RU2733467C1 - Method for personalized contact hyperthermia based on induction heating of a non-magnetic implant in an alternating magnetic field - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medical equipment, namely to a method for personalized intraoperative contact local hyperthermia for treating locally advanced malignant tumors. Method involves heating a bed of a removed or resected tumor by an intraoperatively manufactured and an individual implant, repeating the shape of the tumor bed, for personalized intraoperative contact local hyperthermia for treating locally spread malignant tumors. Implant comprises a cavity filled with a heat-releasing agent. Heat-releasing agent is a nonmagnetic liquid metal alloy.

EFFECT: technical result consists in increase of specific power of heat release in implant and, as a result, considerable reduction of intensity of alternating magnetic field.

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Description

FIELD OF TECHNOLOGY

The invention relates to medicine, namely to oncology, in particular to providing personalized local hyperthermia in the treatment of locally advanced malignant tumors.

LEVEL OF TECHNOLOGY

Currently, local hyperthermia is considered as one of the promising ways to increase the effectiveness of radiation and combined therapy of cancer patients, as well as an independent method in the treatment of common malignant neoplasms that are not subject to other special methods of treatment [N.R. Datta, et al. Local hyperthermia combined with radiotherapy and- / or chemotherapy: Recent advances and promises for the future. Cancer Treatment Reviews, 2015, V. 41, Issue 9, P. 742-753].

The widest practical application in radiation therapy is found by the method of local ultrahigh-frequency (microwave) hyperthermia. In the clinic, microwave heating of tumors is mainly used at frequencies of 2450 MHz, 915 MHz and 433 MHz.

From the source [Devyatkov ND, Gelvich EA, Mazokhin V.N. A set of equipment for electromagnetic hyperthermia of malignant neoplasms // Med. radiology. - 1987, N 1. - P.73-76] a device for hyperthermia is known, comprising a microwave energy generator and an antenna connected to this generator, which radiates electromagnetic waves to a given area of the patient's body.

The main disadvantages of microwave heating devices are low penetrating power and the possibility of overheating of tissues with high electrical resistance (larynx cartilage, tendons, fascia, bones). As a result, it is impossible to accurately localize heat in tumors of internal organs.

From patent RU 2372116 C2, publ. 11/10/2009, the known method of local ultra-high-frequency (UHF) hyperthermia (capacitive method).

The main disadvantage of this method of hyperthermia is overheating of the subcutaneous fatty tissue, which makes it difficult to selectively heat tumors of internal organs and tissues to hyperthermic temperatures [Shtemler VM, Kolesnikov S.V. Features of the interaction of electromagnetic fields with biological objects. // In the book: "Human and Animal Physiology". - M .: Medicine, 1978, 22, p. 9-67].

From the source [JordanA., Et al. Inductive heating of ferromagnetic particles and magnetic fluids: physical evaluation of their potential for hyperthermia. // International Journal of Hyperthermia, 1993, v. 9, p. 51-68] the known method of hyperthermia, implemented by induction heating introduced into the tumor magnetic fluids based on ferromagnetic nanoparticles.

The disadvantages of this method are the uneven distribution of magnetic nanoparticles in the tumor and problems with the removal of magnetic nanoparticles and tumor decay products from the body.

One of the promising ways to improve accuracy for localizing the effect on tumor cells is the use of intraoperatively manufactured individual implants based on biocompatible polymers, see the patent of the author of the present invention RU 2322199 C1, publ. 20.04.2008.

The use of such implants, modified by the addition of ferromagnetic particles, allows precise localized selective induction heating of biological tissues in an alternating magnetic field, see the patent of the author of the present invention RU 2497489 C1, publ. 11/10/2013.

From patent RU 2565810 C1, publ. 20.10.2015, as well as applications US 20110223255 Al, publ. September 15, 2011 and applications US 2019099618 A1, publ. 04/04/2019, it is known that hyperthermia using induction heating of magnetic materials can be easily combined with other types of anticancer therapy, such as radio and / or chemotherapy.

