A manufacturing method of a degradable inorganic hernia patch

Abstract

The present invention relates to a manufacturing method of a degradable inorganic hernia patch, comprising the following steps: 1), selecting a magnesium ingot with a purity ≥ 99.98%, ultrasonically cleaning the surface of the magnesium raw material to wash away impurities; 2), putting the magnesium ingot into a furnace, using Ar gas protection to isolate magnesium from air, slowly heating up to about 630 °C, waiting for the magnesium ingot to melt, stirring evenly, and pouring into a mold after holding for a period of time; 3), then extruding the ingot into a high-purity magnesium rod with a diameter of 6 mm according to an extrusion ratio of 20:1 - 50:1, with a purity ≥ 99.99%; 4), laser cutting the magnesium rod into high-purity magnesium round pieces with a diameter of 6 mm and a thickness of 2 mm; 5), putting the high-purity magnesium round pieces into a cold pressing mold, cold pressing at room temperature to make a high-purity magnesium thin sheet with a monomer thickness reaching 0.1 - 0.3 mm and a size of 10 × 15 cm; 6), cleaning, drying, and sterilizing the high-purity magnesium thin sheet with epoxyhexane in sequence, then coating a 0.5-mm-thick bioadhesive on one surface of the made thin sheet, and air-drying for standby, thus obtaining a non-mesh and structurally complete high-purity magnesium hernia patch.

Description

Technical Field

[0001] The present invention relates to a method for manufacturing a degradable inorganic hernia patch. Background Art

[0002] Currently, traditional hernia patches are all sheet-like plates composed of grid-like degradable organic materials or metal plates woven from degradable metals. In short, they are all sheet-like plates with a grid shape and mesh holes in the middle. Taking the degradable metal plate as an example, its manufacturing method is usually to form a grid through metal wire weaving or pressing. However, after degradation in the human body, the warp and weft lines of the grid of the metal plate-like object will break, resulting in insufficient strength (the peritoneum needs to have a certain tension to wrap the internal organs / resist the pressure formed by the internal organs - obviously, hernias are likely to occur during constipation or coughing because the internal organ pressure is the greatest at this time). Therefore, due to degradation in the human body, the strength of the grid-like hernia patch made of metal structure will seriously decline in the short term. In severe cases, it may lead to surgical failure, and the abdominal contents will protrude through the hernia defect to the scrotum or subcutaneous tissue, resulting in recurrence or serious complications.

[0003] Why does the absorbable hernia patch with a reticular structure have a short support time and a rapid strength decline? Because the strength of the reticular structure mainly depends on the support of the warp and weft lines. No matter what diameter of wire is used for the warp and weft lines (currently, for some grid-like hernia patches, in order to increase the strength of the warp and weft lines, the method of increasing the diameter of the warp and weft lines is adopted), generally speaking, their diameters will not be particularly large. Therefore, after contacting the tissue fluid, the relatively small-diameter warp and weft lines will break successively, resulting in a decline in the strength of the grid-like absorbable hernia patch, and finally leading to the rupture of the hernia patch, affecting the surgical effect.

[0004] Therefore, the problem of the existing technology lies in the need to find a hernia patch that is degradable but has greater structural strength (slower degradation - on the basis that the thickness of the hernia patch cannot be increased, the time for maintaining the structural strength of the hernia patch depends on the degradation speed of the hernia patch material - but it cannot be completely non-degradable. A completely non-degradable material is a foreign body to the human body, leaving hidden dangers in the human body. If it is removed through surgery, it will cause secondary harm to the human body).

[0005] Similarly, how to manufacture such a hernia patch is also a new technical problem to be solved. Summary of the Invention

[0006] In order to overcome the deficiencies of the existing technology, the purpose of the present invention is to provide a method for manufacturing a hernia patch that is degradable but has greater structural strength (slower degradation speed).

[0007] Experimenters accidentally discovered that non-lattice (plate-shaped), pure magnesium / zinc sheets can also degrade slowly in the human tissue fluid environment, and their degradation rate is very slow.

