A micron-sized sodium fluorescein fiber phantom, its preparation method and application

Abstract

This invention discloses a micron-sized sodium fluorescein fiber phantom, its preparation method, and its applications. The invention first involves adding a sodium fluorescein solution to epoxy resin and initially curing it to a certain viscosity. Then, a sodium fluorescein fiber phantom is prepared using wet spinning technology. A mold with varying depths is fabricated using 3D printing technology, and a TiO2-containing scattering layer is obtained using soft etching. Finally, the scattering layer is coated on the fiber membrane surface to obtain sodium fluorescein phantoms with different scattering thicknesses. Furthermore, by combining the phantom with a convex lens and a 3D-printed hemisphere, the conformability of the fiber is utilized to mimic the vascular structure of the fundus, resulting in an eyeball-shaped phantom. This method is simple to operate and can mass-produce sodium fluorescein phantoms of various concentrations and sizes, potentially providing broad application scenarios in the evaluation of endoscopic and fluorescein surgical navigation equipment and fundus fluorescein angiography equipment.

Description

Technical Field

[0001] This invention belongs to the technical field of medical diagnostic and therapeutic bionic phantoms and fluorescent surgical navigation equipment standardization, specifically relating to a micron-sized sodium fluorescein fiber phantom, its preparation method, and its application. Background Technology

[0002] Fluorescence molecular imaging (FMI) has become a valuable tool for guiding tumor surgery, and various fluorescence-guided surgery (FGS) devices are now available for both open and laparoscopic procedures. While progress has been made in this field, consensus remains lacking regarding quality control measures and system standardization. Establishing standardized fluorescence devices can improve manufacturing reliability, enhance user understanding of the instruments, and facilitate regulatory definition and approval. Therefore, numerous fluorescent biomimetic phantoms simulating the optical properties of tissues have been created to calibrate fluorescence imaging systems. For example, polyurethane-based models have been developed that combine the absorption, scattering, and fluorescence of different components to evaluate multiple system parameters. Phantoms designed with alternative shapes such as cylinders can be better aligned with the imaging field of view of fluorescence molecular endoscopy systems compared to typical bulk phantoms. 3D printing technology has been utilized to fabricate biomimetic phantoms of various shapes, but their size remains limited to the hundreds of micrometers range, still larger than the size of human capillaries. Furthermore, due to the instability of sodium fluorescein in polyurethane, sodium fluorescein-based phantoms have not yet been developed.

[0003] This invention discloses a method for preparing micron-scale sodium fluorescein phantom fibers based on epoxy resin using wet spinning technology. These fibers are then bonded to PDMS (polydimethylsiloxane) scattering layers of varying thicknesses to create phantoms with different scattering depths. By controlling the sodium fluorescein content, a series of concentrations of phantoms can be prepared, enabling the detection of sensitivity in fluorescence imaging devices. Simultaneously, this invention discloses a method for preparing an eyeball-shaped phantom. Utilizing the flexibility and shape adaptability of the fibers, they are arranged on a hemispherical PDMS surface, and by bonding lenses, the evaluation of fluorescein fundus cameras can be achieved. Compared to traditional mold methods and additive manufacturing, this invention's method can mass-produce sodium fluorescein biomimetic phantoms of different concentrations and sizes, offering scalability, customizability, and deployability. This opens up new strategies for evaluating fluorescence surgical navigation devices and fluorescein fundus cameras. Summary of the Invention

[0004] The purpose of this invention is to provide a micron-sized sodium fluorescein fiber phantom, its preparation method, and its applications. This method is simple, can be mass-produced, and yields sodium fluorescein fibers with tunable concentration, size, and scattering depth, showing application potential in fluorescent surgical navigation devices and the evaluation of fluorescein fundus cameras. Furthermore, the method employed in this invention is expected to be applied to various fluorescent materials with different emission wavelengths, such as indocyanine green, methylene blue, IR765, and quantum dots.

