CN116636918A - Thermochemical Ablation Device - Google Patents
Thermochemical Ablation Device Download PDFInfo
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- CN116636918A CN116636918A CN202210141996.2A CN202210141996A CN116636918A CN 116636918 A CN116636918 A CN 116636918A CN 202210141996 A CN202210141996 A CN 202210141996A CN 116636918 A CN116636918 A CN 116636918A
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- alkali metal
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- metal alloy
- ablation device
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
- A61B18/06—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating caused by chemical reaction, e.g. moxaburners
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
- A61B2018/00595—Cauterization
Abstract
The invention relates to a thermochemical ablation device, relates to the technical field of ablation medical treatment, and is used for solving the technical problem of accurate delivery of ablation energy. According to the thermochemical ablation device, the alkali metal alloy is conveyed to a target position (such as a target area tumor tissue) through the ablation needle, and the alkali metal alloy and tissue fluid at the target position react exothermically at the target position to release heat, so that the aim of killing the tumor tissue is fulfilled. Because the alkali metal alloy is in a normal temperature state before reaching the target position, the alkali metal alloy can release heat only when reaching the target position and contacting tissue fluid, the alkali metal alloy can release high-strength heat in a directional manner only at the target position in the treatment process, and the alkali metal alloy has no heating and mechanical puncture damage to peripheral tissues. Therefore, the thermochemical ablation device can realize accurate transmission of ablation energy and realize real in-vivo directional heating.
Description
Technical Field
The invention relates to the technical field of ablation medical treatment, in particular to a thermochemical ablation device.
Background
Minimally invasive interventional tumor treatment is accepted by doctors and patients with the characteristics of safety, effectiveness, minimally invasive and less complications. Current treatment techniques for diseased tissue include cryoablation, microwave ablation, radio frequency ablation, irreversible electroporation ablation, ultrasonic focus ablation, chemical ablation, and the like.
In the aspect of high-temperature heat therapy, the common problem is how to directionally deliver heat to tumor tissues in a target area, so that the tumor can be effectively killed without damaging normal tissues. Regardless of the external heat application device or the thermal therapy probe inserted into the tissue, the heat is guided to the deep tumor from outside to inside, and meanwhile, overheat damage can be caused to the healthy tissue due to heat leakage along the way, so that the situation is more serious under the action of high-intensity heating. Therefore, the existing ablation equipment cannot meet the requirement of accurate ablation energy transmission.
Disclosure of Invention
The invention provides a thermochemical ablation device which is used for solving the technical problem of accurate delivery of ablation energy.
According to a first aspect of the invention, there is provided a thermochemical ablation device comprising a syringe, an ablation needle and a driver connected to the syringe respectively, the syringe being filled with a therapeutic substance, the therapeutic substance in the syringe being delivered to a target site by the driver through the ablation needle;
wherein the therapeutic substance is an alkali metal or alkali metal alloy that reacts exothermically when delivered to the target site.
In one embodiment, the alkali metal is sodium or potassium and the alkali metal alloy is a sodium potassium alloy.
In one embodiment, the interior of the syringe is also filled with a reaction aid, which is water.
In one embodiment, the dose of alkali metal alloy in the syringe is related to the size and/or moisture content of the tumor at the target site.
In one embodiment, the injection rate of the injector is related to the treatment temperature and the amount of injection is related to the size of the tumor at the target site.
In one embodiment, the driver includes:
the driving plate is connected with the plunger of the injector and is used for pushing out the therapeutic substances and the reaction auxiliary agents;
the limiting plate is arranged at one end of the injector, close to the ablation needle, and is used for limiting the front end position of the injector; and
and the guide structure is connected with the driving plate to limit the movement path of the driving plate.
In one embodiment, the number of the injector, the drive plate, the stop plate, and the guide structure is 1 or more.
In one embodiment, the ablation needle comprises a flow inlet pipe and a return pipe sleeved outside the flow inlet pipe, the flow inlet pipe is communicated with the inside of the injector, and the return pipe is connected with the recovery container.
In one embodiment, the number of inflow tubes is 1 or more; the inflow pipes are sequentially sleeved from inside to outside, and are respectively connected with the injector.
