CN110124103A - A kind of active substance release material system and preparation method thereof for tissue repair - Google Patents
A kind of active substance release material system and preparation method thereof for tissue repair Download PDFInfo
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Abstract
The present invention relates to biomedical material, organizational project and medical domains, disclose a kind of active substance release material system for tissue repair, the active substance release material system is made of three outer layer, middle layer, internal layer parts, outer layer is the compound injection aquagel layer of sodium alginate/bioactivity glass/glucolactone, middle layer is the Sodium Alginate Hydrogel Films microballoon layer for being enclosed with reparative factor, and internal layer is the poly lactide-glycolide acid microballoon layer for being enclosed with drug.The invention also discloses the preparation methods of the active substance release material system.Active substance release material system of the invention can be according to the different phase of regeneration in processes of wound repair, orderly release is wrapped in the reparative factor and drug of material internal, the corresponding active material needed for it is provided for the regeneration of different phase, can preferably play the effect of reparative factor synergy.
Description
Technical field
The present invention relates to biomedical material, organizational project and medical domain more particularly to a kind of multilayer active material are slow
Release material system preparation and regeneration and restoration application.
Background technique
Organizational project is divided into two class of vitro tissue engineering and in-vivo tissue engineering, in vitro in organizational project, needs to use
To a large amount of seed cell and growth factor.However, seed cell extracts and amplification in vitro encounters many problems, it is difficult to obtain
High quality and enough seed cells, and growth factor half-life short, expensive, its behavior is difficult to control when using in vivo
System.In order to solve these problems, from the angle of design of material, " tissue inductivity " biomaterial is prepared, this material is certainly
The material is implanted directly into vivo, utilizes the bioactivity induction defect week of the material by the biologically active material of body
It encloses the stem cell in tissue or repairs cell migration to defect.
Natural wound repair is a dynamic, various kinds of cell and the process that bio signal participates in.This dynamic process
It can be roughly classified into four-stage, be post-hemorrhagic period, inflammatory phase, cellular proliferative stage (or organizing the formation of the phase) and tissue weight respectively
The modeling phase.In recent years, it is made some progress using the means repair tissue wound of organizational project, the tissue of research application at present
Engineering rack is mainly active substance release material system, such as high molecular polymer PLGA, PGA microsphere sustained-release system, naturally
Chitosan, sodium alginate, hyaluronic acid gel slow-releasing system, liposome slow-releasing system, composite slow release system etc..But at present
The slow-releasing system of research application can only convey single-activity substance, can only meet specific repairing phase.
Existing document report can promote the reparation of wound tissue using timbering material suitable in organizational project, using certainly
Body cell carries out tissue repair and has also made certain gains, such as itself is participated in repair process using additional cell, utilizes
Certain growth factors and albumen etc. carry out tissue repair etc..But the active material that can satisfy the different wound repair stages is passed
Carrier material system is sent, high molecular polymer poly lactide-glycolide acid PLGA, the PGA microballoon of research application at present is slow
Release system, natural chitosan, sodium alginate, hyaluronic acid gel slow-releasing system, liposome slow-releasing system, composite slow release body
System, haves the defects that as follows: carrying drug inactivation；Water soluble drug clad ratio is low；Bracket aperture is excessive to lead to drug or the factor
It is lost serious；And much study and only focus on some repairing phase in processes of wound repair, and each of repair process
Stage all has a great impact to its last repairing effect.These all limit tissue engineering active material sustained-release material system
In the further development being applied in wound repair.
Poly lactide-glycolide acid is a kind of degradable functional polymer organic compound, has good life
The performance of object compatibility, nontoxic, good encystation and film forming is widely used in the pharmaceutical engineering investigation of materials neck of medicament slow release
Domain.Polylactide-glycolic acid poly closes object slow-releasing system can discharge entrapped drug for a long time, but chemistry used in preparation process
Reagent will lead to the inactivation of partial factors or drug, and be lower than hydrogel system to water-soluble entrapment efficiency.
