CN114392396A - Rotator cuff patch based on silk fibroin gel and preparation method thereof - Google Patents
Rotator cuff patch based on silk fibroin gel and preparation method thereof Download PDFInfo
- Publication number
- CN114392396A CN114392396A CN202210062325.7A CN202210062325A CN114392396A CN 114392396 A CN114392396 A CN 114392396A CN 202210062325 A CN202210062325 A CN 202210062325A CN 114392396 A CN114392396 A CN 114392396A
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- CN
- China
- Prior art keywords
- rotator cuff
- silk protein
- solution
- patch
- fibroin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
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- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
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- A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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Abstract
A rotator cuff patch based on fibroin gel comprises a rotator cuff patch body, a fibroin electrostatic spinning film as a patch base layer, and Mg2+The ionic silk protein gel is loaded with anti-inflammatory agent layer and contains Zn2+The ionic silk protein gel is loaded with a healing promoting drug layer, has full degradation characteristic, realizes early inhibition of inflammatory reaction, promotes osteogenesis in a repair period, achieves the effect of promoting graft integration, and has higher biological safety.
Description
Technical Field
The invention belongs to the field of tissue repair, and particularly relates to a rotator cuff patch based on a silk fibroin gel coating, which is used for repairing rotator cuffs, inhibiting the generation and development of inflammation, facilitating further playing a role in promoting healing, and has higher safety, and a method for preparing the patch.
Background
Rotator cuff tears can cause joint pain, reduced function, stiffness and range of motion limitations, and place a significant economic burden on society. Huge rotator cuff tear means that the tear is larger than 5cm or the rotator cuff injury of more than or equal to 2 tendons is affected, and the current treatment is mainly surgical repair. The function of the shoulder joint of some patients after operation is greatly improved, but the re-tearing rate is higher and can reach 15 to 94 percent. The cause of the reoccurrence is related to factors such as tear size, blood supply, fat infiltration, age, smoking, and muscle atrophy. Research shows that the tearing size and the re-tearing are relatively large, because the tension is an important reason for the failure of the rotator cuff repair operation, the operation mode of huge rotator cuff tearing is still a big problem, and a better method needs to be designed to avoid the re-tearing. The rotator cuff patch is used for replacing a defective tendon, and the tensionless or micro-tension repair is considered to be capable of promoting healing and reducing the occurrence of re-tearing.
Currently clinically used rotator cuff patches include autologous fascia lata or quadriceps femoris patches, allogeneic or xenogeneic acellular dermal patches and synthetic material patches (PET, PTFE, PGA, etc.). Autografts are widely used, but have the problem of donor area lesions. Allografts are widely available without sacrificing autologous tissue, but are at risk for foreign body reactions, long healing times, and host-borne disease. The artificial implant has advantages in terms of biomechanics, but has problems such as foreign body reaction or local inflammation. Therefore, improving the performance of the artificial graft, reducing foreign body reaction or inflammatory reaction and promoting the integration of the artificial graft are key scientific problems in the development of artificial patches.
Disclosure of Invention
The invention aims to provide a rotator cuff patch based on silk protein gel, which is a fully degradable patch, promotes the anti-inflammation of damaged tissues and is beneficial to promoting the healing and repairing of the tissues.
The invention also aims to provide a method for preparing the rotator cuff patch based on silk fibroin gel, which slowly releases medicines, healing promoting molecules and the like along with the degradation of silk fibroin, realizes the early inhibition of inflammatory reaction, promotes osteogenesis in a repair period, and achieves the effect of promoting graft integration.
The technical scheme of the invention is as follows:
a rotator cuff patch comprising a rotator cuff patch body, the rotator cuff patch body comprising:
a patch basal layer, which is an electrostatic spinning film made of fibroin;
the anti-inflammatory drug-loaded layer is prepared from fibroin gel and contains Mg2+Ions;
a healing-promoting drug-loaded layer made of fibroin gel and containing Zn2+Ions;
the anti-inflammatory drug-loaded layer is disposed on the healing promoting drug-loaded layer, and the healing promoting drug-loaded layer is coated on the patch substrate layer.
Preferably, the rotator cuff patch further comprises a sewing area arranged around the rotator cuff patch body, and a plurality of sewing holes are formed in the sewing area to be sewn with the part to be repaired.
