Extracorporeal circulation type ox gall-stone preparation device and method

Abstract

The invention discloses an extracorporeal circulation type bovine gall-stone preparation device and method, and relates to the field of artificial calculus bovis preparation. The device comprises a bile storage tank, double peristaltic pumps, a three-way valve, a tubular reaction unit, a constant-temperature heating jacket, a pH adjusting unit, a controller, an optional concentration unit and the like. The method comprises the following steps: preparing bile reaction liquid containing a lithogenic precursor, initializing parameters, starting a device, and circulating the reaction liquid; adjusting the pH value, concentrating to form a supersaturated environment for nucleation, simulating pulse flow at a periodic variable flow rate to promote dynamic growth, and finally harvesting, cleaning and drying. The gallbladder environment is simulated, living body dependence is avoided, the stone forming period is short, the similarity of the product and natural calculus bovis is high, and automatic large-scale production can be achieved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of artificial cow-bezoar preparation, and particularly relates to an extracorporeal cow gallstone preparation device and method. BACKGROUND

[0002] Cow-bezoar (commonly known as "cow-bezoar") is a kind of precious traditional Chinese medicine with high medicinal value and economic value. At present, the probability of obtaining natural cow-bezoar is low, which cannot meet the market demand. The existing solutions mainly include: In vivo cultivation method: by surgery, a stone core is implanted in the gallbladder of a live cow, and the stone is formed in the live body environment without an extracorporeal reactor. This method has a cycle of several months to several years and high cost, and the surgery can easily cause infection and even death of the cow, causing great damage to animal welfare, and the success rate of stone formation is unstable, which is difficult to scale up.

[0003] Chemical synthesis method: general chemical equipment such as reaction kettle and beaker is used, which is not designed for the physiological characteristics of cow-bezoar stone formation, and cannot simulate the key environment such as bile flow, concentration and flexible gallbladder wall in the gallbladder, and can only match the chemical composition, so the crystal structure and biological activity of the product are quite different from those of natural cow-bezoar, and the drug efficacy is poor and the market acceptance is low.

[0004] In vitro static culture method: bile is placed in a culture dish or beaker, and a stone-forming substance is added for precipitation reaction. This method uses a culture dish or beaker as the core device, and can only realize the static precipitation of bile and stone-forming substances, and cannot simulate the physiological processes such as bile flow, pulse discharge and concentration in the gallbladder, and there is no flexible wall simulation, so the product form and composition are quite different from those of natural cow-bezoar, and the stone formation efficiency and quality are poor.

[0005] In summary, the existing technology either has no extracorporeal reactor or uses general equipment or simple static devices, which cannot simulate the physiological environment of the gallbladder, resulting in long cycle, poor quality and difficulty in scaling up in cow-bezoar preparation.

[0006] Therefore, it is necessary to improve the existing technology to solve the above technical problems. SUMMARY

[0007] In view of the above technical problems, the present application provides an extracorporeal cow gallstone preparation device and method.

[0008] The technical solution for solving the technical problem of the present application is as follows: In a first aspect, the present application provides an extracorporeal cow gallstone preparation device, which comprises a bile storage tank, a first peristaltic pump, a three-way valve and a tubular reaction unit, wherein: The first peristaltic pump is connected to the bile storage tank and the inlet end of the three-way valve through pipelines, one outlet end of the three-way valve is connected to the bile storage tank through a pipeline, and a first circulation branch is formed; A PH sensor is arranged on the first circulation branch; It also comprises a thermostat heating jacket and a second peristaltic pump; wherein: The tubular reaction unit is sleeved with a thermostat heating jacket, another outlet end of the three-way valve is connected with the tubular reaction unit and the second peristaltic pump through a pipeline in series, and the outlet end of the second peristaltic pump is connected with the gallbladder storage tank through a pipeline to form a second circulation branch; A pressure sensor and a temperature sensor are arranged on the pipeline between the tubular reaction unit and the second peristaltic pump; It also comprises a hydrochloric acid storage tank and a micro pump, the hydrochloric acid storage tank and the micro pump are connected with the gallbladder storage tank through a pipeline to form a PH adjusting unit for adjusting the pH value of the gallbladder; It also comprises a controller which is connected with each electrical component.

[0009] Preferably, it also comprises a concentration unit which is connected in series on the pipeline of the second circulation branch and is arranged between the second peristaltic pump and the gallbladder storage tank.

[0010] Preferably, the tubular reaction unit comprises: A hollow pipe body, two ends of the pipe body are respectively detachably connected with an upper end cover and a lower end cover which can be connected with external equipment; A plurality of rope bodies are arranged uniformly in a circumferential direction and are built-in the pipe body; two ends of the rope body are respectively connected with the upper end cover and the lower end cover; A plurality of resin balls are connected with the rope body in a suspended manner as stone cores.

