Note: Descriptions are shown in the official language in which they were submitted.
CA 02347378 2001-04-18
1
Minimally invasive sensor system
The invasion relates to a minimally invasive sensor
system for determining substance concentrations in
the human body. Sensor systems of this type are used
in medical diagnostics, for example to determine the
concentration of glucose in the blood or in the in-
terstitial fluid in the treatment of diabetics.
According to prior art, which is given for example in
D. Moskone et al. "Ultrafiltrate Sampling Device for
Continuous Monitoring," Medical and Biological Engi-
neering and Computing, 1996, volume 34, pages 290 to
294, sensor systems for measuring glucose in the
blood consist of an ultrafiltration probe which is
connected to a thin and long hose f:or storing the
tissue fluid obtained. At regular time intervals,
the tissue fluid obtained and stored in this storage
hose is transferred to a sensor which determines the
CA 02347378 2001-04-18
2
concentration of glucose to be found in the tissue
fluid. The interstitial tissue fluid is here ob-
tained from the subcutaneous tissue with the aid of
negative pressure through an ultrafiltration membrane
in an ultrafiltration probe laid subcutaneously as a
loop. The sample volumes are in the region of sev-
eral 100 nl/min. In order to increase further the
volumes which can be supplied to the sensor, after
collection and interim storage of the tissue fluid
obtained, the latter is in addition diluted by means
of a dilution buffer. What is disadvantageous about
ultrafiltration methods of this type is that such
systems can only be used for sample measurement in
batches, since the measurement of the substance con-
centrations takes place at a considerable time lag as
a result of the .interim storage. Direct monitoring
of substance concentration on the human being is thus
not possible.
A further disadvantage in the use of ultrafiltration
probes consists in the fact that they consist of a
hollow-fibre membrane. These probes must generally
be supported by more stable materials in their inner
lumen. Ultrafiltration probes of this kind are not
only expensive to manufacture but they also have a
diameter which is significantly greater than the di-
ameter of thin steel cannulae which are used for ex-
ample in insulin therapy for diabetics. Understanda-
bly, therefore, the willingness of a diabetic to ac-
cept implantation of thick ultrafiltration probes of
this type is low.
The object of the present invention, therefore, is to
make available a sensor system which permits the
measurement of substance concentration in the blood
or in tissue fluids of living creatures directly,
CA 02347378 2001-04-18
3
continuously and in a minimally invasive manner and
can be applied simply and pleasantly. Furthermore it
is the object of the present invention to make avail-
able uses of such minimally invasive sensor systems.
This object is accomplished by the minimally invasive
sensor system according to claim 1 and the use of a
minimally invasive sensor system of this type accord-
ing to claim 22.
The minimally invasive sensor system according to the
invention has a support to which a probe for sampling
fluid from the tissues of living creatures and a flow
sensor are disposed. The flow sensor has a sensor
element and a flow channel which is in spatial con-
tact with the sensor element. The flow channel and
the cavity of the hollow probe are directly connected
to one another. What is advantageous about the mini-
mally invasive sensor system according to the inven-
tion is in particular its small design as a result of
the compact arrangement of probe and sensor element
on/at a support and the direct measurement of the
small amounts of tissue fluids obtained. In this way
interim storage or dilution of the tissue fluids ob-
tained, before measuring the substance concentrations
in the sensor, become superfluous. Consequently di-
rect, really continuous and minima:Lly invasive deter-
mination of substance concentrations in the blood or
in the tissues o.f a living creature, especially a hu-
man being is possible. Furthermore, through the
small design and small dimensions both of the sup-
port, of the flow sensor and also in particular of
the hollow probe, the stress to the patient is only
very low, such that acceptance of the minimally inva-
sive sensor system according to the invention is con-
siderably higher with patients than is the case with
CA 02347378 2001-04-18
4
measurement methods according to prior art.
The sensor system according to the invention can be
used to determine physical, chemical and/or biochemi-
cal properties, especially substance concentrations
in the living creature, especially in its tissues and
body fluids, in vivo.
Advantageous developments of the minimally invasive
sensor system according to the invention and its uses
are given in the respective dependent claims.
To receive the tissue or body fluids, the hollow
probe has microscopic and/or macroscopic apertures.
