阅读说明：本技术 一种基于荧光三维影像的离子聚焦装置 (Ion focusing device based on fluorescence three-dimensional image ) 是由 孙宗丽 伦俊杰 孟凡瑞 于 2021-05-11 设计创作，主要内容包括：本发明涉及一种基于荧光三维影像的离子聚焦装置,离子聚焦装置与控制单元连接,离子聚焦装置设置在离子束的发射路径上并将通过深度调节板的扩散的离子束聚焦在靶区,离子聚焦装置包括离子聚焦组件,离子聚焦组件包括第一透镜和第二透镜,第一透镜和第二透镜分别通过电磁控制的机械架独立进行角度参数和位置参数的控制；第一透镜设置在深度调节板的离子束输出路径上,由深度调节板降低能量并扩散的离子束通过第一透镜的折射形成平行的离子束,控制单元控制第二透镜将平行的离子束聚焦在靶区的目标点。本发明调整离子束的路径并使得离子束聚焦,根据肿瘤位置的位移直接进行离子束的聚焦点的适应性调整,照射的精确度更高,对健康组织的损害更小。(The invention relates to an ion focusing device based on a fluorescent three-dimensional image, which is connected with a control unit, the ion focusing device is arranged on an emission path of an ion beam and focuses the diffused ion beam passing through a depth adjusting plate on a target area, the ion focusing device comprises an ion focusing assembly, the ion focusing assembly comprises a first lens and a second lens, and the first lens and the second lens independently control angle parameters and position parameters through an electromagnetic control mechanical frame respectively; the first lens is disposed on an ion beam output path of the depth adjustment plate, the ion beam whose energy is reduced by the depth adjustment plate and which is diffused forms a parallel ion beam by refraction of the first lens, and the control unit controls the second lens to focus the parallel ion beam on a target point of the target area. The invention adjusts the path of the ion beam and focuses the ion beam, and directly adjusts the focusing point of the ion beam according to the displacement of the tumor position, so that the irradiation precision is higher, and the damage to healthy tissues is less.)

1. An ion focusing device based on fluorescence three-dimensional images is characterized in that the ion focusing device is connected with a control unit,

the ion focusing means is provided on an emission path of the ion beam and focuses the diffused ion beam passing through the depth adjustment plate on a target region, wherein,

the ion focusing device at least comprises an ion focusing assembly, the ion focusing assembly comprises a first lens and a second lens, and the first lens and the second lens independently control angle parameters and position parameters through an electromagnetic control mechanical frame respectively;

the first lens is disposed on an ion beam output path of the depth adjustment plate so that the ion beam reduced in energy by the depth adjustment plate and diffused forms a parallel ion beam by refraction of the first lens,

the control unit controls the second lens to focus the parallel ion beam at a target point of the target area.

2. The ion focusing device based on fluorescence three-dimensional image of claim 1, further comprising a displacement detection device capable of determining the displacement of tumor tissue based on fluorescence spectrum emitted from the probe.

The displacement detection device determines a position to be irradiated based on at least fluorescence data of the fluorescent probe, and the displacement detection device determines a displacement of the position to be irradiated based on a change in the fluorescence data;

in response to the displacement information of the position to be irradiated sent by the displacement detection device, the control unit controls the depth adjustment plate and at least one ion focusing assembly capable of focusing the ion beam to adjust the path of the ion beam until the irradiation point of the ion beam is matched with the position to be irradiated.

3. The fluorescent three-dimensional image based ion focusing device according to claim 2 or 3, wherein the control unit adjusts position parameters and angle parameters of lenses in the depth adjustment plate and ion focusing assembly in real time based on the displacement of the tumor tissue monitored by the displacement detection device, so that the ion beam irradiates the target region at a designated energy and position.

4. The apparatus of any one of claims 1 to 3, wherein the ion focusing device is a three-dimensional fluorescence imaging device,

the depth adjustment unit includes at least a depth adjustment plate which is a right-angled pyramid and an inclined surface is disposed toward the first lens,

the control unit can control the irradiation depth variation of the ion beam by adjustment of the penetration thickness of the depth adjustment plate on the ion beam path.

5. The apparatus of any one of claims 1 to 4, wherein the ion focusing device is a three-dimensional fluorescence imaging device,

the physical parameters of the depth adjustment plate, the first lens and the second lens are stored in a database connected to the control unit,

the database stores a plurality of adjustment schemes and adjustment parameters of the ion beam path, so that the control unit can rapidly obtain the adjustment parameters according to the irradiated target area position.

6. The apparatus according to any one of claims 1 to 5, wherein when a relatively thin ion beam is required to irradiate the target region of the tumor tissue, especially the tumor tissue near healthy tissue, the control unit adjusts the positions and angles of the depth adjustment plate, the first lens and the second lens to make the focused ion beam be at the target region.

7. The apparatus according to any one of claims 1 to 6, wherein when the target region to be irradiated is not located in the edge region of the tumor tissue, the control unit is capable of adjusting the second lens to move out of the path of the ion beam, such that the parallel ion beam transmitted by the first lens irradiates the tumor cell in a state of non-focusing on the target region with a larger irradiation area.

