Photocurable composition for manufacturing biliary stent with shape memory properties by using 3D printer, and biliary stent with shape memory properties, using same

Abstract

The present invention relates to a photocurable composition for manufacturing a biliary stent with shape memory properties by using a 3D printer, and a biliary stent with shape memory properties, using same. The surface of CNC is modified so as to be uniformly mixed in the photocurable composition, the mechanical properties of a 3D-printed output obtained using same are improved, and due to uniform mixing in the photocurable composition, transparency can be improved, and shape memory behavior characteristics can be exhibited in response to thermal stimulation. In addition, a patient-customized biliary stent using a photocurable composition for 3D printing is provided. Compared to a conventional photocurable composition, printing accuracy is further improved such that a biliary stent is manufactured more precisely, and mechanical properties are enhanced such that a patient-customized biliary stent can be provided.

Description

Photocurable composition for manufacturing a biliary duct stent having shape memory properties using a 3D printer and a biliary duct stent having shape memory properties using the same

[0001] The present invention relates to a photocurable composition for manufacturing a bile duct stent having shape memory properties using a 3D printer, and a bile duct stent having shape memory properties using the same.

[0002] Stents, which are widely used in medicine, are utilized in interventional procedures to restore patency to narrowed areas within the body where the lumen through which blood, food, and body fluids travel is narrowed due to atherosclerosis, thrombosis, benign and malignant tumors, post-surgical complications, or pathological causes. This procedure began in the 1980s and continues to be performed as an important procedure to this day.

[0003] These stents are broadly classified into non-vascular and vascular stents, and self-expanding stents are well known, which generally have a metal or polymer mesh structure and possess inherent elasticity, contracting when an external force is applied and returning to their original state when the external force is removed.

[0004] The aforementioned stent procedures are broadly classified into vascular stent implantation and non-vascular stent implantation.

[0005] The former vascular stent insertion procedure is known as a method of expanding narrowed blood vessels by making a hole of about 3mm to 4mm in the thigh, pushing a thin tube called a 'catheter' up the femoral artery to the site of the lesion, and then inserting a stent.

[0006] The latter non-vascular stent insertion procedure is known as a surgical method in which a balloon catheter tube is inserted internally to expand the narrowed area and inflate the balloon in order to secure food intake when the esophagus becomes blocked or progresses due to stenosis caused by cancerous tissue, etc., making oral food intake impossible.

[0007] Stents used in the aforementioned two procedures have been disclosed to date with improved stent functions based on various structures.

[0008] Unless for a special purpose, such stents typically form a hollow cylindrical body of a predetermined length having multiple rhombus-shaped spaces (cells) by crossing superelastic shape memory alloy wires or stainless steel wires at different locations or connecting crooked and ribbed sections in a hook shape.

[0009] Meanwhile, to expand a narrowed lumen caused by stenosis or other lesions, a stent procedure is known in which the stent is fixed in place by being caught on various sphincter tissues within the human organ, and the procedure is performed on the bile duct, etc.

[0010] In other words, as mentioned above, conventional stents have merely been developed in various structures to improve function.

[0011] Furthermore, the insertion of a biliary stent is intended to restore patency at the site of stenosis; therefore, when inserting the stent into the stenotic area, it must be inserted in a minute size and subsequently expand to the original size of the blood vessel. While currently developed technologies utilize shape-memory materials to enable expansion after introduction into the body, as mentioned above, it is impossible to manufacture customized stents tailored to the varying degrees of stenosis among patients, thus requiring further development in this area.

[0012] [Prior Art Literature]

[0013] [Patent Literature]

[0014] KR 10-1691121 B1

[0015] The objective of the present invention is to provide a photocurable composition for manufacturing a bile duct stent having shape memory properties using a 3D printer, and a bile duct stent having shape memory properties using the same.

[0016] Another objective of the present invention is to provide a photocurable composition for 3D printing that modifies the surface of a CNC to be uniformly mixed into a photocurable composition, thereby improving the mechanical properties of a 3D printed output using the same, and also improves transparency and exhibits shape memory behavior characteristics due to thermal stimulation as it is uniformly mixed into the photocurable composition.

[0017] Another objective of the present invention is to provide a patient-specific biliary stent using the photocurable composition for 3D printing, which further improves printing accuracy compared to existing photocurable compositions, thereby enabling more precise fabrication of the biliary stent and providing a patient-specific biliary stent with enhanced mechanical properties.

[0018] To achieve the above-mentioned objective, the present invention relates to a photocurable composition for manufacturing a bile duct stent having shape memory properties using a 3D printer, comprising a photocurable resin; and cellulose nanocrystals (CNC), wherein the surface of the cellulose nanocrystals is modified with an acrylic monomer.

[0019] In addition, the cellulose nanocrystal may be a sulfuric-acid-hydrolyzed CNC (S-CNC).

[0020] In addition, the acrylic monomer may be selected from the group consisting of MMA (Methyl Methacrylate), BMA (n-Butyl Methacrylate), IBMA (iso-Butyl Methacrylate), EDMA (Ethyleneglycol Dimethacrylate), MAA (Mathacrylic acid), IA (Itaconic acid), AA (Acrylic acid), LMA (Lauryl methacrylate), EMA (Ethyl methacrylate), EA (Ethyl acrylate), MA (Methyl acrylate), and mixtures thereof.

[0021] In addition, the above photocurable composition can improve dispersion stability by mixing a photocurable resin and cellulose nanocrystals (CNC) and mixing them according to ultrasonic treatment for 60 seconds or more.

