In-vivo photo-curing photo-thermal filling device and application thereof

Abstract

The invention relates to an in-vivo photo-curing photo-thermal filling device and application thereof. The in-vivo photo-curing photo-thermal filling device comprises an intervention catheter and an in-vivo photo-curing photo-thermal filling agent. The interventional catheter comprises an outer tube, and a first optical fiber, a second optical fiber and an inner tube which are arranged in the outer tube, the first optical fiber and the second optical fiber are used for transmitting laser with different wavelengths; an inner cavity is formed in the inner pipe and is used for injecting an in-vivo photocuring photo-thermal filling agent; the far ends of the first optical fiber and the second optical fiber protrude out of the far end of the inner tube, and the far end of the outer tube protrudes out of the far ends of the first optical fiber and the second optical fiber; a target area can be filled with the in-vivo photocuring photo-thermal filler through the inner pipe, and meanwhile the in-vivo photocuring photo-thermal filler is irradiated and cured through lasers with different wavelengths.

Description

Technical Field

[0001] The present application relates to the field of biomedicine, and in particular to an in vivo photocuring photothermal filling device and its application. Background Art

[0002] Liver cancer ranks third among malignant tumors. Currently, hepatic artery embolization (TAE) has replaced radiotherapy and become the primary treatment for unresectable liver cancer. Clinically, the embolic materials used in TAE include gelatin sponge, iodized oil emulsion, anhydrous alcohol and microspheres / capsules. However, these embolic materials have certain limitations. Gelatin sponge is relatively large and cannot enter small blood vessels after swelling with water; iodized oil emulsion and anhydrous alcohol can damage the endothelium of small blood vessels, and their reflux phenomenon may cause infarction of adjacent organs; although microspheres / capsules can encapsulate anticancer drugs, they may cause excessive embolism and misembolization.

[0003] Photothermal therapy (PTT), as a phototherapy strategy for tumors, has attracted widespread attention due to its safety and effectiveness. The key to photothermal therapy lies in the two links of photothermal agents and lasers. At present, although metal-based photothermal agents have high photothermal conversion efficiency, they are expensive and are not conducive to widespread clinical application. Although carbon-based materials have a large photothermal conversion area, they have poor absorption capacity under near-infrared light irradiation. Semiconductor-based materials have the advantages of high photothermal performance and low cost, but they often need to be further processed into nanoformulations to enhance specificity and tumor targeting capabilities. Some organic photothermal agents also need to be modified and nanoformulated to improve their photothermal conversion efficiency, solubility, biocompatibility, and tumor targeting capabilities.

[0004] In the past few decades, the research and development of phototherapy drugs and equipment for cancer treatment has progressed rapidly, but key problems such as laser penetration have limited its wide clinical application except for some skin disease indications. Most current lasers irradiate the surface of the body or irradiate through endoscopic balloon catheters, and cannot effectively irradiate deep tumors, such as diode lasers used in dentistry and ophthalmology. Although there have been some reports of non-vascular interventional photothermal therapy (IPTT), the lesions are approached through natural cavities (such as the urethra) or through percutaneous puncture. Compared with the commonly used iodine interstitial brachytherapy in clinical practice, IPTT not only has a higher survival rate, but also can inhibit the metastasis of pancreatic tumors. However, non-vascular interventional photothermal therapy can only affect the surface of the target organ, and it is still impossible to penetrate and effectively treat tumors located in deep layers. Moreover, the photothermal agent used in non-vascular interventional photothermal therapy has poor targeting and still needs to be administered intravenously. Not only does it not solve the targeting problem of the photothermal agent, it also makes the treatment process complicated and cumbersome, reduces the treatment effect, and may also damage normal tissues.

[0005] At present, photothermal therapy is rarely used in clinical practice, and its more serious problem is that the research on photothermal agents and lasers is separated from each other. A large number of preclinical studies focus on the characterization of new photothermal agents, while clinical studies usually focus on the development of integrated laser equipment systems that do not rely on exogenous agents. Therefore, the convenient and targeted combination of the two may be the key breakthrough to break the current dilemma of photothermal therapy. Summary of the invention

[0006] Based on this, one embodiment of the present application provides an in vivo photocuring photothermal filling device, which can achieve photo-cross-linking embolization and photothermal agent-mediated photothermal therapy in channels such as blood vessels, forming a double guarantee.

[0007] The technical solutions include the following:

[0008] An in vivo photocuring photothermal filling device, comprising an interventional catheter and an in vivo photocuring photothermal filling agent;

[0009] Wherein, the interventional catheter comprises an outer tube, and a first optical fiber, a second optical fiber and an inner tube arranged in the outer tube;

[0010] The first optical fiber and the second optical fiber are used to transmit lasers of different wavelengths;

[0011] The inner tube has an inner cavity for injecting the in vivo light-curing photothermal filler;

[0012] The distal ends of the first optical fiber and the second optical fiber protrude from the distal end of the inner tube, and the distal end of the outer tube protrudes from the distal ends of the first optical fiber and the second optical fiber;

[0013] The in vivo light-curing photothermal filler can be filled into a target area in a channel such as a blood vessel through the inner tube, and simultaneously cured by laser irradiation of different wavelengths.

[0014] In one embodiment, the first optical fiber and the second optical fiber transmit laser light with wavelengths of 365 nm to 1200 nm, respectively and independently.

[0015] In one embodiment, the first optical fiber transmits laser light with a wavelength of 365 nm to 700 nm.

[0016] In one embodiment, the second optical fiber transmits laser light with a wavelength of 400 nm to 1200 nm.

[0017] In one embodiment, the laser power density of the first optical fiber transmitted laser is 1 mW / cm 2 ~1 W / cm 2 , and / or, the laser power density of the second optical fiber transmission laser is 0.1 W / cm2 ~20.0 W / cm 2 .

[0018] In one embodiment, the laser irradiation of the second optical fiber is divided into a first stage and a second stage, and the laser power density of the transmission laser in the first stage is 0.1 W / cm 2 ~20.0 W / cm 2 The laser power density of the second stage transmission laser is 0.1 W / cm 2 ~20.0 W / cm 2 .

[0019] In one embodiment, the distal ends of the first optical fiber and the second optical fiber protrude from the distal end of the inner tube by 1 mm to 5 mm; the distal end of the outer tube protrudes from the distal ends of the first optical fiber and the second optical fiber by 1 mm to 5 mm.

[0020] In one embodiment, the number of the first optical fiber and the number of the second optical fiber are independently greater than or equal to 2.

[0021] In one embodiment, the material of the inner tube and the outer tube independently includes one or more of polytetrafluoroethylene and polyethylene.

[0022] In one embodiment, the outer diameter of the catheter is less than or equal to 3.0 mm. Optionally, the outer diameter of the catheter is 0.8 mm to 3.0 mm.

[0023] In one embodiment, the in vivo light-curable photothermal filler comprises a photothermal agent, a photo-crosslinked hydrogel and a photoinitiator.

[0024] In one embodiment, the photo-crosslinked hydrogel includes one or more of methacrylic anhydride gelatin (GelMA), methacrylated hyaluronic acid (HAMA), polyethylene glycol diacrylate (PEGDA), polylactic acid-co-glycolic acid (PLGA), alginate-based hydrogel and methacrylated sodium carboxymethylcellulose hydrogel.

[0025] In one embodiment, the photothermal agent includes one or more of indocyanine green, Prussian blue, polydopamine, 11-chloro-1,1'-di-n-propyl-3,3,3',3'-tetramethyl-10,12-trimethyleneindotricarbonyl iodide (IR780), porphyrin compounds, gold nanoparticles, silver nanoparticles, graphene and carbon nanotubes.

[0026] In one embodiment, the photoinitiator includes lithium phenyl (2,4,6-trimethylbenzoyl) phosphate (LAP), sodium phenyl (2,4,6-trimethylbenzoyl) phosphite (NAP), 2,4,6-trimethylbenzoyl-diphenylphosphine oxide (TPO), riboflavin, phenyl bis (2,4,6-trimethylbenzoyl) phosphine oxide (Irgacure819), tetramethylethylenediamine, 2-hydroxy-1-(4-(2-hydroxyethoxy)phenyl)-2-methylpropanone (Irgacure2959) and benzoin methyl ether (2-methoxy-1,2-diphenylethanone).

