CN1318100C - Chitosan-calcium alginate gel microsphere soft tissue reinforced material and its preparation method and application - Google Patents
Chitosan-calcium alginate gel microsphere soft tissue reinforced material and its preparation method and application Download PDFInfo
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- CN1318100C CN1318100C CNB2003101247037A CN200310124703A CN1318100C CN 1318100 C CN1318100 C CN 1318100C CN B2003101247037 A CNB2003101247037 A CN B2003101247037A CN 200310124703 A CN200310124703 A CN 200310124703A CN 1318100 C CN1318100 C CN 1318100C
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Abstract
The present invention relates to a soft tissue reinforcing material of a chitosan-calcium alginate gelatin microsphere. A chitosan membrane is coated by a calcium alginate gelatin microsphere which is then mixed with sodium alginate to form gelatin, wherein the particle diameter of the calcium alginate gelatin microsphere is from 1 to 2000 mum. The present invention of the soft tissue reinforcing material comprises: firstly, sodium alginate solution is prepared into a calcium alginate gelatin microsphere which is then formed into a membrane with chitosan solution so as to prepare a chitosan-calcium alginate gelatin; the chitosan-calcium alginate gelatin microsphere is mixed with the sodium alginate solution so as to prepare the soft tissue reinforcing material of the chitosan-calcium alginate gelatin microsphere. The soft tissue reinforcing material of the present invention is mainly used for minimally invasive treatment of diseases caused by structural relaxation of partial soft tissues, such as stress incontinence, gastro esophageal reflux, paralysis of unilateral vocal cord, etc. The soft tissue reinforcing material can be used in the field of aesthetic medicine, such as breast plump, face-plasty, etc. The soft tissue reinforcing material can be implanted by a subcutaneous injection method or an intradermal injection method and other implanting method according to requirements.
Description
Technical field
The present invention relates to a kind of local injection and implant the soft tissue enhancement material, relate in particular to a kind of chitosan-calcium alginate gel bead soft tissue enhancement material.
The invention still further relates to the preparation method of above-mentioned material.
The invention still further relates to the application of above-mentioned material.
Background technology
At present at stress incontinence, gastroesophageal reflux disease and unilateral vocal cord paralysis etc. because the disease treatment that the local soft tissue structural relaxation caused adopts operation suspention and the local means such as reinforcing material of implanting to treat [document 1:Ghoniem GM more, Elgamasy AN, Elsergany R, et al.Grades of intrinsic spincteric deficiency (ISD) associated with female stressurinary incontinence.Int Urogynecol J, 2002:13 (2): 99-105.].Wherein, local injection is implanted the soft tissue enhancement material and is belonged to Wicresoft and hinder Therapeutic Method.The principle of this Therapeutic Method is: with some drugs and the lax soft tissue part of chemicals injecting structure, improve the partial relaxation degree, improve the ability of local proof pressure, thereby make its normal function of this organized renewing or outward appearance.Aesthetic medicine fields such as this Therapeutic Method also is widely used in and enlarges the bosom, facial plasty.This Therapeutic Method, because clinical operation is simple to operate, the patient suffering is few, and therapeutic effect is remarkable, so clinical practice is more.The key problem in technology of this Therapeutic Method is the development of embedded material, require embedded material to meet no antigen (non-antigenic), no animal migration (non-migrating), do not have again requirement [document 2:Bent AE such as absorbability (non-resorbable) and easy transplantability (easily implantable), Tutrone RT, McLennan MT, et al.Treatment of intrinsic sphincter deficiency usingautologous ear chondrocytes as a bulking agent.Neurourol Urodyn, 2001; 20 (2): 157-165.].Embedded material [the document 3:Van Kerrebroeck P that is used for this respect experimentation and clinical treatment at present, Ter Meulen F, Farrelly E, et al.Treatment of stress urinaryincontinence:recent developments in the role of urethral injection.Urol Res, 2003; 30 (6): 356-362.] have 1) the politef microsphere, it is easy to migration in vivo bibliographical information, and can produce granuloma in the part; 2) autologous fat is though good biocompatibility absorbs rapid, poor effect again in the body; 3) glutaraldehyde cross-linking bovine collagen albumen easily produces anaphylaxis, and trace glutaraldehyde is residual harmful; 4) silicones ball, ceramic microsphere etc., owing to reasons such as implantation mode and costs, application also is restricted.
