用于骨重建的微创植入生物材料

韩峰 ,  刘昭 ,  魏强 ,  丁路光 ,  余丽 ,  王佳媛 ,  王欢 ,  张维东 ,  余颖康 ,  赵彦涛 ,  陈嵩 ,  李斌

工程（英文） ›› 2025, Vol. 46 ›› Issue (3) : 24 -49.

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工程（英文） ›› 2025, Vol. 46 ›› Issue (3) : 24 -49. DOI: 10.1016/j.eng.2024.01.031
研究论文

用于骨重建的微创植入生物材料

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Minimally Invasive Implantable Biomaterials for Bone Reconstruction

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摘要

近年来，由事故或骨相关疾病所引发的骨损伤大幅增加。在这一背景下，生物材料在骨组织再生与修复治疗中的应用日益广泛，已成为不可或缺的治疗手段。与传统骨再生材料相比，具有微创特性的可注射生物材料（包括生物陶瓷类和聚合物类）在临床应用中展现出独特优势。本文系统综述了微创植入式生物材料在骨重建领域的最新研究进展，重点探讨了其促进成骨的不同机制及其在骨科领域的多元化应用。通过对生物陶瓷和聚合材料的深入分析，我们详细阐述了这些材料在骨折愈合、椎体强化、骨植入物固定、骨肿瘤治疗以及感染性骨缺损修复等方面的临床应用。同时，本文还着重介绍了具有多功能性和生物响应特性的新型可注射生物材料的研究进展。最后，基于当前研究现状，我们总结了该领域面临的主要挑战，并对未来临床治疗的发展方向进行了展望。

Abstract

Bone injuries induced by accidents or bone-related disease have dramatically increased in the past decades. The application of biomaterials has become an inextricable part of treatment for new bone formation and regeneration. Different from traditional bone-regeneration materials, injectable biomaterials—ranging from bioceramics to polymers—have been applied as a means of promoting surgery with a minimal intervention approach. In this review, we summarize the most recent developments in minimally invasive implantable biomaterials for bone reconstruction and different ways to achieve osteogenesis, with a focus on injectable biomaterials for various applications in the orthopedic field. More specifically, bioceramics and polymeric materials, together with their applications in bone fracture healing, vertebral body augmentation, bone implant fixation, bone tumor therapy, and bone-defect-related infection treatment are reviewed in detail. Recent progress in injectable biomaterials with multiple functionalities and bioresponsive properties is also reviewed. Finally, we summarize the challenges in this field and future directions for clinical treatment.

关键词

骨 / 再生 / 可植入生物材料 / 生物医学应用 / 微创手术

Key words

Bone / Regeneration / Implantable biomaterials / Biomedical applications / Minimal intervention

引用本文

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韩峰,刘昭,魏强,丁路光,余丽,王佳媛,王欢,张维东,余颖康,赵彦涛,陈嵩,李斌. 用于骨重建的微创植入生物材料[J]. 工程（英文）, 2025, 46(3): 24-49 DOI:10.1016/j.eng.2024.01.031

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1 引言

事故或骨相关疾病（如骨肿瘤、感染和骨质疏松症等）引起的骨损伤十分常见[1]。绝大多数情况下，需要外科手术恢复受损骨骼的功能。微创手术（minimally invasive surgeries, MISs）切口较小，可以简化手术过程、减轻疼痛，以及减少并发症的总体发生率。MISs的发展对骨移植替代物提出了新的要求。理想情况下，MISs的骨移植替代物应该具有良好的生物相容性、可吸收性和成骨性能。对于用于承重和易感染部位的材料来说，足够的力学性能和抗感染性能是非常重要的。此外，此类材料应方便操作，以便精准地运送到目标部位，并填充形状不规则的骨缺损。因此，对于可实现微创手术的新技术和新材料的需求量很大[2]。

目前，自体骨移植仍然是骨重建领域的金标准。然而，它们的应用受到供应短缺和移植过程中可能发生二次损伤的限制。同种异体骨移植物的供应相对较多，但存在传播疾病和免疫排斥反应的风险，其愈合效果不如自体骨移植物[3]。更重要的是，虽然骨替代材料的功能通常具有损伤小和促进骨再生的优势，但是将自体移植物或同种异体移植物加工成适合MIS [4]的不同大小或形状是一项难点。因此，进一步开发易于塑性且具有促进骨再生能力的合成材料，在各种应用中仍然有很高的需求（图1）。在过去的几年里，许多研究都集中在微创生物材料上，并发表了针对不同临床应用（即骨缺损和感染）和生物材料组分（即天然聚合物和合成聚合物）的微创生物材料类的综述[5‒7]。随着微创生物材料研究的不断深入，其促成骨机制也越来越受到人们的关注。

