CN110368519B - Orthopedic adhesive based on mussel mucin - Google Patents
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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Abstract
The invention provides an orthopedic adhesive containing D-galactosamine glycosylation modified mussel mucin, Tween 80 and BMP-2, an adhesive kit with the components packaged respectively and application of the adhesive kit. The adhesive of the invention can release BMP-2 slowly under the condition of basically keeping the adhesive performance, and realize better recovery promoting effect on complete fracture.
Description
Technical Field
The invention belongs to the field of biomedical materials containing active protein and the field of regenerative medicine, and particularly provides an orthopedic adhesive containing D-galactosamine glycosylation modified mussel mucin, Tween 80 and BMP-2, an adhesive kit with the components packaged respectively and application of the adhesive.
Background
Bone morphogenetic protein-2 (BMP-2) is a key factor for promoting osteogenesis, and belongs to a TGF-alpha family member. BMP-2 is a main signal molecule for differentiating cells into mineral sedimentary osteoblasts and plays a role in inducing osteoblast differentiation. The compound is expressed in limb growth, endochondral ossification and fracture, plays an important role in bone growth, development and regeneration and repair, is considered to be a good medicament active ingredient for treating bone diseases such as fracture, bone defect and the like, and has been approved to be put on the market by various related fillers and injected medicaments by regulatory departments. The main problem in the use of BMP-2 is its short half-life, t after intravenous injection1/2Only 6-7min, so the injection route has difficulty in sustaining effective concentrations to the target site, the need for long-term (greater than 30 days) growth and recovery of damaged bone.
Mussel Adhesive Protein (MAP) is a protein complex secreted by the foot secretory gland of mussels, and the super-strong viscosity of the mussels is the key to firmly attach the mussels to reefs and to resist the impact of sea waves. Mussel mucin has the advantages of wide adhesion range, high strength, good water resistance, good biocompatibility and degradability, etc., and is considered to be a good biological adhesive. The only bioadhesive currently marketed (non-cosmetic or wound dressing) for mussel mucin is CELL-TAK from BD Bioscience, which is used for tissue adhesion, whereas genetically engineered products are significantly less adhesive than natural extract products due to lack of processing of the mussel foot glands.
The main reason for the widespread use of mussel mucin adhesives is their high price (CELL-TAK 1mg requires nearly ten thousand mussels to be extracted, the price is initially over $ 200, and currently still requires $ 80). The idea for solving the problem is to improve the extraction process and the genetic engineering production method, start from improving the effect of the mussel mucin adhesive, and prepare products with the effect obviously superior to that of the existing adhesive (such as fibrin glue), so that the market can accept higher price of the products. The BMP-2 is loaded on the mussel mucin adhesive, and the strong adhesive property and the BMP-2 bone growth promoting function of the mussel mucin adhesive are utilized to treat diseases such as fracture, especially the condition of difficult fixation such as comminuted fracture, and the like, and the mussel mucin adhesive is a promising medicament.
Disclosure of Invention
Applicants have discovered that after a certain degree of glycosylation modification of mussel mucin, there is more microstructure formation or retention of successive positions to BMP due to changes in cross-linking properties resulting from reduced thiol content, and that long-term sustained release of BMP-2 is possible with surfactants (which also aid in microstructure formation) while substantially maintaining mussel mucin binding capacity. The adhesive is obviously superior to the prior similar adhesive products in the effects of adhesive strength and bone recovery when used for fixing broken bones and treating fractures.
In one aspect, the invention provides an adhesive kit comprising separately packaged modified mussel mucin, Tween surfactant, BMP and a 5% acetic acid solution.
Further, Tween is Tween 80, and BMP is BMP-2.
Further, the adhesive contains the modified mussel mucin, Tween 80 and BMP-2 in a mass ratio of 1-3:5-10:0.5-1, and the amount of 5% acetic acid solution is more than that required for preparing the mussel mucin into 1mg/mL solution.
Further, the adhesive contains modified mussel mucin, Tween 80 and BMP-2 in a mass ratio of 1:6:0.5, and the amount of 5% acetic acid solution is more than that required for preparing the mussel mucin into 1.5mg/mL solution.
Further, the modified mussel mucin is glycosylation modified.
Further, the modified mussel mucin is a D-galactosamine glycosylation modification.
Further, the preparation process of the modified mussel mucin comprises the following steps: preparing mussel mucin into 0.5% suspension, adding D-galactosamine 5 times the weight of mussel mucin and glutamine transaminase of 20U/g mussel mucin into the suspension, adjusting pH to 7.0, reacting at 40 deg.C for 4h, inactivating enzyme at 80 deg.C for 5min, dialyzing for 24h to remove excessive D-galactosamine, and lyophilizing to obtain modified mussel mucin.
