硫酸软骨素及衍生物在医药领域中的研究进展
Advanced Research of Chondroitin Sulfate and Its Derivatives in the Medicine Field

作者: 田 雪 , 彭旭东 * , 尹 娇 , 张冉冉 :青岛大学附属医院眼科,山东 青岛;

关键词: 抗肿瘤硫酸软骨素生物材料药物递送系统组织工程Antitumor Chondroitin Sulfate Biological Material Drug Delivery System Tissue Engineering

摘要:
硫酸软骨素(chondroitin sulfate, CS)是一种天然糖胺聚糖(glycosaminoglycan,GAG),具有多重药理作用及结构可塑性。作为一类生物多糖,CS除了具有抗炎、抗肿瘤、促进细胞再生、抗病毒等生物活性外,其本身也作为生物材料在医学领域,如眼科、骨科、肿瘤等方向广泛应用。本文针对CS在病理生理与免疫系统中的生物学特性,及其在药物输送系统和组织工程中的应用进行概述,为其后续的开发研究提供理论依据。

Abstract: Chondroitin sulfate (CS) is a natural glycosaminoglycan (GAG), which has multiple pharmacological effects and structural plasticity. As a kind of biological polysaccharide, CS not only has anti-inflammatory, anti-tumor, promoting cell regeneration, anti-virus and other biological activities, but also has been widely used as a biological material in medical fields such as ophthalmology, orthopaedics, tumors and other fields recently. This article summarizes the biological characteristics of CS in pathophysiology and immune system, and its application in drug delivery system and tissue engineering, providing theoretical basis for its subsequent development and research.

1. 引言

硫酸软骨素(chondroitin sulfate, CS)是一种天然来源的生物活性大分子,属于糖胺聚糖(Glycosaminoglycan, GAG)类,不仅是细胞外基质(extracellular matrix, ECM)的主要组分,而且通常与膜蛋白连接形成硫酸软骨素蛋白聚糖(chondroitin sulfate proteoglycan, CSPG)分布在几乎所有细胞表面 [1],是多功能信号分子和调节剂,与细胞因子、生长因子和酶等相互作用 [2],对炎症 [3]、肿瘤进展和转移 [4]、血管重塑 [5]、抗氧化 [6] 等许多生理过程产生深刻的影响。

CS的糖链包括重复β-1,3-连接的N-乙酰基半乳糖胺和β-1,4-连接的D-葡糖醛酸二糖单元 [6],根据硫化物的位置和程度分为CSO,CSA,CSC,CSD,CSE五种类型,除了硫酸盐基团位置的可变性外,不同的硫酸盐基团也具有明显不同的生物活性 [7],例如具有3-O-磺基–葡萄糖醛酸残基的CS被证明有刺激神经突生长的功能 [8],岩藻糖基硫酸软骨素的硫酸化岩藻糖残基有抗炎、刺激造血等多种活性 [9]。

作为生物多糖,CS具备多价性、分子量可控性以及强大的可设计性 [10],受到聚合物科学研究者的青睐。CS良好的黏着性、生物相容性,生物降解性以及细胞靶向性 [11],使其被广泛应用于制备靶向输送系统,旨在将药物、细胞或基因嵌入到复合生物材料,进行定位输送并在特定条件下释放,从而减少毒副作用,延长药物作用时间,提高药效学功能,或克服抑制组织的免疫原性降低排异风险等方面 [12]。此外,CS还被广泛用作生物支架参与骨、软骨、角膜、皮肤和神经组织工程领域 [13]。本文将对CS的生物活性及生物材料在医药领域应用的研究进展进行综述。

2. CS的生物学活性

2.1. 角膜修复

CS是角膜基质的成分之一,化学性质稳定,无毒、无刺激性,被用于保存角膜以及眼科手术复合黏弹剂。CS能稳定细胞代谢的微环境,为细胞的移行提供构架,促进角膜上皮细胞的移行,减轻炎症反映,从而促进角膜创伤的愈合 [14],因此CS复方滴眼液在临床被用于治疗角膜损伤以及干眼症 [15]。角膜损伤后的修复过程由ECM、细胞因子和HCEC等常驻细胞共同参与的 [16],血小板裂解物是富含血液生长因子的血液衍生物质,CS每个重复的双糖单位带有两个负电荷,可通过静电作用与血小板裂解物中的带正电的生长因子结合。Sandri等 [17] 向市售隐形眼镜中加载了CS以及血小板裂解物,增强药物在角膜前区域的持久性并促进伤口愈合。