陶瓷、聚合物和金属等都可作为骨重建的候选材料。虽然钛和镁等金属在骨科中有着广泛的应用，但本文重点关注可注射的陶瓷和聚合物。根据骨重建方法的临床需求，陶瓷和聚合物可以采取多孔块体、膏状和颗粒状的形式。为了满足MIS的需求，这些材料通常被加工成糊状或颗粒，通过针头注射到受伤部位[8]。可注射的骨缺损修复材料造成的创伤小，可塑性好，可以携带生长因子（growth factors, GFs）、种子细胞等，也可以填充不规则的骨缺损。这些材料被认为是骨科MIS的合适选择，引起了广泛的关注。用于MIS的可注射聚合物的典型例子是聚甲基丙烯酸甲酯[poly(methyl methacrylate), PMMA]。反应前，PMMA呈水状，且黏度较高，在注入目标组织后固化。由于PMMA具有自固化特性和优异的力学性能，在椎体强化、螺钉固定等方面的应用取得了巨大成功[9‒10]。应用于椎体强化时，PMMA可以恢复椎体高度，增强其力学强度，减轻患者疼痛。但PMMA具有生物惰性和不可降解的性质，限制了它的进一步应用。这些缺点导致骨组织和PMMA之间形成纤维囊，大大降低了整合强度。此外，PMMA的高刚度和与骨组织的长期接触会产生应力遮挡效应[11]。因此，具有高生物活性和生物降解性的新一代可注射生物材料引起了越来越多的关注。

生物陶瓷，如生物活性玻璃（bioactive glass, BG）、磷酸钙和硫酸钙已被证明能够直接与骨组织结合[12]。最为人熟知的生物陶瓷是磷酸钙骨水泥（calcium phosphate cements, CPC）。CPC作为膏状注射剂可用于填补骨缺损，已表现出良好的生物相容性和骨再生效果[13]。鉴于其自固化能力和可调节的注射性，CPC已被认为可以作为PMMA的替代品用于骨折愈合和植入物固定。可注射水凝胶是另一种具有微创干预潜力的材料。水凝胶具有三维、高度水合的聚合物网络，在注射过程中可以像液体一样流动，一旦被输送到目标部位，水凝胶就会发生交联固化。种子细胞也是组织工程中的一个重要因素。当与细胞结合时，水凝胶和微球可以作为骨组织工程的支架[14]。临床需求不断推动着骨替代材料的发展：从生物惰性材料到生物活性材料，再到现在向着具有多种功能和生物特性的材料发展。这些材料不仅具有可注射性和生物活性，而且具有血管生成能力，能够治疗骨相关疾病[15]。此外，一些生物材料可以对环境变化做出反应，从而积极参与骨修复和再生过程[16]。不同的可注射材料可通过基质生物矿化、血管生成和免疫调节等方式实现骨再生。材料的发展极大地促进了MIS的发展，为临床医生提供了更多的选择。

本文重点关注可用于微创治疗的植入式生物材料，主要介绍了生物陶瓷和高分子聚合物材料，综述了它们在骨科领域的各种应用、多功能和生物响应材料的最新进展，以及促进成骨的不同方式。最后，对未来用于骨重建的生物材料进行了展望。

2 用于骨再生的微创植入式生物材料的分类

2.1 生物陶瓷

生物陶瓷是指可用于生物医学应用的陶瓷。第一代生物陶瓷包括生物惰性材料，如氧化锆和氧化铝等，它们被用作人造股骨头[17]。虽然这些材料的强度足以支撑机体，但它们会引发异物反应，使其被无细胞胶原蛋白囊包裹而与周围组织隔离[18‒19]。Hench发明的BG开启了生物活性材料的新时代。BG含有46.1%的SiO2、26.9%的CaO、24.4%的Na2O和2.6%的P2O5，是第一种可以与骨结合而不形成纤维瘢痕组织的生物材料[20]。后来，Kokubo发明了具有高抗弯和抗压强度的磷灰石-硅灰石（apatite-wollastonite, A-W）玻璃陶瓷[21]。此后，越来越多的生物活性陶瓷，包括磷酸钙基、硫酸钙基和硅酸钙基生物陶瓷，被用于生物医学产品[22]。在骨科领域，BG、羟基磷灰石[Ca10(PO4)6(OH)2, HA]和β‐三磷酸钙[β-Ca3(PO4)2, β-TCP]已成为自体移植物的重要替代品[23‒24]。HA和双相磷酸钙（biphasic calcium phosphates, BCP）已被用于制备具有核-壳结构的多孔生物陶瓷颗粒，可以增强骨髓间充质干细胞（mesenchymal stem cells, MSCs）的成骨能力[25]。部分材料已经表现出成骨诱导能力，刺激成骨祖细胞分化为成骨细胞[26]。