The induction heating methods described in the inventions disclosed in RU 2565810 C1, US 20110223255 Al and US 2019099618 A1 are the closest analogs to the claimed method of treatment according to the present invention. These methods are based on heating a composite tissue-replacing implant containing magnetic (ferromagnetic, ferrimagnetic, or superparamagnetic) particles by absorbing the energy of an alternating magnetic field in the sub-MHz range. The electromagnetic field of the selected frequency range is poorly absorbed by biological tissues, therefore, their unwanted heating is negligible. Only the implant and the tissues directly adjacent to it are exposed to heating, which ensures a high degree of hyperthermia localization.

As magnetic fillers in the closest analogues, magnetic micro- or nano-particles are used, which are introduced into porous or gel-like biocompatible implants, see US 20110223255 Al, or magnetic fluids filling elastic hollow implants, or small ferromagnetic objects (balls, threads, cylinders, needles ) introduced directly into the tumor, see US 2019099618 A1, or incorporated into biocompatible polymer implants, see RU 2497489 C1, RU 2565810 C1, US 2019099618 A1.

The disadvantage of implants based on magnetic micro- and nanoparticles, including in the form of magnetic fluids, is the relatively low specific thermal power generated in an alternating magnetic field of the sub-MHz range, and, as a consequence, the need to use high amplitudes of alternating magnetic fields (more than 5 kA / m), which can present both technological and physiological problems.

When using small ferromagnetic particles in the form of balls or needles, the disadvantage is the possibility of overheating of tissues or a polymer implant in the area of contact with a ferromagnet due to the low thermal conductivity of biocompatible materials and, as a consequence, thermal destruction of tissues or polymer matrix.

SUMMARY OF THE INVENTION

The technical problem solved by the proposed method of heating an individual implant consists in improving the known method by reducing the uneven heating of the implant and excluding its thermal destruction at the point of contact of the polymer matrix with the ferromagnetic filler.

The technical result achieved by the implementation of the developed implant and the method consists in increasing the specific power of heat release in the implant and, as a consequence, a significant decrease in the intensity of the alternating magnetic field.

In the present invention, it is proposed to use a non-magnetic liquid fusible metal alloy based on indium and gallium in intraoperatively manufactured implants as a heat-generating agent. The property of macroscopic volumes (1 ml and more) of such non-magnetic alloys to undergo intense induction heating in alternating fields with a frequency of 50-300 kHz, which has not been described anywhere else. Such heating, which is comparable to the heating of ferromagnetic samples, becomes possible due to the significantly larger, in comparison with ferromagnets, thickness of the skin layer of the nonmagnetic conducting material.

The technical result of the claimed invention is achieved through the use in the method of personalized intraoperative contact local hyperthermia for the treatment of locally advanced malignant tumors of the implant, which contains a cavity filled with a heat-generating agent, while the heat-generating agent is a non-magnetic liquid fusible metal alloy.

Moreover, in one of the embodiments of the invention, the non-magnetic liquid low-melting metal alloy is made on the basis of indium and gallium.

In another embodiment, the non-magnetic liquid fusible metal alloy further comprises a component selected from the group of tin, zinc, or a combination thereof.

In an alternative embodiment of the invention, the non-magnetic liquid fusible metal alloy further comprises short-lived radioactive isotopes for conducting contact radiotherapy (brachytherapy).

In this case, in another embodiment, the surface of the implant contains chemotherapy drugs (antitumor, bactericidal, hemostatic) in the form of a film based on a self-decomposing biocompatible polymer.

The implant in one of the embodiments of the invention is made using a 3D printer.

Moreover, in one of the embodiments of the invention, the implant is a plastic silicone container that repeats the shape of the tumor bed when filled with a non-magnetic liquid low-melting metal alloy.

The implant in one of the embodiments of the invention contains a group of chambers, while it is configured to fill a specified number of chambers from the general group with a non-magnetic liquid low-melting metal alloy.