The hollow probe can here be configured as a terminal
hollow probe which is open at the end remote from the
flow sensor and/or is perforated or porous on its
surface area. What is thereby accomplished is that
the tissue fluid or the body fluid enters the hollow
probe via the apertures and is transported in the di-
rection of the flow sensor for example by means of a
device for creating a vacuum, especially a suction
pump or a vacuum container which is arranged on the
side of the flow channel of the flow sensor remote
from the hollow probe. When microfluidic elements
are used for the hollow probe, for the hollow connec-
tor between the hollow probe and the flow sensor and
for the flow sensor, particularly small amounts of
tissue fluid can be measured.
In order to stabilise the hollow probe, said probe
can contain a reinforcement support, for example a
wire, a needle or a fibre bundle, for example a
glass-fibre bundle or a carbon-fibre bundle. If this
reinforcement support is removable, it can be removed
after the hollow probe has been placed in the subcu-
CA 02347378 2001-04-18
taneous tissue, such that the minimally invasive sen-
sor system according to the invention is more com-
fortable for the patient to bear.
The flow of the interstitial fluid or the tissue
5 fluid in the direction of the hollow probe and thus
the amount of collected fluid to be measured can be
improved in that at least one electrode which can be
connected as the cathode is disposed on the support.
A large-area anode can be used as the counter-
electrode. When voltage is applied to the cathode,
for example the interstitial fluid is drawn in the
direction of the cathode, i.e. in 'the direction of
the support and thus a flow is created towards the
hollow probe. As a further effect, the skin in the
region of the cathode swells, such that a greater
volume of interstitial fluid is present in the region
of the hollow probe. Ideally the hollow probe itself
or the reinforcement support, insofar as it remains
in the hollow probe, is designed to be electrically
conductive and able to be connected as the cathode.
This produces an alignment of the above-described
electrophoretic/a_lectroosmotic flow of the intersti-
tial fluid towards the hollow probe. The hollow pro-
be can in this case consist of electrically conducti-
ve material, for example stainless steel or a noble
metal, or have an electrically conductive coating
vapour-deposited onto it, for example a metal.
Further strengthening and alignment of the electro-
phoretic/electroosmotic flow of the interstitial
fluid is effected if additional electrodes which can
be connected as the cathode are disposed on the sup-
port.
The hollow probe of the minimally invasive sensor sy-
stem according to the invention is not necessarily
CA 02347378 2001-04-18
6
configured as an ultrafiltration probe. In this case
it is advisable to arrange a fluid filter between the
hollow probe and the flow sensor. Furthermore it is
advantageous to provide a gas-bubb:Le trap in this re-
gion in order to remove undesired gas bubbles from
the fluid flow inside the hollow connector or the
flow sensor, in order to avoid interruptions to the
measuring system.
Since the hollow probe collects interstitial fluid or
body fluid, which besides the substance to be measu-
red contains additional constituents, a pre-
oxidisation reactor can be arranged between the hol-
low probe and the flow sensor to remove these distur-
bing substances.
As flow sensors for the minimally invasive sensor sy-
stem according to the invention are suitable flow
sensors which comprise a base plate, a plate-like
channel support disposed thereon with a channel-like
recess and a plate-like sensor support disposed in
turn thereupon, with a planar recess for incorpora-
ting a sensor element, or which have a planar sensor
element instead of the plate-like sensor support.
The base plate, the channel support and the sensor
support or the sensor element are ;stacked on top of
one another forming a seal with one another, in such
a way that the p:Lanar recess or the planar sensor
element is located above the channel-like recess in
the channel support. This produces a flow sensor
with minimal dimensions which is suitable for conti-
nuously measuring the small amounts of fluid precise-
ly and directly. The hollow probe itself can here be
so disposed on the support that its one end breaks
through the base plate and protrudes into the chan-
nel-like recess in the channel support.
CA 02347378 2001-04-18
7
A further advantageous flow sensor which is suitable
for measuring the small amounts of fluid collected
comprises a plate-like sensor support in which at
least one tapering containment containing the sensor
element is introduced which extends between the two
surfaces of the sensor support and contains at least
one plate connected to the second surface of the sen-
sor support. In the region of the boundary surface
between the sensor support and the plate, for example
in the surface of the sensor support or in the sur-
face of the plate or also respectively partially in
both of them, a ~~hannel-like depression is formed
which is in contact with the smaller aperture of the
containment, which aperture is located on the bounda-
ry surface between sensor support and plate. Thus a
flow sensor is given which, with minimal dimensions
of the flow channel, provides an optimal measurement
of the fluids flowing through.
The support for the minimally invasive sensor system
can be designed simultaneously as the base plate or
as the plate-like channel support of the flow sensor
with a channel-like recess. In this case a particu-
larly compact and simple design of the minimally in-
vasive sensor system according to the invention is
produced.