Sodium Alginate Hydrogel Films are a kind of natural polymer hydrogels, Yi Chengning under the conditions of existing for the multivalent ion
Glue has the properties such as hydrophily, no cytotoxicity, chemical stability, easy plasticity and degradation property.Its hydrophily is water-soluble
The optimal selection of drug or factor encapsulating, but compared with synthesizing polymeric material, critical limiting factor is timbering material
Excessive aperture will lead to the quick release of entrapped drug in structure.
Bioactivity glass (BG) is a kind of activity glass material containing Ca, Mg, Si, with controllable mechanical performance and
Degradation rate, good bioactivity, the inflammatory reaction that can regulate and control site of injury can promote Osteoblast Differentiation and at blood vessel point
Change.But BG is usually powdered or block, form is easy to occur to be lost when in use or is not easy to be used, so
The application range of BG is limited to a certain extent.
It is not solved effectively yet in the problem of biomaterial and medical domain, simulation multistage wound repair, to a variety of
The method of reparative factor use in conjunction reparation still remains very big demand.It is more to tissue engineering bracket in field of tissue engineering technology
Functional slow-release material also still remains very big demand.
Therefore, those skilled in the art is dedicated to developing a kind of active substance release material bodies for tissue repair
System.
Summary of the invention
In view of the above drawbacks of the prior art, the technical problem to be solved by the present invention is to simulate multistage wound to repair
It is multiple, it realizes and use in conjunction reparation is carried out to a variety of reparative factors.
To achieve the above object, the invention discloses a kind of active substance release material system for tissue repair, institutes
Stating active substance release material system includes outer layer, middle layer and internal layer, outer layer covers middle layer, middle layer wrapping inner layer, the outer layer
For Sodium Alginate Hydrogel Films microballoon layer, including sodium alginate, bioactivity glass and additive；The middle layer is sodium alginate water
Gel micro-ball layer includes sodium alginate and reparative factor；The internal layer is poly lactide-glycolide acid microballoon layer, includes
Poly lactide-glycolide acid and repair medicine, the outer layer covers middle layer.
Further, the additive in the outer layer is medicament additive, promotes hydrogel layer compound, is particularly but not limited to
Glucolactone.
Further, in the hydrogel layer, the mass ratio of sodium alginate, bioactivity glass and glucolactone is
1:1:1, the outer layer hydrogel layer are injection aquagel layer.
Further, in the Sodium Alginate Hydrogel Films microballoon layer, in sodium alginate, bioactivity glass and gluconic acid
Quality percent by volume of the ester in hydrogel respectively stands alone as 1%-2%.
Further, in the Sodium Alginate Hydrogel Films microballoon layer, sodium alginate is after calcium ion crosslinking in the form of microballoon
In the presence of.
Further, in the poly lactide-glycolide acid microballoon layer, poly lactide-glycolide acid is with micro-
Spherical state exists.
Further, in the Sodium Alginate Hydrogel Films microballoon layer reparative factor be promote revascularization and tissue repair
The factor.It is preferred that the growth factor of the promotion revascularization and tissue repair of stem cell, human fibroblasts and its secretion.
Further, repair medicine is scar inhibiting factor in the poly lactide-glycolide acid microballoon layer, including
But it is not limited to small molecule anti-scarring drug, polypeptide or monoclonal antibody.
The present invention also provides the above-mentioned active substance release material systems for tissue repair to be used for tissue in preparation
Application in engineering Various Tissues renovating bracket material.
The present invention also provides a kind of preparation method of active substance release material system for tissue repair, features
It is, comprising the following steps:
Step 1, by repair medicine, be mixed in a certain ratio with poly lactide-glycolide acid solution, according to emulsion method
The poly lactide-glycolide acid microballoon for preparing package repair medicine is stand-by；
The poly lactide-glycolide acid microballoon of step 1 is made into sodium alginate and reparative factor and mixes by step 2
Solution prepares the sodium alginate water of package poly lactide-glycolide acid microballoon and reparative factor according to electrostatic spraying method
Gel micro-ball is stand-by；
The Sodium Alginate Hydrogel Films microballoon and sodium alginate, bioactivity glass and additive of step 2 are made by step 3
Mixed solution is stand-by；
Standing condensation in mold is added in the mixed solution of step 3 by step 4, obtains active substance release material system.