In one embodiment, the injector further comprises a control monitoring unit and a signal sensor, wherein the driver is connected with the control monitoring unit through a signal wire, and the control monitoring unit controls the driver to act on the injector; the signal sensor is connected with the control monitoring unit through a signal wire and is used for monitoring physiological parameters at the target position.
According to a second aspect of the present invention there is provided the use of a pharmaceutical composition comprising an alkali metal or alkali metal alloy in the manufacture of a medicament for the treatment of diseased tissue.
According to a second aspect of the present invention there is provided the use of a pharmaceutical composition in the manufacture of a medical device for the treatment of diseased tissue, the medical device being a syringe filled with the pharmaceutical composition, the pharmaceutical composition comprising an alkali metal or alkali metal alloy.
Compared with the prior art, the invention has the advantages that the alkali metal alloy is conveyed to the target position (such as the tumor tissue of the target area) through the ablation needle, and the alkali metal alloy and tissue fluid at the target position react exothermically at the target position to release heat, so that the aim of killing the tumor tissue is fulfilled. Because the alkali metal alloy is in a normal temperature state before reaching the target position, the alkali metal alloy can release heat only when reaching the target position and contacting tissue fluid, the alkali metal alloy can release high-strength heat in a directional manner only at the target position in the treatment process, and the alkali metal alloy has no heating and mechanical puncture damage to peripheral tissues. Therefore, the thermochemical ablation device can realize accurate transmission of ablation energy and realize real in-vivo directional heating.
Drawings
The invention will be described in more detail hereinafter on the basis of embodiments and with reference to the accompanying drawings.
FIG. 1 is a schematic illustration of the structure of a thermal chemical ablation device in accordance with an embodiment of the invention;
FIGS. 2 and 3 are schematic diagrams of the structure of a driver in an embodiment of the present invention;
FIG. 4 is a schematic view of the structure of an ablation needle in an embodiment of the invention;
FIG. 5a is a graph showing the partial carbonization of target tissue after an in vivo rat alkali metal ablation test using a thermochemical ablation device in accordance with an embodiment of the present invention;
FIG. 5b is a transient temperature response of a thermochemical ablation device to tissue during an in vivo rat alkali metal ablation test reaction using an embodiment of the invention;
FIG. 6a is a photograph of a control group of pathological sections 48h after EMT6 tumor treatment;
FIG. 6b is a photograph of a 48h pathology section NaOH solution ablation group after EMT6 tumor treatment;
FIG. 6c is a photograph of a pathological section hyperthermia group 48h after EMT6 tumor treatment;
FIG. 6d is a photograph of a pathological section of the alkali metal group 48h after EMT6 tumor treatment;
FIG. 7a is a scanning electron microscope image of a cross-sectional structure of pork tissue with a normal pork tissue surface morphology multiplied by 400;
FIG. 7b is a scanning electron microscope image of a pork tissue cross-sectional structure with a cavitation profile x 400 times after alkali metal ablation;
FIG. 7c is a scanning electron microscope image of a cross-sectional structure of pork tissue multiplied by 1600 in the internal structure of the cavity;
FIG. 7d is a scanning electron microscope image of a cross-sectional structure of pork tissue with a structural change x 800 times after alkali metal ablation;
FIG. 8a is a spatial distribution of temperature T at different times;
FIG. 8b is a spatial distribution of pH at different times
FIG. 9 is a graph showing the effect of varying protein levels in tissue on pH profile;
FIG. 10a is a graph showing the effect of tissue moisture content on temperature;
FIG. 10b is tissue moisture content versus C OH- Is a function of (1);
FIG. 11a is an ultrasound image of pork tissue after alkali ablation;
fig. 11b is a selected image of ROI (region of interest);
FIGS. 12a, 12b, 12c and 12d are in vitro experimental samples of pigs, respectively;
fig. 13 is an ex vivo experimental sample after thermochemical ablation (injection rate=120 ul/min, injection amount=60 ul);
FIG. 14 is a graph of temperature response inside a tumor;
FIG. 15 is a graph showing the skin temperature profile of mice during treatment;
16a, 16b, 16c, 16d and 16e are scanned images of the early tumor experimental group 30min before surgery, 30min after surgery, 5 days after surgery, 10 days, 15 days, respectively;
fig. 16f is a scanned image of the control group after 15 days;
FIG. 17 is a schematic representation of tumor volume change;
FIGS. 18a, 18b, 18c, 18d, 18e and 18f are schematic structural views of a thermochemical ablation system.
