
warm water dissolved the tape, and a spin-cast top layer of
silicone (Ecoflex, 50 .mu.m) completed the device. A thin (100
.mu.m), double-sided sheet adhesive (JMS 1400, Label Innovations,
Ontario, Canada) was laser structured to form an outline around the
device. This sheet adhered to the silicone and a handling frame,
either in the form of a printed circuit board containing wireless
transmission electronics, or a simple, thick, elastomeric frame to
facilitate handling of the wired electronics. Anisotropically
conducting films (ACF) established connections to wired data
acquisition electronics. The sensor resistances were then
calibrated to temperatures measured by IR imaging.
[0132] Fabrication of Flexible Printed Circuit Boards: Fabrication
began with a commercially available, dense, tri-layer Cu/PI/Cu
laminate (Pyralux, 6535, DuPont, 18 .mu.m/75 .mu.m/18 .mu.m). Laser
structuring (LPKF U4, LPKF Systems, Germany) patterned conducting
traces and bond pads, with a resolution of 50 .mu.m. Commercially
available SMD resistors, capacitors, along with a Bluetooth
microcontroller (NRF 52, Nordic Semiconductor) and battery, in
addition to the soft electronic components were bonded to the PCB
via reflow soldering.
[0133] Data Acquisition Systems: Data were recorded from the ELA
resistive elements via digital multimeters (DMM) (NI, USB 4065,
National Instruments). Actuation power was supplied with a constant
current source (Keithley 6220, Tektronix). The ESA requires a
voltage output module (NI 9264, National Instruments) that
sequentially actuates each of the ten input channels with 3V, and a
single-channel DMM to measure current. A red LED connected in
series with each channel served as a visual indicator of
multiplexing and the status of each addressed channel. A mechanical
REED relay module (J-Works, 2418, J-Works Inc.) was used to time
multiplex measurements from each of the ten channels. All data were
recorded via custom software designed and programmed in LabView
(National Instruments), and processed with custom algorithms in
Matlab (Mathworks Inc., Natick, Mass.).
[0134] Thermo-Mechanical Modeling and Finite Element Analysis
[0135] Benchtop Experiments: A phantom skin assembly was
constructed for in-vitro evaluation. A distal shunt catheter
(Medtronic, Minneapolis, Minn.) was embedded in a matrix of PDMS
(Sylgard 184, Dow Corning) supported by a 3D printed mold
containing struts to preventing sagging of the catheter. Optical
images of this assembly appear in FIGS. 13A-13C. The depth of the
catheter under the PDMS was 1.1 mm, as seen in FIG. 13B, and the
sensor was laminated onto the free surface of the assembly, as
shown in FIG. 13C. The catheter was connected to a syringe pump,
through which flow rates were varied to yield the experimental data
shown in FIGS. 3A-3K. Water was chosen to be the test fluid for
these experiments. The observed flow rates were 33% higher than
values displayed on the pump, which was corrected for via a simple,
linear calibration, where true flow values were measured with
precise weight measurements on an analytical balance at fixed time
intervals. The syringe pump was allowed to come to steady state at
a flow rate for 180 s before the measurement was made. Each
measurement consisted of a 60 s "off" period with
Q.sub.actuator<0.001 mW/mm.sup.2, followed by a 600 s actuation
("on") period, with Q.sub.actuator=1.45 mW/mm.sup.2, followed by a
180 s off period to return the sensor back to its baseline,
pre-actuation temperature value. Simultaneously, thermographs were
recorded with an IR Camera (FLIR Systems, a6255sc), with a
high-magnification lens. Different skin-thicknesses were achieved
by casting PDMS onto 3D printed molds with negative relief
structures with defined heights and laminating the resulting sheets
onto the fluidic assembly described above.
[0136] Human Study Design: Patients were recruited from an existing
ICU population. The inclusion criterion was any patient with an
implanted ventricular shunt, regardless of whether they were
suspected of shunt malfunction. Patient 1 (36, F) presented with a
Pseudotumor cerebri and suspected shunt malfunction that was then
surgically corrected. Patient 2 (F, 53) presented with a Chiari I
malformation, and was not suspected of shunt malfunction. Patient 3
(M, 32), presented with a Glioblastoma multiform, with no suspected
malfunction, and Patient 4 (F, 58) presented with a Glioblastoma
multiforme with suspected pseudoobstruction due to acute and
prolonged constipation that was resolved with a rigorous bowel
examination. Patient 5 (F, 30) presented with suspected malfunction
due to obstruction, with severely diminished but non-zero flow,
which was confirmed during surgery. Depending on the clinical
condition of the patient, they were either asked to either sit at
45.degree. or completely supine. A single measurement consisted of
placing the sensor on the skin and waiting for 60 s for the sensor
to equilibrate with the skin. Low power thermal actuation (1.6
mW/mm.sup.2) was then supplied for 240 s, and then halted for the
next 120 s, while making continuous temperature measurements of
both the sensors and the actuator. All data recording occurred at 5
Hz and processing used an adjacent-averaging filter with a 10-point
sampling window. Two successive measurements each were made on skin
directly overlying the shunt, and at a skin location adjacent to
the shunt. The shunt was easily located, and alignment marks on the
device allowed for easy alignment. An elastomeric enclosure around
the device facilitated handling of the device.
