A drug controllable delivery and release device based on optical fiber

Abstract

The present invention discloses a drug controllable delivery and release device based on optical fiber, which relates to the field of drug delivery. The drug controllable delivery and release device based on optical fiber of the present invention comprises an optical fiber, a drug, and an excitation light source connected by an optical fiber link; the optical fiber comprises a front end, the front end is used to contact the lesion or probe into the inside of the lesion, and the front end carries a therapeutic drug for the lesion; the front end directly receives the excitation light energy of the excitation light source, or converts the excitation light energy of the excitation light source into other forms of energy to realize light-controlled drug release, releases the drug into the lesion or inside the lesion, and realizes precise treatment of the lesion. The device of the present invention can realize effective light-controlled release of therapeutic drugs for lesions in the body, improve delivery efficiency and drug enrichment rate.

Description

Technical Field

[0001] The present invention relates to the technical field of drug delivery, and in particular to an optical fiber-based drug controllable delivery and release device. Background Art

[0002] More than 90% of the candidate drugs developed worldwide each year fail to pass clinical trials. It is worth noting that in addition to insufficient efficacy, poor material performance, lack of commercial demand and other reasons, 30% of the above candidate drugs fail to pass clinical trials due to uncontrollable toxicity caused by systemic administration. If this uncontrollable toxicity can be improved, for example, through new drug delivery methods that ensure that they are accurately and sufficiently delivered to the lesion site without circulating throughout the body, more candidate drugs will be able to pass clinical trials. Moreover, some abandoned drugs may also be reborn.

[0003] Light-controlled drug release is a potential drug delivery technology that can achieve targeted drug release through the enrichment of photosensitive drugs or carriers in diseased tissues combined with extracorporeal light irradiation. It has the advantages of less trauma, no ionizing radiation, low side effects, and strong spatiotemporal controllability. However, the current light-controlled drug release scheme still relies on drug injection, the mechanism of circulation and metabolism is not yet clear, and the delivery efficiency is difficult to accurately evaluate. More importantly, due to the limited penetration depth of extracorporeal light irradiation, it is difficult to achieve effective light-controlled release of lesions in the body (such as abdominal organ tumors), which restricts the development of light-controlled drug release technology. Summary of the invention

[0004] The purpose of the present invention is to provide a drug controllable delivery and release device based on optical fiber to achieve effective light-controlled release of drugs for lesions in the body, thereby improving delivery efficiency and drug enrichment rate.

[0005] To achieve the above object, the present invention provides the following solution.

[0006] The present invention provides an optical fiber-based drug controllable delivery and release device, comprising: an optical fiber, a drug, and an excitation light source connected by an optical fiber link; the optical fiber comprises a front end, the front end is used to contact a lesion or probe into the inside of a lesion, and the front end carries a therapeutic drug for the lesion; the front end directly receives the excitation light energy of the excitation light source, or converts the excitation light energy of the excitation light source into other forms of energy to realize light-controlled drug release, releases the drug in the lesion or inside the lesion, and realizes precise treatment of the lesion.

[0007] Optionally, the front end contacts the affected area or is inserted into a solid affected area (such as a tumor) through percutaneous or vascular intervention.

[0008] Optionally, the lesions include solid tumors, metastatic tumors, cardiovascular stenosis, traumatic wounds, inflammatory areas and the inside of the skull.

[0009] Optionally, the front end is wrapped with a drug by a photothermal sensitive material and fixed to the surface of the optical fiber, so as to achieve loading of the drug on the optical fiber.

[0010] Optionally, the photothermal photosensitive material generates heat under the excitation of light introduced into the front end to heat up the front end, thereby achieving direct photothermal treatment of the lesion on the one hand, and on the other hand, achieving phase change of the photothermal sensitive material by heating, releasing the drug at the lesion, and realizing the synergistic treatment function of photothermal and drug.

[0011] Optionally, the photothermal sensitive material is a high-temperature phase change gel, which is in a solid phase at human body temperature and in a liquid phase at a temperature higher than human body temperature.

[0012] Optionally, the high-temperature phase change gel can be mixed with drugs at a temperature higher than the human body temperature, and then can be adhered and modified on the optical fiber to achieve drug loading at the front end.

[0013] Optionally, the high temperature phase change gel has high biocompatibility and degradability.

[0014] Optionally, the front end utilizes optical fiber sensing structure and sensor device design and integration to achieve real-time sensing monitoring of changes in multiple characteristic parameters during light-controlled drug delivery and release therapy; the multiple characteristic parameters include temperature and drug release amount.