Reference numerals:
1-a syringe; 11-a plunger;
a 2-driver; 21-a drive plate; 22-limiting plates; 23-guiding structure;
3-an ablation needle; 31-a flow inlet pipe; 311-a first inflow pipe; 312-a second inflow pipe; 32-a return pipe;
311 a-a first inlet; 312 a-a second inlet port; 32 a-a return port;
4-a recovery vessel; 5-controlling the monitoring unit; 6-signal lines; 7-signal sensor.
Detailed Description
The invention will be further described with reference to the accompanying drawings.
As shown in fig. 1, the present invention provides a thermo-chemical ablation device comprising a syringe 1, and an ablation needle 3 and a driver 2 connected to the syringe 1, respectively, the inside of the syringe 1 being filled with a therapeutic substance. More specifically, the interior of the syringe 1 is filled with a therapeutic substance and a reaction aid, and the therapeutic substance in the syringe 1 is delivered to a target site through the ablation needle 3 by the driver 2. Wherein the therapeutic substance is alkali metal or alkali metal alloy, and the reaction auxiliary agent is water. When the therapeutic substance is delivered to the target site, an exothermic reaction occurs under the influence of the reaction aid. And the treatment temperature can be controlled more precisely by adjusting the injection speed of the treatment substance and the reaction auxiliary agent.
The thermochemical ablation device of the invention is characterized in that by means of the water environment naturally existing at the target position, the alkali metal or alkali metal alloy (usually in the microliter scale) which has high-intensity heat release effect and is easy to be absorbed by human body is conveyed to the target position, so that the alkali metal or alkali metal alloy reacts with tissue fluid under the action of the reaction auxiliary agent to generate strong exothermic chemical reaction, thereby achieving the aim of high-efficiency thermal ablation. The metal or alkali metal alloy in the injector 1 is in a normal temperature state, and exothermic chemical reaction can only occur to release heat when tissue fluid is encountered at the target position through the ablation needle 3, so that high-intensity heat can be directionally released only at the target position (the highest temperature of heated tissue can reach more than 200 ℃), and the surrounding tissue is not damaged by heating and mechanical puncture, therefore, the targeted heating performance of the invention is superior to that of a plurality of high-end thermal treatment devices currently existing.
Further, since the invention treats the tissue by exothermic reaction between the alkali metal alloy delivered to the target site, the invention does not cause difficulties in the use of the guiding device and the medical image monitoring instrument; and has good non-electromagnetic property, so that the corresponding temperature information can be obtained by adopting the conventional temperature measuring means such as thermocouples, infrared rays, even temperature measuring type MRI and the like, thereby being very beneficial to the implementation of the operation. It will thus be appreciated that the thermochemical ablation device of the present invention may also include one or more of the thermocouple thermometers, infrared thermometers, or thermometry MRI described above.
Preferably, the alkali metal is sodium or potassium and the alkali metal alloy is a sodium potassium alloy. The benefits of the sodium-potassium alloy are mainly the following. First, sodium-potassium alloy reaction products such as Na after reaction with interstitial fluid + 、K + All are typical constituent elements of normal saline, are typical constituent elements in normal physiological environment in a living body, and are easy to be absorbed by tissues, and can not cause persistent toxicity to the tissues. Second, because the amount of alkali metal delivered to the target site is small, the reaction product can be completely absorbed by human tissues, and no harm is caused to human bodies. Third, OH in the reaction - React with proteins in tumor tissue and are consumed. Fourth, the weak alkaline environment caused by the reaction is found to have unique medical value for inhibiting tumor regeneration in experiments, which is unfavorable for the recurrent growth of tumor cells, thereby solving the problem of strengthening tumor treatment. Thus, in this sense, alkali metals have the dual effect of hyperthermia and chemotherapy, which is therapeutically beneficial.
Therefore, the thermochemical ablation device of the invention carries out thermochemical ablation by using alkali metal or alkali metal alloy, has rapid temperature rise and flexible use, and ensures that the internal directional ablation treatment of deep tumors truly realizes minimally invasive treatment; in addition, the availability of the alkali metal material greatly reduces the cost of tumor treatment. Therefore, the thermochemical ablation device of the invention can realize high local heating which is difficult to realize by a plurality of modern thermal treatment devices with extremely low cost.