TABLE-US-00001 TABLE 1 Table summarizing etiology of, and
measurements made on each patient. Flow Flow Detected Detected
Underlying Malfunction (pre- (post- Imaging Skin Condition Age Sex
Present intervention) intervention) Correlate Irritation 1
Pseudotumor 36 F Y N Y Y.sup.1 N cerebri 2 Chiari I 53 F N Y N/A
N/A N malformation 3 Glioblastoma 32 M N Y N/A N/A N multiforme 4
Glioblastoma 58 F Y N Y Y.sup.2 N multiforme 5 Post- 30 F Y Y
N/A.sup.3 Y.sup.4 N hemorrhagic
TABLE-US-00002 TABLE 2 Table summarizing existing shunt diagnostic
tools and techniques. Time Modality Cost (min) Sensitivity
Specificity PPV NPV X-Ray[1, 2] 440 84 4-26% 92-99% 13 93.9 CT[3-6]
1323 83 54-80% 80-90% 71 90.8 MRI[5-8] 3239 115 40-62.8% 84-92% 75
86.5 RSPS[9-12] 750 45 47-65% 86-92% 71 71 ShuntCheck[13- Unknown
360 80% 100% 58 96 15]*
REFERENCES
[0137] 1. Xu, S., et al., Soft microfluidic assemblies of sensors,
circuits, and radios for the skin. Science, 2014. 344(6179): p.
70-74. [0138] 2. Norton, J. J., 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): p. 3920-3925. [0139] 3. Kim, J., et al.,
Epidermal electronics with advanced capabilities in near-field
communication. small, 2015. 11(8): p. 906-912. [0140] 4.
Dagdeviren, C., et al., Conformal piezoelectric systems for
clinical and experimental characterization of soft tissue
biomechanics. Nature materials, 2015. 14(7): p. 728-736. [0141] 5.
Choi, J., et al., Thin, Soft, Skin-Mounted Microfluidic Networks
with Capillary Bursting Valves for Chrono-Sampling of Sweat.
Advanced healthcare materials, 2017. 6(5). [0142] 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): p. 366ra165-366ra165. [0143] 7. Tian, L., et al.,
Flexible and Stretchable 3.omega. Sensors for Thermal
Characterization of Human Skin. Advanced Functional Materials,
2017. [0144] 8. Krishnan, S., et al., Multimodal epidermal devices
for hydration monitoring. Microsystems & Nanoengineering, 2017.
3: p. 17014. [0145] 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): p. 119-127. [0146] 10. Webb, R. C., S.
Krishnan, and J. A. Rogers, Ultrathin, Skin-Like Devices for
Precise, Continuous Thermal Property Mapping of Human Skin and Soft
Tissues, in Stretchable Bioelectronics for Medical Devices and
Systems. 2016, Springer. p. 117-132. [0147] 11. Webb, R. C., et
al., Thermal transport characteristics of human skin measured in
vivo using ultrathin conformal arrays of thermal sensors and
actuators. PLoS One, 2015. 10(2): p. e0118131. [0148] 12. Webb, R.
C., et al., Epidermal devices for noninvasive, precise, and
continuous mapping of macrovascular and microvascular blood flow.
Sci Adv, 2015. 1(9): p. e1500701. [0149] 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): p. 888-893. [0150] 14. Carslaw, H. S. and J. C.
Jaeger, Conduction of heat in solids. Oxford: Clarendon Press,
1959, 2nd ed., 1959. [0151] 15. Sandby-Moller, J., T. Poulsen, and
H. C. Wulf, Epidermal thickness at different body sites:
relationship to age, gender, pigmentation, blood content, skin type
and smoking habits. Acta Dermato Venereologica, 2003. 83(6): p.
410-413. [0152] 16. Braley, S., The chemistry and properties of the
medical-grade silicones. Journal of Macromolecular
Science--Chemistry, 1970. 4(3): p. 529-544. [0153] 17.
Martinez-Lage, J. F., et al., Severe constipation: an
under-appreciated cause of VP shunt malfunction: a case-based
update. Child's Nervous System, 2008. 24(4): p. 431-435. [0154] 18.
Ragavan, V. V., Evaluation of shunt flow through a hydrocephalic
shunt: a controlled model for evaluation of the performance using
Shuntcheck. 2017: p. 1-4. [0155] 19. Boyle, T. M., J; Neuman, M;
Tamber, M; Hickey, R W; Heuer G, Leonard J; Leonard JC; Keating R;
Chamberlain J; Frim ID, Zakrzewski, Klinge, P; Merck, L; Platt, J;
Bennett, J; Sandberg, ID, Boop, Zorc, J, ShuntCheck versus
Neuroimaging for Diagnosing Ventricular Shunt Malfunction in the
Emergency Department. American Association of Pediatrics, 2017: p.
1-2. [0156] 20. Madsen, J. R., et al., Evaluation of the ShuntCheck
Noninvasive Thermal Technique for Shunt Flow Detection in
Hydrocephalic Patients. Neurosurgery, 2011. 68(1): p. 198-205.
[0157] 21. Recinos, V. A., 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: p. 1-1. [0158] 22. Zhang,
Y., Y. Huang, and J. A. Rogers, Mechanics of stretchable batteries
and supercapacitors. Current Opinion in Solid State and Materials
Science, 2015. 19(3): p. 190-199. [0159] 23. Zhang, Y. H., et al.,
Experimental and Theoretical Studies of Serpentine Microstructures
Bonded To Prestrained Elastomers for Stretchable Electronics.
Advanced Functional Materials, 2014. 24(14): p. 2028-2037. [0160]
24. Zhang, Y., et al., Mechanics of ultra-stretchable self-similar
serpentine interconnects. Acta Materialia, 2013. 61(20): p.
7816-7827. [0161] 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): p. 8062-8070.
Example 2: System Characterization and Use
[0162] FIGS. 24-28 illustrate various features of the devices and
methods described herein. FIG. 24 illustrates the position of the
device and temperature sensors and various parameters used to
calculate temperature and flow-rate in a subdermal conduit
(described in FIG. 24 as "catheter"). Unknown quantities include
skin-related parameters, such as depth of the conduit from the skin
surface (h.sub.skin), as well as thermal conductivity (k) and
diffusivity (.alpha.) of the skin. Known parameters include the
thermal conductivity (k) and diffusivity (.alpha.) of the conduit
and fluid in the conduit, outer and inner diameters of the conduit,
and upstream, downstream distance between the sensors and the
actuator (labeled "heater"), and temperature measured by the sensor
and applied by the heater. In controlled conditions, the flow-rate
(Q) of the fluid in the conduit may be known. From these
parameters, flow-rate may be determined, as summarized in the
flow-chart of FIG. 25.