In another aspect, the present application provides an orthopedic adhesive that is an adhesive product formulated using the above adhesive kit, wherein the concentration of mussel mucin, Tween 80, BMP-2 in a 5% acetic acid solution is 1.5mg/mL, 9mg/mL, 0.75 mg/mL.
In another aspect, the application provides the use of the above-described adhesive kit or adhesive for the preparation of a medicament for the treatment of bone fractures.
Further, the fracture is a complete fracture, preferably a spiral, comminuted or compression fracture.
The mussel mucin in the application can be mussel mucin products extracted from mussel feet, such as CELL-TAK of BD Bioscience which is a commercial mussel mucin finished product, or mussel mucin of various mussels extracted by a method recorded in the prior art or a method improved on the basis of the prior art; various Mefp proteins prepared by genetic engineering methods can also be selected under the condition of permission of characteristics such as viscosity and the like, including but not limited to Mefp-1 to Mefp-6.
The mussels include, but are not limited to, common mussels, thick-shell mussels, perna viridis, and the like.
BMP-2 in this application can be BMP-2 protein, protein mutant, protein active fragment from various sources and having bone morphogenetic activity; the gene can be extracted from natural products or obtained by expressing from various host strains by a genetic engineering method (the gene sequence can be obtained from Genbank, EMBL and other ways); BMP-2 can be obtained by self-extraction/expression from a subject, or can be a commercially available product.
In addition to fractures of various severity and forms, the adhesives of the present application may be used in a variety of other bone injuries, therapeutic orthopedic bone repair, cosmetic orthopedic repair, spinal fusion, joint fusion, and the like, where adhesion and promotion of bone growth is desired.
Drawings
FIG. 1 is a cut-away view of an adhesive-treated fracture model;
FIG. 2 is a section view of a fracture model treated with control adhesive 1;
FIG. 3 is a section view of a fracture model treated with control adhesive 2;
FIG. 4 is a slice view of a blank fracture model.
Examples
Primary reagents and instruments
CELL-TAK Natural Mytilus galloprovincialis mucin extract product: BD Bioscience, designated Mytilus edulis products, containing Mefp-2, Mefp-3;
BMP-2 is produced by enterprises by self, the specific production process refers to the production method (expression in escherichia coli, purification by ion exchange chromatography and detection of escherichia coli host residual protein < 0.005%) in the applicant's CN201910030649.0 Chinese patent application, and the antibiotic residue <0.1ppm is detected by a bacteriostatic loop method;
d-galactosamine, transglutaminase/TGase, Tween 80 from SIGMA/MERCK;
fibrin Glue (FG) is produced by guangzhou pexiu biotechnology limited;
the detection kit for the residual protein of the escherichia coli host is produced by Shanghai Chengxao biological science and technology limited;
the CCK-8 cell proliferation toxicity detection kit is produced by Dalian Meilun biological technology limited company;
the human BMP-2ELISA detection kit is produced by Tianjin Anorikang biotechnology, Inc.;
the MC-949B-KD mechanical testing machine is produced by Guangzhou Minghu technology Limited;
partial chemical modification operation is entrusted to Shanghai pioneer chemical research management company;
part of animal experiments are carried out by the scientific research experiment center/experimental animal center of Beijing university of traditional Chinese medicine;
the rest reagents (mostly analytically pure) and instruments are all made by the conventional brand and model in China.
Example 1 adhesive kit and preparation of adhesive preparation of modified mussel mucin
Preparing CELL-TAK natural mussel mucin mussel into 0.5% suspension by using double distilled water, adding D-galactosamine with the mass 5 times that of the mussel mucin and glutamine transaminase of 20U/g mussel mucin into the suspension, adding NaOH 1M to adjust the pH value to 7.0 for direct reaction (the pH value of the suspension is close to 7 in certain batches), and reacting for 4 hours in a water bath at 40 ℃; inactivating glutamine transaminase for 5min in water bath at 80 deg.C; dialyzing the double distilled water for 24h by using a 1000Da membrane to remove the redundant D-galactosamine (changing the solution for 3 times); and (5) freeze-drying to obtain the modified mussel mucin.
Preparation of the adhesive
The modified mussel mucin is separately stored at 4 ℃ before use, and when in use, the modified mussel mucin is mixed with Tween 80 and BMP-2 which are stored at 4 ℃ in a 5% acetic acid solution pre-cooled to 4 ℃ to prepare an adhesive, wherein the concentrations of the mussel mucin, Tween 80 and BMP-2 are 1.5mg/mL, 9mg/mL and 0.75mg/mL respectively, and the modified mussel mucin is used within 5min after preparation.
