COCE-nozzle head for forming a hollow tubular structure and a forming method

Abstract

The application discloses a COCE- Nozzle nozzle for forming a hollow tubular structure and a forming method, and comprises an outer shell body, a center occupying column is arranged in the outer shell body, the center occupying column is coaxially arranged with the outer shell body, the center occupying column is fixedly connected with the outer shell body through a supporting rib, and a uniform annular extrusion flow channel is formed between the center occupying column and the outer shell body. The application effectively breaks through the core bottleneck of traditional technology in material adaptability, process complexity, equipment threshold and forming stability, provides an advanced and reliable technical platform for organ chips, organoid engineering and regenerative medicine fields, and has remarkable scientific research application value and industrialization prospect.

Description

Technical Field

[0001] This invention relates to the field of hollow tubular structure production technology, and more specifically to a COCE-Nozzle nozzle and molding method for hollow tubular structures. Background Technology

[0002] In the fields of biomanufacturing, organ-on-a-chip, tissue engineering, and regenerative medicine, constructing structurally controllable and functionally adaptable biomimetic hollow tubular structures is a crucial structural foundation for achieving three-dimensional tissue function maintenance, tissue defect repair, and the fabrication of highly realistic organ-on-a-chip structures. These structures can be widely adapted to various fabrication needs, including biomimetic vascular networks, nerve regeneration conduits, and fluid delivery or drainage conduits. Currently, coaxial 3D printing-based extrusion molding technology is one of the key technological pathways for constructing biomimetic tubular structures within the industry.

[0003] However, coaxial 3D printing technology has the following drawbacks: First, the hollow structure forming of existing coaxial 3D printing technology relies on a high degree of matching between the physicochemical properties of the shell forming material and the core sacrificial material. The solvent system, curing conditions, and rheological properties of the two must be strictly matched, which not only limits the range of material selection, but also easily leads to technical defects such as shell swelling and incomplete removal of sacrificial material residues. It cannot flexibly adapt to functional materials of different systems such as hydrogels, biodegradable polymers, and PDMS. On the other hand, DLP photopolymerization technology is limited by the forming principle and can only adapt to photosensitive materials that can be photocrosslinked. It is completely incompatible with non-photosensitive flexible materials and cannot meet the diversified functional requirements of tubular structure body materials in different scenarios such as biomimetic blood vessels, nerve regeneration catheters, body fluid drainage / repair catheters, and cavity tissue scaffolds. Secondly, existing coaxial 3D printing technology requires two independent pneumatic extrusion systems, which demands extremely high precision in the coordinated control of pressure and flow rate of the dual fluid streams. The process parameter matching window is extremely narrow, making operation difficult and equipment investment costs high. At the same time, it must undergo multiple post-processing steps to dissolve and remove sacrificial materials. For soft materials such as hydrogels and low-modulus biodegradable polymers, this can easily cause lumen collapse, structural damage, and internal blockage, resulting in low molding yield and long preparation cycle for single functional tubular structures. It is impossible to achieve stable one-step molding, making it difficult to meet the low-cost, high-yield, large-scale, and customized preparation needs of regenerative medicine, minimally invasive medical devices, and organ-on-a-chip fields. Summary of the Invention

[0004] In view of this, this invention proposes a "Column-Occupied Coaxial Extrusion (COCE)-Nozzle" extrusion printing nozzle, which overcomes the core bottlenecks in the industry: on the one hand, it completely breaks through the material limitations of existing technologies, realizing one-step direct molding of hollow tubular structures without coaxiality, sacrificial materials, or multiple air pressure systems. It is compatible with three major categories of mainstream functional materials, breaks through the material compatibility barrier of photopolymerization technology, and has a molding speed much faster than DLP technology. On the other hand, it completely eliminates the dependence on dual independent extrusion systems. Only a single extrusion system is needed to complete the efficient and stable preparation of hollow structures. It can even be separated from 3D printing equipment and directly realize handheld extrusion molding. It provides an efficient, universal, and flexible manufacturing path for the preparation of hollow tubular structures in multiple fields such as blood vessel construction, nerve regeneration, cavity repair, and organ-on-a-chip, solving the pain points of traditional nozzles such as "strong equipment binding and difficulty in adaptation".

[0005] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: A COCE-Nozzle nozzle for forming hollow tubular structures includes: an outer shell; a central occupant post inside the outer shell; the central occupant post being coaxially arranged with the outer shell; the central occupant post being fixedly connected to the outer shell via supporting ribs; and a uniform annular extrusion channel being formed between the central occupant post and the outer shell.

[0006] Preferably, the nozzle is integrally molded using high-precision DLP photopolymerization technology to achieve customized manufacturing of multiple specifications.

[0007] Preferably, there are four sets of supporting ribs; the four sets of supporting ribs are evenly distributed circumferentially on the outer wall of the central occupant column.

[0008] A method for forming a hollow tubular structure involves using the aforementioned COCE-Nozzle nozzle to extrude a functional printing material with shear-thinning properties through a single-path pneumatic extrusion 3D printer or a standard Luer connector syringe. The material is then cross-linked and cured through physical or chemical means to form a continuous, through-hole hollow tubular structure in one step.

[0009] Preferably, the functional printing material with shear-thinning properties is a hydrogel-based bio-ink, a biodegradable polymer printing ink, or a non-biodegradable flexible polymer printing ink.

[0010] Preferably, the hydrogel-based bio-ink is a composite hydrogel bio-ink containing sodium alginate (SA).