The above and other objects, features, advantages, as well as the technical significance of the present invention will be better understood from the following detailed description of the invention and the figures presented.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the results of heating two model implants in a medical gel that simulates biological tissues.

Figure 2 shows the manufacture of a hollow implant: (a) simulation based on computed tomography; (b) creating a 3D image; (c) 3D printed implant.

CARRYING OUT THE INVENTION

Figure 1 shows the results of heating two model implants in a medical gel that simulates biological tissues. One of the implants, a composite one, is a polymer base with embedded steel balls, the other is a thin-walled sphere filled with a non-magnetic liquid fusible metal alloy based on gallium, indium and tin. Surface temperature of a spherical implant with a diameter of 2 cm, placed in an ultrasound gel, when heated in an alternating magnetic field with a frequency of 90 kHz with an amplitude of 3.6 kA / m. Position 1 on the graph represents a composite implant with a mass fraction of steel balls 1 mm in diameter 50%, and position 2 - a hollow polymer implant filled with galinstan (68.5% - Ga: 21.5% -In: 10.0% - Sn) ...

It should be noted that composite implants are heated more efficiently than implants based on magnetic fluids [Stauffer P.R., Vasilchenko I.L., Osintsev A.M., Rodrigues D.B., Bar-Ad V., Hurwitz M.D., Kolomiets S.A. Tumor bed brachytherapy for locally advanced laryngeal cancer: a feasibility assessment of combination with ferromagnetic hyperthermia. Biomedical Physics and Engineering Express, 2016, vol. 2, no. five].

As can be seen from figure 1, implants based on non-magnetic liquid low-melting metal alloys allow them to be used not only for conducting classical hyperthermia, i.e. heating tissues to a temperature of 40-45 ° C, but also for a more radical method of thermal ablation [Chu, K.F., Dupuy, D.E. Thermal ablation of tumors: biological mechanisms and advances in therapy (2014) Nature Reviews Cancer, volume 14, pages 199-208] (heating of tissues to temperatures above 50 ºС) at moderate values of the alternating magnetic field intensity.

Due to the high thermal conductivity of the liquid metal alloy [VV Roshchupkin. et al. Study of the enthalpy and heat capacity of the gallium-indium-tin alloy. Scientific. tr. "Giredmet", "Research of rare metal alloys". 1976. T. 84. S. 4-5], [Yuriy Plevachuk, Vasyl Sklyarchuk, Sven Eckert, Gunter Gerbeth, Rada Novakovic. Thermophysical Properties of the Liquid Ga – In – Sn Eutectic Alloy. Journal of Chemical and Engineering Data, 2014, v. 59 (3), p. 757-763], its entire volume inside the implant has practically the same temperature, which ensures uniform heating of the tissues adjacent to the implant.

Examples of non-magnetic liquid low-melting metal alloys that are used to fill the implant are:

Alloy T _pl , ° C gallium 76%, indium 24% sixteen gallium 67%, indium 29%, zinc 4% thirteen gallium 82%, tin 12%, zinc 6% 17 gallium 67%, indium 20.5%, tin 12.5% 10.6

In addition, in the implementation of the present invention can be used and other non-magnetic liquid low-melting metal alloys based on indium and gallium with a low melting point.

In the treatment of locally advanced malignant tumors, the developed method of contact local hyperthermia can be used as follows.

On the basis of an intraoperatively made impression of the tumor bed, a 3D image of the implant is created using a 3D scanner, which repeats the shape of the removed tumor bed. The hollow, thin-walled implant is 3D printed from a biocompatible polymer. In the process of computer processing, the necessary channels and chambers are formed in the implant for filling with a non-magnetic liquid low-melting metal alloy, as well as for inserting temperature control sensors.

The implant filled with alloy is fixed in the bed of the removed tumor, the wound is sutured, after which local hyperthermia is performed at a temperature of 43-45 ° C for at least 60 minutes due to induction heating of the implant in an alternating magnetic field. The implant is removed after the end of the treatment and after a few days, after evaluating the effect of hyperthermia, additional special methods of treatment are prescribed: polychemotherapy, radiation therapy.