[0011] Preferably, the tubular reaction unit further comprises a first rope hanging disc and a second rope hanging disc arranged in an up-down manner, two ends of the rope body are respectively connected with quick plug buckles, and the first rope hanging disc and the second rope hanging disc are respectively provided with plug holes corresponding to the quick plug buckles; the quick plug buckles can be plugged into the plug holes; the first rope hanging disc is detachably connected with the upper end cover; the upper end cover is fixedly connected with an upper joint pipe connected with external equipment; a lower joint pipe connected with external equipment is sleeved with the lower end cover in a middle part; the lower joint pipe is sealingly and slidably connected with the lower end cover; one end of the lower joint pipe penetrates into the pipe body through the lower end cover; the lower joint pipe is provided with a limiting piece for limiting the axial displacement of the lower joint pipe; the second rope hanging disc is connected with the lower joint pipe.

[0012] Preferably, the resin ball is provided with a rope penetrating hole through which the rope body penetrates; the resin ball is further provided with a positioning spacer sleeve for positioning the resin ball; the positioning spacer sleeve is interference-connected with the rope body.

[0013] Preferably, a plurality of spaced screw columns are fixedly connected with the upper end cover in an internal top part along a circumferential direction; the first rope hanging disc is provided with positioning holes matched with the screw columns; the top ends of the screw columns penetrate through the positioning holes and are threadedly connected with locking nuts.

[0014] Preferably, the limiting piece is a floating structure, which comprises a spring seat and a compression spring, the spring seat is threadedly connected on the lower joint pipe, the compression spring is sleeved on the lower joint pipe, one end of the compression spring is connected with the lower end cover, and the other end is connected with the spring seat.

[0015] Preferably, the resin balls on adjacent rope bodies are arranged in a staggered manner.

[0016] In the second aspect, the present application provides an assembling method of the extracorporeal circulation type bovine gallstone preparation device, which is used for constructing the extracorporeal circulation type bovine gallstone preparation device, and the specific steps are as follows: S1, making a tubular reaction unit S1.1, component preparation: selecting required components according to design specifications and pretreating the components; S1.2, assembling resin balls, positioning spacers and quick-insert buckles: according to a designed interval, positioning spacers and resin balls are threaded on the rope body; after threading is completed, the quick-insert buckles are connected to both ends of the rope body; S1.3, connecting the rope disc with the rope body the quick-insert buckles are respectively inserted into corresponding insertion holes of the first rope disc and the second rope disc, so as to ensure that the rope body is uniformly circumferential and free of distortion; S1.4, assembling the end cover with the rope disc the first rope disc is inserted into the threaded column of the upper end cover, and a locking nut is screwed; the lower joint pipe is threadedly connected with the second rope disc; S1.5, assembling the upper and lower end covers with the pipe body the above-mentioned whole is threaded into the pipe body, and the upper end cover is fixedly connected with one end of the pipe body; the lower end cover is sleeved on the lower joint pipe, and the position of the lower end cover is adjusted by sliding, so as to fix the other end of the pipe body with the lower end cover; S1.6, installing the limiting piece and tightening the rope body the compression spring is sleeved on the lower joint pipe, one end of the compression spring is attached to the lower end cover, the spring seat is screwed and the compression spring is compressed until the rope body is tight; S2, assembling the whole device S2.1, connecting the pipeline in the order of the bile storage tank→the first peristaltic pump→the inlet of the three-way valve→one outlet of the three-way valve→the bile storage tank, to construct a first circulation branch, and installing a PH sensor on the first circulation branch; S2.2, connecting the pipeline in the order of the other outlet of the three-way valve→the tubular reaction unit→the pressure sensor and the temperature sensor→the second peristaltic pump→the bile storage tank, to construct a second circulation branch; S2.3, connecting the PH adjusting unit The PH adjusting unit is connected in sequence through pipelines according to the hydrochloric acid storage tank, the micro pump and the bile storage tank; S2.4, auxiliary component installation A constant temperature heating jacket is sleeved on the tubular reaction unit; all electrical devices are electrically connected with the controller; S2.5, overall debugging The sealed test and the function test are performed on the connected overall device.

[0017] In a third aspect, the technical scheme further provides an application method of the extracorporeal circulation type bovine gallstone preparation device, which is used for preparing bovine gallstones, and adopts the extracorporeal circulation type bovine gallstone preparation device, and the steps include the following: a1, preparation of a reaction solution: taking fresh or pretreated bovine bile, adding a stone-forming precursor substance, and stirring uniformly; a2, system initialization: injecting the reaction solution into the bile storage tank, and excluding air bubbles; setting temperature, initial pH and circulation flow rate parameters; a3, circulation nucleation: starting the device to make the reaction solution continuously circulate in the tubular reaction unit; slowly reducing the pH value through the pH adjusting unit, and gradually increasing the bile concentration through the concentration unit to create a supersaturated environment, and induce the stone-forming substance to precipitate and grow around the core; a4, dynamic growth: periodically changing the flow rate to simulate physiological pulse flow, so that the precipitated microcrystals collide, aggregate and laminatedly grow in the dynamic environment to form a layered structure similar to natural gallstones; a5, harvesting and post-processing: after the reaction is completed, the formed bovine gallstones are taken out in the tubular reaction unit, and after washing and drying, the finished product is obtained.