[0011] Preferably, the hydrogel-based bio-ink is an SA / polyether F127 diacrylate (F127DA) composite hydrogel or an SA / methacrylamide gelatin (GelMA) composite hydrogel; wherein the SA / F127DA composite hydrogel contains SA, F127DA and a photoinitiator, and is cured by photocrosslinking, ionic crosslinking or a combination of photocrosslinking and ionic crosslinking.

[0012] Preferably, the biodegradable polymer printing ink includes one or more of polylactic acid (PLA), polycaprolactone (PCL), and polyhydroxyalkanoate (PHA).

[0013] Preferably, the biodegradable polymer printing ink is a PHA solution-type printing ink, in which the polyhydroxy fatty acid ester is dissolved in an organic solvent to form the printing ink, and then cured by a non-solvent phase separation method using an aqueous coagulation bath.

[0014] Preferably, the non-degradable flexible polymer ink is a silicone rubber-based flexible polymer ink.

[0015] Preferably, the non-degradable flexible polymer ink is polydimethylsiloxane (PDMS); the polydimethylsiloxane is formed by mixing a prepolymer and a curing agent, and is cured by room temperature curing or heating curing.

[0016] The present invention achieves the following technical effects compared to the prior art: 1) This invention achieves multi-material coaxial co-extrusion and sacrificial material molding without the original COCE-Nozzle nozzle structure, significantly improving manufacturing efficiency. At the same time, it avoids the problems of lumen collapse, blockage and structural damage in the post-processing process from the root, significantly enhancing process stability and providing a stable and reliable technical guarantee for the high-throughput and large-scale preparation of products such as vascularized tissue models, nerve regeneration conduits and microfluidic chips.

[0017] 2) The COCE-Nozzle nozzle of this invention can be manufactured with high precision and personalized customization through DLP technology. Compared with traditional methods, it can achieve precise and flexible control of the inner diameter and wall thickness of the tube by adjusting the size parameters of the nozzle center occupier and the outer shell, and can stably adapt to the physiological scale of human microvessels. At the same time, with the synergistic optimization of extrusion process parameters and cross-linking curing conditions, it can accurately construct a three-dimensional tubular network with complex topology, ensuring the integrity of the channel structure and the unobstructedness of the inner cavity throughout the process. The molded structure has excellent flexibility and mechanical stability, which can meet the requirements of long-term dynamic perfusion culture and in vivo implantation. It provides precise and controllable technical support for the preparation of various biomimetic tubular structures with specific sizes and configurations.

[0018] 3) The COCE-Nozzle technology platform established in this invention possesses excellent material adaptability and equipment compatibility. It is not only applicable to bioactive hydrogel systems such as SA / F127DA, but can also be stably extended to biodegradable polymers such as PHA and non-degradable flexible polymers such as PDMS. A single technology system can cover the molding needs of three major categories of core functional materials. This technology can be widely applied in multiple core fields such as vascularized organoid construction, organ-on-a-chip drug screening model preparation, neural regeneration catheter development, scaffold processing for urinary / biliary tract tissue repair, preparation of minimally invasive diagnostic and therapeutic fluid drainage devices, oral tissue engineering, and aerospace on-orbit tissue construction. Simultaneously, it is compatible with conventional single-channel extrusion 3D printers and ordinary handheld syringes, eliminating the need for expensive professional industrial-grade equipment, significantly lowering the technical entry barrier. It provides a new technical path for regenerative medicine product development, biomedical research and innovation, and the upgrading of minimally invasive medical devices, possessing significant scientific research value and broad industrialization potential. Attached Figure Description

[0019] Figure 1 This is a schematic diagram of a COCE-Nozzle nozzle for forming a hollow tubular structure according to the present invention; Figure 2 A schematic diagram illustrating the design process of the three-dimensional parametric model of the COCE-Nozzle nozzle; Figure 3 This is a schematic diagram of the COCE-Nozzle nozzle extrusion molding process. The enlarged view shows the cross-sectional structure of the hollow tubular structure extruded from the nozzle. Figure 4a Microscopic morphology characterization of four specifications of COCE-Nozzle nozzles: 20G, 18G, 16G, and 14G. Figure 4b The molding performance and process parameters of COCE-Nozzle nozzles of different specifications are tested. Figure 5a This is a cloud map showing the shear pressure distribution of the fluid inside the nozzle's sidewalls. Figure 5b This is a cloud map showing the fluid velocity distribution inside the nozzle. Figure 6a The images show actual extruded hollow tubular structures for each group, as well as a comparison diagram of the designed inner and outer diameters of the channels for each group with the actual molding dimensions. Figure 6b The statistical analysis results show the actual inner and outer diameters of the hollow vascular channels in the hydrogels of each group. Figure 7 Mechanical properties and flexibility characterization of SFD40 composite hydrogel hollow vascular channels; Figure 8a Steady-state rheological curves of pure SA ink and SFD40 composite ink; Figure 8b Transient rheological curves of pure SA ink and SFD40 composite ink; Figure 8c The dynamic rheological curves of pure SA ink and SFD40 composite ink are shown. Figure 8d The FTIR characterization results are for SA, F127, F127DA, and SFD40. Figure 9 A schematic diagram of the SGA flexible hollow tubular structure fabricated based on the COCE-Nozzle nozzle; Figure 10 A schematic diagram of a 3D-printed multilayer biomimetic vascular network and its interconnection experiment; Figure 11a A photograph of the printed snake-shaped hollow tubular structure P34HB; Figure 11b Schematic diagram of the Rhodamine B dye perfusion experiment; Figure 12 A schematic diagram of a flexible hollow tubular structure of PDMS fabricated based on a COCE-Nozzle nozzle; Figure 13a A diagram illustrating the hand-held extrusion process for the hollow tubular structure of the COCE-Nozzle nozzle; Figure 13b A photograph of the finished product of a hollow tubular hydrogel structure prepared by hand-operated extrusion.

