Hydrogel mixing and conveying device with Y-shaped guide pipe and method for delaying solidification of hydrogel

Abstract

The invention provides a Y-shaped catheter hydrogel mixing and conveying device and a method for delaying hydrogel solidification. The Y-shaped catheter hydrogel mixing and conveying device comprises a first injector, a first catheter, a second injector, a second catheter, a Y-shaped connector and a third catheter. The first injector is used for injecting the alginic acid swimming bladder acellular matrix hydrogel into the first conduit. And the second injector is used for injecting the calcium malate cross-linking agent into the second catheter. The first guide pipe and the second guide pipe are connected to two openings of the Y-shaped connector, and the third guide pipe is connected to the other opening of the Y-shaped connector, so that the alginic acid swimming bladder acellular matrix hydrogel and the calcium malate cross-linking agent can be mixed and output outwards from the third guide pipe. The method for delaying solidification of the hydrogel comprises the step of mixing alginic acid swimming bladder acellular matrix hydrogel and a calcium malate cross-linking agent.

Description

Technical Field

[0001] The present application relates to the field of material transportation, and in particular to a Y-shaped catheter hydrogel mixing transportation device and a method for delaying hydrogel solidification. Background Art

[0002] The treatment of alginate-based injectable hydrogel implants has become a promising treatment for ischemic heart failure. Previous clinical trials have injected hydrogels into the myocardium through surgical thoracotomy. In comparison, intramyocardial injection of hydrogels via catheter intervention can reduce surgical risks, make the surgical process easier to perform, cause less damage to the body, and shorten the postoperative recovery time, taking into account both safety and effectiveness.

[0003] However, hydrogels that can be injected through catheters have very strict rheological requirements, including viscosity, rheology, gelation time, and stability under compression. The hydrogel must remain liquid when passing through the catheter, which requires a suitable gelation time to prevent coagulation in the catheter. Once injected into the injured tissue, it can gel again and play a role at the treatment site. In addition to rheological requirements, the lumen size and length of the catheter also limit the maximum viscosity of the injectable hydrogel. Increased flow resistance may lead to very large forces during the hydrogel injection process, thus affecting the usability of the operation or the instability of the catheter assembly.

[0004] Curley CJ, Dolan EB, Otten M, Hinderer S, Duffy GP, Murphy BP. An injectable alginate / extra cellular matrix (ECM) hydrogel towards a cellular treatment of heart failure. Drug Deliv Transl Res. 2019; 9(1): 1-13. doi: 10.1007 / s13346-018-00601-2, (An injectable alginate / extracellular matrix hydrogel for non-cellular treatment of heart failure) discloses the application of alginate hydrogel in minimally invasive myocardial delivery, which is an important step in the clinical transformation of biomaterial research. However, the hydrogel tested in the research process was composed of alginate and porcine heart decellularized matrix, and no other hydrogels were tried.

[0005] For example, when a hydrogel based on alginate and fish bladder cell extracellular matrix is ​​delivered through a conventional 1 m (meter) long catheter, the hydrogel will gel and block the catheter, making the injection process uncontrollable. Therefore, there is a need for further improvement of the delivery device. Summary of the invention

[0006] In order to solve or alleviate at least one of the problems mentioned in the background art, the present application provides a Y-shaped catheter hydrogel mixing delivery device and a method for delaying hydrogel solidification.

[0007] The Y-shaped catheter hydrogel mixing delivery device provided in the embodiment of the present application comprises:

[0008] a first syringe and a first catheter, wherein the first syringe is used to inject the alginate fish swim bladder decellularized matrix hydrogel into the first catheter;

[0009] a second syringe and a second catheter, wherein the second syringe is used to inject the calcium malate cross-linking agent into the second catheter;

[0010] A Y-shaped connector and a third conduit, wherein the first conduit and the second conduit are connected to two openings of the Y-shaped connector, and the third conduit is connected to the remaining opening of the Y-shaped connector, so that the alginate fish maw decellularized matrix hydrogel and the calcium malate cross-linking agent can be mixed and output from the third conduit.

[0011] In at least one embodiment, the Y-shaped catheter hydrogel mixing delivery device comprises a syringe pump configured to control the injection flow rates of the first syringe and the second syringe.