[0163] The active sensing portion of the device is extremely thin
and, therefore, relatively difficult to handle. To assist with
handling, any of the devices described herein may have a handle
layer, including as shown in FIG. 26. A rigid layer, such as a
glass slide, may support any of the devices described herein,
including with an adhesive layer and encapsulation layers. The
device may be peeled off the handle layer and be ready for
conformal contact with the skin.
[0164] FIGS. 27-28 illustrate a carrier substrate having an open
passage through a central portion of the carrier substrate, wherein
the conformable device is positioned in the open passage to provide
improved handling characteristics during application and durability
during use. The carrier substrate in FIG. 27 is circular, and in
FIG. 28 is rectangular. Any number of shapes may be used, including
depending on the application and location of interest.
[0165] The sensor described herein has many potential applications
in wide range of applications, including in the medical field. For
example, bypass vascular grafts, and cardiac stent flow may be
assessed post-procedurally. This involves placing a sensor over an
applicable area with appropriate depth and quantifying flow
parameters. Similarly, sensors applied over large vessels may be
used to assist in detecting micro-emboli pertinent to the
management of diseases such as carotid atherosclerotic disease.
Finally, appropriate pressure readings may be invaluable in
providing non-invasive arterial pressure measurements in the
operating room or angiography suite, abrogating the need for
invasive arterial line placement.
Example 3: Soft Tissue Mounted Flow Sensors
Abstract
[0166] Hydrocephalus and shunt-related expenditures cost the US
system over $2 billion dollars in annual expenses, with 125,000
shunt surgeries per year and an untreated mortality rate estimated
at 50-60%. Existing diagnostics are expensive, inaccurate, and
often harmful or invasive, and can lead to unnecessary admissions,
further testing, or needless surgery. Collaborative efforts between
Northwestern materials engineers headed by Dr. John Rogers
alongside the leadership of neurological surgeons at Northwestern
Memorial Hospital and Lurie Children's Hospital have produced and
validated a noninvasive, thermal biosensor capable of diagnosing
ventricular shunt malfunction.
Applications
[0167] Non-invasive, rapid, accurate detection of shunt
malfunction
[0168] Conformal, painless sensor technology with wireless
capability
[0169] Extended use can capture occult malfunction, akin to a
holter monitor for cerebrospinal fluid
Advantages
[0170] Minimal devices with similar capabilities in market
currently
[0171] Present analogues (i.e.: Shuntcheck) require use of ice
cubes, cumbersome technology and supplementary devices
[0172] Provides minimal, sensitive and rapid detection of flow
through silastic tubing
[0173] Components and manufacturing flows that are compatible with
existing scalable, ISO:13485 compliant approaches
Brief Summary of Technology
[0174] Provided herein are devices that allow for the sensing of
fluid flow through near-surface conduits, both natural and
implanted. Examples of these conduits include near-surface blood
vessels such as veins and arteries, and implanted silicone shunt
catheters for the drainage of excess cerebrospinal fluid in
patients with hydrocephalus. The sensor relies on measurements of
thermal transport through the skin, owing to the fact that
near-surface flow affects thermal transport, causing heat from a
localized heat source to flow preferentially along the direction of
flow. Earlier disclosures have covered concepts relevant to
hydrocephalus diagnostics. This disclosure describes technologies
for advanced clinical deployment, manufacturability and usability
by patients and physicians alike. A feature of the technologies
described below is their immediate relevance to clinical
deployment. Specifically, the components and technologies described
below are compatible with scalable, ISO:13485 compliant
manufacturing approaches, and the key features described are
informed by patient trials. These advances are important to any
related technology seeking regulatory clearance, for example in the
form of a pre-market approval (PMA) or 510(k) from the federal food
and drug administration.
Technical Description
[0175] FIG. 29 provides an overview of new platform technologies
and various aspects of the systems and methods described
herein.
Sensing/Actuating Hardware
[0176] As an example, the sensing hardware involves collections of
thermal actuators (e.g., heating elements) and temperature sensors
with layouts and form factors that allow them to map heat flow
across the skin to reveal near-surface flows and their magnitudes
at depths of up to 8 mm. Their form factors also allow them to
couple closely to the skin, with low thermal masses and interfacial
resistances. We describe three distinct technologies that allow
this:
[0177] Thin film electronic actuators/sensors: These describe any
technologies capable of responding specifically to changes in
temperature with changes in their electronic properties, or capable
of inducing localized temperature changes on demand, with total
thicknesses of <10 .mu.m. Examples of sensing mechanisms include
piezoresistive sensors constructed from metals or semiconducting
materials, that can exhibit either a positive or negative
correlation with changes in temperature, and diodes which exhibit
temperature-dependent turn-on voltages. Examples of actuating
elements include metallic heating coils constructed from metals or
their alloys, that exhibit joule heating on the application of
current.
[0178] 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
surface-mounted, lightweight form-factors that allow for low
thermal mass sensing, and can be easily integrated with flexible
circuit boards via reflow soldering or commercial pick and place
technologies. They are in some cases constituted of metals, metal
oxides and polymers, and are commercially available for a range of
sensing applications from the automotive industry to manufacturing.
The typical sizes of these sensors are 1200 .mu.m.times.600
.mu.m.times.600 .mu.m or less. They exhibit temperature response
times that are <100 ms, and are precise to temperature changes
of 50 mK or better. These results are characterized in in FIG. 30.