[0020] In the diagram: 1. Outer shell; 2. Central occupant column; 3. Supporting ribs. Detailed Implementation

[0021] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0022] This invention discloses a COCE-Nozzle nozzle for forming hollow tubular structures, comprising: an outer shell 1; a central occupant post 2 disposed inside the outer shell 1; the central occupant post 2 being coaxially arranged with the outer shell 1; the central occupant post 2 being fixedly connected to the outer shell 1 by a support rib 3; and a uniform annular extrusion channel being formed between the central occupant post 2 and the outer shell 1.

[0023] The printhead is integrally molded using high-precision DLP photopolymerization technology to achieve customized manufacturing of multiple specifications.

[0024] There are four sets of support bars 3; the four sets of support bars 3 are evenly distributed around the outer wall of the central occupier column 2.

[0025] The outer casing 1 has a conical structure, and the nozzle is fully compatible with a universal Luer connector.

[0026] The nozzle can be manufactured in 14G, 16G, 18G or 20G specifications to fit hollow tubular structures with different inner diameters.

[0027] This invention also discloses a method for forming a hollow tubular structure. Using the aforementioned COCE-Nozzle nozzle, a functional printing material with shear-thinning properties is extruded through a single-path pneumatic extrusion 3D printer or a standard Luer connector syringe. The material is then cross-linked and cured through physical or chemical means to form a continuous hollow tubular structure in one step, without the need for post-processing steps that require material removal.

[0028] The functional printing material with shear-thinning properties is a hydrogel-based bio-ink, a biodegradable polymer printing ink, or a non-biodegradable flexible polymer printing ink.

[0029] Hydrogel bio-inks are composite hydrogel bio-inks containing sodium alginate (SA).

[0030] The hydrogel-based bio-ink is a composite hydrogel of SA / polyether F127 diacrylate (F127DA) or SA / methacrylamide gelatin (GelMA); wherein, the SA / F127DA composite hydrogel contains SA, F127DA and a photoinitiator, and is cured by photocrosslinking, ionic crosslinking or a combination of photocrosslinking and ionic crosslinking.

[0031] The hydrogel-based bio-ink is an SA / F127DA composite hydrogel (i.e., SFD), which contains 6% SA, 40% F127DA and 0.5% photoinitiator by weight and volume percentage. It is cured by a dual crosslinking process of in-situ crosslinking with 405nm ultraviolet light and ionic crosslinking with 2% (w / v) calcium chloride solution. The photoinitiator is LAP.

[0032] Biodegradable polymer printing inks include one or more of polylactic acid (PLA), polycaprolactone (PCL), and polyhydroxyalkanoates (PHA).

[0033] The biodegradable polymer printing ink is a PHA solution-type printing ink. It uses an organic solvent to dissolve polyhydroxy fatty acid esters into printing ink, and then completes the curing through a non-solvent phase separation method with an aqueous coagulation bath.

[0034] The PHA solution is a poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (P34HB) solution; wherein, by mass-volume ratio, the amount of P34HB added is 4-8 g / 100 mL, the solvent is N-methyl-2-pyrrolidone (NMP), and the curing is completed by a non-solvent phase separation method using deionized water as the coagulation bath.

[0035] Non-degradable flexible polymer inks are silicone rubber-based flexible polymer inks.

[0036] The non-degradable flexible polymer ink is PDMS; PDMS is made by mixing prepolymer and curing agent at a mass ratio of 10:1 and curing by thermosetting at a constant temperature of 80℃.

[0037] The COCE-Nozzle nozzle and molding method for hollow tubular structures disclosed in this invention can be applied to the preparation of hollow tubular structures for biomimetic vascular networks, nerve regeneration conduits, body fluid drainage conduits, biodegradable tissue engineering scaffolds, microfluidic chip channels, organoid chips, oral tissue engineering scaffolds, and aerospace on-orbit tissues.

[0038] The present invention also developed a handheld portable printing system adapted to the COCE-Nozzle printhead. The system includes the aforementioned COCE-Nozzle printhead, a 10mL standard Luer syringe, a 405nm handheld UV curing lamp, and a portable power supply (5V / 1A), which can completely eliminate the need for professional 3D printing equipment to form hollow tubular structures.

[0039] The manual pushing rate of the Luer syringe is 0.1-0.5 mL / s; the distance between the handheld UV curing unit and the printing area is 5-10 cm; the single extrusion length is ≤50 cm.

[0040] Through the above-mentioned technological innovations, this invention has successfully constructed a universal manufacturing system for the entire chain of biomimetic hollow tubular structures, effectively breaking through the core bottlenecks of traditional technologies in terms of material compatibility, process complexity, equipment threshold and molding stability. It provides an advanced and reliable technology platform for the fields of organ-on-a-chip, organoid engineering and regenerative medicine, and has significant scientific research application value and industrialization prospects.

[0041] Example 1

[0042] Parametric Design and High-Precision Fabrication Experiment of COCE-Nozzle

[0043] Purpose of this embodiment: This embodiment aims to prepare the COCE-Nozzle nozzle, the core innovation of this invention, to verify the parametric design and high-precision customized manufacturing capability of the nozzle's central occupant column structure, and at the same time, to verify the hydrodynamic rationality of the nozzle's flow channel through finite element simulation, providing core hardware and theoretical support for the stable extrusion molding of various hollow tubular structures in the future.

[0044] Experimental equipment and materials: 3ds MAX 2024 3D modeling software, high-precision digital light processing (DLP) printing system, COMSOL Multiphysics finite element analysis software, 405nm UV curing chamber, CNC ultrasonic cleaning machine; high-precision photosensitive resin, analytical grade isopropanol.