The preparation method of the rotator cuff patch comprises the following steps:
mixing 15 wt% regenerated silk protein solution and 80 wt% PEG solution at equal volume, adding divalent zinc ion (such as zinc sulfate), stirring to obtain zinc ion-containing PEG-silk protein solution, and pouring the solution into flat bottom template with thickness of 0.5 mm. Soaking the preprocessed silk fibroin electrostatic spinning membrane in a PEG-silk fibroin solution for standing, and incubating at room temperature to naturally gelatinize the surface of the electrostatic spinning membrane to obtain a semi-finished product of the artificial rotator cuff patch;
repeatedly preparing a mixture solution of 15 wt% regenerated silk protein and 80 wt% PEG, adding divalent magnesium ion (such as magnesium sulfate), stirring to obtain a magnesium ion-containing PEG-silk protein solution, and pouring the solution into a flat bottom glass template with a thickness of 1.0 mm. And soaking the semi-finished product of the artificial rotator cuff patch in the solution, and incubating at room temperature to naturally gelatinize the surface of the semi-finished product of the artificial rotator cuff patch to obtain a finished product of the artificial rotator cuff patch.
Preferably, in the preparation method of the artificial rotator cuff patch based on silk fibroin gel, the pretreatment of the silk fibroin electrostatic spinning film comprises the following steps:
soaking the fibroin electrostatic spinning membrane (or cutting the fibroin electrostatic spinning membrane into a preset length) in 75 wt% ethanol solution, carrying out ultrasonic treatment for 30 minutes, and washing the surface of the fibroin electrostatic spinning membrane with deionized water after the ultrasonic treatment is finished so as to remove impurities on the surface of the fibroin electrostatic spinning membrane;
and drying the cleaned fibroin electrostatic spinning membrane in a vacuum drying oven at room temperature to constant weight.
Preferably, in the preparation method of the artificial rotator cuff patch based on silk fibroin gel, the regenerated silk fibroin solution is prepared by the following steps:
placing the silkworm cocoons in boiling water with the concentration of sodium bicarbonate being 0.5 wt% for boiling for 30 minutes, washing with water for three times, boiling for 30 minutes again under the same condition, taking out, washing with warm water for three times, washing with deionized water for 4 times, and drying in an oven at 40 ℃ for 24 hours to obtain the degumming silk;
putting the degummed silk into a lithium bromide aqueous solution with the concentration of 9.3mol/L, heating for 1 hour under the condition of water bath at 60 ℃, filtering the dissolved regenerated silk protein solution by using eight layers of gauze to remove insoluble impurities, pouring the filtered solution into a dialysis bag, and dialyzing for three days in deionized water;
and centrifuging the dialyzed solution at 8000 rpm for 10 minutes at 4-10 ℃, filtering with eight layers of gauze, and removing insoluble impurities to obtain the regenerated silk protein solution.
Preferably, in the preparation method of the artificial rotator cuff patch based on silk protein gel, the concentration of divalent zinc ions in the zinc ion-containing PEG-silk protein solution is 2 mg/ml.
Preferably, in the preparation method of the artificial rotator cuff patch based on silk protein gel, the concentration of divalent magnesium and zinc in the magnesium-ion-containing PEG-silk protein solution is 1 mg/ml.
The invention has the following beneficial effects:
the outermost layer contains Mg2+The release period of the ionic silk protein gel anti-inflammatory drug layer is about 3-5 days, and the inner layer contains Zn2+The ionic silk protein gel promotes healing of the drug layer, and the slow release period is about 1-2 weeks;
magnesium ion anti-inflammatory effects are associated with the inhibition of Nitric Oxide (NO) production by activated macrophages. Endogenously produced nitric oxide can induce joint inflammation. Magnesium ions can alleviate arthritic symptoms by interfering with the activation of T lymphocytes and macrophages. The NMDA receptor is a specific ion channel protein and the NMDA receptor subunit NR1 is considered an essential component of all functional receptors. Magnesium ions can inhibit the phosphorylation of NR1, thereby preventing the development of joint inflammation and alleviating pain. In short, magnesium ions may prevent the development of joint inflammation by inhibiting the production of NO in the body and inhibiting NMDA receptors, among other pathways. In addition, magnesium ions are believed to induce macrophage polarization to M2, inhibiting inflammatory responses. The magnesium ions also have good osteogenesis promoting effect, and play a dual regulation and control role in bone tissue regeneration. During the early inflammatory phase, magnesium ions build up an immune microenvironment that promotes bone tissue regeneration by promoting the recruitment and polarization of monocyte-macrophages [2 ]. Currently, magnesium-based biomaterials include a large number of magnesium-containing compounds, such as oxides, phosphates and silicates, which are involved in orthopedic applications such as bone cement, bone scaffolds or implant coatings, and research on magnesium phosphate (MgP) materials as substitutes for calcium phosphate for the treatment of bone defects has also received wide attention.