In one embodiment of the present invention, a 3D image of the implant is created on the basis of a 3D tumor model obtained as a result of its scanning by means of computed tomography or magnetic resonance, X-ray, positron emission and / or any other capable of generating a 3D image of the tumor (see. Figure 2).

In order to exclude unwanted heating of some areas adjacent to the tumor or the bed of the removed tumor, implants with a group of chambers (multi-chambered implants) are used, some of the chambers of which are not filled with a non-magnetic liquid fusible metal alloy.

In an alternative embodiment of the developed method, a plastic silicone container is used as a shell for the implant, which takes the shape of a tumor bed as a result of filling with a non-magnetic liquid low-melting point metal alloy under low pressure.

To carry out chemotherapy combined with hyperthermia, (antitumor, bactericidal, hemostatic) chemotherapy drugs are applied to the surface of the implant in the form of a film based on a self-decomposing biocompatible polymer.

To carry out joint radiotherapy with hyperthermia, short-lived radioactive isotopes of indium and gallium (or other short-lived radioactive isotopes soluble in liquid metal indium and / or gallium) are used.

The simultaneous combined use of chemotherapy and hyperthermia radiotherapy is possible.

In addition, the claimed method of personalized intraoperative contact local hyperthermia for the treatment of locally advanced malignant tumors, including heating the bed of a removed or resected tumor using an intraoperatively made and repeating the shape of the tumor bed of an individual implant can be used in other physiotherapeutic methods of treatment using tissue heating, for example, UHF therapy, paraffin or ozokeritotherapy, etc.

The essence of the method claimed in the present invention is illustrated by the following examples.

Example 1

Patient N., born in 1962 She was admitted to the OKOD on July 4, 2017 with complaints of a tumor in her mouth. From the anamnesis: at the beginning of January 2015 I noticed the presence of a tumor in my mouth, did not go to the doctors. Examined at the OKOD in Kemerovo after edge biopsy of the floor of the mouth tumor. The diagnosis was verified - cancer of the oral cavity T2N0M0 (pathological and histological conclusion No. 624/503 dated 06/28/17 keratinizing squamous cell carcinoma).

Upon admission, the condition was satisfactory, the constitution was asthenic, height 179 cm, weight 72 kg. The skin is clean, the osteoarticular apparatus is normal. Peripheral lymph nodes of all groups, incl. cervical, not palpable. No edema was detected, the borders of the heart were within normal limits. Pulse - 72 beats per minute, clear, rhythmic tones. The rib cage is of the correct shape, symmetrically involved in breathing. Vesicular breathing, no wheezing. The abdomen is soft, painless in all parts. The liver is along the edge of the costal arch, the spleen is not enlarged, the kidneys are not palpable. Karnovsky index - 90.

Local status: on the mucous membrane of the floor of the mouth along the midline there is an exophytic tumor with an area of ulceration up to 3 cm in diameter.

Diagnosis: cancer of the floor of the mouth T2N0M0.

On 07.07.2017, the patient underwent surgery in the amount of resection of the oral mucosa. The position of the patient on the operating table is on the back with a roller under the shoulders, with the head thrown back. Surgical intervention was performed under endotracheal anesthesia with intubation through the right nasal entrance. Intraoral access, departing from the visible borders of the tumor 1 cm, made an electroresection of the tumor of the mucous membrane of the floor of the oral cavity with the simultaneous production of an impression for the implant.

To make the impression, Speedexputty silicone impression mass was used, consisting of a base and an activator. After hardening, the implant was removed from the resected tumor bed and scanned using the Artec Space Spider 3D scanner. The image was processed using Artec Studio 10 software for Windows. VeroDentPlusTM photopolymer used in dentistry was used to print the implant.

A non-magnetic liquid fusible metal alloy Galinstan (Changsha Rich Nonferrous Metals Co., Ltd, China) based on gallium, indium and tin was used as a filler for the implant.

