U.S. patent application number 10/475108 was filed with the patent office on 2004-09-09 for assembly for heat treatment of biological tissues.
Invention is credited to Moonen, Chretien, Quesson, Bruno, Vimeux, Jean Jacques.
Application Number | 20040176680 10/475108 |
Document ID | / |
Family ID | 8862557 |
Filed Date | 2004-09-09 |
United States Patent
Application |
20040176680 |
Kind Code |
A1 |
Moonen, Chretien ; et
al. |
September 9, 2004 |
Assembly for heat treatment of biological tissues
Abstract
The invention concerns an assembly for heat treatment of a
region of a biological tissue (410) comprising energy-generating
means (100) to supply energy to the region; means (200) for
measuring and recording spatial temperature distribution in said
region; a control unit (300) comprising means for point-to-point
digital processing of the temperature distribution in the region.
The invention is characterised in that the energy-generating means
comprise means(110) for spatial and temporal distribution of the
power available to them on said region, the control unit (300)
comprising means (330, 350), based on the temperature distribution,
for controlling the amount and distribution of energy supplied by
the generating means (100).
Inventors: |
Moonen, Chretien;
(Gradignan, FR) ; Quesson, Bruno; (Bordeaux,
FR) ; Vimeux, Jean Jacques; (Blagnac, FR) |
Correspondence
Address: |
D Douglas Price
Steptoe & Johnson
1330 Connecticut Avenue NW
Washington
DC
20036
US
|
Family ID: |
8862557 |
Appl. No.: |
10/475108 |
Filed: |
April 27, 2004 |
PCT Filed: |
April 19, 2002 |
PCT NO: |
PCT/FR02/01352 |
Current U.S.
Class: |
600/411 ;
600/412 |
Current CPC
Class: |
A61B 2017/00084
20130101; A61B 2090/374 20160201; A61N 7/02 20130101; A61B
2017/0084 20130101; A61B 2017/0084 20130101; A61B 2090/374
20160201 |
Class at
Publication: |
600/411 ;
600/412 |
International
Class: |
A61B 005/05 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 20, 2001 |
FR |
01/05410 |
Claims
1. An assembly for the heat treatment of a region of biological
tissue (410) comprising: energy-generating means (100) to supply
energy to the region, means (200) for measuring and recording the
spatial temperature distribution in said region, control unit (300)
comprising numerical processing means for the point-by-point
processing of the spatial temperature distribution in the region,
characterized in that the energy-generating means comprise means
(110) for spatially and temporally distributing the power that they
apply to the aforesaid region, the control unit (300) comprising
means (330, 350) for, on the basis of the temperature distribution,
controlling the amount and distribution of the energy supplied by
the generating means (100).
2. The heat treatment assembly as claimed in claim 1, characterized
in that the control unit (300) further comprises means (340) for
estimating the energy losses in the region of the tissue (410) on
the basis of an estimate of the thermal conductivity and of the
spatial temperature distribution in the region and its
surroundings.
3. The heat treatment assembly as claimed in one of the preceding
claims, characterized in that the control unit (300) comprises
processing means (330, 350) to take account of the thermal
conductivity at each point in the region.
4. The heat treatment assembly as claimed in claim 3, characterized
in that the control unit (300) comprises means (320) for measuring
the temperature at each point of a plurality of points sampling the
region and at regular time intervals and to deduce therefrom an
estimate of the change in temperature as a function of thermal
conductivity from one point of the spatial sample to another.
5. The heat treatment assembly as claimed in one of the preceding
claims, characterized in that the energy-generating means (100)
emit focused ultrasound.
6. The heat treatment assembly as claimed in one of the preceding
claims, characterized in that the means (200) for measuring and
recording the spatial temperature distribution comprise a magnetic
resonance imaging apparatus.