[0018] Compared with the prior art, the above technical scheme has the following advantages or beneficial effects: 1. The extracorporeal circulation type bovine gallstone preparation system designed in the present application creates a stone-forming environment close to that in vivo by using a tubular reaction unit, a constant temperature heating jacket, a peristaltic pump to create a pulse flow, a pH unit to adjust the acid-base, and an optional concentration unit to simulate the concentration of the gallbladder, thereby restoring the physiological environment of the gallbladder and creating a stone-forming environment close to that in vivo, and solving the problem that the product form and composition of the prior art deviate from natural bovine gallstones.

[0019] 2. The present application is independent of the living body and can repeatedly use bile in a closed loop. In addition, multiple channels can be prepared in parallel by increasing the reaction unit, which shortens the cycle and improves the efficiency, and solves the pain point of the prior art that it is difficult to scale up. The controller controls the pump, sensor and other components, adjusts the parameters in real time, reduces manual intervention, avoids the fluctuation of the stone-forming success rate, ensures the consistency of the product quality of different batches, and is easy to standardize and scale up.

[0020] 3. The pipe type reaction unit designed in the application, the resin balls are evenly suspended in the unit through the rope body in the circumferential direction, and the resin balls of adjacent rope bodies are distributed in staggered positions, so as to eliminate the dead angle of the bile flow, so that the bile in the pulse flow state can fully contact with each resin ball, simulate the natural action mode of the bile in the gallbladder and the stone core, and be beneficial to forming the uniform bezoar lamellar structure and good stone quality.

[0021] 4. In the pipe type reaction unit in the scheme, the tension of the rope body can be flexibly adjusted through the compression spring and spring seat structure of the lower joint pipe, so as to ensure that the resin balls are always in a stable suspended state, avoid local over-thick or over-thin stone caused by core shaking, and in addition, the detachable design of the pipe type reaction unit is convenient for taking out the bezoar product formed on the resin balls in the later stage, and convenient operation. BRIEF DESCRIPTION OF DRAWINGS

[0022] The accompanying drawings are included to provide a further understanding of the application, and constitute a part of the specification, together with the embodiments of the application, to explain the application, and do not constitute a limitation on the application.

[0023] Figure 1 is a process flow diagram of the extracorporeal circulating bezoar preparation system.

[0024] Figure 2 is a control block diagram of the extracorporeal circulating bezoar preparation system.

[0025] Figure 3 is a perspective view of the pipe type reaction unit.

[0026] Figure 4 is Figure 3 a sectional view of the pipe type reaction unit.

[0027] Figure 5 is Figure 4 an enlarged schematic view of the A area structure.

[0028] Figure 6 is an assembly drawing of the first hanging rope disc, rope body, resin ball and second hanging rope disc.

[0029] Figure 7 is Figure 6 an enlarged schematic view of the B area structure.

[0030] Figure 8 is Figure 6 an enlarged schematic view of the D area structure.

[0031] Figure 9 is a structural perspective view of the lower joint pipe, compression spring and spring seat.

[0032] BRIEF DESCRIPTION OF DRAWINGS 1. Tubular reaction unit; 11. Tube body; 12. Upper end cap; 13. Upper connector tube; 14. Lower connector tube; 15. Spring seat; 16. Compression spring; 17. Lower end cap; 18. Sealing ring; 19. First rope reel; 110. Threaded post; 111. Rope body; 112. Resin ball; 121. Positioning spacer; 113. Quick-connect buckle; 1131. Post head; 1132. Locking platform; 114. Second rope reel; 2. Bile storage tank; 3. First peristaltic pump; 4. Micro pump; 5. Hydrochloric acid storage tank; 6. pH sensor; 7. Three-way valve; 8. Thermostatic heating mantle; 9. Pressure sensor; 10. Temperature sensor; 11. Second peristaltic pump; 12. Concentration unit; 13. Controller. Detailed Implementation

[0033] Embodiments of the present invention are described in detail below, examples of which are illustrated in the accompanying drawings, wherein the same or similar reference numerals denote the same or similar elements or elements having the same or similar functions throughout. The embodiments described below with reference to the accompanying drawings are exemplary and intended to explain the present invention, and should not be construed as limiting the present invention.

[0034] like Figures 1-9 As shown, this embodiment proposes an extracorporeal circulation bovine gallstone preparation device, including a bile storage tank 2, a first peristaltic pump 3, a three-way valve 7, and a tubular reaction unit 1; wherein: The first peristaltic pump 3 is connected to the bile storage tank 2 and the inlet end of the three-way valve 7 via a pipeline. One outlet end of the three-way valve 7 is connected to the bile storage tank 2 via a pipeline, forming the first circulation branch. A pH sensor 6 is installed on the first circulation branch to monitor the pH value of the bile in real time and provide data support for subsequent pH adjustment.

