Photosensitizer compensation method, tumor treatment device, control system and storage medium

Abstract

The present invention relates to a photosensitizer compensation method, a tumor treatment device, a control system and a storage medium. The photosensitizer compensation method is based on a model of the change of the excited-state photosensitizer concentration over time and a model of the change of the unexcited photosensitizer concentration and the light energy, calculates the optimal value of the unexcited photosensitizer concentration and the optimal value of the light energy when the excited-state photosensitizer concentration is at the optimal value, and calculates the supplementary unexcited photosensitizer concentration and the supplementary light energy accordingly; the tumor treatment device adopts the above compensation method to compensate the excited-state photosensitizer; the control system is used to implement the above compensation control; and the storage medium is used to store software for implementing the above compensation method. The present invention can effectively maintain the excited-state photosensitizer concentration and provide favorable conditions for improving the effect of cyclic photodynamic tumor treatment.

Description

Technical Field

[0001] The present invention relates to an excited state photosensitizer compensation method suitable for photodynamic therapy circulating liquid, a circulating adaptive photodynamic tumor therapy device using the excited state photosensitizer compensation method, and a corresponding control system and storage medium, belonging to the technical field of medical equipment and intelligent control. Background Art

[0002] As a new type of blood virus inactivation technology, photochemical method also has broad prospects in the field of tumor treatment. After being excited by a specific wavelength, the photosensitizer will undergo electron transfer reaction and energy transfer reaction, thereby generating ROS, including singlet oxygen, hydrogen peroxide, hydroxyl free radicals and superoxide anions, etc. These substances will attack tumor cell DNA and cause tumor cell apoptosis. However, after the electron transfer reaction, the excited photosensitizer will be consumed and cannot be regenerated. Only after the energy transfer reaction, the photosensitizer can be regenerated after energy exchange treatment, so the concentration of the excited photosensitizer will continue to decrease (see Figure 1 ), it is difficult to maintain the optimal reaction concentration. According to experimental data and literature, the concentration of excited state photosensitizers in existing photochemical methods can drop to one tenth of the initial concentration within one hour.

[0003] Existing photochemical methods all use a fixed initial concentration and no longer intervene in the photosensitizer concentration, which greatly affects the therapeutic effect and operability of tumors. Therefore, there is an urgent need for a method that can accurately predict and adaptively adjust the concentration of excited-state photosensitizers to the optimal reaction concentration in an effective manner. Summary of the invention

[0004] In order to overcome the above-mentioned defects of the prior art, the present invention provides an excited-state photosensitizer compensation method suitable for photodynamic therapy circulating liquid, a circulating adaptive photodynamic tumor treatment device using this excited-state photosensitizer compensation method, and a corresponding control system and storage medium to effectively maintain the excited-state photosensitizer concentration, thereby providing favorable conditions for improving the effect of circulating photodynamic tumor treatment.

[0005] The technical solution of the present invention is: a method for compensating excited-state photosensitizers in circulating fluids for photodynamic therapy, based on the concentration of excited-state photosensitizers. Over time Changing Models , calculate the optimal value (or optimized value) of excited state photosensitizer concentration :

[0006] ,

[0007] Based on the concentration of excited state photosensitizer Unexcited photosensitizer concentration and light energy (light irradiation energy) Changing Models , calculate the optimal value of the unexcited photosensitizer concentration and the optimal value of light energy :

[0008] ,

[0009] According to the optimal value of the unexcited photosensitizer concentration and the optimal value of light energy Determine the concentration of unexcited photosensitizer added to the photodynamic therapy circulating fluid and the supplementary light energy, that is, based on the optimal value of the unexcited photosensitizer concentration Determining the optimal value of the unexcited photosensitizer concentration to supplement the circulating fluid for photodynamic therapy based on the light energy Determining the supplemental light energy for photodynamic therapy of circulating fluids.