7. The heat treatment assembly as claimed in one of the preceding
claims, characterized in that the amplitude pw of the power to be
supplied at a point {right arrow over (r)} at an instant t+.DELTA.t
is calculated using a relationship of the type: 10 pw = Tp ( r , t
+ t ) - FT - 1 ( T * ( k , t ) - k 2 D t ) FT - 1 ( 1 - - k 2 D t
Dk 2 S * ( k ) ) where Tp({right arrow over (r)},t+.DELTA.t) is the
reference temperature at that point at the moment t+.DELTA.t,
FT.sup.-1 is an inverse Fourier transform, T*({right arrow over
(k)},t) is the Fourier transform of the temperature measured at the
moment t, D is the heat diffusion coefficient for the tissue,
.alpha. is the energy absorption coefficient for the tissue,
S*({right arrow over (k)}) is the Fourier transform of the spatial
distribution of the applied energy S({right arrow over (r)}).
8. Heat treatment assembly according to one of the preceding
claims, characterized in that the energy-generating means (100)
comprise energy sources of the ultrasound, laser, microwave or
radiofrequency type.
Description
[0001] The invention relates to local hyperthermia therapies.
[0002] Local hyperthermia therapies are techniques that are
commonly used to locally treat biological tissues. They consist in
heating a target zone of the biological tissue using an energy
source (laser, microwave, radiofrequency wave, ultrasound,
etc.).
[0003] These techniques offer numerous advantages. From the
qualitative viewpoint, they offer a great deal of potential for
controlling treatments such as gene therapy, the localized
application of drugs, the ablation of tumours, etc. From an
economic viewpoint, they are compatible with ambulatory treatment
of the sick and therefore make it possible to reduce the
hospitalization time.
[0004] In general, local hyperthermia therapies allow medical
interventions the invasive nature of which is reduced to a
minimum.
[0005] Among the types of energy used, focused ultrasound (FUS) is
particularly advantageous because it is able to heat the focused-on
zone, in a non-invasive way, deeply within the biological body,
without significantly heating the tissues adjacent to the
focused-on zone.
[0006] During treatment, the temperature of the target zone and of
its immediate surroundings needs to be controlled precisely and
continuously, although the supply of energy is localized and fast
(of the order of a few seconds). Patent FR 2 798 296 filed on Sep.
13, 1999 in the name of the Centre National de la Recherche
Scientifique (CNRS) describes an assembly for the heat treatment of
biological tissues. The assembly described in that document takes
account of the actual spatial distribution of temperature in the
target zone and in its immediate surroundings. This spatial
distribution makes it possible to estimate precisely how much
energy needs to be applied and to influence the energy source
accordingly. Such an assembly makes it possible both quickly to
obtain the desired temperature in the target zone and to maintain
and control the temperature in this target zone with increased
precision, by comparison with that which was possible with earlier
techniques.
[0007] The disadvantage with this assembly is that it is based on a
model of a heated region that is very localized in space. In
consequence, it allows control over the change in temperature in
the target zone but does not allow control over the temperature
distribution when several energy sources are used or when the
energy is applied simultaneously to several places, for example
using an array of emitters.
[0008] It is an object of the present invention to alleviate these
disadvantages by proposing a heat treatment assembly that allows
extended control of the temperature in a region of the living
tissue and that can be applied without spatial limitation as
regards the application of energy.
[0009] To this end, the invention proposes an assembly for the heat
treatment of a region of biological tissue comprising:
[0010] energy-generating means to supply energy to the region,
[0011] means for measuring and recording the spatial temperature
distribution in said region,
[0012] control unit comprising numerical processing means for the
point-by-point processing of the spatial temperature distribution
in the region, characterized in that the energy-generating means
comprise means for spatially and temporally distributing the power
that they apply to the aforesaid region, the control unit
comprising means for, on the basis of the temperature distribution,
controlling the amount and distribution of the energy supplied by
the generating means.
[0013] The means for spatially and temporally distributing the
power applied consist, for example, of an ultrasound transducer
whose movement in space is controlled. The heated region can
therefore be broader than the initial distribution of the energy
source.
[0014] The heat treatment assembly according to the present
invention advantageously takes account of the spatial temperature
distribution at each point in the region. Unlike the heat treatment
assemblies of the prior art, this characteristic allows control
over the distribution of energy throughout the treated region
rather than simply of the energy applied at a focused-on point. It
thus allows three dimensional and real-time control over the change
in temperature in the treated biological tissue.
