Note: Descriptions are shown in the official language in which they were submitted.
CA 02441489 2003-09-12
Canadian Intellectual Property INDUCING AND CONTOURING ICE FORMATION
Tonal August 20, 2003
Page 3 of 12
2
4
References Cited jReferenced i3y]
6
U.S. F~atent Documents
8
5139496 Aug., 1992 Hed 606/23.
5160313 Nov.. 1992 Carpenter et al. 600136.
5658276 Aug., 1997 Griswold 606/24.
5358931 Oct.. 1994 Rubinsky et al. 514/12.
5654279 Aug., 1997 Rubinsky
5906209 May, 1999 Tortai
12 Other References
14 [1 ] David I. Lee, David E. McGinnis, Rick Feld and Stephen E. Strup
Retroperitoneal laparoscopic cryoablation of small renal tumors: intermediate
results,
16 Urology, Volume 67, Issue 7, January 2003, Pages 83-88 .
18 [2] John C. Saliken, Bryan J. Donnelly & John C. Rewcastle
The evolution & state of the modern technology for prostate crosurgery
Urology, Volume 60, Issue 2 Supplement , Augusf 2002, Pages 26-33.
22 [3] Bruce L. Daniel and Kim Butts
The use of view angle tilting to reduce distortions in MRI of Cryosurgery
24 Magnetic Resonance Imaging, Vol.18, Issue 3, April 2000, pages 289-286.
26 [4] Fahy et al., "Ultrastructure-Function . . . Rat Heart", Cryobiology,
vol. 14, pp. 418-427,
1977.
28
[5] Vinas et al., "Early Hemodynamic . . . Cryogenic Injury'°, Neurol
Res, vol. 17, pp. 465-
468, 1995.
32 [6] (Onik GM, Cohen JK, Reyes GD, et al. Percutaneous radical cryosurgical
ablation of
the prostate under transrectal ultrasound guidance. Cancer 1993; 72: 1291-
1299) and
34 (Lee F, Bahn
36 [7] DK, Mc Hugh TA, et al. Ultrasound- guided percutaneous cryoablation of
prostate
cancer. Radiology 1994; 192:769-776.).
CA 02441489 2003-09-12
Canadian Intellectual Property INDUCING AND CONTOURING ICE FORMATION
Tortal August 20, 2003
Page 4 of 12
REVIEW OF RELATED LITERATURE
2
Carpenter et al (US Patent 5160313 discusses the use of diluent or eluent e.g.
4 ethylsulfoxide, glycerol, propanediol and other compounds to a
transplantable tissue
which has been cryopreserved with an intracellular cryoprotectant to reduce
the level of
6 cryoprotectant in the cells to a substantially non-toxic level. It is not
stipulated nor it is
the purpose of the said invention to sculpture ice formation and increase the
freezing
8 rate difference between cells and cause further damage to targeted tissue as
proposed
in this patent application.
Rubinsky et al (US Patent 5358931 disclosed property thermal hysteresis
proteins from
12 certain fish oils in polar regions in protecting cells and their membranes
from damage
from cold temperature. The purpose is to increase the water crystallization in
the
14 intracellular spaces between targeted cells while decreasing
crystallization in the cells.
The intracellular ice packets should pierce the targeted cell's membrane,
killing the
16 tissue by Koushafar and Rubinsky [9]. However, in this technique freezing
of normal
tissue was observed. This is a reverse of our proposed technique and
methodology.
18
Hed (US Patent 5139496) disclosed the use of ultrasound waves to initiate ice
nucleation within targeted cells. While it is also one of the aims of this
proposed
invention to induce ice formation prior to normal freezing rate, this
invention is using
22 osmotic and nucleatic chemicals and not energies such as ultrasound.
24 Griswold (US Patent 5,658,276) describes the use of wire warmerslheaters to
protect
critical organs and provide means of melting the ice during the thawing
cycles. The
26 proposed invention does not apply external heat to prevent unwanted
freezing but alter
the cells freezing rate through introduction of chemicals.
28
CROSS REFERENCE TO RELATED APPLICATIONS: -
RIGHTS TO INVENTIONS MADE UNDER FEDERALLY-SPONSORED RESEARCH
32 AND DEVELOPMENT: None
34 FIELD OF THE INVENTION
36 This invention relates to the use of chemicals in cryosurgical treatment.
38 SUMMARY OF THE INVENTION
Invention comprises of chemicals and associated technique for sculpturing ice
formation,
increasing the difference in freezing rate between targeted and non-targeted
tissue,
42 inducing ice nucleation at temperature higher than cells' normal freezing
temperature.
44 The chemicals are chosen among nucleatic and osmotic agents.
46 The technique involves the injection of nucleatic and osmotic chemicals to
the targeted
tissue prior to cryosurgical freezing. Then the injection of water prior to
freezing of
48 tissues.
CA 02441489 2003-09-12
2
Canadian Intellectual Property INDUCING AND CONTOURING ICE FORMATION
Tonal August 20, 2003
Page 5 of 12
DETAILED DISCUSSION OF THE IN1/ENTBON
The main drawback in cryosurgery is unwanted freezing of nearby critical
organs)
4 andlor non-targeted tissues.
