In vivo photocured photothermal filling device and applications thereof

Abstract

The application relates to an in-vivo photocuring photothermal filling device and application thereof, which comprises an interventional catheter and an in-vivo photocuring photothermal filling agent; wherein the interventional catheter comprises an outer tube, 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 for transmitting laser beams with different wavelengths; the inner tube has an inner cavity in the inside, which is used for injecting the in-vivo photocuring photothermal filling agent; 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 photocuring photothermal filling agent can be filled to a target area through the inner tube and is cured through irradiation of laser beams with different wavelengths.

Description

Technical Field

[0001] This application relates to the biomedical field, specifically to an in vivo photocuring photothermal filling device and its application. Background Technology

[0002] Liver cancer ranks third among malignant tumors. Currently, hepatic artery embolization (TAE) has replaced radiotherapy as the primary treatment for unresectable liver cancer. Clinically, embolic materials used in TAE include gelatin sponges, iodized oil emulsions, anhydrous alcohol, and microspheres / capsules. However, these embolic materials all have certain limitations. Gelatin sponges are relatively large and cannot penetrate small blood vessels after swelling with water; iodized oil emulsions and anhydrous alcohol can damage the intima of small blood vessels, and their reflux may cause infarction of adjacent organs; while microspheres / capsules can encapsulate anticancer drugs, they may lead to over-embolization and misembolization.

[0003] Photothermal therapy (PTT), as an optical treatment strategy for tumors, has attracted widespread attention due to its safety and efficacy. The key components of PTT lie in the photothermal agent and the laser. Currently, while metal-based photothermal agents boast high photothermal conversion efficiency, their high cost hinders widespread clinical application. Carbon-based materials, although possessing a large photothermal conversion area, exhibit poor absorption capacity under near-infrared light irradiation. Semiconductor-based materials offer advantages in high photothermal performance and low cost, but often require further processing into nanoparticles to enhance specificity and tumor targeting capabilities. Some organic photothermal agents also require modification and nanoparticle formulation to improve their photothermal conversion efficiency, solubility, biocompatibility, and tumor targeting ability.

[0004] Over the past few decades, the development of phototherapy drugs and devices for cancer treatment has progressed rapidly. However, key challenges such as laser penetration limit its widespread clinical application beyond some dermatological indications. Most current lasers irradiate the surface of the body or are administered via endoscopic balloon catheters, failing to effectively target deep tumors, such as diode lasers used in dentistry and ophthalmology. While there are reports of non-vascular interventional photothermal therapy (IPTT), which approaches lesions through natural cavities (such as the urethra) or percutaneous puncture, IPTT offers higher survival rates and can inhibit pancreatic tumor metastasis compared to clinically common iodine interstitial brachytherapy. However, IPTT only affects the surface of the target organ; it cannot penetrate deep tumors for effective treatment. Furthermore, the photothermal agents used in IPTT have poor targeting and still require intravenous injection, which not only fails to solve the targeting problem but also complicates the treatment process, reduces efficacy, and may damage normal tissue.

[0005] Currently, photothermal therapy has limited clinical applications, and a more serious problem lies in the separation of research on photothermal agents and lasers. A large amount of preclinical research focuses on the characterization of novel photothermal agents, while clinical research typically emphasizes the development of integrated laser device systems that do not rely on exogenous reagents. Therefore, conveniently and specifically combining the two may be a key breakthrough in overcoming the current predicament of photothermal therapy. Summary of the Invention

[0006] Based on this, one embodiment of this application provides an in vivo photocuring photothermal filling device, which can realize photocrosslinking embolization and photothermal agent-mediated photothermal therapy in blood vessels and other channels, forming a dual guarantee.

[0007] The technical solutions include the following:

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

[0009] The interventional catheter includes an outer tube, and a first optical fiber, a second optical fiber, and an inner tube disposed within 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 photocurable photothermal filler;

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

[0013] The in vivo photocurable photothermal filler can be filled into the target area within blood vessels and other channels 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 each transmit laser light with wavelengths independently ranging from 365 nm to 1200 nm.

[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 transmitted through the first optical fiber is 1 mW / cm². 2 ~1 W / cm 2 And / or, the laser power density transmitted through the second optical fiber is 0.1 W / cm².2 ~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, wherein the laser power density of the transmitted laser in the first stage is 0.1 W / cm². 2 ~20.0 W / cm 2 The laser power density of the transmitted laser in the second stage is 0.1 W / cm². 2 ~20.0 W / cm 2 .

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

[0021] In one embodiment, the inner tube and the outer tube are made of 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, or optionally, the outer diameter of the catheter is 0.8 mm to 3.0 mm.

[0023] In one embodiment, the in vivo photocurable photothermal filler includes a photothermal agent, a photocrosslinked hydrogel, and a photoinitiator.

[0024] In one embodiment, the photocrosslinked hydrogel includes one or more of methacrylic anhydride gelatin (GelMA), methacrylamide hyaluronic acid (HAMA), polyethylene glycol diacrylate (PEGDA), polylactic acid-glycolic acid copolymer (PLGA), alginate-based hydrogel, and methacrylamide sodium carboxymethyl cellulose 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-trimethyleneindole tricarbon anthocyanin 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)phosphonite (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-diphenyl ethyl ketone).

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

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

[0029] In one embodiment, in the in vivo photocurable photothermal filler, the weight percentage of the photocrosslinked 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 photocrosslinked hydrogel, the photoinitiator, and the photothermal agent are mixed with a phosphate buffer solution to prepare the in vivo photocurable photothermal filler.

[0031] In one embodiment, the photocrosslinked hydrogel is mixed with the phosphate buffer solution, the photoinitiator is added after mixing, and the photothermal agent is added after mixing to prepare the in vivo photocurable photothermal filler.

[0032] In one embodiment, the mixing is carried out at a temperature of 60°C to 70°C.

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

[0034] An in vivo photocurable photothermal filler, wherein the in vivo photocurable photothermal filler includes the in vivo photocurable photothermal filler defined in the in vivo photocurable photothermal filling device, wherein the in vivo photocurable photothermal filler is not subjected to laser irradiation.