[0005] This invention is achieved through the following technical solution:

[0006] A method for preparing a micron-sized sodium fluorescein fiber phantom, the method comprising the following steps:

[0007] (1) Add sodium fluorescein to an organic solvent to dissolve it; weigh epoxy resin components A and B, add them to a beaker, and stir thoroughly; add the sodium fluorescein solution to the epoxy resin and stir until homogeneous;

[0008] (2) Pour the reaction product obtained in step (1) into a syringe and fix it on the injection pump. Push the syringe to collect the injected sodium fluorescein fiber on the roller.

[0009] (3) Weigh TiO2 and add it to ethanol, put it into an ultrasonic cleaner and use it to disperse it by ultrasonication, prepare polydimethylsiloxane PDMS solution, add the uniformly dispersed TiO2 ethanol solution and stir thoroughly.

[0010] (4) A mold with a stepped gradient depth is prepared by 3D printing. The solution prepared in step (3) is poured into the mold and fully cured to obtain PDMS scattering layers of different thicknesses. The scattering layers are fixed on the surface of sodium fluorescein fiber to obtain sodium fluorescein fiber phantoms for evaluation of endoscopes and fluorescent surgical navigation equipment.

[0011] Further, in step (1), sodium fluorescein is dissolved in DMSO at a concentration of 2.5 mg / mL and added to epoxy resin with a mass ratio of A:B = 3:1. The volume of sodium fluorescein solution added is 11 μL - 1.1 mL.

[0012] Further, in step (2), the reaction product is poured into a syringe with a needle diameter of 0.5 mm, the syringe is placed on an injection pump, and then the syringe is pushed at a pressure of 0.35 MPa and a speed of 1 mm / min to extrude the fiber and collect it on a roller with a roller speed of 5-100 rpm.

[0013] Furthermore, in step (3), the concentration of TiO2 in ethanol is 0.33 mg / mL, and when added to PDMS, the content of TiO2 in PDMS is controlled to be 2-8 mg / g.

[0014] Furthermore, in step (4), the gradient of the printing mold is 50um, the step width is 5mm, and there are a total of 9 gradient depths.

[0015] Furthermore, in step (4), the curing temperature of PDMS is 50-70℃.

[0016] A sodium fluorescein fiber phantom prepared by the above-described preparation method.

[0017] The application of the above-mentioned sodium fluorescein fiber phantom in the preparation of an eyeball-shaped phantom; prepared by the following steps:

[0018] A semi-circular concave mold was prepared using 3D printing, and PDMS was poured into it to obtain a PDMS hemisphere. Fluorescein sodium fiber phantoms were arranged in a radial pattern on the surface of the hemisphere. A layer of PDMS was coated on one side of the plano-convex lens plane, and the fiber-covered PDMS hemisphere was bonded to the convex lens to obtain an eyeball phantom.

[0019] Furthermore, the diameter of the sodium fluorescein fiber phantom used is 5-100 μm.

[0020] The beneficial effects of this invention are as follows:

[0021] 1. This invention utilizes epoxy resin as a base material and wet spinning technology to prepare micron-sized sodium fluorescein phantom fibers. Previous reports have described the preparation of fluorescent phantoms, but these primarily employed fluorescent materials such as ICG, with limited research on sodium fluorescein, which is unstable in polyurethane. Furthermore, limitations in the preparation methods prevented the fabrication of phantoms at the capillary scale. This invention utilizes wet spinning technology to mass-produce sodium fluorescein phantom fibers and easily imparts controllable concentration and size characteristics.

[0022] 2. This invention utilizes 3D printing technology and mold method to prepare PDMS scattering layers of different thicknesses, which, when combined with sodium fluorescein fibers, can achieve the preparation of fluorescent phantoms with different scattering thicknesses.

[0023] 3. This invention utilizes PDMS hemispherical and convex lens imaging, as well as the conformability and flexibility of fiber materials, to realize the fabrication of an eyeball-shaped fluorescent phantom, providing a solution for fundus camera evaluation.