8. The ion focusing device based on fluorescent three-dimensional image according to any one of claims 1 to 7, characterized in that the ion focusing device further comprises an ion emission source,

the ion emission source comprises at least one main emission end and a plurality of auxiliary emission ends, the tip angle of the main emission end is larger than that of the auxiliary emission ends, and the diameter of the ion beam emitted by the main emission end is larger than that of the ion beam emitted by the auxiliary emission ends.

9. The apparatus according to claim 8, wherein the control unit turns on the main emission end for emission of the ion beam when the irradiation position is large in response to the three-dimensional image of the tumor tissue transmitted from the image processing unit.

10. The apparatus of claim 8, wherein when the irradiation position is the tumor tissue edge, the control unit is capable of selectively turning off the main emission end and turning on a sub-emission end with a smaller ion beam diameter to irradiate the tumor tissue edge target with a smaller ion beam concentration.

Technical Field

The invention relates to the technical field of fluorescent probe scanning application, in particular to an ion focusing device based on a fluorescent three-dimensional image.

Background

An ion beam refers to a group of ions moving in nearly the same direction at approximately uniform velocity. The ion source is a device for obtaining an ion beam. Among the ion sources most used are plasma ion sources, i.e. ions are extracted from a cluster of plasma by an electric field. The main parameters of such ion sources are determined by the density of the plasma, the temperature and the quality of the extraction system.

The heavy ion beam has the advantages of being used as tumor radiotherapy rays due to unique physical and biological characteristics. The heavy ion treatment achieves good curative effect clinically, and is likely to become an advanced tumor radiotherapy technology. The deep research of the basic biomedicine is expected to provide a theoretical basis for selecting the optimal beam quality for treating the tumor by the heavy ions.

However, the current ion beam needs to pass through the transparent plate for depth adjustment when being emitted, so that the ion beam emitted from the transparent plate is refracted, the ion beam is dispersed, the range of the ion beam emitted at the irradiation target area is wide, and the area of damaging healthy tissues is large.

For example, chinese patent CN101285887B discloses a device for calibrating and calibrating a dose monitoring detector in heavy ion beam cancer therapy, which is structurally characterized in that a collimator, a dose monitoring detector, a mini-ridge filter, a water tank and a standard ionization chamber are sequentially arranged on a beam axis, and the standard ionization chamber is arranged in the water tank. The depth position of a micro-spread Bragg peak (mini-SOBP) of the irradiation beam flow in water is obtained through the measurement of absorbed dose of a standard ionization chamber at different depths in an aqueous medium. And at the depth position, calibrating and calibrating the dose monitoring detector by using the standard ionization chamber to obtain a calibration and calibration factor of the dose monitoring detector for measuring the cancer beam current with the Gaussian distribution micro-broadening Bragg peak. However, the dose detection detector can only detect the depth of the ion beam and adjust the depth of the ion beam every time, but cannot adjust the depth of the ion beam in real time.

Currently, the tumor position is generally determined based on an image formed by a fluorescent probe, but there is no apparatus that directly uses the fluorescent probe for ion beam irradiation. The reason is that even if the fluorescent probe can distinguish the tumor site from the healthy tissue site, the diffused ion beam still irradiates the healthy tissue, and thus the use of the fluorescent probe cannot significantly improve the targeting accuracy of the ion beam irradiation apparatus.

For example, chinese patent CN 102288589B discloses a super-resolution fluorescence microscopy imaging system, which comprises: the device comprises an image collector and an image processor, wherein the image collector is used for collecting a plurality of fluorescence images, and the image processor is connected with the image collector and is used for obtaining super-resolution fluorescence images; the image processor comprises a positioning device for a single fluorescent probe; the searching device is used for searching the maximum value point of each fluorescence image, and the input end of the searching device is connected with the image collector and the output end of the searching device is connected with the positioning device; and the reconstruction device is connected with the positioning device and is used for reconstructing a super-resolution fluorescence image according to the position information of each fluorescence probe output by the positioning device. Although the fluorescence image can realize accurate positioning, the difference and the error exist between the plane image obtained by the fluorescence probe and the three-dimensional outline of the actual tumor tissue, so that a large amount of healthy tissue cells can be damaged even if the ion beam is irradiated according to the fluorescence plane image.

How to obtain a three-dimensional tumor cell image according to a fluorescent probe and perform real-time displacement feedback so that an ion beam can irradiate the tumor cell with ultrahigh precision is a technical problem which is not solved at present.

US2011/0105821a1 discloses ion beam control based on motion sensors, which are video systems that record the position and/or motion of a target volume. In the invention, the deflection device only realizes the angle deflection effect on the ion beam. The first deflection device and the second deflection device are actually positioned at two sides of the wedge-shaped structure, and the first lens and the second lens in the ion beam concentrating assembly are positioned at the output side of the wedge-shaped structure, namely the depth adjusting plate. The optical path structure formed by the invention is also obviously different from the optical path structure of the invention, and the technical effects which can be realized by the two are naturally obviously different.