[0027] In one embodiment, the Young's modulus of the in vivo light-curable photothermal filler is 10 kPa to 100 kPa.

[0028] In one embodiment, the Young's modulus of the in vivo light-curable photothermal filler is 40 kPa to 50 kPa.

[0029] In one embodiment, in the in vivo light-curable photothermal filler, the weight percentage of the photo-crosslinked hydrogel is 10 wt.% to 60 wt.%, the concentration of the photothermal agent is 65 μM to 1290 μM, and the weight percentage of the photoinitiator is 0.01 wt.% to 5 wt.%.

[0030] In one embodiment, the photo-crosslinked hydrogel, the photoinitiator and the photothermal agent are mixed with a phosphate buffered saline solution to prepare the in vivo photocurable photothermal filler.

[0031] In one embodiment, the photo-crosslinked hydrogel is mixed with the phosphate buffered saline solution, and then the photoinitiator is added and mixed, and then the photothermal agent is added and mixed to prepare the in vivo photocurable photothermal filler.

[0032] In one embodiment, the mixing is performed at 60°C to 70°C.

[0033] In one embodiment, the prepared in vivo light-curable photothermal filler is placed at 2°C to 8°C.

[0034] An in vivo light-curing photothermal filler, wherein the in vivo light-curing photothermal filler includes the in vivo light-curing photothermal filler defined in the in vivo light-curing photothermal filling device, and the in vivo light-curing photothermal filler is not irradiated with laser.

[0035] Application of the in vivo photocuring photothermal filling device or the in vivo photocuring photothermal filling agent in the preparation of products for tissue filling and repair.

[0036] Compared with the traditional technology, this application has the following beneficial effects:

[0037] The in vivo photocuring photothermal filling device provided by the present application has the following effects:

[0038] 1. Efficient embolization: The combination of photothermal agent and photocross-linked hydrogel in the in vivo photocurable photothermal filler ensures the stable embolization of the hydrogel in the blood vessels under the action of lasers of different wavelengths transmitted by the catheter, effectively blocking the blood supply. This method of intravascular photocross-linking embolization is highly stable and effective. Compared with traditional embolic substances, the in vivo photocurable photothermal filler is a prefabricated embolic agent before photocross-linking. It can be extruded into any shape and can completely fit the shape of the blood vessel. After being squeezed into the blood vessel, it is irradiated with laser to complete cross-linking in the blood vessel, making it fit the blood vessel more completely, and can form a more lasting and reliable embolic effect. In clinical applications, it can significantly reduce the risk of disease recurrence caused by incomplete embolism, improve the accuracy and success rate of blocking the blood supply to the lesion site, and create more favorable conditions for subsequent treatment.

[0039] 2. High-efficiency photothermal therapy: Vascular-mediated photothermal therapy can accurately destroy diseased tissues and improve the treatment effect. Under the action of the above-mentioned high-efficiency embolization, the photothermal agent in the photocurable photothermal filler in the body can efficiently convert light energy into heat energy under the excitation of the specific wavelength laser transmitted by the catheter, and this heat energy can be highly focused on the diseased tissue. This precise energy transfer mechanism can minimize damage to surrounding normal tissues, causing coagulative necrosis of the diseased tissue under local high temperature, thereby achieving the purpose of removing the lesion. Compared with traditional treatment methods, it greatly improves the efficiency and thoroughness of lesion removal.

[0040] 3. Double insurance: The device combines photo-cross-linking embolization with photothermal therapy to form a double protection mechanism, reducing the risk of treatment and the incidence of complications. On the one hand, the in vivo photocurable photothermal filler of the present application blocks the blood supply to the diseased tissue from a physical level, inhibiting its growth and spread; on the other hand, photothermal therapy destroys the structure and function of diseased cells from a biochemical level. The two complement each other. Even if one of the treatment methods fails to achieve the ideal effect locally, the other method can still play a role. This synergistic effect greatly enhances the reliability of treatment and reduces the problems of insufficient treatment or complications that may occur with a single treatment method, such as recurrence of lesions caused by incomplete embolism and damage to surrounding tissues caused by excessive photothermal therapy.

[0041] 4. Personalized treatment: By adjusting the laser parameters transmitted by the catheter and the ratio of the photocurable photothermal filler in the body, personalized treatment plans for different lesions can be achieved. The lesion conditions (such as lesion size, location, type, etc.) of different patients are different. By accurately adjusting the laser wavelength, power, irradiation time and other parameters, as well as the ratio of photocross-linked hydrogel and photothermal agent, the most suitable treatment plan can be formulated according to the specific condition of each patient. This personalized treatment model can better meet the diverse clinical needs, improve the pertinence and effectiveness of treatment, maximize the treatment effect, further reduce the incidence of adverse reactions, and provide patients with better medical services. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] In order to more clearly illustrate the technical solutions in the embodiments of the present application and to more completely understand the present application and its beneficial effects, the following is a brief introduction to the drawings required for the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present application, and those skilled in the art can obtain other drawings based on these drawings without creative work.

[0043] Figure 1A This is a three-dimensional schematic diagram of the interventional catheter. Figure 1B A schematic cross-sectional view of an interventional catheter.

[0044] Figure 2 The flexibility of the interventional catheter (left) and the continuity of the Gel-ICG photothermal gel extrusion in Example 1 (right).

[0045] Figure 3 The extrusion state of the 645 μM Gel-ICG photothermal gel in Example 1 (left picture, left-1 is ~60°C, left-2 is 4°C) and the vascular filling state of the 645 μM Gel-ICG photothermal gel in Example 1 (right picture).

[0046] Figure 4 The 645 μM Gel-ICG photothermal gel in Example 1 was heated at 0 W / cm 2 (Left), 0.2 W / cm 2 (middle), 0.5 W / cm 2 (Right) Photothermal conversion of laser power density.

[0047] Figure 5 The Gel-ICG photothermal gels with different concentrations in Example 1 were heated to 0.5 W / cm 2 The photothermal conversion efficiency of the power (left figure) and the photothermal conversion power of the 645 μM Gel-ICG photothermal gel in Example 1 at different laser power densities (right figure).

[0048] Figure 6 The stress-strain curves (left figure) of Gel-ICG photothermal water gels with different concentrations in Example 1 and the Young's modulus (right figure) of Gel-ICG photothermal water gels with different concentrations, wherein the Young's modulus of Gel-ICG photothermal water gel with a concentration of 1290 μM is 15.4 ~ 17.5 kPa (with an average value of 16.23 kPa), the Young's modulus of Gel-ICG photothermal water gel with a concentration of 645 μM is 46.3 ~ 49.6 kPa (with an average of 48.36 kPa), and the Young's modulus of Gel-ICG photothermal water gel with a concentration of 129 μM is 90 ~ 108 kPa (with an average of 98.1 kPa).

[0049] Figure 7 The survival rate of Gel-ICG photothermal hydrogels with different concentrations in Example 1 under the MTT method (left figure) and the survival of HUVEC in Gel-ICG photothermal hydrogels detected by the live / dead assay (right figure).

[0050] Figure 8 Infrared thermal imaging image (left) and pathological section image (right) of the rabbit ear treated with 645 μM Gel-ICG photothermal water gel for photothermal-assisted embolization double insurance treatment in Example 1 of transvascular intervention in rabbit ear, black scale bar = 500 μm, white scale bar = 250 μm. DETAILED DESCRIPTION

[0051] In order to make the above-mentioned purposes, features and advantages of the present application more obvious and easy to understand, the specific implementation methods of the present application are described in detail below. In the following description, many specific details are set forth to facilitate a full understanding of the present application. However, the present application can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without violating the connotation of the present application, so the present application is not limited by the specific embodiments disclosed below.

[0052] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0053] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0054] In this article, "laser intensity" refers to the laser power per unit area, also called light intensity or irradiance, usually expressed in watts per square centimeter (W / cm²).