[0022] In addition, the cellulose nanocrystals (CNC) are surface-modified with an acrylic monomer, which improves compatibility with the photocurable resin and allows for uniform dispersion when mixed.

[0023] In addition, the photocurable composition may contain 0.01% to 0.2% by weight of cellulose nanocrystals (CNC) whose surfaces are modified with acrylic monomers relative to the total weight.

[0024] Another invention for achieving the above-mentioned purpose relates to a bile duct stent having shape memory properties comprising the above-mentioned photocurable composition.

[0025] In addition, the above-mentioned biliary stent can restore its shape under body temperature conditions.

[0026] In addition, the above-mentioned biliary stent can be manufactured as a patient-specific product by printing it with a 3D printer using a photocurable composition.

[0027] The present invention modifies the surface of a CNC to be uniformly mixed into a photocurable composition, thereby improving the mechanical properties of a 3D printed output using the same, and also improves transparency and exhibits shape memory behavior characteristics due to thermal stimulation as it is uniformly mixed into the photocurable composition.

[0028] In addition, by using the above-mentioned photocurable composition for 3D printing to provide a patient-specific biliary stent, printing accuracy is further improved compared to existing photocurable compositions, enabling the production of a biliary stent with greater precision and strengthening mechanical properties, thereby allowing it to be provided as a patient-specific biliary stent.

[0029] Figure 1 is a conceptual diagram of surface modification of a CNC according to one embodiment of the present invention, an FT-IR analysis spectrum, and zeta potential measurement results.

[0030] Figure 2 is a test result regarding the dispersibility of a photocurable resin and a surface-modified CNC according to one embodiment of the present invention.

[0031] Figure 3 is a test result regarding the transmittance spectrum and characteristics according to ultrasonic treatment for a photocurable composition including a surface-modified CNC according to one embodiment of the present invention.

[0032] Figure 4 is the measurement result of mechanical properties for a photocurable composition including a surface-modified CNC according to one embodiment of the present invention.

[0033] Figure 5 is the result of evaluating the cell stability of a photocurable composition containing a surface-modified CNC according to one embodiment of the present invention.

[0034] Figure 6 is a printability measurement result for a photocurable composition including a surface-modified CNC according to one embodiment of the present invention.

[0035] FIG. 7 is a test result for the shape memory characteristics of a photocurable composition including a surface-modified CNC according to one embodiment of the present invention.

[0036] The present invention relates to a photocurable composition for manufacturing a bile duct stent having shape memory properties using a 3D printer, comprising a photocurable resin; and cellulose nanocrystals (CNC), wherein the surface of the cellulose nanocrystals is modified with an acrylic monomer.

[0037] Hereinafter, embodiments of the present invention are described in detail so that those skilled in the art can easily implement the invention. However, the present invention may be embodied in various different forms and is not limited to the embodiments described herein.

[0038] Additive manufacturing, which enables the design and direct printing of three-dimensional (3D) objects, can significantly advance industrial and advanced materials research. In particular, the rapid development of 3D printing technology can have a major impact on various medical fields, including surgery, bioengineering, orthopedics, and dentistry.

[0039] Among various 3D printing technologies, UV-curing 3D printing can create complex shapes with precision and fine detail. Since this method uses photopolymerizable resins that solidify when exposed to ultraviolet (UV) light, it is highly suitable for applications requiring high-resolution fabrication.

[0040] A major advantage of UV-curing 3D printing is that transparent 3D structures can be easily produced. These transparent structures are valuable in numerous medical applications, such as medical devices, implants, and orthopedic instruments.

[0041] The transparency of such structures is particularly important for real-time monitoring of processes and clinical outcomes, as well as for visual inspections to evaluate security integrity. This capability is essential for accurate diagnosis and treatment planning. Trimethylolpropane formal acrylate (CTFA) is particularly attractive in biomedical engineering due to its transparency and shape memory properties. To obtain transparent structures using CTFA, the ink must meet specific criteria, including optical transparency, uniformity, and compatibility with UV-curing resins. Optical transparency ensures that the structure appears transparent, while uniformity is crucial for maintaining consistent physical and mechanical properties throughout the material. Additionally, compatibility with UV-curing resins is essential for forming the desired structure by ensuring proper curing of the ink during the printing process.

[0042] However, transparent structures present several problems, such as low crystallinity, reduced mechanical strength, and potential degradation of printing precision. Reduced mechanical strength can impair the durability and practicality of printed structures, while reduced printing precision can hinder the accurate reproduction of complex geometric structures. To overcome these limitations, biocompatible nanomaterials capable of achieving both high transparency and mechanical strength simultaneously are required.

[0043] Nanoparticles can improve the mechanical strength of ink while maintaining transparency, but it is important to optimize the interaction between the nanoparticles and the resin. Surface treatment of the nanoparticles may be necessary for colloidal stability and uniform dispersion. In the present invention, cellulose nanocrystals (CNC) derived from natural cellulose were selected as a reinforcing material due to their large surface area, high aspect ratio, excellent mechanical strength, and biodegradability.

[0044] However, since the surface charge of the CNC differs from that of the resin, chemical surface modification is required. In other words, when using a conventional CNC, there is a problem with poor dispersion stability with the photocurable resin, so measures to address this need to be devised.

[0045] Accordingly, the present invention is characterized by acrylating the CNC to improve compatibility with UV-curing resins, thereby facilitating better dispersion and stronger interactions within the polymer matrix.

[0046] As described above, the composition in which acrylated CNC is mixed with UV-cured CTFA can be manufactured into a high-performance transparent 3D structure by improving mechanical properties and shape memory behavior when manufactured through 3D printing.