[0010] The so-called supplemented unexcited photosensitizer concentration is the unexcited photosensitizer concentration formed by supplementing the unexcited photosensitizer to the photodynamic therapy circulating fluid (the concentration increment after supplementation), and the unexcited photosensitizer concentration after supplementing the unexcited photosensitizer is the sum of the initial unexcited photosensitizer concentration (the unexcited photosensitizer concentration before supplementing the unexcited photosensitizer) and the supplemented photosensitizer concentration; the so-called supplemented illumination energy is the illumination energy implemented after the initial illumination of the photodynamic therapy circulating fluid is completed, for example, the illumination energy implemented along with the supplementation of the unexcited photosensitizer and / or after the supplementation of the unexcited photosensitizer is completed.

[0011] The corresponding excited-state photosensitizer concentration can be constructed (e.g., fitted) based on the experimental results Over time Changing Models and excited-state photosensitizer concentration Unexcited photosensitizer concentration and light energy Changing Models .

[0012] The relevant experiments can be carried out under the same or similar system and circulation operating conditions as the treatment.

[0013] Furthermore, when a constant flow rate cycle is adopted, light intensity or light source power can be used as an indicator of (instead of) light energy; when a periodic intermittent cycle is adopted, the light energy of a single cycle can be used as an indicator of light energy.

[0014] Preferably, according to the optimal value of the concentration of the unexcited photosensitizer The method for determining the concentration of the unexcited photosensitizer supplemented to the photodynamic therapy circulating fluid is to make the concentration of the unexcited photosensitizer in the photodynamic therapy circulating fluid at Within the range (not less than and not greater than ), or in other words, the concentration of the unexcited photosensitizer to be supplemented or the amount of the unexcited photosensitizer to be supplemented is determined based on this goal, wherein: is a coefficient greater than zero and less than 1.

[0015] Further, It can be 0, 20% or 50%, and can be set according to actual needs.

[0016] Preferably, according to the optimal value of the light energy The method of supplementing the light energy for the photodynamic therapy circulating fluid is to make the supplementary light energy at Within the range (not less than and not greater than ), or in other words, to determine the supplementary lighting energy or lighting intensity based on this goal, where is a coefficient greater than zero and less than 1.

[0017] Further, It can be 0, 20% or 50%, and can be set according to actual needs.

[0018] Circulating adaptive photodynamic tumor therapy device, comprising:

[0019] The photodynamic excitation cavity (or photodynamic excitation chamber) is used to contain the circulating liquid that receives light, and is provided with a circulating inlet, a circulating outlet, and an inlet for supplementing photosensitizer. The circulating liquid enters the photodynamic excitation cavity from the circulating inlet, and is mixed with the supplemented photosensitizer in the photodynamic excitation cavity. The circulating liquid output from the photodynamic excitation cavity is sent out from the circulating outlet.

[0020] A photosensitizer replenishing device, used for replenishing the liquid containing the unexcited photosensitizer;

[0021] An illumination device (referred to as a light source) is used to illuminate the liquid in the photodynamic excitation chamber and / or illuminate the liquid in the photosensitizer replenishing device;

[0022] A control system is used to determine the concentration of unexcited photosensitizer and the supplementary illumination energy for photodynamic therapy circulating fluid according to any of the excited-state photosensitizer compensation methods applicable to photodynamic therapy circulating fluid disclosed in the present invention, calculate the required unexcited photosensitizer supplement amount according to the determined supplementary unexcited photosensitizer concentration, control a photosensitizer supplement device (the specific control method depends on the specific setting of the photosensitizer supplement device, which can usually be a working state of a control pump, etc.) to supplement photosensitizer to a photodynamic excitation cavity according to the unexcited photosensitizer supplement amount calculated in this way (the specific control method depends on the specific setting of the photosensitizer supplement device, which can usually be a working state of a control pump, etc.) according to the determined supplementary illumination energy to implement illumination of the liquid in the photodynamic excitation cavity and / or illumination of the liquid in the photosensitizer supplement device (the specific control method depends on the specific setting of the light source, which can usually be a control circuit on / off and / or a working state of a light-emitting element).

[0023] Furthermore, the medical device has at least two working modes: continuous (eg, continuous constant speed) circulation and intermittent (eg, periodic intermittent) circulation. Any working mode can be selected according to actual needs, and switching between different working modes can be performed.