Further, quality percent by volume of the poly lactide-glycolide acid in emulsion method is 6% in step 1；
Further, step 2, sodium alginate soln is the middle viscosity sodium alginate water that quality percent by volume is 2% in 3
Solution；
Further, in step 3 sodium alginate, bioactivity glass, additive mixed solution, wherein sodium alginate,
Bioactivity glass, additive quality percent by volume be respectively 2%；
Further, it is 20-30 degree that condensation temperature is stood in step 4；Condensing time of repose is 5-20 minutes, preferably 5-10
Minute.
Quality percent by volume mentioned in the present invention is grams per milliliter.
Preferably, can will promote the factor of regeneration/facilitate blood vessel be added middle part sodium alginate (SA)/tissue repair because
In son or drug/additive microballoon layer；Internal poly lactide-glycolide acid can be added in the factor for inhibiting scar to generate
(PLGA)/scar inhibiting factor or drug/additive microballoon layer；
Third aspect present invention provides above-mentioned active substance release material system in the application for preparing skin ultrastructure.
Active substance release material system of the invention has regulation inflammation, promotees tissue repair and inhibits the ability of scar,
Internal poly lactide-glycolide acid (PLGA)/scar inhibiting factor or drug/additive microballoon layer, middle part sodium alginate
(SA)/tissue repair factor or drug/additive microballoon layer and external sodium alginate (SA)/bioactivity glass/additive are multiple
Heshui gel layer can orderly be sustained the different factor or drug, simulate in processes of wound repair, secrete in different repairing phases
The physiology course of corresponding reparative factor, can preferably play the effect of reparative factor synergy.
It, can be in regulation inflammatory reaction, promotion group using active substance release material system of the present invention in practice
The angiogenesis promoted in cambium while regeneration is knitted, inhibits the formation of scar, to multistage tissue trauma reparation
With good repairing effect.
Advantageous effects of the invention are as follows:
1, the active substance release material system in the present invention not only has good hydrophily, no cytotoxicity, stabilization
Property, easy plasticity and degradation property, and have the ability for being orderly sustained the corresponding factor/drug, so as to improve organizational project
The monistic defect of sustained release content of slow release stent in clinical application.
2, the active substance release material system in the present invention has multilayered structure, can be according to group in processes of wound repair
Regenerated different phase is knitted, orderly release is wrapped in the reparative factor and drug of material internal, is under different repairing phases
Regeneration provides the corresponding active material needed for it, can preferably play the effect of reparative factor synergy.
In practice, the same of skin tissue regeneration can promoted using active substance release material system of the present invention
When promote angiogenesis in cambium, there is good repairing effect to the wound repair of skin histology.
3, active substance release material system preparation method of the invention is simple, easy to operate, at low cost.It is clinically used for skin
When wound repair, the mode of injection can be used, easy to operate, mitigation patient is painful over the course for the treatment of significantly, reduces medical care people
The working strength of member, using wide, practicability height.
It is described further below with reference to technical effect of the attached drawing to design of the invention, specific structure and generation, with
It is fully understood from the purpose of the present invention, feature and effect.
Detailed description of the invention
Fig. 1 is the optical microscope, glimmering of PLGA MPs@ALGMPs@SA/BG/GDL Hydrogel slow-release material system
Light microscope figure and transmitting scanning electron microscope diagram；
Fig. 2 is PLGA MPs@ALGMPs@SA/BG/GDL Hydrogel slow-release material system in light field and in 560nm
PLGA microballoon distribution map under Laser Scanning Confocal Microscope；
Fig. 3 is the BSA elution profiles figure of PLGA MPs@ALG MPs double-layer structure slow-release material system.
Specific embodiment
Multiple preferred embodiments of the invention are introduced below with reference to Figure of description, keep its technology contents more clear and just
In understanding.The present invention can be emerged from by many various forms of embodiments, and protection scope of the present invention not only limits
The embodiment that Yu Wenzhong is mentioned.