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

[0036] Compared with traditional technologies, this application has the following advantages:

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

[0038] 1. Highly Effective Embolization: The combination of photothermal agent and photocrosslinked hydrogel in the in vivo photocurable photothermal filler, under the action of lasers of different wavelengths transmitted through the catheter, ensures stable embolization of the hydrogel within the blood vessel, effectively blocking blood supply. This intravascular photocrosslinking embolization method has high stability and effectiveness. Compared with traditional embolic materials, the in vivo photocurable photothermal filler is a pre-formed embolic agent before photocrosslinking. It can be extruded into any shape and can completely conform to the shape of the blood vessel. After being extruded into the blood vessel, it is irradiated with a laser to complete crosslinking within the blood vessel, making it more completely conform to the blood vessel and forming a more durable and reliable embolization effect. In clinical applications, it can significantly reduce the risk of disease recurrence due to incomplete embolization, improve the accuracy and success rate of blocking blood supply to the lesion site, and create more favorable conditions for subsequent treatment.

[0039] 2. Highly Efficient Photothermal Therapy: Transvascularly mediated photothermal therapy can precisely destroy diseased tissue, improving treatment efficacy. Under the aforementioned highly efficient embolization, the photothermal agent in the in vivo photocured photothermal filler, excited by a specific wavelength laser transmitted through the catheter, can efficiently convert light energy into heat energy, which can be highly focused on the diseased tissue. This precise energy transfer mechanism minimizes damage to surrounding normal tissues, causing coagulative necrosis of the diseased tissue at localized high temperatures, thereby achieving the goal of clearing the lesion. Compared to traditional treatment methods, this significantly improves the efficiency and thoroughness of lesion removal.

[0040] 3. Dual Protection: This device combines photocrosslinking embolization with photothermal therapy, forming a dual protection mechanism that reduces treatment risks and the incidence of complications. On the one hand, the in vivo photocured photothermal filler of this application physically blocks the blood supply to the diseased tissue, inhibiting its growth and spread; on the other hand, photothermal therapy destroys the structure and function of diseased cells at the biochemical level. The two complement each other; even if one treatment method fails to achieve the desired effect locally, the other can still play a role. This synergistic effect greatly enhances the reliability of the treatment and reduces the potential for insufficient treatment or complications associated with single treatment methods, such as lesion recurrence due to incomplete embolization or damage to surrounding tissues caused by excessive photothermal therapy.

[0041] 4. Personalized Treatment: By adjusting the laser parameters delivered through the catheter and the ratio of the photocurable photothermal filler in vivo, personalized treatment plans can be implemented for different lesions. Different patients have different lesion conditions (such as lesion size, location, and type). By precisely adjusting parameters such as laser wavelength, power, irradiation time, and the ratio of photocrosslinked hydrogel and photothermal agent, the most suitable treatment plan can be formulated according to each patient's specific condition. This personalized treatment mode can better meet diverse clinical needs, improve the targeting and effectiveness of treatment, maximize treatment results while further reducing the incidence of adverse reactions, and provide patients with higher-quality medical services. Attached Figure Description

[0042] To more clearly illustrate the technical solutions in the embodiments of this application and to more completely understand this application and its beneficial effects, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

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

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

[0045] Figure 3 The images show the extruded state of the 645 μM Gel-ICG photothermal gel in Example 1 (left image, left-1 is ~60℃, left-2 is 4℃) and the vascularized state of the 645 μM Gel-ICG photothermal gel in Example 1 (right image).

[0046] Figure 4 The 645 μM Gel-ICG photothermal gel in Example 1 was used at 0 W / cm². 2 (Left image), 0.2 W / cm 2 (Chinese image) 0.5 W / cm 2 (Right figure) Photothermal conversion of laser power density.

[0047] Figure 5 Different concentrations of Gel-ICG photothermal gels in Example 1 were used at 0.5 W / cm². 2 Photothermal conversion efficiency of power (left figure) and photothermal conversion power of 645 μM Gel-ICG photothermal gel in Example 1 at different laser power densities (right figure).

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

[0049] Figure 7 The left figure shows the survival rate of different concentrations of Gel-ICG photothermal gels in Example 1 under the MTT assay, and the right figure shows the survival of HUVECs in the Gel-ICG photothermal gels as determined by the live / dead assay.

[0050] Figure 8 Infrared thermography (left) and pathological section (right) of rabbit ear treated with 645 μM Gel-ICG photothermal gel for photothermal-assisted embolization in Example 1 of transvascular intervention. Black scale bar = 500 μm, white scale bar = 250 μm. Detailed Implementation

[0051] To make the above-mentioned objectives, features, and advantages of this application more apparent and understandable, a detailed description of specific embodiments of this application is provided below. Many specific details are set forth in the following description to provide a thorough understanding of this application. However, this application can be implemented in many other ways different from those described herein, and those skilled in the art can make similar modifications without departing from the spirit of this application. Therefore, this application is not limited to the specific embodiments disclosed below.

[0052] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0053] The term “and / or” as used herein includes any and all combinations of one or more of the related listed items.

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

[0055] In this article, "photocrosslinked hydrogel" is a hydrogel material formed by a photo-initiated crosslinking reaction.

[0056] One embodiment of this 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 inserted into target areas such as blood vessels via an interventional catheter, and simultaneously cured by laser irradiation of different wavelengths, achieving both occlusion and thermotherapy effects, significantly improving the efficacy and stability of embolization treatment.

[0057] In vivo photocurable photothermal fillers have a wide range of applications, not only in endovascular embolization but also in other human pathways, such as treating tracheoesophageal fistulas, bronchopleural fistulas, esophageal and gastric varices, perforated gastric ulcers, intestinal anastomotic leaks, ureteral injuries, bladder fistulas, vaginal fistulas, corneal repair and reinforcement, and neovascularization closure. In the field of cosmetic medicine, these fillers can also be used for subcutaneous filling, including wrinkle filling, facial contouring, and skin tightening and lifting.

[0058] In a specific example, photocrosslinked hydrogels include, but are not limited to, one or more of the following: methacrylic anhydride-modified gelatin, methacryloyl hyaluronic acid, polyethylene glycol diacrylate, polylactic acid-glycolic acid copolymer, alginate-based hydrogels, and methacryloyl carboxymethyl cellulose sodium hydrogels. The aforementioned photocrosslinked hydrogels exhibit high embolization efficacy. By evaluating factors such as the embolization efficacy, biocompatibility, and degradation rate of different hydrogels, the optimal hydrogel can be selected for endovascular embolization therapy. For example, for cases requiring short-term embolization, hydrogels with faster degradation rates can be chosen; while for long-term embolization needs, hydrogels with slow degradation and stability are more suitable, allowing for flexible adjustments to the treatment plan based on the specific condition.