[0012] In at least one embodiment, the Y-shaped catheter-hydrogel hybrid delivery device comprises an injection needle, which is disposed at an end of the third catheter away from the Y-shaped connector.

[0013] In at least one embodiment, the third catheter is a 1 meter long single lumen catheter.

[0014] In at least one embodiment, the first syringe and the second syringe are identical.

[0015] In at least one embodiment, the first conduit and the second conduit are identical.

[0016] In at least one embodiment, the inner diameter of the third conduit is greater than the inner diameter of the first conduit, and the inner diameter of the third conduit is greater than the inner diameter of the second conduit.

[0017] In at least one embodiment, the Y-shaped connector includes a first channel and a second channel with the same inner diameter, and a third channel with an inner diameter larger than the first channel and the second channel, the first channel is connected to the first syringe, the second channel is connected to the second syringe, the third channel is connected to the third catheter, and the first channel, the second channel, and the third channel converge in the Y-shaped connector.

[0018] The method for delaying the solidification of hydrogel provided in the embodiment of the present application is used to delay the solidification of alginate fish maw decellularized matrix hydrogel, and the method comprises mixing the alginate fish maw decellularized matrix hydrogel and a calcium malate cross-linking agent.

[0019] In at least one embodiment, the alginate fish swim bladder decellularized matrix hydrogel and the calcium malate cross-linking agent are mixed in equal amounts.

[0020] The present application designs a Y-shaped catheter structure to enable the alginate fish maw decellularized matrix hydrogel and the calcium malate cross-linking agent to be mixed, so that the alginate fish maw decellularized matrix hydrogel remains in a liquid state in the catheter and then gels after being output to, for example, the myocardium, thereby avoiding the situation where the alginate fish maw decellularized matrix hydrogel blocks the catheter.

[0021] The method for delaying the solidification of hydrogel provided in the present application comprises mixing alginate fish maw decellularized matrix hydrogel and calcium malate cross-linking agent, which can delay the solidification of alginate fish maw decellularized matrix hydrogel. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 A schematic structural diagram of a Y-shaped catheter hydrogel mixing delivery device according to an embodiment of the present application is shown.

[0023] Figure 2 A cross-sectional view of a Y-shaped connector of a Y-shaped catheter-hydrogel hybrid delivery device according to an embodiment of the present application is shown.

[0024] Description of Reference Numerals

[0025] 101 First Syringe

[0026] 102 Second Syringe

[0027] 201 First Catheter

[0028] 202 Second catheter

[0029] 300 Y-Connector

[0030] 310 First Channel

[0031] 320 Second Channel

[0032] 330 Third Channel

[0033] 400 Third catheter

[0034] 500 Injection Needles DETAILED DESCRIPTION

[0035] The exemplary embodiments of the present application are described below with reference to the accompanying drawings. It should be understood that these specific descriptions are only used to teach those skilled in the art how to implement the present application, and are not intended to exhaust all possible methods of the present application, nor to limit the scope of the present application.

[0036] The present application provides a Y-shaped catheter hydrogel mixing delivery device and a method for delaying the solidification of hydrogel.

[0037] See also Figure 1 , Figure 2 The Y-shaped catheter hydrogel mixing delivery device may include a first syringe 101 , a first catheter 201 , a second syringe 102 , a second catheter 202 , a Y-shaped connector 300 and a third catheter 400 .

[0038] The first syringe 101 is used to inject alginate hydrogel integrated with decellularized extracellular matrix derived from fish swim bladder (ALG@dECM, also written as alginate / fish swim bladder decellularized matrix hydrogel) into the first catheter 201. The second syringe 102 is used to inject calcium malate crosslinking agent into the second catheter 202. The first catheter 201 and the second catheter 202 are connected to two openings of the Y-shaped connector 300, and the third catheter 400 is connected to the remaining opening of the Y-shaped connector 300, so that the alginate fish swim bladder decellularized matrix hydrogel and the calcium malate crosslinking agent can be mixed and output from the third catheter 400. The first catheter 201, the second catheter 202, the Y-shaped connector 300, and the third catheter 400 are formed as a Y-shaped catheter as a whole.

[0039] The first catheter 201 and the second catheter 202 may be common medical catheters, veterinary catheters, etc. The third catheter 400 may be a 1 m long single lumen catheter commonly used in interventional surgery. The first syringe 101 and the second syringe 102 may be syringes with a capacity of 1 ml.