[0015] Optionally, the real-time sensing monitoring of the temperature is accomplished by a fiber grating written in the front end.

[0016] Optionally, the real-time sensing monitoring of the drug release amount is performed by a front-end integrated optical fiber Mach-Zehnder interferometer; the optical fiber Mach-Zehnder interferometer is formed by fusion splicing single-mode and multi-mode optical fibers.

[0017] Optionally, the front end is coated with a reflective film structure for reflecting the optical fiber Mach-Zehnder interferometer signal to achieve reflective demodulation.

[0018] Optionally, the optical fiber-based controlled drug delivery and release device also includes a heating light source module, a wavelength division multiplexing module, a background signal light source module and a spectral signal demodulation module to achieve photothermal control and sensor signal demodulation for the front end. Among them, the heating light source module refers to a section of the optical fiber as an active optical fiber, which absorbs 980nm pump light and partially converts heat for heating. The wavelength division multiplexing module is used to simultaneously inject 980nm pump light and 1550nm detection signal light into the front end of the optical fiber by means of wavelength division multiplexing. The background signal light source module uses a 1550nm detection signal light. The spectral signal demodulation module is to access the reflected output light through a spectrometer, and access a signal processing module (such as a computer or other controller) to perform subsequent spectral analysis (spectral wavelength drift, spectral change, etc.).

[0019] Optionally, the device of the present invention can not only achieve minimally invasive collaborative treatment of lesions in the body, but also provide a direct and efficient evaluation device for the development of new drugs.

[0020] According to the specific embodiments provided by the present invention, the present invention discloses the following technical effects:

[0021] The optical fiber-based drug controllable delivery and release device provided by the present invention comprises an optical fiber, a drug, and an excitation light source connected by an optical fiber link; the optical fiber comprises a front end; the front end is used to contact the lesion or probe into the lesion; the front end carries the drug; the front end can directly receive the excitation light energy, or convert it into other forms of energy; the drug is released into the lesion through the direct action of the excitation light or other forms of energy converted by it, so as to realize the light-controlled drug delivery and release treatment of the lesion. The device of the present invention can not only realize the minimally invasive collaborative treatment of deep lesions in the body, but also improve the delivery efficiency and drug enrichment rate. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0023] Figure 1 This is a schematic diagram of the connection relationship of the optical fiber-based drug controllable delivery and release device according to an embodiment of the present invention;

[0024] Figure 2 This is a schematic diagram of the three-dimensional structure of the optical fiber drug delivery and release probe according to an embodiment of the present invention;

[0025] Figure 3This is a simplified planar structural schematic diagram of an optical fiber drug delivery and release probe according to an embodiment of the present invention;

[0026] Figure 4 This is a schematic diagram of the drug release process of the optical fiber drug delivery and release probe according to an embodiment of the present invention;

[0027] Figure 5 This is a schematic diagram of the internal optical path of the optical fiber drug delivery and release probe according to an embodiment of the present invention;

[0028] Figure 6 Fiber Mach-Zehnder interferometer and time response spectrum provided by an embodiment of the present invention;

[0029] Figure 7 A graph showing the relationship between wavelength drift and drug concentration provided in an embodiment of the present invention. DETAILED DESCRIPTION

[0030] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0031] The purpose of the present invention is to provide a drug controllable delivery and release device based on optical fiber to achieve effective light-controlled release of drugs for lesions in the body, improve delivery efficiency and drug enrichment rate, reduce drug toxicity damage to normal organs, and integrate sensing functions to ensure operational safety.

[0032] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the present invention is further described in detail below with reference to the accompanying drawings and specific embodiments.

[0033] The present invention provides an optical fiber-based drug controllable delivery and release device, comprising: an optical fiber, a drug, and an excitation light source connected by an optical fiber link; the optical fiber includes a front end, the front end is used to contact the lesion or probe into the inside of the lesion, and the front end carries a therapeutic drug for the lesion; the front end directly receives the excitation light energy of the excitation light source, or converts the excitation light energy of the excitation light source into other forms of energy to achieve light-controlled drug release, releases the drug into the lesion or inside the lesion, and achieves precise treatment of the lesion. The following provides a specific embodiment of the optical fiber-based drug controllable delivery and release device of the present invention.

[0034] See also Figure 1In a specific embodiment, the present invention provides an optical fiber-based controlled drug delivery and release device, comprising: a controller 100, a spectrometer 101, a signal light source 102, a pump light source 103, a circulator 104, a wavelength division multiplexer 105, and an optical fiber drug delivery and release probe (also referred to as a probe in the present invention) 106.