[0045] Specific implementation steps: 1. The COCE-Nozzle nozzle was fully parametrically modeled using 3ds Max 2024 software. The nozzle is designed as a conical structure adapted to a universal Luer connector. The main body includes an outer shell 1, a central occupier 2 coaxially integrated with the outer shell 1, and four sets of circumferentially distributed support ribs 3 on the outer side wall of the central occupier 2. The central occupier 2 is fixedly connected to the inner side wall of the outer shell 1 through the support ribs 3. A uniform annular extrusion channel is formed between the outer shell 1 and the central occupier 2. Four nozzle models of different specifications (20G, 18G, 16G, and 14G) were designed simultaneously. By adjusting the inner diameter parameters of the central occupier 2 and the outer shell 1, the nozzle was adapted to meet the fabrication requirements of hollow tubular structures with different inner diameters.

[0046] 2. Export the completed 3D model as a standard STL format, import it into a high-precision DLP printing system, set the printing layer thickness to 20μm, and use high-precision photosensitive resin to complete the integrated printing of the nozzle, ensuring the coaxial accuracy of the central occupant post 2 and the outer shell 1.

[0047] 3. Place the printed printhead sample in analytical grade isopropanol and ultrasonically clean for 5 minutes to thoroughly remove any uncured resin residue on the surface and in the flow channels. After cleaning, place the printhead in a 405nm UV curing chamber to complete UV post-curing, and finally obtain the COCE-Nozzle printhead product.

[0048] 4. Using COMSOL Multiphysics finite element analysis software, numerical simulations were performed on the fluid pressure and velocity fields inside the nozzle to verify the rationality of the annular extrusion channel design and provide a theoretical basis for the subsequent optimization of extrusion process parameters.

[0049] Implementation Results: This embodiment successfully produced four sets of COCE-Nozzle nozzles of different specifications: 20G, 18G, 16G, and 14G. Microscopic characterization results showed that the nozzle's overall structure was intact and defect-free, the coaxiality deviation between the central occupier and the outer shell was less than 2%, and the annular extrusion channel was uniform and regular, without deformation or clogging issues (see [link to documentation]). Figure 4a The finished product is stably compatible with general-purpose Luer connector injectors and conventional single-channel extrusion 3D printing equipment. Its stable extrusion working pressure is negatively correlated with the nozzle specification, and smooth and controllable extrusion can be achieved within the range of 0.5 to 5 bar (see [link]). Figure 4b Finite element simulation results show that the fluid pressure inside the nozzle exhibits a stable gradient distribution along the axial direction of the flow channel. The pressure distribution within the annular extrusion channel is uniform, with no localized high-pressure concentrations, turbulence, or sudden pressure changes. The maximum pressure is controlled within 103 Pa, fully adapting to the working range of conventional single-path pneumatic extrusion systems. Simultaneously, the fluid velocity distribution within the annular extrusion channel is symmetrical and uniform, with no backflow or eddy currents along the central locating column. The velocity at the nozzle outlet is stable and consistent, ensuring uniform and controllable wall thickness of the extruded material (see [reference]). Figure 5a , Figure 5b This design avoids problems such as cavity collapse, uneven wall thickness, and molding interruption during the extrusion process from the source of the flow channel design, and provides a core structural foundation for the stable extrusion molding of hollow tubular structures with different material systems and different application scenarios.

[0050] Figure 4 shows the structural characterization and performance verification of COCE-Nozzle nozzles of different specifications: Figure 4a The microscopic morphology of four specifications of COCE-Nozzle nozzles (20G, 18G, 16G, and 14G) is characterized. The microscopic observation results are shown from top to bottom: nozzle outlet end (bottom), side, and inlet end (top). The scale bar is 1 mm. Figure 4b The left figure shows the statistical results of the inner and outer diameters of the hollow tubular channels prepared by different specifications of COCE-Nozzle nozzles, while the right figure shows the test results of the stable extrusion working pressure corresponding to different specifications of nozzles.

[0051] Figure 5 shows the finite element simulation results of the internal flow field of the COCE-Nozzle nozzle: Figure 5a This is a cloud map showing the shear pressure distribution of the fluid inside the nozzle's sidewalls. Figure 5b Cloud map of fluid velocity distribution inside the nozzle

[0052] Example 2

[0053] Experimental fabrication of biomimetic vascular channels based on COCE-Nozzle SA / F127DA composite hydrogel

[0054] Objective: To verify the adaptability of this invention to hydrogel-based biomaterials, to prepare biomimetic vascular channels that conform to physiological dimensions, and to verify the molding accuracy, structural stability, and mechanical properties.

[0055] Equipment and materials: The 14G COCE-Nozzle nozzle, single-path air pressure extrusion 3D printing platform, 405nm ultraviolet light source, sodium alginate (SA), polyether F127 diacrylate (F127DA), photoinitiator LAP, and 2% (w / v) CaCl2 aqueous solution prepared in this embodiment.

[0056] Specific implementation steps: 1. Preparation of composite hydrogel bio-ink: 10%–40% (w / v) F127DA and 0.5% (w / v) photoinitiator LAP were dissolved in deionized water and placed in a 4°C refrigerator overnight to ensure complete dissolution. Then, 6% (w / v) SA was added and stirred thoroughly. The mixture was centrifuged at 3000 rpm for 10 minutes at 4°C to remove air bubbles, resulting in four groups of SA / F127DA composite hydrogel inks with different F127DA concentrations, labeled as SFD10, SFD20, SFD30, and SFD40, respectively.