[0047] The above composition is a photocurable composition that can be applied to 3D printing and can exhibit appropriate mechanical properties suitable for use as a biliary stent. As previously explained, when applied as a biliary stent, it exhibits shape memory behavior characteristics, so after entering a narrowed biliary duct, it can be restored to its original shape to exert an effect.

[0048] In addition, when the photocurable composition of the present invention is applied to a 3D printer, that is, a 3D printer using the stereolithography (SLA) or digital light source processing (DLP) method, a higher level of printing precision can be achieved.

[0049] In the case of the aforementioned biliary stent, existing biliary stents are manufactured in various shapes, which may not only be shapes intended to enhance the effectiveness of application as a biliary stent but may also be shapes more suitable for the patient's condition.

[0050] Accordingly, the photocurable composition of the present invention increases printing precision, enabling printing into a precise structure, and thereby enables printing into bile duct stents of various shapes.

[0051] Specifically, the present invention may relate to a photocurable composition for manufacturing a bile duct stent having shape memory properties using a 3D printer, comprising a photocurable resin; and cellulose nanocrystals (CNC), wherein the surface of the cellulose nanocrystals is modified with an acrylic monomer.

[0052] More specifically, the cellulose nanocrystal (CNC) may be included as an additive composition in a photocurable composition, and the cellulose nanocrystal may be an additive composition for 3D printing that improves mechanical properties and increases the printing precision of 3D printing, with the surface modified with an acrylic monomer.

[0053] As described above, the present invention selects CNC among various reinforcing materials as the additive composition. However, in the case of CNC, there is a problem in that it is difficult to mix with the photocurable resin due to poor dispersion stability with the photocurable resin, as described below. To resolve this problem, the present invention is characterized by using surface-modified CNC.

[0054] In addition, to increase dispersion stability with the photocurable resin, the surface is modified using an acrylic monomer, and when the surface-modified CNC is mixed with the photocurable resin and used, not only can mechanical properties be improved, but the printing precision and shape memory characteristics of 3D printing can also be further improved, and the problem of reduced transparency due to the use of reinforcing materials does not occur, thereby enabling application to various fields as described above.

[0055] The photocurable composition may contain cellulose nanocrystals (CNC) whose surfaces are modified with acrylic monomers in an amount of 0.01% to 0.2% by weight relative to the total weight, preferably 0.1% by weight. Within this range, not only are excellent mechanical properties exhibited, but printing precision and shape memory characteristics can also be improved.

[0056] The above cellulose nanocrystals may be sulfuric-acid-hydrolyzed CNC (S-CNC), but any CNC capable of surface modification using acrylic monomers may be used without limitation.

[0057] The above acrylic monomer is selected from the group consisting of MMA (Methyl Methacrylate), BMA (n-Butyl Methacrylate), IBMA (iso-Butyle Methacrylate), EDMA (Ethyleneglycol Dimethacrylate), MAA (Mathacrylic acid), IA (Itaconic acid), AA (Acrylic acid), LMA (Lauryl methacrylate), EMA (Ethyl methacrylate), EA (Ethyl acrylate), MA (Methyl acrylate), and mixtures thereof, preferably MAA, but is not limited to the above examples, and any acrylic monomer capable of improving the dispersion stability of CNC through surface modification can be used without limitation.

[0058] The cellulose nanocrystals whose surfaces are modified with acrylic monomers may have a zeta potential of -35mV to -55mV. As described above, the surface properties of the CNCs whose surfaces are modified with acrylic monomers are altered, which can improve dispersion stability with photocurable resins.

[0059] A photocurable composition for 3D printing according to another embodiment of the present invention may include the additive composition of the present invention.

[0060] The above photocurable composition may include a photocurable resin. The photocurable resin is trimethylolpropane formal acrylate (CTFA), but is not limited to the above example; any photocurable resin that can be uniformly mixed with the additive composition of the present invention, is transparent, and exhibits shape memory properties may be used without limitation.

[0061] The above photocurable composition comprises a photocurable resin and an additive composition, wherein the cellulose nanocrystals in the additive composition are surface-modified with an acrylic monomer, thereby improving compatibility with the photocurable resin and allowing for uniform dispersion when mixed.

[0062] As described above, the CNC of the present invention is characterized by being surface-modified with an acrylic monomer, and the acrylic monomer surface-modified as described above is characterized by having improved compatibility with the photocurable resin and being uniformly dispersed.

[0063] Typically, CNCs manufactured by the acid-hydrolysis method contain hydroxyl groups (-OH) and sulfation functional groups on their surface, making them susceptible to chemical modification and exhibiting hydrophilic characteristics, which results in poor compatibility with hydrophobic photocurable resins. In other words, CNCs are not easily mixed with photocurable resins, leading to phase separation and aggregation phenomena upon mixing. To resolve these issues, the present invention modifies the CNC using an acrylic monomer as described above. The CNCs whose surfaces are modified with acrylic monomers as described above exhibit excellent compatibility with photocurable resins and can be uniformly dispersed. Due to this improved dispersion characteristic, the surface-modified CNCs uniformly dispersed within the photocurable resin can exhibit improved mechanical strength characteristics. Furthermore, as described above, the surface-modified CNCs uniformly dispersed due to the improved compatibility characteristic do not affect the transparency of the photocurable resin.

[0064] Accordingly, the photocurable composition for 3D printing of the present invention may have a transparency of 80% or more in the transmittance spectrum. Typically, when reinforcing fillers are mixed, a problem may occur in which the transparency is lowered due to the influence of the reinforcing fillers.