[0055] Herein, "photo-crosslinked hydrogel" is a hydrogel material formed by a photo-induced crosslinking reaction.

[0056] An embodiment of the present application provides an in vivo photocurable photothermal filler, which includes a photothermal agent, a photocrosslinked hydrogel, and a photoinitiator. The in vivo photocurable photothermal filler can be filled into a target area of ​​a channel such as a blood vessel through an interventional catheter, and can be cured by laser irradiation of different wavelengths to play a blocking and thermal therapy role, greatly improving the effect and stability of embolization therapy.

[0057] In vivo light-curing photothermal fillers have a wide range of applications, not only in intravascular embolization, but also in other human channels, such as the treatment of tracheoesophageal fistula, bronchopleural fistula, esophageal gastric varices, gastric ulcer perforation, intestinal anastomotic leakage, ureteral injury, bladder fistula, vaginal fistula, corneal repair and reinforcement, and new blood vessel occlusion. In the field of cosmetic medicine, this filler can also be used for subcutaneous filling, including wrinkle filling, facial contouring, and skin tightening and lifting.

[0058] In a specific example, the photo-crosslinked hydrogel includes, but is not limited to, one or more of methacrylic anhydride gelatin, methacrylated hyaluronic acid, polyethylene glycol diacrylate, polylactic acid-glycolic acid copolymer, alginate-based hydrogel, and methacrylated sodium carboxymethylcellulose hydrogel. The above-mentioned photo-crosslinked hydrogel has a high embolic effect. By evaluating factors such as the embolic effect, biocompatibility, and degradation rate of different hydrogels, the optimal hydrogel can be selected for intravascular embolization therapy. For example, for situations where short-term embolism is required, a hydrogel with a faster degradation rate can be selected; for long-term embolism requirements, a hydrogel that degrades slowly and is stable is more suitable, which allows the treatment plan to be flexibly adjusted according to the specific condition.

[0059] In a specific example, the photothermal agent includes but is not limited to indocyanine green, Prussian blue, polydopamine, 11-chloro-1,1'-di-n-propyl-3,3,3',3'-tetramethyl-10,12-trimethylene indotricarbonyl iodide salt, porphyrin compounds, gold nanoparticles, silver nanoparticles, graphene and carbon nanotubes. One or more of the above-mentioned photothermal agents have good photothermal conversion efficiency and biocompatibility. By comparing the therapeutic effects, safety and cost of different photothermal agents, the optimal photothermal agent can be selected for photothermal therapy.

[0060] In a specific example, the photo-crosslinked hydrogel is methacrylic anhydride gelatin, and the photothermal agent is indocyanine green. The present application selects a combination of indocyanine green and methacrylic anhydride gelatin to prepare an in vivo photocurable photothermal filler, which has low cost, higher safety, less damage to surrounding tissues, more stable and more effective embolization in blood vessels, and a high photothermal conversion rate, which makes the embolization treatment effect and photothermal treatment effect better, and realizes the treatment of photothermal-assisted double-safety embolism through vascular intervention single-lumen dual-fiber catheter.

[0061] In a specific example, the photoinitiator includes lithium phenyl (2,4,6-trimethylbenzoyl) phosphate, sodium phenyl (2,4,6-trimethylbenzoyl) phosphite, 2,4,6-trimethylbenzoyl-diphenylphosphine oxide, riboflavin, phenyl bis (2,4,6-trimethylbenzoyl) phosphine oxide, tetramethylethylenediamine, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, and benzoin methyl ether (2-methoxy-1,2-diphenylethanone).

[0062] In a specific example, the Young's modulus of the in vivo light-curing photothermal filler is 10 kPa to 100 kPa. If the Young's modulus exceeds this range, the embolic material will be hard and have poor elasticity if the Young's modulus is too large, and the embolic material will be soft if the Young's modulus is too small, and the embolic effect may be poor, causing embolism or inflammatory response. Different Young's moduli can be appropriately selected within this range according to different scenarios. For example, for embolic treatment of arterial malformations, especially basket-shaped arterial malformations, the blood flow impact is relatively small, and the required range of Young's modulus can be relatively wide.

[0063] In a specific example, the Young's modulus of the in vivo light-curing photothermal filler is 40 kPa to 50 kPa. The in vivo light-curing photothermal filler with a Young's modulus within this range is suitable for materials used to embolize circulating blood vessels or blood vessel extremities, ensuring that the filler can smoothly fill the blood vessel cavity and maintain a stable embolization state.

[0064] In a specific example, in the in vivo photocurable photothermal filler, the weight percentage of the photocrosslinked hydrogel is 10 wt.% to 60 wt.%, optionally, the weight percentage of the photocrosslinked hydrogel is 10 wt.%, 15 wt.%, 20 wt.%, 25 wt.%, 30 wt.%, 35 wt.%, 40 wt.%, 45 wt.%, 50 wt.%, 55 wt.%, 60 wt.%, or a range between any two of the above values. In a specific example, the weight percentage of the photocrosslinked hydrogel is 10 wt.% to 40 wt.%. In a specific example, the weight percentage of the photocrosslinked hydrogel is 10 wt.% to 20 wt.%.

[0065] In a specific example, in the in vivo photocurable photothermal filler, the concentration of the photothermal agent is 65 μM to 1290 μM, and optionally, the concentration of the photothermal agent is 65 μM, 129 μM, 258 μM, 387 μM, 516 μM, 645 μM, 774 μM, 903 μM, 1032 μM, 1161 μM, 1290 μM, or a range between any two of the above values. In a specific example, in the in vivo photocurable photothermal filler, the concentration of the photothermal agent is 258 μM to 1161 μM, and the embolic effect of the embolic agent in this range is better.

[0066] In a specific example, in the in vivo photocurable photothermal filler, the weight percentage of the photoinitiator is 0.01 wt.% to 5 wt.%, optionally, the weight percentage of the photoinitiator is 0.01 wt.%, 0.02 wt.%, 0.05 wt.%, 0.1 wt.%, 0.15 wt.%, 0.2 wt.%, 0.25 wt.%, 0.3 wt.%, 0.35 wt.%, 0.4 wt.%, 0.45 wt.%, 0.5 wt.%, 1 wt.%, 2 wt.%, 3 wt.%, 4 wt.%, 5 wt.%, or a range between any two of the above values. In a specific example, in the in vivo photocurable photothermal filler, the weight percentage of the photoinitiator is 0.1 wt.% to 0.5 wt.%.

[0067] In a specific example, a photo-crosslinked hydrogel, a photoinitiator, and a photothermal agent are mixed with a phosphate buffered saline solution to prepare an in vivo photocurable photothermal filler.

[0068] In a specific example, a photo-crosslinked hydrogel is mixed with a phosphate buffered saline solution, a photoinitiator is added to the mixture, and a photothermal agent is added to the mixture to prepare an in vivo photocurable photothermal filler.

[0069] In a specific example, the mixing is performed at 60°C to 70°C.

[0070] In a specific example, the prepared in vivo light-curing photothermal filler is placed at 2° C. to 8° C., and after being placed, it has better fluidity, continuity and stability when squeezed out of the catheter.

[0071] Compared with the in vitro cross-linked microspheres, the in vivo photocurable photothermal filler of the present application is a prefabricated hydrogel before photocrosslinking, which can be extruded into any shape, not limited to spherical and linear, and can completely fit the shape of the blood vessel to form a completely sealed embolic effect. After the in vivo photocurable photothermal filler of the present application is squeezed into the blood vessel, it is irradiated with a laser to complete crosslinking in vivo, so that it can more completely fit the blood vessel and effectively embolize, avoiding accidental embolism.

[0072] One embodiment of the present application also provides an in vivo photocuring photothermal filling device, which includes an interventional catheter and the above-mentioned in vivo photocuring photothermal filler; wherein the interventional catheter includes an outer tube 1, and a first optical fiber 2, a second optical fiber 3 and an inner tube 4 arranged in the outer tube 1. The first optical fiber 2 and the second optical fiber 3 are used to transmit lasers of different wavelengths. The inner tube 4 has an inner cavity inside, which is used to inject the in vivo photocuring photothermal filler. The distal ends of the first optical fiber 2 and the second optical fiber 3 protrude from the distal end of the inner tube 4, and the distal end of the outer tube 1 protrudes from the distal ends of the first optical fiber 2 and the second optical fiber 3. The distal end of the outer tube 4 is a single-lumen channel, and the inner tube 4, the first optical fiber 2 and the second optical fiber 3 are all passed into the single-lumen channel.