[0057] 2. Load the composite hydrogel ink into the printing barrel, install the COCE-Nozzle printhead, connect it to the single-path air pressure extrusion system, and complete the extrusion molding of linear, serpentine, and branched hollow tubular structures on the printing platform.

[0058] 3. After extrusion printing, a 405nm ultraviolet light source is turned on for in-situ photocrosslinking to achieve preliminary channel shaping; then the molded structure is immersed in a 2% (w / v) CaCl2 aqueous solution for 10 minutes to complete secondary ionic crosslinking and obtain a hydrogel biomimetic blood vessel channel.

[0059] Implementation Results: A continuously permeable hydrogel hollow vascular channel with controllable inner diameter was successfully fabricated. The SFD40 constituent dimensions deviated very little from the design values. (See [link to documentation]) Figure 6a , Figure 6b The formed channel possesses excellent flexibility and mechanical stability, allowing for knotting, stretching, compression, and rebound without damage. It exhibits mechanical properties matching those of human physiological tubular tissues, making it suitable for various applications such as blood vessels, nerve conduits, and cavity repair scaffolds, meeting the requirements for long-term perfusion culture of organ-on-a-chip (see [link]). Figure 7 ).

[0060] Figure 6 shows the molding accuracy of hollow vascular channels in SA / F127DA composite hydrogels with different ratios: Figure 6a The images show actual extruded hollow tubular structures for each group, as well as a comparison diagram of the designed inner and outer diameters of the channels and the actual molding dimensions for each group. Figure 6b The statistical analysis results show the actual inner and outer diameters of the hollow vascular channels in each group of hydrogels.

[0061] Figure 7 The mechanical properties and flexibility of the SFD40 composite hydrogel hollow vascular channel are characterized. From left to right, the results of tensile knotting, compression, and rebound performance tests of the molded channel are shown, verifying that the hollow vascular channel has excellent flexibility and mechanical stability.

[0062] Example 3

[0063] Rheological properties and composition characterization of SA / F127DA composite hydrogel bio-ink

[0064] Purpose of this implementation: This embodiment aims to systematically characterize the rheological properties and chemical structure of SA / F127DA composite hydrogel bio-ink, verify its shear thinning and rapid viscosity recovery characteristics suitable for COCE-Nozzle extrusion molding, and provide a materials science basis and process basis for the stable extrusion of subsequent hollow tubular structures.

[0065] Experimental equipment and materials: rotational rheometer, Fourier transform infrared spectrometer (FTIR); sodium alginate (SA), polyether F127 diacrylate (F127DA), photoinitiator LAP, deionized water.

[0066] Specific implementation steps: 1. Bio-ink formulation: SA and SFD40 bio-inks were formulated according to the method in Example 2.

[0067] 2. Steady-state rheological performance testing: A rotational rheometer was used, with the shear rate set within the range of 0.01–100 s⁻¹. -1 The viscosity of the two inks was tested as a function of shear rate to verify the shear-thinning property.

[0068] 3. Transient rheological performance testing: Alternating step shear mode was used, first applying low shear (1s) -1 60s), then apply high shear (100s) -1 (10s), then resumed low shear (1s) -1 (60s) to test the viscosity recovery ability of the ink, simulating the extrusion-static setting process.

[0069] 4. Dynamic rheological properties test: Set the frequency to 1Hz and perform stress scan (0.1~1000Pa) to test the changes in storage modulus (G') and loss modulus (G'') of the two inks with shear stress, and determine the linear viscoelastic region and yield stress.

[0070] 5. FTIR structural characterization: Fourier transform infrared spectroscopy was used to characterize the four samples SA, F127, F127DA, and SFD40 across the entire wavelength range (4000–500 cm⁻¹). -1 Scanning was used to analyze the chemical structure and functional group changes of the composite hydrogel.

[0071] Implementation results: Both SFD40 composite ink and pure SA ink exhibit typical shear-thinning characteristics, with viscosity decreasing as the shear rate increases; the initial viscosity of SFD40 ink (10 5 Pa·s) is much higher than that of pure SA ink (10 Pa·s) 2 Pa·s), possessing superior extrusion molding fidelity and effectively preventing post-extrusion cavity collapse (see...). Figure 8aBoth inks exhibit a sharp drop in viscosity under high shear, but recover rapidly upon returning to low shear. The SFD40 ink demonstrates significantly better viscosity recovery efficiency and final viscosity than the pure SA ink, perfectly adapting to the COCE-Nozzle extrusion-setting process and ensuring immediate stability of the hollow structure (see [link]). Figure 8b The storage modulus (G') and yield stress of SFD40 composite ink are significantly higher than those of pure SA ink, with a wider linear viscoelastic region and significantly improved mechanical strength, providing sufficient structural support for the formation of vascular channels (see [link]). Figure 8c The SFD40 composite hydrogel retains the characteristic functional groups of both SA and F127DA, confirming the successful composite of the two components and providing a structural basis for the material's dual crosslinking properties (see [link]). Figure 8d ).

[0072] This embodiment demonstrates that the SFD40 composite hydrogel ink possesses excellent shear thinning, rapid viscosity recovery characteristics, and mechanical properties, making it fully compatible with the COCE-Nozzle extrusion molding process and an ideal bio-ink for constructing biomimetic vascular channels.

[0073] Figure 8 shows the rheological properties and chemical structure characterization of the SA / F127DA composite hydrogel bio-ink: Figure 8a Steady-state rheological curves (viscosity-shear rate) of pure SA ink and SFD40 composite ink were obtained to verify the shear thinning characteristics. Figure 8b The transient rheological curves (viscosity-time) of pure SA ink and SFD40 composite ink were used to verify the rapid viscosity recovery capability during the extrusion process. Figure 8c The dynamic rheological curves (storage modulus G', loss modulus G''-shear stress) of pure SA ink and SFD40 composite ink are used to characterize the mechanical properties and yield stress. Figure 8d The chemical structure of the composite hydrogel was verified by FTIR analysis of SA, F127, F127DA, and SFD40.