Similarly, commercially available, surface-mounted resistors, when
wired together in series on a flexible circuit board serve as
thermal actuators on the application of a voltage. The spacing and
layout of these components determines localized thermal transport
into underlying layers of tissue. Infrared images and optical
images shown in FIG. 3I illustrate these concepts. The flexible
circuit materials can be constructed of metals (e.g., Copper, Al,
Nickel, chromium, or their alloys/combinations) or polymers (e.g.
polyimide, polyether ether ketone, polyester, polyethylene
terephthalate) with combined thicknesses of <1 mm. Exemplary
performance of these devices is shown in FIGS. 35-37.
[0179] For both approaches 1) and 2), changes in the piezoresistive
or other electronic properties are converted to precise, measurable
changes in voltage or current using a customized analog
conditioning circuit. This voltage or current is then digitized via
an analog to digital converter (ADC), rendering the signal suitable
for wired or wireless data transmission. This circuit can consist
of Wheatstone bridges, voltage dividers, amplifiers and
combinations of these. An example of an analog circuit, along with
a circuit simulation, consisting of an NTC temperature sensor,
wheatstone bridge and an operational amplifier appears in FIG. 32,
and is capable of temperature measurements of <5 mK precision
across an ADC range of 2-5V.
[0180] Optical Approaches: This encompasses a set of technologies
designed to optically measure flow through near-surface conduits
such as shunts via thermal transport measurements, either in
addition to, or independent of the approaches described above.
Broadly, these approaches can be divided into two techniques:
[0181] Colorimetric approaches: The arrangement of thermochromic
dyes around an actuating element, as described by Gao, et. al [1]
allows for the quantitative imaging of heat flow through biological
tissue. Images can be recorded via a commercial camera, or through
a camera built into a commercial smartphone, and exploit image
processing algorithms capable of converting subtle color changes
into thermal maps with <100 mK temperature resolution. Examples
of such constructions are in FIG. 33.
[0182] Infrared/Thermal imaging: The availability of low-cost,
commercially available infrared imaging technologies, many of which
can seamlessly integrate with a smartphone camera allows for
imaging of thermal transport directly through a thermal camera. An
example of such a commercially available imager is in FIG. 34, with
representative examples of infrared images in the presence (top)
and absence (bottom) of flow in a benchtop system.
[0183] Both of the above optical approaches require thermal
actuation, which can proceed either via the approaches described in
points 1-2, or through wireless, inductive power coupling to an
on-board receiver coil, as in Gao, et. al[1]
Packaging and Encapsulation
[0184] We have developed packaging and encapsulation strategies
with the following goals:
[0185] Insulation from thermal noise: The introduction of a thermal
foam or gel allows for the removal of ambient convective noise. The
effects of this foam are shown in FIGS. 35-37, wherein the
introduction of a foam increases the signal to noise performance an
order of magnitude.
[0186] Soft, flexible, user-friendly: The addition of an
elastomeric substrate, superstrate and shell allow for easy
modulation of external appearance, with a soft finish. These
features can be accomplished via casting or molding, as shown in
FIG. 38.
[0187] Strong, non-irritating adhesion to human skin: The use of
customized, silicone or acrylate based adhesive with adhesion
energies of <1000 N/m accomplish this.
[0188] Easy alignment with shunt, accomplished with alignment
markers.
[0189] The miniaturized form factor, alignment markers are visible
in FIG. 39, where a measurement made by the platform can clearly
distinguish between instances where flow is present and absent,
respectively, on a patient with an implanted shunt. Further
examples on a patient's volar wrist vein and collar bone, along
with in vitro data on a temperature controlled hot-plate are shown
in FIG. 40, illustrating the stability of the temperature sensors,
and representative data in the presence (vein) and absence
(collarbone) of flow induced anisotropies, respectively. FIG. 41
shows the sensor working on a patient with a shunt in an
IRB-approved study.
Electronics
[0190] This disclosure involves the following advanced electronics
features, specifically in the context of a wearable, wireless flow
sensor, with near-term opportunities in monitoring flow through
shunts in patients with hydrocephalus:
[0191] Multiple temperature sensors (>2), interfacing and being
multiplexed by multiple ADCs on-board the Bluetooth chip. These
could be addressed directly to ADC pins, or rapidly addressed via a
miniaturized multiplexing unit. The addition of multiple sensors
provides redundancy in the measurement, and also ensures larger
tolerances to positional uncertainties. Schematics and benchtop
data from a 4-sensor embodiment are shown in FIGS. 42-44.
[0192] The inclusion of a coiled wire to wirelessly inductively
couple power into the circuit for powering, wireless recharging, or
for operations on the Bluetooth chip such as waking it up from deep
sleep mode. A schematic of such a system is shown in FIG. 45.
[0193] The inclusion of relevant power management components, such
as regulators, DC-DC converters, and rectifying circuit elements
such as diodes and capacitors to form full or half wave
rectifiers.
[0194] The use of frequencies for power transfer that are
compatible with near-field communication protocols (e.g., 13.56
MHz).
[0195] The use of gate actuation schemes to switch large loads to
the actuator with low current outputs from the Bluetooth chip.
[0196] Each of the above features contributes to system level
usability, as borne out by multiple patient trials.
Software
[0197] 1. Creation of a firmware embedded application (henceforth
referred to as the "Application") that can operate on a Nordic
Semiconductor NRF52 development board or System on Chip (SoC).
[0198] 2. The Application will be able to read from four
temperature sensors attached to the development board at a rate of
3 samples per second or greater.
[0199] 3. The Application will transmit the temperature readings to
a Bluetooth 4.0 stream, where the data can then be received by a
paired Bluetooth 4.0 capable device.
[0200] 4. The Application will have a time indicator for each
temperature sample taken. This will also be transferred on the
Bluetooth 4.0 data stream.
