U.S. patent application number 15/619110 was filed with the patent office on 2017-09-28 for apparatus and methods for determining a property of a tissue.
This patent application is currently assigned to Clinical Laserthermia Systems AB. The applicant listed for this patent is Clinical Laserthermia Systems AB. Invention is credited to Par H. Henriksson, Karl-Goran Tranberg.
Application Number | 20170274216 15/619110 |
Document ID | / |
Family ID | 40511699 |
Filed Date | 2017-09-28 |
United States Patent
Application |
20170274216 |
Kind Code |
A1 |
Henriksson; Par H. ; et
al. |
September 28, 2017 |
Apparatus And Methods For Determining A Property Of A Tissue
Abstract
An apparatus for determining a thermal property of tissue
includes a base unit with one or more energy source and at least
two, preferably detachable, leads. The distal end of each lead,
which is introduced into the tissue to be treated, has at least two
longitudinally spaced temperature measuring elements to measure
surrounding tissue temperature and at least two longitudinally
spaced electrode surfaces for applying current to the tissue. Each
distal end is also provided with an element which uses energy
emitted by the sources of energy to heat up the surrounding tissue.
The base unit has computing elements, current generating elements
for generating an alternating current, and conductance determining
elements for determining the tissue conductance between pairs of
electrode surfaces based on the alternating current applied by the
current generating elements to the tissue. Methods for using the
device and leads for use in the device are also described.
Inventors: |
Henriksson; Par H.; (Lund,
SE) ; Tranberg; Karl-Goran; (Lund, SE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Clinical Laserthermia Systems AB |
Lund |
|
SE |
|
|
Assignee: |
Clinical Laserthermia Systems
AB
Lund
SE
|
Family ID: |
40511699 |
Appl. No.: |
15/619110 |
Filed: |
June 9, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13593427 |
Aug 23, 2012 |
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15619110 |
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12680635 |
Mar 29, 2010 |
8753381 |
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PCT/SE2008/051089 |
Sep 26, 2008 |
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13593427 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 2018/208 20130101;
A61N 5/0601 20130101; A61B 18/24 20130101; A61B 2017/00084
20130101; A61B 2017/00026 20130101; A61B 2018/00988 20130101 |
International
Class: |
A61N 5/06 20060101
A61N005/06; A61B 18/24 20060101 A61B018/24 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 28, 2007 |
SE |
SE0702204-9 |
Claims
1. An apparatus for thermal treatment of a tumor, said apparatus
comprises: a first lead configured to be arranged into said tumor
such that a distal portion of said first lead is positioned within
the tumor, said first lead comprises a heat source, wherein said
heat source is a light source connectable to a light conducting
fibre for conducting light from said light source to a point at
said distal portion of said first lead; a thermal sensor configured
to be positioned at or near a boundary of the tumor for measuring a
first temperature; whereby said first lead comprises a light energy
emission area, and is further provided with a scale and a sleeve
with a reference point for determining a depth of said light energy
emission area, when said first lead is being positioned; a control
unit configured for adjusting a power output of said heat source
based on said measured first temperature, so that said first
temperature is a constant temperature.
2. The apparatus according to claim 1, wherein said thermal sensor
is a thermistor probe.
3. The apparatus according to claim 1, wherein said thermal sensor
is positioned on said first lead.
4. The apparatus according to claim 1, comprising a further lead
positionable within and/or near boundaries of said tumor, said
further lead comprising a further thermal sensor for measuring a
second temperature.
5. The apparatus according to claim 4, wherein said thermal sensor
is a thermistor probe.
6. The apparatus of claim 4, wherein said further lead comprising a
further heat source.
7. The apparatus of claim 2, wherein said thermistor probe
comprises a plurality of longitudinally separated thermal
sensors.
8. The apparatus of claim 1, comprising a computer aided image
analysis to provide information about size and location of tumours,
vessels and bile ducts in 3-D views.
9. The apparatus of claim 1, comprising display means for
displaying information related to said temperatures.
10. The apparatus of claim 6, wherein said further heat source is a
laser light source connectable to a light conducting fibre for
conducting light from said light source to a point at said
lead.
11. The apparatus of claim 1, wherein said sleeve comprises a
locking means to lock said sleeve and said first lead in
position.
12. The apparatus of claim 1, wherein said sleeve is movable with
respect to said first lead.
13. The apparatus of claim 1, wherein said control unit is
configured to carrying out said thermal treatment for a period of
30 minutes.
14. The apparatus of claim 4, wherein said control unit is
configured for calculating a temperature of said tumour between
said thermal sensors and said further thermal sensors.
15. The apparatus of claim 1, wherein said first temperature is in
a range of 42.5.degree. C. to 48.degree. C. during treatment.
16. The apparatus of claim 1, wherein said light energy emission
area is a light transparent energy emission window, or a bare fibre
tip, or a diffusor.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/593,427 filed Aug. 23, 2012 entitled
Apparatus And Methods For Determining A Property Of A Tissue, which
is a continuation U.S. patent application Ser. No. 12/680,635 filed
Mar. 29, 2010 entitled Apparatus And Methods For Determining A
Property Of A Tissue (now U.S. Pat. No. 8,753,381 issued Jun. 17,
2014), which is the U.S. National Phase of and claims priority to
International Patent Application No. PCT/SE2008/051089,
International Filing Date Sep. 26, 2008, entitled Apparatus And
Methods For Determining A Property Of A Tissue, which claims
priority to Swedish Patent Application No. SE0702204-9 filed Sep.
28, 2007 entitled Apparatus And Methods For Determining A Property
Of A Tissue, all of which are hereby incorporated herein by
reference in their entireties.
FIELD OF THE INVENTION
[0002] The present invention relates to devices and methods for
determining a property of a tissue.
BACKGROUND OF THE INVENTION
[0003] The liver is the most common site for tumours, which may be
cither primary or secondary (metastases). In the Western world
hepatic tumours usually represent metastatic disease. The main
cause of death for patients with colorectal cancer (incidence:
about new 6 000 cases in Sweden in 2004) is the presence of liver
metastases, which affect about half of these patients. Breast
cancer is the most common cancer in women with 6 900 new cases in
Sweden in 2004. Prostate cancer is the most common cancer in men
with a current incidence of 9 900 patients/year in Sweden. Lung
cancer is the third most common cancer in Sweden, with 3 200 new
cases each year. Cancer of the pancreas accounts for about 2% of
new cancer (900 new cases in Sweden in 2004) but has a poor
prognosis. The relative 10-year survival rate is 1.3% for women and
1.5% for men. It is particularly important to find a better therapy
for this disease. The above-mentioned cancers are examples of solid
tumours that are suitable for interstitial thermotherapy.
Therapy of Solid Tumours
[0004] Standard Treatments.
[0005] Surgical resection is the mainstay of treatment with
curative intent and is combined with adjuvant chemotherapy in
diseases for which cytostatic drugs have a demonstrable effect.
Chemotherapy is the sole treatment when the aim of treatment is
palliative. Cytostatic drugs are usually given systemically via the
intravenous or oral routes but may also be given regionally via
intra-arterial infusion. Irradiation seems to be inferior to
surgical resection with regard to local efficacy.
[0006] Minimally Invasive Therapies, Including Local Destruction
Methods.
[0007] Some methods, like radiofrequency ablation (RFA),
laser-induced hyperthermia, cryotherapy and percutaneous ethanol
injection (PEI) have been used rather extensively. Others like
microwave coagulation or photodynamic therapy, have been used less
often in patients with solid tumours. Some, like
electrochemotherapy or high intensity focused ultrasound, arc being
developed.
