CN102423927A - PLGA-PEG-PLGA inlaid mineralized collagen coating and its preparation method - Google Patents
PLGA-PEG-PLGA inlaid mineralized collagen coating and its preparation method Download PDFInfo
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- CN102423927A CN102423927A CN2011102710020A CN201110271002A CN102423927A CN 102423927 A CN102423927 A CN 102423927A CN 2011102710020 A CN2011102710020 A CN 2011102710020A CN 201110271002 A CN201110271002 A CN 201110271002A CN 102423927 A CN102423927 A CN 102423927A
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Abstract
The invention discloses a PLGA (poly(lactic-co-glycolic acid))-PEG (poly(ethylene glycol))-PLGA inlaid mineralized collagen coating and its preparation method. The method of the invention conducts electrochemical deposition, adjusts deposition parameters, constructs a mineralized collagen coating with a porous structure on a metal implant surface, and inlays a temperature sensitive polymer PLGA-PEG-PLGA into the structure, so that the coating becomes an excellent drug slow release system and can be used for controlled release of biotic factors, antibiotics and other drugs in vivo. PLGA-PEG-PLGA can make sol-gel conversion with temperature variation. On account of the characteristic, biotic factors and antibiotics, etc. are loaded under a sol state of PLGA-PEG-PLGA, under the gel state of which the drugs can be released, thus optimizing the slow release behavior of the coating. The coating prepared by the method of the invention can make use of mineralized collagen to transmit biological signals and the temperature sensitive polymer to control drug release effectively, so that the coating can has high biological responsiveness as well as a good drug slow release function simultaneously, thus boasting wide application prospects in hard bone tissue repair field.
Description
Technical field
The present invention relates to a kind ofly possess high biological response property simultaneously (the English full name of PLGA is poly (lactic-co-glycolic acid), and it is polylactic acid-glycolic guanidine-acetic acid copolymer that Chinese standard is named with metal implant that can be efficiently medicament-carried surface PLGA-PEG-PLGA; The English full name of PEG is poly (ethylene glycol), and the name of Chinese standard is a polyethylene glycol) the copolymer mineralized collagen coating of inlaying and preparation method thereof.
Background technology
Mineralized collagen is composited by synthos and collagen, and is similar with composition with the structure of nature bone.Research shows that (2009,29 (21): 3105-3116), this composite has excellent bionical performance, can effectively promote the bone integration process, improves new bone and forms ability for Dawson JI, et al. Biomaterials.Through modes such as electrochemical deposition, spin-coating method, biomimetic methods tropocollagen molecule and phosphate are assembled on the metal substrate, form the mineralized collagen coating.The metal implant that obtains not only possesses metal favorable mechanical performance, and can utilize mineralized collagen to improve the biologically active of material.But then, in order further to improve the success rate of bone prosthesis, often need be in implant loaded with growth, antibiotic etc, make it slowly continue in the affected part to discharge, in the regular hour, play effectiveness.And for the block drug carrier material, coating is generally thinner, and is less relatively to the carrying capacity of medicine, causes the diffusion of medicine in loading material fast, and its valid density can't maintain certain level in the time at long enough.
For reaching the slowly-releasing purpose, require medicine can get into carrier material in a large number, and can slowly continue in vivo to discharge.This can change the high molecular polymer that produces the sol-gel phase change that responds according to outside microenvironment through adding in controlled drug delivery system and realize.Wherein, PLGA-PEG-PLGA has great application prospect as the temperature sensitive polymer material that possesses thermo-responsive and good biocompatibility simultaneously.This material is a colloidal sol when critical solution temperature (about 28 ℃) is following, forms gel because hydrophobic interaction reinforcement or hydrogen bond are damaged when temperature rises.Below critical solution temperature,, drug molecule is wrapped in the gel rubber system, slows down medicine release in vivo itself and medicine blend.Relevant research (Song ZM; Et al. Journal of Colloid and Interface Science; 2011; 354:116-123) reported that the temperature-sensing property that utilizes PLGA-PEG-PLGA makes it carry out the purpose that the original position structural change reaches effective medicine carrying release with temperature, but generally under its block hydrogel state, used, found to have itself and the compound report of processing coating of other materials.