[0073] The in vivo light-curing photothermal filler can be filled into the target area of ​​the channel such as the blood vessel through the inner tube 4, and solidified by laser irradiation of different wavelengths, playing a blocking and thermal therapy role, greatly improving the effect and stability of embolization treatment.

[0074] In a specific example, the first optical fiber 2 and the second optical fiber 3 transmit laser beams with wavelengths independently ranging from 365 nm to 1200 nm.

[0075] In a specific example, the first optical fiber 2 transmits a laser with a wavelength of 365 nm to 700 nm. In a specific example, the first optical fiber 2 transmits a laser with a wavelength of 405 nm.

[0076] In a specific example, the second optical fiber 3 transmits a laser with a wavelength of 400 nm to 1200 nm. In a specific example, the second optical fiber 3 transmits a laser with a wavelength of 700 nm to 1200 nm. In a specific example, the second optical fiber 3 transmits a laser with a wavelength of 808 nm.

[0077] In a specific example, the laser power density of the laser transmitted by the first optical fiber 2 is 1 mW / cm 2 ~1 W / cm 2 In a specific example, the laser power density of the laser transmitted by the first optical fiber 2 is 40.0 mW / cm 2 ~60.0 mW / cm 2 In a specific example, the laser power density of the laser transmitted by the first optical fiber 2 is 50.0 mW / cm 2 .

[0078] In a specific example, the laser power density of the laser transmitted by the second optical fiber 3 is 0.1 W / cm 2 ~20.0 W / cm 2 In a specific example, the laser power density of the laser transmitted by the second optical fiber 3 is 0.2 W / cm 2 ~0.5 W / cm 2 .

[0079] In a specific example, the in vivo light-curing photothermal filler can be filled into the target area of ​​the blood vessel through the inner tube 4, and solidified by laser irradiation of the first optical fiber 2 and the second optical fiber 3. Optionally, the time of laser irradiation of the first optical fiber 2 is 1 min to 10 min (for example, 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min or 10 min), and the time of laser irradiation of the second optical fiber 3 is 2 min to 20 min (for example, 2 min, 10 min, 20 min, 50 min, 100 min, 150 min or 20 min). Optionally, the irradiation is divided into two stages. In the first stage, the first optical fiber 2 and the second optical fiber 3 are irradiated with laser for 1 min to 10 min for curing, and in the second stage, the second optical fiber 3 is irradiated with laser for 1 min to 20 min for photothermal treatment.

[0080] In a specific example, the laser power density of the first stage transmission laser of the second optical fiber 3 is 0.1 W / cm 2 ~20.0 W / cm 2 The laser power density of the second stage transmission laser of the second optical fiber 3 is 0.1 W / cm 2 ~20.0W / cm 2 .

[0081] In a specific example, the distal ends of the first optical fiber 2 and the second optical fiber 3 protrude 1 mm to 5 mm from the distal end of the inner tube 4. This effectively prevents the filler from prematurely cross-linking and blocking the catheter channel due to premature contact with the fiber laser during the injection process, ensuring that the filler can be smoothly injected into the target area and completely cross-linked.

[0082] In a specific example, the distal end of the outer tube 1 protrudes 1 mm to 5 mm from the distal ends of the first optical fiber 2 and the second optical fiber 3. The optical fibers are always protected by the outer tube 1, which enhances the stability and safety of the catheter during use and reduces potential risks caused by damage to the optical fibers.

[0083] In a specific example, the number of the first optical fiber 2 and the second optical fiber 3 is independently greater than or equal to 2. The present application can use multiple multimode optical fibers or specially designed optical fibers to simultaneously transmit lasers of different wavelengths. By optimizing the design and manufacturing process of the optical fiber, the transmission efficiency and stability of the optical fiber are improved to meet the needs of simultaneously achieving photo-crosslinking embolization and photothermal therapy.

[0084] In a specific example, the material of the inner tube 4 and the outer tube 1 independently includes one or more of polytetrafluoroethylene (PTFE) and polyethylene (PE). The present application can select different catheter materials according to different treatment scenarios. By optimizing the structure and material of the catheter, the flexibility and biocompatibility of the catheter are improved to meet the treatment needs of different vascular locations and lesion types.

[0085] In a specific example, the outer diameter of the catheter is less than or equal to 3.0 mm, and optionally, the outer diameter of the catheter is 0.8 mm to 3.0 mm. The present application can design catheters of different sizes, such as microcatheters, ultramicrocatheters, etc., according to the specific needs of treating blood vessels of different sizes. By matching different catheter sizes with different blood vessels, the best treatment effect can be achieved.

[0086] One embodiment of the present application also provides a safe and efficient method for transvascular double-safety embolization, which is operated by using the above-mentioned catheter and the in vivo light-cured photothermal filler. The method implements photothermal-assisted double-safety embolization treatment via a single-lumen dual-fiber catheter for vascular intervention.

[0087] In a specific example, the method includes transmitting lasers of two wavelengths, 405 nm and 808 nm, and simultaneously delivering an in vivo photocurable photothermal filler containing indocyanine green and methacrylic anhydride gelatin hydrogel, to achieve photocrosslinking embolization of methacrylic anhydride gelatin and photothermal therapy mediated by indocyanine green in the blood vessel, forming a double guarantee. This method can not only significantly improve the treatment effect, but also reduce the risk of complications, opening up new ideas for new methods of intravascular photocrosslinking hydrogel embolization and intravascular photothermal therapy.

[0088] One embodiment of the present application also provides the use of the in vivo photocuring photothermal filling device in the preparation of products for treating tumors.

[0089] The in vivo photocuring photothermal filling device of the present application solves the following technical problems:

[0090] 1. Difficulties of in vivo photocrosslinking: Currently, the crosslinking process of most methacrylic anhydride gelatin hydrogels is carried out in vitro, that is, the hydrogel is first prepared into the desired shape and size, then crosslinked by light irradiation in vitro, and finally injected into the body. However, for intravascular treatment, in vivo photocrosslinking is more ideal because it can ensure that the hydrogel forms a stable embolic structure immediately after reaching the target location, and can adapt to the size of different blood vessels. However, a major problem facing in vivo photocrosslinking is the penetration of light. Due to the complexity of the vascular structure and the absorption and scattering of light by blood, in vivo photocrosslinking becomes difficult.

[0091] 2. Dual-wavelength laser transmission problem: Most of the fiber optic catheters on the market can only transmit lasers of a single wavelength. This limits the possibility of simultaneously realizing in vivo photo-cross-linking embolization and photothermal therapy. Single-wavelength fiber optic catheters cannot meet the needs of multiple treatments, requiring the use of multiple catheters or multiple operations during the treatment process, which not only increases the patient's pain and risk of infection, but also prolongs the treatment time. Moreover, the transmission of lasers of different wavelengths in optical fibers requires specific optical conditions and material properties. The existing single-wavelength fiber optic catheters do not take into account the need to simultaneously transmit two wavelengths of lasers in design and manufacturing. The core structure, refractive index distribution and other parameters cannot effectively support the stable transmission of dual-wavelength lasers, thereby limiting the clinical application and development of multiple treatment methods.

[0092] 3. Targeting issues of photothermal agents: In clinical practice, photothermal therapy faces the problem that it is difficult for photothermal agents to accurately reach the target site. In traditional photothermal therapy methods, the distribution of photothermal agents in the body through systemic injection is often difficult to control, and there is a lack of effective targeted delivery mechanisms. After injection, photothermal agents are easily diffused throughout the body through blood circulation, and cannot specifically gather around the diseased tissue. This non-targeted distribution will not only reduce the effect of photothermal therapy at the lesion site, but may also cause unnecessary damage to normal tissues.