[0024] Furthermore, in the continuous cycle working mode, the control system calculates the supplementary unexcited photosensitizer flow rate required to supplement the unexcited photosensitizer concentration based on the real-time unexcited photosensitizer concentration at the inlet side of the photodynamic excitation cavity and the circulating liquid flow rate, controls the photosensitizer supplementing device to supplement (input) the unexcited photosensitizer (for example, a solution of unexcited photosensitizer) into the photodynamic excitation cavity with the calculated supplementary unexcited photosensitizer flow rate, calculates the illumination intensity or light source power required to supplement the illumination energy based on the real-time unexcited photosensitizer concentration at the inlet side of the photodynamic excitation cavity and the circulating liquid flow rate, and controls the illumination device to continuously (continuously) illuminate the liquid in the photodynamic excitation cavity with the calculated illumination intensity or light source power; in the periodic intermittent cycle working mode, based on the supplementary The unexcited photosensitizer replenishment amount required to replenish the unexcited photosensitizer concentration is calculated based on the initial unexcited photosensitizer concentration and the amount of circulating liquid in the photodynamic excitation cavity during the unexcited photosensitizer replenishment stage. The control system calculates the illumination intensity or light source power required to replenish illumination energy within the set illumination time (illumination time within this stage / cycle) based on the initial unexcited photosensitizer concentration and the amount of circulating liquid in the photodynamic excitation cavity during the unexcited photosensitizer replenishment stage. The photosensitizer replenishment device is controlled to replenish (input) the unexcited photosensitizer (for example, a solution of unexcited photosensitizer) into the photodynamic excitation cavity with the calculated unexcited photosensitizer replenishment amount. The illumination device is controlled to illuminate the liquid in the photodynamic excitation cavity with the calculated illumination intensity or light source power within the set illumination time.

[0025] Furthermore, the photosensitizer replenishing device includes an unexcited photosensitizer source (eg, a corresponding storage tank) and a physiological saline source (eg, a corresponding storage tank), with or without a mixing cavity (or mixing chamber).

[0026] When the photosensitizer replenishing device is provided with a mixing chamber, the unexcited photosensitizer source is connected to the mixing chamber via an unexcited photosensitizer output tube, an unexcited photosensitizer output pump (e.g., a peristaltic pump) is provided on the unexcited photosensitizer output tube, the physiological saline source is connected to the mixing chamber via a physiological saline output tube, a physiological saline output pump (e.g., a peristaltic pump) is provided on the physiological saline output tube, and the mixing chamber is connected to (including integrated with) a photodynamic excitation chamber, so as to replenish the unexcited photosensitizer to the photodynamic excitation chamber.

[0027] When the photosensitizer replenishing device is not provided with a mixing chamber, the unexcited photosensitizer source is connected to the photodynamic excitation chamber through an unexcited photosensitizer output tube, and the unexcited photosensitizer output tube is provided with an unexcited photosensitizer output pump. The physiological saline source is connected to the photodynamic excitation chamber through a physiological saline output tube, and the physiological saline output tube is provided with a physiological saline output pump, which is used to input the unexcited photosensitizer (solution) and the physiological saline matched with the unexcited photosensitizer into the photodynamic excitation chamber, and the liquids entering the photodynamic excitation chamber are mixed with each other to effectively replenish the unexcited photosensitizer.

[0028] According to actual needs, a device for adding other substances (liquids), such as distilled water, may also be provided in the photosensitizer replenishing device. Similarly, the device for adding other substances also uses the substance source (such as a corresponding storage tank) and a corresponding output pipe connecting the substance source and the mixing chamber, and an output pump (such as a peristaltic pump) is provided on the output pipe to implement and control the delivery of the substance to the mixing chamber.

[0029] If necessary, a mixing / stirring mechanism may be provided in the mixing chamber, for example, a stirrer may be provided, or the access mode of each output pipe to the mixing chamber may be reasonably provided, so as to achieve stirring and mixing by means of the output liquid flow.

[0030] Preferably, the mixing chamber is provided with a liquid oxygenation device, the liquid inlet of the liquid oxygenation device is connected to the oxygenation liquid outlet of the mixing chamber through an oxygenation pipe, the liquid outlet of the liquid oxygenation device is connected to the mixing chamber through an oxygenation reflux pipe, and an oxygenation circulation pump (for example, a peristaltic pump) is provided on the oxygenation pipe and / or the oxygenation reflux pipe.