Furthermore, on the one hand, due to the differences in understanding to the person skilled in the art; on the other hand, since the inventor has studied a lot of documents and patents when making the present invention, but the space is not limited to the details and contents listed in the above, however, the present invention is by no means free of the features of the prior art, but the present invention has been provided with all the features of the prior art, and the applicant reserves the right to increase the related prior art in the background.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides an ion beam control device based on fluorescent probe scanning, which at least comprises an accelerator provided with an ion beam deflection assembly and a control unit, wherein the control unit is used for controlling the ion beam deflection assembly to adjust the irradiation direction of an ion beam, a depth adjusting unit is arranged on the emission path of the ion beam, the depth adjusting unit at least comprises a depth adjusting plate and at least one ion focusing assembly capable of focusing the ion beam, and the ion focusing assembly focuses the diffused ion beam passing through the depth adjusting plate on a target area. Compared with the diffusion effect of the ion beam due to the depth adjustment in the prior art, the proper ion beam focusing can form an accurate point to irradiate and strike the tumor cells, so that the accidental injury to the healthy tissue is reduced when the tumor tissue is irradiated.

Preferably, the device also comprises a displacement detection device which can determine the displacement of the tumor tissue based on the fluorescence spectrum emitted by the probe. The displacement detection device is used for collecting fluorescence of the fluorescent probe, so that the boundary between the tumor tissue and the healthy tissue can be defined. When the ion beam irradiation is used, the control unit can adaptively change the path and the depth by adjusting a depth adjusting plate, a lens and the like on the path based on the displacement adaptability of the tumor tissue, so that the ion beam irradiation does not generate irradiation errors due to the respiration of a patient, and the irradiation efficiency of the ion beam is improved.

Preferably, the control unit establishes a communication connection with the displacement detection device, and the control unit adjusts the position parameters and the angle parameters of the depth adjustment plate and the lenses in the ion focusing assembly in real time based on the displacement of the tumor tissue monitored by the displacement detection device, so that the ion beam irradiates the target region at a designated energy and position.

The ion focusing assembly includes a first lens disposed on an ion beam output path of the depth adjustment plate so that the ion beam reduced in energy by the depth adjustment plate and diffused forms a parallel ion beam by refraction of the first lens, and a second lens controlled by the control unit to focus the parallel ion beam at a target point of the target region. The focused irradiation of the present invention enables more precise irradiation of the edges of the tumor tissue than the diffuse irradiation of the prior art.

Preferably, the apparatus further comprises an image processing unit for processing and forming an image containing position information of the tumor tissue based on the fluorescence data collected by the displacement detecting device, and an image display unit for displaying the image containing the position information of the tumor tissue. The image processing unit can quickly form the position information of the tumor tissue based on the fluorescence data, and the control unit is favorable for quickly adjusting the path of the ion beam.

Preferably, the displacement detection device comprises at least two spectral sensors with different collection angles, and the at least two spectral sensors are arranged in the vicinity of the position to be irradiated in a symmetrical or asymmetrical manner. If only one spectral sensor is used, the stacking of the fluorescence may cause errors in the light detection of other regions by the spectral sensor. The two different setting modes of the collection angle can repeatedly collect the fluorescence data of a certain area point under the condition that the error of the fluorescence data collected by the two spectral sensors on the area point is larger than a preset error threshold value, so that the collection error of fluorescence can be eliminated, the accurate tumor position emitting fluorescence can be obtained, and the tumor position and the displacement precision can be improved.

Preferably, the at least two spectral sensors are arranged in a symmetrical manner with respect to the acquisition angle in the vicinity of the position to be illuminated. The collection angles are symmetrically arranged, so that the tumor tissue can be collected at an angle in a complete range, and the fluorescence of a local area is avoided.

Preferably, the displacement detection means determines the position to be irradiated based on at least fluorescence data of the fluorescent probe, and the displacement detection means determines the displacement of the position to be irradiated based on a change in the fluorescence data; in response to the displacement information of the position to be irradiated sent by the displacement detection device, the control unit controls the depth adjustment plate and at least one ion focusing assembly capable of focusing the ion beam to adjust the path of the ion beam until the irradiation point of the ion beam is matched with the position to be irradiated.

Preferably, an image processing unit is connected with the control unit, and the image processing unit can determine a three-dimensional image of the area to be irradiated based on the fluorescence intensity of the fluorescent probe and the position of the point source.

Preferably, the control unit replaces the ion beam of the corresponding diameter based on the physical feature of the position to be irradiated in response to the three-dimensional image information of the region to be irradiated sent by the image processing unit.

The invention also provides an ion focusing device based on the fluorescent three-dimensional image, which is connected with the control unit, the ion focusing device is arranged on an emission path of the ion beam and focuses the diffused ion beam passing through the depth adjusting plate on a target area, wherein the ion focusing device at least comprises an ion focusing assembly, the ion focusing assembly comprises a first lens and a second lens, and the first lens and the second lens independently control the angle parameter and the position parameter through an electromagnetic control mechanical frame respectively; the first lens is disposed on an ion beam output path of the depth adjustment plate so that the ion beam reduced in energy by the depth adjustment plate and diffused forms a parallel ion beam by refraction of the first lens, and the control unit controls the second lens to focus the parallel ion beam at a target point of the target region.

Preferably, the ion focusing device further comprises a displacement detection device capable of determining the displacement of the tumor tissue based on the fluorescence spectrum emitted by the probe, the displacement detection device determines the position to be irradiated based on at least fluorescence data of the fluorescent probe, and the displacement detection device determines the displacement of the position to be irradiated based on the change of the fluorescence data; in response to the displacement information of the position to be irradiated sent by the displacement detection device, the control unit controls the depth adjustment plate and at least one ion focusing assembly capable of focusing the ion beam to adjust the path of the ion beam until the irradiation point of the ion beam is matched with the position to be irradiated.