[0035] The controller 100 is connected to the spectrometer 101, the signal light source 102 and the pump light source 103 respectively. The signal light source 102 is connected to the incident light interface of the circulator 104. The spectrometer 101 is connected to the output light interface of the circulator 104. The middle interface of the circulator 104 is connected to the first incident light interface of the wavelength division multiplexer 105. The pump light source 103 is connected to the second incident light interface of the wavelength division multiplexer 105. The output light interface of the wavelength division multiplexer 105 is connected to the optical fiber drug delivery release probe 106.

[0036] See also Figure 2 and Figure 3 The optical fiber drug delivery release probe 106 includes an optical fiber Mach-Zehnder interferometer 200 , an optical fiber Bragg grating 201 , a drug-loaded coating 202 and a drug 203 .

[0037] The optical fiber Mach-Zehnder interferometer 200 is made by fusion splicing a multimode optical fiber 204 and a single-mode optical fiber 205. A reflective film 206 is coated on the front end face of the single-mode optical fiber 205 away from the multimode optical fiber 204. During preparation, the multimode optical fiber 204 and the single-mode optical fiber 205 are fusion spliced, and the end face of the single-mode optical fiber 205 is sliced ​​and then placed in a vacuum gold coating apparatus to coat the reflective film 206 on the end face.

[0038] The single-mode optical fiber 205 is an active optical fiber doped with rare earth ions. The rare earth ions doped in the active optical fiber 205 will undergo energy level transition and generate a large amount of heat during ion relaxation under the activation of a corresponding wavelength, thereby achieving a temperature rise at the active optical fiber 205.

[0039] The fiber Bragg grating 201 is written on the active optical fiber 205. During preparation, the fiber Bragg grating 201 is written on the active optical fiber 205 using a phase mask method. The fiber Bragg grating 201 is usually written on the front end of the active optical fiber 205 because the front end enters the body first, and writing on the front end can effectively monitor the temperature in the body.

[0040] The drug-loaded coating 202 wraps the drug 203 and fixes it on the surface of the active optical fiber 205, serving as the front end of the optical fiber drug delivery release probe 106. The drug-loaded coating 202 is made of photothermal sensitive material. In some embodiments, the photothermal sensitive material is a high-temperature phase-change gel, such as a low-melting-point hydrogel or a low-melting-point agarose, which is in a solid phase at human body temperature and in a liquid phase at a temperature higher than that of the human body. And the high-temperature phase-change gel has high biocompatibility and degradability. The drug concentration carried in the drug-loaded coating 202 and the water content of the hydrogel in the drug-loaded coating 202 can be set according to actual needs.

[0041] During preparation, the drug 203 is added when the drug-loaded coating 202 is in liquid state, and stirred evenly, and after cooling, the drug-loaded coating 202 containing the drug 203 is formed. The drug-loaded coating 202 encapsulates the drug 203 and fixes it on the surface of the active optical fiber 205 of the optical fiber Mach-Zehnder interferometer 200. When the temperature of the drug-loaded coating 202 rises to a suitable temperature, the phase change occurs, thereby releasing the drug 203 encapsulated in the hydrogel, such as Figure 4 shown.

[0042] In order to prepare the drug-loaded coating 202 encapsulating the drug 203, the present invention also provides a low-melting-point hydrogel quantitative condensation fixation technology and a low-melting-point hydrogel layer technology with high mechanical strength, which requires the use of a polytetrafluoroethylene capillary and a drying oven. Specifically, a polytetrafluoroethylene capillary with a specified inner diameter is sleeved on the surface of the probe sensing area (i.e., the active optical fiber 205 part), and the molten drug-loaded hydrogel is injected into the polytetrafluoroethylene capillary using a needle tube, and left to cool. After cooling, the polytetrafluoroethylene capillary is taken out. The probe with the drug-loaded hydrogel layer fixed is placed in a drying oven to remove excess water, and a drug-loaded coating 202 with high mechanical strength can be obtained.

[0043] The internal optical path of the fiber optic drug delivery release probe 106 is as follows: Figure 5 See Figure 1 , Figure 3 and Figure 5 , the incident light 207 of the fiber optic drug delivery release probe 106 includes a first signal light and a second signal light. The signal light source 102 is used to input the first signal light into the fiber optic Mach-Zehnder interferometer 1 and the fiber Bragg grating 4. Specifically, the signal light source 102 can be a broadband light source or a single wavelength unit. The pump light source 103 is used to input the second signal light into the fiber optic Mach-Zehnder interferometer 200. Specifically, the pump light source 103 can use near-infrared pumping.