[0035] The device also includes a constant temperature heating jacket 8 and a second peristaltic pump 11; wherein: A constant temperature heating jacket 8 is fitted onto the tubular reaction unit 1. The other outlet end of the three-way valve 7 is connected in series with the tubular reaction unit 1 and the second peristaltic pump 11 through a pipeline. The outlet end of the second peristaltic pump 11 is connected to the bile storage tank 2 through a pipeline, forming a second circulation branch. Specifically, the other outlet end of the three-way valve 7 is connected to the inlet of the tubular reaction unit 1, i.e., the upper connector pipe 13, through a pipeline. The outlet of the tubular reaction unit 1, i.e., the lower connector pipe 14, is connected to the second peristaltic pump 11 through a pipeline. The outlet end of the second peristaltic pump 11 is connected back to the bile storage tank 2 through a pipeline, forming a closed loop.

[0036] The first peristaltic pump 3 is used for bile circulation and mixing; the second peristaltic pump 11 can output pulse flow to simulate gallbladder contraction.

[0037] A pressure sensor 9 and a temperature sensor 10 are arranged on the pipeline between the tubular reaction unit 1 and the second peristaltic pump 11, so as to monitor the bile pressure and temperature in the branch, and ensure the stability of the stone formation environment.

[0038] The device further comprises a hydrochloric acid storage tank 5 and a micro pump 4, and the hydrochloric acid storage tank 5 and the micro pump 4 are connected with the bile storage tank 2 through pipelines to form a pH adjusting unit for adjusting the pH value of the bile. The pH adjusting unit is used for accurately controlling the acid-base environment. According to the pH data of the bile collected by the pH sensor, the hydrochloric acid is accurately added into the bile storage tank 2, so that the pH value of the bile is adjusted to a proper value, and the stone formation reaction condition is optimized.

[0039] The whole device further comprises a controller 13 which is connected with each electrical component for control, so as to realize automatic control.

[0040] In some embodiments, the whole device further comprises an optional concentration unit 12 which is connected in series on the pipeline of the second circulating branch and arranged between the second peristaltic pump 11 and the bile storage tank 2.

[0041] The components will be described in detail as follows: The control components of the controller 13, the first peristaltic pump 3, the second peristaltic pump 11, the micro pump 4, the constant temperature heating jacket 8, the pH sensor, the pressure sensor 9, the temperature sensor 10 and the concentration unit 12 are electrically connected. The pH, temperature and pressure data collected by each sensor can be received in real time, and each execution component can be automatically triggered to act, such as adjusting the flow rate of the first peristaltic pump 3 and the second peristaltic pump 11, controlling the power of the constant temperature heating jacket 8, and adjusting the drop amount of the micro pump 4 (adjusting the pH), so as to realize automatic operation of the whole process and reduce manual intervention.

[0042] The bile storage tank 2 is used for storing raw bile and stone formation inducer (bovine gallstone pathogenic bacteria) required for preparing bovine gallstones.

[0043] The constant temperature heating jacket 8 is sleeved outside the tubular reactor, and is used for maintaining the temperature in the reactor at 38-39℃ (the physiological temperature of bovine gallbladder), so as to avoid that the temperature fluctuation affects the precipitation and growth of stone formation substances.

[0044] The concentration unit 12 can simulate the water reabsorption function of the gallbladder to bile, gradually increase the concentration of stone formation substances in the bile, and promote the efficient progress of the stone formation reaction. In this embodiment, the concentration unit 12 can adopt a hollow fiber ultrafiltration membrane assembly.

[0045] The above components are all conventional structures, and the specific structures will not be described here.

[0046] Regarding the tubular reaction unit 1, it is a core of the device and also one of the biggest innovations of the scheme. The tubular reaction unit 1, as the core carrier of stone formation reaction, is used in cooperation with the constant temperature heating jacket 8, the peristaltic pump, the pH adjusting unit and the concentration unit 12 to form a complete physiological environment simulation system. The tubular reaction unit 1 mainly includes the tube body 11, the string body 111 and the resin ball 112. The following will be specifically introduced: The hollow tube body 11 provides a closed reaction space for the generation of bovine bile; the two ends of the tube body 11 are respectively detachably connected with the upper end cover 12 and the lower end cover 17 which can be connected with external equipment; wherein the detachable connection mode includes but is not limited to threaded connection, plug-in connection and the like. The detachable design is convenient for subsequent installation of the string body 111, the resin ball 112 and harvesting of products.

[0047] In some embodiments, the material of the tube body 1111 can be selected from flexible or semi-rigid materials such as medical silicone tubes or polytetrafluoroethylene tubes; wherein the medical silicone tube has flexibility and can simulate the physical properties of the gallbladder wall, which is suitable for the dynamic flow environment of bile; the polytetrafluoroethylene tube has corrosion resistance and biocompatibility, which ensures that the bile is not contaminated during long-term use, and meets the hygiene requirements of in vitro stone formation.