[0065] The above photocurable composition may have a transparency of 80% or more in the transmittance spectrum even when containing 0.1% by weight or more of an additive composition relative to the total weight. As described above, the present invention is characterized by minimizing the effect on transparency despite additionally including reinforcing fillers to enhance mechanical properties.

[0066] To achieve the above effects, the photocurable composition can improve dispersion stability by mixing the photocurable resin and the additive composition and mixing them by ultrasonic treatment for 60 seconds or more. It is characterized by increased transparency by improving dispersibility through ultrasonic treatment rather than simply mixing the CNC based on surface modification.

[0067] The above photocurable composition may additionally include a photoinitiator. The photoinitiator may include BP, TPO, DCP, BPO, DPPO, etc., and preferably DPPO (2-hydroxy-2-methylpropiophenone), but is not limited to the above examples, and any photoinitiator capable of preparing a photocurable composition may be used without limitation.

[0068] Preparation Example and Test Method

[0069] A-CNC manufacturing

[0070] A-CNC was prepared using sulfuric acid hydrolysis CNC (S-CNC) powder (Celluforce, Montreal, Canada). First, a homogeneous aqueous suspension (1 wt%) of S-CNC was prepared by magnetic stirring at 200 rpm for 30 minutes. Subsequently, a mixed solution was prepared by mixing 0.1 g of potassium persulfate and 1 g of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) with the S-CNC suspension in a three-necked round-bottom flask. 10 mL of methacrylic acid (MAA, Junsei Chemical Co. Ltd., Japan) was added dropwise to the mixed solution using a syringe pump at 70°C, and the solution was stirred at 600 rpm for 2, 4, and 6 hours. The solution was cooled to room temperature and ultracentrifuged at 8000 rpm. The supernatant was removed to separate the A-CNC, and then it was resuspended in distilled water for purification. The purification process was repeated three times. The resulting gel-like solution was freeze-dried for three days, and the dried A-CNC was stored at room temperature until use.

[0071] Preparation of a photocurable composition for 3D printing

[0072] 1 wt% of phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide (Irgacure 819, BASF) was added to CTFA (Miwon Specialty Chemical Co., Ltd.) and dispersed by sonication for 1 minute at 70% amplitude using an ultrasonic disperser (VCX-130, SONICS, United States) equipped with a 13 mm diameter solid probe (630-0560, SONICS, United States). After dispersing the photoinitiator (DPP0) in CTFA, the mixture was cooled, and then 0.05, 0.1, and 0.2 wt% of A-CNC were added. The complex suspension was mixed using a vortex mixer (SI-0246A Vortex-Genie2, Scientific Industries Inc., USA) for 1 minute, and then sonicated at 70% amplitude for various durations (0, 30, 60, 120 seconds). During sonication, the bottles containing the ink were placed in an ice bath to prevent overheating.

[0073]

[0074] Printability of photocurable compositions

[0075] The 3D CAD design model was generated using Rhinoceros 5.0 (Robert McNeel & Associates, USA) and sliced ​​using Anycubic Photon Workshop software (Anycubic, Shenzhen, China). The print slice parameters were set to a layer thickness of 100 μm, an exposure time of 3 seconds, and an off-time of 1 second between slices. 3D printing was performed using an LCD 3D printer (Photon Mono 2, Anycubic, Shenzhen, China).

[0076] Chemical structure of A-CNC

[0077] The chemical structure of the S-CNC after grafting was analyzed by performing Fourier Trans Infrared (FTIR) spectroscopy (Nicolet iS5, Thermo Scientific, Waltham, Massachusetts, USA). FTIR spectroscopy was performed with a wavenumber range of 4000–500 cm⁻¹. -1 At a resolution of 4cm -1 , performed with scan number 32.

[0078] Surface charge of A-CNC

[0079] The surface charges of S-CNC and A-CNC suspensions prepared at 2, 4, and 6 hours were analyzed using a Malvern Zetasizer (Nano ZS90, Malvern Panalytical, Malvern, United Kingdom).

[0080] Thermal stability of A-CNC

[0081] The thermal stability of the A-CNC was determined by simultaneous thermogravimetric analysis (SDT, TA Instruments, New Castle, United States) at a heating rate of 10°C / min in a nitrogen environment at temperatures ranging from 25°C to 600°C. Samples were dried in an oven at 80°C for 10 minutes prior to testing, and approximately 1 mg of dried sample was used for each test.

[0082] Dispersibility of complex suspensions

[0083] The hydrodynamic diameter of the composite suspension was measured using a zetasizer (ZSU 3150, Malvern Instruments, Malvern, UK). Each sample was diluted 10-fold with isopropyl alcohol (99.8%, SAMCHUN, Korea). The transmittance of the composite suspension was measured using a UV-visible spectrometer (Optizen POP, Mecasys Co., Ltd, South Korea) in the wavelength range of 380–420 nm in spectral mode and 405 nm in luminous intensity mode. Changes in the transmittance of the composite resin were measured at 405 nm in motion mode for 60 minutes at 5-minute intervals.

[0084] Turbidity of a suspension

[0085] To evaluate the colloidal stability of the composite ink during an extended 3D printing process, the turbidity of the A-CNC / CTFA composite resin was measured using the Tyndall effect. A commercially available laser pointer equipped with a dark red laser diode near 650 nm was used. 10 ml of photocurable resin was filled into a 20 ml vial. The laser was aimed at a height of 1 cm from the bottom of the vial, and photographs were taken in a dark environment. After the suspension had stood for 1 hour, another set of photographs was taken.