[0040] The applicant found that the alginate fish bladder decellularized matrix hydrogel is easy to solidify in the catheter when it is transported alone through the catheter, and the gelation of the alginate fish bladder decellularized matrix hydrogel can be delayed by the calcium malate cross-linking agent that can slowly release calcium ions. Based on this, the present application designs a Y-shaped catheter hydrogel mixing delivery device to mix the alginate fish bladder decellularized matrix hydrogel and the calcium malate cross-linking agent, so that the mixed material can remain in a liquid state in the third catheter 400, and then gel after being output to, for example, the myocardium. It is beneficial to the clinical transformation process of injecting the alginate fish bladder decellularized matrix hydrogel into the myocardium through a minimally invasive intervention process.

[0041] It is understandable that gelled hydrogels with high and stable storage modulus can withstand the pressure of myocardial contraction and relaxation in myocardial tissue, and repeatedly deform while maintaining the stability of the internal structure of the material. After myocardial infarction, ischemic myocardial tissue will be replaced by scar tissue. Compared with the original myocardium, the elasticity of scar tissue is significantly reduced, the thickness of the ventricular wall is thinner, and the amplitude of ventricular wall movement is reduced. Long-term development will cause the patient's heart function to decline. When the hydrogel is injected into the scar tissue, the hydrogel gels, and the scar tissue can withstand greater pressure and deformation, improving the uncoordinated movement of the scar tissue and the surrounding myocardium, regulating the overall movement of the ventricle after myocardial infarction, and protecting heart function.

[0042] In addition, the material mixing position of the device provided in the present application is located at the Y-shaped connector 300, rather than outside the mixing and conveying device (such as the material preparation area before injection). This can strictly control the time between material mixing and the material entering the injection position to avoid premature gelation, so that the material can be smoothly injected through the catheter and the gelation process, for example in the myocardium, can be controlled.

[0043] In one embodiment, the Y-shaped catheter hydrogel mixing delivery device further includes a syringe pump (not shown in the figure), which is configured to control the injection flow rate of the first syringe 101 and the second syringe 102. The syringe pump can be a dual micro-syringe pump.

[0044] In one embodiment, the first syringe 101 and the second syringe 102 can be the same, and the injection speeds of the first syringe 101 and the second syringe 102 can be the same, so that the alginate fish maw decellularized matrix hydrogel and the calcium malate cross-linking agent can be mixed in equal amounts of 1:1.

[0045] In one embodiment, the first conduit 201 and the second conduit 202 may be identical. The inner diameter of the third conduit 400 is larger than the inner diameter of the first conduit 201 and the inner diameter of the second conduit 202. For example, the sum of the cross-sectional areas of the first conduit 201 and the second conduit 202 may be equal to the cross-sectional area of ​​the third conduit 400.

[0046] In one embodiment, see Figure 2 The Y-shaped connector 300 includes a first channel 310 and a second channel 320 having the same inner diameter, and a third channel 330 having an inner diameter greater than that of the first channel 310 and the second channel 320. The first channel 310 is connected to the first syringe 101, the second channel 320 is connected to the second syringe 102, and the third channel 330 is connected to the third catheter 400.

[0047] In one embodiment, see Figure 1The Y-shaped catheter hydrogel mixed delivery device further includes an injection needle 500, which is disposed at the end of the third catheter 400 away from the Y-shaped connector 300. The injection needle 500 may be a 26G injection needle 500 with an outer diameter of 0.45 mm and an inner diameter of 0.25 mm.

[0048] Exemplarily, the use of the Y-shaped catheter hydrogel hybrid delivery device may include the following steps.

[0049] The first syringe 101 is filled with alginate fish maw decellularized matrix hydrogel, and the second syringe 102 is filled with calcium malate cross-linking agent.

[0050] The injection volume is set on the injection pump, and the first syringe 101 and the second syringe 102 are installed correspondingly to the injection pump. Figure 1 As shown, the first syringe 101, the second syringe 102, the first catheter 201, the second catheter 202, the Y-shaped connector 300, the third catheter 400, and the injection needle 500 are installed in place.