[0048] The string body 111 is circumferentially and uniformly arranged and is built-in the tube body 11; the two ends of the string body 111 are respectively connected with the upper end cover 12 and the lower end cover 17. The connection of the string body 111 with the upper / lower end cover 17 can be direct connection or indirect connection.

[0049] The resin ball 112 is a stone-forming core and is connected to the string body 111 in a spaced manner. The uniform arrangement of the string body 111 ensures that the bile flowing through the tube body 11 can fully contact each resin ball 112, avoiding local accumulation of stone-forming substances; the spaced suspension of the resin ball 112 can prevent adjacent resin balls 112 from colliding and adhering, ensuring that the surface of each resin ball 112 can uniformly deposit stone-forming substances, and finally generate bovine bile with regular shape.

[0050] In some embodiments, the connection mode of the resin balls 112 and the rope body 111 includes but is not limited to adhesive fixing, tethering connection and the like, and as a preferred mode, threading connection can be adopted. Specifically, the resin ball 112 is provided with a rope threading hole, and the rope body 111 penetrates through the rope threading hole. Further, a positioning spacer 121 for positioning the resin ball 112 is provided, and the positioning spacer 121 is connected with the rope body 111 in an interference fit. Each resin ball 112 is provided with a rope threading hole with a diameter adapted to that of the rope body 111, and the rope body 111 directly penetrates through the rope threading hole, so as to ensure that the resin ball 112 and the rope body 111 are connected in a "shaft-hole" mode, avoiding the displacement and rotation of the resin ball 112 under the impact of the pulse flow, and completely eliminating the local stone blanking or accumulation caused by the core displacement.

[0051] In some embodiments, the rope body 111 is preferably a medical-grade nylon wire, which has good biocompatibility, high strength, is not easy to break in a dynamic bile flow, and does not release impurities, meeting the hygiene standards of the biological fluid environment.

[0052] In some embodiments, in order to improve the operation flexibility, the tubular reaction unit 1 further has the following structural features: The tubular reaction unit 1 further comprises a first rope hanging disc 19 and a second rope hanging disc 114 arranged in an up-down mode, and the two ends of the rope body 111 are respectively connected with quick plug buckles 113. The first rope hanging disc 19 and the second rope hanging disc 114 are respectively provided with plug holes adapted to the quick plug buckles 113. The quick plug buckle 113 comprises a stud 1131, and the middle part of the stud 1131 is provided with a slit. The slit divides the top part of the stud 1131 into two parts, and each part is provided with a clamping table 1132. The cross-sectional shape of the clamping table 1132 is triangular. When the two clamping tables 1132 are pressed inward, the slit provides space for the inward contraction of the clamping table 1132, so that the clamping table 1132 smoothly passes through the plug hole until the clamping table 1132 extends out, and the edge of the clamping table 1132 is larger than the diameter of the plug hole, so as to realize clamping.

[0053] The first rope hanging disc 19 is detachably connected with the upper end cover 12. The detachable connection mode includes but is not limited to threaded connection, bolt connection, plug-in connection, clamping connection and the like. In some embodiments, the detachable connection mode specifically adopts the following structure: a plurality of spaced screw columns 110 are fixedly connected to the top inside of the upper end cover 12 in a circumferential direction, the first rope hanging disc 19 is provided with positioning holes adapted to the screw columns 110, and the top ends of the screw columns 110 penetrate through the positioning holes and are threadedly connected with locking nuts.

[0054] In some embodiments, the screw columns 110 and the locking nuts can be made of polytetrafluoroethylene or stainless steel.

[0055] The upper end cover 12 is fixedly connected with an upper joint pipe 13 connected with external equipment, the middle part of the lower end cover 17 is sleeved with a lower joint pipe 14 connected with external equipment, the lower joint pipe 14 is in sealing sliding connection with the lower end cover 17, an installation hole is formed in the middle part of the lower end cover 17, and a sealing ring 18 is arranged on the inner wall of the installation hole; the lower joint pipe 14 and the lower end cover 17 can slide relative to each other; one end of the lower joint pipe 14 penetrates into the inside of the pipe body 11 through the lower end cover 17; the lower joint pipe 14 is provided with a limiting piece for limiting the axial displacement of the lower joint pipe 14; the second rope winding disc 114 is connected with the lower joint pipe 14, and specifically, the lower joint pipe 14 and the second rope winding disc 114 can be connected in a threaded connection mode.

[0056] The limiting piece can adopt the structure of a clamp, and considering the convenience of adjusting the tightness of the rope body 111, the limiting piece can also be a floating structure, which includes a spring seat 15 and a compression spring 16; the spring seat 15 is threadedly connected to the lower joint pipe 14, and the compression spring 16 is sleeved with the lower joint pipe 14; one end of the compression spring 16 is connected with the lower end cover 17, and the other end is connected with the spring seat 15. The tension of the rope body 111 in the pipe type reaction unit 1 can be flexibly adjusted through the compression spring 16 and the spring seat 15 structure of the lower joint pipe 14, so as to ensure that the resin balls 112 are always in a stable suspended state, and avoid the local stone being too thick or too thin due to the core shaking; in addition, the detachable design of the pipe type reaction unit 1 facilitates the later taking out of the cholecalculus products formed on the resin balls 112, and is convenient to operate.