Summary of the invention
The object of the present invention is to provide a kind of that be easy to inject, to chitosan human body safety, lower-cost-calcium alginate gel bead soft tissue enhancement material.
Another object of the present invention is to provide a kind of method for preparing above-mentioned material.
For achieving the above object, soft tissue enhancement material provided by the invention is mixed by chitosan-calcium alginate gel bead and sodium alginate soln and forms, form mixture and implant the soft tissue enhancement material as local injection, promptly by calcium alginate gel bead coating-layer chitosan film, mix the formation gel state with sodium alginate soln, wherein the particle diameter of calcium alginate gel bead is 1-2000 μ m, calcium alginate gel bead and chitosan solution are 1 with volume ratio: 1-1: 10 film forming, the volume ratio of chitosan-calcium alginate gel bead and sodium alginate soln are 10: 1-10: 30.
Preparation method of the present invention and parameter are as follows:
The raw material that the present invention adopts is to be widely used in polysaccharide biomaterial sodium alginate biomedical research and application, that have excellent biological compatibility and chitosan.
The present invention is 0.1～4.0% sodium alginate soln with w/v, at 0.01～1.0mol/LCaCl
2Solution is coagulation bath or is under the condition of decentralized photo with calcium carbonate, calcium lactate, calcium oxalate granule, preparation calcium alginate gel bead (CAM), and the particle diameter of calcium alginate gel bead is between 1～2000 μ m.Then with calcium alginate gel bead and 0.1～4.0% (w/v) chitosan solution for preparing by volume 1: 1-1: 10 film forming make chitosan-calcium alginate gel bead.
The sodium alginate soln of chitosan-calcium alginate gel bead and 0.1～4.0% (w/v) is mixed, the mixed proportion of chitosan-calcium alginate gel bead and sodium alginate is 10: 1～10: 30 (volume ratio), thereby prepares chitosan-calcium alginate gel bead soft tissue enhancement material.More than operation is all carried out under aseptic condition.
Need to prove, about the method for preparing calcium alginate gel bead is a known technology, all can prepare calcium alginate gel bead of the present invention such as methods such as adopting static sessile drop method, Pneumatic Liquid dripping method, emulsifying/internal gelation, membrane emulsifying/internal gelation.For simplicity's sake, the present invention is not described in detail these known technologies.The play-by-play of relevant these known technologies can be consulted:
Static sessile drop method [consult document: Hommel M, Sun AM, Goosen M F A.Dropletsgeneration.Canadian patent No.1241598,1988];
Pneumatic Liquid dripping method [consult document: Miyawaki O., Nakamura K., Yano T..Agric.Biol.Chem.1980,44:2865-2870];
The emulsifying/internal gelation [is consulted document: Poncelet D, Lencki R, Beaulieu C et al.Production of alginate beads by emulsification/internal gelation.I.Methodology.Appl.Microbiol.Biotechnol., 1992,38:39～45; ], [Poncelet D, Poncelet De Smet B, Beaulieu C et al.Production of alginate beads byemulsification/internal gelation.II.Physicochemistry.Appl.Microbiol.Biotechnol., 1995,43:644～650; ], [Liu Qun, Ma Xiaojun, Liu tuck inside the sleeve hole, a kind of emulsifying/internal gelation prepares the method for calcium alginate gel beads, Chinese patent, application number 01109449.4, publication number 1374338];
Chitosan-calcium alginate gel bead and sodium alginate soln can be to mix or two kinds of distinct methods such as dispersion:
1. chitosan-the calcium alginate gel bead for preparing sucks in the sodium alginate soln by utensils such as suction pipes, makes its mix homogeneously by stirring, and forms gel state;
2. sodium alginate soln is dispersed in chitosan-calcium alginate gel bead under stirring, and forms gel state.
