技术领域technical field
本发明涉及一种可注射磷酸钙/天然高分子复合材料及其制备方法和应用，属于生物医用材料领域。The invention relates to an injectable calcium phosphate/natural polymer composite material and its preparation method and application, belonging to the field of biomedical materials.
背景技术Background technique
据统计，全球每年因先天畸形、肿瘤切除、交通事故等造成的颅颌面软硬组织畸形或缺损新增患者人数超100万，而有面部整形美容需求的人数更是无法统计。According to statistics, there are more than 1 million new patients with craniofacial soft and hard tissue deformities or defects caused by congenital malformations, tumor resections, and traffic accidents worldwide every year, and the number of people who need facial plastic surgery cannot be counted.
自1899年液体石蜡作为皮肤软组织填充剂首次用于临床以来，世界各国学者对注射填充材料及其临床应用进行了深入研究，并取得了多项进展，越来越多的注射填充剂被广泛用于美容皮肤科及整形外科等领域，以求通过注射的方法矫正人体外形缺陷及畸形。Since liquid paraffin was first used clinically as a skin and soft tissue filler in 1899, scholars from all over the world have conducted in-depth research on injection filling materials and their clinical applications, and have made many progresses. More and more injection fillers are widely used. In the fields of cosmetic dermatology and plastic surgery, in order to correct human body shape defects and deformities through injection.
目前市场上的面部整形美容材料以充填材料为主，包括自体脂肪组织移植、天然或人工合成的生物材料。自体脂肪移植有较好的效果，但脂肪的存活率仍然偏低且不稳定，往往需要二次手术来矫正。天然或人工合成的充填材料主要包括可降解生物材料(胶原、透明质酸钠、聚乳酸、羟基磷灰石、聚乙烯醇等)、非降解生物材料(硅胶、聚丙烯酰胺、聚烷基酰胺等)、以及它们的复合物(聚甲基丙烯酸甲酯+胶原、甲基丙烯酸羟乙酯+透明质酸钠等)。非降解生物材料则存在一些潜在的风险，如异物肉芽肿，材料移位等，当出现问题时不易取出，从而给患者带来极大的伤害；可降解生物材料有较高的生物安全性，但吸收快，维持时间短，一般在0.5-1年内恢复原来状态，难以长期维持塑性效果；复合型生物材料可适度延长维持时间，是临床上不错的选择，但也存在一些问题，如产生肉芽肿等。Currently, the facial plastic surgery materials on the market are mainly filling materials, including autologous adipose tissue transplantation, natural or synthetic biomaterials. Autologous fat transplantation has a good effect, but the survival rate of fat is still low and unstable, and often requires secondary surgery to correct it. Natural or synthetic filling materials mainly include degradable biomaterials (collagen, sodium hyaluronate, polylactic acid, hydroxyapatite, polyvinyl alcohol, etc.), non-degradable biomaterials (silica gel, polyacrylamide, polyalkylamide etc.), and their complexes (polymethyl methacrylate + collagen, hydroxyethyl methacrylate + sodium hyaluronate, etc.). Non-degradable biomaterials have some potential risks, such as foreign body granuloma, material displacement, etc., and it is not easy to take out when there is a problem, which will bring great harm to patients; degradable biomaterials have higher biological safety, However, the absorption is fast and the maintenance time is short. Generally, it returns to its original state within 0.5-1 year, and it is difficult to maintain the plastic effect for a long time. The composite biomaterial can moderately prolong the maintenance time, which is a good choice in clinical practice, but there are still some problems, such as granulation. swelling etc.
上述的这些填充材料随着应用的日益广泛暴露出它们的缺点，有的组织反应较重，有的降解速度很快，远没有达到理想的效果。The above-mentioned filling materials have exposed their shortcomings with the increasing application. Some tissue reactions are severe, and some degrade quickly, which is far from achieving the desired effect.