In addition to the above adhesives, a control adhesive 1 was prepared directly from unmodified CELL-TAK natural mussel mucin, Tween 80, BMP-2;
the control adhesive 2 was prepared with fibrin glue kit from Guangzhou Beixiu Biotechnology Ltd.
CCK-8 cell proliferation toxicity experiments carried out according to kit specifications (CCK-8 cell proliferation toxicity detection kit, Dalian Meiren biological technology Co., Ltd.) show that the cytotoxicity of the adhesive is CTS 0-I grade, and the safety of the adhesive is preliminarily verified.
Example 2 adhesive and control adhesive adhesion Performance testing
12 male New Zealand big ear rabbits (2.5 kg) were selected, and the left forelimb intact ulna was taken immediately after sacrifice, the middle section was cut vertically with an electric saw, and then the fracture was bonded using 60. mu.L of the adhesive prepared in example 1, control adhesive 1 and control adhesive 2 products, and left to stand for 30min under pressure for 10min for testing.
The mechanical properties (three-point bending resistance test, acceleration of 1mm/min and fulcrum distance of 2cm) are tested by a mechanical tester, and the average value of the three samples is taken. The results are shown in Table 1.
TABLE 1 flexural Strength of Adhesives bonded to bone specimens
It can be seen from the above table that the adhesive property of the mussel mucin is significantly superior to that of the existing fibrin glue, and the adhesive property of the mussel mucin after glycosylation modification is still reduced to a small extent and is still significantly superior to that of the existing fibrin glue.
EXAMPLE 3 in vitro BMP2 Release assay
0.5mL of each of the adhesive prepared in example 1 and the control adhesive 1 was taken, manually pressed into a sheet having a diameter of about 1cm, and after setting for 1 hour, it was placed in a dialysis bag, which was placed in 15mL of PBS buffer solution containing 0.2% sodium azide and having a pH of 7.0; the sample was left at 37 ℃ for 12 hours, 24 hours, 120 hours, 240 hours, 480 hours, 720 hours, and 960 hours, and 1ml of the sample was sampled (1 ml of PBS buffer solution of pH7.0 containing 0.2% sodium azide was added thereto), and the BMP-2 concentration was measured by ELISA according to the instructions of the kit (human BMP-2ELISA detection kit, manufactured by Tianjin Anorikang Biotechnology Ltd.), and the cumulative release percentage was calculated by conversion. The results are shown in table 2:
it can be seen that tween 80 is added to promote the formation of microstructures such as a mussel mucin spherical sheet layer and the like to play a certain slow release role on BMP-2 white, the glycosylation modification of the glycomussel mucin further enhances the slow release role (the mechanism may lie in the change of cross-linking performance caused by the reduction of the content of sulfydryl after glycosylation, more microstructures are formed or positions which are connected with BMP are reserved), and the BMP-2 release capacity which is prolonged to more than 30 days can more effectively support the repair of fractured bone (the main repair period after human fracture is generally considered to be more than 60 days).
EXAMPLE 4 preparation of Rabbit fracture model test Rabbit fracture model of Adhesives and control Adhesives
12 male New Zealand big-ear white rabbits (2.5 kg) were selected and divided into 4 groups (adhesive 1, control adhesive 2, blank) on average. The left forelimb was dehaired and sterilized after anesthesia using 10mg/kg ketamine hydrochloride ear-edge intravenous injection.
A2 cm incision is made on the middle section of the left forelimb ulna side, and after other tissues are separated, the ulna is vertically sawed off by an electric saw to cause fracture type damage.
Treatment of rabbit fracture models
After the fracture and wound were washed with physiological saline, 40. mu.L of the adhesive prepared in example 1, control adhesive 1 and control adhesive 2 products were applied between the fractured ends of the fracture, or the wound was sutured with medical tape after pressurizing the fractured ends for 180 seconds without any treatment.
Three days of antibiotic (100 million units of penicillin) treatment was given after surgery.
Observation of therapeutic effects
Killing the strain after normal feeding for 90 days, and taking a sample within 1cm of two ends of a cut part; fixing with 10% formalin for 24h, embedding in paraffin, and observing by staining HE section, wherein the results are shown in FIGS. 1-4; the other two ulna bones from one side of the model were tested for bending strength according to the method of example 2. The results are shown in Table 3:
TABLE 3 flexural Strength of adhesive-treated rabbit fracture models
| Adhesive agent | Average flexural Strength (MPa) |
| Adhesive agent | 98.77 |
| Control adhesive 1 | 74.42 |
| Control adhesive 2 | 69.38 |
| Blank space | 47.26 |
The three adhesives were all degraded well after 90 days, with no significant residue visible in the slice. The bone fracture repairing effect of the BMP-30 day slow release adhesive is obviously better than that of a contrast adhesive 1 and a contrast adhesive 2 with poor slow release effect (the contrast adhesive 1 and the contrast adhesive 2 have close effects, and the BMP with short slow release time basically has no auxiliary repairing effect or is related to sample individual difference), which shows that callus is basically disappeared and cells are arranged closely and tidily. The bending strength corresponds substantially to the healing effect exhibited by the section.