Ion focusing device the control unit adjusts the position parameters and angle parameters of the depth adjustment plate, lenses in the ion focusing assembly in real time based on the displacement of the tumor tissue monitored by the displacement detection device so that the ion beam irradiates the target region at a specified energy and position.

Ion focusing device the depth adjustment unit includes at least a depth adjustment plate which is a right angle cone and an inclined surface is provided toward the first lens, the control unit can control the irradiation depth change of the ion beam by adjustment of the penetration thickness of the depth adjustment plate on the ion beam path.

Preferably, the physical parameters of the depth adjustment plate, the first lens and the second lens are stored in a database connected to the control unit, and the database stores several adjustment schemes and adjustment parameters of the ion beam path, so that the control unit can rapidly obtain the adjustment parameters according to the irradiated target position.

Preferably, when a relatively thin ion beam is required to irradiate a target region of tumor tissue, especially tumor tissue located adjacent to healthy tissue, the control unit makes the focused ion beam be located at the target region by adaptively adjusting the positions and angles of the depth adjustment plate, the first lens and the second lens.

Preferably, when the irradiated target region is not located in the edge region of the tumor tissue, the control unit can adjust the irradiation by moving the second lens out of the path of the ion beam, so that the parallel ion beam transmitted by the first lens irradiates the tumor cell in a state of non-focusing on the target region with a larger irradiation area.

Preferably, the ion focusing device further comprises an ion emission source, the ion emission source comprises at least one main emission end and a plurality of auxiliary emission ends, the tip angle of the main emission end is larger than that of the auxiliary emission ends, and the diameter of the ion beam emitted by the main emission end is larger than that of the ion beam emitted by the auxiliary emission ends.

Preferably, the control unit turns on the main emission end for emission of the ion beam when the irradiation position is large in response to the three-dimensional image of the tumor tissue sent by the image processing unit.

Preferably, when the irradiation position is the tumor tissue edge, the control unit can select to close the main emission end and open a secondary emission end with a smaller ion beam diameter, so as to irradiate the edge target area of the tumor tissue with the smaller ion beam concentration.

Drawings

FIG. 1 is a schematic diagram of an ion beam control apparatus of the present invention;

fig. 2 is a schematic diagram of the logical structure of the ion beam control apparatus of the present invention;

FIG. 3 is a schematic diagram of one embodiment of an ion beam control apparatus of the present invention;

FIG. 4 is a schematic diagram of another embodiment of an ion beam control apparatus of the present invention;

FIG. 5 is a schematic view of one embodiment of an ion emission source according to the present invention.

List of reference numerals

1: a patient; 2: tumor tissue; 3: a fluorescent probe; 4: a control unit; 5: an image processing unit; 6: an image display unit; 10: an accelerator; 11: an ion beam deflection assembly; 12: a depth adjustment plate; 13: a first lens; 14: a second lens; 15: a first spectral sensor; 16: a second spectral sensor; 20: an ion emission source; 21: a main transmitting end; 22: a first secondary transmitting end; 23: a second secondary transmitting end; 24: and a third secondary transmitting end.

Detailed Description

The following detailed description is made with reference to the accompanying drawings.

Aiming at the defects of the prior art, the invention provides an ion beam control device based on fluorescent probe scanning, which can determine the three-dimensional position of tumor tissue by scanning the fluorescence emitted by the fluorescent probe in the tumor tissue, carry out adaptive deflection aiming at a displaced patient, and adjust the depth and the diameter of an ion beam according to the fluorescence intensity and the position of the tumor to be irradiated, so that the ion beam can be irradiated with the corresponding diameter, the irradiation precision of the ion beam is improved, and the damage of healthy tissue is reduced.

In the invention, the control unit and the image processing unit can be one or more of a server, a processor and an application-specific integrated chip which have data processing capacity and can generate control instructions. The image display unit is a device having a screen capable of displaying an image.

The invention provides an ion beam control device based on fluorescent probe scanning, which at least comprises an ion emission source, an accelerator, a displacement detection device and a depth adjusting device. The ion emission source, the accelerator, the displacement detection device and the depth adjustment device are respectively in signal connection with the control unit in a wired or wireless mode.

The accelerator is primarily composed of a synchrotron or synchrocyclotron, in which ions of equal mass or equal energy can be progressively accelerated to a higher energy ion beam. The energy of the ion beam in the accelerator is adjustable so that the accelerator can irradiate tumor tissue staggered in depth.

The irradiation depth of the ion beam is adjusted by adjusting the energy of the ion beam, so that the tumor tissue can be scanned layer by layer.

Due to the complexity of the accelerator control function, the energy of the ion beam cannot be moved fast enough or with the necessary accuracy to the specified tumor tissue or patient position. The depth adjustment unit of the present invention changes the depth of the ion beam by performing adaptive depth adjustment on the ion beam, i.e., the depth adjustment unit adaptively changes the path length of the ion beam. The depth adjustment unit is capable of varying the energy of the ion beam such that a maximum dose loading region, a so-called bragg maximum of the ion beam, predetermined by the acceleration energy, occurs at different depths of the ion beam. The penetration depth is varied by a depth adjustment unit such that a bragg maximum is generated in the desired layer. The depth adjustment unit is provided on an electromagnetically controlled sliding mechanical frame so that the depth adjustment unit can be rapidly moved within milliseconds to accommodate displacement of the target area.

