CN112023123B - 一种用于口腔修复的抑菌凝胶材料及其制备方法 - Google Patents
一种用于口腔修复的抑菌凝胶材料及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种可用于口腔修复的凝胶材料的制备方法,包括:(1)双凝胶网络组分的制备;(2)胶原蛋白基抗菌凝胶材料组分的制备;(3)辅助抑菌组分的制备;(4)预混液的制备;(5)凝胶成型。所述凝胶材料具有较强的抑菌作用,另外在凝胶固化过程中加入聚乙二醇‑聚‑L‑赖氨酸和矿物质离子,使凝胶在口腔环境中耐酸能力强,稳定性好;由于矿物质离子与凝胶分子中的羧基和氮原子上的孤对电子形成配位键,使胶液凝固时间较短,机械强度好,同时减慢凝胶的降解时间。
Description
技术领域
本发明属于医用材料领域,具体涉及一种用于口腔修复或凹陷填充的抑菌凝胶材料及其制备方法。
背景技术
在我国,由于生活习惯和传统观念的问题,使得人们不太重视口腔卫生护理,从而导致口腔发炎、溃烂。另外需要拔牙、牙种植的患者逐渐向年轻化发展。拔牙后,牙齿残缺处及周围牙龈多出现炎症,在止血和消炎后,仍需数周或数月的稳定期才能进行植入牙种植,在这期间牙齿残缺处会有大量病菌等微生物聚集,减慢伤口愈合时间。另外,一些牙齿例如智齿等拔除后,原牙齿存在的牙龈残缺部位愈合时间较长,此时,拔牙后伤口的后处理显得尤为重要,如何在牙种植前或拔牙后很好的护理,避免细菌滋生而感染,同时加快创伤部位修复是口腔领域的工作者研究的热点问题。
相关问题亟待解决的一个很重要的原因是市场需求量较大,众所周知,牙齿的形貌会影响一个人的整体气质,牙齿畸形不仅会影响面部美观,而且会影响面部发育、颞下颌关节和牙周组织的健康、口腔卫生护理,更甚会影响一个人的心理健康。当今社会随着人们的生活水平越来越好,大家也逐渐更关注自己的形象问题,为了拥有更好看的牙齿选择牙齿矫正术的人越来越多,而且大部分需求者为青少年。根据个人牙齿的情况,在牙齿矫正前需要拔牙的例子非常普遍,有些甚至需要拔掉3-4颗增生的牙齿。拔牙后,在如此大的口腔创面暴露的情况下,止血、消毒、抑菌等防止创伤感染的措施必须要给予高度重视。拔牙虽然是小手术,但是预防拔牙后的感染却是我们必须重视的问题。相关调查表明,拔牙后出现轻微感染的几率为70%,出现中度感染的几率为10%。众所周知,一旦拔牙后的创口发生感染,不仅会出现明显的疼痛,创口周围出红肿,同时伴随着发烧等身体不适的症状,甚至有可能出现心脏、颅内等感染,后果非常严重。
通常情况下,拔牙后医生会选择填充明胶类海绵,明胶海绵有吸血和压迫止血的作用,由于明胶海绵是质轻软而多孔的海绵状物,具吸水性,所以其在口腔中会因为患者饮食或饮水出现膨胀或缩小,特别容易出现脱落现象,给使用带来诸多不便。另外,在齿槽外科拔牙后的患者经常会出现一些并发症,如干槽症、拔牙位置出血时间长及骨腔愈合较慢等,通常情况下医生会在拔牙后填充胶原蛋白。胶原蛋白由于是机体的主要结构蛋白,所以抗原活性低、刺激性较小、细胞毒性小,作为填充物能很好的止血。但是胶原蛋白通常会在患者的口腔患处保留3-7天,在口腔大量微生物聚集的情况下患处容易发生感染,而且胶原蛋白本身并没有很好的杀菌抑菌作用。
目前用于拔牙后创口部位修复和填充材料的相关报道较少,专利文献CN105031747A公开了一种可吸收拔牙创护理组合物,所述组合物由可吸收生物高分子材料和生物活性矿物质粉体矿物质制成。此组合物降解时间较短,能在拔牙窝初期愈合过程中起到促进创面愈合的作用,但是发明人在组合物中添加了大量的矿物质粉体,忽略了所述组合物在进入口腔后凝固时间的问题,而且矿物质离子含量过多造成口感不适,生物相容性差,影响创面愈合。