[0008] As compared to surgical resection, the advantages of local
tumour destruction include a) selective tissue damage which leads
to a smaller immunosuppression and a smaller release of growth
factors, b) minimal treatment morbidity and mortality, and c) the
possibility to use chemotherapy in a more efficient way since
chemotherapy can be started before or at the time of local
therapy.
Interstitial Laser Hyperthermia
[0009] Interstitial laser hyperthermia is a thermal technique,
which destroys tumours by absorption of light. Early experimental
and clinical studies used an Nd-YAG laser and bare fibres inserted
into the centre of a tumour, which created lesions that were 1.5 cm
in diameter or less. It was soon apparent that clinical application
would require larger lesions and improved control of the tissue
effect. Methods to improve lesion size included multi-fibre
systems, diffuser type fibres and vascular inflow occlusion.
However the standard application of interstitial laser hyperthermia
results in evaporisation and carbonisation of tissue and relatively
unpredictable tissue damage and lesion size. This has led to the
development of feedback control systems that monitor temperature
within tissue by means of temperature sensors placed at various
distances from the point of treatment and which are interfaced with
a computer and a laser. The idea of these systems is that the laser
output is adjusted to return the monitored temperature to the
desired temperature level when the monitored temperature rises
above a set temperature or falls beyond a set temperature. It is
thus possible to maintain a substantially constant temperature over
a desired period of time at the measuring points which surround a
known volume of tissue, which is intended to give a high degree of
precision with respect to both lesion size and type of cellular
damage.
[0010] One of the advantages of feedback control of the treatment
effect is that it ensures reproducible and cytotoxic temperatures
in the periphery of tumour tissue. Another way to control lesion
size is to use a dose planning system, which enables lesion size to
be calculated for different tissues, output powers and treatment
durations. Planning of local treatment can also be integrated with
computer aided image analysis to give information about the size
and location of tumours, vessels and bile ducts in 3-D views.
[0011] However such methods only determine the temperature in the
vicinity of the temperature sensor(s) and give no information on
whether the required temperature has been achieved throughout the
tissue that is supposed to be treated.
Interstitial Laser Thermotherapy (ILT)
[0012] Interstitial laser thermotherapy (ILT) is a variant of
interstitial laser hyperthermia where the focus is on killing
tumour cells at temperatures of 46-48.degree. C., i.e. at
temperatures that do not cause tumour antigens to coagulate.
Consequently ILT eventually produces cell death while still
allowing the presentation of intact tumour antigens. These cause an
inflammatory local reaction and this can produce an efficient
immune response, both in rats and in human patients. This is in
contrast to ablative techniques that use higher temperatures and
thus cause instantaneous necrotisation of the tissue. This is also
in contrast to traditional hyperthermia that uses significantly
lower temperatures, i.e. <42.5.degree. C., and long exposure
times.
[0013] For feedback control of the laser power one or more
thermometers (thermistors or thermocouples) placed within the
tumour and/or at the tumour boundary have commonly been used. One
of the disadvantages with this type of monitoring is that it
requires interstitial positioning of probes and thus additional
preparations. It is advantageous to encase the monitoring device,
e.g., a thermistor probe, with the laser fibre close to the laser
tip, avoiding separate punctures for temperature measurement.
[0014] A problem that has occurred during feedback control using
thermometers is that they only measure the local temperature and
are unable to detect if overheating (or insufficient heating)
occurs in tissue which is not close to the thermometer. Overheating
is undesirable as it may lead to carbonisation and/or necrotic
breakdown of the tissue. Carbonisation may be present as a black
layer surrounding the heat source which layer impairs light
penetration and reduces the distance that light can propagate in
the tissue. Rapid necrotic breakdown can cause poisoning.
Insufficient heating is undesirable as it leads to ineffective
treatment of the tissue. Attempts to determine changes in the
electrical properties of tissue caused by heating have used
implanted leads provided with electrodes to measure the impedance
or transfer properties of the tissue and thermistors or
thermocouples to measure temperature--tissue impedance
thermography. Using different frequencies for the current used in
impedance measurements it is possible to measure impedances in
tissue local to the measuring electrodes as well as tissue further
away. However the results have hitherto been considered unreliable
as the values of the impedance or transfer property obtained when
the temperature readings reach an elevated steady state (i.e. a
constant temperature, for example 46.degree. C.) have changed
continuously in such a way that it appears that they are
drifting--see FIG. 4 and FIG. 5. These figures show temperature and
impedance against time at three distances from the laser tip. Both
graphs have a similar pattern showing that changes in the measured
tissue properties, in this case the measured impedance, follow
changes in the tissue temperature, and that an irreversible change
in the impedance occurs such that the impedance at, for example,
40.degree. C. at the beginning of the experiment is not the same as
the impedance at 40.degree. C. at the end of the heating phase.
Similarly FIG. 6, which shows conductance against temperature for a
tumour using information gathered from the experimental results
shown in FIG. 2 "Conductance versus temperature at 44 kHz and 1 MHz
for an EMT6 tumour in vivo" in "The effect of hyperthermia-induced
conductivity changes on electrical impedance temperature mapping,"
M. A. Esrick, D. A. McRae, Phys. Med. Biol. 39 (1994) 133-144,
shows that the conductance of EMT6 tumour tissue in vivo while
being heated from 37.degree. C. to 45/46.degree. C. over a period
of 19 minutes varies substantially linearly. From this figure it is
possible to determine that the conductivity of this tissue at a
current frequency of 44 kHz and 37.degree. C. is around 3.5 mS, at
46.degree. C. it is around 3.85 mS. Looking at this limited range
the thermal coefficient is 0.038 mS/.degree. C. when measured at 44
kHz. When measured at 1 MHz the conductivity at 37.degree. C. is
around 5.152 mS, at 45.degree. C. it is around 5.8 mS. Looking at
this limited range the thermal coefficient is 0.081 mS/.degree. C.
when measured at 1 MHz.
Cancer Therapy Using Laser Devices
[0015] Mueller et al. (DE 3931854, 1991) presented an invention
based on an MRI tomograph for tumour location and monitoring during
interstitial laser irradiation of tumours, e.g., in the liver, via
quartz light conducting fibres. The invention was said to relieve
the patient from surgery, long hospitalisation and to enable tumour
removal with small side effects for the patient. In this invention
a multiplanar x-ray device is coupled to the MRI tomograph to
enable the fibres to be placed in the tumour using point ion probes
and the coordinates of the tumour to be determined by MRI
tomography.
[0016] When performing an interstitial heat treatment of cancer
tumours a feedback system that is able to present information to
the user regarding the progress and outcome of the treatment is
crucial. In prior art devices and methods, treatment is often
performed based on experience collected during previous treatments
and the session time is set based on this knowledge. As a secondary
means for treatment control, the tissue temperature may be
monitored at a limited number of measurement points. In many cases
the treatment time is set to a period longer than that which is
actually required as reliable means for feedback regarding how the
tissue is responding to the heating, the "tissue effects," do not
exist. For the same reason the desired result cannot be obtained in
many cases as the temperature distribution is not uniform in the
target area and proper positioning of the temperature sensors
cannot be ensured. As a temperature sensor can only sense the local
temperature there is no way of checking if there are cold spots
outside the local area, such cold spots being caused, for example,
by blood vessels passing through the tissue and conducting away the
heat.
SUMMARY OF THE INVENTION
[0017] Using the present invention it is possible to overcome at
least some of the problems with prior art devices and methods for
thermal treatment of tissue. In a first aspect of devices and
methods in accordance with the present invention a tissue
electrical property which varies with temperature is monitored
across a portion of the tissue being treated while a feedback
system controls the heating of the tissue to maintain a desired
elevated tissue temperature, and the treatment is determined to be
complete when, at the maintained desired tissue temperature,
substantially no further changes are detected in the monitored
electrical property.