[0057] In some embodiments, the resin balls 112 on adjacent rope bodies 111 are arranged in a staggered manner. If the resin balls 112 on adjacent rope bodies 111 are in an aligned state, that is, distributed at the same axial height, a transverse obstruction will be formed inside the pipe type reaction unit 1, and when the bile, especially the pulse flow driven by the peristaltic pump, flows through, the previous row of resin balls 112 will block the contact path of the rear row of resin balls 112, resulting in a flow dead angle behind the resin balls 112. The staggered arrangement can stagger the resin balls 112 on adjacent rope bodies 111 in the axial height, so as to avoid the obstruction formed by the alignment of the resin balls 112, so that the bile can fully flush each resin ball 112 without dead angle. The staggered arrangement can also not waste the stone-forming core, and each resin ball 112 can contact the bile, reducing the “empty core” (no cholecalculus) or “less core” (less cholecalculus) situation. The staggered arrangement can ensure that the full surface of each resin ball 112 is exposed to the bile flow: whether it is the front surface, side surface or back surface of the resin ball 112, it can be continuously flushed and contacted with the stone-forming components (bilirubin, cholic acid, etc.) in the bile, effectively avoiding the waste of the core due to obstruction.

[0058] In addition, the staggered arrangement can also make the product more uniform: all resin balls 112 are in contact with bile under the same conditions, and the generated gallstones are more uniform in thickness and composition; specifically, the staggered arrangement allows all resin balls 112 to be in the same contact conditions: the flow, flow rate, and composition concentration of the bile contacted by each resin ball 112 are basically the same, and the generated gallstones are highly uniform in thickness and shape (mostly regular spherical shape); at the same time, uniform bile contact can avoid local component accumulation, ensure that the content distribution of effective components such as bilirubin and cholic acid in the gallstone is uniform, and more close to the composition ratio of natural gallstone, thereby improving the medicinal value.

[0059] As can be seen from the above description, the pipe type reaction unit 1 designed by the present application suspends the resin balls 112 in the unit through the rope body 111 in a circumferential direction, and the resin balls 112 of adjacent rope bodies 111 are staggered, which eliminates the dead angle of bile flow, so that the bile in the pulse flow state can fully contact each resin ball 112, simulates the natural action mode of bile in the gallbladder and the stone core, and is beneficial to the formation of uniform gallstone layered structure and good stone quality.

[0060] In summary, the application effect of the present application is: Firstly, the in-vitro circulation type gallstone preparation system designed by the present application forms stones through the pipe type reaction unit 1, controls temperature through the constant temperature heating jacket 8, creates pulse flow through the peristaltic pump, adjusts acid and alkali through the pH unit, and optionally simulates gallbladder concentration through the optional concentration unit 12, restores the physiological environment of the gallbladder, and creates a stone formation environment close to the in-vivo environment, thereby solving the problem that the product form and composition of the prior art deviate from natural gallstone.

[0061] Secondly, the bile can be repeatedly used in a closed loop without relying on living bodies, and multiple channels can be prepared in parallel by increasing the reaction unit, thereby shortening the cycle and improving the efficiency, and solving the pain point of difficult scaling of the prior art. The controller 13 controls the pump, sensor and other components, adjusts the parameters in real time, reduces manual intervention, avoids the fluctuation of stone formation success rate, ensures the consistency of product quality of different batches, and is easy to standardize and scale production.

[0062] Specific application examples: a1. Preparation of reaction solution: Collect fresh bile from healthy cattle, and remove large impurities by centrifugal filtration. Add 50 mg of bilirubin, 100 mg of cholesterin powder and 5 mL of bile stone pathogenic bacteria solution extracted by E. coli to each liter of bile, and stir uniformly.

[0063] a2. Initialization: 2L of reaction solution is injected into the bile storage tank. Set the control system parameters: temperature 38.5℃, initial pH 7.2, first peristaltic pump 3 flow rate 10 mL / min (stable circulation), and second peristaltic pump 11 set to work once every 60 minutes, each time running at a pulse flow rate of 50 mL / min for 2 minutes (simulating gallbladder contraction).

[0064] a3. Operation: Start the device. The controller 13 automatically drops hydrochloric acid through the micro pump 4, slowly reduces the system pH to 6.8 within 24 hours and maintains it. At the same time, the concentration unit 1212 is started to work for 1 hour every 12 hours, part of the water is removed, and the bile concentration is gradually increased.

[0065] a4. Monitoring and growth: The system is continuously operated for 15 days. Through the transparent wall of the tubular reaction unit 1, it can be observed that brown-yellow substances gradually deposit and thicken on the core.

[0066] a5. Harvesting: Stop the system operation, open the tubular reaction unit 1, and take out the core with attached gallstones. The surface is gently rinsed with deionized water, and then placed in a desiccator for low-temperature (40°C) vacuum drying for 48 hours.