[0031] Any suitable oxygen enrichment device that can achieve effective contact / mixing of the liquid with oxygen to increase the oxygen content in the liquid can be used.

[0032] A control system adapted for a cyclic adaptive photodynamic tumor treatment device determines the concentration of unexcited photosensitizer and the supplementary illumination energy for photodynamic therapy circulating fluid according to any of the excited-state photosensitizer compensation methods for photodynamic therapy circulating fluid disclosed in the present invention, calculates the required unexcited photosensitizer supplement amount according to the determined supplementary unexcited photosensitizer concentration, controls a controlled device (e.g., any of the cyclic adaptive photodynamic tumor treatment devices disclosed in the present invention) to supplement circulating fluid (e.g., photodynamic therapy circulating fluid of the present invention) with unexcited photosensitizer according to the unexcited photosensitizer supplement amount thus calculated, and controls the controlled device to illuminate the circulating fluid during and / or after the unexcited photosensitizer supplement is completed according to the determined supplementary illumination energy.

[0033] A non-transitory computer-readable storage medium stores computer instructions for implementing any of the excited-state photosensitizer compensation methods for photodynamic therapy circulating fluid disclosed in the present invention.

[0034] The present invention has the following beneficial effects: it has an adaptive compensation mechanism for excited-state photosensitizers, which can keep the excited-state photosensitizers at an optimal / preferable reaction concentration, so that photochemical reactions can be carried out with high efficiency and tumor cells can be killed better; since the model on which the compensation mechanism relies is based on the experimental results of changes in the concentration of excited-state photosensitizers, it conforms to the laws of nature, and can reasonably add unexcited-state photosensitizers to an optimal concentration through optimization and selection, and at the same time, an adaptive mechanism is used to automatically adjust the illumination energy to excite the photosensitizers to the electron exchange energy level, thereby ensuring that the concentration of the excited-state photosensitizers is maintained at an optimal / preferable reaction concentration; since the illumination excitation can be implemented in a photodynamic excitation cavity, can also be implemented in a photosensitizer replenishing device, or can be implemented partially in the photodynamic excitation cavity and partially in the photosensitizer replenishing device, the setting mode of the light source can be selected according to actual needs; in addition, this device can also be used for thermal perfusion therapy, and in this application scenario, only physiological saline or distilled water is required, and there is no need to mix and add photosensitizers. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 is a graph showing the concentration of the excited-state photosensitizer changing with time;

[0036] Figure 2 is the concentration of excited photosensitizer and the concentration of unexcited photosensitizer and the binary function surface diagram of the excitation energy E;

[0037] Figure 3 is a flow chart of the compensation mechanism of excited-state photosensitizer of the present invention;

[0038] Figure 4 is a schematic diagram of the treatment device of the present invention in the general treatment mode of thermal cycle photochemical method;

[0039] Figure 5 is a schematic diagram of the treatment device of the present invention in a cyclic photochemical blood treatment mode;

[0040] Figure 6 is a schematic diagram of the treatment device of the present invention in a combined treatment mode of tumor cells and blood components;

[0041] Figure 7 It is a schematic diagram of the filtering device of the present invention isolating impurities from the treatment fluid. DETAILED DESCRIPTION

[0042] According to known natural laws and related research, high-concentration photosensitizers generally have higher inactivation efficacy than low-concentration photosensitizers. However, studies have also found that there is a phenomenon in which lower-concentration photosensitizers have higher inactivation efficacy than higher-concentration photosensitizers. This phenomenon may be due to the aggregation of unexcited photosensitizer molecules exceeding the optimal concentration, thereby hindering light excitation of photosensitizers, and ultimately leading to a decrease in inactivation efficiency. Therefore, when replenishing photosensitizers consumed by photochemical reactions, the photosensitizer concentration needs to be controlled at an optimal value: if the photosensitizer concentration is too low, it will not provide enough electrons for the electron transfer reaction after excitation to generate enough ROS; if the photosensitizer concentration is too high, it will be difficult to be effectively excited due to the aggregation effect, and may bring unknown side effects.