[0086] mechanical properties

[0087] The mechanical strength of the printed resins was measured using a universal testing machine (UTM, GB / LRX Plus, Lloyd, West Sussex, United Kingdom) equipped with a 500 N load cell. Uniaxial tensile tests were performed according to ASTM D412 specifications for elastomers. The tests were conducted at a speed of 0.5 mm / s. Tensile strength and fracture strain were determined as the stress and strain at specimen failure, respectively. The elastic modulus was defined as the initial slope of the stress-strain curve. To perform Weibull analysis, 15 tensile tests were performed on CTFA / A-CNC and CTFA / S-CNC composites at various concentrations (0.05, 0.1, and 0.2 wt%). The survival probability as a function of ultimate tensile stress was fitted to an asymmetric sigmoid curve. Fitting and analysis were performed using the nonlinear analysis function of GraphPad Prism software.

[0088] Thermomechanical cycle characteristic test

[0089] The cyclic creep behavior and stress relaxation of each material were evaluated using dynamic mechanical analysis (DMA, Q800, TA Instruments, New Castle, United States) in stress relaxation mode. The temperature was set between 37 and 80°C, and a cycle of 2% elongation followed by 60 minutes of recovery was applied. The cycle test was repeated 13 times.

[0090] Thermal Induction Shape Memory Analysis

[0091] Thermally induced shape memory behavior was evaluated using 3D printed samples made of CTFA and A-CNC / CTFA resins. The printed samples were initially softened in a water bath maintained at 85°C for 30 seconds. The deformed samples were then transferred to a 4°C ice bath for 30 seconds to be rapidly fixed. The samples were then immersed in a 40°C water bath to observe shape recovery behavior.

[0092] To quantitatively evaluate shape memory performance, a fold-deploy test was performed. A rectangular sample with a length of 50 mm, a width of 20 mm, and a thickness of 2 mm was 3D printed. This sample was folded into a U-shape, and the two parallel blades were placed in a water bath at 85°C for 30 seconds. After deformation, the shape was fixed in an ice water bath at 4°C for 30 seconds. The U-shaped specimen was immersed in water at 40°C for 3 minutes, and the angle (θf) between the blades was measured. The shape recovery ratio (Rr) was calculated using the following equation.

[0093]

[0094] Cell viability

[0095] Cell viability assays were performed according to the ISO-10993-5 standard for NIH-3T3 fibroblasts. Cells were cultured in DMEM medium (Sigma Aldrich, St. Louis, United States) containing 8% fetal bovine serum (Thermo Fisher Scientific, Waltham, United States) and 2% penicillin / streptomycin (Sigma Aldrich, St. Louis, United States) at 37°C and 5% CO₂. Cell viability was evaluated using UV-cured CTFA from the culture medium and the extract solution from the composite sheet. Cells (3.5 x 10³ cells / well) were cultured in 96-well plates with 100 μL of the extract solution at 37°C and 5% CO₂ for 24 hours. The MTT assay was performed using a standard protocol. Absorbance was measured at 570 nm using an ELISA reader (Varioskan ALF, Thermo Fisher Scientific, Waltham, United States).

[0096] Cell adhesion

[0097] For cell adhesion analysis, 10 mm inner diameter wells were printed using DLP with a composite ink consisting of CTFA and 0.1 wt% S-CNC and A-CNC. 3 Х 10 4 Cells were inoculated into each well and cultured at 37°C at 5% CO₂ for 24 hours. Cells were washed with PBS, stained with 1 mM CytoFluor-AM / DMSO and 1.5 mM propidium iodide (MAX-View, Korea) for 20 minutes, and then observed using a fluorescence microscope (Celena S Digital Imaging System, Korea).

[0098] test

[0099] The surface of S-CNC was modified with acrylic functional groups using a TEMPO-assisted reaction (Fig. 1a). S-CNC, which consists of crystalline cellulose particles generally extracted via acid hydrolysis, is susceptible to chemical modification due to the presence of hydroxyl and sulfate functional groups on its surface. S-CNC is known for its high mechanical strength, making it suitable as a nanofiller for composite materials. However, its hydrophilicity limits its compatibility with hydrophobic resins such as CTFA. When CTFA, a highly hydrophobic acrylate resin, is mixed with S-CNC, phase separation and aggregation occur. This aggregation reduces colloidal stability, increases light scattering, and leads to a diffusion curing process, which can significantly lower print fidelity.

[0100] To solve these problems, A-CNC was synthesized by modifying the surface of S-CNC to acrylate its functional groups. The modification reaction improves the chemical affinity between A-CNC and the acrylic groups of CTFA, thereby increasing the miscibility between A-CNC and CTFA and enhancing the colloidal stability of the composite ink. MAA was used as the monomer for modification, K₂S₂O₅ was used as the catalyst, and TEMPO acted as a crosslinking inhibitor at 70°C. After the reaction, the final product was centrifuged to obtain a powder and freeze-dried.

[0101] The FTIR spectrum confirmed surface modification of the S-CNC through acrylation (Fig. 1b). 3334 cm⁻¹ -1 The broad peak corresponds to the stretching vibration of the hydroxyl (-OH) group, whereas 2900 cm⁻¹ -1 The peak is attributed to CH stretching vibrations. Additionally, a peak attributed to COC stretching vibrations of the cellulose backbone was observed. After surface modification with MAA, the peak at 1704 cm⁻¹ was attributed to C=O stretching vibrations. -1A new peak appeared, confirming successful surface modification of the S-CNC. The appearance of this peak was consistent across various reaction times of 2, 4, and 6 hours, which confirms the importance of reaction time in achieving proper chemical surface modification.