专利文献CN105688288A公开了一种胶原基复合口腔修复膜材料,所述膜材料的制备方法包括,首先对胶原进行交联改性,再进行胶原的自组装、进一步交联与预钙化处理,最后进行仿生矿化制备得到用于口腔修复的膜材料。该膜材料可做为骨架材料,口腔舒适度差,使用不便,而且制备过程复杂,工艺步骤较多,成本高,投入市场中患者的接受度较低。
除了胶原蛋白,近年来壳聚糖由于优良的生物官能性和相容性、血液相容性、安全性、微生物降解性等优良性能被广泛关注,其在食品、美容、生物医学等诸多领域的应用研究取得了重大进展。壳聚糖是甲壳素的主要衍生物,是甲壳素脱除乙酰基后的产物—脱乙酰甲壳素,是一种可降解的生物相容性材料,具有良好的抗菌作用。它具有与黏多糖相似的结构特点,在组织中分布广泛,是细胞膜有机组成成分之一。高脱乙酰度的壳聚糖具有良好的生物相容性、体内可降解性、成膜性、可塑性,医用级的壳聚糖一般脱乙酰度≥90%,此外壳聚糖还具有促创伤愈合性、抗菌性和药物缓释性等优良的医疗特性和易于加工成型性等众多优点。在国内,以壳聚糖为母体的壳聚糖凝胶由于具有较好的机械强度和化学性质稳定性,在医药领域成为一种有应用前景的生物多聚物,尤其在皮肤、口腔、眼睛、关节等软组织领域应用得到越来越多的研究。
专利文献CN105457107A公开了一种双功能层口腔修复膜,所述修复膜由疏松多孔层与致密抑菌层两层组成,疏松多孔层由Ⅰ型胶原、氧化多糖和β-磷酸三钙组成,致密抑菌层由Ⅰ型胶原与氧化壳聚糖复合组成。该修复膜成分简单,仅可作为口腔患处的屏障膜使用,效果与明胶海绵、胶原蛋白相似。
专利文献CN103007338A公开了一种温度敏感型水凝胶或溶剂敏感型凝胶;所述温度敏感型水凝胶的相转变温度为25℃-36℃范围中的温度,当温度低于相转变温度时,该凝胶材料为液态,当温度高于相转变温度时,该凝胶材料为固态;所述溶剂敏感型凝胶是指该凝胶材料不溶于水,易溶于其它溶剂,当其溶于溶剂中时为液态,当溶剂减少后其为固态。然而,该凝胶材料具有较差的抑菌性和降解性,容易造成细菌滋生。而且所述凝胶材料由于变量的不可控性导致在使用过程中具有不稳定性,实际应用价值差。
专利文献CN103920192A公开了一种载生物活性因子的温敏复合凝胶载体的制备方法,该方法包括向溶胶中加入脂联素、Ca2+、煅烧骨粉,形成载生物活性因子的温敏复合凝胶载体。此凝胶载体具有治疗作用,对药物具有缓释作用,该发明着重改善的是生物活性因子缓释技术和温敏凝胶凝固技术,没有关注凝胶的抑菌性和在口腔中的降解问题。
CN201580084926公开了一种口腔抗菌凝胶剂及其制备方法,包括以下成分:去离子水、过氧化尿、凉感剂、燕麦抗敏剂、泊洛沙姆407、泊洛沙姆188,各成分以重量百分比计,其中去离子水占54.95%、过氧化尿占23%、凉感剂占0.05%、燕麦抗敏剂占1%、泊洛沙姆407占20%、泊洛沙姆188占1%,其制备过程中通过加入过氧化尿能够起到消毒的功能,通过加入泊洛沙姆407和泊洛沙姆188,使溶液能够进行凝胶化,便于人们的使用和给药,通过加入凉感剂,能够让使用者在使用到个过程中去除口臭且保证口腔持久的凉爽,通过添加燕麦抗敏剂,能够起到口腔抗过敏的效果。
CN201611254353提供了一种治疗小儿口腔溃疡的水凝胶及其制备方法。其组分包括贻贝软组织提取物、胰蛋白酶、蜂蜜、维生素C、维生素B1、维生素B2、烟酰胺、维生素B12、水溶性薄荷脑以及凝胶基质。