生物陶瓷可以加工成颗粒、支架或水泥的形式，以满足各种临床需求。在微创治疗中，生物陶瓷通常以糊状物的形式注射到受伤部位。目前，该领域的研究主要试图解决力学强度高的生物陶瓷降解性能差，而降解性能好的骨水泥无法达到合适的力学强度的问题。因此，寻找具有良好力学性能的可降解骨水泥成为研究的重点。

2.1.1 生物陶瓷的可注射性

无机颗粒之间的摩擦力阻碍了生物陶瓷在注射器中的流动，因此，对于可注射体系来说，液相是必不可少的。水溶液或非水溶液，如甘油和聚乙二醇[poly (ethylene glycol), PEG]，都可以作为注射的液相[27]。生物陶瓷与液体混合形成膏状后，可通过单膏状或双膏状注射器输送至骨折部位。在预混合体系中，生物陶瓷与液相结合，直接注射到骨缺损处。在非预混合体系中，反应性成分被分成两部分，两种膏状物质在注射器中混合后触发反应，然后在特定递送部位硬化[28]。为了达到理想的可注射性和固化效果，液固（liquid-to-powder, L/P）比、颗粒大小和形状以及液相的选择是必须考虑的因素。例如，较高的L/P比通常会导致较强的可注射性[29]。而且，有研究表明，圆形颗粒比不规则形状颗粒的可注射性更强[30]。为了进一步方便生物陶瓷的处理，现已开发了预混（或即用）生物陶瓷[31]。这些生物陶瓷通常在注射前与非水溶剂混合，输送到体内后，非水溶剂与体液交换，导致生物陶瓷硬化[32]。预混型生物陶瓷可以极大地方便临床处理，并以微创的方式降低手术风险（图2）[33]。

2.1.2 生物陶瓷的成分

根据化学成分，生物陶瓷可分为不同的类别：磷酸钙、硅酸钙、氧化锆、氧化铝和磷酸盐基或硅酸盐基玻璃。在这些材料中，磷酸钙基生物陶瓷被最广泛地应用于骨重建。这些生物陶瓷包括含有钙离子（Ca2+）和正磷酸盐（PO43-）、偏磷酸盐（PO3-）或焦磷酸盐（P2O74-）的材料。在这些相中，正磷酸钙（表1）的研究最为广泛[34‒35]。磷酸钙基生物陶瓷在骨再生领域的广泛应用，主要是由于其与人体骨矿物质的化学相似性。HA和β-TCP是骨重建中最常用的磷酸钙[36]。HA是溶解度最低的正磷酸钙，而β-TCP是最易溶的[37]。这两种化合物的结合产生了所谓的双相陶瓷，这种陶瓷因其优异的成骨特性受到越来越多的关注[38]。最近，人们对其他基于磷酸钙的生物陶瓷也给予了很大的关注，包括磷酸三钙[α-Ca3(PO4)2, α-TCP]、二水磷酸二钙[CaHPO4·2H2O, DCPD]和无定形磷酸钙（amorphous calcium phosphate, ACPs）[39‒41]。硅酸钙基材料是另一类重要的生物陶瓷，其中最常见的有硅酸钙（CaSiO3）、硅酸二钙（Ca2SiO4, C2S）和硅酸三钙（Ca3SiO5, C3S）。多孔β-硅酸钙陶瓷在兔颅骨缺损模型中表现出优异的骨形成能力[42]。进一步的研究表明，在含有不同细胞的共培养系统中，β-硅酸钙显著增强了血管形成和成骨分化[43]。最著名的硅酸钙基生物陶瓷是矿物三氧化物聚集体（mineral trioxide aggregate, MTA），它已被用作牙科牙根管填充材料[44]。MTA的主要成分是硅酸三钙和硅酸二钙。它具有良好的密封性、生物相容性和磷灰石形成能力，在牙科中极具优势[45]。一些商业MTA产品被包裹在胶囊中，可以混合并直接注射到空腔中[46]。