发明内容Contents of the invention
为了解决上述问题，本发明提供了一种新的面部微整形材料，其为可注射磷酸钙/天然高分子复合材料，可以灌装至专用注射器中，通过医用钝针将该材料直接注射植入到面部需整形或塑形部位，一定时间后材料中的天然高分子逐步降解吸收，而磷酸钙陶瓷颗粒与自体骨逐渐融合为一体，进而达到持久塑形的作用。In order to solve the above problems, the present invention provides a new facial microplastic material, which is an injectable calcium phosphate/natural polymer composite material, which can be filled into a special syringe, and the material can be directly injected and implanted through a medical blunt needle When it comes to the part of the face that needs plastic surgery or shaping, the natural polymer in the material will gradually degrade and absorb after a certain period of time, and the calcium phosphate ceramic particles will gradually fuse with the autologous bone to achieve a lasting shaping effect.
本发明可注射磷酸钙/天然高分子复合材料，它是含有磷酸钙与天然高分子或其衍生物的复合物，其中，天然高分子或其衍生物为透明质酸钠、胶原、壳聚糖、硫酸软骨素中的一种或几种。The injectable calcium phosphate/natural macromolecule composite material of the present invention is a compound containing calcium phosphate and natural macromolecules or derivatives thereof, wherein the natural macromolecules or derivatives thereof are sodium hyaluronate, collagen, chitosan , one or more of chondroitin sulfate.
其中，所述磷酸钙是添加有0-20％生物活性玻璃的近球形羟基磷灰石或双相磷酸钙(羟基磷灰石和磷酸三钙两相构成的复合物)陶瓷颗粒，其粒径为20-100μm。Wherein, the calcium phosphate is a subspherical hydroxyapatite or biphasic calcium phosphate (composite composed of two phases of hydroxyapatite and tricalcium phosphate) ceramic particles added with 0-20% bioactive glass. 20-100μm.
其中，所述磷酸钙是添加有5-10％生物活性玻璃的双相磷酸钙陶瓷颗粒，其粒径为20-40μm。Wherein, the calcium phosphate is biphasic calcium phosphate ceramic particles added with 5-10% bioactive glass, and its particle size is 20-40 μm.
其中，所述天然高分子衍生物是透明质酸钠、胶原、壳聚糖、硫酸软骨素经适度化学改性后获得，具有良好的生物相容性和适度的粘流特性。Wherein, the natural polymer derivative is obtained by moderate chemical modification of sodium hyaluronate, collagen, chitosan, and chondroitin sulfate, and has good biocompatibility and moderate viscous flow characteristics.
其中，所述的可注射磷酸钙/天然高分子复合材料为膏状物，其中磷酸钙的固含量为60-90(w/w)％，天然高分子或其衍生物的固含量为0.05-1.0(w/w)％，其余为水。Wherein, the injectable calcium phosphate/natural polymer composite material is a paste, wherein the solid content of calcium phosphate is 60-90 (w/w)%, and the solid content of natural polymer or its derivatives is 0.05- 1.0(w/w)%, the rest is water.
其中，所述的磷酸钙陶瓷颗粒的固含量为65-75(w/w)％，天然高分子或其衍生物的固含量为0.1-0.6(w/w)％，其余为水。Wherein, the solid content of the calcium phosphate ceramic particles is 65-75 (w/w)%, the solid content of the natural polymer or its derivatives is 0.1-0.6 (w/w)%, and the rest is water.
本发明还提供了前述可注射磷酸钙/天然高分子复合材料的制备方法，具体包括如下步骤：The present invention also provides a preparation method for the aforementioned injectable calcium phosphate/natural polymer composite material, specifically comprising the following steps:
1)将天然高分子或其衍生物配制成适合粘度的水溶液；1) Prepare the natural polymer or its derivatives into an aqueous solution with a suitable viscosity;
2)制备含生物活性玻璃的磷酸钙陶瓷颗粒：将羟基磷灰石(或双相磷酸钙)微粉和生物活性玻璃微粉分散到浓度0.5-1.5％的聚乙烯醇水溶液中，转入球磨机中进行球磨，得到浆料，再将该浆料通过蠕动泵输送至喷雾干燥机中进行喷雾干燥处理，收集喷雾干燥粉并在600-1100℃下烧结，然后通过标准分样筛对烧结后粉体进行筛分，得到粒径为20-100μm的含生物活性玻璃的磷酸钙陶瓷颗粒；2) Preparation of calcium phosphate ceramic particles containing bioactive glass: disperse hydroxyapatite (or biphasic calcium phosphate) micropowder and bioactive glass micropowder into polyvinyl alcohol aqueous solution with a concentration of 0.5-1.5%, and transfer them to a ball mill Ball milling to obtain slurry, and then transport the slurry to a spray dryer for spray drying treatment through a peristaltic pump, collect spray-dried powder and sinter at 600-1100°C, and then pass the sintered powder through a standard sampling sieve Sieving to obtain calcium phosphate ceramic particles containing bioactive glass with a particle size of 20-100 μm;
3)称取步骤2)得到的磷酸钙陶瓷颗粒，加入到步骤1)得到的天然高分子或其衍生物的水溶液中，充分搅拌使固体颗粒在溶液中均匀分散，得到所需的膏状复合物；3) Weigh the calcium phosphate ceramic particles obtained in step 2), add them to the aqueous solution of the natural polymer or its derivatives obtained in step 1), stir well to make the solid particles uniformly disperse in the solution, and obtain the desired paste composite thing;
4)将步骤3)得到的磷酸钙/天然高分子膏状复合物通过灌装设备灌注至注射器中，灭菌处理，得到所需的可注射磷酸钙/天然高分子复合材料制品。4) The calcium phosphate/natural polymer paste compound obtained in step 3) is poured into a syringe through a filling device, and sterilized to obtain the desired injectable calcium phosphate/natural polymer composite product.