Chitosan provided by the invention-calcium alginate gel bead local injection implants that the soft tissue enhancement material is primarily aimed at stress incontinence, gastroesophageal reflux disease, unilateral vocal cord paralysis etc. because treatment is hindered by the Wicresoft of the disease that the local soft tissue structural relaxation is caused, also can be widely used in simultaneously enlarge the bosom, aesthetic medicine field such as facial plasty.
The present invention has following effect:
1. after Zhi Bei chitosan-calcium alginate gel bead soft tissue enhancement material is implanted, can be stably fixed in the local organization or on every side;
2. after chitosan-calcium alginate gel bead soft tissue enhancement material is implanted, can form the protuberance entity in the part, and keep definite shape, have higher-strength, the volume conservation rate is more than 72%;
3. after chitosan-calcium alginate gel bead soft tissue enhancement material is implanted, only form thin fibers encapsulation layer on every side in local organization (protuberance entity), do not produce significantly inflammatory reaction, histological examination is normal;
4. after chitosan-calcium alginate gel bead soft tissue enhancement material was implanted, laboratory animal regional nodes histological examination proof chitosan-calcium alginate gel bead did not have migration;
5. after chitosan-calcium alginate gel bead soft tissue enhancement material was implanted, body can keep normal activities, does not produce toxic and side effects;
6. after chitosan-calcium alginate gel bead soft tissue enhancement material is implanted, dissect and reclaim chitosan-calcium alginate gel bead, chitosan-calcium alginate gel bead still can keep higher sphericity, not have a distortion substantially, and keeps certain intensity.
Compare with the present invention, the feature and the effect of background technology are as follows:
1. simple calcium alginate gel injection;
2. will adopt different gel process, add the homology fibroblast and use the injection injection effect of the sodium alginate preparation of modifying to contrast by RGD sequence peptide;
3. concrete gel process has preceding calcium alginate gelization of injection and injection back calcium alginate gelization;
4. zoopery shows, each average external volume conservation rate of organizing eight week back subcutaneous injections protuberance entities does not wait 19% to 88%, does not add wherein that the highest average external volume conservation rate is 58% in the experimental group of homology fibroblast;
5. histological examination shows at protuberance and has formed the thin layer fibers encapsulation around the entity.
Description of drawings
Fig. 1: vernier caliper measurement mouse subcutaneous injection animal model protuberance entity parameter.
The specific embodiment
The technology of preparing of calcium alginate gel bead is a known technology, and all adopting the static sessile drop method to prepare calcium alginate gel bead among the embodiment is the example explanation.
Embodiment 1
Chitosan-calcium alginate gel bead soft tissue enhancement material preparation: under the aseptic condition, 2.0% (w/v) sodium alginate soln is at 1.0mol/L CaCl
2Solution is to prepare particle diameter mainly at the calcium alginate gel bead of 400～600 μ m by the static sessile drop method under the condition of coagulation bath, and with calcium alginate gel bead and 0.7% (w/v) chitosan solution with 1: 7 volume ratio film forming, mix with 10: 20 volume ratios with the sodium alginate soln of 0.5% (w/v) then, obtain chitosan-calcium alginate gel bead soft tissue enhancement material.
Embodiment 2
Chitosan-calcium alginate gel bead soft tissue enhancement material preparation: under the aseptic condition, 0.5% (w/v) sodium alginate soln is at 0.01mol/L CaCl
2Solution is to prepare particle diameter mainly at the calcium alginate gel bead of 250-800 μ m by the static sessile drop method under the condition of coagulation bath, and with calcium alginate gel bead and 0.2% (w/v) chitosan solution with 1: 1 volume ratio film forming, mix with 10: 10 volume ratios with the sodium alginate soln of 2.0% (w/v) then, obtain chitosan-calcium alginate gel bead soft tissue enhancement material.