[0059] In a specific example, the photothermal agent includes, but is not limited to, one or more of indocyanine green, Prussian blue, polydopamine, 11-chloro-1,1'-di-n-propyl-3,3,3',3'-tetramethyl-10,12-trimethyleneindole tricarbon anthocyanin iodide, porphyrin compounds, gold nanoparticles, silver nanoparticles, graphene, and carbon nanotubes. The above photothermal agents exhibit 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 one specific example, the photocrosslinked hydrogel is methacrylic anhydride-modified gelatin, and the photothermal agent is indocyanine green. This application selects an in vivo photocurable photothermal filler prepared from a combination of indocyanine green and methacrylic anhydride-modified gelatin. This filler is low-cost, safer, causes less damage to surrounding tissues, provides more stable and effective embolization in blood vessels, and exhibits a high photothermal conversion rate, resulting in better embolization and photothermal treatment effects. Photothermal-assisted double-insurance embolization is achieved via a vascular interventional single-lumen dual-fiber catheter.

[0061] In one specific example, the photoinitiator includes lithium phenyl(2,4,6-trimethylbenzoyl)phosphate, sodium phenyl(2,4,6-trimethylbenzoyl)phosphonite, 2,4,6-trimethylbenzoyl-diphenylphosphine oxide, riboflavin, phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide, tetramethylethylenediamine, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone, and benzoin methyl ether (2-methoxy-1,2-diphenyl ethyl ketone).

[0062] In a specific example, the Young's modulus of the in vivo photocurable photothermal filler is 10 kPa to 100 kPa. If the Young's modulus exceeds this range, the embolic material will be too hard and lack elasticity; if the Young's modulus is too low, the embolic material will be too soft, potentially leading to poor embolization and causing embolization errors or inflammatory reactions. Depending on the specific scenario, different Young's moduli can be appropriately selected within this range. For example, for the embolization treatment of arterial malformations, especially basket-shaped arterial malformations, where blood flow impact is relatively small, a wider range of Young's modulus requirements can be applied.

[0063] In a specific example, the Young's modulus of the in vivo photocurable photothermal filler is 40 kPa to 50 kPa. In vivo photocurable photothermal fillers with a Young's modulus in this range are suitable for use in embolized blood vessels or capillaries, ensuring that the filler can smoothly fill the blood vessel lumen and maintain a stable embolization state.

[0064] In one specific example, the weight percentage of the photocrosslinked hydrogel in the in vivo photocurable photothermal filler 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 one specific example, the weight percentage of the photocrosslinked hydrogel is 10 wt.% to 40 wt.%. In one specific example, the weight percentage of the photocrosslinked hydrogel is 10 wt.% to 20 wt.%.

[0065] In one specific example, the concentration of the photothermal agent in the in vivo photocurable photothermal filler is 65 μM to 1290 μM. 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 any range between two of the above values. In one specific example, the concentration of the photothermal agent in the in vivo photocurable photothermal filler is 258 μM to 1161 μM, and embolic agents within this range have better embolic effects.

[0066] In one specific example, the photoinitiator in the in vivo photocurable photothermal filler has a weight percentage of 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 one specific example, the photoinitiator in the in vivo photocurable photothermal filler has a weight percentage of 0.1 wt.% to 0.5 wt.%.

[0067] In one specific example, a photocrosslinked hydrogel, a photoinitiator, and a photothermal agent were mixed with a phosphate buffer solution to prepare an in vivo photocurable photothermal filler.

[0068] In one specific example, a photocrosslinked hydrogel is mixed with a phosphate buffer solution, then a photoinitiator is added and mixed again, followed by a photothermal agent to prepare an in vivo photocurable photothermal filler.

[0069] In one specific example, the mixing was carried out at 60°C to 70°C.

[0070] In one specific example, when the prepared in vivo photocurable photothermal filler is placed at 2℃~8℃, the smoothness, continuity and stability of the extrusion from the conduit are better.

[0071] Compared to in vitro cross-linked microspheres, the in vivo photocurable photothermal filler of this application is a pre-formed hydrogel before photocrosslinking. It can be extruded into any shape, not limited to spheres or linear shapes, and can completely conform to the shape of blood vessels, forming a completely sealed embolization effect. After being extruded into blood vessels, the in vivo photocurable photothermal filler of this application is irradiated with a laser to complete crosslinking in vivo, making it more completely conform to blood vessels and effectively embolize them, avoiding misembolization.

[0072] One embodiment of this application also provides an in vivo photocurable photothermal filling device, which includes an interventional catheter and the aforementioned in vivo photocurable 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 disposed within 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 internal cavity for injecting the in vivo photocurable photothermal filler. The distal ends of the first optical fiber 2 and the second optical fiber 3 protrude beyond the distal end of the inner tube 4, and the distal end of the outer tube 1 protrudes beyond 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-cavity channel, and the inner tube 4, the first optical fiber 2, and the second optical fiber 3 all extend into the single-cavity channel.

[0073] The in vivo photocurable photothermal filler can be filled into the target area of ​​blood vessels and other channels through the inner tube 4, and then cured by laser irradiation of different wavelengths, which plays a role in blocking and thermotherapy, greatly improving the efficacy and stability of embolization treatment.

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

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

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

[0077] In a specific example, the laser power density transmitted through the first optical fiber 2 is 1 mW / cm². 2 ~1 W / cm 2 In a specific example, the laser power density transmitted through the first fiber 2 is 40.0 mW / cm². 2 ~60.0 mW / cm 2 In a specific example, the laser power density transmitted through the first fiber 2 is 50.0 mW / cm². 2 .

[0078] In a specific example, the laser power density transmitted through the second fiber 3 is 0.1 W / cm². 2 ~20.0 W / cm 2 In a specific example, the laser power density transmitted through the second fiber 3 is 0.2 W / cm². 2 ~0.5 W / cm 2 .

[0079] In a specific example, the in vivo photocurable 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 the first optical fiber 2 and the second optical fiber 3. Optionally, the laser irradiation time of the first optical fiber 2 is 1 min to 10 min (e.g., 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, or 10 min), and the laser irradiation time of the second optical fiber 3 is 2 min to 20 min (e.g., 2 min, 10 min, 20 min, 50 min, 100 min, 150 min, or 20 min). Optionally, the irradiation is divided into two stages: the first stage is cured by laser irradiation of the first optical fiber 2 and the second optical fiber 3 for 1 min to 10 min, and the second stage is photothermal therapy by laser irradiation of the second optical fiber 3 for 1 min to 20 min.

