CN101947147A - Method for chemically treating biological tissue materials - Google Patents
Method for chemically treating biological tissue materials Download PDFInfo
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- CN101947147A CN101947147A CN 201010217261 CN201010217261A CN101947147A CN 101947147 A CN101947147 A CN 101947147A CN 201010217261 CN201010217261 CN 201010217261 CN 201010217261 A CN201010217261 A CN 201010217261A CN 101947147 A CN101947147 A CN 101947147A
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Abstract
The invention relates to a method for chemically treating biological tissue materials. The method comprises the following steps of: treating the biological tissue materials by using aldehyde solution to make aldehyde groups and amino groups in the materials crosslinked; treating the materials by using EDC/NHS and solution of diamine to activate carboxyl groups in the materials, and performing the crosslinking between the carboxyl groups activated later and the amino groups. The method is easy to implement, further improves moisture-heat stability of the tissue, increases the modulus of the tissue, improves mechanical property of the tissue and prevents calcification of the tissue.
Description
Technical field
The present invention relates to the chemical treatment method of biological organization material, the lobe leaf that is specifically related to bioprosthesis valve is handled.
Background technology
At present, the artificial valve can be divided into two kinds of bioprosthetic valve and mechanical prosthetic valves.Compare with mechanical prosthetic valve, bioprosthetic valve has its superiority of generally acknowledging: (1) comparison operators closes physiological central flow channel, and effectively the valve bore is bigger, and pressure gradient is little, good hemodynamics performance; (2) thromboembolism and haemolysis complication are low, generally do not need long-term anticoagulant therapy; (3) under the similar prerequisite of two class valve replacement postoperative survival rates, the quality of life of bioprosthetic valve displacer is better.
Biovalve is generally drawn materials from animal membrane tissues such as porcine aortic valve, Cor Sus domestica bag, bovine pericardium, through crosslinking Treatment, makes then on the metal rack or polymeric stent of a fixed structure.The main constituent of these animal tissues is collagen and elastin laminin, and required elasticity of implant and mechanical property can be provided.
The chemically treated principle of biological organization material is with the collagen cross-linking in the tissue, and the essence of collagen cross-linking be functional group in the collagen cross-linking reaction has taken place.Functional group in the collagen mainly comprises amino basically from amino acid whose residue, three kinds of groups of carboxyl and hydroxyl.With the biological cardiac valves is example, and present chemically treated method is basically based on glutaraldehyde.The mechanism of crosslinking of glutaraldehyde is to generate not (Schiff) alkali of west by aldehyde radical in the aldehyde and amino reaction, if add some anti-calcification processing, crosslinked effect increases.For example, patent publication No. is the processing method that the patent of invention of CN1084768A discloses a kind of anti-calcification Cardiac valve prosthesis of epoxychloropropane processing, handles main and amino reaction of epoxychloropropane by epoxychloropropane, unnecessary amino can be got rid of, but the degree of cross linking can't be increased; Patent publication No. is that the patent of invention of CN1415383A has been announced a kind of the implantation with the method for modifying of organization material and material modified, handle valve by hydroxyl chromium, hydroxyl chromium can crosslinked carboxyl, can further improve the degree of cross linking, but this processing method has been introduced heavy metal ion, and the softness inadequately that tissue is become.
Summary of the invention
Based on above-mentioned shortcoming, the invention provides the chemically treated method of a kind of biological organization material.This method is carried out dual crosslinked to amino and carboxyl, select suitable cross-linking reagent, and that has avoided causing because of zero distance is crosslinked organizes the hardening problem, has improved the degree of cross linking of organizing and has kept the pliability organized simultaneously.
The invention provides a kind of chemical treatment method of biological organization material, this method comprises earlier with aldehydes solution-treated biological organization material, use 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC), N-maloyl imines (NHS) and diamidogen mixed solution to handle again then, make the amino of material and carboxyl all obtain crosslinked.
Described biological organization material is the organization material based on collagen protein, preferably porcine aortic valve, Cor Sus domestica bag, bovine pericardium or bovine jugular vein lobe.
Described chemical treatment method comprises: utilize single aldehyde of 0.2～1% earlier or dialdehyde carries out crosslinked to tissue or sealing, preferred single aldehyde is positive propionic aldehyde, and preferred dialdehyde is a glutaraldehyde.And then carry out after-treatment with EDC/NHS, and the carboxyl in the activated material, it is crosslinked that carboxyl and amino are carried out.Simultaneously, add a kind of diamidogen, increase the carboxyl and the amino degree of cross linking as cross-linking agent.Preferred diamidogen can be ethylenediamine, propane diamine, butanediamine, pentanediamine, hexamethylene diamine, polyetheramine, hydroxyl diamidogen.Handle if adopt glutaraldehyde to do the first step,, therefore should select the less diamidogen of molecular weight because crosslinked generation has increased post-treatment reagents and has been penetrated into the difficulty of organizing the depths, as hexamethylene diamine or 1,3-two amidos-2-propanol; If adopt positive propionic aldehyde to carry out amino sealing, then can select the bigger diamidogen of polyetheramine equimolecular.