Wang等 [18] 用羟基琥珀酰亚胺基团修饰的CS与兔角膜进行交联,能够改善正常角膜和圆锥角膜的力学性质,恢复圆锥角膜的胶原密度和排列,并且角膜细胞的促炎基因表达显著下调,提供了一种有效、安全和生物相容的角膜加固方法。从其他物种获得的脱细胞角膜用于角膜移植是角膜工程研究热点之一,然而脱细胞角膜在去除细胞内容物和抗原后仍会引起免疫反应导致移植排斥 [19]。最新研究 [20] 发现CS的引入可以恢复纤维基质扭曲的构象变化,减少移植排斥。将山羊脱细胞角膜与氧化的CS交联后植入兔角膜基质中培养3个月,发现胶原纤维构象恢复,角膜上皮细胞向植入结构的迁移,消除了脱细胞角膜的高免疫反应性。因此认为CS交联脱细胞角膜基质可作为同种异体移植物的有效替代物。

2.2. 免疫调节

不同生物组织中提取的CS具有不同的硫酸化模式和不同分子量结构,在免疫调节中的作用也不尽相同 [21]。早年研究中,CS 通过细胞表面受体介导,降低p38丝裂原活化蛋白激酶和信号调节激酶1/2的磷酸化,从而抑制NF-κB的核易位,减少促炎细胞因子如TNF-α、IL-6以及促炎酶如磷脂酶A2、环氧合酶2、基质金属蛋白酶-13和一氧化氮合酶2释放的抗炎途径在软骨细胞中得到证明 [22] [23],CS还可能通过该途径增加骨保护素的表达,抑制破骨细胞的激活 [24]。Calamia等 [25] 从人类关节软骨细胞分泌组中鉴定出18种可被CS调节的蛋白质,并且用IL-1b刺激正常软骨细胞后观察到CS通过减少几种补体成分(CFAb,C1S,CO3和C1R)直接降低炎症反应,并且发现CS以浓度依赖的方式促进血管生成抑制剂血小板反应蛋白-1的增加,可能是CS在骨关节炎(osteoarthritis, OA)中抗新生血管生成的潜在机制。Korotkyi等 [26] 发现CS可使大鼠膝关节软骨中OA诱导的前列腺素过氧化物酶2和转化生长因子-β表达上调被抑制。表明CS作为药物可能有助于控制炎性应激的关节分解代谢作用,可用于预防关节退行性变。这些研究解释了CS减轻OA症状,缓解关节损伤的潜在机制。

Canas等 [27] 证实大鼠星形胶质细胞炎症中CS阻止NF-κB p65亚基转运到细胞核从而抑制NF-κB活化,同时该过程没有涉及Janus激酶/信号转导子和转录激活子(JAK/STAT)途径的蛋白,最可能是通过抑制Toll样受体-4 (TLR-4)介导的炎症通路来实现的。炎症过程中巨噬细胞可被激活为促炎表型或抗炎表型,前者可分泌多种促炎细胞因子和趋化因子,例如活性氧(ROS),一氧化氮(NO),肿瘤坏死因子-α (TNF-α),白介素-1β (IL-1β),IL-6,IL-8等清除抗原 [28],而后者可以产生炎症抑制因子,例如IL-10和精氨酸酶-1以抑制炎症和促进组织修复 [29]。CS的抗炎活性众所周知,但对巨噬细胞的激活机制尚不明确。Wu等 [30] 发现CS以浓度依赖方式刺激小鼠巨噬细胞RAW 264.7产生ROS,促进巨噬细胞吞噬大肠杆菌,程度与阳性对照组近似。CS对促炎因子NO,IL-6和TNF-α的生成具有一定的增强作用,但均低于阳性对照组,而对抗炎因子IL-10的增强作用明显高于阳性对照组。认为CS具有潜在的促进清除外来入侵并增强宿主免疫的功能。实验中还应用多种模式识别受体抗体探究CS对巨噬细胞激活的通路,首次发现TLR-2参与CS介导的巨噬细胞活化。