[0008] The applicant guesses the underlying principle as follows. First, its strength. Since there is no lattice, when it has not degraded, it meets the surgical strength requirements for hernia patches. Second, it can achieve natural degradation in the human body eventually. It's just that the final effect is relatively slow. Moreover, this slow degradation rate exactly meets the strength-time requirements for a surgical patch. The term "strength-time" is created by the applicant to describe the strength requirement per unit time. Because pure magnesium / zinc sheets have a relatively slow degradation rate, their structure remains relatively intact during the time required for surgery (spanning the natural repair time of the entire hernia defect). Thus, it ensures that its strength (determined by both structure and material) remains at a relatively stable level within a fixed time period. And pure magnesium / zinc sheets can also be made into the spatial structure form of a hernia patch due to the processing characteristics of the metal.

[0009] To verify the degradation characteristics of pure magnesium / zinc sheets made into hernia patches in the human body, that is, to verify the above theory, the experimenters designed the following experiment. At a temperature of 36.5°C and a humidity maintained between 50 - 70%, magnesium and zinc materials were made into thin sheets and placed in Hanks solution (used to simulate the human abdominal cavity environment).

[0010] Degradation rate (mm / year) Pure zinc 0.013 Zinc with 1wt% magnesium 0.016 Zinc with 3wt% magnesium 0.019 Zinc with 6wt% magnesium 0.025 Zinc with 9wt% magnesium 0.03

[0011] Test materials Degradation rate (mm / year) Pure magnesium 0.035 Magnesium with 1wt% zinc 0.076 Magnesium with 3wt% zinc 0.106 Magnesium with 6wt% zinc 1.07 Magnesium with 9wt% zinc 2.19

[0012] From the above experimental data, the applicant found that when the purity of the magnesium / zinc sheets was controlled between 1 - 6% and the thickness was controlled at 0.1 mm, the entire patch was completely degraded in the human body within one year. (Due to the peristalsis of internal organs, under the acting force of the internal organ extrusion, the degradation rate of the patch is faster - the experimental patch has no internal organs to squeeze it.) Therefore, based on these experimental data, if we want the patch to be naturally degraded in the human body within one year, we need to make corresponding adjustments in the process.

[0013] Provide the following technical solution: A method for making a degradable inorganic hernia patch, characterized in that: select a magnesium block with a purity controlled between 1 - 6%, ultrasonically clean the surface of the magnesium raw material to remove impurities;

[0014] Put the magnesium ingot into a furnace, use Ar gas to protect it from contact with air, slowly heat it to about 630°C, wait for the magnesium ingot to melt, stir evenly, keep it warm for a period of time and then pour it into a mold;

[0015] Subsequently, the ingot is extruded into a high-purity magnesium rod with a diameter of 6 mm according to an extrusion ratio of 20:1 - 50:1, and the purity is controlled between 1% - 6%.

[0016] The magnesium rod is laser cut into high-purity magnesium discs with a diameter of 6 mm and a thickness of 2 mm.

[0017] The high-purity magnesium discs are placed in a cold pressing mold and pressed at room temperature into high-purity magnesium thin sheets with a monomer thickness of 0.1 - 0.3 mm (here, the size is enlarged to 0.3 mm considering the extrusion effect of the internal organs on the patch during the patching operation, resulting in an accelerated degradation effect. The same applies hereinafter).

[0018] The high-purity magnesium thin sheets are successively cleaned, dried, and sterilized with epoxyhexane to obtain high-purity magnesium hernia patches.

[0019] Since it has been stated above that both the magnesium sheet and the zinc sheet conform to the above theory, the above technical solution is extended to: replacing magnesium in the above technical solution with zinc, specifically:

[0020] A method for manufacturing a degradable inorganic hernia patch: 1), Select a zinc ingot with a purity ≥ 99.98%, ultrasonically clean the surface of the zinc raw material to remove impurities.

[0021] 2), Place the zinc ingot in a furnace, use Ar gas to isolate the zinc from the air, slowly heat up to about 450 °C, wait for the zinc ingot to melt, stir evenly, and pour it into a mold after holding for a period of time.

[0022] 3), Subsequently, the ingot is extruded into a high-purity zinc rod with a diameter of 6 mm according to an extrusion ratio of 20:1 - 50:1, and the purity ≥ 99.99%.