[0102] Zeta potential measurements confirm that S-CNC was successfully synthesized into A-CNC. The zeta potential values ​​of S-CNC and A-CNC at 2, 4, and 6 hours were -48.92±1.38, -42.43±0.35, -41.7±0.92, and -39.88±1.30, respectively (Fig. 1c). The high negative zeta potential value of A-CNC is similar to that of S-CNC, which may indicate that deformation occurred mainly at the C2 and C3 positions rather than the C6 sulfate group of the cellulose structure.

[0103] The transmittance spectrum of the A-CNC / CTFA composite resin (Fig. 2a) shows that transparency is significantly improved in the 380–420 nm range as the acrylation reaction time increases.

[0104] Specifically, the photoinitiation of the composite resin occurred at 405 nm, and the transparency of the CTFA composite resin containing S-CNC was approximately 60%, mainly due to high turbidity. This turbidity is attributed to light scattering at the interface of the unmixed S-CNC within the CTFA resin. As the acrylation reaction time increased, the transparency gradually improved, reaching a maximum of 93%. This improvement is due to the more uniform dispersion of A-CNC with the resin matrix and improved compatibility.

[0105] The hydrodynamic diameter of A-CNC in CTFA resin decreased as the acrylation reaction time increased (Fig. 2c). While S-CNC exhibited micrometer-scale aggregation within the CTFA resin, A-CNC acrylated by surface modification was dispersed at a much smaller size under the same dispersion conditions. The reduction in hydrodynamic diameter reflects the improved dispersion and uniform distribution of A-CNC in the resin matrix, which is important for improving printability and mechanical properties.

[0106] Figures 2d and 2e are optical images of composite resins containing S-CNC and A-CNC at various concentrations in CTFA, respectively. The transparency of the resin containing S-CNC decreased rapidly, showing an opaque appearance at concentrations of 0.1 wt% or higher. On the other hand, A-CNC maintained relatively high transparency even at concentrations exceeding 0.1 wt%, confirming excellent dispersibility resulting from surface acrylation.

[0107] The transmittance spectra of the S-CNC / CTFA and A-CNC / CTFA composite resins further confirm that the transparency of S-CNC / CTFA has decreased significantly (Figs. 2f and 2g). However, the decrease in transparency of A-CNC was significantly smaller, which confirms the improved compatibility and dispersion of A-CNC within the resin matrix even at higher concentrations (Fig. 2h).

[0108] The dispersion of A-CNC within the CTFA resin can be improved through ultrasonic treatment. The transparency of the composite resin ink varies depending on the ultrasonic treatment time (Fig. 3). It can be confirmed that the transparency of the composite resin ink increases with the ultrasonic treatment time, thereby improving the dispersion of A-CNC within the resin matrix (Figs. 3a and 3b).

[0109] The improved transparency suggests that the A-CNC is more evenly distributed, reducing light scattering and enhancing optical clarity. As the ultrasonic treatment time increases, the hydrodynamic diameter of the dispersed A-CNC decreases, implying that the agglomerated A-CNC is separated by the ultrasonic treatment and re-agglomeration is prevented (Fig. 3c).

[0110] Maintaining colloidal stability in composite inks is critical for 3D printing processes, which typically take a long time to complete. The colloidal stability of dispersed A-CNC / CTFA composite resins was investigated under static conditions for more than 30 minutes. Figure 3d shows the non-ultrasonicated composite resin ink in the initial stage. An adjacent image of the laser beam passing through the resin shows the Tyndall effect, confirming that a colloid has formed in the initial state. The Tyndall effect, which is the scattering of light by colloidal particles, can be observed through a beam of light passing through a mixture and serves as an indicator of colloidal stability.

[0111] However, in the A-CNC / CTFA composite resin that was not sonicated, the A-CNC settled after 30 minutes of storage, and the Tyndall effect disappeared (Fig. 3e). The increase in transmittance during the 60-minute storage period was due to the detection beam path being located in the center of the cuvette and the particles settling (Fig. 3f).

[0112] On the other hand, Fig. 3g relates to a composite resin ink treated with ultrasound for 120 seconds. The sustained Tyndall effect suggests that A-CNC was well dispersed in the CTFA resin. Colloidal stability was maintained during a storage period of 30 minutes, the Tyndall effect remained constant (Fig. 3h), and the transmittance at 405 nm remained high (Fig. 3i). The transparency of the ultrasound-treated composite resin ink was preserved over time, and it was stably dispersed without significant sedimentation. These observations confirm that ultrasound effectively improves the dispersion of A-CNC in CTFA resin, thereby maintaining colloidal stability and preventing sedimentation.

[0113] In addition, the elastic modulus of the composite resin ink was monitored in-situ during the photocuring process at various concentrations of A-CNC (Fig. 4a). At all concentrations, the elastic modulus changed significantly within 30 seconds after light exposure, exhibiting rapid photopolymerization characteristics. This rapid increase in the elastic modulus implies that efficient crosslinking properties can be achieved in the presence of A-CNC without hindering the photopolymerization process. The storage modulus (G′), which represents the elastic behavior of the material, increased significantly upon the addition of A-CNC. The greatest improvement was observed at 0.1 wt% A-CNC in the composite resin (Fig. 4b). The increase in G′ indicates improved stiffness and mechanical stability of the composite material, making it suitable for applications requiring robust mechanical properties. The loss modulus (tan δ) is defined as the ratio of the loss modulus (G′′) to G′ and is an important parameter for understanding the viscoelastic behavior of the material. A lower tan δ indicates stronger solid-like behavior and reduced energy loss as heat. The loss factor was lowest at 0.1 wt% A-CNC, which means that the material at this concentration achieved the highest level of solidification and structural integrity (Fig. 4c). This optimal concentration strikes a balance between sufficient crosslinking and mechanical reinforcement, which can contribute to the overall improvement of the composite material.