[0201] 5. The Application will be able to activate a heating
element or collection of heating elements through a button or
option on the application screen.
[0202] 6. Creation of a windows/android/iOS application (henceforth
referred to as the "Application") that can operate on the Windows
10 Home Operating System, Android or iPhone environments
respectively.
[0203] 7. The Application will require to operate that the device
it is being operated on supports Bluetooth 4.0 through the
operating system.
[0204] Application.
[0205] 8. The Application will be able to read the data stream from
the Application.
[0206] 9. The Application will be able to graph the 4 temperature
readings on the same plot, or on different plots, along with other
relevant quantities
[0207] 10. The Application will be able to update the graph as new
data is sent from the Application.
[0208] 11. The application will be able to perform mathematical
operations relevant to the conversion of thermal signals to
quantitative flow rates.
[0209] Additional features include, but are not limited to:
[0210] Text reminders to the user for periodic checks.
[0211] Instructions for use, integrated directly into the app, as a
step by step guide with cartoons, etc.
[0212] Quick-link interfaces to the hospital and/or attending
physician
[0213] An example of such an application is provided in FIG.
46.
[0214] Clinical Protocols:
[0215] We include our clinical protocols and checklists, developed
in conjunction with the sensor, to reduce inter-operator
variability, and increase patient and physician use. Examples are
in FIGS. 47-48, with clinical data validating these protocols in
FIG. 47.
[0216] While established shunt diagnostics are alternatives to this
new technology, there is one competitor that has developed a device
based on similar thermal principals. ShuntCheck, developed by the
late Dr. Samuel Neff in 2005, utilizes an ice-pack based thermal
cooling system connected to a Windows PC DAQ. While it has
established itself with 12 years, 11 manuscripts or abstracts,
largely positive studies demonstrating its value and over $3
million in NIH funding, the technology is cumbersome and
time-consuming. Marketing efforts and publicity have been sparse
until this year. Though Phase III trials are underway at NeuroDX
and may ultimately demonstrate equivalence to clinical measures,
the device's cumbersome, multi-step protocol; equivocal or negative
past clinical studies; and need for ice-pack cooling have limited
its acceptance. Additionally, patient discomfort due to prolonged
skin cooling (detrimental for pediatric diagnostics) and absence of
chronic monitoring further limits its diagnostic relevance.
[0217] To our knowledge, there is no other comparable wireless
noninvasive shunt diagnostic, with or without biometric
capabilities or epidermal properties, in the research literature or
the commercial domain.
REFERENCES RELATED TO EXAMPLE 3
[0218] 1. Gao, L., et al., Epidermal photonic devices for
quantitative imaging of temperature and thermal transport
characteristics of the skin. Nat Commun, 2014. 5: p. 4938.
Example 4--Exemplary Schematics
[0219] FIG. 50 provides an example of a thermal sensing device 100
that uses an array of resistors 142 as a thermal actuator 140. The
thermal actuator 140 is positioned between an upstream temperature
sensor 120 and a downstream temperature sensor 130 along a
potential fluid flow path, for example, an artery, vein or shunt.
Both the temperature sensors 120, 130 and the thermal actuator 140
are supported by a substrate 110. Either the upstream temperature
sensor 120, the downstream temperature sensor 130 or both may be an
array or plurality of temperature sensors.
[0220] In some embodiments, the device 100 may further comprise 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. Additionally, a
microprocessor 160 may also be provided in operable communication
with the temperature sensors 120, 130 and/or the thermal actuator
140.
[0221] FIG. 5I provides an example cross-sectional schematic of a
thermal sensing device 100 that includes an insulating layer 200
and a discontinuous thermally conductive layer 210. Again, the
thermal actuator 140 is positioned between an upstream temperature
sensor 120 and a downstream temperature sensor 130 along a
potential fluid flow path, for example, an artery, vein or shunt.
Both the temperature sensors 120, 130 and the thermal actuator 140
are supported by a substrate 110.
[0222] The temperature sensors 120, 130 and the thermal actuator
140 are encapsulated by an insulating layer 200, for example, a
foam which reduces outside 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 superstrate 202. A discontinuous
thermally conductive layer 210 may be included proximate to the
temperature sensors 120, 130, the thermal actuator 140 or both.
Additionally, an adhesive layer 220 may be included for
establishing and maintain contact with a tissue of a subject or
patient.
Example 5: Long-Term, Continuous Measurements of CSF Hydrodynamics
In Vivo
[0223] Hydrocephalus is a common and debilitating condition
resulting in the buildup of cerebrospinal fluid in the ventricles
of the brain. It affects >1,000,000 people in the United States,
including >350,000 children. The current standard of care for
hydrocephalus is the surgical implantation of a ventricular shunt
assembly to drain the excess fluid away from the brain and into a
distal absorptive site such as the peritoneal cavity.
Unfortunately, shunts have an extremely high failure rate (50% over
the first two years and about 10% for every year thereafter), and
diagnosing shunt malfunction accurately presents a significant
clinical challenge due to ambiguous symptoms such as headaches and
nausea. Additionally, real-time in vivo CSF hydrodynamic remain
poorly understood, frustrating the development of advanced shunt
technology. As an example, shunt intermittency is a well-known
phenomenon but varies in frequency and magnitude in each patient.
As a result, a working but intermittent shunt can be mistaken for
shunt failure when tested with a shunt tap or other well-known
diagnostic techniques, such as ice-pack mediated cooling. We
introduce a wearable, thermal-transport based sensor that relies on
anisotropic thermal transport to make precise measurements of shunt
flow rate. In this example, we build on those platforms to provide
a clinically focused device constructed entirely from commercially
available components and using techniques that are aligned with
scalable manufacture. The resulting fully wireless, miniaturized
embodiment possesses a set of properties in accuracy, precision,
size, weight and cost that represent a significant improvement.