The experiments prove that the adhesive has excellent adhesive performance and bone recovery promoting capacity, and has obviously better effect than the conventional adhesive when used for treating fracture, particularly spiral, comminuted or compression fracture.
The primary reason for using the more expensive finished CELL-TAK mussel mucin product in the examples is the lack of other high quality natural extracted mussel mucins on the market. Although the applicant can obtain similar effect by using self-extracted mussel mucin, the applicant cannot provide a source of mussel mucin with stable effect due to the kind and season of mussels, and the research is inconvenient. Thus, in experiments the applicant has been using finished CELL-TAK mussel mucin products, which may be marketed in view of further stabilising and optimising the mucin extraction and modification process, using self-extracted mussel mucin.
Claims (8)
1. An adhesive kit comprising separately packaged modified mussel mucin, Tween surfactant, BMP and a 5% acetic acid solution; wherein the modified mussel mucin is glycosylation modified.
2. The adhesive kit according to claim 1, wherein the Tween is Tween 80 and the BMP is BMP-2.
3. The adhesive kit of claim 2, wherein the adhesive comprises modified mussel mucin, Tween 80, BMP-2 in a mass ratio of 1-3:5-10:0.5-1, and the 5% acetic acid solution is in excess of that required to formulate the mussel mucin as a 1mg/mL solution.
4. The adhesive kit of claim 3, wherein the adhesive comprises modified mussel mucin, Tween 80, BMP-2 in a mass ratio of 1:6:0.5, and the 5% acetic acid solution is in excess of that required to formulate the mussel mucin as a 1.5mg/mL solution.
5. The adhesive kit of claim 1, wherein the modified mussel mucin is a D-galactosamine glycosylation modification.
6. An adhesive kit according to claim 5, wherein the modified mussel mucin is prepared by: preparing mussel mucin into 0.5% suspension, adding D-galactosamine 5 times the weight of mussel mucin and glutamine transaminase of 20U/g mussel mucin into the suspension, adjusting pH to 7.0, reacting at 40 deg.C for 4h, inactivating enzyme at 80 deg.C for 5min, dialyzing for 24h to remove excessive D-galactosamine, and lyophilizing to obtain modified mussel mucin.
7. An orthopedic adhesive that is an adhesive product formulated using the adhesive kit according to claims 1-6, wherein the mussel mucin, Tween 80, BMP-2 are formulated at a concentration of 1.5mg/mL, 9mg/mL, 0.75mg/mL in a 5% acetic acid solution.
8. Use of an adhesive kit according to any one of claims 1-6 or an adhesive according to claim 7 for the preparation of a medicament for the treatment of bone fractures.
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| CN102065882A (en) * | 2008-04-14 | 2011-05-18 | 阿道恰公司 | Osteogenic composition including a complex growth factor/amphiphilic polymer, a soluble cation salt, and an organic substrate |
| CN104645313A (en) * | 2015-01-28 | 2015-05-27 | 南京航空航天大学 | Mussel mucoprotein gel for repairing and reliving itching and preparation method of mussel mucoprotein gel |
| WO2017101026A1 (en) * | 2015-12-15 | 2017-06-22 | 江阴市本特塞缪森生命科学研究院有限公司 | Composition of mussel adhesive protein and growth factor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102065882A (en) * | 2008-04-14 | 2011-05-18 | 阿道恰公司 | Osteogenic composition including a complex growth factor/amphiphilic polymer, a soluble cation salt, and an organic substrate |
| CN104645313A (en) * | 2015-01-28 | 2015-05-27 | 南京航空航天大学 | Mussel mucoprotein gel for repairing and reliving itching and preparation method of mussel mucoprotein gel |
| WO2017101026A1 (en) * | 2015-12-15 | 2017-06-22 | 江阴市本特塞缪森生命科学研究院有限公司 | Composition of mussel adhesive protein and growth factor |
Non-Patent Citations (2)
| Title |
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| 《Marine-Inspired Polymers in Medical Adhesion》;Diederik W. R. Balkenende等;《Eur Polym J》;20190404;第1-27页 * |
| 《海洋生物黏附蛋白研究进展》;廖智，申望，王日昕;《浙江海洋学院学报(自然科学版)》;20071231;第26卷(第4期);第439-447页 * |
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