[0080] In a specific example, the laser power density of the transmitted laser in the first stage of the second optical fiber 3 is 0.1 W / cm². 2 ~20.0 W / cm 2 The laser power density of the second stage of transmission laser in the second fiber 3 is 0.1 W / cm². 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 from the distal end of the inner tube 4 by a distance of 1 mm to 5 mm. This effectively prevents the filler from prematurely cross-linking and blocking the conduit 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 beyond the distal ends of the first optical fiber 2 and the second optical fiber 3. This ensures that the optical fibers are always protected by the outer tube 1, enhancing the stability and safety of the conduit during use and reducing potential risks caused by damage to the optical fibers.

[0083] In a specific example, the number of first optical fibers 2 and second optical fibers 3 is independently greater than or equal to two. This 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 fibers, the transmission efficiency and stability of the optical fibers are improved to meet the needs of simultaneously achieving photocrosslinking embolization and photothermal therapy.

[0084] In one specific example, the inner tube 4 and the outer tube 1 are independently made of one or more of polytetrafluoroethylene (PTFE) and polyethylene (PE). This application allows for the selection of different catheter materials depending on the specific treatment scenario. By optimizing the catheter's structure and materials, its flexibility and biocompatibility are improved to meet the treatment needs of different vascular sites and lesion types.

[0085] In a specific example, the outer diameter of the catheter is less than or equal to 3.0 mm; alternatively, the outer diameter of the catheter is 0.8 mm to 3.0 mm. This application can design catheters of different sizes, such as microcatheters and ultramicrocatheters, to meet the specific needs of treating blood vessels of different sizes. By matching different catheter sizes to different blood vessels, the optimal therapeutic effect can be achieved.

[0086] This application also provides a safe and efficient transvascular double-insurance embolization method, which utilizes the aforementioned catheter and an in vivo photocurable photothermal filler. This method achieves photothermal-assisted double-insurance embolization treatment via a vascular interventional single-lumen dual-fiber catheter.

[0087] In one specific example, the method involves simultaneously delivering an in vivo photocurable photothermal filler containing indocyanine green and methacrylic anhydride-modified gelatin hydrogel using lasers of both 405 nm and 808 nm wavelengths. This achieves photocrosslinking embolization of the methacrylic anhydride-modified gelatin and photothermal therapy mediated by indocyanine green within the blood vessel, providing dual protection. This method not only significantly improves treatment efficacy but also reduces the risk of complications, opening up new avenues for intravascular photocrosslinked hydrogel embolization and intravascular photothermal therapy.

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

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

[0090] 1. Challenges of In Vivo Photocrosslinking: Currently, most crosslinking processes for methacrylic anhydride-based gelatin hydrogels are performed in vitro. This involves first preparing the hydrogel to the desired shape and size, then crosslinking it in vitro using light, and finally injecting it into the body. However, for endovascular therapy, in vivo photocrosslinking is more ideal because it ensures the hydrogel forms a stable embolic structure immediately upon reaching the target site and can adapt to different blood vessel sizes. However, a major challenge in in vivo photocrosslinking is light penetration. The complexity of vascular structures and the absorption and scattering of light by blood make in vivo photocrosslinking difficult.

[0091] 2. Dual-wavelength laser transmission issues: Most fiber optic catheters on the market can only transmit a single wavelength of laser light. This limits the possibility of simultaneously achieving in vivo photocrosslinking embolization and photothermal therapy. Single-wavelength fiber optic catheters cannot meet the needs of multiple treatments, requiring the use of multiple catheters or multiple procedures, which not only increases patient suffering and infection risks but also prolongs treatment time. Furthermore, the transmission of different wavelengths of laser light in optical fibers requires specific optical conditions and material properties. Existing single-wavelength fiber optic catheters are not designed and manufactured with the simultaneous transmission of two wavelengths of laser light in mind; their core structure, refractive index distribution, and other parameters cannot effectively support stable dual-wavelength laser transmission, thus limiting the clinical application and development of various treatment methods.

[0092] 3. Targeting Issues with Photothermal Agents: Clinically, photothermal therapy faces the challenge of precisely delivering photothermal agents to the target site. In traditional photothermal treatments, the distribution of photothermal agents injected systemically is often difficult to control, lacking an effective targeted delivery mechanism. After injection, the photothermal agent easily diffuses throughout the body via the bloodstream, failing to specifically accumulate around the diseased tissue. This non-targeted distribution not only reduces the effectiveness of photothermal therapy at the lesion site but may also cause unnecessary damage to normal tissues.

[0093] 4. Hydrogel Blockage of Delivery Channels: In intravascular photothermal hydrogel therapy, premature cross-linking of the hydrogel may block the delivery channels. When the hydrogel cross-links prematurely during delivery, it forms solid or semi-solid substances that may accumulate within the delivery channels, thus blocking them. Once the channels are blocked, not only will subsequent hydrogel delivery to the lesion site be hindered, affecting the treatment effect, but additional procedures may be required to clear the blockage, increasing the complexity of the treatment and patient discomfort. It may even lead to serious intravascular complications such as thrombosis and vascular inflammation.

[0094] 5. Fiber Optic Protection Issues: Fiber optic cables are susceptible to damage during intravascular procedures, affecting laser transmission and treatment efficacy, and potentially even causing safety issues. In the complex environment of interventional vascular therapy, fiber optic cables face several potential damage factors. First, the bending, twisting, and stretching movements of blood vessels can generate mechanical stress on the fiber optic cable; prolonged or frequent exposure to this stress can lead to breakage or damage. Second, if extremely thin fibers are exposed within a blood vessel, they are highly likely to scratch or puncture the vessel wall, causing bleeding and seriously threatening the patient's safety and health. Therefore, fiber optic cable protection is a crucial technical issue in endovascular treatment.

[0095] The embodiments of this application will be described in detail below with reference to examples. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of this application. For experimental methods in the following embodiments where specific conditions are not specified, please refer to the guidelines given in this application, or follow experimental manuals or conventional conditions in the art, or follow the conditions recommended by the manufacturer, or refer to experimental methods known in the art.

[0096] In the specific embodiments described below, the measurement parameters involving raw material components may have slight deviations within the weighing accuracy range unless otherwise specified. Temperature and time parameters are subject to acceptable deviations due to instrument testing accuracy or operational precision.