[0043] On the other hand, within a certain range, the higher the light energy, the better the excitation effect on the photosensitizer. However, when the light energy reaches a certain threshold, the excitation effect will drop significantly. This is because higher excitation energy will cause the electrons of the photosensitizer to jump to a higher energy level, while the excited photosensitizer cannot contribute electrons at a higher energy level, and then the electron transfer reaction cannot occur, which ultimately leads to a decrease in inactivation efficiency. Therefore, when light excites the newly added photosensitizer, the light energy also needs to be controlled at the optimal value.

[0044] See also Figure 3 The present invention adopts a compensation mechanism for the concentration of excited-state photosensitizer to compensate the concentration of excited-state photosensitizer in real time from two aspects: 1) increasing the concentration of unexcited photosensitizer, and 2) supplementing the light energy used to excite the photosensitizer.

[0045] The concentration of the unexcited photosensitizer and the optimal illumination energy can be determined / selected according to the following methods.

[0046] 1) Optimal unexcited photosensitizer concentration and unexcited photosensitizer concentration selection

[0047] Figure 1 The model (curve) of the change of the concentration of the excited state photosensitizer with time after the photosensitizer is irradiated with appropriate light (for example, UVB can be used in general) at pH = 7 An example is the degradation curve of excited state photosensitizer. This model (function) curve can be fitted based on multiple experimental results.

[0048] The first derivative of Represents the decreasing rate of the excited state photosensitizer concentration. When the decreasing rate reaches the minimum value When the photosensitizer produces ROS at the highest efficiency, the concentration of excited state photosensitizer in this state can be expressed as Therefore, the concentration of excited-state photosensitizer should be kept at or near within a certain range, for example, within the range.

[0049] The calculation of is shown in formula ①:

[0050]

[0051] Excited state photosensitizer concentration Unexcited photosensitizer concentration and light energy Therefore, there is a binary function of the excited-state photosensitizer concentration ,like Figure 2 This function surface can also be obtained by fitting multiple experimental results.

[0052] Similarly, The second derivative of Represents the decreasing rate of the excited state photosensitizer concentration. When the decreasing rate reaches the minimum value When , the photosensitizer produces ROS most efficiently.

[0053] According to formula ②, the optimal value of the unexcited photosensitizer concentration can be obtained: The concentration of the unexcited photosensitizer can be selected to be the optimal value of the unexcited photosensitizer concentration or within the range of ±50% of the optimal value ( ) within the selection.

[0054]

[0055] 2) Optimal light energy (light energy used to excite photosensitizer) and light energy selection

[0056] As shown in the above formula ②, the optimal value of the unexcited photosensitizer concentration is calculated. When the optimal value of light energy is obtained The supplementary lighting energy can be selected at its optimal value or within the range of ±50% of the optimal value ( ) within the selection.

[0057] According to the need for photosensitizer excitation, a suitable spectral light source can be used as the illumination light source of the photodynamic excitation chamber.

[0058] The cyclic adaptive photodynamic tumor treatment device of the present invention is based on the compensation mechanism of the excited state photosensitizer concentration, and is used to implement the thermal cycle photochemical method to treat tumors. For example, the temperature of the treatment liquid containing the excited state photosensitizer is precisely controlled at 42-45°C (preferably 43°C), and it is continuously circulated and flushed at the treatment target (e.g., solid tumor), thereby inducing tumor cell apoptosis by utilizing the high temperature environment and ROS generated by the photosensitizer.

[0059] Compared with traditional photochemical tumor therapy, thermal cycling photochemical method not only utilizes the difference in tolerance of tumor cells and normal tissue cells to high temperature environment (tumor cells will suffer irreversible damage if they are exposed to an environment of about 43°C for more than 1 hour, while normal tissue cells can tolerate up to 47°C), but also utilizes the high permeability of cell membranes in high temperature environments to increase the speed at which excited state photosensitizers enter tumor cells, significantly increasing the inactivation rate of tumor cells.