2.1.3 生物陶瓷的种类

不可生物降解骨水泥中的生物陶瓷。PMMA于1958年首次应用于临床，作为全髋关节置换术的骨水泥[47]。研究者进行了许多尝试，来进一步提高PMMA的性能，如提高其生物活性、降低其弹性模量和聚合温度、增加其孔隙度以促进骨骼生长[48‒50]。例如，用蓖麻油和亚油酸改性的PMMA水泥已被证明杨氏模量会降低[51]。这种改性水泥的力学强度更接近于骨质疏松的松质骨，可以大大降低强化后相邻椎体骨折的发生率。其他研究集中在提高PMMA水泥的生物活性，主要方法为使用生物活性材料，如γ-甲基丙烯氧基丙基三甲氧基硅烷（γ-methacryloxypropyltrimethoxysilane, MPS）和乙酸钙[52]、HA和骨形态发生蛋白-2（bone morphogenetic protein-2, BMP-2）[53]、硅酸盐生物陶瓷[54]或BG [55]。这些生物活性材料可促进PMMA骨水泥的成骨性，从而使骨水泥与宿主骨更好地整合。尽管PMMA在临床上取得了成功，但其不可降解，而理想的骨填充材料应具有良好的降解能力，可逐渐被骨组织所取代。

生物可降解骨水泥。（1）磷酸钙基骨水泥。CPC是很有前景的骨替代材料，尽管其相对较低的强度和易碎性限制了其在强化椎体中的应用。CPC的力学强度受孔隙率、成分、前驱体粒度和液相组分等因素的影响[29,56]。L/P比的降低可降低骨水泥的孔隙率，从而使其具有更高的力学强度。然而，为了保持水泥的可注射性，需要保证最低用水量[57]。为了调节CPC的力学行为，研究者加入了其他成分，包括介孔BG [58]、无水磷酸二钙与二氧化钛[59]，以及纳米二氧化硅[60]。此外，添加纤维状和须状填充物已被证明可以有效增强CPC性能[61‒62]。例如，聚乙烯醇[poly(vinyl alcohol), PVA]纤维的掺入可以提高CPC的抗弯强度和韧性[63]。添加5 wt%硅酸钙纤维可使CPC的抗压强度从14.5 MPa提高到50.4 MPa [64]。另一项研究表明，壳聚糖纤维在不影响CPC弹性模量的情况下，将其韧性提高了数百倍，同时保持了其抗弯强度[65]。有报道称，减小前驱体的粒径可以改善CPC的力学性能和可注射性[66]。然而，细颗粒比粗颗粒具有更大的比表面积和更快的水解速率，从而导致凝结时间更短[67]。

液体成分也是影响CPCs力学行为的重要因素。CPCs由固相和液相组成，其中液相通常是水。然而，当水作为液相时，水泥会迅速凝固，不能均匀混合。如果加入柠檬酸或其盐（如柠檬酸钠）等缓凝剂，则可以延缓水化过程，使操作时间得以延长，可以使两相充分混合[68]。以柠檬酸或柠檬酸钠为液体组分的CPCs更易操作，L/P比降低，可显著提高水泥的抗压强度[69‒70]。近年来，许多研究都集中在将聚合物物质加入液相中以加强CPCs的无机网络结构。聚丙烯酸[71]、聚γ-谷氨酸及其锶盐[72]和硅化羟丙基甲基纤维素均可以提高CPCs的力学性能。用甲基丙烯酸缩水甘油酯衍生右旋糖酐在CPCs中原位交联聚合制备了双凝水泥，最佳抗压强度超过98.3 MPa [73]。通过将PEG基水凝胶与CPC网络结合，可大大提高CPCs的韧性[74]。在这些研究中，聚合基质被整合成一个双网络结构，这大大提高了CPCs的力学性能，使其抗压强度高达74.4 MPa [75]。尽管有这些改进，目前的CPCs仍然较脆，力学强度差。因此，开发具有足够力学强度的CPCs仍迫在眉睫。

（2）硫酸钙基骨水泥。硫酸钙是最古老的骨替代材料之一，Bahn在1892年的一份报道[76]中首次将其用作骨填充物。由于其良好的生物活性、可注射性和骨诱导性，它被认为是一种很有前景的骨修复材料[77]。硫酸钙水泥的固化是基于半水合硫酸钙与水的反应，形成最终产物二水硫酸钙。该固化反应温和，放热量低，因此，作为骨空洞填充物使用时，对周围组织损害小。但由于其力学强度低、吸收率高，单独使用硫酸钙不宜用于椎体强化[78]。硫酸钙水泥可以通过掺入中孔生物玻璃[79]、铁酸铋[80]、纳米HA与胶原蛋白[81]等颗粒进行性能增强。另一种策略是将硫酸钙水泥与其他类型的骨水泥结合使用，以克服其弱点。例如，在硫酸钙水泥中加入硅酸三钙，以改善其力学性能和可降解性[82]。此外，将CPC [83]和磷酸镁水泥（magnesium phosphate cement, MPC）[84]分别与硫酸钙水泥结合，可制成物理化学性能增强的复合水泥。但目前硫酸钙水泥的力学强度仍无法满足承重需求，因此需要进一步研究以扩大其在椎体强化方面的应用。