环磷酰胺是一种常用化疗药物,有骨髓抑制以及心脏毒性等副作用 [31]。粒细胞集落刺激因子是造血糖蛋白增殖因子,可刺激中性粒细胞、血细胞增殖。Niu等 [9] 从海参中提取了两种FCS (FCShp, FCSht),证明二者对CTX诱导的骨髓抑制小鼠的造血功能恢复具有有益的作用。FCShp、FCSht实验组小鼠血浆中白细胞、红细胞、中性粒细胞,淋巴细胞和血小板再生良好,与粒细胞集落刺激因子对照组无显著差异。实验组中小鼠脾脏组织形态恢复,而对照组仅表现为细胞聚集。另外,TNF-α和IL-6被认为是心脏毒性反应中炎症反应的指标,FCShp、FCSht治疗可将血浆中TNF-α,IL-6降低到接近正常水平。

CS糖链的硫酸化模式、功能基团可修饰性,以及CS的来源和分子量等都是影响CS在免疫调节中发挥不同作用的因素,对其机制的深入研究可以为治疗多种疾病提供新的思路。

2.3. 保护软骨

骨关节炎属于退行性病变,并且伴随各种促炎因子的释放,目前常用的抗炎药及镇痛药仍以缓解症状为主,因此新的治疗途径以降低骨关节结构伤为重点,CS的抗炎活性及软骨保护活性对骨关节炎中的软骨细胞增殖和ECM再生有益 [32]。

近期临床试验 [33] 比较了CS联合氨基葡糖与塞来昔布治疗膝骨关节炎的疗效和安全性,结果表明6个月后CS联合氨基葡糖用药在减轻疼痛、僵硬、功能受限和关节肿胀方面具有与塞来昔布相近的疗效。研究 [34] 显示单独口服CS在缓解症状性膝骨关节炎患者疼痛和改善功能方面优于安慰剂,与塞来昔布相似。足够的临床数据支持口服CS是对症治疗OA安全、有效方法,Wildi等 [35] 使用核磁共振成像观察到使用CS治疗膝关节OA患者从6个月开始软骨体积损失显著减少。Terencio等 [36] 在大鼠骨关节炎模型上证明了CS-氨基葡糖在体内有软骨保护作用,并观察到炎症因子水平降低。最新研究 [37] 还发现在全膝关节置换术女性患者的骨关节炎样品中总的CS浓度和CSA二糖显著降低(p < 0.05),推测CSA下调是软骨破坏的潜在机制,可作为骨关节炎软骨退化的诊断标志和治疗方向。

这些发现提示了CS对关节结构修复作用,并为其在膝骨关节炎中的作用方式提供了新的体内信息。CS对软骨的保护作用,使它在软骨粘合剂,软骨细胞支架,可注射水凝胶药物载体等软骨工程中大量应用。

2.4. 调节肿瘤生长

天然CS广泛存在于细胞表面和ECM中,影响细胞行为和ECM生物力学和生物化学性质。最新的研究发现CS硫酸化模式的改变可能对某些抗体结合能力产生影响。Pudelko等 [38] 提出了肿瘤细胞中CSC的积累对癌症进展和转移的可能存在双重影响。仍然可以肯定的是,肿瘤转移可以被外源CS有效抑制 [39],如外源性CSE通过竞争机制干扰癌细胞自身的CSE与正常组织高亲和性受体结合 [40],FCS可以通过阻断P选择素和L选择素介导的信号传导而抑制肿瘤转移 [41],近期Liu等 [42] 提取并制备了低分子量FCS,在鼠Lewis肺癌模型中低分子量FCS以剂量依赖性方式显著抑制LLC的生长和转移,低分子量FCS还可抑制血管内皮生长因子的表达、诱导细胞周期停滞、下调基质金属蛋白酶水平来发挥抗肿瘤作用。