[0114] The stress-strain curve (Fig. 4d) relates to the tensile properties of composite resins containing 0.1 wt% A-CNC and S-CNC. It can be confirmed that the reinforcing effect was induced by CNC, as both composites showed improved tensile strength compared to the sample prepared solely from CTFA. However, the A-CNC composite exhibited a stronger reinforcing effect on tensile strength due to its higher miscibility with the resin.

[0115] The A-CNC composite exhibited higher tensile strength than the S-CNC composite (Fig. 4e), which is attributed to more effective stress transfer within the matrix and a stronger load-bearing capacity. Both the A-CNC and S-CNC composites had lower fracture strains than the sample containing only CTFA (Fig. 4f), which confirms that brittleness increases as a result of reinforcement. This is a typical trade-off for improved tensile strength.

[0116] Young's modulus, which reflects the stiffness of the composite material, increased significantly in CTFA using A-CNC composite material. Young's modulus was greatly improved due to the combination of increased tensile strength and reduced strain, resulting in higher stiffness (Fig. 4g). This confirms that A-CNC is more effective in reinforcing composite materials, making them stiffer under load and more resistant to deformation.

[0117] Tensile strength and elastic modulus increased with increasing A-CNC content, reaching a maximum value at 0.1 wt% (Fig. 4h). Adding A-CNC exceeding 0.1 wt% resulted in a decrease in tensile strength, which may imply that the optimal dispersion of A-CNC within the CTFA matrix occurs at 0.1 wt% (Fig. 4i). As the A-CNC concentration increased, the composite became more brittle, leading to a decrease in fracture strain (Fig. 4j). The elastic modulus increased with increasing A-CNC content due to the effective load-bearing capacity imparted by well-dispersed A-CNC particles within the polymer matrix. However, the elastic modulus decreased slightly at >0.1 wt% A-CNC, which may be due to particle aggregation disrupting the uniform stress distribution and reducing the stiffness of the composite (Fig. 4k).

[0118] Tensile strength and elastic modulus were observed in 0.1 wt% A-CNC, which is attributed to optimal nanoparticle dispersion, which can improve mechanical properties. Additionally, at concentrations >0.1 wt%, the transmittance of the composite resin ink decreased, and the photocuring process was hindered due to A-CNC aggregation, resulting in reduced reinforcement efficiency.

[0119] A-CNC and S-CNC CTFA composites were analyzed by calculating the Weibull coefficient (reflecting material reliability) and characteristic strength (providing estimates for material life) using Weibull statistics. The reliability (or survival probability) of the materials at various thicknesses according to the type and concentration of S-CNC and A-CNC is shown in Figures 4(l) and 4(m), exhibiting specific survival probability values ​​at 3 MPa. At 2 MPa, both materials showed similar reliability across all thicknesses. However, a significant difference was observed between 0.1 wt% A-CNC and S-CNC at 3 MPa, with A-CNC demonstrating significantly higher reliability than S-CNC.

[0120] Under conditions where 0.1 wt% A-CNC and S-CNC were added, the survival probability fitting curve shifted to the right compared to the control CTFA, confirming that the survival probability was improved. The median survival stress of the control CTFA was recorded as 1.849 MPa, while for 0.1 wt% A-CNC it was significantly higher at approximately 4.38 MPa. On the other hand, the median survival stress of 0.1 wt% S-CNC was ~2.26 MPa, confirming the difference in durability between the two composites.

[0121] As the concentration of A-CNC increased from 0 to 0.05 and 0.1 wt%, the survival probability in terms of tensile strength improved, but at 0.2 wt%, the probability tended to decrease. Overall, the durability performance comparison showed that the survival probability was highest at 0.1 wt% A-CNC, demonstrating excellent mechanical reliability at this concentration.

[0122] The cytotoxicity analysis of CTFA sheets containing various concentrations of A-CNC was performed using the MTT assay. The relative metabolic activity % of NIH3T3 cells was found to have decreased slightly to 85.6% for samples containing only CTFA sheets. In contrast, CTFA sheets containing 0.05 wt%, 0.1 wt%, or 0.2 wt% of A-CNC showed no significant change in relative metabolic activity %, exhibiting values ​​of 84.6%, 87.6%, and 84.6%, respectively (Fig. 5a). These results indicate that the incorporation of A-CNC fillers into CTFA does not have a negative effect on cell viability.

[0123] Furthermore, microscopic images revealed that the CTFA sheet did not adhere to the cells. The number of cells on the CTFA surface decreased after one day of inoculation, and round cell morphology was observed on the surface. In contrast, the cells on the control surface were well spread and flat, exhibiting the typical morphology of adherent cells (Fig. 5b-e). Moreover, after washing the surface with fresh medium, only a few cells remained on the CTFA surface, indicating the anti-contamination properties of the material.

[0124] The resolution of the printed structure was affected by the ultrasonic treatment process used during the preparation of the composite resin ink. Figures 6(a) and 6(b) show the effect of ultrasonic treatment on the resolution of the xy plane. The intended design consisted of concentric circles and parallel linear shapes with widths of 0.1, 0.25, 0.5, and 1.0 mm. Without ultrasonic treatment, the A-CNC of the resin exhibited significant aggregation, resulting in low resolution and uneven printing. On the other hand, ultrasonic treatment for 2 minutes resulted in high-resolution printing with sharp and distinct features, demonstrating that uniform dispersion of the A-CNC in the resin is essential for maintaining the high fidelity of the photocurable resin.