[0074] Example 4

[0075] Integrated Construction and Performance Verification Experiment of Bionic Tubular Networks

[0076] Objective: To verify the integrated construction capability of the COCE-Nozzle technology of this invention for tubular networks with complex topological structures, to complete the controllable preparation of single-stage continuous flow channels and multi-layer independent flow channels respectively, and to simultaneously verify the internal cavity connectivity, structural integrity and interlayer independence of the formed channels, so as to provide a feasible process solution for the practical application of multi-cavity organ-on-a-chip, branched nerve conduit and multi-pathway body fluid drainage device.

[0077] Experimental equipment and materials: 14G specification COCE-Nozzle nozzle prepared in this invention, single-channel pneumatic extrusion 3D printing platform with temperature control module, 405nm ultraviolet light source, SGA2 composite hydrogel bio-ink (6%SA+2%GelMA+0.5%LAP), 2% (w / v) CaCl2 aqueous solution, Rhodamine B dye, and sodium fluorescein dye.

[0078] Specific implementation steps: 1. Construction and Continuity Verification of a Single-Level Serpentine Vascular Network: SFD40 composite hydrogel ink was prepared, vacuum degassed, and loaded into the printing barrel. A 14G COCE-Nozzle nozzle was installed and connected to the single-path pneumatic extrusion system of the 3D printing platform. The printing environment temperature was set to 37℃, the extrusion pressure to 2.5 bar, the nozzle movement speed to 5 mm / s, and the distance between the nozzle and the printing platform to 1.5 mm. A serpentine flow path was planned to complete the extrusion molding of a single-level continuous vascular network. During the printing process, 405nm ultraviolet light was simultaneously turned on for in-situ preliminary cross-linking. After printing, the structure was placed in a 2% CaCl2 aqueous solution to complete secondary ionic cross-linking. Rhodamine B dye solution was prepared and injected from one end of the flow channel using a syringe. The continuity of the flow channel cavity was observed under a microscope.

[0079] 2. Construction and structural independence verification of multi-layer independent vascular network: Based on the optimal printing parameters of the single-level flow channel, an additional printing layer thickness of 1.55 mm was set. Through layered path planning, a three-dimensional vascular network with two independent flow channels was printed in an integrated manner. After printing, double cross-linking and curing were performed using the same process. Rhodamine B (red) and sodium fluorescein (green) dyes were injected into the two independent flow channels respectively. The dye distribution of the two flow channels was observed under a fluorescence microscope to verify the structural independence and integrity of the flow channels.

[0080] Implementation Results: This embodiment successfully achieved the integrated fabrication of biomimetic vascular networks of varying complexity. The single-level serpentine vascular network structure remained intact, without collapse or broken fibers. Rhodamine B dye perfusion experiments showed that the flow channels were continuous and unobstructed throughout, allowing the dye to flow smoothly from the inlet to the outlet, confirming that the formed vascular network possesses excellent luminal connectivity and structural integrity (see [link to documentation]). Figure 9 Based on this, a three-dimensional vascular network with two independent flow channels was successfully constructed. The two flow channels were without misalignment or leakage. After perfusion with two different fluorescent dyes, smooth dye flow was observed within each flow channel, with no cross-mixing or cross-flow, verifying the structural independence and sealing integrity of the multilayer vascular channel (see [link to documentation]). Figure 10 This embodiment demonstrates that the technology of the present invention can stably achieve precise and controllable fabrication from single-stage continuous flow channels to multi-layer independent three-dimensional networks, fully adapting to the multi-channel, hierarchical functional application requirements of official chips.

[0081] Figure 9 The SGA flexible hollow tubular structure was prepared based on the COCE-Nozzle nozzle; the complete internal cavity continuity of the molded hollow tubular structure was verified by the Rhodamine B dye infusion experiment.

[0082] Figure 10 Experiments were conducted to demonstrate the patency of a 3D-printed multilayer biomimetic vascular network; patency was confirmed by injection of Rhodamine B and green fluorescent dye.

[0083] Example 5

[0084] Experimental Preparation of P34HB Biodegradable Polymer Hollow Tubular Structure Based on COCE-Nozzle Nozzle

[0085] Objective: To verify the adaptability of this invention to biodegradable polymer materials, to prepare biodegradable hollow tubular structures that can be used in tissue engineering, to verify the structural continuity and molding stability, and to adapt to the application needs of clinical implantation scenarios such as peripheral nerve regeneration catheters, biodegradable implantable drainage catheters, and cavity tissue repair scaffolds.

[0086] Equipment and materials: The 14G specification COCE-Nozzle nozzle, single-path air pressure extrusion 3D printing platform, poly(3-hydroxybutyrate-4-hydroxybutyrate) (P34HB), N-methylpyrrolidone (NMP), and deionized water prepared in this embodiment.

[0087] Specific implementation steps: 1. Preparation of P34HB printing ink: Add 6g of P34HB powder to 10mL of NMP solvent, stir at room temperature for 12h until completely dissolved, centrifuge at 3000rpm for 10 minutes at room temperature to remove bubbles, and obtain uniform P34HB printing ink.

[0088] 2. Load P34HB ink into the printing cartridge, install the COCE-Nozzle printhead, connect to the single-path air pressure extrusion system, and complete the extrusion molding of serpentine and spiral hollow tubular structures on the printing platform.