综上,虽然现有技术公开了多种口腔凝胶,但是通常作为口腔黏膜部位的药物或生物活性因子的载体,作为填充材料时存在着凝胶生物相容性、机械强度和降解性等问题。
另外,在齿外科拔牙后的骨槽或牙窝部位,目前市场上缺乏具备杀菌抑菌作用、促进创面愈合和抑菌的填充式凝胶材料,从而在口腔大量微生物聚集的情况下抑制患处感染,促进口腔修复。
发明内容
为了弥补和改善现有技术的不足,本发明提供一种可用于口腔修复的凝胶材料,所述凝胶材料主要包括羧甲基化修饰的羟丙基壳聚糖与透明质酸类双凝胶网络组分、胶原蛋白基抗菌凝胶材料组分和辅助抑菌组分。
本发明所述凝胶材料可用于口腔创伤修复或凹陷填充,其中,所述口腔创伤包括口腔发炎或溃烂造成的创面,所述凹陷填充包括拔牙后暴露的牙骨槽或牙龈凹陷。
本发明的技术方案如下。
首先,本发明提供一种用于口腔修复的抑菌性凝胶材料的制备方法,包括如下步骤:
(1)双凝胶网络组分的制备:取羧甲基化修饰的羟丙基壳聚糖与透明质酸或透明质酸接枝物混合,加入甘油磷酸钠、纳米羟基磷灰石,恒温静置1~2h,干燥,灭菌;
(2)胶原蛋白基抗菌凝胶材料组分的制备:取羧甲基壳聚糖溶于水形成质量浓度为0.5%~5%的溶液,加入不均一多糖,溶解后加入氯化钙或磷酸三钙,搅拌均匀;加入1~2倍质量的胶原蛋白-稀醋酸水溶液、甘油和抗菌组分,避光条件下搅拌3~5h,冷却至室温,冷冻干燥,灭菌;
(3)辅助抑菌组分的制备:取海藻酸钠、羧甲基壳聚糖和氯化钙水浴加热下在水中搅拌溶解,加入乳酸链球菌肽及L-乳酸,搅拌20~30min至溶液呈半透明稠胶状;加碘甘油混合液,室温下搅拌2~5h,真空干燥,辐照灭菌;
(4)预混液的制备:分别将上述步骤的组分溶解制成溶液,混合,加入聚乙二醇-聚-L-赖氨酸和矿物质离子,25~40℃下搅拌得到凝胶预混液;
(5)凝胶固化:调整凝胶预混液的pH至7.0~7.5,在30~37℃下预混液逐渐由流体状态变为半流体状态直至最终凝胶,形成用于口腔修复的凝胶材料。
其中,本发明上述方法中,所述步骤(1)中羧甲基化修饰的羟丙基壳聚糖与透明质酸或透明质酸接枝物混合形式包括:羧甲基化修饰的羟丙基壳聚糖溶液与透明质酸或透明质酸接枝物溶液混合,或羧甲基化修饰的羟丙基壳聚糖与透明质酸或透明质酸接枝物加入水中混合。
优选的,所述羧甲基化修饰的羟丙基壳聚糖溶液质量浓度为1%~3%,透明质酸或透明质酸接枝物溶液质量浓度为0.5%~2%。
优选的,所述羧甲基化修饰的羟丙基壳聚糖与透明质酸或透明质酸接枝物的质量用量比为10:1~3。
所述透明质酸接枝物选自:透明质酸接枝甲基丙烯酸缩水甘油酯、透明质酸接枝聚乙二醇单甲醚、透明质酸接枝十八烷基聚合物等中的一种或两种以上的组合。
优选的,所述甘油磷酸钠、纳米羟基磷灰石均为药品级,双凝胶网络组分制备步骤中甘油磷酸钠和纳米羟基磷灰石在溶液中的质量分数分别为0.1%~0.3%、0.1%~0.5%。
优选的,所述步骤(1)中恒温温度为50~60℃。
优选的,所述步骤(1)中干燥方式为真空干燥,温度为50~60℃。
优选的,所述步骤(2)中反应在不锈钢反应釜中进行。
优选的,所述步骤(2)中不均一多糖选自透明质酸或硫酸软骨素中的一种或两种的组合。
优选的,所述羧甲基壳聚糖与不均一多糖的质量比为1:0.1~0.3。
优选的,所述步骤(2)中胶原蛋白的稀醋酸水溶液质量浓度为2%~5%。
所述抗菌组分选自抗菌肽或其他无刺激性气味抗菌组分,优选抗菌肽;所述抗菌肽来源于植物、鱼类、软体动物或甲壳类动物,也可来源于细菌,如短杆菌肽、多粘菌素E、乳酸链球菌肽等。在本发明中,所述抗菌组分优选自乳酸链球菌肽。
优选的,所述步骤(2)胶原蛋白基抗菌凝胶材料组分溶液中甘油和抗菌组分的质量分数分别为0.5%~1%、0.05%~0.3%。