[0018] In a second aspect of devices and methods in accordance with
the present invention, by initially establishing data regarding the
tissue properties and then combining this data with the temperature
measurements in known positions with regard to the heat source and
further combining this information with two- and/or
three-dimensional electrical property measuring (i.e. tissue
transfer function and/or conductivity and/or impedance measurement)
and correlating the actual changes of these properties in the
tissue to the expected change in tissue properties based on the
initial data, it is possible to extract information in a
three-dimensional space regarding the non-reversible tissue effect
that is a result of ongoing heat treatment. It is subsequently
possible to determine the point in the treatment where the desired
tissue effect has been obtained and to inform the user that the
treatment is complete and successful. Furthermore it is also
possible to detect when ongoing treatment is failing to achieve the
expected change in tissue properties and to provide a signal to an
operator that the treatment is not proceeding as planned.
[0019] The present invention achieves this by providing implantable
leads, each provided with impedance measuring electrode surfaces
and temperature measuring means, the leads being connectable to a
base unit provided with current generating means, measuring means
for measuring the electrical property of the electrical path
between 2 electrode surfaces and control means, the control means
being adapted to use electrical property and temperature readings
from the leads to determine a temperature-dependent property of
tissue in which the leads are implanted.
BRIEF DESCRIPTION OF THE FIGURES
[0020] FIG. 1 shows schematically a first embodiment of a thermal
device in accordance with the present invention;
[0021] FIG. 2 shows schematically a second embodiment of a thermal
device in accordance with the present invention;
[0022] FIG. 3 shows schematically a first embodiment of a digital
system for measuring the electrical properties of tissue;
[0023] FIGS. 4 and 5 show experimental results of impedance and
temperature against time during heating and cooling of tissue;
[0024] FIG. 6 shows experimental data which indicates that changes
in tissue conductance are linear following slow heating to
46.degree. C.;
[0025] FIGS. 7-11 show graphs showing the effect of temperature on
conductivity for different tissue models at two different current
frequencies.
DETAILED DESCRIPTION OF THE INVENTION
[0026] In the following, directions are given in respect to the
skin of a patient or the surface of an organ or tissue, thus the
expression "above" means outside the skin or outside the surface of
an organ or boundary of a tissue and is not dependent on the actual
orientation of the patient, organ or tissue. Depths or levels or
distances inside or outside a patient or organ are, unless
otherwise stated, measured in the direction perpendicular to the
skin of the patient or the surface of an organ or tissue. Distances
between components are measured from edge-to-edge unless otherwise
stated.
[0027] A first embodiment of a thermal device in accordance with
the present invention is shown schematically in FIG. 1. Thermal
device 1 comprises a base unit 3 and a plurality of insertable
leads. In this example, in order to avoid clutter in the
illustration, the thermal device 1 has been represented as having
just two leads 5, 7 but in practice it is possible that only one
lead will be used for example for the treatment of small tissue
volumes and that more than 2 leads will be used for example for the
treatment of larger volumes of tissue. Larger number of leads can
be used if it is desired to reduce treatment time, or if they are
required for reasons of efficiency for example if the maximum
extension of the tissue being treated is larger than can be
reliably treated with just two leads--typically when using lasers
as the source of energy, leads are placed 2-3 cm apart. Preferably
each lead 5, 7 is easily detachable from base unit 3 so that leads
can be easily replaced for reasons of hygiene when a different
patient is to be treated. The distal end of the each lead 5, 7 is
intended to introduced though the skin 9 of a patient into, or into
the vicinity of, the tissue to be treated e.g. tumour tissue 11.
Preferably, to enable accurate positioning, at least the portion of
each lead intended to be inserted into a patient is made
sufficiently rigid so that it doesn't bend during insertion and
use.
[0028] Base unit 3 may comprise one source of energy attached to a
plurality of leads, but preferably it comprises a plurality of
sources of energy. In this embodiment one source of energy in the
form of an infrared laser 13, 15 is provided for each lead 5, 7, so
in this example base unit 3 comprises 2 lasers, the output of each
laser 13, 15 being controllable individually. Preferably each of
said laser 13, 15 has a maximum optical output power level in the
region of 1-50 watts. The lasers preferably provide light energy of
a wavelength that is efficiently absorbed by animal tissue in order
to heat said tissue. Preferably the lasers operate in the
wavelength range of 700 to 1300 nm, more preferably at 805 or 1064
nm. Preferably each source is a solid-state semiconductor laser as
these have small dimensions and high efficacy. Alternatively each
source of energy could be an Nd-YAG laser or similar, however these
devices have the disadvantage of being less efficient and larger
than semiconductor lasers. Preferably the optical output power of
each laser can be independently controlled by a control system such
as a microprocessor or microcomputer 17, arranged in base unit 3,
and provided with appropriate operating software and hardware.
Preferably base unit 3 is provided with user input means such as at
least one keyboard 19, mouse, touch screen, tablet or the like, to
enable a user to control the operation of the system and display
means 21 such a screen, monitor, light panel, or other display to
provide measured and/or calculated and/or processed information to
the user. Such information can include for example, one or more of
the electrical properties of the tissue between electrodes, the
position of leads with respect to each other and/or the target
tissue to be treated, and tissue temperatures.
[0029] The output laser light from laser 13 can be fed to an
optical fibre 25 which is inside lead 5 and extends to the distal
end 27 of lead 5. The output laser light from laser 15 can be fed
to an optical fibre 29 which is inside lead 7 and extends to the
distal end 35 of lead 7. Each distal end 27, 35 is provided with a
tissue heating element, in this example a laser light transparent
energy emission window 32 resp 34 or bare fibre tip at a short
distance, e.g. between 0 and 40 mm, from the extremity of the
distal end 27, 35. Preferably each window has a length L1 of
between 1 and 15 mm. In this embodiment an optical fibre tip 31,
resp. 33 through which laser light is transported to the distal end
27, 35 is positioned in each window so that the laser light can
leave the lead 5, 7, be absorbed by, and heat the surrounding
tissue. The optical fibre tip can be in the form of a bare fibre, a
diffuser or some other means to guide the distribution of the laser
light.
[0030] Each distal end 27, 35 is further provided with spaced apart
distal and intermediate electrode surfaces, for example in the form
of conducting electrode plates, wires, projection, depressions or,
as shown here, electrode rings 37, 39, resp. 41, 43. Electrode
surfaces are made from conductive media such as silver, platinum,
gold or similar and during a treatment it is intended that said
electrode rings are in electrical contact with the tissue.
Preferably the width of an electrode surface in the longitudinal
direction of a lead can be from 0.1 mm to 5 mm, preferably 0.5 to 2
mm, although larger or smaller dimensions are also conceivable.
Optionally a conductive paste, gel, liquid or similar may be
provided to the electrode surfaces during use to ensure reliable
electrical contact. Distal electrode rings 37, 41 may be placed
closer to the extremity of each lead 5, 7 than said windows 32, 34
and are preferably within a distance L2 of 0-10 mm from the distal
end of windows 32, resp 34. Intermediate electrode rings 39, 43 are
positioned further away from the extremity of their respective
leads preferably at a distance of L3 of 0-40 mm from the proximal
end of window 32, 34. Thus in this embodiment of the present
invention each window 32 resp. 34 may be positioned between a pair
of electrode rings 37, 39 resp. 41, 43.
[0031] Note that if, as disclosed above, window 32, 34 is placed at
the extremity of the lead, (i.e. 0 mm from the extremity) then the
pair of electrode surfaces (and any further electrode surfaces) are
positioned further away from the extremity than the window and are
longitudinally spaced apart. Preferably the longitudinal distance
between a pair of neighbouring electrode rings on a lead is less
than 55 mm, more preferably less than 40 mm, e.g. 6 mm or 10 mm,
and preferably is greater than 3 mm.