The thermo-chemical ablation device is a device capable of realizing real in-vivo directional heating, can effectively solve the difficulties faced by the traditional thermo-therapeutic equipment, and provides a great possibility for realizing high-efficiency low-cost treatment of tumors in the future.
In some embodiments, as shown in fig. 2 and 3, the driver 2 includes a drive plate 21, a limit plate 22, and a guide structure 23. The drive plate 21 is connected to the plunger 11 of the syringe 1 for pushing out the therapeutic substance and the reaction aid. A stop plate 22 is provided at the end of the syringe 1 near the ablation needle 3 for defining the front end position of the syringe 1. The guide structure 23 is connected to the driving plate 21 to limit a movement path of the driving plate 21.
Before treatment, a dose of therapeutic substance and a reaction aid may be added to the syringe 1, which is injected as required for treatment. The injection mode of the injector 1 is related to the tumor property, for example, the injection speed can be adjusted according to the treatment temperature, and the injection amount can be set according to the tumor size. The injection speed and the injection quantity of the syringe 1 can thus be adjusted instead of being constant.
Further, the drive plate 21 may be connected to the motor by a worm and gear mechanism. Thereby, the rotation motion of the worm gear can be converted into the linear motion of the driving plate 21 under the driving of the motor.
In addition, the driving plate 21 may be connected to a cylinder or an electric cylinder, and the driving plate 21 is driven to move by the cylinder or the electric cylinder, so as to push the plunger 11 of the syringe 1.
The number of the syringe 1, the driving plate 21, the limiting plate 22 and the guide structure 23 is 1 or more. In the embodiment shown in fig. 2, the number of the injector 1, the driving plate 21, the limiting plate 22 and the guiding structure 23 is 2, and the 4 parts are in one-to-one correspondence.
The guide structure 23 may be provided on the base plate 24, and the guide structure 23 may be a structure capable of restricting a movement path, such as a guide groove or a guide rail.
The diameter of the ablation needle 3 used for puncturing is small (about 0.5 mm), so that mechanical trauma to the tissue caused by puncturing is effectively avoided. Specifically, the ablation needle 3 includes an inflow tube 31 and a return tube 32 fitted around the outside of the inflow tube 31, the inflow tube 31 communicates with the inside of the syringe 1, and the return tube 32 is connected to the recovery tank 4 through a recovery tube.
Further, the number of the inflow pipes 31 is 1 or more; the plurality of inflow pipes 31 are sleeved in sequence from inside to outside, and the plurality of inflow pipes 31 are respectively connected with the injector.
In the embodiment shown in fig. 4, the number of the inflow pipes 31 is two, the two inflow pipes 31 are a first inflow pipe 311 and a second inflow pipe 312, respectively, and the rear end of the first inflow pipe 311 is a first inflow port 311a which is communicated with the interior of the syringe 1; the second inflow tube 312 is sleeved outside the first inflow tube 311, and a second inflow port 312a communicating with the inside of the syringe 1 is formed at the rear end thereof. Different substances can be input to the target position through the first inflow port 311a and the second inflow port 312a. For example, the alkali metal alloy may be supplied to the target position through the first inlet 311a, and the liquid water may be supplied to the target position through the second inlet 312a to adjust the amount of heat released from the alkali metal alloy. The return pipe 32 is sleeved outside the second inflow pipe 312, the rear end of the return pipe 32 is provided with a return port 32a, and the waste generated by treatment can be conveyed to the recovery container 4 for recovery through the return port 32 a.
Since the alkali metal and water or the alkali metal alloy and water are fed to the target position through the inflow pipe 31 to react, the pressure at the target position is increased, and the reacted waste is pressed into the return pipe 32 from the front end of the return pipe 32. Alternatively, the return pipe 32 may be connected to a pump body through which the waste is sucked.
In some embodiments, the thermochemical ablation device of the present invention further comprises a control monitoring unit 5 and a signal sensor 7, as shown in fig. 1, the driver 2 being connected to the control monitoring unit 5 by a signal line 6, the control monitoring unit 5 controlling the driver 2 to act on the injector 1. The signal sensor 7 is connected to the control monitoring unit 5 via a signal line 6, the signal sensor 7 being used for monitoring a physiological parameter at the target location.