[0060] At the same time, compared with the existing technology, the circulating flushing method can ensure that the excited state photosensitizer is always at the optimal concentration without directly irradiating the treatment target, thereby indirectly achieving the effect of direct light treatment, but avoiding the side effects of direct irradiation of the treatment site and the problem of difficult operation.

[0061] As a preferred embodiment, the excited state photosensitizer can be subjected to oxygen treatment according to actual needs, which ensures that the excited state photosensitizer will undergo electron transfer reaction rather than energy transfer reaction to the greatest extent, so that its concentration is as close to the above-mentioned excited state photosensitizer degradation curve as possible.

[0062] Any suitable control system (data processor) may be used to implement relevant data processing and control, a control system may be constructed using central control and data processing or other suitable methods, and any storage medium capable of storing software may be used as a non-transitory computer-readable storage medium for storing the corresponding software / program.

[0063] The control system may include a central processing unit and a storage unit. The storage unit uses a non-transitory computer-readable storage medium to store corresponding software. The central processing unit implements corresponding control with the support of the software.

[0064] The following are several embodiments of the cyclic adaptive photodynamic tumor treatment device of the present invention.

[0065] Example 1 (general treatment mode):

[0066] Figure 4The basic structure of the treatment device of the present invention in the general treatment mode is shown, and the treatment part or treatment target is mainly the cavity. Peristaltic pump 1, peristaltic pump 2 and peristaltic pump 3 are used to mix distilled water, physiological saline and photosensitizer (solution) (specifically according to actual needs) to form a flushing solution, and pump it into the photodynamic excitation cavity, or according to the treatment needs, part of the peristaltic pump is used to pump the required part of the liquid into the photodynamic excitation cavity, and the photosensitizer is excited by light treatment with a spectral source (UVA or UVB or UBC) in the excitation cavity; at the same time, peristaltic pump 4 can pre-pump oxygen into the photosensitizer solution, so that the photosensitizer solution contains enough oxygen to ensure that the subsequent excited state photosensitizer undergoes an electron transfer reaction. The excitation cavity delivers an excited-state photosensitizer flushing liquid containing oxygen, which is heated and temperature-controlled (maintained at 42°C to 45°C) by a temperature (constant temperature) control module (heater / heat exchanger), and then reaches the target treatment site (e.g., cavity) through a peristaltic pump 5 (and corresponding pipelines / flushing facilities), and continuously flushes the target treatment site, inducing apoptosis of tumor cells in the target treatment site while mechanically flushing away free tumor cells. The peristaltic pump 6 can extract the flushing liquid containing free tumor cells from the target treatment site, filter it to remove free tumor cells and other free impurities such as cell clumps, tissues, and blood clots, and then return it to the photodynamic excitation cavity, while replenishing the excited-state photosensitizer to ensure that the concentration of the excited-state photosensitizer is still at the optimal concentration in the next cycle (see Figure 7 ). A control system (central control and data processing module) can be set up to control the operation of the treatment device, and the pump speed (of each pump), light intensity and temperature control are all controlled.

[0067] Embodiment 2 (Blood Treatment Mode)

[0068] Figure 5The basic structure of the treatment device of the present invention in the blood treatment mode is shown, which can be used to treat specific blood components (such as treatment / processing of plasma or monocytes). Since blood cells cannot tolerate an environment exceeding 38°C, compared with the first embodiment, the blood treatment mode no longer performs additional heating treatment on the blood cells, eliminating the need for a heating device. At the same time, in order to maintain the body's fluid balance, the amount of additional fluid injected into the human body cannot exceed 15% of the body's total blood volume. Therefore, in the blood treatment mode, no additional distilled water is injected, the distilled water source and the corresponding output tube and peristaltic pump 1 are eliminated, and a blood component separation device and corresponding pipeline settings are added. In this treatment mode, the peristaltic pump 4 collects blood through the blood collection end, and after the collected blood (whole blood) is separated by components, the blood components that need to be irradiated are sent to the photodynamic excitation chamber through the pump 5, mixed with the flushing liquid (the supplementary liquid containing unexcited photosensitizer, which is a mixture of physiological saline and photosensitizer), and are treated with light from the spectral source (UVA or UVB or UBC). The blood components that are not irradiated are connected to the output pipeline of the photodynamic excitation chamber, and are sent back to the human blood system through the blood return end by the peristaltic pump 6 together with the output of the photodynamic excitation chamber. If all blood components are not irradiated, the filtering / separation device will also block the blood components outside the photodynamic excitation chamber, so the photodynamic excitation chamber irradiates the circulating liquid containing only the photosensitizer (the same is true for the following embodiment three). Other parts and control systems are the same or similar to embodiment one.