[0032] Electrode rings 37, 41 are longitudinally separated from
electrode rings 39, 43 by a distance L1+L2+L3. While L1, L2 and L3
for lead 5 may be same as L1, L2 and L3 for lead 7 and, in the
event additional leads are used, all additional leads it is not a
necessity but to permit accurate positioning it is necessary that
the distance between electrode surfaces on each lead is known.
[0033] Each electrode ring 37-43 is connected by its respective
electrical conductor 45, 47, 49, 51 to the switchable output of a
current generator 50 and the switchable inputs of a measuring
circuit 52 preferably able to measure an electrical property of the
electrical path between any pair of electrode rings. In order to
illustrate the present invention an embodiment is now described in
which circuit 52 is a conductance measuring circuit of the type
well-known in the prior art which comprises an amplifier and
analogue-to-digital converter. The use of other measuring circuits
which measure one or more of the properties conductance,
resistance, impedance and capacitance is also conceivable. Current
generator 50 is controllable to produce alternating current of
known amplitude and, preferably, known phase and, preferably, is
switchable between at least two frequencies, one low frequency, for
example less than 500 Hz or 1 kHz or 5 kHz or 10 kHz or 50 kHz or
100 KHz and one high frequency e.g. greater than 200 kHz or 500 kHz
or 1 MHz or 2 MHz. The possibility of using different frequencies
during conductance measuring allows the conductance of different
volumes of tissue to be measured (and the conductivity to be
calculated if the conduction path length is known)--a form of
tomography. This is because the current path between electrodes
depends partly on the frequency used--lower frequency currents,
e.g. 1 kHz, follow curved paths between electrodes while higher
frequencies, e.g. 100 kHz, follow more direct paths. Current
generator 50 and conductance measuring circuit 52 are controllable
by control system 17 so that, preferably, it is possible to measure
the conductance between any pair of electrode rings 37-43, 71-81
and at any desired frequency. This can be achieved, for example by
using digital storage means and a digital to analogue converter 56.
An example of such a digital system for measuring the electrical
properties of tissue, shown schematically in FIG. 3, could comprise
digital storage means in the form of digital memory 54 containing a
signal loop which produces a cyclical signal which sweeps from a
low frequency (e.g. 500 Hz) to a high frequency (e.g. 200 kHz) over
a period of a few seconds, e.g. 5 seconds or 10 seconds and then
repeats. This signal is transmitted to a digital to analogue
converter 56 connectable by a multiplexer 58 to any pair of
electrode rings--which electrode rings could be on the same lead or
on different leads. The resulting electrical properties of the
tissue between this pair of electrode rings are then sampled and
converted to a digital signal by signal conditioner 60 and the
values of the properties recorded in the memory 54 against the
signal which caused them. As shown in FIG. 3, these recorded
signals can be used to produce a representation 62, 64, 66 of the
transfer function in the frequency domain of the tissue that the
electrodes are in. Each type of tissue has a certain transfer
function depending on density, cell size, vascularity, etc. The
electrical properties e.g. the conductance or impedance or transfer
function of the tissue will change during thermal treatment as the
physical properties of the tissue change and thus the transfer
function in the frequency domain of the tissue will change as the
tissue changes. Reference 62 shows a hypothetical representation in
the frequency domain of tissue in a first state, e.g. before
thermal treatment and reference 64 shows a hypothetical
representation of the same tissue during a step in thermal
treatment of the tissue where the temperature of the tissue is
higher than that of the tissue in the first state. Reference 66
shows a hypothetical representation in the frequency domain of the
same tissue after it has been killed by thermal treatment.
[0034] An improved digital system for measuring the electrical
properties of tissue could have two signal channels. The first
channel having a signal loop of the type mentioned above and the
second channel containing a synchronisation signal which is used to
synchronise the measurement and to improve the resolution in time.
The synchronisation signal can be organised as one synchronisation
pulse per sweep (in combination with a controller system that
ensures that the following samples are timed correctly) or one
pulse for each sampling point. The solution is very simple and in
spite of this it will enable very complex measurements. A
digitalised sweep signal, for instance from 500 Hz or 1 kHz to 100
kHz or 2 MHz or white noise or pink noise or the like having a
certain pattern is stored in the digital memory device. The digital
data is fed to a two channel digital to analogue converter in which
channel 1 holds the sweep signal and channel 2 contains a
synchronisation signal. The sweep signal is feed to an amplifier,
for instance a variable gain amplifier which may be controlled from
the control system in order to adjust the amplitude to the desired
level. The amplifier signal is fed to a multiplexing device that
allows the signal to be feed to any of the selected electrode
pairs. An amplifier circuit measures the applied voltage and
resulting current and phase. A resistor is connected in series with
the signal path to allow current measurement. An
analogue-to-digital converter and timing circuit samples the signal
at times synchronised by means of the synchronisation signal with
the sweep pattern fed to the electrodes. Digitised signals are
stored in memory along with synchronisation information. The stored
information can be fed to the control system which preferably is
adapted to performing signal processing, for example an averaging
of the repeated signals, that will improve the signal quality.
[0035] In the following the symbol `Z` is used to refer to the
measured electrical properties of tissue through which electricity
is conducted between two sensing electrode. If measurements are
taken at just one frequency then Z could be the conductance or
impedance of the tissue. If measurements are taken at more than one
frequency then Z would be a transfer function of the tissue It is
possible to determine a transfer function in a number of ways, for
example by using a number for frequencies (as described above),
scanning, white or pink noise or the like in combination with FFT
or FT ((Fast) Fourier Transformation)). In the following
description, the device and methods of using it will be illustrated
by examples where the conductance of tissue is measured but it is
understood that the invention is also applicable to devices and
methods where impedance and/or a transfer function of tissue is
measured.
[0036] Normally the conductance of tissue increases with heating
and this increase is substantially fully reversible upon cooling
back to 37.degree. C. if the tissue is only heated to approximately
5-6.degree. C. above its normal temperature (where 37.degree. C. is
the normal temperature for human tissue). Further heating, for
example to 9.degree. C. above the normal temperature, will cause
cell death (without causing cells to burst) which causes some
irreversible changes in conductance along with some reversible
changes in conductance--i.e. the conductance of the dead tissue
when cooled back to 37.degree. C. is not the same as its
conductance at 37.degree. C. before it was heated.
[0037] At least each distal and intermediate electrode ring 37-43
is preferably provided with its own thermal sensor such as a
thermistor 55, 57, 59, 61, so that the temperature in the vicinity
of the electrode ring can be measured. It is also conceivable to
provide other electrode rings with their own thermal sensors. By
attaching the thermal sensor to an electrode surface or building it
into the electrode surface the local temperature at which
conductance measurements are being made can be reliably determined.
As an alternative a thermal sensor can be provided adjacent to an
electrode surface.
[0038] Each thermistor 55-61 is connected by its respective pair of
electrical conductors 63, 65, 67, 69 to a control circuit 71 of
control system 17 which permits control system 17 to determine the
temperature of each thermistor 55-61. Control circuit 71 can, for
example, comprise a conventional Wheatstone bridge circuit of the
type well-known to be useful for measuring temperature when used in
connection with thermistors.
[0039] A plurality of depth sensing electrode surfaces for example
in the form of conducting electrode plates, wires, projections,
depressions or, as shown here, such as electrode rings 71, 73, 75
resp. 77, 79, 81 are placed on each lead 5, 7. Electrode rings are
made from conductive media such as silver, platinum, gold or
similar. Preferably the width of an electrode ring in the
longitudinal direction of a lead can be from 0.1 mm to 5 mm,
preferably 0.5 to 2 mm, although larger or smaller dimensions are
also conceivable. Optionally a conductive paste, gel, liquid or
similar may be provided to the electrode surfaces during use to
ensure reliable electrical contact. First depth sensing rings 71,
77 are positioned at a predetermined distance from the respective
intermediate electrode rings 39, 43, e.g. at a distance of between
5-15 mm, e.g. 5 mm or 10 mm or 15 mm, from intermediate electrode
rings 39, 43 in the direction towards the proximal end of the lead.