[0044] The fiber Mach-Zehnder interferometer 200 is used to reflect and interfere the first signal light to form a Mach-Zehnder interference signal. The active fiber 205 in the fiber Mach-Zehnder interferometer 200 is used to absorb the second signal light and activate the rare earth ions inside the active fiber 205 to increase the temperature. The fiber Bragg grating 201 is used to reflect the first signal light to form a Bragg reflection signal.

[0045] The spectrometer 101 is used to receive the reflected light (i.e., the third signal light) 208 output by the optical fiber drug delivery and release probe 106. The third signal light 208 includes the interference signal of the optical fiber Mach-Zehnder interferometer 200 and the reflection signal of the optical fiber Bragg grating 201. The resonant characteristic wavelength in the Mach-Zehnder interference signal can characterize the change of the drug-loaded coating 202 outside the active optical fiber 205. The Bragg resonant wavelength in the Bragg reflection signal can characterize the temperature change of the active optical fiber 205. Therefore, in order to realize the monitoring of the delivery and release process of the drug 203, the present invention combines the optical fiber Mach-Zehnder interferometer 200 with the optical fiber Bragg grating 201. The optical fiber Mach-Zehnder interferometer 200 is used to monitor the phase change of the drug-loaded coating 203 loaded with the drug 202, and the optical fiber Bragg grating 201 is used to monitor the temperature of the active optical fiber 205 during the treatment process.

[0046] Specifically, the spectrometer 101 performs preliminary demodulation on the third signal light 208, generates a corresponding spectrum and sends it to the controller 100. For the spectrum lines in the spectrum of the third signal light 208, since the intensity of the Bragg reflection signal is significantly greater than the intensity of the Mach-Zehnder interference signal, and the waveform is thin, the corresponding spectrum lines are superimposed like an interference peak with another thin peak, and the signal can be easily distinguished. Then, by analyzing the third signal light 208 and referring to the second signal light, the Bragg reflection signal spectrum can be decoupled from the spectrum. The temperature change during the drug release process is monitored according to the Bragg resonant wavelength in the Bragg reflection signal. Similarly, the optical fiber Mach-Zehnder interferometer 200 also has temperature sensitivity, so in demodulation, it is necessary to first use the Bragg grating reflection signal to demodulate the temperature information, and after obtaining the temperature, the resonant characteristic wavelength of the spectrum is processed to remove the temperature information contained therein, leaving only the drug release information. Thus, the release amount of the drug 202 carried in the drug-loaded coating 203 is monitored according to the resonant characteristic wavelength in the Mach-Zehnder interference signal spectrum.

[0047] The optical fiber-based controlled drug delivery and release device provided by the present invention fully exploits the surface functionalization and sensing structure performance of the optical fiber, and loads the drug on the optical fiber through the design of surface-coated photothermal sensitive materials, so that the drug-loaded optical fiber can be probed into deep lesions in the body by means of endoscopy or intervention, thereby achieving precise drug delivery, improving delivery efficiency and drug enrichment rate, and reducing drug toxicity damage to normal organs. Furthermore, the drug in the drug-loaded coating is stimulated by the optical fiber photothermal effect for light-controlled release of drug therapy, and direct photothermal therapy of the lesion can be achieved by heating the active optical fiber, completing the photothermal and drug synergistic therapy of the lesion and improving the efficacy. On the other hand, the present invention uses an optical fiber Mach-Zehnder interferometer and an optical fiber Bragg grating to achieve real-time monitoring and feedback of drug release and temperature parameters during treatment, ensuring controllable efficacy and operational safety.

[0048] Furthermore, based on the optical fiber-based controlled drug delivery and release device, the present invention also provides an optical fiber-based controlled drug delivery and release method, comprising:

[0049] S1: The front end of the optical fiber drug delivery and release probe 106 is brought into contact with the lesion or inserted into the lesion.

[0050] The front end of the probe is used to contact the affected part (also called the lesion) or to probe into the affected part. The front end of the probe carries the drug 203; the front end of the probe directly receives the excitation light energy through the optical fiber link or converts it into other forms of energy; the drug 203 is released to the affected part through the excitation light energy or other forms of energy converted from it, so as to achieve precise light-controlled drug delivery and release treatment to the affected part.