[0069] Example 3 (Combined treatment mode of tumor cells and blood components)

[0070] Figure 6 The basic structure of the treatment device of the present invention in the combined treatment mode of tumor cells and blood components is shown, which can be used to treat specific blood components (such as treatment / processing of plasma or monocytes). Since tumor cells and blood component cells can tolerate different light energies and wavelengths, compared with the second embodiment, the main difference of this embodiment is that the blood component separation device adopts a multi-component separation device that can separate relevant blood components and tumor cells, and a switching valve (for example, a three-way valve) is set at the specific blood component output port and the tumor cell output port of the multi-component separation device. The specific blood component output port and the tumor cell output port are respectively connected to the two single-way ports (single-way inlet) of the switching valve, and the common port (common outlet) of the switching valve is connected to the inlet of the delivery pump after separation. The multi-component separation device can work in two different separation modes, one is to separate tumor cells (liquid containing tumor cells), and the other is to separate specific blood components that need to be treated with photosensitizers. According to the specific treatment mode implemented, the separation mode of the multi-component separation device is switched (selected), and the connection state of the switching valve is switched (selected) at the same time, so that the components (liquids) to be treated in the corresponding treatment mode can be separated and sent to the photodynamic excitation cavity for photosensitizer treatment, and the remaining liquids can be directly fed into the output pipeline of the photodynamic excitation cavity through the short pipe.

[0071] The therapeutic device of the present invention combines the photochemical principle and the method of treating tumors with thermal cycle technology, and has an adaptive compensation mechanism for excited-state photosensitizers, which can keep the excited-state photosensitizers at the optimal reaction concentration, so that photochemical reactions can be more effectively carried out to kill tumor cells. When the control system predicts or detects that the concentration of the excited-state photosensitizer is lower than the optimal reaction concentration, the system will reasonably add unexcited photosensitizers to the optimal concentration, and at the same time use an adaptive mechanism to automatically adjust the illumination energy to excite the photosensitizer to the electron exchange energy level, thereby ensuring that the concentration of the excited-state photosensitizer is ultimately maintained at the optimal reaction concentration. Therefore, the present invention can continuously kill tumor cells with the highest efficiency and prevent tumor metastasis caused by various reasons. It has been experimentally verified that compared with the existing photochemical method, the present invention significantly improves the killing efficiency of tumor cells.

[0072] Unless otherwise specified or when one preferred or optional technical means is a further limitation of another technical means, the preferred and optional technical means disclosed in the present invention can be arbitrarily combined to form several different specific implementation methods.

Claims

1. A method for compensating an excited-state photosensitizer in a circulating fluid for photodynamic therapy, characterized in that Based on the concentration of excited state photosensitizer Over time Changing Models , calculate the optimal concentration of excited state photosensitizer : ， Based on the concentration of excited state photosensitizer Unexcited photosensitizer concentration and light energy Changing Models , calculate the optimal value of the unexcited photosensitizer concentration and the optimal value of light energy : ， According to the optimal value of the unexcited photosensitizer concentration and the optimal value of light energy Determine the concentration of unexcited photosensitizer added to the circulating fluid for photodynamic therapy and the amount of light added, Based on the optimal value of the unexcited photosensitizer concentration The method for determining the concentration of the unexcited photosensitizer supplemented to the photodynamic therapy circulating fluid is to make the concentration of the unexcited photosensitizer in the photodynamic therapy circulating fluid at In the range of is a coefficient greater than or equal to zero and less than 1; Based on the optimal value of light energy The method of supplementing the light energy for the photodynamic therapy circulating fluid is to make the supplementary light energy at In the range of is a coefficient greater than or equal to zero and less than 1.

2. The method for compensating an excited-state photosensitizer in a circulating fluid for photodynamic therapy according to claim 1, characterized in that is 20% or 50%.