Second depth sensing rings 73, 79 are positioned a further distance
away from the distal end, e.g. at a distance of between 5-15 mm
e.g. 5 mm or 10 mm or 15 mm, from first depth sensing electrode
rings 71, 77. Similarly third depth sensing electrode rings 75, 81
and any further depth sensing electrode rings (not shown) are
positioned further away from the distal ends and preferably with
the same separation of between 5-15 mm e.g. 5 mm or 10 mm or 15 mm,
from the adjacent depth sensing electrode ring. It is not required
that the distance between rings is the same but the distance
between the rings on each lead has to be known or standardised in
order to allow accurate positioning by triangulation. The actual
distance between depth sensing electrode surfaces can be selected
depending on the accuracy of depth measurement required. The closer
together that the surfaces are, then the more accurate the depth
measurements will be.
[0040] One or more leads may optionally be provided with readable
memory 78 and the information regarding electrode surface positions
on the lead can be stored in the memory of the lead. Preferably
this information is inputted into the memory by the manufacturer of
the lead. During use of such a lead the control unit can extract
the information regarding electrode positions from the lead and use
it in triangulation calculations. Preferably the memory is
resistant to X-ray and gamma radiation in order to permit
sterilisation of the leads. Preferably the memory is ferro-magnetic
random access memory (FRAM). In the event that leads without memory
containing information on electrode positions are used or the
memory is not accessable by the control unit, preferably means are
provided for user input of such information to the control
unit.
[0041] Each depth sensing electrode ring 75, 81 is connected by a
conductor (not shown for clarity of illustration) to the switchable
output of current generator 50 and the switchable inputs of
conductance measuring circuit 52. Preferably conductance measuring
circuit 52 is arranged to be able to measure the conductance
between any pair of distal, intermediate or depth sensing electrode
rings at any desired frequency, e.g. frequencies between 500 Hz and
2 MHz.
[0042] Thermal device 1 is intended to thermally treat tissue,
especially diseased tissues, for example a tumour. In order to do
this, the lead or leads which will be used to heat tissue have to
be accurately placed both with respect to the unhealthy tissue e.g.
the cells of a tumour which has to be killed and, in the case two
or more leads are used, also with respect to each other. In a first
illustration of a method for positioning leads, it is intended that
at least the window 32, 34, and distal electrode ring and
intermediate electrode ring 37, 39, 41, 43 (and their respective
thermal sensors 55, 57, 59, 61) of each of two leads is to be
placed inside a tumour 11. In some cases the leads are intended to
be positioned such that the window 32, 34, and distal electrode
ring and intermediate electrode ring of each lead are outside the
tumour--this is illustrated in FIG. 1 by a tumour 11' shown in
dashed lines. The position of the tumour in relation to other
features of the patients body is assumed to be known, e.g. from
previously or simultaneously performed imaging. One or more leads
5, 7 are positioned on the skin of the patient immediately above
the tumour and pushed through the skin 9 and healthy 10 tissue of
the patient towards the tumour. As the exact position and/or size
of the tumour may have changed since the imaging was performed and
it may be difficult or impossible to determine the boundaries of
the tumour with imaging methods, it is useful to determine when the
windows 32, 34, and if the extent of the tumour allows, the distal
ends 27, 35 and distal and intermediate electrode rings 37, 39, 41,
43 are inside the tumour 11. The relative positioning of the
electrodes rings (and hence the leads they are attached to) can be
determined by measuring the conductance between pairs of electrode
rings. Normally the conductivity and transfer function of tumour
tissue is different from healthy tissue. During insertion of a lead
e.g. lead 5, the conductance between distal and intermediate
electrode rings 35 and 37 is monitored. Lead 5 is positioned above
the tumour 11 and is inserted through the skin towards the tumour
11. Distal electrode ring 37 enters the body of the patient first
and it is then followed by intermediate electrode ring 39. No
current will flow between distal electrode ring 37 and intermediate
electrode ring 39 until intermediate electrode ring 39 comes into
contact with tissue, at which point a certain conductance value
will be measured between electrode rings 37 and 39. Next the
conductance between intermediate electrode ring and first depth
sensing electrode ring 71 can be monitored. No current will flow
between them until first depth sensing electrode ring 71 comes into
contact with the skin of the patient. As the lead is introduced
further into the patient, second, third and any further depth
sensing electrode rings will come into contact with the patient's
tissue and the depth of the lead in the patient can be determined
from knowledge of which electrode ring pairs have a conductance
which indicates that they have entered the patient. Thus if the
lead is intended to be inserted so that the distal end is intended
to be 40 mm below the skin of the patient, and there is a depth
sensing electrode ring positioned 30 mm from the distal end and a
further depth measuring electrode positioned 40 mm from the distal
end, then, assuming that the lead has been inserted perpendicularly
to the skin of the patent, the depth of the distal end will be 40
mm below the skin of the patient when the further depth measuring
electrode positioned 40 mm from the distal end comes into contact
with the skin and current, preferably alternating current, starts
to flow between the depth sensing electrode ring positioned 30 mm
from the distal end and the further depth measuring electrode
positioned 40 mm from the distal end.
[0043] During insertion of the lead, the conductance between some
or all of the permutations of combinations of pairs of electrode
rings can be monitored. This can be used to see if the electrical
properties of the tissues through which the lead is passing are the
same. Normally healthy tissue has a different conductivity to that
of tumour tissue. In those cases, by monitoring changes in the
conductance as a lead is being inserted into tissue, it is possible
to determine changes in conductivity and hence detect when the lead
has entered, or is close to, tumour tissue. For example, during
insertion of the lead the conductance measured between the distal
electrode ring and intermediate electrode ring is monitored or
sampled after both electrode rings have entered healthy tissue. The
conductance remains substantially the same until distal electrode
37 enters the tumour, or is in the immediate vicinity of the
tumour, at which point the conductivity may change. If it does
change, then it will continue to change until the intermediate
electrode ring 39 closely approaches or enters the tumour (assuming
that the tumour is deep enough to contain both distal and
intermediate electrode rings). As long as both distal and
intermediate electrode rings 37, 39 remain in the area of the
tumour further movement of the lead should not result in any
significant change in conductance between electrode rings 37 and
39. If the conductance does change unexpectedly then this could be
a sign that there is a problem, for example that the distal
electrode ring has exited the tumour field, or entered a blood
vessel inside the tumour or there is a malfunction, and appropriate
action, such as repositioning a lead or replacing a lead, would
need to be taken.
[0044] Once lead 5 is at the required depth inside the tumour and
if more than 1 lead is to be used in the treatment then the same
procedure can be followed with lead 7 and an}' other leads.