In use, the thermochemical ablation device of the present invention mounts a syringe 1 filled with a therapeutic substance to a driver 2 and connects an ablation needle 3 to a delivery tube at the forward end of the syringe 1. The ablation needle 3 is then inserted into the lesion tissue. The control and monitoring unit 5 controls the drive plate 21 to push the plunger 11 of the syringe 1, thereby extruding the therapeutic substance from the syringe 1. The therapeutic substance enters the inflow tube 31 of the ablation needle 3 through the delivery tube and is discharged from the front end into the lesion tissue, thereby performing the treatment. The waste material resulting from the treatment is discharged through the return tube 32 of the ablation needle 3 and through the return tube into the return reservoir 4.
The dosage of the alkali metal alloy in the injector 1 is related to the size and/or water content of the tumor at the target site, and the amount of exothermic heat can be regulated by selecting the appropriate dosage of alkali metal alloy with the content of interstitial fluid at different target sites. In the selection of alkali metal materials, the invention adopts solid alkali metal and liquid alkali metal compound with proper proportion. At present, the heating effect of the two materials on the tissues is preliminarily confirmed.
According to a second aspect of the present invention there is provided the use of a pharmaceutical composition comprising an alkali metal or alkali metal alloy in the manufacture of a medicament for the treatment of diseased tissue.
According to a second aspect of the present invention there is provided the use of a pharmaceutical composition in the manufacture of a medical device for the treatment of diseased tissue, the medical device being a syringe filled with the pharmaceutical composition, the pharmaceutical composition comprising an alkali metal or alkali metal alloy.
The use of the pharmaceutical composition of the present invention for treating diseased tissue will be described in detail below.
Some representative results of experiments performed on anesthetized rats using the thermochemical ablation device of the present invention are shown in fig. 5a and 5 b. At the time of the experiment, 0.02g of an alkali metal reagent was injected into the liver of a rat through the syringe 1 and the ablation needle 3. Fig. 5a reflects the situation of partial carbonization of the target tissue, while fig. 5b represents the transient temperature response of the tissue during the sodium reaction, which results in the same reveal a rather strong heating effect, with a maximum temperature of even more than 220 ℃, which is difficult to achieve with the current state of the art hyperthermia methods. At the initial stage of reaction, the temperature of the injection site can be quickly raised to 90 ℃, and then gradually lowered; by adding proper moisture to the injection site, a high temperature can be generated which instantaneously inactivates tumor cells, which is a quite unique minimally invasive heating characteristic of alkali metal thermochemical ablation over traditional hyperthermia devices. The amount of heat released can be specifically regulated and controlled according to the treatment requirement in practical application.
It has now been demonstrated that alkali thermochemical ablation can extend survival time in Balb/c mice transplanted with EMT6 and can inhibit tumor growth in model mice. Fig. 6a, 6b, 6c and 6d show histopathological section views of EMT6 tumor after untreated, naOH ablation, thermal ablation and alkali ablation. Control tumor cells were clearly visible and exhibited a large number of mitotic cells. In contrast, liquid necrosis was shown in the reaction zone of the NaOH solution treatment group, and the pathological section fig. 6b shows a transition zone between the reaction zone and normal tissue, the left cell structure disappeared, the right cell spacing increased, but the nuclei remained. The hyperthermia group exhibited coagulation necrosis, but some of the tumor cells were still visible without destruction, as indicated by the arrows in fig. 6 c. The cytoplasm of the alkali metal treatment group has enhanced eosinophilia and is homogeneously red-stained. The cell spacing increases, the cell structure disappears, and the nucleus is completely dissolved.