[0067] a6. Results: A plurality of brown-yellow gallstones with spherical shape, hard texture, smooth surface, and obvious layered structure are finally obtained, with an average diameter of about 8 mm and a total weight of about 5 grams. Preliminary tests show that the main components (bilirubin, cholesterol, bile acid) and content are highly consistent with natural bezoar.

[0068] From the above description, it can be seen that the preparation method has the following advantages: Multi-dimensional simulation: For the first time, multiple key physiological factors such as temperature, pH, concentration, and pulse flow are comprehensively simulated in vitro, and the physiological environment of the gallbladder is restored in multiple dimensions, creating an environment close to in vivo stone formation.

[0069] High efficiency and speed: By actively controlling and optimizing stone formation conditions, the stone formation period is shortened from several years in vivo to several weeks or even days, greatly improving efficiency.

[0070] High product quality: The stones formed in a dynamic flow environment have more similar microstructure (such as layered structure, crystal arrangement) and chemical composition to natural bezoar, and have better efficacy.

[0071] Controllable and repeatable: All process parameters (temperature, pH, flow rate, time) can be accurately digitized and controlled, ensuring consistency and repeatability of the production process and product quality, and facilitating standardized and large-scale production.

[0072] Humanity and environmental protection: Completely avoids the pain and risk to animals caused by live surgery, in line with animal welfare ethics requirements, and is a humane and sustainable production method.

[0073] Low cost: The device can be continuously used in a loop, and the main consumption is bile raw materials, with overall production cost much lower than in vivo cultivation method.

[0074] The above describes the specific embodiments of the application in combination with the drawings, but is not a limitation on the protection scope of the application. Various modifications or variations made by those skilled in the art on the basis of the technical solutions of the application without creative labor are still within the protection scope of the application.

Claims

1. An extracorporeal circulation bovine gallstone preparation device, characterized in that, Includes a bile storage tank (2), a first peristaltic pump (3), a three-way valve (7), and a tubular reaction unit (1); wherein: The first peristaltic pump (3) is connected to the inlet end of the bile storage tank (2) and the three-way valve (7) through a pipeline. One outlet end of the three-way valve (7) is connected to the bile storage tank (2) through a pipeline, forming the first circulation branch. A pH sensor (6) is installed on the first circulation branch. It also includes a constant temperature heating jacket (8) and a second peristaltic pump (11); wherein: A constant temperature heating jacket (8) is fitted on the tubular reaction unit (1). The other outlet end of the three-way valve (7) is connected in series with the tubular reaction unit (1) and the second peristaltic pump (11) through a pipeline. The outlet end of the second peristaltic pump (11) is connected to the bile storage tank (2) through a pipeline to form a second circulation branch. A pressure sensor (9) and a temperature sensor (10) are installed on the pipeline between the tubular reaction unit (1) and the second peristaltic pump (11). It also includes a hydrochloric acid storage tank (5) and a micro pump (4), which are connected to the bile storage tank (2) by pipelines to form a pH adjustment unit for adjusting the pH value of bile; It also includes a controller (13), which is connected to each electrical component for control.

2. The extracorporeal circulation bovine gallstone preparation device according to claim 1, characterized in that, It also includes a concentration unit (12), which is connected in series on the pipeline of the second circulation branch and is located between the second peristaltic pump (11) and the bile storage tank (2).

3. The extracorporeal circulation bovine gallstone preparation device according to claim 1 or 2, characterized in that, The tubular reaction unit (1) includes: A hollow tube (11) with an upper end cap (12) and a lower end cap (17) that can be detachably connected to external equipment at both ends of the tube (11). Several ropes (111) are evenly spaced around the circumference and are placed inside the tube (11); the two ends of the ropes (111) are connected to the upper end cap (12) and the lower end cap (17) respectively; Several resin balls (112), serving as the core of the stone, are suspended at intervals on the rope (111).

4. The extracorporeal circulation bovine gallstone preparation device according to claim 3, characterized in that, The tubular reaction unit (1) also includes a first rope reel (19) and a second rope reel (114) arranged vertically. Quick-connect buckles (113) are connected to both ends of the rope (111). The first rope reel (19) and the second rope reel (114) are respectively provided with corresponding insertion holes. The quick-connect buckles (113) can be inserted into the insertion holes. The first rope reel (19) is detachably connected to the upper end cover (12). The upper end cover (12) is fixedly connected to external equipment. The upper connector tube (13) is connected, and the lower end cover (17) is fitted with a lower connector tube (14) that is connected to external equipment. The lower connector tube (14) and the lower end cover (17) are sealed and slidably connected. One end of the lower connector tube (14) passes through the lower end cover (17) and enters the interior of the tube body (11). The lower connector tube (14) is provided with a limiting member for limiting the axial displacement of the lower connector tube (14). The second hanging rope disc (114) is connected to the lower connector tube (14).