Here, too, the sensor system can comprise a substrate
configured plate-like and into which a containment
tapering between the two surfaces is introduced, the
containment containing the sensor element and having
on the side facing the support or the side facing the
channel a tapered smaller aperture.
In this arrangement too, the hollow probe can be so
disposed on the support that it breaks through the
CA 02347378 2001-04-18
8
support configured as the base plate of the sensor
element and protrudes into the channel. Support,
hollow probe and sensor thus form an extremely com-
pact unit with very short paths of the obtained fluid
S between the removal point in the tissue and the sen-
sor element.
The minimally invasive sensor system according to the
invention can be used in particular to determine ana-
lyte concentrations in tissues or body fluids in vi-
vo, in particular to determine the glucose concentra-
tion in the blood and/or the interstitial fluid of
the subcutaneous tissue of a human being. The field
of application therefore relates in particular to me-
dical, in particular human medical diagnostics and
therapeutics, use in diabetes therapy for controlling
the blood sugar level and determining the doses of
insulin to be used being to the fore. Some advanta-
geous embodiments of the minimally invasive sensor
system according to the invention are described be-
low.
The figures show:
Fig. 1 a minimally invasive sensor system accor-
ding to the invention;
Fig. 2 a further minimally invasive sensor system
according to the invention;
Fig. 3 two sensor elements for a minimally invasi-
ve sensor system according to the inventi-
on;
Fig. 4 a further minimally invasive sensor system
according to the invention;
CA 02347378 2001-04-18
9
Fig. 5 a sensor for a minimally invasive sensor
system according to the invention;
Fig. 6 a further flow sensor for a minimally inva-
sive sensor system according to the inven-
tion;
Fig. 7 a minimally invasive sensor system accor-
ding to the invention;
Fig. 8 a minimally invasive sensor system accor-
ding to the invention;
Fig. 9 a minimally invasive sen;>or system accor
ding to the invention;
Fig. 10 hollow probes for a minimally invasive sen-
sor system according to i=he invention;
Fig. 11 a further minimally invasive sensor system
accord_Lng to the invention.
Fig. 1 shows examples of the use of a minimally inva-
sine sensor system according to thE~ invention. The
minimally invasive sensor system in Fig. 1a comprises
a support 2, on which a flow sensor 5 with a flow
channel 6 is arranged.
Furthermore, in extension of the f:Low channel 6, a
hollow connector extends to a hollow probe 3. The
hollow probe 3 is disposed in the support 2 and prot-
rudes beyond the support 2 on the side remote from
the flow sensor 5. Furthermore, the flow channel 6
is connected on t=he side remote from the hollow con-
nector 4 via a hollow connector 7 to a system module
8. The system module 8 is furthermore connected via
.....~.,~,,~...~..~..~... _ _ _m_,~,"~,.",~.,.~..~,~.,..~.m,.,..... ......~._
., ...._w_ ~....__
CA 02347378 2001-04-18
two electrical supply lines 9, 10 to the sensor ele-
ment of the flow sensor 5, via which the measurement
signal detected is led. The system module 8 contains
electronics E, a battery B for supplying power to the
5 electronics E, a suction pump P, in order to apply
negative pressure to the hollow connector 7, the flow
channel 6, the hollow connector 4 <~nd the hollow pro-
be 3, and a collecting vessel C for the fluids ente-
ring the system module via the hol:Low connector 7.
10 The measurement values obtained with the aid of the
sensor system and other system dat<~ can be displayed
in the system module 8 via a display D.
As shown in Fig. la, the support 2 lies on a skin
surface 1 with the side on which the hollow probe 3
protrudes from the support 2. This means that the
hollow probe penetrates the skin surface 1 and re-
aches the subcutaneous tissue of the patient.
With the aid of the vacuum created by the suction
pump B in the ho:Llow probe 3, the hollow connectors
4, 7 and the flow channel 6, interstitial subcutane-
ous tissue fluid is sucked up through the hollow pro-
be 3 and pumped via the hollow connector 4 to the
flow channel 6 of the flow sensor .5 and on through
the hollow connector 7 to pump P and then into the
collecting vesse:L C. The volumes of the hollow con-
nectors 4 and 7 and of the flow channel 6 are very
small.
Fig. lb shows a minimally invasive sensor system ba-
sically similar to that of Fig. 1a. Therefore the
same elements are also designated with the same refe-
rence numerals as in Fig. la. In ;addition to Fig.