The mechanism of alkali thermochemical ablation therapy includes thermal effects, chemical effects, and cavitation effects. Wherein the heat effect mainly comes from the reaction of alkali metals such as sodium, potassium and the like with water to release a large amount of heat, and simultaneously, the alkali metal saponified adipose tissue can also generate a large amount of heat; the chemical effect mainly results from the formation of a large amount of OH after the reaction - High concentration of OH - Can catalyze the hydrolysis of peptide bonds, shift the reaction balance to the positive direction, thoroughly hydrolyze the peptide bonds and lead a large amount of OH - The generation of (a) disrupts the adjustment of the pH balance by the carbonate system; visual alkali is observed by scanning electron microscope on pork tissueThe tissue after metal ablation is uneven, bubbles with irregular shapes and diameters of about tens to hundreds of micrometers are distributed throughout, more fibrous particles appear, and cavitation effect is obvious. Scanning electron microscope images of the cross-sectional structure of pork tissue as shown in fig. 7a, 7b, 7c and 7 d.
Based on the heat injury equation of Arrhenius, the activation energy and frequency factor of three therapies are obtained by quantitatively analyzing the rule of the change of the apoptosis rate of EMT6 tumor cells with the action time under the heat treatment, chemical effect and thermochemical effect and the injury rate under the three treatment modes through a flow cell sorter. As shown in Table 1, the results show that the rate of damage K of the thermochemical treatment is within a certain temperature range c Heat treatment K greater than that at the same dose h Sum of damage rate of chemical treatment K n (K c >K h +K n ) Thermochemical damage was demonstrated to be not just a linear superposition of thermal and chemical effects, but rather a synergistic interaction.
TABLE 1 activation energy, frequency factor and injury rate
On the basis, the influence of factors such as the ablation speed of alkali metal, the water content of tissue, the blood perfusion rate and the like on the fluid transportation is evaluated, the temperature and the spatial distribution of each reaction product are analyzed, and more quantitative analysis results with guiding significance are obtained. The spatial distribution of the time T and the pH is shown in fig. 8a and 8b, respectively. After sodium is injected into the tissue, the temperature increases sharply at the sodium water junction, and gradually decreases as the reaction distance increases. This is because the heat release is mainly concentrated at the sodium water junction, the reaction product OH - The decomposition reaction on protein molecules also releases a part of heat. FIG. 9 is a graph showing the effect of tissue protein content on pH profile. As can be seen from the figure, OH as the protein concentration increases - So that the diffusion in the tissue is reduced and the pH distribution is changedSteeper, the range of the alkaline zone is also progressively smaller, all due to OH - And protein.
Because the influence of the water content on the temperature field and the concentration field is obvious, the ablation dosage is controlled by adjusting the water content of the target tissue, which is a very convenient regulation and control means. When alkali metal ablation is used for tissues with higher water content, the dose needs to be appropriately reduced. As in fig. 10a and 10b, tissue moisture content versus temperature and C, respectively OH- Is a function of (a) and (b).
For the discrimination and efficacy evaluation of the thermal coagulation zone after thermal ablation, ultrasound images are used for evaluating the hyperthermia (fig. 11a and 11 b), and texture characteristic parameters with larger variation are selected as efficacy evaluation means. The ultrasonic influence method provides an effective measure for the curative effect evaluation and real-time monitoring of the alkali metal thermal ablation method.
By collecting B ultrasonic images of pork tissues and B ultrasonic images of normal tissues after alkali metal ablation, 19 parameters such as a gray level histogram, a gray level symbiotic matrix and the like are analyzed in total by utilizing an analysis method of image texture characteristics, and 20 experimental results are counted, wherein the parameters with larger change rate after ablation are as follows: and 4 parameters such as gray average value, gray standard deviation, contrast of 0 degree and 45 degrees in a gray co-occurrence matrix in the gray histogram. Wherein, the increase of the gray average value shows that the heating leads the amplitude of the ultrasonic echo to be increased, the ultrasonic is difficult to penetrate, and the characteristic is well verified from the hardening of the tissue after the tissue is heated; the larger gray standard deviation shows that the larger non-uniformity of the ablated coagulation area, which indicates that the layering phenomenon of the ablated area is obvious. The increased contrast in the gray level co-occurrence matrix also illustrates that the tissue non-uniformity after ablation is increased.