[0024] 4. The process of this invention is simple and controllable, with a short preparation cycle, is safe and pollution-free, and inexpensive. Fluorescent phantoms with different emission bands can be flexibly prepared according to actual production requirements, showing broad application prospects in the evaluation of endoscopes and fluorescent surgical navigation equipment. Attached Figure Description

[0025] To more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0026] Figure 1 This is a schematic diagram of the experimental apparatus for preparing sodium fluorescein fibers in step 2 of this invention;

[0027] Figure 2 This is a schematic diagram of sodium fluorescein fibers of different sizes obtained in step 2 of this invention;

[0028] Figure 3 This is a schematic diagram of the PDMS scattering layer with stepped, gradually varying thickness obtained in step 4 of this invention.

[0029] Figure 4 This is a schematic diagram of the eyeball-shaped phantom obtained in step 5 of the present invention. Detailed Implementation

[0030] The following is a further description of the invention, but not a limitation thereof.

[0031] Example 1:

[0032] (1) Add sodium fluorescein to dimethyl sulfoxide (DMSO) and dissolve it (concentration 2.5 mg / ml); weigh 9 g of epoxy resin component A and 3 g of epoxy resin component B, add them to a beaker and stir thoroughly; add 1 μL of sodium fluorescein DMSO solution to the epoxy resin and stir evenly.

[0033] (2) See Figure 1 The reaction product obtained in step (1) is poured into a syringe with a diameter of 0.5 mm and fixed to a syringe pump. The syringe is then pushed to collect the injected sodium fluorescein fibers on a roller. Due to the low sodium fluorescein content, the fluorescence signal of the obtained sodium fluorescein fibers is too weak to be observed under a microscope.

[0034] Example 2:

[0035] (1) Add sodium fluorescein to DMSO and dissolve it (concentration 2.5 mg / ml); weigh 9 g of epoxy resin component A and 3 g of epoxy resin component B, add them to a beaker and stir thoroughly; add 1.5 mL of sodium fluorescein DMSO solution to the epoxy resin and stir evenly.

[0036] (2) Pour the reaction product obtained in step (1) into a syringe with a diameter of 0.5 mm and fix it on the injection pump. Push the syringe to collect the injected sodium fluorescein fibers on the roller. Due to the high DMSO content, the viscosity of the epoxy resin polymer is affected, and the mechanical properties of the collected fibers are insufficient, making it impossible to maintain the fiber shape.

[0037] Example 3:

[0038] (1) Add sodium fluorescein to DMSO and dissolve it (concentration 2.5 mg / ml); weigh 9 g of epoxy resin component A and 3 g of epoxy resin component B, add them to a beaker and stir thoroughly; add 100 μL of sodium fluorescein DMSO solution to the epoxy resin and stir evenly.

[0039] (2) Pour the reaction product obtained in step (1) into a syringe with a diameter of 0.5 mm and fix it on the injection pump. Push the syringe to collect the injected sodium fluorescein fiber on the roller.

[0040] (3) Weigh 2g of TiO2 and add it to 50mL of ethanol. Place it in an ultrasonic cleaner and use it to disperse it by ultrasonication. Prepare a polydimethylsiloxane (PDMS) solution and add 50uL of the uniformly dispersed TiO2 ethanol solution. Stir thoroughly. Because the amount of TiO2 added is too low, the scattering layer cannot play its corresponding role.

[0041] Example 4:

[0042] (1) Add sodium fluorescein to DMSO and dissolve it (concentration 2.5 mg / ml); weigh 9 g of epoxy resin component A and 3 g of epoxy resin component B, add them to a beaker and stir thoroughly; add 200 μL of sodium fluorescein DMSO solution to the epoxy resin and stir evenly.

[0043] (2) Pour the reaction product obtained in step (1) into a syringe with a diameter of 0.5 mm and fix it on the injection pump. Push the syringe to collect the injected sodium fluorescein fiber on the roller.

[0044] (3) Weigh 2g of TiO2 and add it to 6mL of ethanol. Place it in an ultrasonic cleaner and use it to disperse it by ultrasonication. Prepare a polydimethylsiloxane (PDMS) solution and add 500uL of the uniformly dispersed TiO2 ethanol solution. Stir thoroughly. Because the added TiO2 content is too high, the scattering layer cannot play its corresponding role.