Zinc (Zn) is an essential trace element of the human body, and is usually present in bone tissues, and about 30% of zinc in the body is present in bone tissues. Zinc plays an important role in the formation, development, mineralization and maintenance of healthy bones. In addition, as a medium for skeletal development and growth, zinc deficiency in a human body can cause dwarfism, osteoporosis, skeletal developmental retardation and the like. Previous in vitro studies have shown Zn2+Can improve the osteogenesis of stem cells and enhance mineral deposition. Zinc produces a matrix of collagen filaments as a matrix for biomineralization deposition. Zinc has also been found to exchange calcium at sites of bone regeneration, increasing ALP (alkaline phosphatase) activity, which is associated with bone calcification, supporting osteogenic regeneration. Osterix is a zinc-based finger-containing transcription factor, and is reported to proliferate and promote osteogenic differentiation of mesenchymal stem cells, thereby increasing expression of markers associated with osteogenic activity. Divalent zinc ions also inhibit the metabolism and growth of bacteria by interacting with sulfhydryl groups on bacterial enzymes. In addition, zinc in the sugar phosphotransferase system and the ATPase, respectively, inhibits sugar transport and acid tolerance, thereby reducing ATP synthesis in glycolytic cells, resulting in bacterial growth inhibition. Zinc is widely used as an antibacterial agent and a bone-proliferating agent, and plays an important role in the antibacterial of dental implants and the treatment of bone defects and osteoporosis.
In the process of tissue repair, the patch of the invention not only has certain anti-inflammatory effect, but also has full degradation characteristic, and has no foreign body residue in vivo. The combination of gelatin can alleviate foreign body reaction caused by the implantation of the patch. Compared with the similar patch (such as a combination of cellulose film and gelatin material), the patch of the invention is more outstanding in promoting osteogenesis.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Drawings
FIG. 1 is a schematic structural view of one embodiment of an artificial rotator cuff patch provided by the present invention;
FIG. 2 is a graph of immunohistochemical IL-1 β expression results;
fig. 3 is a staining map of the area of the experimental group b of the tendinous bones.
Detailed Description
The present invention is further described in detail below with reference to the attached drawings so that those skilled in the art can implement the invention by referring to the description text.
It will be understood that terms such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other elements or groups thereof.
In the rotator cuff patch provided in this example, a fibroin film was formed by electrospinning and used as the base layer of the patch.
The rotator cuff patch was 1mm thick and had three dimensions: 4 × 6 × 1, 4 × 4 × 1, 3 × 4 × 1, and a sewing region and a sewing hole are formed around the periphery. A belt is arranged on the device, so that the tissue can be plugged in the operation without sewing, and the sticking is mainly performed.
In one embodiment, the rotator cuff patch further comprises a sewing area arranged on the periphery of the rotator cuff patch body, and a plurality of sewing holes are formed in the sewing area to be sewn with a part to be repaired.
In one embodiment, the rotator cuff patch body is further covered with silk fibroin gel for loading molecules (Mg) for inhibiting inflammation2+Ions) and healing-promoting molecules (Zn)2+Ions).
Example 1 preparation of a Patch
The regenerated silk protein solution is prepared by the following steps:
placing the silkworm cocoons in boiling water with the concentration of sodium bicarbonate being 0.5 wt% for boiling for 30 minutes, washing with water for three times, boiling for 30 minutes again under the same condition, taking out, washing with warm water for three times, washing with deionized water for 4 times, and drying in an oven at 40 ℃ for 24 hours to obtain the degumming silk;
putting the degummed silk into a lithium bromide aqueous solution with the concentration of 9.3mol/L, heating for 1 hour under the condition of water bath at 60 ℃, filtering the dissolved regenerated silk protein solution by using eight layers of gauze to remove insoluble impurities, pouring the filtered solution into a dialysis bag, and dialyzing for three days in deionized water;
and centrifuging the dialyzed solution at 8000 rpm for 10 minutes at 4-10 ℃, filtering with eight layers of gauze, and removing insoluble impurities to obtain the regenerated silk protein solution.