Pan等 [43] 指出与正常脑组织相比,CSA和CSC在人脑胶质瘤组织中的表达上调,并且上调的程度与脑胶质瘤恶性程度正相关,因此可能代表了神经胶质瘤治疗中的目标。Zhang等 [44] 发现小鼠癌症模型及卵巢癌,宫颈癌,食道癌或肺癌患者的血浆胎盘样硫酸软骨素A含量均高于健康对照组,提出血浆胎盘样硫酸软骨素A可能是一种非侵入性生物标志物,可用于多种类型实体肿瘤患者的筛查和监测硫酸软骨素蛋白聚糖-4 (CSPG-4)在黑色素瘤、乳腺癌、神经母细胞瘤等多种恶性疾病中过表达,在肿瘤细胞的生长和存活以及扩散和转移中发挥作用,因此许多研究致力于以CSPG4为靶点开发抗癌方法,例如在嵌合抗原受体T细胞免疫治疗中,胶质母细胞瘤中CSPG4的高表达极大地降低了细胞逃逸的风险 [45]。Harrer [46]、Kristina [4] 对上述机制做了详细综述。

2.5. 促进生物矿化

生物矿化 [47] 是机体代谢产物中无机元素在有机环境调控下选择性析出并形成高度有序的矿化物的过程,如牙齿、骨骼中羟基磷灰石(hydroxyapatite, HAP)的形成。在新骨形成过程中非胶原糖蛋白对HAP成核起到重要调节作用,因为它们丰富的酸性基团对钙离子具有很强的亲和力,通过增加局部钙浓度来加速羟基磷灰石晶体成核 [48] [49],富含硫酸盐和羧酸盐基团的CS被认为是羟基磷灰石成核和生长的有效促进剂 [50] [51],可充当组织矿化的中间体,在成骨过程中调节矿物质晶体的沉积和生长形态 [52]。有人指出CS通过抑制HAP晶体介导的矿化过程中“过饱和驱动界面结构失配”过程 [53] 来帮助形成高度有序的HAP。

Xiao等 [50] 发现CS对HAP形态的影响可能与CS的结构有关。CS是重复的二糖单元的线性多糖,其阴离子特性使带正电的钙离子均匀地沉积在材料表面,吸引带负电的磷酸根离子,从而启动了HAP在ChS上的结晶过程。在低浓度的CS中获得了纤维状HAP,当溶液中CS的浓度增加时,糖链相互交联形成二维网络结构,可获得较大的片状HAP,HAP的结晶度与CS浓度成正相关。天然胶原蛋白在ECM中为生物矿化提供了重要的机械支撑和生物调节作用。最新实验 [54] 将CS交联固定在胶原纤维上能够提高HAP矿化速度,且HAP晶体在材料中的排列近似于生物中胶原矿物形态。随机光学重建显微术结果证实了CS为HAP优先形成提供了特定的成核位点。将CS固定在脱矿牙本质模型中进行48小时再矿化,观察到4~5 μm的新形成的再矿化层,类似于完整牙本质,未经修饰的牙本质仅出现了极薄的修复层。这些研究为理解生物大分子CS在生物矿化功能提供了新见解。

2.6. 抗病毒作用

CS具有多种抗病毒的生物活性。登革热病毒分泌的NS1通过与CSE和硫酸乙酰肝素的相互作用附着在宿主细胞表面 [55],因此外源性CSE具有靶向登革病毒包膜蛋白的抗病毒活性 [56]。Jinno等 [57] 发现来源于鱿鱼软骨的CSE具有抗1型人T细胞白血病病毒的活性。CSE可以与重组1型人T细胞白血病病毒包膜蛋白直接相互作用抑制病毒粒子与白血病细胞的结合,并抑制合胞体形成。FCS-1对艾滋病病毒,特别是T-20耐药株表现出高效的抗病毒活性,他能有效地结合重组HIV-1 gp120蛋白,通过干扰病毒进入细胞而有效抑制艾滋病毒复制 [58]。2型单纯疱疹病毒进行粘膜感染的第一步是通过与宿主细胞膜上天然存在的某些糖胺聚糖结合,Galus等 [59] 利用这种相互作用设计了基于CS的仿生超分子六角形纳米组件,这种生屏障可以像“陷阱”一样专门捕获病毒并避免其附着在细胞上,具有更好的抗病毒活性。因此,特定类型的CS作为病毒抑制剂有进一步开发的巨大潜力。