[0051] Since the front end of the probe contains a photothermal photosensitive material, it is possible to convert light energy into heat energy to heat up the front end. The front end of the probe wraps the drug 203 in a photothermal release gel manner and is fixed to the surface of the active optical fiber 205 to achieve loading of the drug on the optical fiber. The photothermal release gel used is a high-temperature phase change gel, which is in a solid phase at human body temperature and in a liquid phase at a temperature higher than that of the human body. The high-temperature phase change gel used can be mixed with the drug 203 at a temperature higher than that of the human body, and can then be adhered and modified on the optical fiber to achieve loading of the drug 203 at the front end. In addition, the high-temperature phase change gel has high biocompatibility and degradability.

[0052] During treatment, the front end of the probe can contact the affected area or be inserted into the affected area (such as a tumor) through percutaneous or vascular intervention.

[0053] S2: The controller 100 controls the signal light source 102 and the pump light source 103 to be turned on.

[0054] In some embodiments, the signal light source 102 is used to generate a signal light of 1550nm. The pump light source 103 is used to generate a pump light of 980nm. Correspondingly, a 980 / 1550nm wavelength division multiplexer 105 is used. At this time, the signal light source 102 is connected to the incident light interface of the circulator 104; the spectrometer 101 is connected to the output light interface of the circulator 104; the middle interface of the circulator 104 is connected to the 1550nm incident light interface of the 980 / 1550nm wavelength division multiplexer 105; the pump light source 103 is connected to the 980nm incident light interface of the 980 / 1550nm wavelength division multiplexer 105; and the output light interface of the 980 / 1550nm wavelength division multiplexer 105 is connected to the optical fiber drug delivery release probe 106.

[0055] The 980 / 1550nm wavelength division multiplexer 105 simultaneously injects the 980nm pump light and the 1550nm signal light into the probe by means of wavelength division multiplexing.

[0056] After passing through the complete optical path, the third signal light entering the spectrometer 101 can be analyzed to obtain the Mach-Zehnder interference signal and the Bragg reflection signal of the optical fiber drug delivery release probe 106 .

[0057] S3: The signal light emitted by the signal light source 102 passes through the circulator 104 and the wavelength division multiplexer 105 in sequence, and then is incident on the rear end of the optical fiber drug delivery and release probe 106 as the first signal light, that is, the end where the multimode optical fiber 204 is located.

[0058] S4: The optical fiber Mach-Zehnder interferometer 200 reflects and interferes the first signal light to form a Mach-Zehnder interference signal.

[0059] The front end of the probe of the present invention is plated with a reflective film structure to reflect the Mach-Zehnder interferometer signal to achieve reflective demodulation. Figure 5 It can be seen that the optical fiber drug delivery release probe 106 of the present invention is like a reflective probe structure as a whole, thanks to the reflective film 206 coated on the front end. The advantage of the reflective structure is that it can directly enter the body like a probe. Reflective demodulation means that the incident end and the reflection receiving end are on the same side, that is, the incident light 207 and the reflected light 208 are both through the same end, that is, the signal light can be incident at one end, and the demodulation system can also be connected to this end at the same time to demodulate the signal light reflected from the incident signal light (which carries a lot of information at this time).

[0060] S5: The fiber Bragg grating 201 reflects the first signal light to form a Bragg reflection signal.

[0061] S6: The pump light emitted by the pump light source 103 passes through the wavelength division multiplexer 105 and is incident on the rear end of the optical fiber drug delivery and release probe 106 as the second signal light.

[0062] S7: The active optical fiber 205 in the optical fiber Mach-Zehnder interferometer 200 absorbs the second signal light and activates the rare earth ions inside the active optical fiber 205 to increase the temperature.

[0063] The rare earth ions inside the active optical fiber 205 will undergo energy level transition under the pumping activation of the second signal light and generate a large amount of heat during ion relaxation, thereby achieving a temperature rise at the active optical fiber 205. Specifically, the 980nm pump light enters the probe through the rear end of the probe. When passing through the active optical fiber 205, the rare earth ions (Er 3+ , Yb 3+ ) will absorb the 980nm pump light, resulting in a series of electronic transitions, and the unstable valence state will undergo thermal relaxation to release heat, thereby heating the front end of the probe. The front end of the probe is wrapped with a photothermal sensitive material drug coating 202 carrying a drug 203 (such as an anti-tumor drug). It will soften and melt as the temperature of the front end rises, and the drug 203 wrapped by the material will be released to start treating the affected area (such as a tumor). Under photothermal conditions, the therapeutic effect of the drug will be enhanced due to changes in blood flow, vascular permeability, and pH in the affected area. In addition, tumors are heat-intolerant, so photothermal itself also has a killing effect on tumors.