本发明还提供了前述可注射磷酸钙/天然高分子复合材料在面部微整形中的应用。The present invention also provides the application of the above-mentioned injectable calcium phosphate/natural polymer composite material in micro-plastic surgery of the face.
本发明还提供了一种面部微整形的方法，步骤如下：取前述可注射磷酸钙/天然高分子复合材料，植入面部需整形部位的软组织与骨膜之间，即可。The present invention also provides a method for micro-plastic surgery of the face, the steps are as follows: take the aforementioned injectable calcium phosphate/natural polymer composite material, and implant it between the soft tissue and the periosteum of the part of the face where plastic surgery is required.
其中，植入的方法是注射。Among them, the method of implantation is injection.
本发明可注射磷酸钙/天然高分子复合材料，采用本发明方法植入体内一定时间后，其中的天然高分子被降解吸收，而磷酸钙陶瓷颗粒与自体骨组织逐渐融合为一体，可以达到持久塑形的作用，且颗粒无明显游走和移位，塑形效果良好，临床应用前景良好。The injectable calcium phosphate/natural polymer composite material of the present invention, after being implanted in the body for a certain period of time by the method of the present invention, the natural polymer in it is degraded and absorbed, and the calcium phosphate ceramic particles and the autologous bone tissue are gradually fused together, which can achieve long-lasting The effect of shaping, and the particles have no obvious migration and displacement, the shaping effect is good, and the clinical application prospect is good.
下面通过具体实施方式对本发明做进一步详细说明，但是并不是对本发明的限制，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。The present invention will be further described in detail below through specific embodiments, but it is not a limitation of the present invention. According to the above-mentioned content of the present invention, according to common technical knowledge and conventional means in this field, without departing from the above-mentioned basic technical idea of the present invention. Various other modifications, substitutions, or changes may also be made.
附图说明Description of drawings
图1可注射磷酸钙/天然高分子复合材料样品；Figure 1 Injectable calcium phosphate/natural polymer composite material sample;
图2可注射磷酸钙/天然高分子复合材料动物体内植入3个月后的组织切片染色分析。Fig. 2 Staining analysis of tissue sections 3 months after implantation of injectable calcium phosphate/natural polymer composites in animals.