[0015] Advantageously, the control unit of the heat treatment
assembly may comprise means for estimating the energy losses in the
region of the tissue on the basis of an estimate of the thermal
conductivity and of the spatial temperature distribution in the
region and its surroundings. This allows the temperature
distribution in the heat treated tissues to be changed more quickly
toward a reference distribution.
[0016] In one embodiment of the invention, the control unit
comprises processing means to take account of the thermal
conductivity at each point in the region.
[0017] In particular, the control unit may comprise means for
measuring the temperature at each point of a plurality of points
sampling the region and at regular time intervals and to deduce
therefrom an estimate of the change in temperature as a function of
thermal conductivity from one point of the spatial sample to
another.
[0018] According to this implementation, the image of the region of
the biological tissue is broken down into voxels and each voxel is
associated with a point in the region. The processing unit
associates a thermal conductivity and a temperature with each
point. This "point-by-point" breakdown advantageously allows the
change in temperature to be controlled throughout the region of the
biological tissue.
[0019] Advantageously, the energy-generating means may emit focused
ultrasound. Focused ultrasound allows heat to be supplied to a
localized zone, non-invasively, even if this zone is situated deep
within the human body or the animal.
[0020] Advantageously, the means for measuring and recording the
spatial temperature distribution comprise a Magnetic Resonance
Imaging apparatus (MRI). MRI allows full and non-invasive mapping
of the temperatures in the zone being treated, with good spatial
resolution (of the order of 1 millimeter) and excellent precision
(of the order of 1.degree. C.). Furthermore, the data collected by
MRI can easily be numerically processed.
[0021] In one implementation of the invention, the amplitude pw of
the power to be supplied at a point {right arrow over (r)} at an
instant t+.DELTA.t is calculated using a relationship of the type:
1 pw = Tp ( r , t + t ) - FT - 1 ( T * ( k , t ) - k 2 D t ) FT - 1
( 1 - - k 2 D t Dk 2 S * ( k ) )
[0022] where Tp({right arrow over (r)},t+.DELTA.t) is the reference
temperature at that point at the moment t+.DELTA.t, FT.sup.-1 is an
inverse Fourier transform, T*({right arrow over (k)},t) is the
Fourier transform of the temperature measured at the moment t, D is
the heat diffusion coefficient for the tissue, .alpha. is the
energy absorption coefficient for the tissue, S*({right arrow over
(k)}) is the Fourier transform of the spatial distribution of the
applied energy S({right arrow over (r)}).
[0023] In this way, at each moment, the energy to be applied is
automatically controlled by the processing means so as to force the
temperature to follow a predefined reference profile. This
characteristic makes it possible to ensure optimum safety for the
patient. In practice, what this amounts to is calculating the power
pw to be applied between two successive temperature measurements
obtained by MRI.
[0024] Of course, the energy-generating means for inducing
hyperthermia in the region of the tissues being treated comprise
energy sources of the ultrasound, laser, microwave or
radiofrequency type.
[0025] Other features and advantages will become further apparent
from the description which follows, which is purely illustrative
and nonlimiting and is to be read with reference to the attached
figures among which:
[0026] FIG. 1 schematically depicts the heat treatment assembly
according to the invention;
[0027] FIG. 2 depicts the change in temperature at the focal point
of the transducer as a function of time when the method is applied
to an acrylamide gel (test sample);
[0028] FIG. 3 depicts the change in power of the focused ultrasound
as a function of time when the method is applied to an acrylamide
gel;
[0029] FIG. 4 depicts a change in temperature at the focus point of
the transducer as a function of time when the method is applied to
a fresh meat sample;
[0030] FIG. 5 depicts the change in power of the focused ultrasound
as a function of time when the method is applied to a fresh meat
sample;
[0031] FIG. 6 represents the change in temperature at the focal
point of the transducer as a function of time when the method is
applied in vivo to the thigh of a rabbit;
[0032] FIG. 7 depicts the change in power of the focused ultrasound
as a function of time when the method is applied to the thigh of a
rabbit;
[0033] FIG. 8 depicts the variation in the minimum difference
between the simulated temperature and the reference profile as a
function of the error on the diffusion and absorption parameters of
the treated tissues, which error is calculated as the ratio 2 ( D /
) erroneous ( D / ) optimum
[0034] FIG. 9 depicts the variation in the standard deviation of
the difference between the simulated temperature and the reference
profile as a function of the error on the diffusion and absorption
parameters of the treated tissues, which error is calculated as the
3 ( D / ) erroneous ( D / ) optimum .