3. CS在生物材料领域的应用

3.1. 生物粘合剂

Wang等 [60] 开发了适用于软骨组织的CS粘合剂,弥补了临床上骨科粘合剂中生物相容性和粘合力度不足的缺陷。对CS进行甲基丙烯酸酯和醛基化学官能化,形成两个功能臂:一个臂提供与生物材料共价结合位点和增强材料强度,另一个臂通过醛基与组织表面上存在的胺共轭联接。CS粘合剂作为植入的生物材料和天然软骨组织之间的粘附层,具有很强的粘附力和稳定的整合性,显著促进植入物和软骨组织之间的融合。

Reyes等 [61] 报道了一种基于氧化硫酸软骨素与聚乙烯醇胺通过席夫碱反应合成的粘合剂,在兔眼模型中,伤口渗漏前最大眼压明显高于标准缝合技术。Strehin等 [62] 在猪眼模型中使用羟基琥珀酰亚胺活化的CS/聚乙二醇胺封闭角膜小切口,能够恢复大于200毫米汞柱眼压,且该粘合剂对角膜中发现的主要细胞类型无毒,术后炎症反应小,无疤痕形成。这些结果证实了硫酸软骨素基粘合剂不仅简化手术过程,还可以可以解决缝线引起的炎症、散光、继发性新血管等并发症 [63]。

3.2. 药物递送系统

已有实验证明使用CS构建的药物载体具有合适的流体动力学直径,可控制的表面电荷,优选的包封率,无毒性和抵抗原性 [64] [65],由于其与CD44有极强的亲和力,利用CD44受体介导的内吞作用设计的CS药物载体是肿瘤治疗研究热点 [66] [11]。近期更多的研究将CS设计多种形式的药物载体应用于医疗领域,具有良好的前景。

3.2.1. 水凝胶

骨髓间充质干细胞(Mesenchymal Stem Cell, MSC)及其分泌因子具有抗炎和抗血管生成以及促进伤口愈合的特性 [67],Fernandes-Cunha等 [68] 制备了CS-透明质酸粘弹性凝胶递送冻干的MSC,实验证明水凝胶可促进大鼠的角膜机械伤和化学烧伤的愈合,还能减少碱性角膜烧伤后的疤痕和新血管。Giuseppina等 [69] 开发了一种CS和羟丙基甲基纤维素的热敏水凝胶载体,利用静电结合方式装载血小板溶解产物,协同发挥刺激细胞增殖的作用,可有效治疗角膜损伤。肿瘤组织中的谷胱甘肽浓度远高于正常组织,CS可与谷胱甘肽敏感的二硫键交联,在CD44介导的内化作用后在肿瘤细胞中特异性降解,降低对正常组织的毒性。Zhang等 [70] 利用该原理开发了靶向CD44的可编程药物输送系统,利用CS水凝胶外壳包裹化疗药物核心粒子。24小时内在血浆谷胱甘肽浓度下仅检测到低于10%的游离药物,正常组织谷胱甘肽浓度下检测到约20%的游离药物,而在肿瘤谷胱甘肽浓度下,药物分子在最初的30分钟内释放可达50%,之后24小时内持续释放。体内实验证明给药体系具有CD44靶向输送能力,显著增强药物对肿瘤的抑制。

3.2.2. 纳米颗粒

Liu等 [71] 设计了氧化还原/酶响应硫酸软骨素–脱氧胆酸(CSCD)自组装的纳米粒子,由于透明质酸酶-1可以降解CS,该纳米粒子具有谷胱甘肽/透明质酸酶-1双敏感药物释放特性。CSCD纳米颗粒装载多烯紫杉醇与单纯给药相比,可使黑色素瘤的体积和肺转移均减少。基因治疗是近年研究热点,在治疗性基因靶向递送中使用纳米颗粒作为载体可以达到避免遗传物质降解、定向输送、提高转染率的目的。Zorzi等 [72] 制备了CS与阳离子明胶杂化纳米颗粒装载基因片段,证明聚阴离子CS的加入有效降低了阳离子聚合物的细胞毒性,并保证稳定的细胞摄取率及pDNA的转染率。Chen等 [73] 使用CS在聚酰胺酰胺树状大分子上进行改性制成纳米颗粒,通过CD44介导的内吞作用提高肿瘤细胞对颗粒内装载的miR-34a的摄取效率,增强了诱导细胞周期停滞和细胞凋亡的作用,并且显示出良好的安全性。非淀粉多糖大分子无法被胃和小肠中的酶消化,但可以被结肠中的微生物水解,因此非常适合制备结肠靶向药物递送系统。Zu等 [74] 证明CS的表面修饰赋予了纳米粒子结肠癌靶向给药的能力,并显著提高了喜树碱抗结肠癌活性。最新研究中 [75],将CS附着到超顺磁性氧化铁纳米粒子(SPION)表面,CS-SPION注射到大鼠的黑质中后,纳米粒子表现出低毒性和低内吞作用,并高度分布在靠近神经元细胞体和突触的细胞间隙中。这可能是因为CS是神经纤维网的主要组成部分之一,有包围神经元细胞体、树突和突触的趋势。Tan等 [76] 制备了装载有地塞米松的(3-氨基甲基苯基)硼酸硫酸软骨素(APBA-CS)基纳米结构脂质纳米颗粒,存在于颗粒外层的APBA-CS可以与眼粘蛋白中的唾液酸形成复合物,提高药物的角膜渗透性,克服泪液周转,鼻泪管引流,瞬目及生理屏障对角膜药物利用造成限制 [77],是药效增强。