6 A means to counteract this adverse effect is the use of a urethra) warmer in
prostate
cryosurgery. Warm water is circulated through a catheter inserted into the
urethra to
8 prevent urethra) fistula and impotence. Other adjacent non-targeted and
surrounding
tissues are still at risk of freezing.
Another attempt is by means of a magnetostrictive polymer tube positioned
nearest to
12 the probe's tip where thermal exchange happens. It shuts off at a set
temperature or is
shut manually to block incoming cold supply instantly. This however, does not
address
14 the tissues' response to already supplied cold temperature. Ice formed in
tissues extend
uncontrollably from the targeted location.
16
Moreover, preventing unwanted freezing is dependent on the surgeon's skill to
18 accurately positioned the cryosurgical probes to the exact location of
targeted tumor and
at minimum contact with critical organs throughout the freezing. Still, ice
formation
expands uncontrollably at cryogenic temperatures.
22 It is therefore the object of this invention to provide a reproducible
technique to sculpture
ice formation during cryosurgery and means to instantly control ice formation.
By doing
24 so, provide a more reliable freezing treatment.
26 The above objective is accomplished effectively by manipulating the
response of cells to
cold supply instead.
28
Response of cells is manipulated effectively in this invention by introducing
nucleatic and
osmotic agents to the targeted tissue. The chemicals are chosen among
polyhydric
alcohols such as glycerols and mannitol; carbohydrates such as trehalose and
sucrose;
32 free amino acids and their derivates, including proline, taurine and beta-
alanine; urea
and ethylene amines such as trimethyl amone oxide (TMAO) and betaine together
and
34 are bio-compatibles.
36 These chemicals induce ice formation at temperature higher than the normal
temperature of cells. Thus, create great difference in the rate of ice
formation between
38 targeted and non-targeted tissues. Non-targeted tissues can then greatly be
spared
from freezing. Moreover, these chemicals induce greater production of
destructive ice
within targeted cells.
42 Concentrations of the above chemicals vary from 0.5M to 2.5M. Concentration
that yield
the maximum water absorption and rate of ice formation for each of the said
chemicals
44 vary for each chemical.
46 The preferred chemical specification: 2.5M L-Proline 99+°!°,
2.5M of Glycerol 99+% ,
2.5M of Taurine 99%, 1.5M Beta-Aianine 99+%, 1.5M of Betaine 98%, 1.5M Sucrose
48 98%, 1.5M D-mannitol 98%, 0.5M D-Trehalose dihydrate, 1.5M or 2.5M of Urea
99+%.
CA 02441489 2003-09-12
Canadian Intellectual Property INDUCING AND CONTOURING ICE FORMATION
Tortal August 20, 2003
Page 6 of 12
2 Associated Technique:
For each chemical, the volume is about 10% of the tumor volume. The chemicals
are
4 injected to targeted tumor volume prior to freezing. Vllater is injected
after the chemical
is injected, ten minutes later.
6
The added water counteracts any adverse effects of water displacing from non-
targeted
8 areas as caused by the chemicals and provide greater cellular strain.
Freezing zone can be extended to a desired distance from the margin of the
tumor or
targeted tissue by also injecting the chemical to this area.
12
14
Cryosurgical freezing should be started after another ten minutes.
The injection to the tumor is guided by ultrasound as for subcutaneous
targets. Ice
16 formation is monitored using ultrasound and open MRI.
18 Tissue temperature is monitored using thermocouples placed within the
target volume,
critical organs and non-targeted nearby tissues.
Established lethal temperatures range from -25°C such as in prostate
cryosurgery to -
22 40°C e.g. in breast cryosurgery. Thus, freezing is stopped when this
temperature is
reached.
24
The combined hastening of ice formation and creation of greater cellular
strain within the
26 targeted tissue results to optimum cellular destruction even prior to
reaching the lethal
temperatures.
28
Biopsies and MRI images will be taken before and after the cryosurgical
procedure when
ice is melted to ensure maximum cellular destruction to point of rupture has
been
achieved in the procedure, and unwanted freezing of non-targeted tissue has
been
32 minimized.
34 Experiments and studies performed for this invention showed a more
remarkable
destruction of targeted tissues injected with the chemicals than those not
injected.
36
Rates of ice formation and water absorption of sample tissues treated with the
various
38 chemicals show tremendous increase.
BEST MODE FOR CARRYINC9 OIJT THE IN!/ENTION
42
Preparing the Chemicals:
44 To produce:
46 1 ) 2.5M of L-Proline 99+% (Molecular weight = 115.13):
48 Dissolve 287.82 grams of L-Proline 99+% in one liter of water.
CA 02441489 2003-09-12
Canadian Intellectual Property INDUCING AND CONTOURING ICE FORMATION
Tortal August 20, 2003
Page 7 of 12
2 2) 2.5M of Glycerol 99+%
4 Dissolve 230.22 grams of Glycerol 99+% in one liter of water.
6 3) 2.5M of Taurine 99%
8 Dissolve 315.38 grams of Taurine 99% in one liter of water.
4) 1.5M Beta-Alanine 99+%
12 Dissolve 133.64 grams of Beta-Alanine 99% in one liter of water.
14 5) 1.5M of Betaine 98%
16 Dissolve 175.72 grams of Betaine 98% in one liter of water.
18 6) 1.5M Sucrose 98%
Dissolve 513.45 grams of Sucrose 98% in one liter of water.