Embodiment 1
Raw material used in the present embodiment, equipment are known product, are obtained by purchase commercial product.It is as described below
SA, that is, sodium alginate, ALG, that is, calcium alginate, PLGA, that is, poly lactide-glycolide acid, BG, that is, bioactivity glass, GDL are
Glucolactone, CM, that is, conditioned medium, PVA, that is, polyvinyl alcohol.
Bioactivity glass is a kind of bioactivity glass containing Ca, Si, P ternary system, has bioactivity glass
Controllable mechanical performance and degradation rate, the characteristics such as good bioactivity.
Glucolactone is a kind of coagulator, can be used as medicament additive, has nontoxic, oral administration, and solidification effect is good
The features such as, it can be applied in pharmaceutical preparation.
Internal layer poly lactide-glycolide acid/scar inhibiting factor or drug/additive microballoon layer, can be abbreviated as
MPs layers of PLGA；Middle layer sodium alginate/tissue repair factor or drug/additive microballoon layer can be abbreviated as MPs layers of ALG；Outer layer
Sodium alginate/bioactivity glass/glucolactone compound water congealing glue-line can be abbreviated as SA/BG/GDLHydrogel layers.
1, PLGA MPs layers, the system of Hydrogel layers of active substance release material system of MPs layers of ALG and SA/BG/GDL
It is standby
(1) 100mg PLGA powder is dissolved in and is stirred continuously the PLGA solution for being prepared 3.3% in 3mL chloroform.
Pirfenidone is dissolved in dimethyl sulfoxide, is configured to pirfenidone mother liquor, and PLGA solution is added in 10mg pirfenidone
In stir evenly.Above-mentioned solution is added in the PVA solution of 30ml2%, after quickly stirring 5min, is stirred at low speed overnight；
(2) solution in step (1) is centrifuged, removes supernatant, freezing is dry after rinsing precipitating three times using deionized water
It is dry to obtain PLGA MPs, for use；
(3) 2g sodium alginate powder is dissolved in being stirred continuously in 100mL conditioned medium and viscosity seaweed in 2% is prepared
Sour sodium-CMC model based sols.The PLGA MPs of 100mg step 2 is taken to be added in 10ml sodium alginate-CMC model based sols,
It stirs evenly.According to parameters such as voltage 11kV, fltting speed 0.5ml/h, injection gauge 24G, positive and negative anodes distance 1cm to above-mentioned
Solution carries out electrostatic spray operation, is received using the calcium chloride solution that concentration is 2M spraying.Centrifugation removal supernatant after receiving
Liquid, is rinsed three times using deionized water and what is be freeze-dried arrives PLGA MPs@ALG MPs, for use；
(4) 2% SA solution is uniformly mixed with the BG powder mull that quality volume (grams per milliliter) percentage is 2%, then
The GDL powder and quality volume (grams per milliliter) percentage that addition quality volume (grams per milliliter) percentage is 2% are 2%
PLGA MPs ALG MPs powder is uniformly mixed and is configured to sodium alginate, bioactivity glass, gluconic acid lactone quality volume
(grams per milliliter) percentage is 2% mixed solution.It takes the above-mentioned mixed solution of about 500 μ L that standing condensation in mold is added to survive
Property material sustained-release material system PLGA MPs@ALGMPs@SA/BG/GDL Hydrogel.
2, PLGA MPs layers, Hydrogel layers of active substance release material system of MPs layers of ALG and SA/BG/GDL it is micro-
See structural analysis
(1) optical microscope structural analysis
The active substance release material system prepared is used into optical microphotograph sem observation bracket three parts structure.Fig. 1 (A)
For multiple orderly slow-releasing system mirror structure figure, Fig. 1 (B) is multiple orderly slow-releasing system fluorescence microscope structure chart.Such as Fig. 1
(A) shown in, under ordinary optical microscope, in active substance release material system there are transparent ALG MPs and use black
Dotted line marks；In ALG MPs, there are multiple smaller PLGA MPs.As shown in Fig. 1 (B), in fluorescence optical microscope
Under, it is marked there are the ALG MPs of light green fluorescence and in active substance release material system using white dashed line；In ALG
In MPs, there are the PLGA MPs of multiple smaller red fluorescences.