（3）其他可生物降解骨水泥。研究人员已开发出新型无机和复合骨水泥，以满足椎体强化的要求。硅酸钙水泥的主要成分包括硅酸三钙和硅酸二钙，其具有优异的生物活性、密封能力和整合性能。将粉末与水混合后，形成黏稠的胶状凝胶，最终固化成坚硬的结构。可注射性对于硅酸钙水泥的临床应用至关重要。虽然L/P比的增加提高了可注射性，但这可能会影响水泥的其他性能。明胶等添加剂可以将水泥转化为更具注射性的膏体[85]。研究发现明胶的存在明显改善了水泥的抗冲蚀和脆性性能，而不会对其力学强度产生不利影响，并且使水泥的断裂特征从脆性变为韧性断裂[86]。硅酸三钙与海藻酸钠结合，可形成一种新型复合水泥，具有更好的抗冲蚀性、成型性、可注射性和更高的抗压强度（54 MPa）[87]。研究人员采用硅酸盐粉末（固相）和磷酸铵溶液（液相）制备了新型快凝硅酸钙水泥，使凝结时间缩短至9 min以内[88]。

MPCs本质上是酸碱水泥，其中氧化镁和磷酸铵分别作为碱性组分和酸性组分[89]。MPCs在室温下可发生反应，具有凝固快、早期抗压强度高的特点。添加剂是提高MPCs可注射性的重要因素，尤其是乳酸、甘油、壳聚糖和柠檬酸可以增加液相黏度，改善水泥颗粒的湿度[90]。壳聚糖MPC的抗水性增强，经过28天的培养，复合水泥的抗压强度可达到42 MPa [91]。将元高岭土掺入MPC后，凝固时间延长（最长可至52 min），放热减少[92]。在MPC中使用柠檬酸作为凝固缓凝剂，可适当延长凝固时间（从11 min延长至17 min），并提高抗压强度（最大可达76 MPa）[93]。调整磷酸盐的粒度和使用硼酸钠作为缓凝剂，可改善MPC的放热情况和凝固动力学[89]。与C3S（25 MPa）和MPC（64 MPa）相比，硅酸三钙/MPC（C3S/MPC）复合骨水泥的抗压强度最高（87 MPa）[94]。

近期，为了克服传统骨水泥的缺点，研究者开始探索可注射的无机/有机复合水泥[95]。例如，复合水泥可以模拟天然组织的优异强度和韧性。在这些水泥中，磷酸钙纳米颗粒和二磷酸盐功能化的透明质酸被用来形成可注射、坚固、内聚的纳米复合水凝胶[96]。当磷酸钙纳米颗粒与明胶纳米球结合制备可注射的胶体有机-无机复合凝胶时，凝胶表现出明显增强的凝胶弹性、剪切变薄和自愈行为[97]。利用硅化羟丙基甲基纤维素制备复合水凝胶，可形成杂化互穿网络[98]。将BG与PVA、PEG相结合，可制备出高抗压强度的可注射复合水泥（图3）[99]。用硼酸BG颗粒和壳聚糖溶液制备的新型可注射硼酸BG水泥具有优异的注射性和抗压性能，其抗压强度为(31 ± 2) MPa [100]。此外，研究人员还制备了一套由PEG和HA纳米颗粒组成的弹性纳米复合材料。在PEG水凝胶中加入15%的HA纳米颗粒，与纯聚合物水凝胶相比，韧性显著提高。这一结果可归因于nHA增强共价交联PEG网络的能力[101]。这些研究表明，将无机颗粒与有机网络结合是制备可注射和可生物降解骨水泥的一种很有前景的策略。

2.2 水凝胶

水凝胶是一种具有三维结构的亲水性聚合物网络体系。迄今为止，可注射水凝胶由于其独特的优势，在骨组织工程中得到了广泛的应用，通过它可以很容易地针对缺损部位进行非侵入性治疗。水凝胶可以增强受伤骨的力学性能，也可递送多种生物分子[102‒103]。用于骨修复的理想水凝胶易于生产，具有生物相容性和可注射性，并能持续释放适当的活性GF。可注射的水凝胶体系有利于骨缺损修复，并且可以在缺损部位原位固化。