5. The extracorporeal circulation bovine gallstone preparation device according to claim 4, characterized in that, The resin ball (112) has a rope hole through which the rope body (111) passes; it also includes a positioning spacer (121) for positioning the resin ball (112), the positioning spacer (121) being interference-fitted with the rope body (111).

6. The extracorporeal circulation bovine gallstone preparation device according to claim 5, characterized in that, The top of the upper cover (12) is fixedly connected with several threaded posts (110) at intervals along the circumference. The first hanging rope disc (19) is provided with a positioning hole that matches the threaded post (110). The top of the threaded post (110) passes through the positioning hole and is threaded with a locking nut.

7. An extracorporeal circulation bovine gallstone preparation device according to claim 4 or 6, characterized in that, The limiting component is a floating structure, which includes a spring seat (15) and a compression spring (16). The spring seat (15) is threadedly connected to the lower connector tube (14), and the compression spring (16) is sleeved and connected to the lower connector tube (14). One end of the compression spring (16) is connected to the lower end cover (17), and the other end is connected to the spring seat (15).

8. The extracorporeal circulation bovine gallstone preparation device according to claim 7, characterized in that, The resin balls (112) on adjacent ropes (111) are staggered.

9. A method for assembling an extracorporeal circulation bovine gallstone preparation device, characterized in that, The specific steps for constructing the extracorporeal circulation bovine gallstone preparation device as described in claim 8 are as follows: S1, Constructing a tubular reaction unit (1) S1.1, Component preparation: Select the required components according to the design specifications and perform pretreatment; S1.2 Assembly of resin ball (112), positioning spacer (121) and quick-connect buckle (113): According to the design spacing, the positioning spacer (121) and resin ball (112) are threaded onto the rope body (111); after the threading is completed, quick-connect buckles (113) are attached to both ends of the rope body (111). S1.3, the hanging rope disc is connected to the rope body (111). The quick-release buckles (113) are inserted into the corresponding holes of the first hanging rope reel (19) and the second hanging rope reel (114) respectively to ensure that the rope body (111) is uniform in circumference and without twisting; S1.4, Assembly of end cap and hanging rope tray The first rope reel (19) is inserted into the threaded post (110) on the upper end cover (12) and the locking nut is screwed on; the lower connector tube (14) is threaded to the second rope reel (114). S1.5, Assembly of the tube body (11) and the upper and lower end caps (17) The assembled whole is inserted into the tube (11), and the upper end cap (12) is fixedly connected to one end of the tube (11); A lower end cap (17) is fitted onto the lower connector pipe (14), and the position of the lower end cap (17) is adjusted by sliding to fix the lower end cap (17) to the other end of the pipe body (11); S1.6, Installation of limiting components and tightening of rope (111) The lower connector tube (14) is fitted with a compression spring (16), one end of the compression spring (16) is attached to the lower end cap (17), the spring seat (15) is screwed in and the compression spring (16) is compressed until the rope (111) is taut; S2, Assembly of the entire device S2.1, the bile storage tank (2) → first peristaltic pump (3) → three-way valve (7) inlet → three-way valve (7) outlet → bile storage tank (2) are connected by pipeline to form a first circulation branch, and a pH sensor (6) is installed on the first circulation branch. S2.2, the second circulation branch is constructed by connecting the other outlet of the three-way valve (7) → tubular reaction unit (1) → pressure sensor (9), temperature sensor (10) → second peristaltic pump (11) → bile storage tank (2) through the pipeline; S2.3, pH adjustment unit connection A pH adjustment unit is constructed by connecting the hydrochloric acid storage tank (5) → micro pump (4) → bile storage tank (2) through pipelines. S2.4, Auxiliary component installation A constant temperature heating jacket (8) is fitted onto the tubular reaction unit (1); all electrical components are electrically connected to the controller (13); S2.5, Overall Debugging Perform sealing and functional tests on the connected assembly.

10. A method for using an extracorporeal circulation bovine gallstone preparation device, for preparing bovine gallstones, characterized in that, The extracorporeal circulation bovine gallstone preparation device according to any one of claims 3-8 includes the following steps: a1. Preparation of reaction solution: Take fresh or pre-treated ox bile, add stone-forming precursors, and stir well. a2. System initialization: Inject the reaction solution into the bile storage tank and remove air bubbles; set the temperature, initial pH, and circulation flow rate parameters. a3. Circulating nucleation: Start the device to make the reaction liquid continuously circulate in the tubular reaction unit (1); slowly reduce the pH value through the pH adjustment unit and gradually increase the bile concentration through the concentration unit (12) to create a supersaturated environment and induce the stone-forming material to precipitate and grow around the core; a4. Dynamic growth: Periodically change the flow rate to simulate physiological pulse flow, so that the precipitated microcrystals collide, aggregate, and grow in layers in a dynamic environment, forming a layered structure similar to natural gallstones. a5. Harvesting and post-processing: After the reaction is completed, the formed gallstones are taken out from the tubular reaction unit (1), and after cleaning and drying, the finished product is obtained.

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