[0045] Example 5:

[0046] (1) Add sodium fluorescein to DMSO and dissolve it (concentration 2.5 mg / ml); weigh 9 g of epoxy resin component A and 3 g of epoxy resin component B, add them to a beaker and stir thoroughly; add 100 μL of sodium fluorescein DMSO solution to the epoxy resin and stir evenly.

[0047] (2) Pour the reaction product obtained in step (1) into a syringe with a diameter of 0.5 mm and fix it on the injection pump. Push the syringe to collect the injected sodium fluorescein fiber on the roller.

[0048] (3) Weigh 2g of TiO2 and add it to 6mL of ethanol. Place it in an ultrasonic cleaner and use it to disperse it by ultrasonication. Prepare a polydimethylsiloxane (PDMS) solution and add 50uL of the well-dispersed TiO2 ethanol solution. Stir thoroughly.

[0049] (4) Use 3D printing to prepare a mold with a stepped gradient depth. Pour the solution prepared in step (3) into the mold and cure it at 100°C. Due to the high curing temperature, the bubbles in PDMS cannot be expelled in time, and the resulting scattering layer contains bubbles.

[0050] Example 6:

[0051] (1) Add sodium fluorescein to DMSO and dissolve it (concentration 2.5 mg / ml); weigh 9 g of epoxy resin component A and 3 g of epoxy resin component B, add them to a beaker and stir thoroughly; add 500 μL of sodium fluorescein DMSO solution to the epoxy resin and stir evenly.

[0052] (2) See Figure 2 The reaction product obtained in step (1) is poured into a syringe with a diameter of 0.5 mm and fixed on the injection pump. The syringe is pushed to collect the injected sodium fluorescein fiber on the roller.

[0053] (3) Weigh 2g of TiO2 and add it to 6mL of ethanol. Place it in an ultrasonic cleaner and use it to disperse it by ultrasonication. Prepare a polydimethylsiloxane (PDMS) solution and add 50uL of the well-dispersed TiO2 ethanol solution. Stir thoroughly.

[0054] (4) Use 3D printing to prepare a mold with a stepped gradient depth. Pour the solution prepared in step (3) into the mold and cure it at room temperature. Because the curing temperature is too low, the required curing time is too long, which will cause the TiO2 in PDMS to be unevenly distributed.

[0055] Example 7:

[0056] (1) Add sodium fluorescein to DMSO and dissolve it (concentration 2.5 mg / ml); weigh 9 g of epoxy resin component A and 3 g of epoxy resin component B, add them to a beaker and stir thoroughly; add 100 μL of sodium fluorescein DMSO solution to the epoxy resin and stir evenly.

[0057] (2) Pour the reaction product obtained in step (1) into a syringe with a diameter of 0.5 mm and fix it on the injection pump. Push the syringe to collect the injected sodium fluorescein fiber on the roller.

[0058] (3) Weigh 2g of TiO2 and add it to 6mL of ethanol. Place it in an ultrasonic cleaner and use it to disperse it by ultrasonication. Prepare a polydimethylsiloxane (PDMS) solution and add 50uL of the well-dispersed TiO2 ethanol solution. Stir thoroughly.

[0059] (4) See Figure 3 3D printing was used to prepare a mold with a stepped gradient depth. The solution prepared in step (3) was poured into the mold and cured at 50-70℃ to obtain a stepped scattering layer with different depths. The scattering layer was fixed on the surface of sodium fluorescein fiber to obtain a sodium fluorescein fiber phantom that can be used for evaluation of fluorescent surgical navigation equipment.

[0060] (5) A semi-circular concave mold was prepared by 3D printing, and PDMS was poured in to obtain a PDMS hemisphere. Fluorescent sodium fiber phantoms were arranged in a radial pattern on the surface of the hemisphere. A layer of PDMS was coated on one side of the plano-convex lens plane. The fiber-covered PDMS hemisphere was bonded to a convex lens with a focal length of 30mm. The resulting eyeball phantom could not be imaged under the fundus camera due to its excessively large focal length.