水凝胶可以用多种聚合物制备而成。天然聚合物具有良好的生物相容性和生物降解性，可以与细胞相互作用，为细胞黏附、迁移和增殖提供合适的微环境。与天然体系相比，合成水凝胶的优势在于其可控制的物理化学性质。水凝胶较差的力学性能限制了其在骨骼承重部位的应用。因此，迫切需要在保持水凝胶生物相容性、可注射性等优势的同时，提高其力学性能。然而，许多研究已经表明大多数水凝胶的力学性能和生物相容性是相互独立的，各种化学试剂的使用可能会影响水凝胶的生物相容性。目前的研究主要集中在通过小分子无机盐的Hoffmeister效应来调节水凝胶的力学性能。然而，水凝胶中含盐量过高可能会降低其生物相容性，限制其在生物医学领域的应用。因此，研究人员也提出在保持良好生物相容性的同时，通过改变交联方式或交联程度、构建双网状水凝胶、添加纳米颗粒等方法来改善水凝胶的力学性能[104]。

2.2.1 天然聚合物制成的水凝胶

天然聚合物的成分类似于天然细胞外基质（extracellular matrix, ECM），具有促进细胞增殖和黏附的能力[105]。与成骨因子、生物活性分子或细胞结合的天然聚合物表现出优异的骨修复能力[106‒111]。常见的天然聚合物包括透明质酸、壳聚糖、海藻酸盐、纤维蛋白、肝素（heparin, Hep）和明胶。透明质酸是一种糖胺聚糖（glycosaminoglycan, GAG），存在于ECM中，广泛分布于人体各部位。它由交替的双糖连接单元组成，是唯一的非硫酸化GAG。透明质酸基水凝胶由于其天然来源，具有生物相容性、非免疫原性和非炎症性。将透明质酸与热敏性聚合物结合，如泊洛沙姆（poloxamer）[112]、Pluronic F127 [113]和聚（N-异丙基丙烯酰胺）[poly(N-isopropylacrylamide), PNIPAAm] [114]，可以获得热敏性水凝胶。此外，原位化学交联透明质酸水凝胶可以通过席夫碱[115‒116]、迈克尔加成[117]和酶催化[118‒119]反应得到。壳聚糖具有优异的生物相容性和免疫刺激活性，可通过自然界中广泛存在的几丁质去乙酰化制备[120]。当作为可注射水凝胶使用时，壳聚糖可以通过温度[121‒122]和pH [123]触发凝胶化，并且可以在体内被溶菌酶[121]和壳聚糖酶[124]降解。海藻酸盐也因其温和的凝胶化过程和可降解性而被广泛应用于生物医学领域[125‒126]。它可以通过Ca2+、Ba2+和Sr2+等阳离子的螯合作用形成可注射的凝胶。但由于生理条件下阳离子在水凝胶中会发生扩散，离子交联海藻酸盐水凝胶的力学性能和降解性能不足[127]，限制了其在生物医学领域的应用。除离子交联外，还可通过酶交联[128‒129]和席夫碱交联[126]制备可注射的海藻酸盐水凝胶。

纤维蛋白是凝血酶作用于纤维蛋白原而形成的一种蛋白质，其在凝血的最后阶段起到止血作用。可注射的纤维蛋白凝胶可以通过多种方式由可溶性纤维蛋白原胶凝而形成，其力学性能可以根据所用纤维蛋白原、凝血酶或酶的浓度来调整[130]。Hep是一种带有硫酸盐负电荷的GAG，主要分布在肝脏中，。以Hep为基础的水凝胶可以通过物理[131]和化学交联（即通过酶[132]、迈克尔加成[133‒134]或席夫碱[135]）获得。明胶是胶原蛋白部分水解的产物[136]，蛋白酶K可以快速水解明胶水凝胶[137]。通过酶交联[138]和席夫碱交联[139]可以增强凝胶的稳定性。以明胶-水-甘油（gelatin-water-glycerol, GWG）为原料可制备一种伽马辐照后仍稳定的凝胶，显示出作为广谱注射载体的潜力。研究人员将这些特性归因于甘油的加入，即甘油通过氢键增加了明胶的化学势。当负载脱矿骨基质时，GWG支架表现出优异的成骨性能[140]。