Summary of the invention
The objective of the invention is to deficiency, the mineralized collagen coating and the preparation method that provide PLGA-PEG-PLGA to inlay to prior art.This coating is deposited on the metal implant surface, makes it possess the function of high biological response property and high-efficiency sustained-release medicine.
The objective of the invention is to realize: the mineralized collagen coating that a kind of PLGA-PEG-PLGA inlays through following technical scheme; It comprises a metal substrate; Said metallic substrate surfaces has deposited porous mineralized collagen coating, inlays PLGA-PEG-PLGA in the porous mineralized collagen coating.
The preparation method of the mineralized collagen coating that a kind of above-mentioned PLGA-PEG-PLGA inlays, it comprises following steps:
(1) metallic substrate surfaces preliminary treatment: comprise metallic substrate surfaces is cleaned, controls roughness, handles oxide skin(coating) etc.;
(2) preparing electrolyte, utilization is electrochemically-deposited in the metal implant surface and obtains porous mineralized collagen coating: contain Ca in the electrolyte of preparation
2+, H
2PO
4 -, H
2O
2And collagen, their concentration is respectively 4～8mmol/L, 8～16 mmol/L, 0.1～0.6g/L and 15～20 mmol/L, and the pH of electrolyte is 4.3～4.6; Metal substrate is a negative electrode, and platinum electrode is an anode, and it is 37 ℃ water-bath that electrolyte places temperature, and distance is 1～2cm between negative electrode and the anode, adopts constant voltage mode, and the deposition voltage scope is 2.0～2.5V, and sedimentation time is 30～60min; Electrochemical deposition is used washed with de-ionized water with metal substrate, natural air drying after finishing;
(3) PLGA-PEG-PLGA is added deionized water and be mixed with the colloidal sol that concentration is 3～6g/L; The metal substrate that the surface that makes is had porous mineralized collagen coating is dipped in the above-mentioned solution; At 4～20 ℃ of held 5～10h; At 35～40 ℃ of held 5～10h, make PLGA-PEG-PLGA colloidal sol change gel into then, be embedded in the porous coating; Take out metal substrate and oven dry at last, make the mineralized collagen coating that PLGA-PEG-PLGA copolymer of the present invention is inlayed.
The invention has the beneficial effects as follows; The present invention adopts electrochemical preparation to have the mineralized collagen coating of loose structure; Utilize its loose structure to inlay the PLGA-PEG-PLGA temperature sensitive polymer, thereby significantly improved the slowly-releasing behavior of coating, make it when possessing high biological response property medicine; Efficient slowly growth factors released, antibiotic, the protein medicaments etc. of carrying also are with a wide range of applications in os osseum organization restoration field.
Description of drawings
Fig. 1 is under 37 ℃, medicine release profiles under the different PLGA-PEG-PLGA concentration in PLGA-PEG-PLGA and the vancomycin hydrochloride mixed liquor;
Fig. 2 is 4 ℃ and 37 ℃ of following PLGA-PEG-PLGA concentration medicine release profiles when being 3g/L, and the concentration of vancomycin hydrochloride is 4g/L in the mixed liquor.
The specific embodiment
The mineralized collagen coating that PLGA-PEG-PLGA among the present invention inlays comprises a metal substrate, and metallic substrate surfaces has deposited porous mineralized collagen coating, inlays PLGA-PEG-PLGA in the porous mineralized collagen coating.
PLGA-PEG-PLGA is a temperature sensitive polymer, during temperature change sol-gel transition can take place, and changes critical-temperature and is about 28 ℃.Medicine loads in the coating in low temperature (< 28 ℃), and (37 ℃) discharge when body temperature.
The preparation method of the mineralized collagen coating that the PLGA-PEG-PLGA copolymer that the present invention relates to is inlayed comprises following steps:
1, metallic substrate surfaces preliminary treatment: comprise metallic substrate surfaces is cleaned, controls roughness, handles oxide skin(coating) etc.
2, preparing electrolyte, utilization is electrochemically-deposited in the metal implant surface and obtains porous mineralized collagen coating.