The individual implant was sutured with a thick thread, the end of which was fixed with adhesive tape in the corner of the mouth on both sides. Hemostasis of the surgical wound. Stitches on the wound.

Immediately thereafter, a session of local intraoperative contact hyperthermia was performed for one hour. The area of tissue adjacent to the implant was heated to a temperature of 43-44 ° C.

The implant was removed on 07/09/2017. On the tenth day after the removal of the implant, a course of postoperative radiation therapy was started on the Rokus-M apparatus, ROD - 2 Gy, 5 times a week, SOD - 44 Gy, for a course of 22 sessions.

The patient was discharged in satisfactory condition under the supervision of an oncologist every 3 months. At the last examination on October 24, 2019, no data on relapse and metastases were found. The observation continues.

Example 2

Patient Z., born in 1954 was hospitalized in OKOD on July 6, 2017 with complaints of a tumor in the mouth. From the anamnesis: at the beginning of March 2017, he drew attention to the presence of a tumor in the mouth, did not go to doctors. Examined in the OKOD in Kemerovo after edge biopsy of the floor of the mouth tumor. The diagnosis was verified - cancer of the oral cavity T3N0M0 (pathological and histological conclusion No. 644/512 dated 06/30/17 keratinizing squamous cell carcinoma).

Upon admission, the condition is satisfactory, the constitution is asthenic, height 165 cm, weight 58 kg. The skin is clean, the osteoarticular apparatus is normal. Peripheral lymph nodes of all groups, incl. cervical, not palpable. No edema was detected, the borders of the heart were within normal limits. Pulse - 80 beats per minute, clear, rhythmic tones. The rib cage is of the correct shape, symmetrically involved in breathing. Vesicular breathing, no wheezing. The abdomen is soft, painless in all parts. The liver is along the edge of the costal arch, the spleen is not enlarged, the kidneys are not palpable. Karnovsky index - 90.

Local status: on the mucous membrane of the floor of the mouth to the left of the midline, there is a mixed tumor up to 6 cm in diameter, passing to the alveolar ridge of the lower jaw on the left.

Diagnosis: cancer of the floor of the mouth T3N0M0.

On July 10, 2017, the patient underwent surgery in the volume of resection of the mucous membrane of the floor of the oral cavity with resection of the alveolar ridge of the lower jaw on the left. The position of the patient on the operating table is on the back with a roller under the shoulders, with the head thrown back. Surgical intervention was performed under endotrachial anesthesia with intubation through the right nasal entrance. Intraoral access, departing from the visible borders of the tumor 1 cm, made an electroresection of the tumor of the mucous membrane of the floor of the oral cavity with resection of the alveolar ridge of the lower jaw on the left while maintaining the integrity of the bone with the simultaneous production of an impression for the implant.

To make the impression, Speedexputty silicone impression mass was used, consisting of a base and an activator. After hardening, the implant was removed from the resected tumor bed and scanned using the Artec Space Spider 3D scanner. We used Artec Studio 10 software for Windows to process the image. To print the implant, we used VeroDentPlusTM photopolymer used in dentistry.

A non-magnetic liquid low-melting metal alloy Galinstan (Changsha Rich Nonferrous Metals Co., Ltd, China) based on gallium, indium and zinc was used as a filler for the implant.

The individual implant was sutured with a thick thread, the end of which was fixed with adhesive tape in the corner of the mouth on both sides. Hemostasis of the surgical wound. Stitches on the wound.

Immediately thereafter, a session of local intraoperative contact hyperthermia was performed for one hour. The area of tissue adjacent to the implant was heated to a temperature of 43-44 ° C.

The implant was removed on 12.07.2017. On the tenth day after the removal of the implant, a course of postoperative radiation therapy was started on the Rokus-M apparatus, ROD - 2 Gy, 5 times a week, SOD - 44 Gy, for a course of 22 sessions.