Importantly, the size and construction of the platform allow it to
be worn continuously over extended periods, enabling, for the first
time, long-term, continuous measurements of CSF hydrodynamics in
vivo.
[0224] Fully integrated flow sensing using commercially-available
components:
[0225] Fabrication An exploded view illustration of the sensor is
in FIG. 53A. 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 structures conducting traces and bond pads on a
dense, trilayer laminate material of copper-polyimide-copper (18
.mu.m-75 .mu.m-18 .mu.m). Reflow soldering using low temperature
solder paste allows for the precise, rapid placement of
miniaturized surface mounted device (SMD) elements onto the board.
Separately, a thin silicone sheet (Silbione, Bluestar Silicones 100
.mu.m) is spin-cast onto a smooth glass slide, surface treated to
be hydrophobic. Importantly, it is semi-cured in order to enhance
its adhesion. Flash curing the entire assembly at 100.degree. C.
for 120 s ensures robust adhesion between the silicone and the
device. A top silicone layer is then drop cast and cured at
70.degree. C. for 60 minutes to form a 300 .mu.m superstrate. A
UV-Ozone treatment of the top surface renders it hydrophilic, and
in-situ curing of a soft, flat (3 mm) poly-urethane foam layer
(FlexFoam, Smooth On Inc.) over the sensing and actuating
components ensures robust insulation from ambient thermal noise.
Separately, a thin (<2 mm) silicone (Silbione) shell (FIG. 61)
is formed by casting a liquid precursor into a pair of customized
male and female fittings, milled from commercially available
Aluminum in a 3-axis CNC milling machine, and curing at 100.degree.
C. for 15 minutes. A UV-Ozone treatment of the superstrate layer on
the device and the shell creates a hydrophilic interface, and the
two surfaces are bonded by curing at 70.degree. C. for 6 hours.
Laser cutting the outline of the sensor and mounting a commercially
available, skin-safe, laser-cut adhesive completes the
fabrication.
[0226] Working Principles: The sensing platform relies on
measurements of thermal transport yielded by combinations of
thermal sensors and actuators, closely thermo-mechanically coupled
to the underlying skin, with the soft, flexible construction of the
device ensuring a tight thermo-mechanical coupling to the
underlying skin. The sensing platform comprises a thermal actuator
and a set of coplanar temperature sensors located upstream and
downstream of the underlying shunt catheter (FIG. 54A). The
actuator is constructed from a series of fixed, surface mounted
resistors (230 um.times.300 um.times.600 um) electrically connected
in series and laid out in a circular, densely packed array. The
packing density of the resistors represents a tradeoff between
yield, with high densities exceeding the capabilities of commercial
and place technologies, and thermal transport considerations.
Packing densities of <40 .OMEGA./mm.sup.2 result in uneven
thermal transport and significant in-plane thermal dissipation. The
application of a fixed, controlled voltage results in localized
thermal actuation of 1.7 mW/mm.sup.2, causing a local temperature
increase of .about.5K (FIG. 54B). As described in previous reports,
the presence of flow underlying the actuator results in anisotropic
thermal transport (FIG. 54C). Commercially available negative
temperature coefficient (NTC) temperature sensors constructed from
metallic oxides form high-precision (2 mK), low-hysteresis
temperature sensors whose resistance varies approximately linearly
in a biological relevant regime (FIG. 56). The low thermal masses
of these elements result in equilibration times of .about.60 s with
underlying tissue. Locating these elements upstream and downstream
of the actuator along the direction of the shunt captures the
effects of flow, with the downstream and upstream temperature
measurements (T.sub.Downstream,T.sub.upstream) bifurcating (FIGS.
54D-54C). The resulting temperature differential,
T=(T.sub.Downstream-T.sub.upstream) obeys a non-monotonic but
well-understood relationship with flow rate across a range relevant
to CSF flow through shunts (FIG. 54E), extensively described in a
previous report. The average temperature of the two sensors,
T.sub.average=(T.sub.Downstream+T.sub.upstream)/2 can be used to
differentiate between high flow and low flow values with the same
levels of thermal anisotopy, by capturing the net temperature
decrease brought about by the convective effects of flow at high
rates (FIG. 54E). Skin thickness plays a key role in regulating
thermal transport to the underlying shunt, and an increased skin
thickness will result in diminished signal to noise, with 6 mm
representing an outer limit for reliable measurements.
[0227] Positional uncertainties and ambient thermal noise represent
two key potential sources of error. Positional uncertainties are
mitigated by the following steps: 1) the addition of two additional
temperature sensors, one each upstream and downstream affords an
increased positional and rotational tolerance. These effects are
shown in FIGS. 61-62, where the sensor can accommodate positional
uncertainties of up to 5 mm and rotational uncertainties of
.about.23.degree.. 2) The addition of alignment markers along the
center-line of the sensor/actuator axis (seen in FIG. 53B) allows
for physicians/practitioners to align the device immediately after
palpating the shunt. 3) The addition of an insulating layer, such
as a foam layer, above the sensing/actuating elements significantly
alleviates ambient thermal noise, as seen in FIG. 64. The devices
and methods provided herein, therefore, may be described as having
a rotational and/or translational positional tolerance, including
accommodation of a rotational misalignment of up to 23 degrees
and/or translational misalignment of up to 5 mm, without
significantly impacting performance. This is a significant
improvement, as in use a practical challenge is achieving precise
alignment with the underlying flow conduit.