[0023] 4), The zinc rod is laser cut into high-purity zinc discs with a diameter of 6 mm and a thickness of 2 mm.

[0024] 5), Place the high-purity zinc discs in a cold pressing mold and press them at room temperature into high-purity zinc thin sheets with a monomer thickness of 0.1 - 0.3 mm and a size of 10 × 15 cm.

[0025] 6), After the high-purity zinc thin sheets are successively cleaned, dried, and sterilized with epoxyhexane, apply a 0.5 mm thick bioadhesive on one surface of the prepared thin sheet, air dry and set aside to obtain a non-mesh, structurally complete high-purity zinc hernia patch.

[0026] In the above experiment, another phenomenon was also discovered. When the purity of the magnesium / zinc sheet is higher, its degradation rate in the human body is slower. This prompts the applicant that when using pure magnesium / zinc sheets as patches, the thickness and purity need to be controlled to meet the strength requirements. Generally speaking, slowing down the degradation rate is the primary condition for ensuring strength. From the experimental data, slowing down the degradation rate / increasing the time for the patch to maintain a certain strength requires increasing the purity of the magnesium / zinc sheet. Therefore, during production, the relative process needs to be improved. Thus, another technology is provided:

[0027] Considering the degradation law suggested by the above experiment, the above-provided technical solution is further optimized as follows: The purity of the material is greater than 99.99%.

[0028] The above experiment proved that at a temperature of 36.5°C and a humidity maintained at 50 - 70% in an environment where magnesium and zinc materials are placed in Hanks' solution, compared with magnesium / zinc containing impurities, high-purity magnesium / zinc can prevent the degradation rate from being too fast. (The higher the purity, the slower the degradation rate in the human body).

[0029] Based on the hint from this experimental result (1 - 6%), the above-provided technical solution is further optimized as follows: The material is replaced with a Zn-xMg binary alloy, and the ratio of the two is: x = 0.5 - 5 wt.%. Specifically: According to the Zn-Mg binary alloy phase diagram, a high-purity melting process is used to prepare degradable Zn-xMg alloy materials with different Mg contents, and the ratio of the two is: x = 0.5 - 5 wt.%;

[0030] Ultrasonically clean the surfaces of the zinc and magnesium raw materials to remove impurities;

[0031] Put the zinc block into the furnace, protect it with Ar gas, slowly heat it to about 430°C. After the zinc ingot melts, put the magnesium in, stir evenly, keep it warm for a period of time, and then pour it into the mold;

[0032] Subsequently, extrude the ingot into zinc-magnesium alloy rods with a diameter of 6 mm according to a certain extrusion ratio of 20:1, 50:1;

[0033] Laser cut the zinc-magnesium alloy rods into zinc-magnesium alloy circular sheets with a diameter of 10×15 cm and a thickness of 2 mm;

[0034] Put the zinc-magnesium alloy circular sheets into a cold pressing mold and press them into zinc-magnesium alloy thin sheets with a monomer thickness of 0.1 - 0.3 mm at room temperature;

[0035] Wash, dry, and sterilize the zinc-magnesium alloy thin sheets with epoxyhexane in sequence to obtain a high-purity inorganic / zinc-magnesium alloy hernia patch.

[0036] Magnesium / zinc is an essential nutrient element for the human body. As biodegradable metals, magnesium and zinc can degrade in the human body, and the degraded magnesium and zinc ions have good biocompatibility with the human body. wt.% is the weight percentage, which represents different weight ratios in the Zn and Mg alloys, ranging from 99.5% Zn 0.5% Mg to 95% Zn 5% Mg.