The texture features of the ultrasonic image can indirectly reflect the thermal ablation effect of alkali metal and can be used as the basis for distinguishing the thermal solidification zone. Statistics indicate that the gray scale value of the ultrasound image increases by 50% and above and the gray standard deviation increases by 110% and above after thermal coagulation of the tissue. The contrast ratio of 0 degree and 45 degree in the gray level co-occurrence matrix is increased by about 80 percent, and the contrast ratio of 90 degree is increased by about 50 percent; the variation of the energy values in the gray co-occurrence matrix is also large. Studies suggest that, in order to make the determination of the thermal ablation region more accurate, the joint determination may be performed by comprehensively utilizing the change of the relevant parameters, for example, when the gray value is increased by 50% or more, the gray standard deviation is increased by 100% or more, and the contrast in the gray co-occurrence matrix is increased by 30% or more, the tissue at this time may be determined to be a coagulated tissue.
Based on prior theoretical analysis and experimental studies, a specific application of the above-described thermochemical ablation device of the invention, for example, a thermochemical ablation system, is shown in fig. 18a, 18b, 18c, 18d, 18e and 18 f. The system completes related type inspection in a certain medical instrument inspection center and meets the specifications of GB9706.1-2007 and GB 9706.27-2005 standards; the flow rate accuracy can be controlled to below 2%, the performance exceeds that of the common injection control products on the market. The experimental use condition also proves that the system has outstanding performances in speed control, dosage control, safety control and the like.
Before the living animal test, an in-vitro animal test is carried out, and an ablation test is carried out on the in-vitro muscle tissue, liver, kidney and lung tissue (shown in fig. 12a, 12b, 12c and 12 d) of the pig, so that the technical parameters required by the animal test are initially explored. Fig. 13 shows that the injection speed of the injector 1 is 120 mu L/min, the injection quantity is 60 mu L of the ablated sample, local cokes and ablated liquefied tissues are obviously visible at the edge, and the injection condition is proved to be safe and controllable for the in-vitro muscle tissues.
In the experiments of alkali metal thermochemical ablation treatment of tumors in mice, the temperature-time curve (fig. 14) recorded by a temperature sensor according to the injection process of the NaK alloy in the central area of the tumor tissue shows that the basal body temperature of the mice is about 37 ℃, and the internal temperature of the tumor tissue can be rapidly increased to about 100 ℃ after the reaction starts. The temperature then drops rapidly and remains above 50 ℃ for about 20s.
From the surface temperature distribution map of mice in the treatment process, the temperature of the injection part can be rapidly increased within 2-3 seconds at the initial reaction stage after NaK alloy injection, and then the high temperature range is gradually reduced. Throughout the process, the high temperature region is concentrated at the tumor tissue. The skin temperature profile of the mice during the treatment is shown in fig. 15.
Furthermore, CT scanning is carried out on the tumor of the mouse at the same time, and the change of the tumor volume is intuitively observed. As shown in fig. 16a, 16b, 16c, 16d and 16e, fig. 16a, 16b, 16c, 16d and 16e are scanning images of an early tumor experimental group 30min before operation, 30min after operation, 5 days after operation, 10 days, 15 days, fig. 16f is a scanning image of a control group 15 days after operation, the pre-operation tumor height is 8mm, the post-operation height is reduced by 5mm, and there is no substantial change in the following 15 days. And tumors grew to 20mm high after 15 days in the control group.
By observing the tumor tissue changes of experimental mice before and after the thermochemical ablation treatment, the NaK alloy thermochemical ablation treatment is verified to have a killing effect on tumor cell tissues, and only about 15 mu L of pure NaK alloy is needed to completely ablate an early tumor tissue, and no systemic toxic reaction is found. The thermo-chemical ablation system realizes the accurate injection of mu L level, and provides reliable technical support for pushing the alkali metal thermo-chemical ablation technology to clinic. The thermochemical ablation treatment can become a new thermal treatment means, overcomes the defect that the heat cannot be directly transmitted to the tumor tissue in the existing thermal treatment means, and achieves the aim of killing tumor cells by directly playing a role in the tumor tissue through the accurate and reliable split type alkali metal injection device.
The thermochemical ablation system provided by the embodiment of the invention is used for carrying out an ablation experiment on subcutaneous tumors of mice, the experimental mice are divided into three groups, namely an early tumor group, a middle and late tumor group and a control group, and the effect of alkali metal thermochemical ablation on the early tumor group mice and the middle and late tumor group mice is observed and compared with the control group experimental mice, so that the alkali metal thermochemical ablation has obvious killing effect on the tumor tissues of the mice. The alkaline environment generated after ablation has a destructive effect on the growth of tumor cells, and the alkaline environment generated after thermochemical ablation is also shown to have the effect of tumor inhibition (shown in figure 17).