优选的,所述步骤(3)中羧甲基壳聚糖的脱乙酰度为90%以上。
本发明方法中,所述碘甘油混合液组成为:碘0.5-1wt%,KI 1-2wt%,氯化钠2-5wt%,甘油20-30wt%,余量为水。
优选的,所述步骤(3)具体操作过程为:按重量份,取海藻酸钠1~3份、羧甲基壳聚糖1~5份和氯化钙0.2~0.5份水浴加热下在150~250份水中搅拌溶解,加入乳酸链球菌肽0.1~1份及L-乳酸1~5份,搅拌20~30min至溶液呈半透明稠胶状;滴加入碘甘油混合液20~30份,室温下搅拌2~5h,10~20℃下真空干燥,辐照灭菌。
优选的,所述步骤(4)中溶剂选自蒸馏水、注射用水或生理盐水。
本发明中,步骤(4)各组分溶液中,所述双凝胶网络组分溶液的质量浓度为1%~5%,优选为1%~3%;所述胶原蛋白基抗菌凝胶材料组分溶液的质量浓度为1%~10%,优选为3%~6%;所述辅助抑菌组分溶液的质量浓度为1%~10%,优选为2%~5%。
优选的,所述步骤(4)中按组分净重计,双凝胶网络组分:胶原蛋白基抗菌凝胶材料组分:辅助抑菌组分:聚乙二醇-聚-L-赖氨酸:矿物质离子重量比为0.5~2:1:0.1~1:0.01~0.03:0.01~0.05。更优选的,所述组分质量比为0.5~1:1:0.2~0.5:0.01:0.05。
所述的聚乙二醇-聚-L-赖氨酸可商购得到或按照本领域现有技术的一般方法制备得到。
优选的,所述步骤(4)中矿物质离子选自可溶性金属离子盐,例如Ca2+、Mg2+、Fe2+、Zn2+的一种或两种以上金属盐的组合,优选钙离子盐。
优选的,所述步骤(4)中还包括加入药物,所述药物可选自抗菌剂、抗敏剂或消炎剂,例如维生素C、地喹氯铵、甲硝咪唑、西地碘等。
本发明还提供由上述本发明制备方法制备的凝胶材料在口腔创伤修复或口腔凹陷填充中的用途,其中,所述口腔创伤包括口腔发炎或溃烂造成的创面,所述凹陷填充包括拔牙后的牙槽凹槽或牙龈凹陷。
其中,所述凹槽包括拔牙后的骨槽或牙窝部(例如智齿拔除后的牙龈凹槽)。
本发明还提供一种使用上述凝胶材料的方法,包括:将所述液态凝胶材料注入口腔相应凹槽部位或涂敷于口腔其他创伤部位;或将已经凝固成型的凝胶填充入相应凹槽部位或贴敷于口腔其他创伤部位。
本发明所使用的原材料例如羟丙基壳聚糖可源自商购产品或按照本领域的一般方法制备得到。
本发明提供一种羧甲基化修饰的羟丙基壳聚糖的制备方法。示例性地,包括如下步骤:
(1)称取10~15g羟丙基壳聚糖溶于适量水中,室温搅拌0.5~2h后,加入2~3倍摩尔量质量分数为30~40%的NaOH溶液,搅拌碱化1~2h;
(2)加入100~150ml异丙醇充分搅拌,缓慢分批加入或滴加加入氯乙酸水溶液,氯乙酸水溶液的摩尔量为羟丙基壳聚糖的3~5倍;
(3)滴加完毕后升温至60~65℃,反应4~6h,得到均一透明液体,冷却至室温;
(4)反应液用透析分子量为2~4Kda的透析膜进行透析,去除小分子杂质后调节pH至中性,用丙酮沉淀并纯化产物,得到羧甲基化修饰的羟丙基壳聚糖。
本发明所述的水选自:蒸馏水、纯化水、去离子水中的一种或两种以上的组合;优选的,所述水选自蒸馏水。
本发明的技术效果:
(1)本发明所述双凝胶网络组分可形成致密的骨架网络结构,使得胶原蛋白基抗菌凝胶材料和辅助抑菌组分紧密的附着在网络结构中。
(2)在凝胶固化过程中加入聚乙二醇-聚-L-赖氨酸和矿物质离子。由于聚乙二醇-聚-L-赖氨酸属于碱性氨基酸聚合物,能有效提高凝胶的耐酸能力,使凝胶在口腔环境中稳定性更好。矿物质离子的加入不仅能为口腔创面的修复提供营养物质,而且凝胶分子中的羧基和氮原子上的孤对电子可以与矿物质金属离子形成配位键,使凝胶在凝固过程中形成的结构更致密,机械强度更好。