After the fibroin is prepared into an electrostatic spinning membrane, the following pretreatment is carried out:
shearing the fibroin electrostatic spinning membrane into a preset length, soaking the membrane in 75 wt% ethanol solution, carrying out ultrasonic treatment for 30 minutes, and washing the surface of the fibroin electrostatic spinning membrane with deionized water after the ultrasonic treatment is finished so as to remove impurities on the surface of the fibroin electrostatic spinning membrane. And drying the cleaned fibroin electrostatic spinning membrane in a vacuum drying oven at room temperature to constant weight.
Mixing the regenerated silk protein solution with the mass fraction of 15% and the PEG solution with the concentration of 80% in equal volume. Adding medicine zinc sulfate, and magnetically stirring to obtain mixed solution of zinc sulfate/regenerated silk protein and PEG, wherein the concentration of zinc sulfate is 5mg/ml (divalent zinc concentration is 2 mg/ml). The solution was poured into a flat bottom glass template with a thickness of 0.5 mm. Soaking the preprocessed fibroin electrostatic spinning membrane in the solution for standing, incubating for a period of time at room temperature, and naturally gelatinizing the mixed solution on the surface of the electrostatic spinning membrane to obtain a semi-finished product of the artificial rotator cuff patch;
repeatedly preparing a mixture solution of 15% regenerated silk protein and 80% PEG, adding drug magnesium sulfate, and magnetically stirring uniformly to obtain a magnesium sulfate/regenerated silk protein and PEG mixed solution, wherein the concentration of the magnesium sulfate is 5mg/ml (the concentration of divalent zinc is 1 mg/ml). The solution was poured into a flat bottom glass template with a thickness of 1.0 mm. And soaking the semi-finished product of the artificial rotator cuff patch in the solution, incubating for a period of time at room temperature, and naturally gelling on the surface of the semi-finished product of the artificial rotator cuff patch to obtain a finished product of the artificial rotator cuff patch.
Fig. 1 is a schematic diagram of an embodiment of a patch prepared according to the present invention, which includes a fibroin electrospun membrane as a patch base layer 1, and a first fibroin-loaded anti-inflammatory drug layer 4, a second fibroin-loaded biological factor layer 2, a third fibroin-loaded biological factor layer 3, and a fourth fibroin-loaded anti-inflammatory drug layer 5.
Example 2 Performance testing
Animal experiment grouping: a. silk protein spinning cloth group; b. fibroin spun silk fibroin gel group.
And (3) weaving of the patch: the two ends of the patch are woven by sewing threads, so that the patch is used for sewing the residual end of the rotator cuff and the head end of the humerus. The size of the patch after weaving is 10mm long, 4mm wide and 1mm thick, and is suitable for rabbit infraspinatus tendon suture model. And performing biomechanical test on the sewn patch to meet the maximum requirement of lacerated musculus spinatus of the rabbit of about 130N.
The preparation method comprises the following steps of preparing 2.5-3.5kg of New Zealand white rabbits, preparing skin of shoulder joints after anesthesia, making parallel incisions of about 4cm above infraspinatus tendon, carrying out blunt separation layer by layer, and exposing the infraspinatus tendon. The infraspinatus muscle was resected against the humeral stop and the stump and the bone surface were reshaped.
Making 2 1mm bone passages at the stopping point of the humerus head, threading the residual end of the infraspinatus, sewing the suture thread back to the original stopping point through the bone passages, sewing one end of the patch with the tendon, and fixing the other end of the patch near the stopping point through the bone passages to perform reinforced repair. Suturing layer by layer, sterilizing incision, and injecting penicillin.
And thirdly, cage culture after operation without restricting movement. Local anti-inflammatory monitoring (immunohistochemistry), histological observation (HE, Masson), infraspinatus fat infiltration, biomechanical testing were performed at 1, 6, 12 weeks after surgery.