1a, here however an electrode which can be connected
as the cathode i5 disposed on the hollow probe 3.
CA 02347378 2001-04-18
11
Furthermore on the side facing the skin surface, the
support 2 contains a large-area anode. Cathode 11
and anode 12 are connected to the system module 8 via
electrical connections 13, 14, via which module vol-
tage can be applied to both. These voltages and cur-
rents are genera=ed with the aid o:f the battery B and
the electronics E in the system module 8. As a re-
sult of the voltage applied, in the subcutaneous re-
gion an electrophoretic/electroosmotic flow of the
interstitial body fluid towards tha_ cathode 11 is
produced. This ~~an lead to a considerably greater
flow of the interstitial tissue fluid to the hollow
probe 3 and into the hollow probe 3.
This effect can be further strengthened by, as shown
in Fig. 1c, a further additional cathode being arran-
ged on the support 2 on the side facing the skin sur-
face 1, which cathode is also wired from the system
module 8 via an electrical connection 16. This ca-
thode 15 causes in the subcutaneous tissue an addi-
tional electrophoretic/electroosmotic flow of the in-
terstitial tissue fluid. Since a divergence of the
electrophoretic/electroosmotic flow occurs per-
pendicular to the skin surface l, which can be caused
by the less permeable upper layers of the skin, under
the uppermost layer of skin there is swelling of the
skin in the immediate vicinity of the hollow probe 3.
Thus in this manner, a greater volume of the inter-
stitial tissue fluid can be conveyed through the hol-
low probe 3 with the aid of the pump P to the flow
sensor 5. The additional reference numerals designa-
te the same elements as those in Figs. la and 1b.
Fig. 2 shows a further embodiment of a minimally in-
vasive sensor system according to the invention. It
has a support 2 and a channel support 17 with a chan-
CA 02347378 2001-04-18
12
nel 18 located therein and a channel cover 19 with an
aperture 20. The support 2, the channel support 17
and the channel cover 19 are disposed the one above
the other forming a seal with one another. Further-
more in Fig. 2a, which is an exploded view of the
sensor system according to the invention from Fig.
2b, is shown a sensor 5, the external dimensions of
which correspond to the dimensions of aperture 20 in
the channel cover 19. The sensor 5 has two sensor
contact surfaces 21, 22 to derive the electrical mea-
surement signals. On the side of t:he support remote
from the channel support is disposed a hollow probe 3
which extends through support 2 into the channel 18
of the channel support 17.
Fig. 2b shows this minimally invasive sensor system
in assembled state. The same elements are therefore
provided with the same reference numerals. In addi-
tion to Fig. la, the electrical measurement signal
leads 9, 10 are drawn in, which are connected to the
sensor contact surfaces 21, 22. As can be recognised
here, the sensor element 5 is so disposed that it is
located along the channel 18 between the hollow probe
and an external channel aperture 24. At the external
channel aperture 24 is disposed a hollow connector 7,
for example a ho~~e, forming a seal by means of a seal
23. The interstitial fluid or blood received by the
hollow probe 3 is now transported through the hollow
probe 3 and channel 18 past the sensor element 5 to
the external channel aperture 24 and on through the
hollow connector 7.
The support 2, the channel support 17 and the channel
cover 19 can be manufactured from polyester film by
means of film technology. The different layers are
connected by means of hot laminating or by gluing.
CA 02347378 2001-04-18
13
Placing the sensor element 5 in aperture 20 is effec-
ted in such a way that the lower side of the sensor
element is securely connected to the surface of the
channel support 1.7 by gluing or contact pressure.
Here the active =sensor surface protrudes on the un-
derside, not shown, of the sensor 5 into the channel
18. The seal 23 consists of a conventional sealing
material such as e.g. silicone.
Fig. 3 shows two sensor elements such as can be used
for example as sensor elements 5 iTl Fig. 2.
The sensor element used in Fig. 3a is described for
example in the German patent application P 41 15 414,
the disclosure ow which is hereby :incorporated in
this application. The sensor elemc=_nt comprises a si-
licon substrate 25 which consists at its surface of a
dielectric layer 26 formed from SiO~ and/or Si3N4.
Apertures in the shape of a truncated pyramid are in-
troduced into the silicon substrate by anisotropic
etching. These so-called containments 35 are covered
at their inner surface with an electrode layer 27,
27', 27" , 27" ', formed for example from platinum or
Ag/AgCl. The containments are filled with a membrane
material 28 formed from PVA with the enzyme GOD for a
glucose sensor. On the underside of the sensor ele-
ment the membrane 28, 28' is exposed and forms the
active membrane 29, 29'. This forms simultaneously
the upper limitation of the channel 18 of Fig. 2.