[0061] Example 8:

[0062] (1) Add sodium fluorescein to DMSO and dissolve it (concentration 2.5 mg / ml); weigh 9 g of epoxy resin component A and 3 g of epoxy resin component B, add them to a beaker and stir thoroughly; add 100 μL of sodium fluorescein DMSO solution to the epoxy resin and stir evenly.

[0063] (2) Pour the reaction product obtained in step (1) into a syringe with a diameter of 0.5 mm and fix it on the injection pump. Push the syringe to collect the injected sodium fluorescein fiber on the roller.

[0064] (3) Weigh 2g of TiO2 and add it to 6mL of ethanol. Place it in an ultrasonic cleaner and use it to disperse it by ultrasonication. Prepare a polydimethylsiloxane (PDMS) solution and add 50uL of the well-dispersed TiO2 ethanol solution. Stir thoroughly.

[0065] (4) Use 3D printing to prepare a mold with a stepped gradient depth. Pour the solution prepared in step (3) into the mold and solidify it at 50-70℃ to obtain a stepped scattering layer with different depths. Fix the scattering layer on the surface of sodium fluorescein fiber to obtain a sodium fluorescein fiber phantom that can be used for evaluation of fluorescent surgical navigation equipment.

[0066] (5) A semi-circular concave mold was prepared by 3D printing, and PDMS was poured in to obtain a PDMS hemisphere. Fluorescein sodium fiber phantoms were arranged in a radial pattern on the surface of the hemisphere. A layer of PDMS was coated on one side of the plano-convex lens plane. The fiber-covered PDMS hemisphere was bonded to a convex lens with a focal length of 8mm. The resulting eyeball phantom could not be imaged under the fundus camera due to its small focal length.

[0067] Example 9:

[0068] (1) Add sodium fluorescein to DMSO and dissolve it (concentration 2.5 mg / ml); weigh 9 g of epoxy resin component A and 3 g of epoxy resin component B, add them to a beaker and stir thoroughly; add 100 μL of sodium fluorescein DMSO solution to the epoxy resin and stir evenly.

[0069] (2) Pour the reaction product obtained in step (1) into a syringe with a diameter of 0.5 mm and fix it on the injection pump. Push the syringe to collect the injected sodium fluorescein fiber on the roller.

[0070] (3) Weigh 2g of TiO2 and add it to 6mL of ethanol. Place it in an ultrasonic cleaner and use it to disperse it by ultrasonication. Prepare a polydimethylsiloxane (PDMS) solution and add 50uL of the well-dispersed TiO2 ethanol solution. Stir thoroughly.

[0071] (4) Use 3D printing to prepare a mold with a stepped gradient depth. Pour the solution prepared in step (3) into the mold and cure PDMS at 50-70℃ to obtain a stepped scattering layer with different depths. Fix the scattering layer on the surface of sodium fluorescein fiber to obtain a sodium fluorescein fiber phantom that can be used for evaluation of fluorescent surgical navigation equipment.

[0072] (5) See Figure 4 A semi-circular concave mold was prepared using 3D printing, and PDMS was poured into it to obtain a PDMS hemisphere with a diameter of 24 mm. Fluorescein sodium fiber phantoms were arranged in a radiating pattern on the surface of the hemisphere. A layer of PDMS was coated on one side of a plano-convex lens. The fiber-covered PDMS hemisphere was then bonded to a convex lens with a focal length of 16 mm to obtain an eyeball phantom that can be imaged under a fundus camera. The diameter of the fluorescein sodium fiber phantoms used was 5-100 μm, and the diameter of the convex lens was 25.4 mm with a focal length of 16 mm.

[0073] It should be noted that in step (2), the reaction product is poured into a syringe with a needle diameter of 0.5 mm, the syringe is placed on the injection pump, and then the syringe is pushed at a pressure of 0.35 MPa and a speed of 1 mm / min to extrude the fiber and collect it on the roller. The roller speed is 5-100 rpm.