[0037] Continuing to observe the above degradation experiment, during the degradation process of the magnesium / zinc plate-like material, it degrades in the form of pitting corrosion. They will gradually degrade in the chloride ion-containing environment in the body, and many pore-like structures (penetrating the upper and lower surfaces) will form on the surface of the magnesium / zinc material. These pores provide the pathways required for the growth and crawling of human tissues, especially fibroblasts and capillaries. In other words, during degradation, the plate-shaped patch will form a mesh-like structure similar to that of the prior art. However, before the pores are formed, the structural strength it provides is far greater than that of the mesh-shaped patch (the structural strength of the plate is greater than that of the mesh-shaped mesh, and also greater than that of the "plate-like object" with pre-formed microchannels). In other words, in terms of strength comparison, the plate-shaped patch is equivalent to having an additional "before perforation" state compared to the mesh-shaped patch, and the strength of the patch during this "before perforation" state fully meets the surgical requirements of the patch. Therefore, the time during which the plate-shaped patch can provide qualified strength is significantly higher than that of the mesh-shaped patch.

[0038] To verify this theory, the following experiment was designed: At a temperature of 36.5°C, using a compressive testing machine to detect, after soaking in simulated body fluid for 3 months, the maximum compressive strengths of the plate-shaped magnesium patch, mesh magnesium patch, and ordinary degradable patch are shown in the following table:

[0039] Maximum compressive strength Plate-shaped magnesium patch 850 mmHg Mesh magnesium patch 500 mmHg Ordinary degradable patch 700 mmHg

[0040] This experiment perfectly verifies the above theory and also proves that the plate-shaped patch indeed has greater strength as speculated before the experiment in terms of strength.

[0041] Furthermore, one side of the hernia patch is coated with a bioadhesive. The bioadhesive can be a bioadhesive containing the ingredient of Bletilla striata. During production, 10%-50% by mass of Bletilla striata powder is put into the bioadhesive and mixed evenly, then coated on the hernia patch and air-dried for later use.

[0042] During long-term surgeries, the applicant found that the bioadhesive itself has the functions of hemostasis, accelerating wound healing, and adhesion (bioadhesives in the prior art can achieve this effect, such as protein-based adhesives, the bioadhesive "Duo Mo Bang", and SUP glue). Therefore, the applicant tried to combine the bioadhesive with the patch, attempting to play the role of the bioadhesive during patch surgeries.

[0043] The applicant adopted the simplest idea. One surface of the hernia patch was coated with 0.5 mm of bioadhesive and left to dry for later use.

[0044] To verify the above theory, the following animal experiments were designed: The magnesium patch was placed on an open fresh abdominal wound, and the bleeding on the wound surface stopped after about 3 minutes; The bioadhesive was applied to an open fresh abdominal wound, and the bleeding on the wound surface stopped after about 1.5 minutes; The magnesium patch was coated with bioadhesive and then placed on an open fresh abdominal wound, and the bleeding on the wound surface stopped after about 1 minute. See the following table:

[0045]

[0046]

[0047] After adding Bletilla striata, because Bletilla striata contains mucilage (a variety of polysaccharides, starch, which can shorten the coagulation time and inhibit fibrinolysis, and can form an artificial thrombus to stop bleeding) and volatile oil, the mucilage and starch it contains strengthen the adhesive effect of the bioadhesive. The volatile oil it contains strengthens the effect of the bioadhesive in accelerating wound healing. And after the bioadhesive is mixed with the mucilage and starch of Bletilla striata: On the one hand, it adheres to the wound at the surgical (hernia) site, enabling the wound to stop bleeding faster.

[0048] On the other hand, during the experimental surgery stage, a technical effect was discovered. The patch coated with bioadhesive adhered to the wound at the surgical (hernia orifice) site, playing a pre-fixation role, which facilitated the subsequent suturing of the patch and the hernia orifice by the surgeon. During traditional suturing, it was necessary to first fix / hold the patch on the hernia orifice and then pass a needle through the patch and the hernia orifice. Under endoscopic surgery, there was a lack of conditions to fix / hold the patch on the hernia orifice. However, for the patch coated with bioadhesive-Bletilla striata powder, due to its pre-fixation technical effect, when it was spread flat on the hernia orifice and gently pressed for a while, it could adhere to the hernia orifice. At this time, when suturing, there was no need to fix / hold the patch on the hernia orifice separately, which brought great convenience to endoscopic hernia repair surgery, greatly reduced the difficulty of the surgery, and greatly improved the effect of the repair surgery. This move was completely unexpected. The applicant originally only adopted the most common (traditional) method, only coating the bioadhesive (containing Bletilla striata, or directly using the glue as the bioadhesive) on one side surface of the patch. The original intention was only that the bioadhesive on this surface could help the wound on this side heal faster and reduce the bleeding time and blood loss after contacting the wound in this part. However, unexpectedly, the adhesive effect of the bioadhesive caused the patch to adhere to the hernia orifice without the need for separate fixation, bringing great convenience to endoscopic hernia repair surgery where the patch cannot be fixed separately.