Immunohistochemical IL-1. beta. expression results in groups a and b after one week are shown in FIG. 2, and immunohistochemical inflammatory responses in group b are low. As shown in fig. 3, cartilage regeneration occurred in the 12 week group b area and the regenerated tissue was more orderly arranged. Biomechanics: maximum tensile force at 12 weeks: the silk protein spinning silk protein gel group is 142.11 +/-9.73N, and the silk protein spinning silk protein gel group is 95.02 +/-8.23N.
While embodiments of the invention have been disclosed above, it is not limited to the applications listed in the description and the embodiments, which are fully applicable in all kinds of fields of application of the invention, and further modifications may readily be effected by those skilled in the art, so that the invention is not limited to the specific details without departing from the general concept defined by the claims and the scope of equivalents.
Claims (7)
1. A rotator cuff patch based on silk fibroin gel, comprising a rotator cuff patch body, characterized by comprising:
a patch basal layer is formed by electrostatic spinning of fibroin;
the anti-inflammatory drug-loaded layer is prepared from fibroin gel and contains Mg2+Ions;
a healing-promoting drug-loaded layer made of fibroin gel and containing Zn2+Ions;
the anti-inflammatory drug-loaded layer is disposed on the healing promoting drug-loaded layer, and the healing promoting drug-loaded layer is coated on the patch substrate layer.
2. The silk protein gel-based rotator cuff patch according to claim 1, further comprising a suture region disposed around the rotator cuff patch body and having a plurality of suture holes for suturing with a portion to be repaired.
3. The method for preparing a rotator cuff patch based on silk protein gel according to claim 1, comprising the steps of:
mixing 15 wt% of regenerated silk protein solution and 80 wt% of PEG solution in equal volume, adding divalent zinc ions, uniformly stirring to obtain PEG-silk protein solution containing zinc ions, pouring the solution into a flat-bottom template, keeping the thickness of 0.5mm, soaking the pretreated silk protein electrostatic spinning membrane in the PEG-silk protein solution, standing, and incubating at room temperature to naturally form gel on the surface of the electrostatic spinning membrane to obtain a semi-finished product of the artificial rotator cuff patch;
repeatedly preparing a mixture solution of 15 wt% of regenerated silk protein and 80 wt% of PEG, adding divalent magnesium ions, uniformly stirring to prepare a magnesium-containing PEG-silk protein solution, pouring the solution into a flat bottom glass template, wherein the thickness of the solution is 1.0mm, soaking the semi-finished product of the artificial rotator cuff patch in the solution, and incubating at room temperature to naturally gelatinize the surface of the semi-finished product of the artificial rotator cuff patch to obtain a finished product of the artificial rotator cuff patch.
4. The method for preparing a rotator cuff patch based on fibroin gel according to claim 3, wherein the method for pretreating a fibroin electrospun membrane comprises:
soaking the fibroin electrostatic spinning membrane in 75 wt% ethanol solution, carrying out ultrasonic treatment, and washing the surface of the fibroin electrostatic spinning membrane with deionized water.
5. The method for preparing a rotator cuff patch based on silk protein gel according to claim 3, wherein the concentration of divalent zinc ions in the zinc ion-containing PEG-silk protein solution is 2 mg/ml.
6. The method for preparing a rotator cuff patch based on silk protein gel as claimed in claim 3, wherein the concentration of divalent magnesium zinc in the magnesium ion-containing PEG-silk protein solution is 1 mg/ml.
7. The method for preparing a rotator cuff patch based on silk protein gel according to claim 3, wherein the regenerated silk protein solution is prepared by the following steps:
putting the degummed silk into a lithium bromide aqueous solution, heating for 1 hour under the water bath condition of 60 ℃, filtering the dissolved regenerated silk protein solution by using eight layers of gauze to remove insoluble impurities, pouring the filtered solution into a dialysis bag, and dialyzing for three days in deionized water; and (3) centrifuging the dialyzed solution at the rotating speed of 8000 rpm for 10 minutes at the temperature of 4-10 ℃, filtering by eight layers of gauze, and removing insoluble impurities again to obtain the regenerated silk protein solution.
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| CN114533231A (en) * | 2022-04-27 | 2022-05-27 | 杭州锐健马斯汀医疗器材有限公司 | Balloon body and preparation method and application thereof |
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