The electrode layers 27, 27', 27" and 27" ' can be
electrically tapped by means of sensor contact surfa-
ces, as are represented by reference numerals 21, 22
in Fig. 2.
Fig. 3b shows a sensor element such as is known from
German patent P 41 37 261.1-52, the disclosure of
CA 02347378 2001-04-18
14
which is hereby incorporated in this application. A
. double matrix membrane 31 is securely attached to a
sensor element support 30 with an opening 36. This
membrane consists for example of a paper which is sa-
y turated with a gel which contains the enzyme GOD
(glucose oxidasej. To the membrane material 31 are
attached two electrodes 33 and 34 by vapour depositi-
on or screen printing. Electrode 33 consists of pla-
tinum and electrode 34 is an Ag/AgCl electrode. An
active free membrane surface 32 in opening 36 here
forms the upper germination of channel 18 of Fig. 2.
Electrodes 33 and 34 correspond to the sensor contact
surfaces 21, 22 of Fig. 2.
In Fig. 4 is a minimally invasive sensor system simi-
lar to the one shown in Fig. 2, such that the same
reference numerals again designate the same elements
as in Fig. 2. Unlike Fig. 2, a further plate-like
filter support 3'7 is now disposed between the support
2 and the channel support 17, the filter carrier con-
taming a recess with a filter membrane 38 disposed
therein. The recess is here disposed in the region
of channel 18 in channel support 17 and itself forms
a part of the channel. The hollow probe 3 is so ar-
ranged that it is connected to the recess for the
filter membrane 38 in the filter support 37 on the
side of the recess associated with support 2. Sup-
port 2, filter support 37, channel support 17, sensor
support 19 and sensor element 5 are connected to one
another to form a seal in the same manner as in Fig.
2. In this example, the fluid which is collected by
the hollow probe 3 is now led through the filter mem-
brane 38 and only then enters channel 18 in channel
support 17 and is conveyed further on sensor element
5 to the external aperture 24 of the channel. Unde-
sired substances can be filtered out by a filter mem-
CA 02347378 2001-04-18
brane of this sort in the case where no ultrafiltra-
tion probe is used as the hollow probe.
Figs. 5 and 6 show flow sensors corresponding to tho-
se in Fig. 3a, the flow channel being however inte-
5 grated into the sensors.
Sensors of this type are known from the German patent
P 44 08 352, the disclosure of which is hereby incor-
porated in the present application. The sensor con-
sists of a silicon substrate 25 in which containments
10 35 are located. The containments 35 contain sensor
membrane materia:L 28 and electrodes 27, 27" , which
protrude into the containment. The containments ta-
per from one side of the silicon substrate 25 to the
other side of the silicon substrate 25. On the side
15 of the containments with the smaller aperture, a
channel 39 is introduced into the silicon substrate
by anisotropic etching, which substrate is in spa-
tial contact witx~ the active smaller apertures 29,
29', forming membrane surfaces, of the containments.
20 This channel is closed with a glass cover 90, which
is connected in a sealed manner to the silicon sub-
strate by anodic bonding. Thus there is formed in
the silicon substrate 25 a channel 39 in which the
fluid collected by the hollow probe is led past the
25 active membrane surfaces 29, 29'.
The achievable diameters of the channel 39 lie in the
region between several 10 to several 100 Vim, such
that very small sample volumes can be measured. In
the arrangement shown in Fig. b, in addition to the
sensor elements 28, 28', feed apertures 41, 42 are
introduced into the silicon substrate 25, and extend
from one side of the silicon substrate to the other
and are connected to the channel 39'. Through this
CA 02347378 2001-04-18
16
feed/drainage aperture 41 or 92, the measurement me-
dium is led towards channel 39 (aperture 41) or away
from channel 39 (aperture 42). In this case therefo-
re the channel 39' does not emerge on the end face of
the silicon substrate 25' since it is limited in
length.