[0074] In step (3), the concentration of TiO2 in ethanol is 0.33 mg / mL, and when added to PDMS, the content of TiO2 in PDMS is controlled to be 2-8 mg / g.

[0075] In step (4), the gradient of the printing mold is 50um, the step width is 5mm, and there are a total of 9 gradient depths.

[0076] It is worth mentioning that the sodium fluorescein fiber phantom prepared in this invention can be combined with a scattering layer prepared by 3D printing and with reasonable optical path design to achieve the evaluation of equipment such as confocal microscopes, fluorescence endoscopes, and fluorescence fundus cameras.

[0077] It should be noted that, in the above embodiments of the present invention, other different solutions obtained by making specific selections within the range of steps, components, proportions, and process parameters recorded in the present invention can all achieve the technical effects recorded in the present invention, so the present invention will not list them one by one.

[0078] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

[0079] The above embodiments are only used to illustrate the design concept and features of the present invention, and their purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly. The protection scope of the present invention is not limited to the above embodiments. Therefore, all equivalent changes or modifications made based on the principles and design ideas disclosed in the present invention are within the protection scope of the present invention.

Claims

1. A method for preparing a micron-sized sodium fluorescein fiber phantom, characterized in that, The method includes the following steps: (1) Dissolve sodium fluorescein in DMSO to a concentration of 2.5 mg / mL; weigh epoxy resin components A and B with a mass ratio of 9 g: 3 g, add them to a beaker, and stir thoroughly; add 11 uL-1.1 mL of sodium fluorescein solution to the epoxy resin and stir until homogeneous. (2) Pour the reaction product obtained in step (1) into a syringe and fix it on the injection pump. Push the syringe to collect the injected sodium fluorescein fiber on the roller. (3) Weigh TiO2 and add it to ethanol. Place it in an ultrasonic cleaner and use it to disperse it by ultrasonication. Prepare a polydimethylsiloxane PDMS solution. Add the uniformly dispersed TiO2 ethanol solution and stir thoroughly. The concentration of TiO2 in ethanol is 0.33 mg / mL. When adding it to PDMS, control the content of TiO2 in PDMS to be 2-8 mg / g. (4) A mold with a stepped gradient depth is prepared by 3D printing. The solution prepared in step (3) is poured into the mold and fully cured to obtain PDMS scattering layers of different thicknesses. The scattering layers are fixed on the surface of sodium fluorescein fiber to obtain a sodium fluorescein fiber phantom for evaluation of endoscopes and fluorescent surgical navigation equipment. The curing temperature of PDMS is 50-70℃.

2. The method for preparing a micron-sized sodium fluorescein fiber phantom according to claim 1, characterized in that, In step (2), the reaction product is poured into a syringe with a needle diameter of 0.5 mm, the syringe is placed on the injection pump, and then the syringe is pushed at a pressure of 0.35 MPa and a speed of 1 mm / min to extrude the fiber and collect it on the roller. The roller speed is 5-100 rpm.

3. The method for preparing a micron-sized sodium fluorescein fiber phantom according to claim 1, characterized in that, In step (4), the gradient of the printing mold is 50um, the step width is 5mm, and there are a total of 9 gradient depths.

4. A sodium fluorescein fiber phantom prepared by the preparation method according to any one of claims 1-3.

5. The use of the sodium fluorescein fiber phantom as described in claim 4 in the preparation of an eyeball-shaped phantom.

6. The application according to claim 5, characterized in that, Includes the following steps: A semi-circular concave mold was prepared using 3D printing, and PDMS was poured into it to obtain a PDMS hemisphere. Fluorescein sodium fiber phantoms were arranged in a radial pattern on the surface of the hemisphere. A layer of PDMS was coated on one side of the plano-convex lens plane. The fiber-covered PDMS hemisphere was then bonded to the convex lens to obtain an eyeball phantom. The focal length of the convex lens used was 16mm.

7. The application according to claim 6, characterized in that, The diameter of the sodium fluorescein fiber phantom used is 5-100 μm.

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