[0051] The injection pump is started, and the alginate fish maw decellularized matrix hydrogel and the calcium malate cross-linking agent are simultaneously pushed through the pump and mixed in the Y-shaped connector 300, and then extruded after passing through the third catheter 400 and the injection needle 500, and gelled in the injected tissue. The storage modulus of the alginate fish maw decellularized matrix hydrogel after gelation increases and remains over time, for example, stabilizes at more than 1000 Pa after 5 minutes.

[0052] When the Y-shaped catheter hydrogel mixed delivery device was actually used in a rat experiment, the speed of a single push injection was 10 μL / s, and the 1-meter-long third catheter 400 could be used for 10 minutes without being blocked.

[0053] The method for delaying the solidification of hydrogel provided in the present application is used to delay the solidification of alginate fish maw decellularized matrix hydrogel. The method comprises mixing the alginate fish maw decellularized matrix hydrogel and a calcium malate crosslinker.

[0054] Furthermore, the alginate fish maw decellularized matrix hydrogel and the calcium malate cross-linking agent may be mixed in equal amounts.

[0055] It should be understood that the method for delaying the decellularization of alginate swim bladder matrix hydrogel developed in the present application can also be applied in fields other than medical treatment.

[0056] The above is a preferred embodiment of the present application. It should be pointed out that for those skilled in the art, several improvements and modifications can be made without departing from the principles of the present application. These improvements and modifications should also be regarded as the scope of protection of the present application.

Claims

1. A Y-shaped catheter hydrogel mixing delivery device, characterized in that: include: A first syringe (101) and a first catheter (201), wherein the first syringe (101) is used to inject alginate fish swim bladder acellular matrix hydrogel into the first catheter (201); A second syringe (102) and a second catheter (202), wherein the second syringe (102) is used to inject the calcium malate cross-linking agent into the second catheter (202); A Y-shaped connector (300) and a third conduit (400), wherein the first conduit (201) and the second conduit (202) are connected to two openings of the Y-shaped connector (300), and the third conduit (400) is connected to the remaining opening of the Y-shaped connector (300), so that the alginate fish maw acellular matrix hydrogel and the calcium malate cross-linking agent can be mixed and output outward from the third conduit (400).

2. The Y-shaped catheter hydrogel mixing delivery device according to claim 1, characterized in that: It comprises a syringe pump, which is configured to control the injection flow rate of the first syringe (101) and the second syringe (102).

3. The Y-shaped catheter hydrogel mixing delivery device according to claim 1, characterized in that: It comprises an injection needle (500), wherein the injection needle (500) is arranged at the end of the third catheter (400) away from the Y-shaped connector (300).

4. The Y-shaped catheter hydrogel mixing delivery device according to claim 1, characterized in that: The third catheter (400) is a single-lumen catheter with a length of 1 meter.

5. The Y-shaped catheter hydrogel mixing delivery device according to claim 1, characterized in that: The first syringe (101) and the second syringe (102) are identical.

6. The Y-shaped catheter hydrogel mixing delivery device according to claim 1, characterized in that: The first conduit (201) and the second conduit (202) are identical.

7. The Y-shaped catheter hydrogel mixing delivery device according to claim 1, characterized in that: The inner diameter of the third conduit (400) is greater than the inner diameter of the first conduit (201), and the inner diameter of the third conduit (400) is greater than the inner diameter of the second conduit (202).

8. The Y-shaped catheter hydrogel mixing delivery device according to claim 1, characterized in that: The Y-shaped connector (300) comprises a first channel (310), a second channel (320) having the same inner diameter, and a third channel (330) having an inner diameter greater than that of the first channel (310) and the second channel (320); the first channel (310) is connected to the first syringe (101); the second channel (320) is connected to the second syringe (102); the third channel (330) is connected to the third catheter (400); and the first channel (310), the second channel (320), and the third channel (330) are converged in the Y-shaped connector (300).

9. A method for delaying the solidification of a hydrogel, for delaying the solidification of alginate fish maw decellularized matrix hydrogel, characterized in that: The alginate fish maw decellularized matrix hydrogel and the calcium malate cross-linking agent are mixed.

10. The method for delaying the solidification of hydrogel according to claim 9, characterized in that: The alginate fish maw decellularized matrix hydrogel and the calcium malate cross-linking agent are mixed in equal amounts.

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