另外,凝胶中如果根据需要添加其他具有治疗作用的药物分子时,矿物质离子的加入量还能通过调控凝胶结构的致密性从而间接调控药物的释放速度。
(3)与现有口腔修复材料相比,本发明所提供凝胶材料还具有以下优势:1,作为凹陷部位填充材料时生物相容性好,具有良好的抑菌作用,防止口腔创面感染;2,在口腔中凝固时间短,有效防止凝胶流失的问题;3,口腔内稳定性较好,机械强度高;4,在复杂的口腔环境中耐酸能力强;5,降解速度适中,降解物无毒,避免了凝胶长期滞留带来的口腔污染和过快降解带来的频繁补充缺陷。
附图说明
图1凝胶材料的细胞毒性试验结果
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明的部分实施例,而不是全部。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
制备羟丙基壳聚糖
在三颈瓶中加入20g壳聚糖,50mL质量分数为15%的NaOH溶液和异丙醇200mL,室温下搅拌碱化1h,然后加入45mL质量分数为10%的四甲基氢氧化铵溶液和200mL环氧丙烷,室温下搅拌30min后升温至60℃,回流搅拌反应8h,反应结束后用体积比1:1的盐酸水溶液中和至pH=7,用丙酮沉淀出产物,抽滤得到粗产物。将所得粗产物通过反复溶解、沉淀提纯,先将所得粗产物溶于去离子水中,再向其中倾入过量乙醇,使产物沉淀,过滤,重复纯化步骤2~3次,烘干,即得羟丙基壳聚糖。
实施例2
制备羧甲基化修饰的羟丙基壳聚糖
称取10g实施例1制备的羟丙基壳聚糖溶于适量蒸馏水中,室温搅拌0.5h后,加入2倍摩尔量的质量分数为35%的NaOH溶液,搅拌碱化2h后,加入150ml异丙醇充分搅拌后,缓慢分批加入或滴加加入氯乙酸水溶液,氯乙酸水溶液的摩尔质量为羟丙基壳聚糖的4倍,滴加完毕升温至65℃,反应5h,得到均一透明液体,冷却至室温,倒出反应液,用透析分子量为3Kda的透析膜透析去除小分子杂质后,调节pH至中性,用丙酮沉淀并纯化产物,得到羧甲基化修饰的羟丙基壳聚糖。
实施例3
制备聚乙二醇-聚-L-赖氨酸
将1g L-赖氨酸和当量20%过量的三光气,于20mL四氢呋喃溶剂中50℃反应至澄清后再反应1h,即转化成L-赖氨酸-N-羧基-环内酸酐的结构。获得的L-赖氨酸-N-羧基-环内酸酐单体粗产物经四氢呋喃与正己烷重结晶纯化三次后得最终产物待用。
将2g单甲氧基聚乙二醇伯胺(Mn=2000g mol-1)在Schlenk瓶中50℃油浴真空干燥大约6h,后冷却到室温;将制备的L-赖氨酸-N-羧基-环内酸酐溶解于干燥二甲基甲酰胺中,然后用注射器抽取后转移至Schlenk瓶中在氮气保护及室温下反应;利用红外光谱分析仪确认反应完成后,取少量样品配制成5mg/mL进行SEC/LLS(体积排除色谱/激光散射)测试,确定多分散性与分子量;过量乙醚沉淀后,用少量三氟乙酸溶解产物,加入5倍当量的氢溴酸,在冰水浴中4h后用乙醚沉淀;用稀HCl调节pH值;使产物溶于水中,透析,冷冻干燥得到产物;计算引发的聚氨基酸嵌段的聚合度DPn为110,得到最终产物聚乙二醇-聚-L-赖氨酸(PEG50-b-PLL110)。
实施例4
凝胶材料1的制备
S1:双凝胶网络组分的制备:取10g质量浓度为2%的羧甲基化修饰的羟丙基壳聚糖溶液与2g质量浓度为1%的透明质酸溶液混合,充分搅拌使其溶解完全;加入药品级的甘油磷酸钠30mg和纳米羟基磷灰石60mg,恒温60℃下静置2h,在50℃下真空干燥,灭菌后保存备用;