The displacement detection device comprises at least two spectral sensors, and can detect fluorescence spectra in the tumor tissue and determine the position coordinates of the tumor tissue. The spectral sensor is capable of collecting data of a fluorescence spectrum emitted by the fluorescent probe. For example, the near-infrared sensor can detect parameters such as light intensity, brightness, light position and the like of near-infrared light emitted by the fluorescent probe.

Preferably, the tumor tissue contains a fluorescent indicator substance. For example, the indicator substance is an ATP-sensitive liposome. The ATP sensitive liposome has the functions of active tumor targeting, ATP sensitive fluorescence emission, drug release switch and in-vivo long circulation, and realizes the combination of tumor diagnosis by near infrared fluorescence imaging and tumor irradiation on the same liposome.

The ATP sensitive fluorescent probe liposome is a nano vesicle formed by encapsulating an ATP sensitive nucleotide double strand carrying adriamycin into a lipid bilayer membrane coupled with tumor targeting polypeptide. The ATP sensitive nucleotide double strand is formed by self-assembling an ATP sensitive nucleotide single strand coupled with a fluorescent dye and an ATP sensitive nucleotide complementary single strand coupled with a fluorescence quencher according to the base complementary pairing principle. The lipid bilayer membrane coupled with the tumor targeting polypeptide consists of polyethylene glycol phosphatidyl ethanolamine coupled with the tumor targeting polypeptide, phospholipid and cholesterol, wherein the molar ratio of the polyethylene glycol phosphatidyl ethanolamine coupled with the tumor targeting polypeptide to the phospholipid to the cholesterol is (2-8) to (42-78) to (20-50). The average particle size of the drug-loaded ATP sensitive liposome with the near-infrared fluorescence imaging function is about 100nm, and the drug-loaded ATP sensitive liposome can reach tumor tissues through physical targeting, namely the enhanced penetration and retention effect (EPR effect) of tumor capillaries, and can reach the tumor tissues through active targeting due to the coupling of tumor targeting polypeptides with high specificity and high stability. By the double targeting effect, the tumor targeting efficiency is obviously improved, and the high specificity imaging of the tumor is realized.

The drug-loaded ATP sensitive liposome utilizes intracellular high-concentration ATP as a fluorescence switch, a probe signal is in a silent state in the blood circulation process after intravenous injection enters a human body, a drug is adsorbed on a nucleotide double strand and is not released, the nucleic acid double strand in a high-concentration ATP environment is released after entering tumor cells, a fluorescence signal is turned on, the fluorescence intensity is obviously improved, the signal-to-noise ratio between tumor/normal tissues and blood is greatly improved, meanwhile, a large amount of drug is rapidly released, and the accurate tracing effect of early/small-volume tumors is further realized.

The displacement detection device determines the displacement position of the tumor tissue according to the fluorescence spectrum released by the tumor tissue so as to determine the displacement of the tumor tissue. The position of the tumor tissue is determined through the fluorescence spectrum, the ion beam can be controlled to cut the tumor tissue only, and the damage of the ion beam to the healthy tissue is avoided.

Preferably, the accelerator is capable of keeping the energy of ions in the ion beam constant, but is incapable of keeping the number of ions per location point constant over time. In order to achieve equal ion beam dose uptake at each location in the tumor tissue, the present invention further includes an ionization acquisition assembly capable of monitoring ion beam current intensity in real time. The ionization acquisition component is arranged in the path of the ion beam and acquires the intensity value of the ion beam. The ionization collection assembly is capable of collecting a dwell time of the ion beam at a location point of the tumor tissue. After the irradiation amount reaches a specified dose, the control unit controls the ion beam to move to a next position point and irradiate. That is, the control unit cuts the scan volume of the tumor tissue into a grid, and sequentially performs resection of the tumor tissue in the grid region.

The more tumor tissue at a certain location, the higher the overall intensity of the near infrared fluorescence. The image processing unit can form a three-dimensional tumor tissue image according to the fluorescence emitted by the fluorescent probe in the tumor tissue. For example, the displacement detection device laterally collects two-dimensional position information of the tumor tissue, longitudinally collects longitudinal position information of the tumor tissue, and synthesizes the two-dimensional position information and the longitudinal position information into three-dimensional image information of each point of the tumor tissue.

As shown in fig. 1, a patient 1 lies on an irradiation table. The fluorescent probe 3 in the tumor tissue 2 emits fluorescence. The ion beam exit of the accelerator 10 is provided with an ion beam deflection unit 11, and the ion beam deflection unit 11 can adjust the emission direction of the ion beam based on the control of the control unit. The emitted ion beam reaches the target area after passing through the depth adjusting device.

In the prior art, the depth of the ion beam is adjusted by moving a shutter that deflects in two opposing wedge dimensions (e.g., X and Y), such as in two directions perpendicular to each other. When the depth (dose) of the ion beam needs to be adjusted to be low, the blocking depth of the baffle is increased to reduce the energy of the ion beam. When the depth (dose) of the ion beam needs to be adjusted to be high, the energy of the ion beam is increased by reducing the blocking depth of the baffle. However, the wedge-shaped baffle reduces the energy of the ion beam, and the wedge-shaped structure of the baffle also enables the ion beam penetrating through the baffle to have the functions of translation and diffusion, so that the ion beam irradiated on a patient is not focused but diffused at multiple points, and the possibility of damaging healthy tissues is increased.