Fig. 7 shows now the use of a sensor element accor-
ding to Fig. 6 in a sensor system which corresponds
to that of Figs. 2 and 3. The same reference nume-
rats therefore designate the same elements as in the-
se figures. In contrast to Fig. 2, the channel sup-
port 17' no longer has a single channel 18. Rather
the channel is divided into two portions 18' and 18"
separated from one another by a web. Channel portion
18' extends between the hollow probe aperture on the
sensor element side and aperture 20 in the sensor
support. The second channel portion 18" extends si-
deways to the first channel portion 18' below apertu-
re 20 of the sensor support 19 and the external aper-
ture 24, the two channel portions 18 and 18" merely
being in contact with one another 'via aperture 20 of
the sensor support 19. Sensor element 5" with the
sensor contact surfaces 21' and 22" is now a sensor
element as per Fig. 6. Here the sensor element 5"
is so disposed in aperture 20 that the feed aperture
41 from Fig. 6 is in communication with channel por-
tion 18' and the discharge aperture 42 of Fig. 6 with
channel portion 18" . Thus the fluid to be measured
is led from the Follow probe via channel portion 18'
and feed aperture 41 through channel 39' past sensor
elements 28, 28' and then via the discharge aperture
42 and channel portion 18" out of the sensor system
according to the invention. Channel 39' can be con-
figured as a capillary throttle to control the fluid
flow via the flow resistance of channel 39'. This
CA 02347378 2001-04-18
17
technique is known from German patent P 44 10 224,
the disclosure of which is hereby incorporated into
the present application.
In order to convey the fluid to be measured from the
hollow probe past. the sensor element 5" , in the in-
ter communicating cavities of the sensor system ac-
cording to the invention a vacuum is produced. For
this purpose a very simple container or a vacuum con-
tainer (vacutainer) can be attached to aperture 24 of
channel portion 18" . As a result of the high flow
resistance of channel 39' with a law channel cross-
section, the fluid which enters channel 39' via the
hollow probe 3 is then conveyed at practically a con-
stant flow rate. The flow resistance can also be in-
creased by channel 39' being itself lengthened on the
chip.
The sensor system shown in Fig. 7 c:an be further de-
veloped as shown in Fig. 8. In addition to the ar-
rangement, as Shawn in Fig. 7 and therefore also de-
signated with the respective corresponding reference
numerals, a further channel 43 is located in the
channel cover 19' as the vacuum channel. This chan-
nel 43 runs around aperture 20 and is separated from
the latter by a web. Furthermore c:hannel aperture
18' in channel support 17' is slightly extended at
the side so that it also covers the vacuum channel
43. The vacuum channel 43 consequently connects, in
addition to aperture 20, channel apertures 18' and
18" . Between channel support 17' and channel cover
19' there is now situated a gas-permeable membrane in
the region in which channel aperture 18' and vacuum
channel 43 communicate. This means that at the sides
of the gas-permeable membrane facing the vacuum chan-
nel 43, the vacuum applied by the pump P or the
CA 02347378 2001-04-18
18
vacutainer to aperture 24 is present. If gas bubbles
are contained in the measurement medium which reaches
the channel portion 18' through the hollow probe 3,
the gas is led away with the aid of the vacuum pre-
y sent on the vacuum channel side of the gas-permeable
membrane, via the gas-permeable membrane 44 into the
vacuum channel 43. Therefore the measurement medium,
which cannot flow through the gas-:permeable membrane
but enters the integrated flow channel 39' of Fig. 6
of the sensor element 5" , is degasified. It is also
possible to lay a separate vacuum line, e.g. a hose
between vacuum channel 43 and system module 8 (see
Fig. 1) .
Fig. 9 shows an embodiment according to that shown in
Fig. 2, in which however there are integrated in the
support 2' electrodes which serve the electrophore-
tic/electroosmotic transport of the measurement medi-
um in the subcutaneous tissue. Corresponding ele-
ments are however designated with corresponding refe-
rence numerals to those in Fig. 2.
On a support 2' is disposed at an angle an electri-
cally conductive hollow probe 3' formed from stain-
less steel, which extends from the underside of sup-
port 2' into the channel 18 in the channel support 17
and the cavity of which communicates with channel 18.
In support 2' are disposed furthermore electrical
track conductors 48, 49 and 50, electrically insula-
ted from one another and which are provided with con-
nection contacts 51, 52 or 53 for .applying voltages.
Track conductor 49 is here electrically connected to
the hollow probe. Furthermore on the surface of sup-
port 2' facing the skin surface a:re located two
electrodes 12' and 15' which are connected in an
electrically conductive manner to 'the track conduc-
CA 02347378 2001-04-18
19
tors 50 or 48 via feedthroughs of support 2'. Elec-
trode 12' is here a large-area anode which is dispo-
sed roughly centrally on the underside of support 2'.