[0093] 4. The problem of hydrogel blocking the transport channel: In intravascular photothermal hydrogel therapy, premature cross-linking of the hydrogel may block the delivery channel. When the hydrogel cross-links prematurely during the delivery process, solid or semi-solid substances will be formed, which may accumulate in the delivery pipeline, thereby blocking the channel. Once the channel is blocked, not only will the subsequent hydrogel be unable to be smoothly delivered to the lesion site, affecting the treatment effect, but additional operations may also be required to clear the blockage, increasing the complexity of the treatment and the patient's pain, and may even cause serious intravascular complications such as thrombosis, vascular inflammation, etc.

[0094] 5. Fiber protection issues: Fibers are easily damaged during intravascular operations, which can affect laser transmission and treatment effects, and may even cause safety issues. In the complex environment of vascular interventional treatment, optical fibers face a variety of potential damage factors. First, the bending, twisting, and telescopic movements of blood vessels can produce mechanical stress on the optical fiber. Long-term or frequent stress may cause the optical fiber to break or break. Secondly, if extremely thin optical fibers are exposed in blood vessels, they are very likely to scratch or puncture the vessel wall, causing a certain range of bleeding, which seriously threatens the safety and health of patients. Therefore, in intravascular treatment, the protection of optical fibers is a crucial technical issue.

[0095] The embodiments of the present application will be described in detail below in conjunction with examples. It should be understood that these examples are only used to illustrate the present application and are not intended to limit the scope of the present application. The experimental methods for which specific conditions are not specified in the following examples are preferably referred to the guidance provided in the present application, and can also be based on the experimental manual or normal conditions in this area, can also be based on the conditions recommended by the manufacturer, or refer to experimental methods known in the art.

[0096] In the following specific embodiments, the measured parameters of raw material components may have slight deviations within the range of weighing accuracy unless otherwise specified. For temperature and time parameters, acceptable deviations caused by instrument test accuracy or operation accuracy are allowed.

[0097] Example 1

[0098] Schematic diagram of transvascular dual-fiber interventional microcatheter (referred to as interventional microcatheter) Figure 1A and Figure 1B As shown, it includes an outer tube 1, and a first optical fiber 2, a second optical fiber 3 and an inner tube 4 arranged in the outer tube.

[0099] In one embodiment, the proximal ends of the first optical fiber 2 and the second optical fiber 3 are used to connect to the laser light source device. The inner tube 4 has an inner cavity for injecting a photocurable photothermal filler into the body.

[0100] In one embodiment, the distal ends of the first optical fiber 2 and the second optical fiber 3 protrude from the distal end of the inner tube 4 , and the distal end of the outer tube 1 protrudes from the distal ends of the first optical fiber 2 and the second optical fiber 3 .

[0101] The in vivo light-curing photothermal filler can be filled into the target area of ​​the blood vessel through the inner tube 4 and simultaneously cured by laser irradiation of different wavelengths.

[0102] In one embodiment, the distal end of the inner tube 4 is 1 mm to 5 mm away from the distal ends of the first optical fiber 2 and the second optical fiber 3; the distal ends of the first optical fiber 2 and the second optical fiber 3 are 1 mm to 5 mm away from the distal end of the outer tube.

[0103] The interventional microcatheter simultaneously transmits lasers of different wavelengths through two optical fibers (a first optical fiber 2 and a second optical fiber 3) connected to different lasers; a photocurable photothermal filler is directly injected into the target area through the inner cavity of an inner tube 4 in the microcatheter, which effectively solves the problem of clinical targeting of photothermal agents and improves the accuracy and effectiveness of photothermal therapy.

[0104] In one embodiment, the distance between the end (distal end) of the inner tube 4 and the end of the optical fiber is 1 mm to 5 mm, which effectively prevents the filler from prematurely cross-linking and blocking the catheter channel due to premature contact with the optical fiber laser during the injection process, ensuring that the filler can be smoothly injected into the target area and completely cross-linked. In one embodiment, the distance between the end of the optical fiber and the end (distal end) of the outer tube 1 is 1 mm to 5 mm, so that the optical fiber is always under the protection of the outer tube 1, enhancing the stability and safety of the microcatheter during use, and reducing the potential risks that may be caused by damage to the optical fiber.

[0105] In one embodiment, the first optical fiber 2 and the second optical fiber 3 transmit lasers with wavelengths of 365 nm to 1200 nm, respectively. In one embodiment, the first optical fiber 2 transmits lasers with wavelengths of 365 nm to 700 nm. In one embodiment, the second optical fiber 3 transmits lasers with wavelengths of 400 nm to 1200 nm. In one embodiment, the first optical fiber 2 and the second optical fiber 3 transmit lasers with wavelengths of 405 nm and 808 nm, respectively.

[0106] In one embodiment, the laser power density of the laser transmitted by the first optical fiber 2 is 1 mW / cm 2 ~ 1 W / cm 2 In one embodiment, the laser power density of the laser transmitted by the second optical fiber 3 is 0.1 W / cm 2 ~20.0 W / cm 2 .

[0107] In one embodiment, the laser irradiation of the second optical fiber 3 is divided into a first stage and a second stage. The laser power density of the transmission laser in the first stage is 0.1 W / cm 2 ~20.0 W / cm 2 The laser power density of the second stage transmission laser of the second optical fiber 3 is 0.1 W / cm 2 ~20.0 W / cm 2 .

[0108] In one embodiment, the number of the first optical fiber 2 and the number of the second optical fiber 3 are independently greater than or equal to 2.

[0109] In one embodiment, the materials of the inner tube 4 and the outer tube 1 independently include one or more of polytetrafluoroethylene (PTFE) and polyethylene (PE).

[0110] The main materials involved in the embodiment are as follows: polytetrafluoroethylene (PTFE) heat shrink tubing, 100 µm fiber jumper, 808 nm multimode pump light source, 405 nm semiconductor laser, methacrylic anhydride gelatin (Gelatin-methacryloyl, GelMA), photoinitiator phenyl (2,4,6-trimethylbenzoyl) lithium phosphite (LAP), one-fold phosphate buffered saline (1×PBS), and indocyanine green (ICG).

[0111] Example, preparation of the interventional microcatheter:

[0112] Black polytetrafluoroethylene (PTFE) heat shrink tubes with inner diameters of 0.6 mm and 1.0 mm were coaxially installed, and two fiber jumpers with a diameter of 100 µm were inserted between the heat shrink tubes. The end (proximal end) of one fiber jumper was connected to an 808 nm multimode pump light source, and the end (proximal end) of the other fiber jumper was connected to a 405 nm semiconductor laser. The end (distal end) of the fiber jumper was 2 mm away from the inner and outer Teflon heat shrink tubes, and the end (distal end) of the inner and outer Teflon heat shrink tubes was 4 mm away. The black polytetrafluoroethylene (PTFE) heat shrink tube was heated to shrink it into an interventional microcatheter with an inner diameter of 0.5 mm and an outer diameter of 1.0 mm. Interventional catheters with outer diameters of 0.8 mm to 3 mm were prepared according to the above method.

[0113] For example, the in vivo light-curable photothermal filler (abbreviated as photothermal gel) includes 20 wt.% GelMA, 0.25 wt.% LAP and 645 μM (0.5 mg / mL) ICG, named Gel-ICG photothermal gel.

[0114] Preparation of Gel-ICG photothermal gel: Weigh 0.4032 g of SunP Gel G1 (methacrylic anhydride gelatin, GelMA) lyophilized powder, add 1800 µL of 1× phosphate buffered saline (1×PBS), and dissolve in a 65°C water bath until there is no precipitation or dense bubbles. Add 200 µL of phenyl (2,4,6-trimethylbenzoyl) lithium phosphite (LAP) photoinitiator, vortex and place in a 65°C water bath to mix evenly. Then weigh 0.001 g of indocyanine green for injection (National Medicine Standard H20055881), vortex and mix evenly, and place in a 65°C water bath until the indocyanine green is completely dissolved.

[0115] According to the above method, the amount of indocyanine green was changed to prepare Gel-ICG photothermal water gels with different indocyanine green concentrations (0 μM-1290 μM, for example, 0 μM, 129 μM, 258 μM, 645 μM, 1290 μM).