3.2.3. 纳米胶囊

近年来,药物输送和诊断成像集成给药系统在医药领域成为研究焦点 [78]。在代谢活跃癌细胞表面,乳铁蛋白(lactoferrin, LF)被发现与乳铁蛋白膜内化受体(LRP1, LRP2)和转铁蛋白受体(TFR1, TFR2)结合增加 [79]。量子点 [80] (quantum dots, QD)是一种高荧光产量的半导体纳米粒子,在电子/能量转移机制下,QD与乳铁蛋白在体外结合时,QD处于荧光淬灭状态,被细胞摄取后恢复荧光功能,可用作癌细胞的荧光成像探针。AbdElhamid等 [81] 使用逐层静电组装技术制备了具有荧光标记功能的CS纳米胶囊,装载难溶性药物塞来昔布和厚朴酚治疗乳腺癌。具有阴离子特性的CS为中间层,既可以包裹脂质载药颗粒,又可以将带阳离子的LF-QD共轭物结合到胶囊表面,可利用共聚焦激光扫描显微镜进行体内追踪。该团队还尝试将一层阳离子明胶结合到荧光CS纳米胶囊表面,阳离子明胶可被肿瘤过表达的基质金属蛋白酶降解 [82],进一步增强了胶囊与肿瘤细胞结合的特异性 [83]。实验证明,纳米胶囊有效提高药物水溶性,双重靶向作用增强肿瘤细胞药物摄取率,显著抑制肿瘤生长,体内免疫原性实验证明了纳米胶囊良好的生物相容性。这种稳定、安全、高效、多功能给药系统具备强大的开发潜力和广阔的应用前景。

3.3. 细胞支架

优质细胞支架的关键特性是为细胞粘附,增殖和分化提供合适的底物。细胞与ECM之间的相互作用在初期细胞迁移到伤口区域以及肉芽组织的收缩中起着至关重要的作用 [84],因此,将CS、明胶(gelati, GEL)、透明质酸(hyaluronic acid, HA)等ECM成分加入生物支架是影响细胞活性以促进组织再生的有效方法。CS可以提供丰富的信号识别位点,通过结合多种生长因子来调节细胞生长和发育 [13],是设计细胞支架时不可忽视的生物材料。

3.3.1. 纳米纤维支架

静电纺丝是一种制备纳米级连续纤维的技术,电纺纤维支架具有高表面积体积比值适合细胞附着,并促进营养供应和氧气的运输以促进细胞生长 [85]。Pezeshki-Modaress等 [86] 应用静电纺丝技术制备GEL-CS纳米纤维支架,经过CS改良后的纳米纤维支架具有稳定性和高孔隙率,更近似于天然ECM结构,人成纤维细胞可在支架上可呈梭形样附着并分布良好。Bhowmick等 [87] 制备了GEL-HA-CS负载丝胶蛋白电纺纳米纤维支架,来模拟皮肤天然ECM的微观结构和组成,研究表明纳米纤维支架可促进人成纤维细胞、角质形成细胞和骨髓间充质干细胞的粘附和增殖,从基因表达分析等实验证实角质形成细胞可刺激骨髓间充质干细胞分化,达到加快愈合、减少瘢痕的生物学功能。