[0089] 3. Immediately after extrusion molding, the printed structure is placed in a deionized aqueous phase coagulation bath. The material is cured by a non-solvent phase separation method. After soaking for 24 hours, it is taken out and rinsed with deionized water 3 times to obtain the final P34HB biodegradable hollow tubular structure.

[0090] Results: A complete and continuous P34HB biodegradable polymer hollow tubular structure was successfully prepared. The channel has a uniform inner diameter without collapse and clear openings at both ends. Rhodamine B dye infusion experiments verified that the channel showed no leakage or blockage throughout, and excellent internal permeability (see [link to documentation]). Figure 11a , Figure 11bIt can stably adapt to the preparation needs of clinical implantation scenarios such as peripheral nerve defect repair catheters, biodegradable tissue engineering scaffolds, and in vivo implantable drainage catheters.

[0091] Figure 11: P34HB biodegradable polymer hollow tubular structure prepared based on COCE-Nozzle nozzle Figure 11a A physical image of the printed snake-shaped P34HB hollow tubular structure (the openings at both ends of the channel are marked in red). Figure 11b The Rhodamine B dye infusion experiment was conducted to verify that the molded hollow tubular structure has complete internal cavity continuity.

[0092] Example 6

[0093] Preparation of PDMS non-degradable polymer hollow tubular structure based on COCE-Nozzle nozzle

[0094] Objective: To verify the adaptability of this invention to non-degradable polymer materials, to prepare a degradable hollow tubular structure that can be used as a body fluid conduit, and to verify the permeability and molding stability of the hollow tubular structure.

[0095] Equipment and materials: 14G specification COCE-Nozzle nozzle, single-path air pressure extrusion 3D printing platform, PDMS SE1700, curing agent, and high temperature drying oven prepared in this embodiment.

[0096] Specific implementation steps: 1. Mix PDMS SE1700 and curing agent at a ratio of 10:1 and stir evenly. Centrifuge at 3000 rpm for 10 minutes at room temperature to remove bubbles and obtain uniform PDMS pre-cured printing ink.

[0097] 2. Load the PDMS pre-cured printing ink into the printing barrel, install the COCE-Nozzle printhead, connect to the single-path air pressure extrusion system, and complete the extrusion molding of serpentine and spiral hollow tubular structures on the printing platform.

[0098] 3. After extrusion molding, the printed structure is immediately placed in an 80℃ oven for cross-linking for 6 hours to obtain the final non-degradable hollow tubular structure of PDMS, which is then woven into the shape of a Chinese knot and injected with Rhodamine B dye.

[0099] Results: A complex three-dimensional flexible hollow tubular structure of PDMS was successfully fabricated. Even when knotted or bent, the channel maintained its structural integrity without collapse or damage. Rhodamine B dye infusion experiments verified that the channel was leak-free throughout, with complete internal continuity and excellent optical transparency (see [link to documentation]). Figure 12 It is perfectly suited to the preparation needs of minimally invasive diagnostic and treatment scenarios such as body fluid drainage catheters, microfluidic organ-on-a-chip, and flexible implantable devices.

[0100] Figure 12 : A flexible hollow tubular structure of PDMS was prepared based on the COCE-Nozzle printhead; the left figure is a physical image of the PDMS hollow tubular structure with a complex bending configuration printed; the right figure is a Rhodamine B dye infusion experiment, which verifies that the hollow tubular structure still maintains structural integrity and has a continuous cavity without leakage even when it is knotted and bent.

[0101] Example 7

[0102] Validation of Handheld Syringe Extrusion Molding Based on COCE-Nozzle Nozzle

[0103] Purpose of this implementation: This embodiment aims to verify the adaptability of the COCE-Nozzle molding system to be independent of professional 3D printing equipment, to confirm the feasibility of handheld extrusion molding based on ordinary syringes, and to fully verify the operational flexibility, low-threshold adaptability and on-site rapid preparation capability of this technology.

[0104] Experimental equipment and materials: 14G COCE-Nozzle printhead prepared in this invention, 10mL standard Luer connector syringe, 405nm handheld UV curing lamp; SGA2 hydrogel bio-ink (2% GelMA), 2% (w / v) CaCl2 aqueous solution.

[0105] Specific implementation steps: 1. Prepare SGA2 hydrogel bio-ink, stir at room temperature until completely dissolved, then degas under vacuum for 30 minutes to thoroughly remove air bubbles from the ink, ensuring the continuity of the extrusion process and the integrity of the molded structure; 2. Load the degassed SGA2 hydrogel ink into a 10mL standard Luer connector syringe, install a 14G COCE-Nozzle printhead, and manually and slowly push the syringe piston to expel the air remaining in the printhead and syringe, so as to avoid defects such as broken filaments and tube wall damage during the extrusion process. 3. Using a handheld syringe, the piston pressing rate is manually controlled to continuously extrude a hollow tubular structure onto the printing substrate. During the extrusion process, a 405nm handheld UV curing lamp is used for in-situ irradiation to achieve the initial shaping of the extruded structure. After hand-operated extrusion, the shaped structure is placed in a 2% (w / v) CaCl2 aqueous solution to complete ionic crosslinking and curing, and finally the hollow tubular structure product prepared by hand-operated extrusion is obtained.

[0106] Implementation Results: This embodiment demonstrates that the COCE-Nozzle molding system can completely operate independently of professional 3D printing equipment, achieving continuous and well-defined hollow tubular structures through extrusion using only a standard commercial syringe. The molded structure, after double cross-linking, exhibits uniform tubular walls and a clear, unobstructed internal cavity. The molding effect shows no significant difference from samples prepared using professional printing equipment, fully demonstrating the excellent operational flexibility and adaptability of this technology (see [link to documentation]). Figure 13a , Figure 13b This feature significantly lowers the application threshold of this technology, making it perfectly adaptable to various application scenarios such as ordinary laboratories without professional printing equipment, customized scaffold preparation during clinical surgery, on-orbit tissue construction in aerospace, and customized rapid on-site prototyping.