Electrode 15' is disposed to the side of the point at
which the hollow probe 3' breaks through support 2'
above the free end of the obliquely disposed hollow
probe 3' on the underside of support 2' and serves as
the cathode. This cathode 15' is a platinum cathode
or an Ag/AgCl cathode. The outer end of the hollow
probe 3' has a pointed tip and is open at the front
as is usual for cannulae in medical technology. Not
represented, however, is an embodiment in which the
hollow probe is perforated on its outer peripheral
surface so that in this case an even greater sample
volume can be removed from the subcutaneous tissue.
If now via conta~~ts 51 and 52 a negative voltage is
applied to the cathode 15' or the :hollow probe 3' and
a positive voltage is applied to t:he anode 12' via
the connection c~~ntact 53, an electrophore-
tic/electroosmotic transport of the interstitial
fluid is produced in the direction of the hollow pro-
be 3'. Furthermore the tissue below the cathode 15'
swells, such that an increased volume of interstitial
fluid is available to be taken as a sample. Since
the cathode 15' is disposed directly above the free
end of the hollow probe 3', the flow of the intersti-
tial fluid is directed towards the open end of the
hollow probe 3', and this results in further improved
sampling.
If the hollow probe 3' is itself not electrically
conductive, the electrical contact to the column of
fluid in the hol:Low probe 3' is provided via contact
11' (Fig. 9a).
Fig. 9b shows the sensor system described in Fig. 9a
CA 02347378 2001-04-18
in assembled state.
Fig. 10 shows various embodiments of a hollow probe
3' for a minima lly invasive sensor system according
to the invention. The hollow probe 3' comprises a
5 cylindrical body formed from stainless steel. It is
electrically conductive and can simultaneously act as
the hollow probe and as the cathode, for example in
the embodiment o:f a sensor system according to Fig.
9. The outer end of these hollow probes can have a
10 pointed tip and be open at the front as is usual for
cannulae in medical technology. It can also be per-
forated on its peripheral surface or be provided with
pores.
Fig. lOb shows a hollow probe 3" which is produced
15 from Teflon, polyamide or some othc=_r plastics materi-
al and thus has hose-like properties. The Teflon
membrane can here be perforated on its surface area
and thus be permeable for the interstitial fluid.
Perforation of this type in Teflon or other membrane
20 materials can be produced by means of lasers. With
corresponding perforation, the hollow probe 3" can
also be used as an ultrafiltration hollow fibre.
The hose-like consistency of the hollow probe 3" re-
presented in Fig. lOb means that the vacuum in the
hollow probe lumen possibly produces a collapse of
the hollow probe during measurement.. Therefore the
hollow probe is provided with a reinforcement support
54, for example a wire which can simultaneously serve
as the hollow probe cathode. Two or more wires can
also be twisted to form a reinforcement support.
In Fig. lOc is shown a further reinforced hollow pro-
be 3" ', the reinforcement support 55 comprising a
CA 02347378 2001-04-18
21
fibre bundle. Carbon-fibre bundles or glass-fibre
bundles are particularly suitable for this purpose.
If carbon-fibre bundles are used as reinforcement
supports, they can simultaneously nerve as cathodes
as a result of their electrical conductivity.
The hollow probes described here typically have out-
side diameters of between 0.1 and 2 mm, preferably
however, between 0.4 and 0.5 mm.
The hollow probes according to Fig. 10 can also be
produced from such otherwise ~>nown materials as are
used for dialysi~~ and ultrafiltrati.on hollow fibres.
It is also possible to configure the reinforcement
support 54 as a gas-bubble trap. To this end, the
reinforcement support consists e.g. of a Teflon hose,
the wall of whicr: is gas-permeable. The inner lumen
of the Teflon hose is connected to vacuum. This hap-
pens in a similar manner to that in the embodiment
according to Fig. 8 via a channel 43.
A further embodiment of a sensor system according to
the invention is represented in Fig. 11 in conjunc-
tion with Fig. 2. Corresponding elements are desi-
gnated by corresponding reference numerals to those
in Fig. 2. In contrast to Fig. 2, however, hollow
probe 3 is here replaced by a flexible hollow probe
3I" formed from a perforated Teflon catheter. This
flexible hollow probe cannot, however, be easily
inserted into the subcutaneous tissue. In hollow
probe 3I~ there is therefore a stabilisation needle
CA 02347378 2001-04-18
22
57 as a reinforcement support. This needle is intro-
duced through a silicone septum 56 on the channel co-
ver 19 through channel 18 in the channel support 17
into the hollow probe 3I~. The septum 56 must here
be sufficiently impermeable to maintain the vacuum
created in channel 18. What is advantageous about
this embodiment is that the stabilisation needle 57
can be removed by pulling it out of the hollow probe
3I" as soon as the hollow probe 3I" is inserted into
the subcutaneous tissue. By this :means the stress on
the support for the minimally invasive sensor system
during the bearing time is greatly reduced and pati-
ents' acceptance of a sensor system of this type is
increased.