Among the present invention, contain Ca in the electrolyte of preparation
2+, H
2PO
4 -, H
2O
2And collagen, their concentration is respectively 4～8mmol/L, 8～16 mmol/L, 15～20 mmol/L and 0.1～0.6g/L, and the pH of electrolyte is 4.3～4.6 (the NaOH solution with 0.25～1mol/L is regulated).Metal substrate is a negative electrode, and platinum electrode is an anode, and it is 37 ℃ water-bath that electrolyte places temperature, and distance is 1～2cm between negative electrode and the anode, adopts constant voltage mode, and the deposition voltage scope is 2.0～2.5V, and sedimentation time is 30～60min.Electrochemical deposition is used washed with de-ionized water with metal substrate after finishing, and natural air drying obtains the metal substrate that the surface has porous mineralized collagen coating.
Mineralized collagen is the compound of collagen and calcium phosphate mineral, and this mineralized collagen layer is not the accurate three-dimensional structure of porous when loading temperature sensitive polymer, for holding PLGA-PEG-PLGA suitable steric requirements is provided.
3, PLGA-PEG-PLGA is added deionized water and be mixed with the colloidal sol that concentration is 3～6g/L; The metal substrate that the surface that makes is had porous mineralized collagen coating is dipped in the colloidal sol; (4～20 ℃) are placed 5～10h at a lower temperature; (35～40 ℃) are placed 5～10h under higher temperature then, make PLGA-PEG-PLGA colloidal sol change gel into, are embedded in the porous coating.Take out metal substrate and oven dry at last, make the mineralized collagen coating that PLGA-PEG-PLGA copolymer of the present invention is inlayed.
PLGA-PEG-PLGA is a temperature sensitive polymer, and temperature when raising sol-gel transition can take place, and changing critical-temperature is about 28 ℃, and it is a collosol state during medicine carrying, is gel state during release.
Use of the present invention is following: the mineralized collagen coating that the PLGA-PEG-PLGA copolymer that the present invention is prepared is inlayed is dipped in 10～12h in the drug solution; The temperature of drug solution is 4～20 ℃; Make medicine fully be written into this coating; The temperature of drug solution is warming up to 35～40 ℃ of continued and places 2～5h then, at last with coated and dried.Growth factor, the antibiotic etc of said medicine for needing to carry, drug concentration is regulated according to practical situations.According to temperature environment in the body, medicament slow release carries out about 37 ℃.
Extracorporeal releasing experiment carries out in PBS solution (pH is 7.0～7.4), utilizes ultraviolet specrophotometer to measure release amount of medicine.37 ℃ of following PLGA-PEG-PLGA are gel state, and the burst that can slow down the initial stage medicine discharges, prolong drug action time.
In the mineralized collagen coating that PLGA-PEG-PLGA copolymer of the present invention is inlayed, the mineralized collagen coating that electro-deposition obtains has loose structure, for holding PLGA-PEG-PLGA and drug molecule certain space is provided.Simultaneously, a certain amount of PLGA-PEG-PLGA combines with mineralized collagen, but does not cover whole mineralized collagen layer, makes mineralized collagen still can bring into play the function of its high biological responding, effectively promotes the bone integration process.Less than the critical solution temperature of PLGA-PEG-PLGA the time; It is a collosol state, and drug molecule can be written into coating, when temperature rises to 37 ℃ of left and right sides; PLGA-PEG-PLGA changes gel into; Its compact texture has certain barrier effect to the diffusion of drug molecule, thereby realizes coating sustained-released effect, the action time of prolong drug.
Below in conjunction with instantiation the present invention is described, it is more obvious that the object of the invention and effect will become.