由天然聚合物制成的水凝胶的一个缺点是其机械强度较差，这限制了其在承重部位的应用。为了扩大其临床应用范围，人们已经使用了许多方法来增强水凝胶力学性能并增加其生物活性。例如，与单网络水凝胶相比，由两个互穿或半互穿的聚合物网络组成的双网络水凝胶，具有更好的机械性能[141]。以壳聚糖基的双网络水凝胶为例，将短链壳聚糖与共价交联聚丙烯酰胺网络通过氢键结合制备的水凝胶力学性能明显增强[142]。基于海藻酸盐[143]和透明质酸[144]的水凝胶的力学性能也可以通过双网络得到增强。此外，将纳米颗粒掺入水凝胶中已被证明是增强天然聚合物基水凝胶力学性能的有效方法。这类纳米颗粒包括四氧化三铁纳米颗粒[145]、纳米二氧化硅[146]、金纳米棒[147]、氧化石墨烯[148]等。利用点击化学[149‒150]和超分子化学[151]也可以改善天然聚合物的力学性能。

2.2.2 合成聚合物制成的水凝胶

最常用的合成聚合物包括多肽、PEG或聚环氧乙烷[poly(ethylene oxide), PEO]、聚半乳糖醛酸[poly(galacturonic acid), PGA]及其共聚物，如PEG-聚乳酸（polylactide, PLA）和PEG-b-聚己内酯（PEG-b-polycaprolactone, PEG-PCL）。合成聚合物的性能可以根据特定的应用进行调整。与天然聚合物相比，合成聚合物具有可靠的原料来源和较长的保质期[152‒153]。然而，合成聚合物的生物相容性不如天然聚合物，而且一些合成聚合物的降解会产生有毒副产物[154]。含有合成聚合物的水凝胶可以作为药物、生物活性因子和生物大分子的优良载体。例如，含有末端马来酰亚胺基团功能化的四臂PEG大分子并负载溶葡萄球菌酶的PEG水凝胶，能够有效杀死细菌并促进骨折愈合[155]。将氧化普鲁兰和八臂PEG肼交联制备的可注射聚合水凝胶，通过加载地塞米松，可抑制炎症并诱导成骨细胞分化（图4）[156]。通过选择合适的节段，可以进一步制备热凝胶共聚物[157]。例如，聚乳酸-聚乙二醇（PEG-polylactide-glycolide, PLGA）共聚物表现出优异的热凝胶行为，即在体温下形成水凝胶，而在室温下以液体存在。PEG-PCL水凝胶作为原位成胶载体，可实现地塞米松的缓释，促进骨再生[158]。此外，通过将热敏PEG-PCL-PEG（PECE）共聚物与胶原蛋白和纳米HA结合，获得了具有成骨活性的支架，这种组合物具有良好的生物相容性，可用于引导骨再生[159]。强骨黏接剂越来越受欢迎[160]，例如，以液体疏水性光交联聚（丙交酯-丙二醇-丙交酯）二甲丙烯酸酯[poly(lactide-co-propylene glycol-colactide) dimethacrylates, PmLnDMA]为软骨相，以PmLnDMA包封的甲基丙烯酸HA纳米颗粒（PmLnDMA/MH）为矿化软骨下骨相的可注射型疏水胶黏剂，可用于治疗骨软骨缺损、骨关节炎和骨质疏松症[161]。

尽管有上述优点，水凝胶的进一步应用仍受其生物活性差、有毒副产物等缺点的限制。因此，人们将生物活性物质和化学实体偶联到合成聚合物中，以提高水凝胶的综合性能[162]。为了提高水凝胶的成骨性能，可以用精氨酸-甘氨酸-天冬氨酸（arginine-glycine-aspartic acid, RGD）修饰水凝胶[163]。RGD修饰的聚合物能有效促进细胞黏附，并且功能化的水凝胶能提高间充质干细胞的活力[164]。另一项研究表明，负载RGD的水凝胶可增强碱性磷酸酶（alkaline phosphatase, ALP）活性[165]。生物材料结构的化学修饰也可以促进矿化。例如，在水凝胶中加入磷酸基团不仅可以保持其生物降解性，还可以促进被包裹的间充质干细胞的矿化[166‒167]。

2.3 负载细胞的可注射生物材料

种子细胞在组织修复中发挥着重要作用。最近，研究表明，细胞移植在治疗骨缺损方面具有广阔的前景。间充质干细胞可能因其独特的增殖和分化能力而发挥关键作用[168]。不同来源的干细胞，如骨髓间质细胞（bone-marrow stromal cells, BMSCs）和脂肪源性干细胞（adipose-derived stem cells, ASCs），被广泛用于骨损伤修复。组织源性间充质干细胞不仅具有多向分化的能力，而且具有以下优点：①干细胞具有较强的增殖和分化能力；②细胞的免疫原性较低；③干细胞容易获得；④扩增培养条件稳定、均匀，便于大规模扩增和质量控制；⑤是适合用于组织工程的种子细胞，因可多次使用且冷冻后细胞损失小；⑥便于收集，易于储存和运输，且伦理争议较少[169‒170]。先前的研究表明，含有干细胞的多种生物材料能够诱导成骨并促进骨缺损愈合[14,171]。