[0035] One of the embodiments of the invention is described
hereinbelow in detail. By way of example, this embodiment of the
invention corresponds to a local hyperthermia treatment assembly
using focused ultrasound (FUS) controlled by magnetic resonance
imaging (MRI).
[0036] As depicted in FIG. 1, such an assembly comprises:
[0037] ultrasound generating means 100,
[0038] anatomical and temperature mapping means 200,
[0039] a temperature control unit 300,
[0040] a sample holder 400 for the biological tissue 410 to be
treated.
[0041] In the embodiment of the invention described here, the
energy-generating means 100 are made up of a transducer 110 able to
be moved by a hydraulic system, of a sinusoidal signal generator
120, of an amplifier 130 and of a converter 140 connecting the
sinusoidal signal generator 120 to the control unit 300.
[0042] The transducer 110 has a diameter of 90 mm with a radius of
curvature of 80 mm. The focal length can be adjusted electronically
between 50 and 125 mm and the position of the focal region can be
altered mechanically in the horizontal plane in a field of 80
mm.times.80 mm. It operates at 1.5 MHz. The input signal is
generated by a multi-channel square wave generator. The signals are
filtered so as to avoid interference with the magnetic resonance
instruments that operate, for example, at 63 MHz for a 1.5T MRI
apparatus.
[0043] The generator 120 is, for example, a multichannel generator
(Corelec) driven by a serial connection. The system for moving the
transducer in a horizontal plane is, for example, a hydraulic
system driven by a serial link.
[0044] The aforesaid two links are connected, for example, to the
PC receiving the MRI images in real time and producing temperature
maps so as to allow the desired feedback control of
temperature.
[0045] The mapping means 200 are able to measure and record the
spatial temperature distribution. They comprise, for example, an
MRI apparatus of the ACS NT 1.5 T type marketed by Philips.RTM.
(Best, Netherlands). The control unit 300 in particular comprises a
work station 310 of the PC type, marketed by Dell.RTM.. The PC is
able to control the ultrasound generator 100 and the system for
moving the transducer 110. In this device, all the parameters
concerned with the application of energy by focused ultrasound can
therefore be adjusted through the work station: the power of the
ultrasound, the focal length and the position of the transducer
110. The work station further comprises a graphics interface so
that the progress of the intervention can be viewed in real
time.
[0046] The control unit 300 also comprises means for alleviating
and numerically processing the spatial temperature distribution
320, means for determining the value of the power 330 that needs to
be supplied to a target zone of the controlled region, means 340
for estimating thermal energy losses in the region considered and
control means 350 for controlling the energy-generating means. The
control means 350 tell the energy-generating means 100 to deliver
the amount of power determined by the means for determining the
power level 330.
[0047] The sample holder 400 comprises a support 420. This support
contains the transducer 110 and a surface coil (MRI signal
receiver). The support 420 is placed in a water-filled reservoir so
as to ensure optimum propagation of the focused ultrasound toward
the target tissues. The water is kept at a constant temperature of
38.degree. C. using a water bath temperature controller (for
example polysciences, model 9110-BB, IL, USA) to avoid the tested
samples cooling.
[0048] The object of an automatic temperature control method is to
force the temperature at a given position in the region of the
samples for treatment to follow a reference profile Tp(t). The
change in temperature in space and in time is given by the bio-heat
equation [1] that takes account of the coefficient of energy
absorption by the tissue (.alpha.) and the coefficient of diffusion
of heat into the tissue (D): 4 T ( r , t ) t = D 2 T ( r , t ) + S
( r ) pw ( t ) [ 1 ]
[0049] where T({right arrow over (r)},t) is the temperature map,
.gradient..sup.2 is the Laplace operator, S({right arrow over (r)})
is the spatial distribution of the applied energy and pw(t) is its
amplitude.