[0107] Figure 13 shows the verification of the extrusion molding effect of the handheld syringe based on the COCE-Nozzle nozzle; among which... Figure 13a A diagram showing the process of hand-operated extrusion of a hollow tubular structure for the COCE-Nozzle nozzle (the dashed box indicates the continuous hollow tubular structure being extruded). Figure 13b A photograph of the finished product of a hollow tubular hydrogel structure prepared by hand-operated extrusion.

[0108] The core technological innovation of this invention lies in the construction of a universal hollow tubular structure integrated manufacturing system based on COCE-Nozzle. Through original nozzle structure design, molding process optimization, and the development of a full-scenario adaptability solution, it achieves efficient, precise, and universal construction of functional hollow tubular structures in the fields of regenerative medicine, minimally invasive medical devices, and organ-on-a-chip. Compared with existing technologies, this invention has the following significant differences and core advantages: 1. This invention proposes an original principle for hollow structure molding based on a high-precision 3D printing customized nozzle. By digitally parametrically designing and fabricating a COCE-Nozzle nozzle with a built-in coaxial central occupant column structure, the cross-sectional shape of the extruded material is directly controlled by the annular extrusion channel between the central occupant column and the outer shell. The structural transformation from traditional solid fiber to continuous hollow tube can be achieved in one step of extrusion. This design breaks through the technical limitations of traditional extrusion molding in terms of molding principle. It can achieve direct and stable molding of hollow tubular structures without the need for a complex dual-path coaxial extrusion system, core sacrificial material, and multi-step post-processing.

[0109] 2. This invention develops a multi-material compatible and low-barrier manufacturing technology that adapts to the needs of all scenarios. This technology does not require changes to the core structure of the nozzle. It can stably support three major categories of core functional materials: hydrogels, biodegradable polymers, and PDMS, by simply adapting the process parameters. This covers the needs of all scenarios, including the construction of biomimetic blood vessels, nerve conduits, body fluid conduits, and the fabrication of microfluidic devices. At the same time, the nozzle is compatible with conventional single-channel extrusion 3D printing equipment and can also be directly adapted to ordinary syringes to achieve handheld extrusion molding. It does not require expensive professional industrial-grade equipment, which greatly reduces the entry barrier for research and development. It has the ability to adapt to all scenarios, including standardized mass production and customized on-site preparation.

[0110] The above description is merely a preferred embodiment of the present invention and does not constitute any limitation on the technical scope of the present invention. Therefore, any minor modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention shall still fall within the scope of the technical solution of the present invention.

Claims

1. A COCE-Nozzle nozzle for forming hollow tubular structures, characterized in that, include: The outer shell (1) has a central occupant column (2) inside it; the central occupant column (2) is coaxially arranged with the outer shell (1); the central occupant column (2) is fixedly connected to the outer shell (1) by a support rib (3); a uniform annular extrusion channel is formed between the central occupant column (2) and the outer shell (1).

2. The COCE-Nozzle nozzle for forming hollow tubular structures according to claim 1, characterized in that, The nozzle is integrally molded using high-precision DLP photopolymerization technology to achieve customized manufacturing of multiple specifications.

3. A method for forming a hollow tubular structure, characterized in that, Using the COCE-Nozzle nozzle as described in claim 1, functional printing material with shear-thinning properties is extruded through a single-pass pneumatic extrusion 3D printer or a standard Luer connector injector, and cross-linked and cured by physical or chemical means to obtain a continuous hollow tubular structure in one step.

4. The method for forming a hollow tubular structure according to claim 3, characterized in that, The functional printing material with shear-thinning properties is a hydrogel-based bio-ink, a biodegradable polymer printing ink, or a non-biodegradable flexible polymer printing ink.

5. The method for forming a hollow tubular structure according to claim 4, characterized in that, The hydrogel-type bio-ink is a composite hydrogel bio-ink containing sodium alginate (SA).

6. The method for forming a hollow tubular structure according to claim 5, characterized in that, The hydrogel-based bio-ink is an SA / polyether F127 diacrylate (F127DA) composite hydrogel or an SA / methacrylamide gelatin (GelMA) composite hydrogel; wherein, the SA / F127DA composite hydrogel contains SA, F127DA and a photoinitiator, and is cured by photocrosslinking, ionic crosslinking or a combination of photocrosslinking and ionic crosslinking.

7. The method for forming a hollow tubular structure according to claim 4, characterized in that, The biodegradable polymer printing ink includes one or more of polylactic acid (PLA), polycaprolactone (PCL), and polyhydroxyalkanoates (PHA).

8. The method for forming a hollow tubular structure according to claim 7, characterized in that, The biodegradable polymer printing ink is a PHA solution-type printing ink, which uses an organic solvent to dissolve the polyhydroxy fatty acid ester into printing ink and then completes the curing through a non-solvent phase separation method using an aqueous coagulation bath.

9. The method for forming a hollow tubular structure according to claim 4, characterized in that, The non-degradable flexible polymer ink is a silicone rubber-based flexible polymer ink.

10. A method for forming a hollow tubular structure according to claim 9, characterized in that, The non-degradable flexible polymer ink is polydimethylsiloxane (PDMS); the polydimethylsiloxane is formed by mixing a prepolymer and a curing agent, and is cured by room temperature curing or heating curing.

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