[0125] Figures 6(c) and 6(d) show fine images of the lateral profiles of the printed structures. The printed structures obtained using a low-dispersion composite resin without ultrasonic treatment showed irregular layers and uneven edges. In contrast, the printed structures obtained using a resin ultrasonically treated for 2 minutes were smooth, even, and had clean edges, demonstrating that ultrasonic treatment is effective in improving layer uniformity and overall print quality.

[0126] The printability and clarity of the composite resin ink were further confirmed by printing various biomedical structural features (Figs. 6e-f). Printed structures obtained using appropriately ultrasonically treated resin exhibited high structural stability and were defect-free. It was confirmed that they can be applied to cylindrical stent, trachea, and semilunar models with uniform mesh lines.

[0127] Figure 7(a) compares the shape recovery process of rectangular 3D printed samples prepared using CTFA and A-CNC / CTFA. The samples were initially deformed into a U-shape at 85°C and then fixed in a 4°C ice bath to maintain the deformed shape. Then, the samples were immersed in a 40°C water bath to induce shape recovery. Figure 7(b) shows the shape recovery rate (Rr) as a function of time for both CTFA and A-CNC / CTFA samples. The sequential images and shape recovery rate show that the A-CNC / CTFA sample recovers its original shape at a faster rate compared to the control CTFA sample, which highlights its superior shape memory performance.

[0128] This improved recovery speed is due to the increase in the elastic modulus of the printed material by adding A-CNC, as shown in the previous mechanical property analysis. A higher elastic modulus allows the polymer to maintain its original state more strongly, which can lead to a faster recovery process.

[0129] Figure 7(c) shows the shape memory performance of the stent model, displaying the original shape, the deformed shape, and the recovered shape. The stent returns to nearly its original shape when exposed to recovery conditions, demonstrating the potential of this material in biomedical applications where precise shape restoration is important. Figure 7(d) visually shows the application of the stent within a model blood vessel. As the stent recovers its original shape, it effectively expands the constricted portion of the blood vessel, demonstrating the potential for using this material in minimally invasive medical procedures such as angioplasty.

[0130] In addition, for the above shape restoration, the recovery condition is applied at a temperature range similar to body temperature, such as 35°C to 40°C, and it can be confirmed that it returns to almost its original shape.

[0131] Although preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements by those skilled in the art using the basic concept of the present invention as defined in the following claims also fall within the scope of the present invention.

[0132]

[0133] This application was filed with the support of the following tasks:

[0134] 1. Project ID: 2410012515

[0135] 2. Project No.: 20023781

[0136] 3. Ministry Name: Ministry of Trade, Industry and Energy

[0137] 4. Project Management Agency: Korea Institute of Industrial Technology Planning and Evaluation

[0138] 5. Research Project Name: Bioindustry Technology Development

[0139] 6. Research Project Title: Development of Symbiotic Biocompatible Medical Device Materials and Commercialization Technology for Patient-Specific Direct-Printed Biliary Stents and Orthodontic Appliances

[0140] 7. Organizing Institution: Yonsei University Industry-Academic Cooperation Foundation

[0141] 8. Research Period: April 1, 2023 – December 31, 2027

[0142] The present invention relates to a photocurable composition for manufacturing a bile duct stent having shape memory properties using a 3D printer, and a bile duct stent having shape memory properties using the same.

Claims

1. Photocurable resin; and It includes cellulose nanocrystals (CNC), The above cellulose nanocrystals have a surface modified with an acrylic monomer. Photocurable composition for manufacturing a biliary stent having shape memory properties using a 3D printer.

2. In Paragraph 1, The above cellulose nanocrystals are sulfuric-acid-hydrolyzed CNCs (S-CNCs). Photocurable composition for manufacturing a biliary stent having shape memory properties using a 3D printer.

3. In Paragraph 1, The above acrylic monomer is selected from the group consisting of MMA (Methyl Methacrylate), BMA (n-Butyl Methacrylate), IBMA (Iso-Butyl Methacrylate), EDMA (Ethyleneglycol Dimethacrylate), MAA (Mathacrylic Acid), IA (Itaconic Acid), AA (Acrylic Acid), LMA (Lauryl Methacrylate), EMA (Ethyl Methacrylate), EA (Ethyl Acrylate), MA (Methyl Acrylate), and mixtures thereof. Photocurable composition for manufacturing a biliary stent having shape memory properties using a 3D printer.

4. In Paragraph 1, The above photocurable composition improves dispersion stability by mixing a photocurable resin and cellulose nanocrystals (CNC) and mixing them by ultrasonic treatment for 60 seconds or more. Photocurable composition for manufacturing a biliary stent having shape memory properties using a 3D printer.

5. In Paragraph 4, The above cellulose nanocrystals (CNC) are surface-modified with acrylic monomers to improve compatibility with photocurable resins, so that they are uniformly dispersed when mixed. Photocurable composition for manufacturing a biliary stent having shape memory properties using a 3D printer.

6. In Paragraph 1, The above photocurable composition comprises 0.01% to 0.2% by weight of cellulose nanocrystals (CNC) whose surfaces are modified with acrylic monomers, relative to the total weight. Photocurable composition for manufacturing a biliary stent having shape memory properties using a 3D printer.

7. A photocurable composition according to any one of claims 1 to 6 Biliary duct stent having shape memory properties.

8. In Paragraph 7, The above-mentioned biliary stent restores its shape under body temperature conditions. Biliary duct stent having shape memory properties.

9. In Paragraph 7, The above-mentioned biliary stent is manufactured as a patient-specific product by printing with a 3D printer using a photocurable composition. Biliary duct stent having shape memory properties.

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