Embodiment 3
Chitosan-calcium alginate gel bead soft tissue enhancement material preparation: under the aseptic condition, 1.5% (w/v) sodium alginate soln is at 0.1mol/L CaCl
2Solution is to prepare particle diameter mainly at the calcium alginate gel bead of 100-600 μ m by the static sessile drop method under the condition of coagulation bath, and with calcium alginate gel bead and 1.0% (w/v) chitosan solution with 1: 5 volume ratio film forming, mix with 10: 15 volume ratios with the sodium alginate soln of 1.0% (w/v) then, obtain chitosan-calcium alginate gel bead soft tissue enhancement material.
Embodiment 4
Chitosan-calcium alginate gel bead soft tissue enhancement material preparation: under the aseptic condition, 2.0% (w/v) sodium alginate soln is at 1.0mol/L CaCl
2Solution is to prepare particle diameter mainly at the calcium alginate gel bead of 500-1000 μ m by the static sessile drop method under the condition of coagulation bath, and with calcium alginate gel bead and 0.4% (w/v) chitosan solution with 1: 10 volume ratio film forming, mix with 10: 5 volume ratios with the sodium alginate soln of 0.1% (w/v) then, obtain chitosan-calcium alginate gel bead soft tissue enhancement material.
Application examples
Chitosan-calcium alginate gel bead soft tissue enhancement material mouse subcutaneous injection is implanted zoopery.
Receptor: kunming mice, the male and female dual-purpose, 30,18～22g, available from Dalian Medical Univ zoopery center, normal diet is fed, random diet, room temperature (22～25) ℃.
Mice is divided into two groups, 15 every group.Use microsyringe at mouse back subcutaneous injection 0.8ml chitosan-calcium alginate gel bead soft tissue enhancement material for first group, produce protuberance entity (semiellipsoid, see accompanying drawing 1), in injection back same day, 1,2,3 ..., measure protuberance entity parameters (protuberance physical length a, protuberance entity width b, protuberance entity height c) 8 weeks, calculate protuberance entity volume (2 π abc/3) and protuberance entity volume conservation rate (be defined as this time protuberance entity measuring volume and swell the percentage ratio of ratio of entity measuring volume the first time).2,4,8 weeks were put to death the part mice in the injection back, reclaimed chitosan-calcium alginate gel bead, and made tissue slice, carried out histological examinations such as HE dyeing.Organize in contrast for second group, at mouse back subcutaneous injection 0.8ml 0.9% (w/v) NaCl solution (normal saline), form the protuberance entity, observe and measure protuberance entity change in volume with microsyringe.
Zoopery is the result show, swells entity volume conservation rate generally within 80%, and the chitosan-calcium alginate gel bead of 8 weeks back recovery is still complete, and keeps sphericity preferably.Physiological activity state and the body weight of animal are normal.Histological examination shows, injects local organization and only forms thin fibers encapsulation layer, significantly inflammatory reaction of generation on every side.The histological examination of laboratory animal regional nodes shows that chitosan-calcium alginate gel bead does not have migration; Control group mice protuberance entity all disappeared in 1 day.
Zoopery proof chitosan-calcium alginate gel bead local injection embedded material has higher intensity, can be good at fixing at the implanting tissue position, and biocompatibility is good, meets the basic demand of implanting the soft tissue enhancement material as local injection.
Comparative example: according to document 1 report, the injection of use calcium alginate gel, and adopt different gel process and adding homology fibroblast and use the sodium alginate of modifying by RGD sequence peptide to compare, 8 all zoopery results show, each average external volume conservation rate of organizing eight week back subcutaneous injections protuberance entities does not wait 19% to 88%, does not add wherein that the highest average external volume conservation rate is 58% in the experimental group of homology fibroblast.And, though add the volume conservation rate that has improved the protuberance entity with the fibril archeocyte to a certain extent, also brought problems such as difficult storage, clinical practice popularization difficulty and use cost increase substantially simultaneously.Add RGD and not only can increase substantially cost, and this result of study shows that also it adds not improve injects the average external volume conservation rate that the back forms the protuberance entity.