In view of the drawbacks of the prior art, the depth adjustment apparatus of the present invention includes at least a depth adjustment plate 12 and an ion focusing assembly capable of focusing an ion beam. The ion focusing assembly comprises at least a first lens 13 and a second lens 14 arranged adjacently. The first lens 13 and the second lens 14 are preferably electric convex lenses that allow ions to pass therethrough. The invention is not limited to the selection of the convex lens, and the ion focusing assembly can also be arranged as an assembly formed by other ion lenses and capable of realizing the same function.

As shown in fig. 1 to 4, the depth adjustment plate 12 is a right-angled pyramid, and the inclined surface is disposed toward the first lens 13. The ion beam emitted from the ion beam deflection unit 11 partially loses energy when passing through the depth adjustment plate 12. Due to the refraction effect of the right-angled cone structure of the depth adjustment plate, the ion beam passing through the depth adjustment plate 12 has a tendency to diffuse. The diffused ion beam is absorbed into the first lens 13 to be restored to a parallel ion beam. The parallel ion beams pass through the second lens 14 and are focused together at their focal points to form an ion beam irradiation spot.

During the path of the ion beam passing through the depth adjusting device, the energy loss of the ion beam caused by the first lens and the second lens is fixed, and only the energy attenuation of the ion beam by the depth adjusting plate is adjustable. Therefore, the control unit can control the irradiation depth variation of the ion beam by the adjustment of the penetration thickness of the depth adjustment plate 12 on the ion beam path.

Compared with the prior art, the invention can enable the ion beam to finally irradiate the tumor tissue emitting the near-infrared fluorescence in a focusing mode, so that the tumor tissue is damaged with accurate precision, and the probability of damaging the healthy tissue is reduced.

Preferably, as shown in fig. 3 and 4, the first lens and the second lens are independently controlled for an angle parameter and a position parameter, respectively, by an electromagnetically controlled mechanical stand. When a target area of tumor tissue needs to be irradiated by a thinner ion beam, especially when the tumor tissue close to healthy tissue is irradiated, the control unit enables the converged ion beam to be in the target area by adaptively adjusting the positions and the angles of the depth adjusting plate, the first lens and the second lens, and the irradiation accuracy is improved. Preferably, the focal length parameters of the first lens and the second lens are known and stored in a database in advance, so that the control unit can adjust the position and the angle of the lenses based on the irradiation position and the depth calculated by the control unit or the image processing unit. The distance between the first lens and the second lens can be detected and acquired by a position sensor provided on the machine frame.

When the target area of the patient is displaced due to respiration, the control unit can irradiate the tumor tissue by adjusting the penetration thickness of the depth adjusting plate 12 to an adaptive depth, so that the phenomenon of insufficient ion beam depth or excessive ion beam depth is avoided.

Because the tumor tissue and the healthy tissue have clear edge boundaries due to the near-infrared fluorescence emitted in the tumor tissue, the irradiation of the tumor tissue with the edge boundaries needs higher irradiation precision, the healthy tissue is better protected, and the patient is promoted to recover as soon as possible.

Preferably, as shown in fig. 4, when the irradiated target region is not located in the peripheral region of the tumor tissue, the position of the irradiated target region is not deviated. At this time, the control unit can adjust by moving the second lens out of the path of the ion beam so that the parallel ion beam transmitted by the first lens irradiates the target region with a larger irradiation area. With this arrangement, the diameter of the parallel ion beam can be increased, and the tumor cell can be irradiated in a non-focused state, thereby shortening the irradiation time.

Preferably, the positions of the first lens 13 and the second lens 14 are each adjustable in real time by electromagnetically controllable moving mechanisms, so that the finally focused ion beam can be moved at different parts of the tumor tissue. The control unit calculates the displacement of the depth adjustment plate 12, the first lens 13, and the second lens 14 in real time based on the depth and the position of the next irradiation point within the target area, thereby moving the depth adjustment plate 12, the first lens 13, and the second lens 14 in real time to cause the ion beam to change the path direction and focus on the target irradiation point of the target area.

The ion focusing assembly of the present invention is not limited to use in controlling the path of an ion beam, but can be used for other purposes.

Preferably, the physical parameters of the depth adjustment plate 12, the first lens 13 and the second lens 14 are stored in a database connected to the control unit. Preferably, several adjustment schemes and adjustment parameters of the ion beam path are stored in the database, so that the control unit can rapidly obtain the adjustment parameters according to the irradiated target region position.

Compared with the condition that the ion beam is irradiated on the edge of the tumor dispersedly in the prior art, the method realizes irradiation striking with smaller diameter and higher precision by focusing the ion beam, can reduce the probability of irradiating the healthy tissue when treating the tumor tissue close to the healthy tissue, and protects more healthy tissues.

The ion emitting end in the prior art is set to be one, because the ion beam has a diffusion state after being subjected to depth adjustment, even if the diameter of the ion beam is adjusted, the improvement of the accuracy of irradiation on tumor tissues is not obvious. In conventional ion emission control, X-rays are used to form a two-dimensional tumor tissue image, and the irradiation position, particularly the tumor edge position, is also deviated, so that even if the ion beam diameter is adjusted, more healthy tissues are damaged.