具体实施方式Detailed ways
实施例1本发明可注射磷酸钙/透明质酸钠复合材料的制备Embodiment 1 Preparation of injectable calcium phosphate/sodium hyaluronate composite material of the present invention
1、制备方法1. Preparation method
1)取经1,4-丁二醇缩水甘油醚(BDDE)改性(改性程度6-10％)的透明质酸钠(分子量1000kDa，山东华熙福瑞达生物医药有限公司)衍生物配制成10ml 2.5％的水溶液；1) Prepared with sodium hyaluronate (molecular weight 1000kDa, Shandong Huaxi Freda Biomedical Co., Ltd.) modified by 1,4-butanediol glycidyl ether (BDDE) (modification degree 6-10%) into 10ml of 2.5% aqueous solution;
2)取15g粒径70-100μm的羟基磷灰石陶瓷颗粒，加入到上述透明质酸钠溶液中搅拌均匀，形成膏状复合物(磷酸钙陶瓷颗粒的固含量60(w/w)％，透明质酸钠的固含量为1.0(w/w)％)；2) Take 15g of hydroxyapatite ceramic particles with a particle size of 70-100 μm, add them to the above-mentioned sodium hyaluronate solution and stir evenly to form a paste compound (the solid content of the calcium phosphate ceramic particles is 60 (w/w)%, The solid content of sodium hyaluronate is 1.0 (w/w)%);
粒径70-100μm的羟基磷灰石陶瓷颗粒的制备：将羟基磷灰石微粉分散到1.5％聚乙烯醇水溶液中，转移至球磨机中球磨24小时，形成颗粒分散性良好的浆料，通过蠕动泵输送至喷雾干燥机中进行喷雾干燥处理，收集喷雾干燥粉于1100℃下烧结，然后用标准分样筛对烧结后粉体进行筛分处理，得到平均粒径70-100μm的近球形羟基磷灰石陶瓷颗粒。Preparation of hydroxyapatite ceramic particles with a particle size of 70-100 μm: disperse hydroxyapatite micropowder into 1.5% polyvinyl alcohol aqueous solution, transfer to a ball mill and mill for 24 hours to form a slurry with good particle dispersibility. The pump is transported to the spray dryer for spray drying treatment, the spray dried powder is collected and sintered at 1100 ° C, and then the sintered powder is sieved with a standard sample sieve to obtain nearly spherical hydroxyphosphorus with an average particle size of 70-100 μm Gray stone ceramic particles.
3)将上述膏状复合物灌装至注射器中，灭菌处理，获得可注射磷酸钙/透明质酸钠复合材料制品(附图1)。3) Fill the above paste compound into a syringe, and sterilize it to obtain an injectable calcium phosphate/sodium hyaluronate composite product (Fig. 1).
实施例2本发明可注射磷酸钙/胶原复合材料的制备Embodiment 2 Preparation of injectable calcium phosphate/collagen composite material of the present invention
1、制备方法1. Preparation method
1)取医用胶原配制成10ml 1.0％的水溶液；1) Take medical collagen and prepare 10ml of 1.0% aqueous solution;
2)取30g粒径为40-70μm的双相磷酸钙陶瓷颗粒(羟基磷灰石/磷酸三钙＝70/30)，加入到上述胶原溶液中搅拌均匀，形成膏状复合物(磷酸钙陶瓷颗粒的固含量为75(w/w)％，胶原的固含量为0.25(w/w)％)；2) Take 30g of biphasic calcium phosphate ceramic particles (hydroxyapatite/tricalcium phosphate=70/30) with a particle size of 40-70 μm, add them to the above collagen solution and stir evenly to form a paste-like composite (calcium phosphate ceramic The solid content of the particles is 75 (w/w)%, and the solid content of the collagen is 0.25 (w/w)%);
粒径40-70μm的双相磷酸钙陶瓷颗粒的制备：将双相磷酸钙微粉分散到1.0％聚乙烯醇水溶液中，转移至球磨机中球磨24小时，形成颗粒分散性良好的浆料，通过蠕动泵输送至喷雾干燥机中进行喷雾干燥处理，收集喷雾干燥粉于800℃下烧结，然后用标准分样筛对烧结后粉体进行筛分处理，得到粒径为40-70μm的近球形双相磷酸钙陶瓷颗粒。Preparation of biphasic calcium phosphate ceramic particles with a particle size of 40-70 μm: Disperse the biphasic calcium phosphate micropowder into a 1.0% polyvinyl alcohol aqueous solution, transfer to a ball mill and mill for 24 hours to form a slurry with good particle dispersion, through peristaltic The pump is transported to the spray dryer for spray drying treatment, the spray dried powder is collected and sintered at 800 ° C, and then the sintered powder is sieved with a standard sample sieve to obtain a nearly spherical dual-phase particle size of 40-70 μm Calcium phosphate ceramic particles.
3)将上述膏状复合物灌装至注射器中，灭菌处理，获得可注射磷酸钙/胶原复合材料制品。3) Filling the above paste compound into a syringe and sterilizing it to obtain an injectable calcium phosphate/collagen composite material product.