[0097] Example 1

[0098] A schematic diagram of a transvascular dual-fiber interventional microcatheter (hereinafter referred to as interventional microcatheter) is shown below. 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 disposed inside the outer tube.

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

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

[0101] The in vivo photocurable photothermal filler can be filled into the target area of ​​the blood vessel through the inner tube 4, and then 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 transmits lasers of different wavelengths simultaneously through two optical fibers (first optical fiber 2 and second optical fiber 3) connected to different lasers. The photocurable photothermal filler is directly injected into the target site through the inner lumen of the inner tube 4 of the microcatheter, which effectively solves the problem of targeting photothermal agents in clinical practice 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. This effectively prevents the filler from prematurely cross-linking and blocking the conduit channel due to premature contact with the fiber laser during injection, ensuring that the filler can be smoothly injected into the target area and completely cross-linked. In another 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, ensuring that the optical fiber is always protected by the outer tube 1. This enhances the stability and safety of the microcatheter during use and reduces potential risks caused by damage to the optical fiber.

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

[0106] In one embodiment, the laser power density transmitted through the first optical fiber 2 is 1 mW / cm². 2 ~ 1 W / cm 2 In one embodiment, the laser power density transmitted via the second optical fiber 3 is 0.1 W / cm². 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 transmitted laser in the first stage is 0.1 W / cm². 2 ~20.0 W / cm 2 The laser power density of the second stage of transmission laser in the second fiber 3 is 0.1 W / cm². 2 ~20.0 W / cm 2 .

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

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

[0110] The main materials involved in the examples are as follows: polytetrafluoroethylene (PTFE) heat shrink tubing, 100 µm fiber optic patch cord, 808 nm multimode pump light source, 405 nm semiconductor laser, gelatin-methacryloyl (GelMA), photoinitiator lithium phenyl (2,4,6-trimethylbenzoyl)phosphonite (LAP), 1×PBS, and indocyanine green (ICG).

[0111] Example of the fabrication of this interventional microcatheter:

[0112] Black polytetrafluoroethylene (PTFE) heat shrink tubing with inner diameters of 0.6 mm and 1.0 mm was coaxially mounted, and two 100 µm diameter fiber optic patch cords were inserted between the tubing. One fiber optic patch cord (proximal end) was connected to an 808 nm multimode pump source, and the other fiber optic patch cord (proximal end) was connected to a 405 nm semiconductor laser. The distal ends of the fiber optic patch cords were 2 mm away from both the inner and outer Teflon heat shrink tubing, with a 4 mm distance between the distal ends of the inner and outer Teflon heat shrink tubing. The black PTFE heat shrink tubing was heated to shrink 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 ranging from 0.8 mm to 3 mm were prepared using the above method.

[0113] For example, an in vivo photocurable photothermal filler (referred to as photothermal gel) comprises 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×PBS, and dissolve in a 65°C water bath until no precipitate or dense bubbles remain. Add 200 µL of lithium phenyl (2,4,6-trimethylbenzoyl)phosphonite (LAP) photoinitiator, vortex, and place in a 65°C water bath to mix thoroughly. Then weigh 0.001 g of indocyanine green for injection (National Drug Approval Number H20055881), vortex to mix thoroughly, and place in a 65°C water bath until the indocyanine green is completely dissolved.

[0115] Gel-ICG photothermal gels with different indocyanine green concentrations (0 μM-1290 μM, for example 0 μM, 129 μM, 258 μM, 645 μM, 1290 μM) were prepared by changing the amount of indocyanine green according to the above method.

[0116] This interventional microcatheter utilizes a vascular channel to locate the target area under X-ray imaging. An embolic agent, such as Gel-ICG photothermal gel, is injected into the lumen of the inner tube 4. Simultaneously, a laser from the first fiber 2 (e.g., 405 nm) is used to crosslink methacryloyl gelatin (GelMA) to form an embolism, while a laser from the second fiber 3 (e.g., 808 nm) triggers 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 embolization materials, photocurable materials have good fluidity when uncured, which can better conform to the shape and direction of blood vessels, ensure complete filling of target vascular branches, and reduce the risk of treatment failure due to uneven material distribution.

[0118] In this method, photothermal therapy initiated by the second fiber 3 (e.g., 808 nm) achieves precise spatial selectivity and high efficiency. It can also be combined with other treatment methods to enhance therapeutic effects, such as chemotherapy, immunotherapy, and photodynamic therapy. Compared to percutaneous photothermal therapy, transvascular interventional photothermal therapy is less obstructed by superficial tissues such as skin and muscles, providing sufficient energy to reach the lesion site while avoiding percutaneous injury. In the first stage, the first fiber 2 (e.g., 405 nm) and the second fiber 3 (e.g., 808 nm) are simultaneously excited, at a ratio of 0.2 W / cm². 2 The thermotherapy increased the fluidity of the photothermal gel, making it more filling of the entire blood vessel and promoting in vivo photocuring. The second stage involved a second fiber 3 (e.g., 808nm) laser at 0.5 W / cm². 2 High-temperature treatment directly causes irreversible cell damage, thus achieving photothermal therapy.

[0119] Example 2

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

[0121] In this embodiment, a photothermal hydrogel was prepared using polyethylene glycol diacrylate (PEGDA). PEGDA was dissolved in an indocyanine green solution of a certain concentration to prepare a hydrogel precursor solution, wherein the weight percentage of PEGDA in the photothermal hydrogel was 60 wt.%. A photoinitiator (Irgacure 819, 12.5 mg / mL) was added to the solution and mixed thoroughly, with a photoinitiator / PEGDA weight ratio of 0.02 wt.%. The concentration of indocyanine green was any one of 129 μM, 258 μM, 645 μM, or 1290 μM.

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

[0123] In this embodiment, the wavelength of the laser transmitted by the first optical fiber 2 is 420 nm, and the laser power density is 5 mW / cm². 2 ~10 mW / cm 2 The laser irradiation of the second fiber 3 is divided into a first stage and a second stage; the wavelength of the transmitted laser in the first stage is 808 nm, and the laser power density is 0.1 W / cm². 2 ~1.0 W / cm 2 The wavelength of the laser transmitted in the second stage of the second fiber 3 is 808 nm, and the laser power density is 0.1 W / cm². 2 ~1.0 W / cm 2 .