CS能够改良纤维支架的机械性能。Sadeghi等 [88] 制备了CS杂化纳米纤维支架,并且研究了不同CS含量对纳米纤维的机械性能、生物学性能的影响。CS比率为15%时,这种纳米纤维在干燥状态下拉伸强度高达4 MPa,在湿润状态下断裂伸长率为200%,增强韧性材料可增强临床应用的灵活性。Saporito等 [89] 将GEL-CS纳米纤维制成植入贴片,并且负载血小板裂解物作为生长因子的来源,用于先天性心脏缺陷手术后的心脏修复。纳米纤维结构中CS的存在增强了贴片的弹性,适合体内适应心脏收缩。实验中还发现纤维支架有效地促进了内皮细胞、心肌细胞的粘附和增殖,但没有明显刺激成纤维细胞的增殖,这一性能可协助年轻患者进行心肌修复,保持心肌细胞活力并减少手术后成纤维细胞生长失控导致的的胶原沉积。

3.3.2. 水凝胶支架

CS是软骨细胞生存为环境的重要组分,并且具备抗炎、促进血管生长等功效 [90],是制备软骨组织工程中的复合生物材料的研究热点。在软骨工程中,可注射水凝胶是极具发展潜力的替代细胞输送支架,因为它们可以原位成形,模拟自然组织,并填充任何形状的缺损。Gao等 [91] 研制了以Ⅱ型胶原和活化CS为基质的可注射、可自交联的仿生水凝胶。水凝胶中的软骨细胞形态良好,基质发生重塑,具有良好的再生活力。Zhou等 [92] 制备CS-II型胶原复合水凝胶支架负载干细胞治疗椎间盘髓核退行性变。体外研究表明支架具有诱导干细胞分化的作用;大鼠尾椎模型中注射水凝胶后,椎间盘高度、含水量、细胞外基质合成和变性髓核的结构部分恢复,并能促进髓核特异性基因的表达。Fan等 [93] 用羧甲基壳聚糖和氧化的CS制备的可注射水凝胶,加入了壳聚糖–牛血清白蛋白微球结构改善其机械及生物性能,该体系可作为注射支架输送软骨细胞和大分子药物。

如目前研究认为CSPG对人神经中枢损伤的重塑过程具有双重影响,可能通过轴突的硫酸化方式来调节 [94],但其机制仍存在争议。Karumbaiah等 [95] 使用光交联方法制备了CSA为主的水凝胶,发现水凝胶对神经营养因子如碱性成纤维细胞生长因子、脑源性神经营养因子、表皮生长因子、和抗炎因子IL-10有富集作用,并且具有促进神经干细胞生长和自我更新的潜力。神经干细胞在治疗脊髓损伤时优先分化为星形胶质细胞,神经元形成相对较少。Liu等 [96] 证明将神经干细胞包裹在硫酸软骨素甲基丙烯酸酯(CS-MA)水凝胶中可以抑制星形胶质细胞分化,促进脊髓损伤的修复。体外实验表明CS-MA水凝胶中星形胶质细胞比例明显少于对照组;在大鼠后肢瘫痪模型中,应用CS-MA水凝胶后在第1周观察到2个关节恢复运动,3周后观察到后肢承重能力,明显领先于对照组,同时前肢的异常性疼痛样反应减少,相应的组织改变也在基因、分子层面得到印证。CS-MA水凝胶支架无疑在恢复功能和减轻感觉异常方面起着重要作用。

3.3.3. 多孔支架

Lai等 [97] 利用明胶0.25% CS制备的泡沫角膜支架具有较高的含水量、透光率和渗透营养素含量,亲水性和力学性能与天然角膜相当,与兔角膜基质细胞具有良好的生物相容性,表现出较强的细胞增殖和生物合成能力。Zhou等 [98] 采用盐浸,冷冻干燥和交联方法制备了建了用于关节软骨修复的CS-丝素蛋白多孔支架,在兔骨软骨缺损模型中观察到应用了CS的支架能够更好的保持软骨细胞表型,减少白介素-1β诱导的软骨细胞炎症反应,增强软骨自我修复的能力。Yu等 [99] 模仿气管软骨细胞外基质的组成和结构,采用单向冷冻干燥法制备了明胶–硫酸软骨素–透明质酸–聚乙烯醇支架,湿润状态下支架均表现出与天然软骨相似的压缩弹性模量,具有良好的机械稳定性,利用定向的微管结构,采用动态培养的方法促进细胞向支架内生长。Singh等 [100] 制备了聚电解质络合介导的壳聚糖(chitosan, CH)和CS的纳米生物玻璃复合支架。CS改良后的支架具有较大的孔径,利于细胞向支架中心的迁移或浸润,在潮湿条件下进行压缩测试中表现出海绵状的行为,溶涨率测试中减少了CH支架过度的溶胀表现,增强了在水合条件下支架的结构稳定性。生物学实验观察到培养的成骨细胞在CS-CH上的生物矿化显着高于CH,有利于新骨的形成。