[0064] It can be seen that the front end of the optical fiber drug delivery release probe 106 of the present invention generates heat under the excitation of the introduced light, which heats up the front end. On the one hand, direct light therapy of the affected area can be achieved. On the other hand, the phase change of the drug-loaded coating 202 is achieved through light excitation, and the drug 203 is released to the affected area and inside the affected area, thereby realizing the synergistic treatment function of photothermal and drug.

[0065] S8: When the temperature of the drug-carrying coating 202 rises to a temperature higher than the human body temperature, a phase change occurs, thereby releasing the encapsulated drug 203 to the lesion.

[0066] The lesion may be a solid tumor, a metastatic tumor, cardiovascular stenosis, a traumatic wound, an inflammatory site, the inside of the skull, etc.

[0067] S9: The third signal light 208 including the Mach-Zehnder interference signal and the Bragg reflection signal is emitted from the rear end of the optical fiber drug delivery release probe 106 and transmitted to the spectrometer 101 via the wavelength division multiplexer 105 and the circulator 104 .

[0068] S10 : Preliminarily demodulating the third signal light through the spectrometer 101 , generating a corresponding spectrum and sending it to the controller 100 .

[0069] The spectrometer 101 receives the third signal light 208 reflected by the probe, and receives the controller 100 for subsequent spectrum analysis, such as spectrum wavelength drift, spectrum change, etc.

[0070] Generally, the front-end light and heat are regulated by adjusting the power of the 980nm pump light. The sensor signal demodulation is to first demodulate the third signal light 208 through the spectrometer 101, process the signal light into a group of spectral data, and then connect the controller (such as a computer) 100 for subsequent spectral analysis after obtaining a series of spectral data.

[0071] S11: The controller 100 obtains the current temperature and the amount of drug released by analyzing the spectrum.

[0072] The front end of the probe of the present invention can utilize the optical fiber sensing structure and sensor device design and integration to realize the sensing monitoring of the changes of multiple parameters (such as temperature and drug release amount) during the treatment process. Specifically, the present invention replaces the sensing part in the Mach-Zehnder interferometer structure with an active optical fiber 205, and writes a Bragg grating 201 on the active optical fiber 205, thereby realizing the dual parameter (temperature, drug release amount) sensing purpose and the heating purpose at the same time.

[0073] During the treatment process, the present invention monitors the temperature of the affected part and the amount of drug released from the affected part. The temperature monitoring is achieved by writing a light Bragg grating 201 on the active optical fiber 205. The drug release monitoring is achieved by constructing an optical fiber Mach-Zehnder interferometer 200 to monitor the changes of the external drug-loaded coating 202 at the front end of the probe. When the drug 203 is released, the external drug-loaded coating 202 will undergo a large refractive index change, which is sensed by the optical fiber Mach-Zehnder interferometer 200.

[0074] S11 specifically includes:

[0075] S11.1: Demodulate the Bragg reflection signal spectrum and the Mach-Zehnder interference signal spectrum from the spectrum.

[0076] Since the intensity of the Bragg reflection signal is significantly greater than the intensity of the Mach-Zehnder interference signal and the waveform is thin, the corresponding spectral lines are superimposed like an interference peak with another thin peak, and the signal can be easily distinguished. By analyzing the third signal light 208 and referring to the second signal light, the Bragg reflection signal spectrum and the Mach-Zehnder interference signal spectrum can be decoupled from the spectrum.

[0077] S11.2: Determine the current temperature based on the Bragg resonance wavelength in the Bragg reflection signal spectrum.

[0078] Real-time monitoring of photothermal therapy temperature is achieved by writing a fiber Bragg grating 201 in the active fiber part at the front end of the fiber. The fiber Bragg grating structure reflects incident light of a specific wavelength (first signal light), and the reflected wavelength is related to temperature, so the temperature change can be demodulated by the reflected light (third signal light).

[0079] Specifically, the maximum wavelength of the resonance peak is determined according to the Bragg resonance wavelength in the Bragg reflection signal spectrum. Then, according to the wavelength-temperature relationship curve measured in advance (which characterizes the corresponding relationship between the actual temperature and the maximum wavelength of the resonance peak in the Bragg reflection signal), the maximum wavelength of the resonance peak in the Bragg reflection signal is substituted into the wavelength-temperature relationship curve to determine the current temperature during the drug release process.

[0080] S11.3: Calculate the wavelength drift based on the Mach-Zehnder interference signal spectrum, and compare the wavelength drift and drug concentration relationship curve to obtain the current drug release amount.