[0124] Example 3

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

[0126] In this embodiment, a photohydrogel was prepared using polydopamine (PDA) and GelMA. GelMA was uniformly dissolved in an indocyanine green solution at 60°C. Under vigorous stirring, PDA was added dropwise to the mixture, and the reaction was carried out at 37°C under nitrogen protection to obtain a hydrogel precursor solution. The solution was purified by dialysis (MW = 14,000) for 3 days at room temperature, followed by the addition of a photoinitiator, 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylphenylacetone (0.5 mg / mL, Irgacure 2959). Specifically, in the photohydrogel, the concentration of PDA was 0.4 mg / mL, the weight percentage of GelMA was 20 wt.%, the concentration of indocyanine green was any one of 129 μM, 258 μM, 645 μM, or 1290 μM, and the concentration of the photoinitiator was 0.5 mg / mL.

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

[0128] Example 4

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

[0130] This embodiment prepares a photothermal gel based on Example 1, comprising 20 wt.% GelMA, 200 μg / mL 11-chloro-1,1'-di-n-propyl-3,3,3',3'-tetramethyl-10,12-trimethyleneindole tricarbon anthocyanin iodide (IR780), and 0.25 wt.% LAP. 0.4032 g of SunP Gel G1 (methacrylic anhydride gelatin, GelMA) lyophilized powder was weighed and added to 1800 µL of 1×PBS phosphate buffer solution, then dissolved in a 65°C water bath until no precipitate or dense foaming material remained. 200 µL of lithium phenyl (2,4,6-trimethylbenzoyl)phosphonite (LAP) photoinitiator was added, vortexed, and then placed in a 65°C water bath to mix thoroughly. Subsequently, IR780 at a concentration of 200 μg / mL was added, and the mixture was vortexed until homogeneous.

[0131] This embodiment of the transvascular dual-fiber interventional microcatheter is basically the same as that in Embodiment 1, except that the wavelength of the laser transmitted by the first fiber 2 in this embodiment is 405 nm and the laser power density is 40 mW / cm². 2 ~50 mW / cm 2 The laser irradiation of the second fiber 3 is divided into a first stage and a second stage; the wavelength of the transmitted laser in the first stage is 780 nm, and the laser power density is 1.0 W / cm². 2 ~2.0 W / cm 2 The wavelength of the laser transmitted in the second stage of the second fiber 3 is 780 nm, and the laser power density is 1.0 W / cm². 2 ~2.0 W / cm 2 .

[0132] Example 5

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

[0134] This embodiment prepares a photothermal gel based on Example 1, comprising 10 wt.% GelMA, 0.25 wt.% LAP, and 645 μM ICG. 0.4032 g of lyophilized gelatin (GelMA) powder was weighed and added to 3600 µL of 1×PBS, then dissolved in a 65°C water bath until no precipitate or dense foamy material remained. 400 µL of lithium phenyl (2,4,6-trimethylbenzoyl)phosphonite (LAP) photoinitiator was added, vortexed, and then placed in a 65°C water bath to mix thoroughly. Subsequently, 0.5 mg of indocyanine green for injection (National Drug Approval Number H20055881) was weighed, vortexed, and placed in a 65°C water bath until the indocyanine green was completely dissolved.

[0135] This embodiment of the transvascular dual-fiber interventional microcatheter is basically the same as that in Embodiment 1, except that the wavelength of the laser transmitted by the first fiber 2 in this embodiment is 405 nm and the laser power density is 40 mW / cm². 2 ~50 mW / cm 2 The laser irradiation of the second fiber 3 is divided into a first stage and a second stage; the wavelength of the transmitted laser in the first stage is 808 nm, and the laser power density is 0.1 W / cm². 2 ~1.0 W / cm 2 The wavelength of the laser transmitted in the second stage of the second fiber 3 is 808 nm, and the laser power density is 0.1 W / cm². 2 ~1.0 W / cm 2 .

[0136] Example 6

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

[0138] This embodiment prepares a photothermal gel based on Example 1, comprising 40 wt.% GelMA, 0.5 wt.% LAP, and 645 μM ICG. 0.4032 g of lyophilized gelatin (GelMA) powder was weighed and added to 800 µL of 1×PBS phosphate buffer solution, then dissolved in a 65°C water bath until no precipitate or dense foamy material remained. 200 µL of lithium phenyl (2,4,6-trimethylbenzoyl)phosphonite (LAP) photoinitiator was added, vortexed, and then placed in a 65°C water bath to mix thoroughly. Subsequently, 0.5 mg of indocyanine green for injection (National Drug Approval Number H20055881) was weighed, vortexed, and placed in a 65°C water bath until the indocyanine green was completely dissolved.

[0139] This embodiment of the transvascular dual-fiber interventional microcatheter is basically the same as that in Embodiment 1, except that the wavelength of the laser transmitted by the first fiber 2 in this embodiment is 405 nm and the laser power density is 40 mW / cm². 2 ~50 mW / cm 2 The laser irradiation of the second fiber 3 is divided into a first stage and a second stage; the wavelength of the transmitted laser in the first stage is 808 nm and the laser power density is 0.1 W / cm². 2 ~1.0 W / cm 2 The wavelength of the laser transmitted in the second stage of the second fiber 3 is 808 nm, and the laser power density is 0.1 W / cm². 2 ~1.0 W / cm 2 .

[0140] test

[0141] The flexibility of the interventional microcatheter and the continuity of the extruded photothermal gels in Examples 1-6 were tested. Figure 2 The interventional microcatheter can be bent arbitrarily to adapt to blood vessels of varying complexity. The photothermal hydrogel extruded from the interventional microcatheter forms a continuous gel.

[0142] The extrusion of the photothermal gels in Examples 1-6 under different conditions was tested, and in vitro experiments verified that the photothermal gels could fill blood vessels of different sizes through a catheter. The smoothness, continuity, and stability of the extrusion of photothermal gels of different concentrations from the catheter were observed under different temperature conditions. Figure 3 The left-middle figure shows the different extrusion states of the 645 μM Gel-ICG hydrogel in Example 1. When freshly prepared at a relatively high temperature (~60℃), the pre-prepared Gel-ICG photothermal hydrogel was in a liquid state and could not be immediately shaped, which affected its cross-linking. However, when the pre-prepared Gel-ICG photothermal hydrogel was placed in a 4℃ refrigerator, the extrusion state was optimal, forming a continuous gel. By precisely controlling experimental parameters and simulating the complex and variable physiological environment in vivo, the extrusion performance of the photothermal hydrogel under various states was recorded in detail, providing crucial data support for ensuring the successful injection of the photothermal hydrogel into target blood vessels via catheter in clinical applications.