实施例3本发明可注射磷酸钙/透明质酸钠-硫酸软骨素复合材料的制备Example 3 Preparation of injectable calcium phosphate/sodium hyaluronate-chondroitin sulfate composite material of the present invention
1、制备方法1. Preparation method
1)取透明质酸钠(分子量500kDa，山东华熙福瑞达生物医药有限公司)和硫酸软骨素(上海阿拉丁试剂公司)配制成10ml含1.5％透明质酸钠和0.5％硫酸软骨素的混合水溶液；1) Take sodium hyaluronate (molecular weight 500kDa, Shandong Huaxi Freda Biomedicine Co., Ltd.) and chondroitin sulfate (Shanghai Aladdin Reagent Company) to prepare 10ml of 1.5% sodium hyaluronate and 0.5% chondroitin sulfate Mixed aqueous solution;
2)取30g粒径为20-40μm的含5％生物活性玻璃(45S5生物玻璃，昆山华侨科技新材料有限公司)的羟基磷灰石陶瓷颗粒，加入到上述透明质酸钠-硫酸软骨素混合溶液中搅拌均匀，形成膏状复合物(磷酸钙陶瓷颗粒的固含量为75(w/w)％，透明质酸钠和硫酸软骨素的固含量为0.5(w/w)％)；2) Take 30g of hydroxyapatite ceramic particles containing 5% bioactive glass (45S5 bioglass, Kunshan Huaqiao Technology New Material Co., Ltd.) with a particle size of 20-40 μm, and add it to the above-mentioned sodium hyaluronate-chondroitin sulfate mixture Stir evenly in the solution to form a paste compound (the solid content of calcium phosphate ceramic particles is 75 (w/w)%, and the solid content of sodium hyaluronate and chondroitin sulfate is 0.5 (w/w)%);
含5％生物活性玻璃的羟基磷灰石陶瓷颗粒的制备：将羟基磷灰石微粉和生物活性玻璃微粉按照95/5的比例混合后分散到0.5％聚乙烯醇水溶液中，转移至球磨机中球磨24小时，形成颗粒分散性良好的浆料，通过蠕动泵输送至喷雾干燥机中进行喷雾干燥处理，收集喷雾干燥粉于1000℃下烧结，然后用标准分样筛对烧结后粉体进行筛分处理，得到粒径约20-40μm的含5％生物活性玻璃的近球形羟基磷灰石陶瓷颗粒。Preparation of hydroxyapatite ceramic particles containing 5% bioactive glass: mix hydroxyapatite micropowder and bioactive glass micropowder according to the ratio of 95/5, disperse them into 0.5% polyvinyl alcohol aqueous solution, transfer to ball mill for ball milling After 24 hours, a slurry with good particle dispersion is formed, which is transported to a spray dryer by a peristaltic pump for spray drying treatment, and the spray-dried powder is collected and sintered at 1000°C, and then the sintered powder is sieved with a standard sampling sieve After treatment, nearly spherical hydroxyapatite ceramic particles containing 5% bioactive glass with a particle size of about 20-40 μm are obtained.
3)将上述膏状复合物灌装至注射器中，灭菌处理，获得可注射磷酸钙/透明质酸钠-硫酸软骨素复合材料制品。3) Filling the above paste compound into a syringe and sterilizing it to obtain an injectable calcium phosphate/sodium hyaluronate-chondroitin sulfate composite product.