Preferably during insertion of lead 7 (top aid in positioning the
lead) and/or once lead 7 has entered the tumour (to determine its
position with respect to other leads) the distance between
electrode rings on the implanted leads can be measured by
triangulation--that is by measuring the conductance or transfer
function between pairs of electrode rings on different leads and
using this to calculate the distance between each such electrode
pair. The readings between pairs of electrode surfaces can be
processed in order to determine the position of the leads both with
respect to the tumour (assuming its position is known) and with
respect to any other leads. As the distance L2 between the
electrode rings 37, 39 and 41, 43 is known, it is possible to
determine the electrical properties of the tumour tissue,
preferably by measuring its conductance at at least two frequencies
to determine its transfer function. The distance between electrode
ring 37 on lead 5 and electrode ring 41 on lead 7 can be determined
by measuring the conductance and/or transfer function Z (37-41)
between this pair of rings. The distance between electrode ring 39
on lead 5 and electrode ring 43 on lead 7 can be determined by
measuring the conductance and/or transfer function Z (39-43)
between this pair of rings. If Z (37-41) and Z (39-43) are the same
then electrode ring 37 and electrode ring 41 are the same distance
apart from each other as electrode ring 39 is from electrode ring
43. This distance can be calculated by dividing the values of these
electrical properties (conductance and/or transfer function) by the
electrical properties determined previously for the known distance
between the distal and intermediate electrodes on the same lead. In
order to determine if the distal ends 27, 335 of leads 5 and 7 are
at the same depth in the patient the conductivities and/or transfer
functions between diagonally opposed pairs of electrode rings can
be measured, i.e. the conductivities and/or transfer functions Z
(37-43) and Z (39-41). If these are the same then the diagonal
distance between electrode rings 37 and 43 is the same as the
diagonal distance between electrode rings 39 and 41. If the
measurements show that Z (37-41) and Z (39-43) are the same and
also that Z (37-43) and Z (39-41) are the same then it can be
assumed that leads 5 and 7 are parallel and have their distal ends
at the same depth. If (37-41) and Z (39-43) are not the same and/or
Z (37-43) and Z (39-41) are not the same then it is possible to
calculate the relative position of the leads with respective to
each other, i.e. how far apart they are, whether they are inclined
with respect to each other and if so, at which angle(s). Preferably
such calculations are made at regular intervals during insertion of
the leads. Said intervals are preferably less than 10 seconds, more
preferably less than 2 seconds and most preferably are less than 1
second, thereby allowing real time monitoring of the position of
electrodes so that the operator implanting the leads can be given
accurate and timely information regarding the position of the leads
as they are being implanted. Of course it is not always intended
that leads should be parallel or at the same depth, as their
intended positions are dictated by the, probably irregular, shape
of the tumour being treated. Using the principal of triangulation
as described above it is possible to verify if leads have the
intended positioning with respect to each other and, preferably,
the tumour.
[0045] It is conceivable that the collected signals and the
resulting data including, but not limited to, calculated distances
and angles between leads, signal phase, voltage and/or current
amplitudes, tissue properties such as impedance, conductance and
tissue effect temperature could be presented to an operator through
an operator interface. If a number of leads are used and any pair
of electrodes can be selected a large number of different current
paths can be selected. Using the result obtained for the different
paths a two-or three-dimensional tomographic image can be
calculated based on the results. Furthermore two electrodes can be
used to feed current though the tissue and the remaining electrodes
can be used to monitor the resulting voltages. This can be used to
further enhance the image resolution both in spatial resolution
quality and in precision. The information could be presented in
numerical form, in graphical form and/or as a calculated
tomographic map in two- or three-dimensions. The choice of
presentation may depend on the number of current paths used to
inform the user about the current state of the tissue and the
progress of the ongoing procedure. By using a sufficiently fast
computer and appropriate software the information could be
presented in real-time, i.e. the collected signals are processed
and updated information presented to the operator in a short period
of time ranging from less than a second to 20 seconds.
[0046] A second embodiment of a thermal device in accordance with
the present invention is shown schematically in FIG. 2. In this
embodiment of a device in accordance with the present invention the
depth of each lead inside a patient is determined with the help of
movable electrodes. Each lead 205, 207 is provided with a movable
sleeve 281, 283 through which the distal end of the respective lead
passes. Sleeves 281, 283 are lockable in place on their respective
sleeves by a locking means such as a locking screw 285, 287. The
distal end of each sleeve 281, 283 is provided with a
sleeve-mounted electrode 289, 291 which is intended to be in
contact with the patient's skin or the tissue being treated during
treatment. Each lead 205, 207 is provided with a graduated scale
293, 295 which can be used to read off the distance that the
sleeve-mounted electrode 289, 291 is from the centre of the window
of the lead. Before insertion of each lead 205, 207 into the
patient, the working depths for the lead is determined, e.g. by
scanning to determine the position of the tissue being treated and
the appropriate depth for each lead to be positioned at. The
appropriate depth can be determined, for example, as the depth that
the centre of the window should be from the skin of the patient or,
as a second example, as the depth that the centre of the window
should be inside an organ, the depth being measured from the
surface of the organ.
[0047] In a method for using the device in accordance with the
second embodiment of the present invention when the depth that the
window should be from the skin is known, each lead 205, 207 is
passed through a respective sleeve 281, 283 until a reference point
of the sleeve, e.g. its upper rim, 297, 299 is adjacent the mark on
the scale which corresponds to the desired working depth. The
sleeve is then locked at this position. For example if the centre
of the window is supposed to be 15 mm below the skin of the patient
then the sleeve is locked with its reference point adjacent the 15
mm mark of the scale so that the sleeve-mounted electrode is
positioned 15 mm away from the centre of the window. The value of
the transfer function of the tissue measured between the
sleeve-mounted electrode and a ring electrode e.g. ring electrode
37 on the same lead will be infinity when there is no electrical
contact between them. The lead can be inserted into the patient
until the sleeve-mounted electrode 289 comes in contact with the
skin of the patient at which point the lead 205 is at the desired
working depth. This point can be determined from the step change in
the transfer function signal which occurs when electrical contact
becomes established between the e.g. ring electrode 37 and the
sleeve-mounted electrode. Second and subsequent leads can be
positioned in the same way. The correct positioning of leads 205,
207 with respect to each other and/or the determination of their
actual positions can be achieved by triangulation as described
above with reference to the first embodiment of the invention.
[0048] In a method for using the device in accordance with the
second embodiment of the present invention when the depth that the
window should be from the surface of an organ, e.g. the surface of
the liver, is known, each lead 205, 207 is passed through a
respective sleeve 281, 283 until a reference point of the sleeve,
e.g. its upper rim, 297, 299 is adjacent the mark on the scale
which corresponds to the desired working depth, i.e. the distance
between the surface of the organ and the window. The sleeve is then
locked at this position. For example if the centre of the window is
supposed to be 20 mm below the surface of the organ of the patient
then the sleeve is locked with its reference point adjacent the 20
mm mark of the scale so that the sleeve-mounted electrode is
positioned 20 mm away from the centre of the window. The value of
the transfer function of the tissue measured between the
sleeve-mounted electrode and a ring electrode e.g. ring electrode
37 on the same lead will be infinity when there is no electrical
contact between them. The lead can be positioned above the organ
and be inserted into the patient. During insertion into the patient
the transfer function and/or conductance between distal and
intermediate electrodes can be measured in order to determine the
conductance and/or transfer function for the tissues and organs
that the lead passes through. The values for these tissues and
organs can then be compared to the values obtained between the
intermediate electrode and the sleeve-mounted electrode to identify
the point at which the sleeve-mounted electrode 289 comes in
contact with the surface of the organ to be treated--at which point
the lead 205 is at the desired working depth. In other words, this
point can be determined from the step change in the conductance
and/or transfer function signal which occurs when electrical
contact becomes established between the intermediate electrode and
the sleeve-mounted electrode. Second and subsequent leads can be
positioned in the same way. The correct positioning of leads 205,
207 with respect to each other and/or the determination of their
actual positions can be achieved by triangulation as described
above with reference to the first embodiment of the invention.