[0143] Furthermore, in vitro experiments further verified the important property that the photothermal hydrogels used in Examples 1-6 via catheters can fill blood vessels of different sizes. Various simulated blood vessel models with different diameters were constructed, covering a wide range from microvessels to larger diameter vessels, to simulate the diversity of the real human vascular system. Experimental results are as follows... Figure 3The right-middle figure clearly shows that the catheter and photothermal 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. This means that the technology can effectively adapt to the differences in blood vessel size among different patients and 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 in Examples 1-6 were characterized. The results for the 645 μM Gel-ICG photothermal gel in Example 1 are as follows: Figure 4 and Figure 5 As shown, near-infrared light with a wavelength of 808 nm was generated by a laser and then vertically irradiated onto the hydrogel. The laser intensity was 0.5 W / cm², and the irradiation time was 5 min. Temperature was recorded and thermal imaging was performed at different time points. Figure 5 The left image shows different concentrations of Gel-ICG photothermal gels at 0.5 W / cm². 2 The photothermal conversion efficiency of the power was demonstrated by the photothermal hydrogel with a concentration of 1290 μM, which gradually increased the temperature to 50 °C within 5 minutes. In contrast, the pure methacrylic anhydride gelatin hydrogel irradiated under the same conditions showed the smallest temperature change, rising only 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 the 645 μM Gel-ICG photothermal gel in Example 1 at different laser power densities, at 0.2 W / cm². 2 Under near-infrared laser irradiation, the temperature can only rise to about 40℃; at 0.5 W / cm²... 2 Under near-infrared laser irradiation, the temperature can rise to around 60℃; while at 0.8 W / cm²... 2 Under laser irradiation, the temperature can rise as high as 90°C. The temperature change of Gel-ICG is closely related to the laser intensity and solution concentration, revealing that Gel-ICG can serve 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-feeding vessels (above 42°C).

[0145] The mechanical properties of the photothermal gels of Examples 1-6 were characterized. Figure 6The left-middle figure shows the stress-strain curves of Gel-ICG photothermal gels with different concentrations in Example 1. As the ICG concentration increases, the stress-strain curves become increasingly flat. Corresponding to the Young's modulus in the right-middle figure, the Young's modulus of the 1290 μM Gel-ICG photothermal gel is 10–20 kPa, indicating that overly soft embolic material may be washed away by blood flow. The Young's modulus of the 129 μM Gel-ICG photothermal gel is around 100 kPa, suggesting that overly rigid embolic material may not adequately fill the blood vessel. The Young's modulus of the Gel-ICG photothermal gel shows a clear trend with changes in the indocyanine green concentration in the hydrogel. As the indocyanine green concentration increases, the Young's modulus gradually decreases. This trend indicates that adjusting the indocyanine green concentration in the hydrogel can effectively control the rigidity of the photothermal gel, thereby allowing its mechanical properties to better adapt to different application requirements.

[0146] To ensure that the photothermal gel can successfully fill the vascular lumen and maintain a stable embolism state, preventing deformation or displacement due to external forces or blood flow impact, and considering the photothermal conversion efficiency, we selected a 645 μM indocyanine green concentration for the photothermal gel with a Young's modulus between 40 and 50 kPa.

[0147] To visually evaluate the biocompatibility of the photothermal gels used in Examples 1-6, the MTT assay and live / dead cell fluorescence staining techniques were employed to assess the quantitative treatment effect of the photothermal gels on human umbilical vein endothelial cells. Figure 7 As shown, the survival rate of HUVEC cells in different concentrations of Gel-ICG photothermal gel remained above 90%, indicating that it had no effect on cell viability and that different concentrations of Gel-ICG photothermal gel did not exhibit cytotoxicity. Fluorescent staining observation of cell samples treated with different concentrations of Gel-ICG photothermal gel, and comparison with the results of the MTT assay, showed good agreement. This further confirms, both intuitively and quantitatively, that the Gel-ICG photothermal gel possesses excellent biocompatibility, strongly validating its potential and feasibility in clinical applications.

[0148] Using a rabbit ear model, a dual-insurance treatment of photothermal-assisted embolization was performed using photothermal gels from Examples 1-6 via transvascular intervention. The relevant effects of treatment with 645 μM Gel-ICG photothermal gel in Example 1 after 7 days are as follows: Figure 8Specifically, after administering inhalation anesthesia to New Zealand white rabbits, the skin around the central auricular artery was disinfected. The central auricular artery was then exposed, and the proximal end of the vessel was clamped with hemostatic forceps. A small incision was made in the vessel, and an interventional microcatheter was inserted and brought to the designated site. Subsequently, the pre-prepared Gel-ICG photothermal gel was slowly extruded, while simultaneously turning on 50 mW / cm². 2 405 nm and 0.5 W / cm 2 An 808 nm laser was used for 1 minute of laser irradiation.

[0149] The experiment was divided into two groups. The concentration of ICG in the Gel-ICG photothermal gel was 645 μM. The Control group was the control group, in which the Gel-ICG photothermal gel was injected only through an interventional microcatheter without irradiation by 405 nm and 808 nm lasers.

[0150] The 405 nm and 808 nm groups were the photothermal embolization experimental groups. A 405 nm laser was used to photocrosslink methacrylic anhydride-modified gelatin hydrogel, and an 808 nm laser was used to photothermally activate indocyanine green. The power density of the 405 nm laser was 50 mW / cm². 2 The irradiation time was 1 minute, and the initial power density of the 808 nm laser was 0.2 W / cm². 2 The irradiation time was 1 minute, and the power density of the 808 nm laser in the later stage was 0.5 W / cm². 2 The irradiation time is 1 minute.

[0151] In the experimental group undergoing photothermal assisted embolization with simultaneous 405 nm and 808 nm laser irradiation, the infrared thermal image ( Figure 8 The left-middle image clearly shows the area of ​​blockage in the blood vessel. This result visually demonstrates that the embolization effect in this experimental group is significant and long-lasting. Pathological section analysis revealed that the blood vessel was enlarged by the retained photothermal gel, and the inner wall of the blood vessel became thinner. Furthermore, section analysis ( Figure 8 (Right image) The gel-ICG photothermal gel was found to remain within the blood vessel. This phenomenon fully confirms that photothermal stimulation has a positive effect on the vascular endothelium, better assisting in embolization therapy. Simultaneously, the local heat generated by 808 nm laser irradiation induces a certain degree of cell denaturation in the vascular endothelium, thereby maintaining the vascular occlusion state and greatly improving the efficacy and stability of embolization therapy. Furthermore, the local high temperature generated by the subsequent 808 nm laser irradiation causes cell denaturation and generates a local immune response, achieving photothermal therapy. These research results provide strong experimental evidence for the effectiveness of the dual-insurance treatment method of transvascular interventional photothermal assisted embolization and offer valuable reference directions for further optimization of this treatment plan.