[0081] Real-time monitoring of the drug release process is achieved through a refractive index sensor, a fiber optic Mach-Zehnder interferometer 200 formed by fusion splicing single-mode and multi-mode optical fibers. The specific principle is as follows: a drug-loaded coating 203 made of a photothermal sensitive material wraps the drug 203. When the temperature at the front end of the probe rises, the photothermal sensitive material begins to soften and melt, and the drug 203 wrapped inside is released to the outside. At this time, the refractive index of the drug-loaded coating 203 on the outside of the optical fiber will change significantly. At this time, the refractive index change is monitored by the refractive index sensitive characteristics of the Mach-Zehnder interferometer, and the drug release amount can be demodulated.

[0082] Specifically, since the fiber optic Mach-Zehnder interferometer 200 has a certain sensitivity to the refractive index, when the external refractive index changes, its interference signal spectrum will undergo an overall drift. The interference signal generally has multiple interference peaks, and the interference peak wavelength is also called the resonant characteristic wavelength. The drug release amount can be demodulated by monitoring the drift of its resonant characteristic wavelength.

[0083] Figure 6 2 is a schematic diagram of the Mach-Zehnder interference signal spectrum when the drug-carrying coating 202 encapsulating the drug 203 undergoes a phase change. Figure 6 As shown, the longer the drug 203 is released, the greater the drug release amount is. After the drug 203 is released, the refractive index of the drug-loaded coating 202 is greatly reduced, resulting in the left shift of the resonant characteristic wavelength, that is, the resonant characteristic wavelength is reduced. Figure 6The interference peak of the Mach-Zehnder interference signal spectrum is manifested as a resonance valley, and the resonance characteristic wavelength at this time is the minimum value wavelength of the resonance valley, that is, the phase change state of the drug-carrying coating 202 encapsulating the drug 203 has a certain corresponding relationship with the minimum value wavelength of the resonance valley in the Mach-Zehnder interference signal spectrum. Therefore, the change of the drug release amount can be monitored according to the minimum value wavelength of the resonance valley in the reflection signal of the fiber Bragg grating 201. The drug release amount is usually characterized by the drug release concentration. Specifically, Figure 7 The relationship between the resonance characteristic wavelength shift and the drug release concentration is shown. Figure 7 It can be seen that there is a linear relationship between wavelength drift and drug release. Therefore, the drug release amount can be demodulated by demodulating the drift of the resonant characteristic wavelength and then corresponding to the linear relationship here.

[0084] S12: The controller 100 adjusts the power and working time of the signal light source 102 and the pump light source 103 according to the current temperature and the drug release amount, so as to control the temperature and the drug release amount.

[0085] During the treatment process, the temperature at the lesion and the amount of drug released are related to the incident light power and the incident time. Therefore, the temperature at the lesion and the amount of drug released can be adjusted by adjusting the power and working time of the signal light source 102 and the pump light source 103.

[0086] In some embodiments, after determining the phase change state of the drug-loaded coating 202 that encapsulates the drug 203, the probe can be functionally modified to perform specific sensing detection on the target molecules and components in the drug to be tested 203, and combined with the refractive index of the coating, the specific detection of the release of the drug to be tested is completed. Among them, functional modification of the probe refers to adding more functions to the probe, such as adding a pH fluorescent group to detect the pH value. Specific sensing detection refers to the use of a more specific method, such as antigen-antibody detection, and the accuracy of such detection is greatly improved compared to refractive index detection. If the coating refractive index detection and specific detection are combined, the accuracy and scalability of the detection can be greatly improved.

[0087] The optical fiber-based controlled drug delivery and release device provided by the present invention can deliver drugs to deep lesions through optical fibers, and combines optical fiber sensing technology with functional means to achieve monitoring of drug delivery and release processes. Furthermore, lesion identification can be performed by adding additional means such as marker detection and endoscopy, which is the prospect and future development of the present invention.

[0088] Compared with the prior art, the present invention has at least the following advantages and beneficial effects:

[0089] 1) Compared with the existing drug delivery technology, the optical fiber-based controlled drug delivery and release device proposed in the present invention can be loaded with photothermal sensitive materials and drugs at the same time, and can accurately complete the precise targeted drug delivery to the affected area regardless of the depth of the lesion.

[0090] 2) Compared with the passive accumulation of conventional drugs at the lesion site, the optical fiber-based controlled drug delivery and release device proposed in the present invention can achieve point-specific light-controlled drug release, ensure drug accumulation at the lesion site, and reduce the impact on other normal tissues and organs.

[0091] 3) The present invention is different from conventional photothermal and photothermal induced therapies based on external laser irradiation. The present invention realizes an endogenous photoexcitation effect and can realize a new "center-to-whole" photothermal synergistic drug diffusion mechanism, which can effectively improve the penetration and retention of drugs in lesions. The treatment can be completed with a single optical fiber probe at a low cost.