S2:胶原蛋白基抗菌凝胶材料组分的制备:在不锈钢反应釜中,取10g羧甲基壳聚糖溶于水形成质量浓度为2%的溶液,加入硫酸软骨素0.2g,搅拌溶解后加入10mg氯化钙,搅拌均匀得到水溶性壳聚糖-不均一多糖混合液;加入相同质量的浓度为2%的胶原蛋白-稀醋酸水溶液(稀醋酸浓度为1wt%)、甘油0.5g和乳酸链球菌肽抗菌组分0.1g,避光条件下搅拌3h,冷却至室温,冷冻干燥,辐照灭菌后保存备用;
S3:辅助抑菌组分的制备:取2g海藻酸钠、3g羧甲基壳聚糖和0.5g氯化钙水浴加热下在200mL纯化水中搅拌溶解,加入乳酸链球菌肽0.5g及L-乳酸3g,搅拌30min至溶液呈半透明稠胶状;滴加25mL碘甘油混合液(碘0.5wt%,KI 1wt%,氯化钠2wt%,甘油20wt%,余量为水,下同),室温下搅拌3h,真空干燥,辐照灭菌后保存备用;
S4:用蒸馏水分别将0.8g双凝胶网络组分、1g胶原蛋白基抗菌凝胶材料组分和0.4g辅助抑菌组分溶解,使其质量浓度分别为2%、3%、2%,混合后再加入10mg聚乙二醇-聚-L-赖氨酸和50mg氯化钙,搅拌均匀得到预混液;调PH至7.0,37℃下继续搅拌,凝胶溶液逐渐凝固,形成可用于口腔修复的凝胶材料。
实施例5
凝胶材料2的制备
S1-S3:除了S2步骤中将抗菌肽组分替换为短杆菌肽0.1g外,其他操作与实施例4中S1-S3步骤相同。
S4:用蒸馏水分别将1g双凝胶网络组分、1g胶原蛋白基抗菌凝胶材料组分和0.5g辅助抑菌组分溶解,使其质量浓度分别为3%、3%、2%,混合后再加入10mg聚乙二醇-聚-L-赖氨酸和50mg氯化钙,搅拌均匀得到预混液;调PH至7.0,37℃下继续搅拌,凝胶溶液逐渐凝固,形成可用于口腔修复的凝胶材料。
效果实施例1
凝胶材料的抑菌试验
取实施例4和实施例5制备的凝胶预混液1mL涂于橡胶板上,制成半径为0.5cm的圆形膜片,备用。将灭菌的培养基倒入培养皿中,每皿约20mL,共12个,倒完后水平放置培养皿,使培养基凝固。每皿加入0.1mL葡萄球菌悬液,用涂布棒均匀涂开。将上述培养皿分为4组,每组3个,分别标记1-3。实验组:用镊子夹取凝胶膜片放在接过种的培养皿,每皿放2片,呈对称放置;阴性对照:每皿加40uL培养基,分两次添加,形成半径约为0.5cm的圆形;阳性对照:每皿加40uL青霉素钠溶液(100U/mL),分两次添加,形成半径约为0.5cm的圆形。将培养皿放入培养箱中,37℃倒置培养48h,观察各培养皿中抑菌圈大小,统计结果如下表所示。
表1 凝胶材料抑菌能力比较
根据上表可以看出,本发明所制备的凝胶材料能有效抑制口腔常见菌葡萄球菌,与阴性对照相比,效果是其3倍左右,与阳性对照青霉素钠溶液相比,抑菌效果相当。两个实验组的凝胶膜片相比,乳酸链球菌肽的抑菌效果稍强于短杆菌肽。
效果实施例2
凝胶材料的细胞毒性试验
取实施例4和实施例5制备的凝胶预混液5mL涂于橡胶板上,制成圆形膜片,将膜片放入100mL MEM细胞培养液中浸提,在培养箱中浸提24h得到浸提液。为了避免因为水分蒸发造成浓度改变后影响实验结果接种细胞,在96孔板外缘一周每孔加入200uL无菌PBS。设计对照孔和调零孔的位置和数量,将巨噬细胞分散在DMEM培养基中制成单细胞悬液,在显微镜下进行细胞计数,以每孔5000左右个细胞将巨噬细胞接种到96孔板上,每孔体积200uL,放入37℃,含5%CO2及饱和湿度的培养箱中培养24h。细胞培养24h后用移液枪将每孔旧培养基吸出,将浸提液原液、稀释2倍、稀释5倍、稀释10倍的浸提液分别加入实验孔中,对照孔和调零孔加新鲜培养基,继续培养24h。取出96孔板,每孔加入20μL MTT溶液,在培养箱中孵育4h,将旧培养基吸出,再每孔加入150μL DMSO,孵育10min。选择490nm波长,在酶联免疫检测仪上测定各孔光吸收值,记录结果。通过公式:细胞活力=(实验组A值-调零孔A值)/(对照孔A值-调零孔A值)计算出不同药物浓度下实验细胞的细胞活力,结果如图1所示。