[0049] In a method for using the device in accordance with the
second embodiment of the present invention when the depth that the
window should be from the surface of an organ is known, each lead
205, 207 is passed through a respective sleeve 281, 283 until a
reference point of the sleeve, e.g. its upper rim, 297, 299 is
adjacent the mark on the scale which corresponds to the desired
working depth. The sleeve is then locked at this position. For
example if the centre of the window is supposed to be 10 mm below
the surface of the organ, e.g. the liver, then the sleeve is locked
with its reference point adjacent the 10 mm mark of the scale so
that the sleeve-mounted electrode is positioned 10 mm away from the
centre of the window, The lead can be inserted into the patient and
the transfer function between the ring electrodes monitored. When
the two ring electrodes enter the healthy tissue of the organ being
treated then a steady transfer function value for healthy tissue
should be recorded between them until the distal ring electrode
enters diseased tissue, e.g. tumour tissue, having a different
transfer function, at which point the value of the measured
transfer function will change constantly until the intermediate
electrode and the distal electrode both are in the same type of
diseased tissue. The transfer function of this tissue can be
recorded and the value of the transfer function between the sleeve
electrode and the intermediate electrode can now be monitored. When
the sleeve-mounted electrode 289 comes in contact with the diseased
tissue the transfer function value that is being measured between
the sleeve-mounted electrode and the intermediate electrode will
correspond to that of the diseased tissue and it can be inferred
that the sleeve-mounted electrode has just entered the diseased
tissue and the window is at the correct working depth. Second and
subsequent leads can be positioned in the same way. The correct
positioning of leads 205, 207 with respect to each other and/or the
determination of their actual positions can be achieved by
triangulation as described above with reference to the first
embodiment of the invention.
[0050] Once leads have been correctly positioned in the diseased
tissue, treatment of the tissue can be performed.
[0051] Theoretically, if tissue was only reversibly affected by
temperature even when heated to 46.degree. C. the tissue could be
heated to 46.degree. C. and temperature responses similar to those
shown in FIG. 7 (temperature and conductance versus time when
conductance is measured at 44 kHz) and FIG. 8 (temperature and
conductance versus time when conductance is measured at 1 MHz)
would be obtained. These models show such a theoretical tissue
being heated from about 2 minutes to about 32 minutes to a desired
temperature of 46.degree. C. with slightly imperfect feedback
control so that the actual temperature oscillates above and below
the desired temperature. The heating is terminated after 32
minutes. The tissue is allowed to cool and the model shows that the
conductance at 37.degree. C. after this prolonged heating is the
same as the conductance at 37.degree. C. before heating. An
equivalent electrical schematic behaving like tissue according to
this theoretical model is very complex as it has a frequency
dependency and a thermal coefficient. It thus consists of
capacitors, inductors, resistors and thermistors connected in
series and in parallel. However when looking at one specific
frequency, the frequency dependent components can be removed and a
very simplified equivalent circuit can be used.
[0052] Thus tissue which is unaffected by heat can be modelled
as:
##STR00001##
[0053] The figure above describes the resistance of a piece of
tissue at a certain frequency and in a limited temperature window.
It has a starting resistance (mainly R2) and a temperature
dependency (variable resistance R1) with a negative temperature
coefficient (i.e. comparable to that of a negative temperature
coefficient (NTC) thermistor). Thus when the temperature increases
the conductivity will go up (i.e. the resulting
resistance/impedance goes down).
[0054] However in real life tissue, when exposed to heat, above a
certain temperature irreversible changes in the properties of the
tissue occur. The conductivity will shift in a way that cannot be
explained in the simplified schematic above. A model for this
real-life tissue is as follows:
##STR00002##
[0055] Simplified equivalent schematic after heat treatment for
real life tissue
[0056] In this figure RX has been added. RX is the irreversible
influence (the "tissue effect") of a heat treatment at a certain
temperature for a certain time.
Normal Conductivity=Starting conductivity+(T.sub.coef*temp
rise)+integrated (Tissue Effect Constant*(Temp rise*time))
[0057] Or (@44 kHz for tumour EMT6 tissue)
3.5 + ( 0.038 * ( T act - 37 ) ) + .intg. t 0 t n T eff * ( T act -
37 ) * T slot ##EQU00001##
When T.sub.slot is a time slot in which a measurement is taken.
[0058] Adapting this model to have the characteristics of EMT6
tumour tissue and plotting temperature and conductance against
time, assuming that it takes 30 minutes for all the tissue in the
conductance path being measured to be heated at 46.degree. C. and
thereby fully irreversibly affected by the elevated temperature,
would give curves similar to those shown in FIG. 9 (temperature and
conductance versus time when conductance is measured at 44 kHz) and
FIG. 10 and FIG. 11 (temperature and conductance versus time when
conductance is measured at 1 MHz), where the line "normal
behaviour" relates to the real life tissue and "expected behaviour"
relates to theoretical tissue of the type shown in FIGS. 7 and 8
which does not suffer irreversible thermal changes. These real life
tissue curves show that in real life tissue the conductance rises
continuously but at decreasing rates before levelling off. The
steepest, first part of the curve up to about 6.5 minutes shows the
reversible change in conductance caused by heating. There then
follows a less steep, second part of the curve up to 30 minutes
which represents increasing numbers of cells in the tissue in the
conductance path being measured undergoing irreversible changes
i.e. are being killed. The third part of the curve, from 30 minutes
until heating is terminated at around 33 minutes, has an average
slope which is horizontal, and this indicates that all the cells in
the tissue in the conductance path being measured have undergone
irreversible changes i.e. are dead. In this part of the curve,
continued heating with feedback control will not cause any further
changes in the tissue in the conductance path being measured, and
the difference in relative conductance between the measured
conductance and the expected conductance (that is, the conductance
that would be expected if the tissue did not undergo irreversible
thermal effects) is at a maximum. At this point further treatment
will not have any beneficial effect in the local area as the tissue
in that region has already been killed.
[0059] A first embodiment of a device in accordance with the
present invention for the thermal treatment of tissue comprises
software and hardware means e.g. a computer, for running the
software for automatically measuring the electrical property of
tissue into which leads connected to the device have been
positioned.
[0060] The software performs the following steps:
[0061] activating sources of energy 13, 15 to provide energy to
tissue heating elements 32, 34. This causes the tissue in the
region near the heating elements to be warmed;
[0062] monitoring the temperature sensed by thermal sensors 55, 57,
59, 61 and controlling the heat provided to tissue heating elements
32, 34 so that a predetermined desired temperature is detected and
maintained at said thermal sensors 55, 57, 59,61. Preferably there
is a feedback system which prevents large swings in the temperature
measured by the thermal sensors;
[0063] measuring, storing and processing the value of an electrical
property between electrode pairs to determine changes in the
measured electrical property, wherein said electrodes are
positioned on different leads. This permits the change in the
electrical property in the electrical path between the leads to be
measured;
[0064] deactivating said sources of energy when, after having
started changing, said value of an electrical property ceases to
change for a predetermined period of time, for example once the
property has remained substantially the same for 1 minute or 2
minutes. The electrical property should change continuously as the
heat spreads and the region of heated tissue increases and more and
more of the tissue in the electrical path in region is killed. Once
no further changes in the electrical property can be detected there
is no need to prolong the heating as the absence of change
indicates that the maximum effect possible by heating in the region
between the leads has been achieved, the heating can be terminated
and, optionally, a signal made to signify that treatment has been
terminated. This signal can alert an operator that the treatment is
finished and the leads may be removed from the patient.
[0065] In a second embodiment of a method to determine the thermal
properties of a tissue in accordance with the present invention,
once leads have been correctly positioned in the diseased tissue,
the conductance thermal coefficients (T.sub.coef) of the tissue can
be measured. Conductance thermal coefficients are defined by the
formula T.sub.coef=.DELTA.Z.sub.f/.DELTA.t, where t is the tissue
temperature in degrees C., and Z.sub.f is the conductance measured
at frequency f.