(2) transmitting scanning electron microscope (SEM) graph structure analysis
The active substance release material system prepared is freeze-dried, dry slow-release material system sample is cut, obtains
To more smooth inner section, using transmitting scanning electron microscope (SEM) in 10kV acceleration voltage after the metal spraying of surface
The cross section structure of lower observation active substance release material system.
Fig. 1 (C) is multiple 600 times of structure charts of orderly slow-releasing system SEM, and Fig. 1 (D) is multiple orderly slow-releasing system SEM
2400 times of structure charts.As shown in Fig. 1 (C), (D), there are the laminated structure of hydrogel, sheets in active substance release material system
Layer surface has protuberant particles, shows and is covered with bioactivity glass (BG) particle.In a panel region, assemble multiple regular circle shapes
Particle PLGA MPs shows that the region is the ALG MPs for wrapping up multiple PLGA MPs.And ALG MPs and SA/BG/GDL
Hydrogel is all hydrogel laminated structure, so distinguishing after the drying without obvious boundary.
(3) Laser Scanning Confocal Microscope graph structure is analyzed
Fig. 2 is PLGA MPs@ALGMPs@SA/BG/GDL Hydrogel slow-release material system in light field and in 560nm
PLGA microballoon distribution map under Laser Scanning Confocal Microscope.As shown in Fig. 2, observed under 560nm Laser Scanning Confocal Microscope its structure and
Linkage interface.ALG microballoon is crosslinked with outer layer BG hydrogel, so the two structural stratification is unobvious.PLGA microballoon presents red
Color fluorescence, dynamic chart reveal PLGA microsphere aggregation region be it is spherical, illustrate where aggregation zone be ALG microballoon region.
3, the two-part orderly sustained release performance of PLGA MPs@ALG MPs in active substance release material system
(1) 100mg PLGA powder is dissolved in and is stirred continuously the PLGA solution for being prepared 3.3% in 3mL chloroform.
Bovine serum albumin (BSA) is dissolved in phosphate buffer solution (PBS), is configured to BSA mother liquor, and 10mg BSA is added
It is stirred evenly in PLGA solution.Above-mentioned solution is added in the PVA solution of 30ml2%, after quickly stirring 5min, was stirred at low speed
Night；
(2) solution in step (1) is centrifuged, removes supernatant, freezing is dry after rinsing precipitating three times using deionized water
It is dry to obtain PLGA MPs, for use；
(3) 2g sodium alginate powder is dissolved in being stirred continuously in 100mL conditioned medium and viscosity seaweed in 2% is prepared
Sour sodium-CMC model based sols.Take PLGA MPs and the 10mg BSA of 100mg step 2 that 10ml sodium alginate-condition training is added
It supports in based sols, stirs evenly.According to voltage 11kV, fltting speed 0.5ml/h, injection gauge 24G, positive and negative anodes distance 1cm
Etc. parameters electrostatic spray operation is carried out to above-mentioned solution, received using the calcium chloride solution that concentration is 2M spraying.After receiving
Centrifugation removal supernatant, is rinsed three times using deionized water and what is be freeze-dried arrives PLGA MPs@ALG MPs, for use；
(4) the PLGA MPs@ALG MPs powder in appropriate step 3 is weighed, is added in PBS and is incubated at 37 DEG C.6h,
12h, 1d, 3d, 6d, 10d, 15d, 20d, 25d collect 200ul supernatant respectively and 200ul PBS are added.Use Micro
BCA Protein Assay Kit is to the sample detection BSA levels of different time points and draws elution profiles.
Fig. 3 is the BSA elution profiles figure of PLGA MPs@ALG MPs double-layer structure slow-release material system.As shown in figure 3,
PLGA MPs@ALG MPs two parts can be sustained out the BSA wrapped up, and show ALG MPs hydrogel in 5 days first and dredge
The outburst of loose porous structure discharges, and then shows the slow sustained release of PLGAMPs macromolecule compact texture in 20 days.BSA
The phenomenon that sustained release, illustrates that active substance release material system has orderly after the first outburst release that elution profiles are shown
Discharge the function of a variety of reparative factor/drugs.