根据图1的结果可以看出,浸提原液以及稀释2-10倍的浸提液,细胞培养后的细胞活力均在0.85以上。由此说明,本发明所制备的凝胶材料对于人体不会有细胞毒性,安全性良好。当凝胶材料中的抑菌组分选择乳酸链球菌肽和短杆菌肽时,凝胶材料的细胞毒性相当,没有显著差异。
实施例6
对比凝胶材料1的制备
双凝胶网络组分的制备、胶原蛋白基抗菌凝胶材料组分的制备和辅助抑菌组分的制备与实施例4相同,不同之处在于配置预混液时不添加聚乙二醇-聚-L-赖氨酸和氯化钙,其余操作均相同。测试凝胶材料的成胶凝固时间、20%降解时间、机械强度。
凝固时间:体外37℃水浴恒温箱中,为了模拟口腔环境,将PH调至6.5,凝胶预混液由液态转化为固态所需时间。20%降解时间:体外37℃水浴恒温震荡箱(30rpm)中,PH为6.5,凝胶材料固化后体积缩小至约80%(此时该体积大小在口腔凹陷填充中易产生明显缝隙且易脱落)的时间。机械强度:取制备的预混液5mL涂于橡胶板上,制成圆形膜片,向膜片施加拉力,膜片破裂时的拉力大小。
实施例7
对比凝胶材料2的制备
双凝胶网络组分的制备、胶原蛋白基抗菌凝胶材料组分的制备和辅助抑菌组分的制备与实施例4相同,不同点在于配置预混液时不添加聚乙二醇-聚-L-赖氨酸,而氯化钙添加0.05g,其余操作均相同。测试凝胶材料的凝固时间、降解时间、机械强度。
实施例8
对比凝胶材料3的制备
双凝胶网络组分的制备、胶原蛋白基抗菌凝胶材料组分的制备和辅助抑菌组分的制备与实施例4相同,不同点在于配置预混液时不添加氯化钙,而聚乙二醇-聚-L-赖氨酸添加0.01g,其余操作均相同。测试凝胶材料的凝固时间、降解时间、机械强度。
效果实施例3
聚乙二醇-聚-L-赖氨酸和氯化钙对凝胶材料的影响
实施例4和实施例6-8制备的对比凝胶材料,其凝固时间(秒,个位数四舍五入)、20%降解时间、机械强度如下表所示。
表2 聚乙二醇-聚-L-赖氨酸和氯化钙对凝胶材料的影响
从上表数据可以看出,在配置预混液时同时添加聚乙二醇-聚-L-赖氨酸和氯化钙时,凝胶的凝固时间最短,而降解时间最慢,机械强度最强;只添加氯化钙效果次之,仅添加聚乙二醇-聚-L-赖氨酸时,对凝固时间和机械强度的改善效果不明显,但是能有效增加凝胶的降解时间,这是由于聚乙二醇-聚-L-赖氨酸属于碱性氨基酸聚合物,能有效提高凝胶的耐酸能力,而口腔环境在多数情况下是酸性,因此聚乙二醇-聚-L-赖氨酸使凝胶在口腔环境中稳定性更好。而矿物质离子如Ca2+的加入能有效缩短凝胶的凝固时间,防止凝固时间过长在口腔中流走,这是由于凝胶分子中的羧基和氮原子上的孤对电子可以与矿物质金属离子形成配位键,使凝胶在凝固过程中形成的结构更致密,因此机械强度更好,降解过程更缓慢。如果凝胶中加入具有消炎抗菌等作用的药物时,此凝胶载体可控制药物缓慢释放,避免药物快速释放造成血药浓度过高的现象,特别适合于一些肾毒性、肝毒性较大的抗生素类药物。
以上具体实施方式只是对本发明内容的示意性说明,不代表本发明内容的限制。尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (10)
1.一种用于口腔修复的抑菌性凝胶材料的制备方法,其特征在于,包括如下步骤:
(1)双凝胶网络组分的制备:取羧甲基化修饰的羟丙基壳聚糖溶液与透明质酸或透明质酸接枝物溶液混合,加入甘油磷酸钠、纳米羟基磷灰石,恒温反应1~2h,干燥,灭菌;
(2)胶原蛋白基抗菌凝胶材料组分的制备:取羧甲基壳聚糖溶于水形成质量浓度为0.5%~5%的溶液,加入不均一多糖,溶解后加入氯化钙或磷酸三钙,搅拌均匀;加入1~2倍质量的胶原蛋白-稀醋酸水溶液、甘油和抗菌组分,避光条件下搅拌3~5h,冷却至室温,冷冻干燥,灭菌;
(3)辅助抑菌组分的制备:取海藻酸钠、羧甲基壳聚糖和氯化钙水浴加热下在水中搅拌溶解,加入乳酸链球菌肽及L-乳酸,搅拌20~30min至溶液呈半透明稠胶状;滴加碘甘油混合液,室温下搅拌2~5h,真空干燥,辐照灭菌;
(4)预混液的制备:分别将上述步骤的组分溶解制成溶液,混合,加入聚乙二醇-聚-L-赖氨酸和矿物质离子,25~40℃下搅拌得到凝胶预混液;
(5)凝胶固化成型:调整凝胶预混液的pH至7.0~7.5,在30~37℃下预混液逐渐由流体状态形成用于口腔修复的抑菌性凝胶材料。
2.根据权利要求1所述的制备方法,其特征在于,步骤(1)中所述羧甲基化修饰的羟丙基壳聚糖溶液质量浓度为1%~3%,透明质酸或透明质酸接枝物溶液质量浓度为0.5%~2%;羧甲基化修饰的羟丙基壳聚糖与透明质酸或透明质酸接枝物质量比为10:1~3。
3.根据权利要2所述的制备方法,其特征在于,所述透明质酸接枝物选自:透明质酸接枝甲基丙烯酸缩水甘油酯、透明质酸接枝聚乙二醇单甲醚、透明质酸接枝十八烷基聚合物中的一种或两种以上的组合。
4.根据权利要求1所述的制备方法,其特征在于,所述双凝胶网络组分制备步骤中甘油磷酸钠和纳米羟基磷灰石在溶液中的质量含量分别为0.1%~0.3%、0.1%~0.5%。
5.根据权利要求1所述的制备方法,其特征在于,所述步骤(2)中不均一多糖选自透明质酸或硫酸软骨素中的一种或两种的组合;羧甲基壳聚糖与不均一多糖的质量比为1:0.1~0.3;所述抗菌组分选自抗菌肽,所述抗菌肽来源于植物、鱼类、软体动物、甲壳类动物或来源于细菌。
6.根据权利要求5所述的制备方法,其特征在于,其中来源于细菌的抗菌肽选自短杆菌肽、多粘菌素E或乳酸链球菌肽。
7.根据权利要求1所述的制备方法,其特征在于,所述步骤(3)具体步骤为:按重量份计,取海藻酸钠1~3份、羧甲基壳聚糖1~5份和氯化钙0.2~0.5份水浴加热下在150~250份水中搅拌溶解,加入乳酸链球菌肽0.1~1份及L-乳酸1~5份,搅拌20~30min至溶液呈半透明稠胶状;然后滴加碘甘油混合液20~30份,室温下搅拌2~5h,10~20℃下真空干燥,辐照灭菌。
8.根据权利要求1所述的制备方法,其特征在于,所述步骤(4)中,按组分净重计,双凝胶网络组分:胶原蛋白基抗菌凝胶材料组分:辅助抑菌组分:聚乙二醇-聚-L-赖氨酸:矿物质离子重量比为0.5~2:1:0.1~1:0.01~0.03:0.01~0.05。
9.根据权利要求1所述的制备方法,其特征在于,所述步骤(4)中还进一步地包括加入药物。
10.根据权利要求1-9任一项所述方法制备得到的抑菌性凝胶材料。
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CN110183672A (zh) * | 2019-05-31 | 2019-08-30 | 天津大学 | PETx聚合物、制备方法以及三维荆棘状传感器界面 |
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