[0049] In order to verify whether this technology is reliable, the animal experiment was designed as follows: the magnesium patch coated with biological glue was reliably fixed on the fresh abdominal wound. It only needed to be pressed (the endoscope head was used under endoscope, which made it easy to press the patch) for 10 seconds, and no sutures were needed to fix it. The patch coated with biological glue was glued to the wound; it took 25 seconds to fix the non-absorbable polypropylene patch on the open fresh abdominal wound, and 6-8 stitches were sutured; it took about 30 seconds to fix the absorbable polyglycolic acid patch on the open fresh abdominal wound, and about 6-8 stitches were sutured; see the table below:

[0050] Patch pressing time Whether fixation is required Magnesium patch with bioadhesive 10 seconds No Non-absorbable polypropylene patch 15 seconds Partially required Absorbable polyglycolic acid patch 20 seconds Partially required

[0051] The experimental results show that the bonding effect of inorganic patch + biological glue even exceeds that of traditional organic patch + biological glue. This experiment proves that the above technical effect is reliable in the endoscopic surgery environment.

[0052] The applicant had a sudden idea and set up the following experiment to observe the degradation of inorganic patches coated with bio-glue in the human body:

[0053] Complete degradation time Magnesium patch 6 months Magnesium patch + bioadhesive 8 months Absorbable polyglycolic acid patch 3 months

[0054] The applicant speculates that this situation occurs because biological glue is not easily soluble in human tissue fluid. Therefore, the patch coated with biological glue on one side blocks the degradation of the patch by tissue fluid before it dissolves, which is equivalent to slowing down the degradation of the patch. Moreover, the degradation of the patch can be further slowed down by adjusting the composition of the glue and the thickness of the coating.

[0055] Experiments have shown that the degradation time of magnesium patches in animals is 6 months. After being coated with biological glue, the degradation time of magnesium patches is extended to 8 months. The degradation time of absorbable polyglycolic acid patches is 3 months.

[0056] In other words, the patch coated with bio-glue can further delay the degradation time of the patch, thereby providing a longer-term strength guarantee.

[0057] Furthermore, the patch is rolled into a cylindrical shape with a diameter of and a length of, and is tied with a degradable thread on the outside. The cylindrical shape is convenient for pre-insertion into the top of the endoscope lumen. After reaching the surgical site, the cylindrical hernia patch is pushed out through the endoscope and placed at the surgical site. The degradable thread on the outside is then cut off with the scissors carried by the endoscope. The hernia patch made of the plate naturally stretches to a flat state due to its own elasticity, and then the surgeon continues the hernia repair surgery on this basis. (The surgical process is described above)

[0058] Compared with the prior art, the present invention has the following beneficial effects:

[0059] 1. The patch produced by the present invention is biodegradable in the human body. The substances formed after degradation are compatible with the human body and harmless to the human body (reference can be made to the degradation research of magnesium-zinc in the human body).

[0060] 2. The patch provided by the present invention provides a patch with greater structural strength through the integrity of its structure. Through the biodegradability of the materials used, micropores penetrating the patch are formed, providing the same pore channels for tissue growth as traditional patches.

[0061] 3. By applying a biological glue on one side of the patch:

[0062] A. It helps the wound stop bleeding quickly;

[0063] B. It delays the degradation rate of the patch,

[0064] C. The patch has the effect of pre-fixation (at the hernia orifice), providing great convenience for endoscopic surgery.

[0065] 4. By adding the ingredient of Bletilla striata in the biological glue, the above functions of the biological glue are enhanced - Bletilla striata contains mucilage (various polysaccharides, starch), which on the one hand has the function of traditional Chinese medicine to help stop bleeding quickly, and on the other hand has the function of glue.