Fig. llb shows this sensor system in assembled state.
Advantageously, the sensor systems according to the
invention can be equipped with flow controls in order
to indicate an interruption of the flow. A particu-
larly simple embodiment of these flow controls arises
from two glucose sensors being disposed the one be-
hind the other in a flow channel 6 of the sensor 5
(see Fig. 1). Since the conventional glucose sen-
sors, generally known in prior art, convert the ana-
lyte by means of enzymes, a smaller glucose concen-
tration is produced at the second sensor in compari-
son with the first sensor. If the signal of the se-
cond sensor now follows the signal of the first sen-
sor in time with a smaller absolute signal, it can be
assumed that the flow of the interstitial tissue
fluid is not interrupted.
_.~..~..w......,~"~,.~,....~.~,_~..~.....,..,.~....~"..~,.,~."...~...~..M
._... .
CA 02347378 2001-04-18
23
Furthermore it is advantageous to arrange a pre-
oxidation reactor before the glucose sensor between
the hollow probe and the sensor element. With the
aid of this reactor, disturbing substances can be
kept away from the sensor by pre-oxidation. Since in
this process there is also a flow over the pre-
oxidation reactor, the ratio of the flows between
pre-oxidation reactor and the downstream glucose sen-
sor can serve as control parameters for the flow of
the interstitial tissue fluid in channel 6 of the
sensor 5 (Fig. 1). A pre-oxidation reactor of this
type, connected upstream, can be produced by means of
the same technology as the sensors described here,
for example as p~=r Fig. 5 and Fig. 6.
In the minimally invasive sensor systems presented in
Figs. 2, 4, 7 to 9, the supports 2, channel support
17, channel cover 19 and the filter support 37 or the
corresponding elements consist of plastics materials
such as polyvinyl chloride (PVC), polyethylene (PE),
polyoxymethylene (POM), polycarbonate (PC), ethylene
propylene copolymer (EPDM), polyvinylidene chloride
(PVDC), polychlorotrifluoroethylene (PCTFE), po-
lyvinyl butyral (PVB), cellulose acetate (CA), poly-
propylene (PP), polymethyl methacrylate (PMMA), po-
lyamide (PA), tetrafluoroethylene hexafluoropropylene
copolymer (FEP), polytetrafluoroethylene (PTFE), phe-
nol-formaldehyde (PF), epoxide (EP), polyurethane
(PUR), polyester (UP), silicone, melamine-
formaldehyde (MF), urea-formaldehyde (UF), aniline-
formaldehyde, capton or the li~:e.
CA 02347378 2001-04-18
24
The supports 2, channel support 17, channel cover 19
and filter support 37 can be connected by gluing,
welding or laminating. Particularly for laminating,
special laminating films are available which can be
hot-laminated (e. g. CODOR film formed from polyethy
lene and polyester of the company TEAM CODOR, Marl,
Germany. The thickness of the individual films for
the supports 2, channel support 17, channel cover 19
or filter support 37 can be between 10 and several
1000 ~,m, preferably about several 100 Vim. The flat
surface dimensions of the support 2 and of the other
supports and covers are in the region of a few cm,
for example 2 x 3 cm for support 2 from Fig. 2. The
underside of the support 2 is again advantageously
provided completely or partially with an adhesive
layer formed from adhesive materials which are compa-
tible with the skin and which provides secure adhesi-
on on the surface of the skin.
The anode 12, cathodes 11 and 15' and the track con-
ductors 48, 49, SO in the corresponding drawings and
likewise the connection contacts 51, 52 and 53 can be
produced by screen printing or a thin-film method.
The materials used for this can be screen printing
pastes based on noble metals and other metals. The
layers produced by means of the than-film method can
comprise noble metals such as platinum, gold, silver
or chloridised silver layers (Ag/AgCl). The thick-
ness of these layers for the anodes, cathodes and
track conductors and connection contacts can be bet-
ween several 100 nm and several ~tm.