[0116] The interventional microcatheter utilizes the vascular channel to find the target area under X-Ray development, and injects an embolic agent such as Gel-ICG photothermal gel through the inner cavity of the inner tube 4, while simultaneously exciting the first optical fiber 2 (e.g., 405 nm) to laser-crosslink methacrylic anhydride gelatin GelMA (Gelatin Methacryloyl, methacrylylated gelatin) to form an embolism, and exciting the second optical fiber 3 (e.g., 808 nm) to laser-trigger indocyanine green (ICG)-mediated photothermal therapy.

[0117] Among them, the photothermal gel initiated by the first optical fiber 2 (e.g., 405 nm) can achieve a high degree of spatial and real-time control. Compared with traditional embolic materials, photocurable materials have good fluidity when not cured, can better conform to the shape and direction of blood vessels, ensure complete filling of target blood vessel branches, and reduce the risk of treatment failure caused by uneven material distribution.

[0118] Among them, the in vivo photothermal therapy triggered by the second optical fiber 3 (e.g., 808 nm) can achieve precise spatial selectivity and efficient treatment, and can be used in combination with other treatment methods to enhance the treatment effect, such as chemotherapy, immunotherapy, and photodynamic therapy. Compared with percutaneous photothermal therapy, transvascular interventional photothermal therapy is not hindered by superficial tissues such as skin and muscle, providing sufficient energy to reach the lesion site and avoiding percutaneous damage. In the first stage, the first optical fiber 2 (e.g., 405 nm) and the second optical fiber 3 (e.g., 808 nm) are excited simultaneously. At this time, 0.2 W / cm 2 Thermotherapy increases the fluidity of the photothermal gel, allowing it to fill the entire blood vessel and promote photocuring in vivo. Phase 2 Second fiber 3 (e.g. 808nm) laser 0.5 W / cm 2 The high temperature treatment directly causes irreversible damage to cells, achieving photothermal therapy.

[0119] Example 2

[0120] The photothermal water gel of this embodiment is basically the same as that of embodiment 1, except that:

[0121] In this embodiment, polyethylene glycol diacrylate (PEGDA) is used to prepare the photothermal water gel. PEGDA is dissolved in a certain concentration of indocyanine green solution to prepare a hydrogel precursor solution, wherein the weight percentage of PEGDA in the photothermal water gel is 60 wt.%. A photoinitiator (Irgacure819, 12.5 mg / mL) is added to the solution and mixed thoroughly, and the weight ratio of photoinitiator / PEGDA is 0.02 wt.%. The concentration of indocyanine green is any one of 129 μM, 258 μM, 645 μM, and 1290 μM.

[0122] This embodiment of the transvascular dual-fiber interventional microcatheter is basically the same as the embodiment 1, except that:

[0123] In this embodiment, the wavelength of the transmission laser of the first optical fiber 2 is 420 nm, and the laser power density is 5 mW / cm 2 ~10 mW / cm 2 The laser irradiation of the second optical fiber 3 is divided into the first stage and the second stage; the wavelength of the transmission laser in the first stage is 808 nm, and the laser power density is 0.1 W / cm 2 ~1.0 W / cm 2 The wavelength of the second-stage transmission laser of the second optical fiber 3 is 808 nm, and the laser power density is 0.1 W / cm 2 ~1.0 W / cm 2 .

[0124] Example 3

[0125] The photothermal water gel of this embodiment is basically the same as that of embodiment 1, except that:

[0126] In this embodiment, polydopamine (PDA) and GelMA are used to prepare photothermal water gel. GelMA is uniformly dissolved in indocyanine green solution at 60°C. Under vigorous stirring, polydopamine is added dropwise to the above mixture and reacted at 37°C under nitrogen protection to obtain a hydrogel precursor solution. After purification by dialysis (MW = 14,000) at room temperature for 3 days, a photoinitiator 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone (0.5 mg / mL, Irgacure2959) is added. Among them, in the photothermal water gel, the concentration of polydopamine is 0.4 mg / mL, the weight percentage of GelMA is 20 wt.%, the concentration of indocyanine green is any one of 129 μM, 258 μM, 645 μM, and 1290 μM, and the concentration of the photoinitiator is 0.5 mg / mL.

[0127] The transvascular dual-fiber microcatheterization in this embodiment is basically the same as that in embodiment 1, except that the wavelength of the transmission laser of the first optical fiber 2 in this embodiment is 365 nm, and the laser power density is 1 mW / cm 2 ~10 mW / cm 2 The laser irradiation of the second optical fiber 3 is divided into the first stage and the second stage; the wavelength of the transmission laser in the first stage is 808 nm, and the laser power density is 0.1 W / cm 2 ~5.0 W / cm 2 The wavelength of the second-stage transmission laser of the second optical fiber 3 is 808 nm, and the laser power density is 0.1 W / cm 2 ~5.0 W / cm2 .

[0128] Example 4

[0129] The photothermal water gel of this embodiment is basically the same as that of embodiment 1, except that:

[0130] In this embodiment, based on the example 1, a photothermal water gel was prepared, including 20 wt.% GelMA, 200 μg / mL 11-chloro-1,1'-di-n-propyl-3,3,3',3'-tetramethyl-10,12-trimethylene indole tricarbonyl iodide salt (IR780), and 0.25 wt.% LAP. Weigh 0.4032 g of SunP Gel G1 (methacrylic anhydride gelatin, GelMA) lyophilized powder, add 1800 μL of one-fold phosphate buffered saline (1×PBS), and dissolve in a 65°C water bath until there is no precipitation and no dense bubbles. Add 200 μL of phenyl (2,4,6-trimethylbenzoyl) lithium phosphite (LAP) photoinitiator, vortex and place in a 65°C water bath to mix evenly. Then add IR780 at a concentration of 200 μg / mL and vortex to mix evenly.

[0131] The transvascular dual-fiber microcatheterization in this embodiment is basically the same as that in embodiment 1, except that the wavelength of the transmission laser of the first optical fiber 2 in this embodiment is 405 nm, and the laser power density is 40 mW / cm 2 ~50 mW / cm 2 The laser irradiation of the second optical fiber 3 is divided into the first stage and the second stage; the wavelength of the transmission laser in the first stage is 780 nm, and the laser power density is 1.0 W / cm 2 ~2.0 W / cm 2 The wavelength of the second-stage transmission laser of the second optical fiber 3 is 780 nm, and the laser power density is 1.0 W / cm 2 ~2.0 W / cm 2 .

[0132] Example 5

[0133] The photothermal water gel of this embodiment is basically the same as that of embodiment 1, except that:

[0134] In this embodiment, based on Example 1, a photothermal gel was prepared, including 10 wt.% GelMA, 0.25 wt.% LAP, and 645 μM ICG. Weigh 0.4032 g of methacrylic anhydride gelatin (GelMA) freeze-dried powder, add 3600 μL of one-fold phosphate buffered saline (1×PBS), and dissolve in a 65°C water bath until there is no precipitation and no dense bubbles. Add 400 μL of phenyl (2,4,6-trimethylbenzoyl) lithium phosphite (LAP) photoinitiator, vortex and place in a 65°C water bath to mix evenly. Then weigh 0.5 mg of indocyanine green for injection (National Medicine Standard H20055881), vortex and mix evenly, and place in a 65°C water bath until the indocyanine green is completely dissolved.

[0135] The transvascular dual-fiber microcatheterization in this embodiment is basically the same as that in embodiment 1, except that the wavelength of the transmission laser of the first optical fiber 2 in this embodiment is 405 nm, and the laser power density is 40 mW / cm 2 ~50 mW / cm 2 The laser irradiation of the second optical fiber 3 is divided into the first stage and the second stage; the wavelength of the transmission laser in the first stage is 808 nm, and the laser power density is 0.1 W / cm 2 ~1.0 W / cm 2 The wavelength of the second-stage transmission laser of the second optical fiber 3 is 808 nm and the laser power density is 0.1 W / cm 2 ~1.0 W / cm 2 .