The active substance release material system of other components of the present invention have and above-mentioned PLGA MPs layers, MPs layers of ALG and
Hydrogel layers of active substance release material system similar appearance of SA/BG/GDL, orderly slow release effect and skin histology wound
The repairing effect of wound.
The preferred embodiment of the present invention has been described in detail above.It should be appreciated that the ordinary skill of this field is without wound
The property made labour, which according to the present invention can conceive, makes many modifications and variations.Therefore, all technician in the art
Pass through the available technology of logical analysis, reasoning, or a limited experiment on the basis of existing technology under this invention's idea
Scheme, all should be within the scope of protection determined by the claims.
Claims (10)
1. a kind of active substance release material system for tissue repair, which is characterized in that the active substance release material
System includes outer layer, middle layer and internal layer, and the outer layer is Sodium Alginate Hydrogel Films layer, including sodium alginate, bioactivity glass
And additive；The middle layer is Sodium Alginate Hydrogel Films microballoon layer, includes sodium alginate and reparative factor；The internal layer is poly- cream
Acid-co-glycolic acid microballoon layer, include poly lactide-glycolide acid and repair medicine, the outer layer covers middle layer,
The middle layer wrapping inner layer.
2. a kind of active substance release material system for tissue repair as described in claim 1, which is characterized in that described
Additive in outer layer is glucolactone.
3. a kind of active substance release material system for tissue repair as claimed in claim 2, which is characterized in that described
In Sodium Alginate Hydrogel Films layer, the mass ratio of sodium alginate, bioactivity glass and glucolactone is 1:1:1, alginic acid
Quality volume (grams per milliliter) percentage of sodium, bioactivity glass and glucolactone in the hydrogel layer is respectively stood alone as
1%-2%.
4. a kind of active substance release material system for tissue repair as described in claim 1, which is characterized in that described
In Sodium Alginate Hydrogel Films microballoon layer, exist in the form of microballoon after sodium alginate and calcium ion crosslinking.
5. a kind of active substance release material system for tissue repair as described in claim 1, which is characterized in that described
In Sodium Alginate Hydrogel Films microballoon layer reparative factor be promote revascularization and the tissue repair factor.
6. a kind of active substance release material system for tissue repair as described in claim 1, which is characterized in that described
Repair medicine is scar inhibiting factor, the including but not limited to anti-scar of small molecule in poly lactide-glycolide acid microballoon layer
Drug, polypeptide or monoclonal antibody.
7. prepared by a kind of active substance release material system for tissue repair such as of any of claims 1-6
For the application in organizational project Various Tissues renovating bracket material.
8. a kind of a kind of active substance release material system for tissue repair as claimed in any one of claims 1 to 6
Preparation method, which comprises the following steps:
Step 1, by repair medicine, be mixed in a certain ratio with poly lactide-glycolide acid solution, prepared according to emulsion method
The poly lactide-glycolide acid microballoon for wrapping up repair medicine out is stand-by；
The poly lactide-glycolide acid microballoon and sodium alginate and reparative factor of step 1 are made into mixed solution by step 2,
The Sodium Alginate Hydrogel Films for preparing package poly lactide-glycolide acid microballoon and reparative factor according to electrostatic spraying method are micro-
Ball is stand-by；
The Sodium Alginate Hydrogel Films microballoon of step 2 is made into sodium alginate, bioactivity glass and additive and mixes by step 3
Solution for later use；
Standing condensation in mold is added in the mixed solution of step 3 by step 4, obtains active substance release material system.
9. a kind of preparation method of the active substance release material system for tissue repair as claimed in claim 8, special
Sign is, in the step (1), quality volume (grams per milliliter) percentage of poly lactide-glycolide acid in emulsion method
It is 6%.
10. a kind of preparation method of the active substance release material system for tissue repair as claimed in claim 8, special
Sign is that it is 20-30 degree that condensation temperature is stood in the step (4), and standing condensation time is 5-20 minutes.
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