[0066] 5. Using magnesium / zinc with a purity greater than 99.99% further delays the degradation rate of the metal. Specific implementation mode

[0067] The following experiment was designed to compare the key index of time-strength of a commercially available non-absorbable organic patch, an absorbable organic patch, an absorbable mesh patch and the plate-shaped magnesium patch of the present application in simulated human tissue fluid (Hanks solution).

[0068]

[0069] From the table, it can be found that the plate-shaped magnesium patch still has a compressive strength of 850 mmHg after 6 months.

[0070] The mesh-shaped magnesium patch has a compressive strength of 500 mmHg after 5 months. In terms of both the degradation time and the strength provided, it is less than that of the plate-shaped magnesium patch.

[0071] Absorbable polyglycolic acid has a compressive strength of 700 mmHg after 3 months and 5 months. Its degradation time is shorter than that of the plate-shaped magnesium patch. That is to say, after 3 months, due to the corrosion of the patch structure, it can no longer provide a structural support with a certain strength (below 700 mmHg).

[0072] The non-absorbable polypropylene patch will not be discussed here. As a foreign body, it remains in the patient's body for life, posing a potential risk.

Claims

1. A manufacturing method of a degradable inorganic hernia patch, characterized in that, It includes the following steps: 1), Select magnesium ingots with a purity of ≥99.98%, ultrasonically clean the surface of the magnesium raw material to wash away impurities; 2), Put the magnesium ingots into a furnace, use Ar gas protection to isolate magnesium from the air, slowly heat up to about 630°C, wait for the magnesium ingots to melt, stir evenly, keep warm for a period of time and then pour into a mold; 3), Subsequently, extrude the ingot into a high-purity magnesium rod with a diameter of 6 mm according to an extrusion ratio of 20:1 - 50:1, with a purity of ≥99.99%; 4), Laser cut the magnesium rod into high-purity magnesium round slices with a diameter of 6 mm and a thickness of 2 mm; 5), Put the high-purity magnesium round slices into a cold pressing mold, and press them into high-purity magnesium thin slices with a monomer thickness of 0.1 - 0.3 mm and a size of 10×15 cm at room temperature; 6), After sequentially cleaning, drying, and sterilizing with epoxyhexane the high-purity magnesium thin slices, coat a 0.5-mm-thick biological glue on one surface of the prepared thin slices, air dry and reserve, then a non-mesh and structurally complete high-purity magnesium hernia patch is obtained.

2. The manufacturing method of a degradable inorganic hernia patch according to claim 1, characterized in that: Roll the patch prepared by the method described in Claim 1 into a cylindrical roll with an outer diameter of 4 mm and a height of 15 cm, and tie it up with silk thread around the periphery.

3. A manufacturing method of a degradable inorganic hernia patch, characterized in that: 1), Select zinc ingots with a purity of ≥99.98%, ultrasonically clean the surface of the zinc raw material to wash away impurities; 2), Put the zinc ingots into a furnace, use Ar gas protection to isolate zinc from the air, slowly heat up to about 450°C, wait for the zinc ingots to melt, stir evenly, keep warm for a period of time and then pour into a mold; 3), Subsequently, extrude the ingot into a high-purity zinc rod with a diameter of 6 mm according to an extrusion ratio of 20:1 - 50:1, with a purity of ≥99.99%; 4), Laser cut the zinc rod into high-purity zinc round slices with a diameter of 6 mm and a thickness of 2 mm; 5), Put the high-purity zinc round slices into a cold pressing mold, and press them into high-purity zinc thin slices with a monomer thickness of 0.1 - 0.3 mm and a size of 10×15 cm at room temperature; 6), After sequentially cleaning, drying, and sterilizing with epoxyhexane the high-purity zinc thin slices, coat a 0.5-mm-thick biological glue on one surface of the prepared thin slices, air dry and reserve, then a non-mesh and structurally complete high-purity zinc hernia patch is obtained.

4. The manufacturing method of a degradable inorganic hernia patch according to claim 3, characterized in that: Roll the patch prepared by the method described in Claim 3 into a cylindrical roll with an outer diameter of 4 mm and a height of 15 cm, and tie it up with silk thread around the periphery.

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