[0136] Example 6

[0137] The photothermal water gel of this embodiment is basically the same as that of embodiment 1, except that:

[0138] In this example, based on Example 1, a photothermal gel was prepared, including 40 wt.% GelMA, 0.5 wt.% LAP, and 645 μM ICG. Weigh 0.4032 g of methacrylic anhydride gelatin (GelMA) freeze-dried powder, add 800 μL of one-fold phosphate buffered saline (1×PBS), and dissolve in a 65°C water bath until there is no precipitation and no dense bubbles. Add 200 μL of phenyl (2,4,6-trimethylbenzoyl) lithium phosphite (LAP) photoinitiator, vortex and place in a 65°C water bath to mix evenly. Then weigh 0.5 mg of indocyanine green for injection (National Medicine Standard H20055881), vortex and mix evenly, and place in a 65°C water bath until the indocyanine green is completely dissolved.

[0139] The transvascular dual-fiber microcatheterization in this embodiment is basically the same as that in embodiment 1, except that the wavelength of the transmission laser of the first optical fiber 2 in this embodiment is 405 nm, and the laser power density is 40 mW / cm 2 ~50 mW / cm 2 The laser irradiation of the second optical fiber 3 is divided into the first stage and the second stage; the wavelength of the transmission laser in the first stage is 808 nm and the laser power density is 0.1 W / cm 2 ~1.0 W / cm 2 The wavelength of the second-stage transmission laser of the second optical fiber 3 is 808 nm, and the laser power density is 0.1 W / cm 2 ~1.0 W / cm 2 .

[0140] test

[0141] The flexibility of the interventional microcatheter and the continuity of the photothermal water gel extruded in Examples 1 to 6 were tested ( Figure 2 The interventional microcatheter can be arbitrarily curved to adapt to blood vessels of different complexity. The photothermal water gel extruded by the interventional microcatheter is in a continuous gel state.

[0142] The extrusion of the photothermal water gel in Examples 1 to 6 under different conditions was tested, and in vitro experiments verified that the photothermal water gel through the catheter can fill blood vessels of different sizes. The characteristics of the smoothness, continuity and stability of the photothermal water gel of different concentrations extruded from the catheter under different temperature conditions were observed. Figure 3 The middle left figure shows the different extrusion states of the 645 μM Gel-ICG hydrogel in Example 1. When the temperature is high (~60°C) just after preparation, the pre-prepared Gel-ICG photothermal water gel is in a liquid state and cannot be formed immediately, which has a certain impact on its cross-linking. After the pre-prepared Gel-ICG photothermal water gel is placed in a 4°C refrigerator, the extrusion state is the best, and it is a continuous colloid. By precisely controlling the experimental parameters and simulating the complex and changeable physiological environment in the body, the extrusion performance of the photothermal water gel in various states is recorded in detail, which provides key data support for ensuring that the photothermal water gel can be smoothly injected into the target blood vessel through the catheter in clinical applications.

[0143] In addition, the important characteristic of the photothermal water gel in Examples 1 to 6 that can fill blood vessels of different sizes through the catheter was further verified in the in vitro experiment. A variety of simulated blood vessel models with different diameters were built, covering a wide range from tiny blood vessels to larger diameter blood vessels, in order to simulate the diversity of the real vascular system of the human body. The experimental results are as follows Figure 3The middle right figure clearly shows that the catheter and photothermal water gel system involved in this application can achieve good filling in simulated blood vessels with diameters ranging from 0.8 mm to 3.0 mm, which means that this technology can effectively adapt to the differences in blood vessel sizes among different patients and different lesion sites in clinical applications, providing a strong basis for personalized treatment and greatly improving the applicability and effectiveness of this treatment method in actual clinical scenarios.

[0144] The photothermal properties of the photothermal gels of Examples 1 to 6 were characterized. The results of the 645 μM Gel-ICG photothermal gel in Example 1 are as follows: Figure 4 and Figure 5 As shown. A laser was used to generate near-infrared light with a wavelength of 808 nm, which was then irradiated vertically onto the hydrogel. The laser intensity was 0.5 W / cm², and the irradiation time was 5 min. The temperature was recorded and thermal images were taken at different time points. Figure 5 The left figure shows the Gel-ICG photothermal gels with different concentrations at 0.5 W / cm 2 The photothermal conversion efficiency of power was 1290 μM, and the temperature of the photothermal hydrogel gradually increased to 50°C within 5 minutes. In contrast, the pure methacrylic anhydride gelatin hydrogel irradiated under the same conditions showed the smallest temperature change, which only rose to 22.7°C, further confirming the high photothermal conversion efficiency of Gel-ICG. Figure 5 The right figure shows the photothermal conversion power of 645 μM Gel-ICG photothermal gel at different laser power densities in Example 1. 2 Under near-infrared laser irradiation, the temperature can only rise to about 40°C; at 0.5 W / cm 2 Under near-infrared laser irradiation, the temperature can rise to about 60°C; at 0.8 W / cm 2 Under laser irradiation, the temperature can rise up to 90°C. The temperature change of Gel-ICG is closely related to the laser intensity and solution concentration, which reveals that Gel-ICG can be used as an excellent photothermal agent under 808 nm laser irradiation. The results show that Gel-ICG solution can induce significant hyperthermia, leading to irreversible damage to tumor blood vessels (above 42°C).

[0145] The mechanical properties of the photothermal water gels of Examples 1 to 6 were characterized. Figure 6The middle left figure is the stress-strain curve of Gel-ICG photothermal water gel with different concentrations in Example 1. As the concentration of ICG increases, the stress-strain curve becomes more and more gentle, corresponding to the Young's modulus in the right figure. The Young's modulus of Gel-ICG photothermal water gel with a concentration of 1290 μM is 10-20 kPa, and too soft embolic materials may be washed away by the blood flow. The Young's modulus of Gel-ICG photothermal water gel with a concentration of 129 μM is about 100kPa, and too hard embolic materials may not be able to fill the entire blood vessel well. The Young's modulus of Gel-ICG photothermal water gel shows an obvious trend of change with the change of indocyanine green concentration in the hydrogel. As the concentration of indocyanine green in the hydrogel increases, the Young's modulus gradually decreases. This trend of change shows that the rigidity of the photothermal water gel can be effectively controlled by adjusting the concentration of indocyanine green in the hydrogel, so that its mechanical properties can better adapt to different application requirements.

[0146] In order to ensure that the photothermal water gel can smoothly fill the blood vessel cavity and maintain a stable embolization state, and prevent deformation or displacement due to external force or blood flow impact, combined with the results of photothermal conversion efficiency, we chose a photothermal water gel indocyanine green concentration of 645 μM with a Young's modulus of 40-50 kPa.

[0147] In order to intuitively evaluate the biocompatibility of the photothermal water gel of Examples 1 to 6, the MTT method and live cell / dead cell fluorescent staining technique were used to evaluate the quantitative treatment effect of the photothermal water gel on human umbilical vein endothelial cells. Figure 7 As shown, in Gel-ICG photothermal water gels with different solution concentrations, the survival rate of HUVEC cells is above 90%, which indicates that it has no effect on the activity of cells and that Gel-ICG photothermal water gels with different concentrations are not cytotoxic. By observing the cell samples treated with Gel-ICG photothermal water gels with different concentrations by fluorescence staining and comparing the results with those of the MTT assay, it was found that the two were in good agreement. This further confirms from both intuitive and quantitative dimensions that Gel-ICG photothermal water gels have excellent biocompatibility, and strongly verifies the potential and feasibility of this photothermal water gel in clinical applications.

[0148] Using the rabbit ear model, the double insurance treatment of photothermal assisted embolization was performed by using the photothermal gel of Examples 1 to 6 through vascular intervention. The relevant effects of the 645 μM Gel-ICG photothermal gel of Example 1 after 7 days of treatment were as follows: Figure 8Specifically, after inhalation anesthesia was performed on New Zealand white rabbits, the skin around the rabbit's central ear artery was disinfected, and then the rabbit's central ear artery was exposed. The proximal end of the blood vessel was clamped with a hemostatic forceps, a small incision was made in the blood vessel, and the interventional microcatheter was inserted and reached the designated site. Then, the Gel-ICG photothermal water gel prepared in advance was slowly extruded, and 50 mW / cm 2 405 nm and 0.5 W / cm 2 The laser was irradiated at 808 nm for 1 min.