[0050] This equation does not take account of perfusion in the
tissues or of the heat produced by metabolism because the heat
generated is neglible by comparison with the amount of heat applied
by focused ultrasound (FUS). The invention generalizes the control
principle based on equation 1 with no constraint regarding the
spatial distribution of the application of energy by taking account
of the heat transfer from each point (or voxel) to each other point
(or voxel). To do that, an analytical solution for equation [1] is
sought in order best to predict the temporal change in temperature
at any point in space as a function of the diffusion and the
application of energy by the source. The Fourier transform on the
spatial coordinates of equation [1] leads to a linear equation of
the first order as a function of time: 5 T * ( k , t ) t = - k 2 DT
* ( k , t ) + S * ( k ) pw ( t ) [ 2 ]
[0051] where T*({right arrow over (k)},t) and S*({right arrow over
(k)}) are the Fourier transforms on the spatial coordinates of
T({right arrow over (r)},t) and S({right arrow over (r)})
respectively.
[0052] A solution can be derived from equation [2] by assuming the
power pw(t) is constant for a given time interval .DELTA.t
(corresponding to the measurement interval for temperature
measurements by MRI): 6 T * ( k , t + t ) = - k 2 D t T * ( k , t )
+ 1 - - k 2 D t Dk 2 S * ( k ) pw [ 3 ]
[0053] In consequence, the power to be applied during At to force
the temperature T({right arrow over (r)}, t+.DELTA.t) to be equal
to a temperature profile Tp({right arrow over (r)}, t+.DELTA.t) can
be derived from the inverse Fourier transform (FT.sup.-1) of
equation [3]: 7 pw = Tp ( r , t + t ) - FT - 1 ( T * ( k , t ) - k
2 D t ) FT - 1 ( 1 - - k 2 D t Dk 2 S * ( k ) ) [ 4 ]
[0054] This type of algorithm makes it possible to ensure optimum
safety for the patient because it makes it possible automatically
to control the temperature. For this, the energy to be applied in
order to force the temperature to follow a predefined reference
profile is evaluated at regular time intervals .DELTA.t. In
practice, what this amounts to is calculating the power pw to be
applied between two successive temperature measurements obtained by
MRI. Ideally, this type of algorithm takes the physical phenomenon
(in this instance the heat diffusion equation) into consideration
and is as robust as possible.
Setting Up the Device
[0055] All the experiments were carried out according to the same
protocol. The position of a reference volume was acquired in order
to define a region of interest and the position of the reference
focal point. The position of the reference volume with respect to
the isocenter of the magnet of the MRI apparatus was recorded so as
to position the transducer 110 and to adjust the focal length.
Next, a repeated scan of this volume was done to prepare the
heating process. This preparation was used to:
[0056] calculate the standard deviation at the temperature mean in
each voxel of the volume so as to estimate the precision of the
temperature measurement,
[0057] correct the position of the transducer 110 and its focal
length; low-power focused ultrasound was applied for a brief period
(of the order of 5s) so as to induce modest hyperthermia (about
+3.degree. C.). This measurement made it possible to check the
coordinates of the position of the image by magnetic resonance and
the position of the transducer and the focal length were adjusted
if necessary,
[0058] evaluate the diffusion D and absorption a parameters of the
tissue: focused ultrasound was applied for a brief period and a
non-linear adjustment was made using the method of least squares to
the curve of the change of temperature at the focal point as a
function of time so as to obtain these parameters.
[0059] Following this preparatory protocol, the desired change in
temperature as a function of time (reference profile Tp({right
arrow over (r)},t)) was programmed and the automatic control
process (equation 4) was begun.
[0060] To allow this process to operate correctly, it was necessary
to synchronize the MRI acquisition and the PC driving the focused
ultrasound. For that, the MRI imaging device generates a TTL (Time
to Live) signal at the start of each scan. This signal was detected
by a built-in interface which switched a relay connected to a
parallel port of the PC. This switching was detected by a
special-purpose routine written in C and the corresponding PC
system times were recorded in a shared memory module used by the
algorithm. The timings thus measured were taken into consideration
in the temperature control algorithm.