Described EDC/NHS is meant the biological buffer solution that contains EDC and NHS.
The concentration of described EDC is 10～500mM, is preferably 20～100mM, most preferably is 30～80mM; The concentration of described NHS is 2～100mM, is preferably 4～20mM, most preferably is 6～10mM; The buffer agent of described biological buffer solution is 2-(N-morpholine) ethyl sulfonic acid (MES) or N-(2-ethoxy) piperazine-N '-2 ethane sulfonic aicd (HEPES), and concentration is 10～100mM, is preferably 20～50mM.
The chemical treatment method of biological organization material provided by the invention, carry out as follows:
(A) it is clean to remove biological organization material rinsing in normal saline of superabundant fats;
(B) biological organization material of handling well in (A) is placed 0.2～1% aldehydes solution, ℃ soaked 2 hours～2 months down room temperature～60, and preferred soak time is 24 hours～48 hours;
(C) biological organization material that (B) handled cleans up, and moves in the buffer solution of certain density EDC/NHS of containing and diamidogen, soaks 2 hours～2 months under the 4 ℃～room temperature, and preferred soak time is 24 hours～48 hours;
(D) last, the biological organization material handled well is stored with 0.2%～0.6% glutaraldehyde solution.
The invention provides a kind of chemical treatment method of biological organization material, this processing method is simple to operation, and the organization material by the preparation of this method, hydroxyl and amino have all participated in crosslinked, hydrothermal stability, mechanical property and calcification performance all increase, and have improved the endurance of tissue greatly.
The specific embodiment
Following examples further specify content of the present invention, but should not be construed as limitation of the present invention.Without departing from the spirit and substance of the case in the present invention, modification or replacement to the inventive method, step or condition are done all belong to scope of the present invention.
If do not specialize the conventional means that used technological means is well known to those skilled in the art among the embodiment.
Embodiment 1 GA and EDC/NHS/ hydroxyl two amine system Combined Processing Cor Sus domestica bags
1) solution ratio: EDC 50mM, NHS 8mM, MES 40mM, 1,3-two amidos-2-propanol 50mM, pH5.0, standby.
2) it is clean to remove Cor Sus domestica peplos rinsing in normal saline of superabundant fats.
3) soak Cor Sus domestica bag, room temperature treatment 24 hours with 0.3% glutaraldehyde (GA).
4) the Cor Sus domestica bag of GA being handled cleans up with normal saline, moves to 1) in the solution for preparing, soaking at room temperature 24 hours.
5) store with 0.2% glutaraldehyde then.
Embodiment 2 positive propionic aldehyde and EDC/NHS/ polyetheramine system Combined Processing Cor Sus domestica bag
1) solution ratio: EDC 80mM, NHS 10mM, MES 65mM, polyetheramine 10mM, pH5.0, standby.
2) it is clean to remove Cor Sus domestica peplos rinsing in normal saline of superabundant fats.
3) soak Cor Sus domestica bag, room temperature treatment 48 hours with 0.6% positive propionic aldehyde.
4) the Cor Sus domestica bag that positive propionic aldehyde was handled cleans up with normal saline, moves to 1) in the solution for preparing, soaking at room temperature 48 hours.
5) store with 0.5% glutaraldehyde then.
Embodiment 3 GA and EDC/NHS/ hexamethylene diamine system Combined Processing Cor Sus domestica bag
1) solution ratio: EDC 30mM, NHS 6mM, MES 30mM, hexamethylene diamine 30mM, pH5.0, standby.
2) it is clean to remove Cor Sus domestica peplos rinsing in normal saline of superabundant fats.
3) soak Cor Sus domestica bag, room temperature treatment 24 hours with 0.3% GA.
4) the Cor Sus domestica bag of GA being handled cleans up with normal saline, moves to 1) in the solution for preparing, soaking at room temperature 24 hours.
5) store with 0.2% glutaraldehyde then.
Embodiment 4 different disposal modes are to Cor Sus domestica bag Effect on Performance
Be treated to contrast with the prior art glutaraldehyde, the Cor Sus domestica bag of these 4 kinds of processing is carried out hot shrinkage temperature, organizes the mensuration of modulus, tensile strength.And this 4 boar pericardium is implanted rat measure calcification degree after 21 days, the result is as shown in the table.