It was found by observation of the alkali thermochemical ablation process that huge energy can be generated in a short time after the alkali metal enters the tumor tissue. Because the tissue structure of the tumor tissue is not sound, the heat dissipation is slower than that of the normal tissue, so that the tumor tissue can maintain high temperature for a longer time, the effect of killing tumor cells can be better achieved, and the influence on the normal cells is smaller.
In conclusion, both theoretical analysis and animal experiments show that the alkali metal thermochemical ablation has unique advantages in tumor treatment, can realize accurate quantitative transportation which is difficult to realize by other thermotherapy methods, and can also play a role in tumor inhibition in the alkaline environment generated in the treatment process.
While the invention has been described with reference to a preferred embodiment, various modifications may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In particular, the technical features mentioned in the respective embodiments may be combined in any manner as long as there is no structural conflict. The present invention is not limited to the specific embodiments disclosed herein, but encompasses all technical solutions falling within the scope of the claims.
Claims (12)
1. A thermochemical ablation device, characterized by comprising an injector (1), an ablation needle (3) and a driver (2) which are respectively connected with the injector (1), wherein the interior of the injector (1) is filled with a therapeutic substance, and the therapeutic substance in the injector (1) is conveyed to a target position through the ablation needle (3) under the action of the driver (2);
wherein the therapeutic substance is an alkali metal or alkali metal alloy that reacts exothermically when delivered to the target site.
2. A thermochemical ablation device according to claim 1, wherein the alkali metal is sodium or potassium and the alkali metal alloy is a sodium-potassium alloy.
3. A thermochemical ablation device according to claim 1 or 2, characterized in that the inside of the syringe (1) is also filled with a reaction aid, which is water.
4. A thermochemical ablation device according to claim 1 or 2, characterized in that the dose of alkali metal alloy in the syringe (1) is related to the size and/or moisture content of the tumor at the target site.
5. Thermochemical ablation device according to claim 1 or 2, characterized in that the injection speed of the injector (1) is related to the treatment temperature and the injection quantity is related to the size of the tumor at the target site.
6. A thermochemical ablation device according to claim 3, wherein the driver (2) comprises:
a drive plate (21), the drive plate (21) being connected to the plunger (11) of the syringe (1) for expelling the therapeutic substance and the reaction aid;
a limiting plate (22), wherein the limiting plate (22) is arranged at one end of the injector (1) close to the ablation needle (3) and is used for limiting the front end position of the injector (1); and
-a guiding structure (23), said guiding structure (23) being connected to said driving plate (21) to limit the movement path of said driving plate (21).
7. The thermochemical ablation device according to claim 6, wherein the number of syringes (1), drive plates (21), stop plates (22) and guide structures (23) is 1 or more.
8. A thermochemical ablation device according to claim 1 or 2, characterized in that the ablation needle (3) comprises a flow inlet tube (31) and a return tube (32) fitted outside the flow inlet tube (31), the flow inlet tube (31) being in communication with the interior of the injector (1), the return tube (32) being connected to a recovery vessel (4).
9. A thermochemical ablation device according to claim 8, characterized in that the number of inflow pipes (31) is 1 or more; the inflow pipes (31) are sleeved in sequence from inside to outside, and the inflow pipes (31) are respectively connected with the injector.
10. The thermochemical ablation device according to claim 1 or 2, further comprising a control monitoring unit (5) and a signal sensor (7), the driver (2) being connected to the control monitoring unit (5) by a signal line (6), the control monitoring unit (5) controlling the driver (2) to act on the injector (1); the signal sensor (7) is connected with the control monitoring unit (5) through a signal line (6), and the signal sensor (7) is used for monitoring physiological parameters at a target position.
11. Use of a pharmaceutical composition for the preparation of a medicament for the treatment of diseased tissue, characterized in that the pharmaceutical composition comprises an alkali metal or an alkali metal alloy.
12. Use of a pharmaceutical composition for the manufacture of a medical device for treating diseased tissue, characterized in that the medical device is a syringe filled with the pharmaceutical composition, the pharmaceutical composition comprising an alkali metal or an alkali metal alloy.
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