Experimental Procedure
[0061] Experiments on phantom gels, fresh meat samples and, in vivo
on rabbit thighs, were carried out on the 1.5 Tesla Philips ACS/NT
system equipped with the Philips prototype focused ultrasound
generator for inducing local hyperthermia. Rabbits were
anesthetized and positioned in such a way that the thigh muscles
were centered approximately on the ultrasound beam. The values of
the coefficients a and D from preliminary measurements are given in
the table below:
1 Acrylamide Rabbit thigh gel Fresh meat (in vivo) D (mm.sup.2
.multidot. s.sup.-1) 0.17 0.36 0.10 .alpha. (.degree. C. .multidot.
s.sup.-1 .multidot. %.sup.-1) 0.33 0.29 0.40
[0062] When the preparatory adjustment phase had been carried out
(see above), the real-time temperature control protocol was
performed.
[0063] In these experiments, a temporal resolution of 1.75 seconds
for 3 parallel slices was obtained, using a "segmented EPI" imaging
technique with the following parameters: an echo time (TE) of 30
ms, a repeat time (TR) of 60 ms and 11 phase encoding steps per TR
with a spatial resolution 1.times.1 mm, 3 mm slice thickness.
[0064] FIGS. 2, 4 and 6 represent the change in temperature at the
focal point of the focused ultrasound transducer as a function of
time, obtained respectively with acrylamide gel, with a sample of
fresh meat, and with a rabbit thigh. The curve in continuous line
represents the reference temperature profile Tp(t) and the symbols
represent the experimental temperature data at the focal point,
measured by temperature MRI. As can be seen in FIG. 6, the
application of focused ultrasound was halted after 170 s. The
temperature then decreased to its initial value, with no control,
on account of the diffusion phenomenon.
[0065] The standard deviation of the difference between the
measured temperature and the reference temperature remained
relatively constant (0.75.degree. C. on average) during the
hyperthermia phase, indicating that the proposed method makes it
possible to perform effective real-time control on the change in
temperature in vivo.
[0066] FIGS. 3, 5 and 7 represent the change in focused ultrasound
power as a function of time when the method is applied respectively
to the acrylamide gel, to the fresh meat sample and to the rabbit
thigh.
[0067] It is evident that the values of the coefficients a and D
can vary during the experiment (as a function of temperature,
because of the denaturing of proteins, change in perfusion, etc.).
It is therefore important to make sure that the proposed
temperature control algorithm is not excessively sensitive to a
variation in these parameters.
[0068] The sensitivity of the quality of the temperature control
was estimated from numerical simulations, by varying the parameters
D and .alpha. over a wide range of values between 30% and 230% and
between 50% and 150%, respectively, of their initially (on the
basis of the preparatory phase) estimated value, in steps of 2%.
For each (.alpha., D) pairing, the change in temperature was
calculated using the power actually applied during the experiment.
The results obtained show that the temperature follows the
temperature profile with an offset and with a fluctuation that vary
to greater or lesser extents. The minimum difference between the
simulated temperature and the reference temperature gives the
offset value and the standard deviation of this difference allows
the amplitude of the fluctuation to be evaluated.
[0069] FIG. 8 depicts the variation in the minimum difference
between the simulated temperature and the reference profile as a
function of the error on the diffusion and absorption parameters of
the treated tissues, which error is calculated as the ratio 8 ( D /
) erroneous ( D / ) optimum
[0070] FIG. 9 depicts the variation in the standard deviation of
the difference between the simulated temperature and the reference
profile as a function of the error on the diffusion and absorption
parameters of the treated tissues, which error is calculated as the
ratio 9 ( D / ) erroneous ( D / ) optimum .
[0071] These results reveal a significant correlation between the
error in D/.alpha. and the precision of the control algorithm. In
addition, it can be seen that an error in estimating .alpha. and D
(due in particular to their variation during the course of the
experiment) has little effect on the quality of the control. These
results confirm the effectiveness and robustness of the proposed
method.
[0072] The real time temperature control of local hyperthermia can
be performed in vivo on a clinical MRI. This simple and predictive
method based on the physical model of the temperature diffusion
depends only on the absorption (.alpha.) and diffusion (D)
coefficients of the tissues. The mathematical expression of the
proposed algorithm is very general and can therefore be applied to
any energy source (focused ultrasound, radiofrequency, laser,
microwaves, etc.) that allows hyperthermia to be induced in
biological tissues. The only condition governing its use is
knowledge of the spatial profile of the application of energy.
* * * * *