Embodiment 1
Collagen is dissolved in the 0.005mol/L acetic acid, and stirring back formation collagen concentration is the solution of 0.5g/L, with Ca (NO
3)
26H
2O and NH
4H
2PO
4Be dissolved in the deionized water, mix forming calcium, phosphorus, H with collagen solution and a small amount of hydrogen peroxide solution
2O
2, collagen concentration is respectively the electrolyte of 8 mmol/L, 16 mmol/L, 15 mmol/L, 0.6g/L, with NaOH solution electrolyte pH is adjusted to 4.3.As negative electrode, platinum electrode is as anode with the titanium plate after the surface preparation, and negative and positive two electrode spacings are 1cm, gets 15ml electrolyte and is placed in 37 ℃ of water-baths, adopts the constant voltage depositional model, voltage 2.5V.Take out titanium-base behind the deposition 30min, natural air drying obtains porous mineralized collagen gradient coating after the washed with de-ionized water.PLGA-PEG-PLGA is added deionized water be mixed with the colloidal sol that concentration is 3g/L, in 4 ℃ of storages.The metal substrate that the surface that makes is had porous mineralized collagen coating is dipped in the above-mentioned solution, at 4 ℃ of held 10h, then at 35 ℃ of held 10h.Take out metal substrate and oven dry at last, make the mineralized collagen coating that the PLGA-PEG-PLGA copolymer is inlayed.The mineralized collagen coating that the PLGA-PEG-PLGA copolymer for preparing is inlayed is dipped in 10h in the vancomycin hydrochloride solution of 4g/L; The temperature of drug solution is 4 ℃; Make medicine fully be written into this coating; Temperature with drug solution is warming up to 35 ℃ of continued placement 2h then, at last with coated and dried.Vitro drug release experiment shows, medicine continues the time of releasing and can reach more than 4 days.
Embodiment 2
Collagen is dissolved in the 0.005mol/L acetic acid, and stirring back formation collagen concentration is the solution of 0.5g/L, with Ca (NO
3)
26H
2O and NaH
2PO
4Be dissolved in the deionized water, mix forming calcium, phosphorus, H with collagen solution and a small amount of hydrogen peroxide solution
2O
2, collagen concentration is respectively the electrolyte of 4 mmol/L, 8 mmol/L, 20 mmol/L, 0.1g/L, with NaOH solution electrolyte pH is adjusted to 4.6.As negative electrode, platinum electrode is as anode with the titanium plate after the surface preparation, and negative and positive two electrode spacings are 2cm, gets 15ml electrolyte and is placed in 37 ℃ of water-baths, adopts the constant voltage depositional model, voltage 2.5V.Take out titanium-base behind the deposition 45min, natural air drying obtains porous mineralized collagen gradient coating after the washed with de-ionized water.PLGA-PEG-PLGA is added deionized water be mixed with the colloidal sol that concentration is 6g/L, in 4 ℃ of storages.The metal substrate that the surface that makes is had porous mineralized collagen coating is dipped in the above-mentioned solution, at 20 ℃ of held 5h, then at 40 ℃ of held 5h.Take out metal substrate and oven dry at last, make the mineralized collagen coating that the PLGA-PEG-PLGA copolymer is inlayed.The mineralized collagen coating that the PLGA-PEG-PLGA copolymer for preparing is inlayed is dipped in 12h in the vancomycin hydrochloride solution of 4g/L; The temperature of drug solution is 20 ℃; Make medicine fully be written into this coating; Temperature with drug solution is warming up to 40 ℃ of continued placement 2h then, at last with coated and dried.Vitro drug release experiment shows, medicine continues the time of releasing and can reach more than 4 days.
Embodiment 3
Collagen is dissolved in the 0.005mol/L acetic acid, and stirring back formation collagen concentration is the solution of 0.5g/L, with Ca (NO
3)
26H
2O and NaH
2PO
4Be dissolved in the deionized water, mix forming calcium, phosphorus, H with collagen solution and a small amount of hydrogen peroxide solution
2O
2, collagen concentration is respectively the electrolyte of 6 mmol/L, 12 mmol/L, 18 mmol/L, 0.4g/L, with NaOH solution electrolyte pH is adjusted to 4.5.As negative electrode, platinum electrode is as anode with the titanium plate after the surface preparation, and negative and positive two electrode spacings are 1.5cm, gets 15ml electrolyte and is placed in 37 ℃ of water-baths, adopts the constant voltage depositional model, voltage 2.0V.Take out titanium-base behind the deposition 60min, natural air drying obtains porous mineralized collagen gradient coating after the washed with de-ionized water.PLGA-PEG-PLGA is added deionized water be mixed with the colloidal sol that concentration is 6g/L, in 4 ℃ of storages.The metal substrate that the surface that makes is had porous mineralized collagen coating is dipped in the above-mentioned solution, at 4 ℃ of held 10h, then at 37 ℃ of held 5h.Take out metal substrate and oven dry at last, make the mineralized collagen coating that the PLGA-PEG-PLGA copolymer is inlayed.The mineralized collagen coating that the PLGA-PEG-PLGA copolymer for preparing is inlayed is dipped in 10h in the vancomycin hydrochloride solution of 4g/L; The temperature of drug solution is 4 ℃; Make medicine fully be written into this coating; Temperature with drug solution is warming up to 40 ℃ of continued placement 2h then, at last with coated and dried.Vitro drug release experiment shows, medicine continues the time of releasing and can reach more than 4 days.