[0228] Wireless Electronics and Signal Conditioning:
[0229] Converting temperature-induced resistance changes on the NTC
to a voltage that can be digitized relies on a Wheatstone bridge
(FIG. 59). The voltage differential across the two arms (sensing
and non-sensing) of the bridge feed into the inverting and
non-inverting inputs of an operational amplifier, whose gain is
tuned via a feedback resistor. The amplified signal is digitized
via a 12-bit analog-digital converter (ADC) built into a Bluetooth
low energy (BLE) System on Chip (SoC), with a full sensing range of
3.3V. The resultant sensor operates linearly in a temperature range
between 28.degree. C. and 40.degree. C. with a precision of 3.5 mK.
Controlled thermal actuation results from 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) whose gate is switched by a general-purpose input/out
(GPIO) pin on the BLE SoC. The actuation power can be tuned by
pulsing the MOSFET at a programmable duty cycle.
[0230] When not in use, the device platform operates in a low
energy, deep "sleep" mode that consumes .about.30 nA of current.
The operation of a momentary switch turns the device on, followed
by a programmable period of advertising. If no pairing occurs, the
device reverts to deep sleep mode, while pairing results in regular
operation. This scheme is illustrated in FIGS. 60A-60D.
[0231] Data acquisition relies on a graphical interface on a tablet
PC that can record and display temperature values from 4 ADCs while
also providing a means for controlling thermal actuation (FIG.
53D).
STATEMENTS REGARDING INCORPORATION BY REFERENCE AND VARIATIONS
[0232] All references throughout this application, for example
patent documents including issued or granted patents or
equivalents; patent application publications; and non-patent
literature documents or other source material; are hereby
incorporated by reference herein in their entireties, as though
individually incorporated by reference, to the extent each
reference is at least partially not inconsistent with the
disclosure in this application (for example, a reference that is
partially inconsistent is incorporated by reference except for the
partially inconsistent portion of the reference).
[0233] The terms and expressions which have been employed herein
are used as terms of description and not of limitation, and there
is no intention in the use of such terms and expressions of
excluding any equivalents of the features shown and described or
portions thereof, but it is recognized that various modifications
are possible within the scope of the invention claimed. Thus, it
should be understood that although the present invention has been
specifically disclosed by preferred embodiments, exemplary
embodiments and optional features, modification and variation of
the concepts herein disclosed may be resorted to by those skilled
in the art, and that such modifications and variations are
considered to be within the scope of this 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 one skilled in the art that the present invention
may be carried out using a large number of variations of the
devices, device components, methods steps set forth in the present
description. As will be obvious to one of skill in the art, methods
and devices useful for the present methods can include a large
number of optional composition and processing elements and
steps.
[0234] When a group of substituents is disclosed herein, it is
understood that all individual members of that group and all
subgroups, are disclosed separately. When a Markush group or other
grouping is 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.
[0235] Every formulation or combination of components described or
exemplified herein can be used to practice the invention, unless
otherwise stated.
[0236] Whenever a range is given in the specification, for example,
a numerical range, a thickness range, a modulus range, a
temperature range, a time range, or a thermal conductivity range,
all intermediate ranges and subranges, as well as all individual
values included in the ranges given are intended to be included in
the disclosure. It will be understood that any subranges or
individual values in a range or subrange that are included in the
description herein can be excluded from the claims herein.
[0237] All patents and publications mentioned in the specification
are indicative of the levels of skill of those skilled in the art
to which the invention pertains. References cited herein are
incorporated by reference herein in their entirety to indicate the
state of the art as of their publication or filing date and it is
intended that this information can be employed herein, if needed,
to exclude specific embodiments that are in the prior art. For
example, when composition of matter are claimed, it should be
understood that compounds known and available in the art prior to
Applicant's invention, including compounds for which an enabling
disclosure is provided in the references cited herein, are not
intended to be included in the composition of matter claims
herein.
[0238] As used herein, "comprising" is synonymous with "including,"
"containing," or "characterized by," and is inclusive or open-ended
and does not exclude additional, unrecited 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 materially affect the basic and novel characteristics
of the claim. In each instance herein any of the terms
"comprising", "consisting essentially of" and "consisting of" may
be replaced with either of the other two terms. The invention
illustratively described herein suitably may be practiced in the
absence of any element or elements, limitation or limitations which
is not specifically disclosed herein.
[0239] One of ordinary skill in the art will appreciate that
starting materials, biological materials, reagents, synthetic
methods, purification methods, analytical methods, assay methods,
and biological methods other than those specifically exemplified
can be employed in the practice of the invention without resort to
undue experimentation. All art-known functional equivalents, of any
such materials and methods are intended to be included in this
invention. The terms and expressions which have been employed are
used as terms of description and not of limitation, and there is no
intention that in the use of such terms and expressions of
excluding any equivalents of the features shown and described or
portions thereof, but it is recognized that various modifications
are possible within the scope of the invention claimed. Thus, it
should be understood that although the present invention has been
specifically disclosed by preferred embodiments and optional
features, modification and variation of the concepts herein
disclosed may be resorted to by those skilled in the art, and that
such modifications and variations are considered to be within the
scope of this invention as defined by the appended claims.