The effect of table 1 pig pericardium channel glutaraldehyde individual processing and aldehyde/EDC/NHS/ diamidogen Combined Processing relatively
As can be seen from Table 1, through the Cor Sus domestica bag of aldehyde/EDC/NHS/ diamidogen Combined Processing, its hot shrinkage temperature, organize modulus, tensile strength and calcification degree all to be significantly improved than prior art.
Claims (11)
1. the chemical treatment method of a biological organization material, it is characterized in that, with aldehydes solution-treated biological organization material, use 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-maloyl imines and diamidogen mixed solution to handle again then earlier.
2. processing method according to claim 1 is characterized in that, described biological organization material is the organization material based on collagen protein.
3. processing method according to claim 2 is characterized in that, described biological organization material is selected from porcine aortic valve, Cor Sus domestica bag, bovine pericardium or bovine jugular vein lobe.
4. according to any described processing method of claim 1-3, it is characterized in that, the concentration of described 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride is 10～500mM, and the concentration of described N-maloyl imines is 2～100mM, and the concentration of described diamidogen is 1mM～500mM.
5. processing method according to claim 4 is characterized in that, the concentration of described 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride is 20～100mM, and described N-maloyl imines concentration is 4～20mM.
6. processing method according to claim 5 is characterized in that, the concentration of described 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride is 30～80mM, and described N-maloyl imines concentration is 6～10mM.
7. processing method according to claim 1 is characterized in that, described diamidogen is selected from alkyl diamidogen, polyetheramine or hydroxyl diamidogen.
8. processing method according to claim 7 is characterized in that, described alkyl diamidogen is selected from ethylenediamine, propane diamine, butanediamine, pentanediamine or hexamethylene diamine.
9. processing method according to claim 7 is characterized in that, described hydroxyl diamidogen is 1,3-two amidos-2-propanol.
10. processing method according to claim 1 is characterized in that, described aldehydes solution is that concentration is 0.2～1% positive propionic aldehyde or glutaraldehyde.
11. processing method according to claim 1 is characterized in that, described method is specifically carried out as follows:
(A) it is clean to remove biological organization material rinsing in normal saline of superabundant fats;
(B) biological organization material of handling well in (A) is placed aldehydes solution, room temperature～60 ℃ following the immersion 2 hours～2 months;
(C) clean up by biological organization material of handling in (B), placing pH value is 4～6 the buffer solution that contains EDC/NHS and diamidogen, and immersion is 2 hours～2 months under the 4 ℃～room temperature;
(D) store with 0.2%～0.6% glutaraldehyde solution.
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102172338A (en) * | 2011-02-28 | 2011-09-07 | 微创医疗器械(上海)有限公司 | Artificial biologic valve gradient immersed chemical modification device |
| CN102423505A (en) * | 2011-10-27 | 2012-04-25 | 微创医疗器械(上海)有限公司 | Method and apparatus for fixing bioprosthetic valve by membrane type pervaporation mode |
| CN104894856A (en) * | 2015-05-19 | 2015-09-09 | 东华大学 | Processing method for improving mechanical properties of silk fibroin nanofiber |
| CN104990882A (en) * | 2015-07-22 | 2015-10-21 | 杭州启明医疗器械有限公司 | In-vitro biological valve calcification evaluation method and anti-calcification factor solution |
| CN108785747A (en) * | 2018-07-07 | 2018-11-13 | 四川大学 | A kind of processing method and its biomaterial improving biomaterial anticalcium performance |
| CN109260517A (en) * | 2018-09-19 | 2019-01-25 | 杭州启明医疗器械有限公司 | One kind can pre-install dry biological cardiac valves and preparation method thereof |
| WO2020057415A1 (en) * | 2018-09-19 | 2020-03-26 | 杭州启明医疗器械股份有限公司 | Preload biological heart valve capable of rapid rehydration and preparation method therefor |
| CN110917399A (en) * | 2019-12-09 | 2020-03-27 | 沛嘉医疗科技(苏州)有限公司 | Anti-calcification method for biomaterial and biomaterial |
| CN111420120A (en) * | 2020-05-28 | 2020-07-17 | 四川大学 | Biological valve with anticoagulation and anti-calcification functions and preparation method thereof |