22
7) 1.5M D-mannitol 98%
24
Dissolve 273.26 grams of D-mannitol 98% in one liter of water.
26
8) 0.5M D-Trehalose dihydrate 99%
28
Dissolve 189.15 grams of D-Trehalose dihydrate 99% in one liter of water.
9) 1.5M or 2.5M of Urea 99+%.
32
For 1.5M Urea: Dissolve 90.09 grams of Urea 99+% in one liter of
34 water.
36 For 2.5M Urea: Dissolve 150.15 grams of Urea 99+% in one liter of
water.
38
Volume of chemicals above is about 10% of the tumor volume.
To administer the correct amount of chemical throughout the targeted volume
for ice
42 sculpturing, it is crucial to determine the volume and exact location of
the targeted tumor.
44 The current method that yields the best estimate of prostate tumor volume
is serum
Prostate Specific Antigen (PSA) with 0.5 Pearson Correlation Coefficient.
46
Tumor volume estimates for other subcutaneous tumors are done by first taking
a
48 Computed Topography (CT) scan or MRI image. The image is then entered to a
CA 02441489 2003-09-12
Canadian Intellectual Property INDUCING AND CONTOURING ICE FORMATION
Tonal August 20, 2003
Page 8 of 12
computer for calculation. The computer reconstructs the image in three-
dimension and
2 performs voxel counting, trapezoid approximation technique and area
summation
calculation.
4
The most accurate biopsy and imaging technique should be used in determining
the
6 stage and location of targeted tumor and its exact location. Such as to
date, for prostate
cancer, Transrectal Ultrasound (TRUS) biopsies as described by Onik could be
used.
Technique for Administering the Chemicals and Maximizing the Effects:
For subcutaneous tumors, the injection of the chemicals and the insertion of
cryosurgical
12 probe should be guided by ultrasound with sector scan transducer. Doppler
ultrasound
that display colored images should give clear distinction of tumor boundary
and normal
14 tissues. Ultrasound must operate at higher frequency for better imaging of
various
tissues and organs such as at least 5 or 7.5MHz.
16
Targeted gland such as prostate can be shrieked using androgen deprivation
technique
18 prior to injecting the chemicals) and performing cryosurgery. Shrinking the
gland
ensures better absorption and distribution of the chemicals. Moreover,
shrinking the
gland decreases the risk of freezing the rectum since the other effect of this
method is
increasing the space between the rectum and the prostate capsule due to the
effect of
22 increasing the amount of fat in the Denonvilliers fascia region [Onik,
"Percutaneous
Prostate Cryoablation].
24
Injecting water in the targeted tissue counteracts any adverse effects of
water displacing from
26 non-targeted areas due to the chemical injected, and creates greater
cellular strain. Water of
volume approximately 50% of the tumor volume should be sufficient. Water can
be injected 10
28 minutes after the injection of the chemical.
Freezing of tissues using cryosurgical probe can begin 10 minutes after
injection of chemicals
and/or after the injection of water. Diameter and shape of probe tip depend on
the diameter,
32 shape and desired extent of ice formation.
34 For sculpturing ice formation, it is critical to monitor the temperatures
and ice formation
of targeted tissue, critical organs and extended freezing areas. Thus,
thermocouples are
36 placed in these areas.
38 Diameter of ice ball and extent of ice crystals formed outside of tumor
volume should be
measured using linear array ultrasound or open MRI during the entire
procedure.
Diameter of ice ball should be graphed with respect to time and temperature.
Rate of ice
ball formation will then be calculated. This is to monitor if treatment plan
was followed in
42 the procedure performed.
44 MRI images will be taken before and after the cryosurgical procedure when
ice is melted to
ensure maximum cellular destruction to point of rupture has been achieved in
the procedure,
46 and unwanted freezing of non-targeted tissue has been minimized.
48 Several cryoprobes are imbedded within the substance of the tumor. Number
of cryoprobes and
CA 02441489 2003-09-12
Canadian Intellectual Property INDUCING AND CONTOURING ICE FORMATION
Tortal August 20, 2003
Page 9 of 12
distances between them depend on the size and shape of tumor. The established
lethal
2 temperature that causes cellular necrosis is at least -25 for prostate
cancer, and -40°C as in the
case of breast carcinoma. In this proposed technique, we expect higher
temperature
4 destructive freezing since we have induced faster rate and maximum amount of
ice formation at
much higher tissue temperature. We already observed greater tissue damage at
less than
6 20°C.
8
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the injection of chemical to the targeted tissue A.
12
Figure 2 shows the injection of chemical to adjacent normal tissue B as
represented by
14 broken curve lines if ice ball formation should be slightly be extended
beyond targeted
tissue.
16
18