3.4. 表面涂层

Yang等 [12] 通过聚乙二醇(PEG)与CS偶联制备了CS-PEG纳米涂层,用于改良门静脉胰岛移植。CS的羧基经化学修饰后与胰岛膜蛋白表面的伯胺基团交联,完整稳定的结合在胰岛表面。实验观察到,CS优异的机械稳定性,保水能力和强大的生物相容性有力的保证了胰岛活性,表现出减少血液凝固,增强胰岛原位血运的重建,提高胰岛细胞在促炎条件下的存活率的积极效果。体外实验显示,在培养7天后胰岛对葡萄糖刺激反应显著增强,且胰岛素分泌量与CS涂层厚度具有一定程度的浓度依赖性,培养第14天时CS-PEG表面工程化的胰岛仍保持完整结构。这种CS-PEG表面涂层可提高胰岛移植的成功率,临床应用前景广阔。

角膜移植术是角膜失明患者视觉康复最常用的方法,高质量供体角膜的短缺促使人们研制人角膜供体的替代品。角膜是无血管组织,房水、泪液中溶解的氧气及活性成分对角膜细胞的存活起到至关重要的作用。Liu等 [101] 通过CS的表面接枝增强了一种新型胶原蛋白(collagen, Col)角膜的保湿容量。Col-CS膜的吸水率为81.9% ± 2.1%,显着高于Col膜的吸水率,并且材料厚度较为恒定,光学性能良好。CS表面接枝后胶原蛋白膜的极限拉伸强度接近天然角膜组织,人角膜上皮细胞在培养12小时后即可随薄膜的伸缩由圆形变为梭形,表现出更紧密的粘附性。

Liu等 [102] 采用逐层法将氧化CS和I型胶原组装到聚丙交酯–乙交酯共聚物(PLGA)支架表面,作为附着无机矿物质的粘合剂涂层。利用CS的矿化功能刺激成骨,同时CS能够调节细胞行为,引导支架与宿主组织之间的骨整合。经过多层修饰PLGA表面纳米羟基磷灰石晶体附着更加均匀牢固,骨髓间充质干细胞的附着、铺展和增殖、成骨分化行为更加活跃。因此,这种新型的多层修饰复合支架可能在骨组织再生方面取得理想的治疗效果。

4. 结论

人们对CS的研究历时悠久,其抗炎、抗凝、促进组织修复等药理作用已在实验及临床中的得到认证。随着研究的深入,发现CS在介导炎症、肿瘤转移及定植、神经元修复过程中可能存在双向机制,进一步明确CS在细胞及ECM中的活性以及在生物信号转导中的作用对于研究抑制肿瘤的生长转移、启动神经再生、调节免疫过程等具有重要指导意义,同时CS在骨关节炎、癌症领域也具备作为新型疾病检测目标的潜力。总之,CS丰富的生物活性、强大的生物相容性,与它的阴离子特性、亲水性、强韧性等机械特性相结合,能够发挥靶向给药,控制释放,减少药物副作用,提高基因稳定性,维持药物浓度,改善药物溶解性,降低移植组织的排异风险,提高细胞存活率,在医药领域具有巨大的研究价值和开发潜力。

基金项目

山东省自然科学基金(编号ZR2019BH004)。

NOTES

*通讯作者。

文章引用: 田 雪 , 彭旭东 , 尹 娇 , 张冉冉 (2020) 硫酸软骨素及衍生物在医药领域中的研究进展。 临床医学进展, 10, 2960-2973. doi: 10.12677/ACM.2020.1012446

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