实施例4本发明可注射磷酸钙/透明质酸钠复合材料的制备Example 4 Preparation of Injectable Calcium Phosphate/Sodium Hyaluronate Composite Material of the Present Invention
1、制备方法1. Preparation method
1)取透明质酸钠(分子量500kDa，山东华熙福瑞达生物医药有限公司)配制成10ml0.5％透明质酸钠水溶液；1) Take sodium hyaluronate (molecular weight 500kDa, Shandong Huaxi Freda Biomedical Co., Ltd.) and prepare 10ml of 0.5% sodium hyaluronate aqueous solution;
2)取90g粒径为20-40μm的含10％生物活性玻璃(45S5生物玻璃，昆山华侨科技新材料有限公司)的羟基磷灰石陶瓷颗粒，加入到上述透明质酸钠混合溶液中搅拌均匀，形成膏状复合物(磷酸钙陶瓷颗粒的固含量为90(w/w)％，透明质酸钠的固含量为0.05(w/w)％)；2) Take 90g of hydroxyapatite ceramic particles with a particle size of 20-40 μm containing 10% bioactive glass (45S5 bioglass, Kunshan Huaqiao Technology New Material Co., Ltd.), add it to the above sodium hyaluronate mixed solution and stir evenly , forming a paste compound (the solid content of calcium phosphate ceramic particles is 90 (w/w)%, and the solid content of sodium hyaluronate is 0.05 (w/w)%);
含5％生物活性玻璃的羟基磷灰石陶瓷颗粒的制备：将羟基磷灰石微粉和生物活性玻璃微粉按照95/5的比例混合后分散到0.5％聚乙烯醇水溶液中，转移至球磨机中球磨24小时，形成颗粒分散性良好的浆料，通过蠕动泵输送至喷雾干燥机中进行喷雾干燥处理，收集喷雾干燥粉于1000℃下烧结，然后用标准分样筛对烧结后粉体进行筛分处理，得到平均粒径约20-40μm的含5％生物活性玻璃的近球形羟基磷灰石陶瓷颗粒。Preparation of hydroxyapatite ceramic particles containing 5% bioactive glass: mix hydroxyapatite micropowder and bioactive glass micropowder according to the ratio of 95/5, disperse them into 0.5% polyvinyl alcohol aqueous solution, transfer to ball mill for ball milling After 24 hours, a slurry with good particle dispersion is formed, which is transported to a spray dryer by a peristaltic pump for spray drying treatment, and the spray-dried powder is collected and sintered at 1000°C, and then the sintered powder is sieved with a standard sampling sieve After treatment, nearly spherical hydroxyapatite ceramic particles containing 5% bioactive glass with an average particle diameter of about 20-40 μm are obtained.
3)将上述膏状复合物灌装至注射器中，灭菌处理，获得可注射磷酸钙/透明质酸钠复合材料制品。3) Filling the above paste compound into a syringe and sterilizing it to obtain an injectable calcium phosphate/sodium hyaluronate composite material product.
以下用实验例的方式来证明本发明的有益效果：Prove the beneficial effect of the present invention in the mode of experimental example below:
实验例1本发明复合材料的修复效果实验Experimental example 1 Repair effect experiment of composite material of the present invention
1、实验方法1. Experimental method
取实施例3制备的可注射磷酸钙/天然高分子复合材料制品，灭菌后通过医用钝针将该膏体材料注射植入新西兰大白兔的大腿肌肉和股骨骨膜之间，形成局部隆起，在整个观察期内植入部位无明显炎性反应，兔子活动度良好。植入后3月，测量局部隆起部位高度和体积无明显变化。进一步处死动物取材，固定包埋后进行组织切片分析。Get the injectable calcium phosphate/natural polymer composite material product prepared in Example 3, after sterilization, inject and implant this paste material between the thigh muscle and the femoral periosteum of New Zealand white rabbits through a medical blunt needle to form a local bulge. During the entire observation period, there was no obvious inflammatory reaction at the implantation site, and the activity of the rabbit was good. Three months after implantation, there was no significant change in the height and volume of the local uplift. The animals were further sacrificed, and tissue slices were analyzed after fixed embedding.
2、实验结果2. Experimental results
实验结果如图2所示，固体颗粒间有明显的组织长入，与宿主骨有较好的融合，且颗粒无明显游走和移位，表现出良好的塑形效果。The experimental results are shown in Figure 2. There is obvious tissue growth between the solid particles, and they are well integrated with the host bone, and the particles have no obvious migration and displacement, showing a good shaping effect.
实验结果说明，本发明可注射磷酸钙/天然高分子复合材料，采用本发明方法植入体内后，其中的天然高分子被降解吸收，而磷酸钙陶瓷颗粒与自体骨组织融合为一体，可以达到持久塑形的作用，临床应用前景良好。The experimental results show that the injectable calcium phosphate/natural polymer composite material of the present invention is implanted in the body by the method of the present invention, the natural polymer therein is degraded and absorbed, and the calcium phosphate ceramic particles are integrated with the autologous bone tissue, which can achieve The role of long-lasting shaping, clinical application prospects are good.
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