Preferably, the ion emitting end in the ion emitting source of the present invention is not limited to one, but two ion beams, three ion beams or more may be emitted. As shown in fig. 5, the ion emission source 20 includes at least one main emission end 21 and a plurality of sub-emission ends. The tip angle of the main emitting end 21 is larger than that of the sub emitting end. The larger the tip angle of the emitting end, the greater the number of atoms that the tip can align with, and the larger the diameter of the emitted ion beam. Therefore, the diameter of the ion beam emitted from the main emission end 21 is larger than that of the ion beam emitted from the sub emission end. The tip angle here means an angle between the tip surface inclined surface and the longitudinal central axis in the longitudinal section of the tip along the axis.

For example, the sub transmitting ends include a first sub transmitting end 22, a second sub transmitting end 23, and a third sub transmitting end 24. The tip angles of the plurality of secondary emission ends can be the same or different.

When the control unit is based on the three-dimensional image of the tumor tissue formed by the image processing unit, the main emission end 21 is opened to emit the ion beam when the irradiation position is large. When the irradiation position is the tumor tissue edge, the control unit can selectively close the main emission end 21 and open one auxiliary emission end with smaller ion beam diameter, so that the edge target area of the tumor tissue is irradiated in a concentrated manner by the ion beam with smaller diameter, the ion beam with smaller diameter is favorable for accurately controlling the irradiation target area position, and the ray damage to the healthy tissue is further reduced.

The control unit can select the ion beam emission end based on the size of the target area, and even open the main emission end 21 and all the auxiliary emission ends to irradiate the tumor tissue in a large area when the area of the target area is large enough. Compared with the arrangement of a single ion emitting end in the prior art, the ion emitting ends can form ion beams with different diameters, and physical characteristics of irradiation positions are selected, so that the irradiation precision of ion beam rays is improved.

Under the condition that the fluorescent probe can clearly display the outline image of the tumor tissue, the ion emission ends are arranged into a plurality of ion emission ends, and the ion beams with different diameters can be used for respectively irradiating the physical characteristics of the tumor tissue. Therefore, only on the basis that the tumor tissue and the healthy tissue have clear boundaries, the arrangement of the plurality of emission ends can further provide differential irradiation for the ion beam irradiation, and the irradiation requirements of the tumor tissue with different physical differences are met, so that the irradiation and damage to the healthy tissue are reduced as much as possible.

Especially for the edge part of the tumor cells with irregular shapes, the ion beam with smaller diameter can obviously irradiate the tumor cells orderly according to the outline of the tumor tissue more flexibly. The finer diameter ion beam damages less healthy tissue when the ion beam is irradiated.

The displacement detection device of the invention is used for detecting the time and position change of the tumor tissue in the irradiation range. The displacement detection means comprise at least a first spectral sensor 15 and a second spectral sensor 16.

The first spectral sensor 15 and the second spectral sensor 16 are able to perform coordinate marking of the tumor tissue location on the body based on the fluorescence spectrum of the tumor tissue and send to the image processing unit. The first spectral sensor 15 and the second spectral sensor 16 may be, for example, a camera device capable of acquiring a fluorescence spectrum. When the body is displaced due to any cause such as respiration, the coordinates of the tumor tissue and the associated time are changed, thereby determining the amount of change in the position of the tumor tissue.

Preferably, the first spectral sensor 15 and the second spectral sensor 16 acquire the coordinate position of the tumor tissue at different spatial angles.

When the body moves and the coordinates of the tumor tissue change, the image processing unit 5 can quickly determine the new location of the tumor tissue. The image display unit 6 can display an image of the irradiation position and the coordinates of the irradiation position. Preferably, the coordinates of the present invention are three-dimensional coordinates containing the longitudinal depth of the tumor.

Compared with the prior art that the position of the tumor tissue is determined through the periodic breathing frequency and the breathing volume of the patient with individual difference, the ion beam can accurately determine the position of the tumor tissue without paying attention to the breathing information of the patient and adaptively adjust the irradiation position, the position determination of the tumor tissue has no individual difference, and the irradiation accuracy is higher.

Preferably, the control unit 4 performs focused ion beam irradiation based on the primary position of the tumor tissue analyzed by the image processing unit 5, thereby reducing the probability that the tumor cells at the primary position continue to diffuse and metastasize after irradiation.

Preferably, the control unit instructs the first and second spectrum sensors 15 and 16 to acquire fluorescence spectra of the tumor tissue and form an image of the tumor tissue, and preferably, the control unit controls the ion beam irradiation to be alternated with the tumor tissue image acquisition, so as to acquire changes of the tumor tissue after each ion beam irradiation.

Preferably, the image processing unit analyzes the image of the tumor tissue using the primary position prediction model, thereby obtaining a prediction of the primary position of the tumor and displaying the prediction on the image display unit that performs the ion beam irradiation.

For example, it is common in the art to take a DNA slice by puncturing and trace the primary location of the tumor by methylation data within the tumor. Methylation data is one of the gene expressions in a cell and can be measured. As the tumor spreads, the methylation data in the tumor at different periods are different, so that the prior art can determine the primary position by tracing the methylation data in the tumor cell genes. However, this method is long in cycle and complicated in operation.

The primary position prediction model is obtained by performing a deep learning algorithm on a plurality of tumor image samples and primary position information.

The deep learning algorithm may be, for example, a convolutional neural network, a LASSO, or other deep learning algorithm.