| CN111569152A (en) * | 2020-05-28 | 2020-08-25 | 四川大学 | Biological valve with anticoagulation and calcification resistance and preparation method thereof |
| CN113499478A (en) * | 2021-07-07 | 2021-10-15 | 成都纽脉生物科技有限公司 | Method for processing biological tissue material |
| WO2021254347A1 (en) * | 2020-06-15 | 2021-12-23 | 杭州启明医疗器械股份有限公司 | Valve material having long-acting antithrombosis property and preparation method therefor |
| CN114796623A (en) * | 2022-03-08 | 2022-07-29 | 四川大学 | Fully-degradable heart occluder coating for promoting myocardial tissue repair and preparation method thereof |
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| US5782931A (en) * | 1996-07-30 | 1998-07-21 | Baxter International Inc. | Methods for mitigating calcification and improving durability in glutaraldehyde-fixed bioprostheses and articles manufactured by such methods |
| CN101537207A (en) * | 2009-04-28 | 2009-09-23 | 中国人民解放军总医院第一附属医院 | Preparation method of tissue engineering xenoskin |
| CN101678152A (en) * | 2007-06-11 | 2010-03-24 | 爱德华兹生命科学公司 | methods for pre-stressing and capping bioprosthetic tissue |
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| US5782931A (en) * | 1996-07-30 | 1998-07-21 | Baxter International Inc. | Methods for mitigating calcification and improving durability in glutaraldehyde-fixed bioprostheses and articles manufactured by such methods |
| CN101678152A (en) * | 2007-06-11 | 2010-03-24 | 爱德华兹生命科学公司 | methods for pre-stressing and capping bioprosthetic tissue |
| CN101537207A (en) * | 2009-04-28 | 2009-09-23 | 中国人民解放军总医院第一附属医院 | Preparation method of tissue engineering xenoskin |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102172338A (en) * | 2011-02-28 | 2011-09-07 | 微创医疗器械(上海)有限公司 | Artificial biologic valve gradient immersed chemical modification device |
| CN102172338B (en) * | 2011-02-28 | 2013-03-20 | 上海微创医疗器械（集团）有限公司 | Artificial biologic valve gradient immersed chemical modification device |
| CN102423505A (en) * | 2011-10-27 | 2012-04-25 | 微创医疗器械(上海)有限公司 | Method and apparatus for fixing bioprosthetic valve by membrane type pervaporation mode |
| CN102423505B (en) * | 2011-10-27 | 2014-12-10 | 上海微创医疗器械（集团）有限公司 | Method and apparatus for fixing bioprosthetic valve by membrane type pervaporation mode |
| CN104894856A (en) * | 2015-05-19 | 2015-09-09 | 东华大学 | Processing method for improving mechanical properties of silk fibroin nanofiber |
| CN104894856B (en) * | 2015-05-19 | 2017-05-03 | 东华大学 | Processing method for improving mechanical properties of silk fibroin nanofiber |
| CN104990882A (en) * | 2015-07-22 | 2015-10-21 | 杭州启明医疗器械有限公司 | In-vitro biological valve calcification evaluation method and anti-calcification factor solution |
| CN104990882B (en) * | 2015-07-22 | 2018-05-01 | 杭州启明医疗器械有限公司 | The method and anticalcium factor solutions of external biological valve calcification evaluation |
| CN108785747A (en) * | 2018-07-07 | 2018-11-13 | 四川大学 | A kind of processing method and its biomaterial improving biomaterial anticalcium performance |
| CN109260517A (en) * | 2018-09-19 | 2019-01-25 | 杭州启明医疗器械有限公司 | One kind can pre-install dry biological cardiac valves and preparation method thereof |
| WO2020057415A1 (en) * | 2018-09-19 | 2020-03-26 | 杭州启明医疗器械股份有限公司 | Preload biological heart valve capable of rapid rehydration and preparation method therefor |
| CN109260517B (en) * | 2018-09-19 | 2020-10-30 | 杭州启明医疗器械股份有限公司 | Prefillable dry biological heart valve and preparation method thereof |
| CN110917399A (en) * | 2019-12-09 | 2020-03-27 | 沛嘉医疗科技(苏州)有限公司 | Anti-calcification method for biomaterial and biomaterial |
| CN111420120A (en) * | 2020-05-28 | 2020-07-17 | 四川大学 | Biological valve with anticoagulation and anti-calcification functions and preparation method thereof |
| CN111569152A (en) * | 2020-05-28 | 2020-08-25 | 四川大学 | Biological valve with anticoagulation and calcification resistance and preparation method thereof |
| WO2021239080A1 (en) * | 2020-05-28 | 2021-12-02 | 杭州启明医疗器械股份有限公司 | Biological heart valve with both anticoagulation and anti-calcification properties, and preparation method therefor |
| WO2021254347A1 (en) * | 2020-06-15 | 2021-12-23 | 杭州启明医疗器械股份有限公司 | Valve material having long-acting antithrombosis property and preparation method therefor |
| CN113499478A (en) * | 2021-07-07 | 2021-10-15 | 成都纽脉生物科技有限公司 | Method for processing biological tissue material |
| CN114796623A (en) * | 2022-03-08 | 2022-07-29 | 四川大学 | Fully-degradable heart occluder coating for promoting myocardial tissue repair and preparation method thereof |
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