[0066] Firstly, the reversible conductance thermal coefficient
(rT.sub.coef) of the tissue is determined by applying heat for a
short period of time, which is sufficiently short such that the
tissue is not heated to temperature where irreversible effects take
place in the tissue. Naturally the length of the period of time
that the heat can be applied for depends amongst others, on the
energy delivered by the heating means, the distance between leads
and the thermal properties of the tissue being heated. Preferably
this heating phase is controlled and monitored by suitable control,
recording and processing software in the control means, arranged so
that heating is terminated if the thermal sensors adjacent to the
heating means in the tissue register a temperature above a
predetermined maximum value, for example 4.degree. C. or 5.degree.
C. above the normal tissue temperature This predetermined maximum
value is chosen to be sufficiently low that there is no risk of
irreversible effects occurring in the tissue. In the following it
is assumed that irreversible effects take place above 43.degree. C.
and that tissue cells will begin to undergo cell death when exposed
to a deadly thermal dose which is greater than a certain value. For
example for tumour cells this deadly thermal dose is assumed to
correspond to being exposed to a temperature of 46.degree. C. for
30 minutes. Temperatures between 43.degree. C. and 46.degree. C.
would therefore require exposure times which are longer than 30
minutes and temperatures above 46.degree. C. would require exposure
times of less than 30 minutes to initiate cell death. By using
thermal sensors which are positioned adjacent to the heating
element, and hence should undergo the highest temperature rise it
is possible to ensure that no tissue is heated above the
predetermined maximum value. Having the thermal sensors attached to
the electrode surfaces used for measuring the electrical property
of the tissue ensures that the exact temperature of the electrode
surface is known. During this heating phase the temperature and
conductance in the near field (i.e. between electrode surfaces and
their associated thermistors which are situated on the same lead)
are monitored. The heating is switched off and the temperature and
conductance allowed to return to the initial value while being
monitored. Preferably this is repeated in order to ensure that no
irreversible changes take place in the tissue. As the heating is
relatively short no permanent tissue effect should be produced. The
undamaged (or reversible) conductance thermal coefficient of the
tissue can be calculated by software in said control unit based on
the changes in conductance and temperature. For example, using the
experimental data mentioned above for EMT6 tumour in vivo, the
software could determine that the conductivity at 44 kHz and
37.degree. C. is 3.5 mS, with a thermal coefficient of 0.038
mS/.degree. C., and the conductivity at 1 MHz at 37.degree. C. is
5.152 mS with a thermal coefficient of 0.081 mS/.degree. C.
[0067] A second step is performed in which heating is intended to
produce near field irreversible effects, namely death of the
diseased tissue, by controlled heating. The control, recording and
processing software causes heat to be applied to the tissue at a
preset temperature above 42.5.degree. C. which is preferably below
48.degree. C., further preferably below 47.degree. C. and most
preferred at 46.degree. C. The preset temperature is chosen so that
it will result in cell death after a period of time but does not
cause tumour antigens to coagulate. This preset temperature is
selected to avoid instant necrotisation, carbonization, coagulation
or ablation of the tissue and thus destruction of the tumour
antigens.
[0068] During this heating the near field tissue conductance and
the temperature are monitored, for example at 10 second intervals.
Heating is continued until no further changes in conductivity occur
in the near field paths being monitored, i.e. the average gradient
of conductance against time is zero. When the conductance gradient
is substantially zero, i.e. the value of the conductance has
reached a substantially constant value, then the tissue change is
permanent and continued heating will not have any further effect on
the tissue in the path being measured. The irreversible thermal
effect on tissue conductance (the "tissue effect") can then be
determined.
[0069] When it is time to treat the diseased tissue, the device can
be programmed to measure the far field tissue conductance, i.e. the
conductance between adjacent leads, both between electrode surfaces
at the same depth in the tissue i.e. straight through the tissue,
and between electrode surfaces at different depths in the tissue,
i.e. diagonally, while the tissue is being heated.
[0070] When proportionally the same irreversible tissue effect has
measured in all of these far field conductance paths (i.e. the
change in conductance which is proportional to the length of each
electrical path being measured) then this means that the tissue in
all the conductance paths between the leads has been heated to the
temperature where cell depth should have occurred. This means that
the heat treatment is complete and can be terminated. Preferably
this is signalled to an operator by a visual and/or audible signal
such as, but not limited to, a screen message, a signal lamp, a
bell, a chime or the like.
[0071] While the invention has been illustrated by devices and
methods in which conductance or a transfer function is measured and
the resulting measurements analysed, it is also conceivable to
modify devices and methods in accordance with the present invention
to use measurements relating to impedance and/or capacitance
instead.
[0072] While the invention has been illustrated with examples in
which a heating element (e.g. a laser light transparent window) on
a lead is intended to be positioned at a depth inside a tissue,
e.g. a tumour, being treated, it is also conceivable to modify
devices and methods in accordance with the present invention so
that the heating element is positioned at or near the boundary of
the tumour--for example near to but outside the tumour.
[0073] While the present invention has been illustrated with
examples of methods and devices in which two or more leads are
implanted in a patient, it is conceivable in a further embodiment
of the present invention that methods and devices may be adapted
for use with a single lead.
[0074] While the present invention has been illustrated with
examples of methods and devices in which a lead comprises two or
more electrode surfaces and two or more thermal sensors, it is
conceivable in a further embodiment of the present invention to use
a lead comprising only one electrode surface and/or only one
thermal sensor.
[0075] It is conceivable in a further embodiment of the present
invention to provide a base unit with a plurality of leads, only
one of which is provided with a movable electrode. In this case
this lead is preferably positioned first and is then used as a
reference lead against which the position of further implanted
leads can be determined.
[0076] While the invention has been illustrated with lasers as the
energy sources, it is possible to use any other suitable source of
energy, such as ultrasound transducers, resistive heaters,
microwave sources, self-regulating Curie metals, self-regulating
positive temperature coefficient resistors, heater elements, hot
liquids, etc.
[0077] While the invention has been illustrated by examples of
embodiments in which thermal sensors are positioned on electrode
surfaces, it is also conceivable to position them beside said
surfaces or at a short distance from them. However the advantage
that the conductance and/or transfer functions measurements can be
accurately correlated to the temperature of the tissue surrounding
the electrodes will be diminished as the distance between thermal
sensors and electrodes increases. Additionally, it is conceivable
to use a plurality of longitudinally separated thermal sensors in
order to determine the temperature gradient along a lead.
[0078] Methods and devices in accordance with the present invention
are suitable for use in automated systems for the positioning of
implantable leads in a patient and/or for the automated treatment
of tissue. In such systems a robot arm or the like is intended to
insert the leads and requires information on the actual position of
the leads as they are being inserted. The actual position of the
leads relative to each other and/or to a reference point on the
placement system and/or the patient during and after insertion can
be determined by means of the present invention. Thermal treatment
of the tissue may then take place.
[0079] In a conceivable use of the present invention for implanting
leads into a patient, the position of at least one lead is
monitored by ultrasound or some other imaging system during
implantation in order to confirm that the lead is indeed being
positioned correctly.
[0080] In all embodiments of the present invention, leads can be
provided with a hollow tube or other distributing means leading to
electrodes and/or thermal sensors to allow the addition of a
conductive fluid to said electrodes and/or thermal sensors in order
to ensure good electrical and/or thermal connection with the
surrounding tissue. Such a distribution means can be used during
thermal treatment to add conductive fluid in order to ensure that
changes in tissue geometry caused by heating, e.g. tissue
shrinkage, do not influence measurements taken using those
electrodes and/or thermal sensors.
[0081] The above described constructions and methods are for
illustrative purposes only and are not intended to limit the scope
of the following claims.
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