[0152] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above 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 embodiments described above are merely illustrative of several implementation methods of this application, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this patent application should be determined by the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. An in vivo photocuring and photothermal filling device, characterized in that, The in vivo photocurable photothermal filling device includes an interventional catheter and an in vivo photocurable photothermal filling agent; The interventional catheter includes an outer tube, and a first optical fiber, a second optical fiber, and an inner tube disposed within 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 photocurable photothermal filler; The distal ends of the first optical fiber and the second optical fiber protrude beyond the distal end of the inner tube, and the distal end of the outer tube protrudes beyond the distal ends of the first optical fiber and the second optical fiber. The in-body photocurable photothermal filler can be filled into the target area through the inner tube and cured by laser irradiation of different wavelengths. The in vivo photocurable photothermal filler includes a photothermal agent, a photocrosslinked hydrogel, and a photoinitiator.

2. The in vivo photocuring and photothermal filling device according to claim 1, characterized in that, The first optical fiber and the second optical fiber each independently transmit laser light with wavelengths ranging from 365 nm to 1200 nm.

3. The in vivo photocuring and photothermal filling device according to claim 2, characterized in that, The first optical fiber transmits laser light with a wavelength of 365 nm to 700 nm.

4. The in vivo photocuring and photothermal filling device according to claim 2, characterized in that, The second optical fiber transmits laser light with a wavelength of 400 nm to 1200 nm.

5. The in vivo photocuring and photothermal filling device according to any one of claims 1 to 4, characterized in that, The laser power density transmitted through the first optical fiber is 1 mW / cm². 2 ~1 W / cm 2 And / or, the laser power density transmitted through the second optical fiber is 0.1 W / cm². 2 ~20.0 W / cm 2 .

6. The in vivo photocuring and photothermal filling device according to claim 5, characterized in that, The laser irradiation of the second optical fiber is divided into a first stage and a second stage. The laser power density of the transmitted laser in the first stage is 0.1 W / cm². 2 ~20.0 W / cm 2 The laser power density of the transmitted laser in the second stage is 0.1 W / cm². 2 ~20.0 W / cm 2 .

7. The in vivo photocuring and photothermal filling device according to any one of claims 1 to 4, 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.

8. The in vivo photocuring and photothermal filling device according to any one of claims 1 to 4, characterized in that, The number of the first optical fiber and the second optical fiber are independently greater than or equal to 2.

9. The in vivo photocuring and photothermal filling device according to any one of claims 1 to 4, characterized in that, The inner tube and the outer tube are made of one or more of polytetrafluoroethylene and polyethylene.

10. The in vivo photocuring photothermal filling device according to any one of claims 1 to 4, characterized in that, The outer diameter of the catheter is less than or equal to 3.0 mm.

11. The in vivo photocuring and photothermal filling device according to claim 10, characterized in that, The outer diameter of the catheter is 0.8 mm to 3.0 mm.

12. The in vivo photocuring and photothermal filling device according to any one of claims 1 to 4, characterized in that, The photocrosslinked hydrogel includes one or more of the following: methacrylic anhydride gelatin, methacrylamide hyaluronic acid, polyethylene glycol diacrylate, polylactic acid-glycolic acid copolymer, alginate-based hydrogel, and methacrylamide sodium carboxymethyl cellulose hydrogel.

13. The in vivo photocuring photothermal filling device according to any one of claims 1 to 4, characterized in that, 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-trimethyleneindole tricarbon anthocyanin iodide, porphyrin compounds, gold nanoparticles, silver nanoparticles, graphene, and carbon nanotubes.

14. The in vivo photocuring and photothermal filling device according to any one of claims 1 to 4, characterized in that, The photoinitiators include lithium phenyl (2,4,6-trimethylbenzoyl)phosphate, sodium phenyl (2,4,6-trimethylbenzoyl)phosphonite, 2,4,6-trimethylbenzoyl-diphenylphosphine oxide, riboflavin, phenyl bis(2,4,6-trimethylbenzoyl)phosphine oxide, tetramethylethylenediamine, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone, and benzoin methyl ether (2-methoxy-1,2-diphenyl ethyl ketone).

15. The in vivo photocuring and photothermal filling device according to claim 1, characterized in that, The Young's modulus of the in vivo photocurable photothermal filler is 10 kPa to 100 kPa.

16. The in vivo photocuring and photothermal filling device according to claim 15, characterized in that, The Young's modulus of the in vivo photocurable photothermal filler is 40 kPa to 50 kPa.

17. The in vivo photocuring and photothermal filling device according to claim 1, characterized in that, In the in vivo photocurable photothermal filler, the weight percentage of the photocrosslinked 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.%.

18. The in vivo photocuring and photothermal filling device according to claim 1, characterized in that, The photocrosslinked hydrogel, the photoinitiator, and the photothermal agent are mixed with a phosphate buffer solution to prepare the in vivo photocurable photothermal filler.

19. The in vivo photocuring and photothermal filling device according to claim 18, characterized in that, The photocrosslinked hydrogel is mixed with the phosphate buffer solution, and then the photoinitiator is added and mixed again. Finally, the photothermal agent is added and mixed to prepare the in vivo photocurable photothermal filler.

20. The in vivo photocuring and photothermal filling device according to claim 19, characterized in that, Mix at 60℃~70℃.

21. The in vivo photocuring and photothermal filling device according to claim 19, characterized in that, The prepared in vivo photocurable photothermal filler was placed at 2℃~8℃.

22. An in-vivo photocurable photothermal filler, characterized in that, The in vivo photocurable photothermal filler includes the in vivo photocurable photothermal filler as defined in the in vivo photocurable photothermal filler device according to claims 1, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21, wherein the in vivo photocurable photothermal filler is not laser irradiated.

23. The use of the in vivo photocurable photothermal filling device according to any one of claims 1-21 or the in vivo photocurable photothermal filling agent according to claim 22 in the preparation of products for tissue filling and repair.

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