Claims (6)
1. chitin-alginic acid calcium gel micro-ball soft tissue enhancement material coats chitosan film by calcium alginate gel bead, and is that the sodium alginate soln of 0.1-4.0% mixes composition with w/v;
Wherein the particle diameter of calcium alginate gel bead is 1-2000 μ m;
The ratio of chitin-alginic acid calcium gel micro-ball and sodium alginate soln counts 10 by volume: 1-10: 30.
2. method for preparing the described chitin-alginic acid calcium of claim 1 gel micro-ball soft tissue enhancement material, its step is, under aseptic condition:
A) being coagulation bath with the solubility calcium saline solution of 0.01～1.0mol/L or being decentralized photo with slightly solubility calcium salt granule, is that 0.1～4.0% sodium alginate soln is prepared into calcium alginate gel bead with w/v;
B) be 0.1～4.0% chitosan solution by volume 1 with the calcium alginate plastic microsphere of step a preparation and w/v: 1-1: 10 film forming make chitin-alginic acid calcium gel micro-ball;
C) be that 0.1～4.0% sodium alginate soln is to mix in 10: 1～10: 30 to form gel state by volume with chitin-alginic acid calcium gel micro-ball and w/v, make chitin-alginic acid calcium gel micro-ball soft tissue enhancement material.
3. preparation method as claimed in claim 2, it is characterized in that, chitosan-calcium alginate gel bead is that sodium alginate soln is dispersed under stirring in the chitin-alginic acid calcium gel micro-ball with mixing of sodium alginate soln among the step c, and forms gel state.
4. preparation method as claimed in claim 2, it is characterized in that, chitosan-calcium alginate gel bead is that chitin-alginic acid calcium gel micro-ball is sucked in the sodium alginate soln with mixing of sodium alginate soln among the step c, stirs and makes its mix homogeneously, and form gel state.
5. preparation method as claimed in claim 2 is characterized in that, described solubility calcium saline solution is a calcium chloride solution; Described slightly solubility calcium salt granule is calcium carbonate, calcium lactate or calcium oxalate.
6. preparation method as claimed in claim 2 is characterized in that, the method for preparing calcium alginate gel bead among the step a is static sessile drop method, Pneumatic Liquid dripping method, emulsifying-internal gelation or membrane emulsifying/internal gelation method.
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| CN1973901B (en) * | 2006-12-07 | 2010-05-19 | 浙江大学 | Composite microsphere preparation of lactic acid-hydroxyacetic acid copolymer and its preparation process |
| CN101857698B (en) * | 2010-06-10 | 2012-06-27 | 厦门大学 | Polystyrene/calcium alginate composite gel microsphere in nuclear shell structure and preparation method thereof |
| CN102286155B (en) * | 2011-05-30 | 2012-11-21 | 武汉大学 | Preparation method of sodium alginate-calcium carbonate hybridized micron particles |
| CN107057085B (en) * | 2017-04-06 | 2019-04-19 | 扬州大学 | A kind of preparation method of calcium alginate sub-micron gel particles |
| CN109528692B (en) * | 2018-12-03 | 2020-11-10 | 王丽萍 | Concentrated growth factor slow-release freeze-dried film and preparation method thereof |
| CN110180018A (en) * | 2019-05-24 | 2019-08-30 | 武汉理工大学 | A kind of preparation method of calcic alginate/chitosan hemostatic microsphere |
| CN112618481B (en) * | 2021-02-22 | 2021-11-09 | 山东第一医科大学附属省立医院(山东省立医院) | Modified hydrogel, modified hydrogel microspheres and preparation method and application thereof |
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| CN1454995A (en) * | 2002-04-29 | 2003-11-12 | 天津市肝胆疾病研究所 | Method of embedding cell or tissue using sodium alginate-chitose-sodium alginate microcapsule |
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| CN1454995A (en) * | 2002-04-29 | 2003-11-12 | 天津市肝胆疾病研究所 | Method of embedding cell or tissue using sodium alginate-chitose-sodium alginate microcapsule |
Non-Patent Citations (1)
| Title |
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| 壳聚糖/海藻酸钠生物微胶囊的研究进展 王勇 解玉冰 马小军，生物工程进展，第19卷第02期 1999 * |
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