3. The method for compensating an excited-state photosensitizer in a circulating fluid for photodynamic therapy according to claim 1, characterized in that is 20% or 50%.

4. Cyclic adaptive photodynamic tumor therapy device, characterized in that include: The photodynamic excitation cavity is used to contain the circulating liquid receiving light, and is provided with a circulating inlet, a circulating outlet and a supplementary photosensitizer inlet. The circulating liquid enters the photodynamic excitation cavity from the circulating inlet and is mixed with the supplementary photosensitizer in the photodynamic excitation cavity. A photosensitizer replenishing device, used for replenishing the liquid containing the unexcited photosensitizer; An illumination device, used for illuminating the liquid in the photodynamic excitation cavity and / or illuminating the liquid in the photosensitizer replenishing device; A control system, for determining the concentration of unexcited photosensitizer supplemented to photodynamic therapy circulating fluid and the supplementary illumination energy according to the method for compensating excited-state photosensitizers for photodynamic therapy circulating fluids as described in any one of claims 1 to 3, calculating the required amount of unexcited photosensitizer supplemented according to the determined concentration of unexcited photosensitizer supplemented, controlling a photosensitizer supplementing device to supplement photosensitizer to a photodynamic excitation cavity according to the unexcited photosensitizer supplemented amount thus calculated, and controlling an illumination device to illuminate the liquid in the photodynamic excitation cavity and / or illuminate the liquid in the photosensitizer supplementing device according to the determined supplementary illumination energy.

5. The cyclic adaptive photodynamic tumor treatment device according to claim 4, characterized in that There are at least two working modes: continuous cycle and intermittent cycle.

6. The cyclic adaptive photodynamic tumor treatment device according to claim 4 or 5, characterized in that The photosensitizer replenishing device includes an unexcited photosensitizer source and a physiological saline source, and is provided with or without a mixing chamber. When a mixing chamber is provided, the unexcited photosensitizer source is connected to the mixing chamber through an unexcited photosensitizer output tube, and an unexcited photosensitizer output pump is provided on the unexcited photosensitizer output tube. The physiological saline source is connected to the mixing chamber through a physiological saline output tube, and a physiological saline output pump is provided on the physiological saline output tube. The mixing chamber is connected to the photodynamic excitation chamber through the mixing chamber output tube, and is used to replenish the mixed liquid containing the unexcited photosensitizer to the photodynamic excitation chamber. When a mixing chamber is not provided, The unexcited photosensitizer source is connected to the photodynamic excitation cavity through an unexcited photosensitizer output tube, and an unexcited photosensitizer output pump is provided on the unexcited photosensitizer output tube. The physiological saline source is connected to the photodynamic excitation cavity through a physiological saline output tube, and the photodynamic excitation cavity is provided with or without a heating device for heating the physiological saline. The physiological saline output tube is provided with a physiological saline output pump for inputting the unexcited photosensitizer and the physiological saline matching the unexcited photosensitizer into the photodynamic excitation cavity, and the liquids entering the photodynamic excitation cavity are mixed with each other to effectively supplement the unexcited photosensitizer.

7. A control system adapted for a cyclic adaptive photodynamic tumor therapy device, characterized in that The method for compensating an excited-state photosensitizer for a circulating liquid in photodynamic therapy as described in any one of claims 1 to 3 determines the concentration of unexcited photosensitizer supplemented to the circulating liquid in photodynamic therapy and the supplementary illumination energy, calculates the required amount of unexcited photosensitizer supplemented according to the determined concentration of unexcited photosensitizer supplemented, controls the controlled device to supplement the circulating liquid with the unexcited photosensitizer according to the unexcited photosensitizer supplemented amount calculated in this way, and controls the controlled device to illuminate the circulating liquid during the process of supplementing the unexcited photosensitizer and / or after the supplementation of the unexcited photosensitizer is completed according to the determined supplementary illumination energy.

8. A non-transitory computer-readable storage medium, characterized in that The computer program product stores computer instructions for implementing the excited-state photosensitizer compensation method for photodynamic therapy circulating fluid as described in any one of claims 1 to 3.

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