Tables
TABLE-US-00003 [0240] TABLE 3 Thermal and geometrical quantities
required for quantitative measurement of flow rate. Quantity Units
Range/Value Measurement k.sub.skin W m.sup.-1 K 0.30-0.50 In vivo
with epidermal transient plane source .alpha..sub.skin
mm.sup.2s.sup.-1 0.07-0.15 In vivo with epidermal transient plane
source H.sub.convection W m.sup.-2 K 6-25 In vitro, fitting to
model k.sub.CSF W m.sup.-1 K 0.5-0.6 Known a priori .alpha..sub.CSF
mm.sup.2s.sup.-1 0.13-0.16 Known a priori k.sub.Catheter W m.sup.-1
K 0.22 Known a priori .alpha..sub.Catheter mm.sup.2s.sup.-1 0.12
Known a priori h.sub.skin mm 1.5 Radiological and acoustic imaging,
transient thermal measurements ID.sub.catheter mm 1.0 Known a
priori OD.sub.catheter mm 1.5 Known a priori
TABLE-US-00004 TABLE 4 Summary of etiology of and measurements made
on each patient. Flow Flow Detected Detected Underlying Malfunction
(pre- (post- Imaging Skin Condition Age Sex President intervention)
intervention) Correlate Irritation 1 Pseudotumor 36 F Y N Y Y.sup.1
N cerebri 2 Chiari I 53 F N Y N/A N/A N malformation 3 Glioblastoma
32 M N Y N/A N/A N multiforme 4 Glioblastoma 58 F Y N Y Y.sup.2 N
multiforme 5 Post- 30 F Y Y N/A.sup.3 Y.sup.4 N hemorrhagic
1. Patient had visualized kinking in the neck region on X-ray post
initial surgery and clinically deteriorated the morning after
initial shunt placement. Radionuclide shunt study showed aberrant
distal flow. 2. Patient deteriorated post-surgery and was found to
have severe stool burden on abdominal CT. After bowel regimen
administered, patient clinically improved and sensor readings
validated resolution of pseudoobstruction. 3. Device was
inadvertently destroyed during final testing and postoperative
readings were unable to be obtained. Patient was noted to have
changes in flow pattern with inspiration and expiration
corresponding to low drainage rate seen in OR due to concomitant
distal and partial proximal obstructions. 4. CT scan demonstrated
interval ventriculomegaly; radionuclide study demonstrated aberrant
flow patterns; X-ray and abdominal CT demonstrated catheter
malpositioned extraperitoneally near liver with adjacent fluid
collection (likely CSF).
TABLE-US-00005 TABLE 5 Raw data measured on each patient Patient
.DELTA.T.sub.sensors/T.sub.actuator .sigma.
T.sub.sensors/T.sub.actuator .sigma. Trial Notes 1 0.0158243
0.005777 0.365 0.0106 On Pre-op, shunt confirmed failure 1 0.028321
0.008057 0.222 0.0098 Off Pre-op, shunt confirmed failure 1
0.2093394 0.021081 0.2916 0.0052 On Post-op, shunt functioning
shunt 1 0.0020478 0.042475 0.2612 0.0148 Off Post-op, shunt
functioning shunt 2 0.0084 0.0057 0.2676 0.0106 Off Functioning
shunt shunt 2 0.0518 0.0072 0.2289 0.011 On Functioning shunt shunt
3 -0.0059732 0.001808 0.1601 0.003 Off Functioning shunt shunt 3
0.0950298 0.003508 0.1815 0.0141 On Functioning shunt shunt 4
-0.0061537 0.010499 0.2104 0.0079 Off Functioning shunt shunt 4
0.0603105 0.00492 0.3 0.0058 On Functioning shunt shunt 4 0.1009913
0.009832 0.2247 0.0086 On Functioning shunt shunt, pumped 5
0.000963 0.033035 NA NA Off Malfunction shunt with flow 5 0.1392
0.0146 0.3297 0.023 On Malfunction shunt with flow
TABLE-US-00006 TABLE 6 Summary of technical challenges and
solutions during patient experiments. Problem Discovery Solutions
Skin During initial patient trials, factors A device enclosure was
constructed to work in adhesion including cleanliness of skin,
tandem with a clinical grade, skin safe adhesive. multiple device
uses and patient The use of such adhesive prevented minor movement
resulted in the delamination and was viable for 10 attempted
delamination of initial device uses in a subsequent trial. The
enclosure gave iterations. weight to the device and prevented
errant movement with patient volatility, and delamination was
minimized by sizing the enclosure to be larger than the area
covered by the adhesive treated sensor. Motion Normal and abnormal
patient AFC cables present a likely source of motion artifact
movement in an initial study related noise. The wireless iteration
of the device resulted in aberrations in combined with subtraction
algorithms and a captured heat data. narrowed accepted data range
(given the obtained sample and future data) have and will continue
to refine and eliminate this artifact. Ease of The initial trial
saw a great deal of The device enclosure ideated resulted in a PDMS
handling difficulty in device handling for the device frame
designed to aid handling by the surgeon. Due to the adhesive
diagnostician. This not only reduced glove related involved,
manipulation with gloved device manipulation but facilitated swift
application fingers was difficult. Excess minimizing patient
discomfort. Devices were more traction put on the device and its
robust and performed admirably through periods elements led to poor
performance of over 10 trials. both in terms of lamination and
noise artifact engendered. Alignment Precise alignment of the
sensor to Winged attachments and central lines on the the skin
overlying tunneled distal enclosure were designed on subsequent
device shunt catheter was occasionally iterations. These improved
most applications from difficult when attempting to multiple
attempts at placement to initial success in approximate its center.
all subsequent trials. The winged attachments also had an
unintended benefit to device handling. Vasculature Patients with
prominent clavicular Benchtop experiments simulated flow rates in
veins and superficial arterial shunts, venous and arterial systems
with varying branches adjacent to underlying flow experiments were
conducted with a fluid shunt tubing were suspected of injector into
multiple caliber tubes. possible contamination. Skin The depth of
tunneled distal shunt Benchtop experiments, radiographic data and
the thickness catheters was suspected to differ academic literature
were consulted in the among patients with varying resolution of
this important question. Anecdotally, habituses. over 10 surgeons
stated that based on feel and experience alone, shunt catheters
were likely 1-8 mm under the skin. Further experiments demonstrated
sensor performance to a depth of 6 mm. Measurements shunt catheter
to surface distance of available computerized tomography scans of
patients was also performed, with an average total thickness of
subcutaneous tissue overlying the distal catheter of 1.52 mm.
Finally, a comprehensive literature search was performed.
Established factors including total soft tissue to bony
protuberance distance to skin (under 2 mm),
* * * * *