Methylation information for each tumor location for which the primary location is known is correlated with physical characteristics of the tumor tissue. For example, a one-to-one association is set. In patients, there is differentiation in the physical characteristics of the spreading tumor tissue. The physical characteristics of the tumor tissue are shown by the image of the tumor tissue.

Preferably, the physical characteristics of the tumor tissue comprise at least information of size, thickness, depth, position on the body, predicted growth time, etc. of the tumor tissue.

And segmenting the tumor tissue image sample to form a plurality of tumor tissue film fragments, and correspondingly associating the coded tumor tissue fragments with corresponding methylation data.

In the invention, a plurality of tumor tissue film fragments are not cut randomly, but are cut completely according to the positions of the tumor tissues. For example, if tumor tissue in the lung grows at two locations, the image of the lung is cut to contain tumor tissue cells at different locations.

Preferably, the image patches of the same tumor tissue comprise tumor patches at multiple angles.

Inputting the known tumor primary position information, tumor metastasis paths and methylation data into a deep learning algorithm for long-term training to obtain the correlation between the physical characteristics of tumor tissues and the tumor metastasis paths.

And inputting another batch of tumor tissue image samples into the image processing unit for testing to obtain the predicted tumor metastasis path and/or primary position.

The prior art method for judging the primary position of a tumor through puncture, section and gene detection has the defects that the operation and the detection must be carried out by a qualified third party, the result period is long, and a patient can be rapidly deteriorated during waiting. The image processing unit method of the invention can allow a hospital to analyze the primary position by the image of the tumor tissue, requires short time and can perform important irradiation aiming at the primary position.

On the basis of injecting ATP sensitive fluorescent probe liposome into a patient body, the displacement detection device in the ion beam irradiation device can generate an image of a tumor tissue by collecting a fluorescence spectrum emitted by the tumor tissue, and can perform important irradiation aiming at a primary position in time, so that the technical effect of ion beam irradiation is better.

The invention discloses an ion beam control method based on fluorescent probe scanning, which at least comprises the following steps:

s1: after the ATP sensitive fluorescent probe liposome is injected into a patient, the fluorescence spectrum information of tumor tissues is collected through a displacement detection device;

s2: determining the position information of the tumor tissue based on the fluorescence spectrum information and generating slice image information;

s3: cutting the slice image information of the tumor tissue to form a plurality of tumor tissue fragments;

s4: analyzing the primary position prediction model based on the tumor tissue fragments to determine at least one primary position and/or tumor metastasis path;

s5: the control unit controls an emission port of the accelerator to irradiate the primary position of the tumor tissue based on the primary position and/or the tumor metastasis path information;

s6: the image processing unit periodically generates tumor tissue images based on the tumor position information acquired by the displacement acquisition device, and compares the changes of the fluorescence spectra of the tumor tissues of the two adjacent images.

S7: the ion focusing assembly focuses the diffused ion beam through the depth adjustment plate at the target region.

S8: the displacement of the tumor tissue is determined based on the fluorescence spectrum emitted by the probe in the tumor tissue, and the position parameters and the angle parameters of the lenses in the depth adjusting plate and the ion focusing assembly are adjusted in real time based on the displacement of the tumor tissue monitored by the displacement detection device, so that the ion beam irradiates a target area with specified energy and position.

Preferably, after the displacement detection device collects the fluorescence spectrum data, the displacement detection device screens the light intensity and position information of the near-infrared fluorescence spectrum data to remove parasitic light data which are not within the light intensity threshold range, so that the precision of the fluorescence data is improved, and an accurate result of the primary tumor position is obtained.

Preferably, the image processing unit forms a three-dimensional contour image of the tumor tissue based on the intensity difference and the position difference of the fluorescence spectrum.

Because the depth of the tumor in a body is different, and the light intensity of the near-infrared fluorescence emitted by the ATP sensitive fluorescent probe liposome is different, which is collected by the displacement detection device, the deep contour of the tumor tissue can be estimated according to the light intensity of the fluorescence, so that the three-dimensional image of the tumor tissue can be obtained.

Preferably, the control unit adjusts the depth and intensity of the ion beam based on the light intensity of the fluorescence spectrum at the position to be irradiated, so that the phenomenon that the ion beam irradiates the tumor tissue too deeply to injure the healthy tissue by mistake can be avoided.

In the present invention, the tumor tissue in the patient is in continuous growth change, so there may be an error between the image before ion beam irradiation and the actual situation. According to the invention, the real-time tumor tissue distribution condition of the patient can be obtained in the irradiation process of the patient through the fluorescence detection emitted by the ATP sensitive fluorescent probe liposome, so that the irradiation of the tumor tissue is avoided being omitted.

It should be noted that the above-mentioned embodiments are exemplary, and that those skilled in the art, having benefit of the present disclosure, may devise various arrangements that are within the scope of the present disclosure and that fall within the scope of the invention. It should be understood by those skilled in the art that the present specification and figures are illustrative only and are not limiting upon the claims. The scope of the invention is defined by the claims and their equivalents.

The present specification encompasses multiple inventive concepts and the applicant reserves the right to submit divisional applications according to each inventive concept. The present description contains several inventive concepts, such as "preferably", "according to a preferred embodiment" or "optionally", each indicating that the respective paragraph discloses a separate concept, the applicant reserves the right to submit divisional applications according to each inventive concept.