The foregoing description is used for the present invention that explains, rather than limits the invention, and in the protection domain of spirit of the present invention and claim, any modification and change to the present invention makes all fall into protection scope of the present invention.
Claims (3)
1. the mineralized collagen coating that PLGA-PEG-PLGA inlays is characterized in that it comprises a metal substrate, and said metallic substrate surfaces has deposited porous mineralized collagen coating, inlays PLGA-PEG-PLGA in the porous mineralized collagen coating.
2. the preparation method of the said PLGA-PEG-PLGA of the claim 1 mineralized collagen coating of inlaying is characterized in that it comprises following steps:
(1) metallic substrate surfaces preliminary treatment: comprise metallic substrate surfaces is cleaned, controls roughness, handles oxide skin(coating) etc.;
(2) preparing electrolyte, utilization is electrochemically-deposited in the metal implant surface and obtains porous mineralized collagen coating: contain Ca in the electrolyte of preparation
2+, H
2PO
4 -, H
2O
2And collagen, their concentration is respectively 4～8mmol/L, 8～16 mmol/L, 0.1～0.6g/L and 15～20 mmol/L, and the pH of electrolyte is 4.3～4.6; Metal substrate is a negative electrode, and platinum electrode is an anode, and it is 37 ℃ water-bath that electrolyte places temperature, and distance is 1～2cm between negative electrode and the anode, adopts constant voltage mode, and the deposition voltage scope is 2.0～2.5V, and sedimentation time is 30～60min; Electrochemical deposition is used washed with de-ionized water with metal substrate, natural air drying after finishing;
(3) PLGA-PEG-PLGA is added deionized water and be mixed with the colloidal sol that concentration is 3～6g/L; The metal substrate that the surface that makes is had porous mineralized collagen coating is dipped in the above-mentioned solution; Place 5～10h at a lower temperature; At higher temperature held 5～10h, make PLGA-PEG-PLGA colloidal sol change gel into then, be embedded in the porous coating; Take out metal substrate and oven dry at last, make the mineralized collagen coating that PLGA-PEG-PLGA copolymer of the present invention is inlayed.
3. preparation method according to claim 2 is characterized in that, in the said step (3), said lower temperature is 4～20 ℃, and said higher temperature is 35～40 ℃.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108982565A (en) * | 2018-05-29 | 2018-12-11 | 四川维思达医疗器械有限公司 | A kind of method of the concentration of electrolyte condition of determining calcium phosphate coating pattern |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1957695B1 (en) * | 2005-12-07 | 2011-02-09 | Ramot at Tel-Aviv University Ltd. | Drug-delivering composite structures |
| CN101984144A (en) * | 2010-10-22 | 2011-03-09 | 浙江大学 | Surface mount method of mineralized collagen gradient coating for medical titanium implant |
-
2011
- 2011-09-14 CN CN2011102710020A patent/CN102423927A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1957695B1 (en) * | 2005-12-07 | 2011-02-09 | Ramot at Tel-Aviv University Ltd. | Drug-delivering composite structures |
| CN101984144A (en) * | 2010-10-22 | 2011-03-09 | 浙江大学 | Surface mount method of mineralized collagen gradient coating for medical titanium implant |
Non-Patent Citations (2)
| Title |
|---|
| 《高等学校化学学报》 20060731 林浩等 "温度敏感的PLGA-PEG-PLGA水凝胶的合成、表征和药物释放" 第1385-1388页 1-3 第27卷, 第7期 * |
| 林浩等: ""温度敏感的PLGA-PEG-PLGA水凝胶的合成、表征和药物释放"", 《高等学校化学学报》, vol. 27, no. 7, 31 July 2006 (2006-07-31), pages 1385 - 1388 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108982565A (en) * | 2018-05-29 | 2018-12-11 | 四川维思达医疗器械有限公司 | A kind of method of the concentration of electrolyte condition of determining calcium phosphate coating pattern |
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Application publication date: 20120425 |