[0149] The experiment was divided into two groups, in which the concentration of ICG in Gel-ICG photothermal water gel was 645 μM: The Control group was the control group, that is, the Gel-ICG photothermal water gel was only injected through the interventional microcatheter, and no 405 nm and 808 nm laser irradiation was performed.

[0150] The 405 nm and 808 nm groups were photothermal embolization groups. The methacrylic anhydride gelatin hydrogel was photocrosslinked by 405 nm laser, and the indocyanine green was photothermally acted by 808 nm laser. The power density of the 405 nm laser was 50 mW / cm 2 The irradiation time was 1 min, and the power density of the 808 nm laser was 0.2 W / cm 2 The irradiation time was 1 min, and the power density of the 808 nm laser was 0.5 W / cm 2 The irradiation time was 1 min.

[0151] In the experimental group that underwent photothermal embolization with both 405 nm laser irradiation and 808 nm laser irradiation, infrared thermal imaging images ( Figure 8 The middle left image clearly shows that there is a blocked area in the blood vessel. This result intuitively shows that the embolization effect of this experimental group is significant and lasting. Through pathological section analysis, it was found that the blood vessels were enlarged by the retained photothermal water gel, the inner wall of the blood vessel became thinner, and through section analysis ( Figure 8 (middle right picture) It was found that Gel-ICG photothermal gel still exists in the blood vessels. This phenomenon fully confirms that photothermal stimulation has a positive effect on the inner wall of the blood vessels, which better assists embolization therapy. At the same time, the local warm energy generated by 808 nm laser irradiation can cause the cells on the inner wall of the blood vessels to undergo a certain degree of degeneration, thereby maintaining the blocked state of the blood vessels, greatly improving the effect and stability of embolization therapy. The local high temperature generated by the later 808 nm laser irradiation causes the cells to denature due to heat, produces a local immune response, and realizes photothermal therapy. This research result provides a strong experimental basis for the effectiveness of the double insurance treatment method of transvascular photothermal assisted embolization, and also provides a valuable reference direction for further optimizing this treatment plan.

[0152] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0153] The above-mentioned embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the attached claims, and the description may be used to interpret the content of the claims.

Claims

1. In vivo photocuring photothermal filling device, characterized in that: The in vivo photocuring photothermal filling device comprises an interventional catheter and an in vivo photocuring photothermal filling agent; Wherein, the interventional catheter comprises an outer tube, and a first optical fiber, a second optical fiber and an inner tube arranged in the outer tube; The first optical fiber and the second optical fiber are used to transmit lasers of different wavelengths; The inner tube has an inner cavity for injecting the in vivo light-curing photothermal filler; The distal ends of the first optical fiber and the second optical fiber protrude from the distal end of the inner tube, and the distal end of the outer tube protrudes from the distal ends of the first optical fiber and the second optical fiber; The in vivo light-curable photothermal filler can be filled into the target area through the inner tube and simultaneously cured by laser irradiation of different wavelengths.

2. The in vivo photocuring photothermal filling device according to claim 1, characterized in that: The first optical fiber and the second optical fiber transmit laser light with wavelengths of 365 nm to 1200 nm, respectively and independently; Optionally, the first optical fiber transmits laser light with a wavelength of 365 nm to 700 nm; Optionally, the second optical fiber transmits laser light with a wavelength of 400 nm to 1200 nm.

3. The in vivo photocuring photothermal filling device according to claim 1 or 2, characterized in that: The laser power density of the first optical fiber transmission laser is 1 mW / cm 2 ~1 W / cm 2 , and / or, the laser power density of the second optical fiber transmission laser is 0.1 W / cm 2 ~20.0 W / cm 2 ; Optionally, the laser irradiation of the second optical fiber is divided into a first stage and a second stage, and the laser power density of the transmission laser in the first stage is 0.1 W / cm 2 ~20.0 W / cm 2 The laser power density of the second stage transmission laser is 0.1 W / cm 2 ~20.0 W / cm 2 .

4. The in vivo photocuring photothermal filling device according to claim 1 or 2, characterized in that: The distal ends of the first optical fiber and the second optical fiber protrude from the distal end of the inner tube by a distance of 1 mm to 5 mm; the distal end of the outer tube protrudes from the distal ends of the first optical fiber and the second optical fiber by a distance of 1 mm to 5 mm.

5. The in vivo photocuring photothermal filling device according to claim 1 or 2, characterized in that: The number of the first optical fiber and the number of the second optical fiber are independently greater than or equal to 2.

6. The in vivo photocuring photothermal filling device according to claim 1 or 2, characterized in that: The materials of the inner tube and the outer tube independently include one or more of polytetrafluoroethylene and polyethylene.

7. The in vivo photocuring photothermal filling device according to claim 1 or 2, characterized in that: The outer diameter of the catheter is less than or equal to 3.0 mm. Optionally, the outer diameter of the catheter is 0.8 mm to 3.0 mm.

8. The in vivo photocuring photothermal filling device according to claim 1 or 2, characterized in that: The in vivo light-curable photothermal filler comprises a photothermal agent, a photo-crosslinked hydrogel and a photoinitiator; Optionally, the photo-crosslinked hydrogel comprises one or more of methacrylic anhydride gelatin, methacryloyl hyaluronic acid, polyethylene glycol diacrylate, polylactic acid-co-glycolic acid, alginate-based hydrogel, and methacryloyl sodium carboxymethylcellulose hydrogel; Optionally, the photothermal agent includes one or more of indocyanine green, Prussian blue, polydopamine, 11-chloro-1,1'-di-n-propyl-3,3,3',3'-tetramethyl-10,12-trimethylene indotricarbonyl iodide, porphyrin compounds, gold nanoparticles, silver nanoparticles, graphene and carbon nanotubes; Optionally, the photoinitiator includes phenyl (2,4,6-trimethylbenzoyl) lithium phosphate, phenyl (2,4,6-trimethylbenzoyl) sodium phosphite, 2,4,6-trimethylbenzoyl-diphenylphosphine oxide, riboflavin, phenyl bis (2,4,6-trimethylbenzoyl) phosphine oxide, tetramethylethylenediamine, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone and benzoin methyl ether (2-methoxy-1,2-diphenylethanone).

9. The in vivo photocuring photothermal filling device according to claim 8, characterized in that: The Young's modulus of the in vivo light-curing photothermal filler is 10 kPa to 100 kPa; Optionally, the Young's modulus of the in vivo light-curing photothermal filler is 40 kPa to 50 kPa.

10. The in vivo photocuring photothermal filling device according to claim 8, characterized in that: In the in vivo light-curable photothermal filler, the weight percentage of the photo-crosslinked hydrogel is 10 wt.% to 60 wt.%, the concentration of the photothermal agent is 65 μM to 1290 μM, and the weight percentage of the photoinitiator is 0.01 wt.% to 5 wt.%.

11. The in vivo light-curing photothermal filling device according to claim 8, characterized in that: Mixing the photo-crosslinked hydrogel, the photoinitiator and the photothermal agent with a phosphate buffered saline solution to prepare the in vivo photocurable photothermal filler; Optionally, the photo-crosslinked hydrogel is mixed with the phosphate buffered saline solution, the photoinitiator is added after the mixing, and the photothermal agent is added after the mixing to prepare the in vivo photocurable photothermal filler; Optionally, mixing is performed at 60°C to 70°C; Optionally, the prepared in vivo light-curable photothermal filler is placed at 2°C to 8°C.

12. An in vivo light-curing photothermal filler, characterized in that: The in vivo light-curing photothermal filler comprises the in vivo light-curing photothermal filler defined in the in vivo light-curing photothermal filling device according to any one of claims 8 to 11, and the in vivo light-curing photothermal filler has not been irradiated with laser.

13. Use of the in vivo photocuring photothermal filling device according to any one of claims 1 to 11 or the in vivo photocuring photothermal filling agent according to claim 12 in the preparation of products for tissue filling and repair.

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