The patient was discharged in satisfactory condition under the supervision of an oncologist every 3 months. At the last examination on December 26, 2018, no data on relapse and metastases were found. The observation continues.

Example 3

Patient Ch., Born in 1959 was hospitalized in OKOD on July 17, 2017 with complaints of hoarseness for 3 months. From the anamnesis: she was treated at the place of residence for 6 months for chronic laryngitis, there was no effect of treatment. Sent to OKOD Kemerovo. During the examination, the diagnosis was made - cancer of the middle part of the larynx T2N0M0 (pathological-histological conclusion No. 657 / 521end. From 13.06.17 squamous cell non-keratinizing cancer).

On admission, the condition is satisfactory, the constitution is asthenic, height 160 cm, weight 51 kg. The skin is clean, the osteoarticular apparatus is normal. Peripheral lymph nodes of all groups, incl. cervical, not palpable. No edema was detected, the borders of the heart were within normal limits. Pulse - 79 beats per minute, clear, rhythmic tones. The rib cage is of the correct shape, symmetrically involved in breathing. Vesicular breathing, no wheezing. The abdomen is soft, painless in all parts. The liver is along the edge of the costal arch, the spleen is not enlarged, the kidneys are not palpable. Karnovsky index - 90.

Local status: with FLS, the left vocal cord is represented by a mixed tumor, passing to the left subglottic space, the larynx lumen is free, mobility on both sides is preserved.

Diagnosis: cancer of the middle part of the larynx T2N0M0.

On 20.07.2017, the patient underwent an operation in the amount of: tracheostomy; thyrotomy; resection of the middle section of the larynx. The position of the patient on the operating table is on the back with a roller under the shoulders, with the head thrown back. Surgical intervention was performed under endotracheal anesthesia. After the tracheostomy was applied, a thyrotomy was performed and an electrical resection of the middle part of the larynx on the left with the subglottic space was performed with the simultaneous production of an impression for the implant.

To make the impression, Speedexputty silicone impression mass was used, consisting of a base and an activator. After hardening, the implant was removed from the resected tumor bed and scanned using the Artec Space Spider 3D scanner. We used Artec Studio 10 software for Windows to process the image. To print the implant, we used VeroDentPlusTM photopolymer used in dentistry.

A non-magnetic liquid low-melting metal alloy Galinstan (Changsha Rich Nonferrous Metals Co., Ltd, China) based on gallium and indium was used as a filler for the implant.

The individual implant was sutured with a thick thread, the end of which was fixed with adhesive tape in the corner of the mouth on both sides. Hemostasis of the surgical wound. Stitches on the wound.

Immediately thereafter, a session of local intraoperative contact hyperthermia was performed for one hour. The area of tissue adjacent to the implant was heated to a temperature of 43-44 ° C.

The implant was removed on July 21, 2017. On the tenth day after the removal of the implant, a course of postoperative radiation therapy was started on the Rokus-M apparatus, ROD - 2 Gy, 5 times a week, SOD - 44 Gy, for a course of 22 sessions.

The patient was discharged in satisfactory condition under the supervision of an oncologist every 3 months. At the last examination on December 20, 2018, no data on relapse and metastases were found. The observation continues.

The absence of thermal destruction of the shell was monitored visually. For controlled 23 cases of implementation of the developed technical solution, no examples of thermal solutions were found. The uniformity of heating of the implant was controlled using an optical temperature sensor (Optocon Fotemp, Germany), the readings of which are independent of external electromagnetic fields. As a result of control of 23 cases of application of the developed method, the absence of uneven heating was found.

Claims (1)

A method of personalized intraoperative contact local hyperthermia for the treatment of locally advanced malignant tumors, including heating the bed of a removed or resected tumor by means of an intraoperatively made and repeating the shape of the tumor bed of an individual implant for personalized intraoperative contact local hyperthermia for the treatment of locally advanced malignant tumors containing a cavity filled with a cavity the heat-generating agent is a non-magnetic liquid metal alloy.

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