[0092] 4) The present invention can utilize the sensor structure integrated in the optical fiber to achieve real-time and accurate feedback of the drug release dose and the temperature at the lesion during treatment, thereby ensuring operational safety.

[0093] 5) The present invention can achieve accurate drug delivery and drug release control, has high permeability and retention, and also has drug release and temperature monitoring functions. It can not only achieve minimally invasive synergistic treatment of deep lesions in the body, but also provide a new drug screening and efficient evaluation system for the development of new drugs.

[0094] The principles and implementation methods of the present invention are described in this article using specific examples. The description of the above embodiments is only used to help understand the method and core idea of ​​the present invention. At the same time, for those skilled in the art, according to the idea of ​​the present invention, there will be changes in the specific implementation methods and application scope. In summary, the content of this specification should not be understood as limiting the present invention.

Claims

1. A drug controllable delivery and release device based on optical fiber, characterized in that: include: Fiber-optic drug delivery release probe and excitation light source connected by a fiber-optic link; The optical fiber drug delivery and release probe comprises an optical fiber Mach-Zehnder interferometer, an optical fiber Bragg grating, a drug-loaded coating and a drug; The front end of the optical fiber drug delivery and release probe is called the probe front end; The front end of the probe is used to contact the lesion or probe into the lesion, and the front end of the probe carries therapeutic drugs for the lesion; The front end of the probe directly receives the excitation light energy of the excitation light source, or converts the excitation light energy of the excitation light source into other forms of energy to realize light-controlled drug release, releases the drug to the lesion, and realizes the treatment of the lesion; The front end of the probe is wrapped with a photothermal sensitive material and fixed to the surface of the optical fiber, so that the drug can be loaded on the optical fiber. The front end of the probe uses optical fiber sensing structure and sensor device design and integration to achieve real-time sensing monitoring of changes in multiple characteristic parameters during light-controlled drug delivery and release therapy; the multiple characteristic parameters include temperature and drug release amount; The real-time sensing monitoring of the drug release amount is completed by an optical fiber Mach-Zehnder interferometer; the optical fiber Mach-Zehnder interferometer is formed by fusion splicing a single-mode optical fiber and a multi-mode optical fiber; The single-mode optical fiber is an active optical fiber doped with rare earth ions; the drug-carrying coating wraps the drug and fixes it on the surface of the active optical fiber, serving as the front end of the probe; In order to prepare the drug-loaded coating wrapped with drugs, a tetrafluoro capillary with a specified inner diameter is placed on the surface of the active optical fiber, and the molten drug-loaded hydrogel is injected into the tetrafluoro capillary using a needle and left to cool. After cooling, the tetrafluoro capillary is taken out; the probe with the drug-loaded hydrogel layer fixed is placed in a drying oven to remove excess moisture, thereby obtaining the drug-loaded coating; The front end of the probe is plated with a reflective film structure for reflecting the optical fiber Mach-Zehnder interferometer signal to achieve reflective demodulation; The front end face of the single-mode optical fiber away from the multi-mode optical fiber is coated with a reflective film; during preparation, the multi-mode optical fiber is fused with the single-mode optical fiber, and the end face of the single-mode optical fiber is sliced ​​and then placed in a vacuum gold coating device to coat the end face with a reflective film.

2. The optical fiber-based drug controllable delivery and release device according to claim 1, characterized in that: The front end of the probe enters the lesion through percutaneous or vascular intervention.

3. The optical fiber-based drug controllable delivery and release device according to claim 1, characterized in that: The lesions include solid tumors, cardiovascular stenosis, traumatic wounds, inflammatory areas and the inside of the skull.

4. The optical fiber-based drug controllable delivery and release device according to claim 1, characterized in that: The photothermal photosensitive material generates heat under the excitation of light introduced into the front end of the probe, which heats up the front end of the probe. On the one hand, direct photothermal treatment of the lesion is achieved. On the other hand, the phase change of the photothermal sensitive material is achieved through temperature increase, and the drug is released at the lesion, thereby realizing the synergistic treatment function of photothermal and drug.

5. The optical fiber-based drug controllable delivery and release device according to claim 4, characterized in that: The photothermal sensitive material is a high-temperature phase-change gel, which is in a solid phase at human body temperature and in a liquid phase at a temperature higher than human body temperature.

6. The optical fiber-based drug controllable delivery and release device according to claim 1, characterized in that: The real-time sensing monitoring of the temperature is completed by the fiber grating written in the front end of the probe.

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