2.3.1 负载细胞的微球和微凝胶

近几十年来，微球和微凝胶在骨组织工程中的应用引起了广泛的关注，因为它们可以用来携带GF、外泌体和细胞。利用微球或微凝胶进行微创手术治疗不规则骨缺损，具有瘢痕小、手术时间短、并发症少、患者舒适度和满意度高等优点。聚合物由于具有良好的生物相容性，可广泛应用于微球的制备。装载ASCs的可注射微球被证明可以促进ASCs的成骨分化并修复小鼠股骨骨不连[172]。磷灰石包被的负载阿托伐他汀（atorvastatin, AT）的可注射PLGA微球也支持ASCs的成骨分化[173]。甲基丙烯酸明胶（methacrylated gelatin, GelMA）制备的多孔形状记忆低温凝胶微球（cryogel microspheres, CMS）可促进人骨髓间质细胞（human BMSCs, hBMSCs）和人脐静脉内皮细胞（humanumbilical vein endothelial cells, HUVECs）的增殖与黏附，从而实现了血管化骨组织的发育[174]。将细胞包裹在微凝胶中可以模拟三维微环境，支持细胞的活力和功能，并保护细胞免受外界环境的影响，这种方法已被广泛应用于组织再生和细胞治疗。已有研究表明，装载细胞的微凝胶的成骨能力明显增强，且微凝胶的矿化速度加快。此外，与细胞混合微凝胶和无细胞微凝胶相比，负载间充质干细胞的微凝胶在大鼠胫骨缺损模型中显著增强了骨形成[175]。负载人间充质干细胞（human MSCs, hMSCs）和BMP-2的PVA微凝胶也能增强hMSCs的成骨分化[176]。

2.3.2 负载细胞的水凝胶

基于细胞的疗法为骨再生提供了新的潜在治疗方案。具有多孔结构的水凝胶可以作为细胞载体，模拟天然ECM微环境。将间充质干细胞包封在可注射的细胞载体（Pluronic F-127）中，载体上装载重组人BMP 4（recombinant human BMP 4, rhBMP4），可促进细胞成骨分化[177]。研究人员还制备了一种可注射的生物活性水凝胶，该水凝胶由海藻酸盐、明胶和纳米HA组成，并装载成骨细胞，被证明可促进细胞的成骨分化[178]。可注射的羟丙基-β-环糊精交联明胶基水凝胶与BMSC结合也可促进骨再生[179]。为了治疗不规则骨缺损，研究人员制备了由GelMA、骨髓间质干细胞和BMP-2组成的光交联复合生物活性支架；该支架促进BMSC成骨向分化，表现出显著的骨再生能力[180]。向BMP-2和血管内皮GF（vascular endothelial GF, VEGF）微载体植入间充质干细胞，并将其掺入含有内皮细胞（endothelial cells, ECs）的可注射海藻酸盐-RGD水凝胶中，所得复合水凝胶可促进血管化成骨[181]。一种基于交联脱细胞骨ECM和脂肪酸修饰壳聚糖的生物杂交水凝胶，被证明可以传递人羊膜干细胞并促进骨修复（图5）[182]。一种独特的细胞浸润性和注射性明胶水凝胶，封装间充质干细胞和淫羊藿素），可通过创造有利于间充质干细胞成骨分化的微环境，有效防止骨矿物质密度下降，促进原位骨再生[183]。

治疗药物的控制递送对骨再生至关重要。一种基于透明质酸和自组装帕米膦酸镁纳米颗粒的生物活性纳米复合水凝胶实现了生物活性离子和小分子药物的局部按需释放，该从水凝胶中释放的镁离子促进了被包裹的hMSCs的成骨分化和ALP的激活，活化的ALP随后催化磷酸地塞米松的去磷酸化，加速水凝胶中地塞米松的释放，进一步促进hMSC成骨向分化[184]。

3 可注射的生物响应材料

生物响应性材料对外界刺激敏感，可以对温度、pH值或压力的变化做出反应，是骨重建的理想材料，其以粒子、水凝胶或复合材料的形式出现。生物响应材料在癌症治疗、疾病诊断以及作为骨修复替代材料方面显示出了巨大的潜力（表2 [185‒196]）。

3.1 热敏生物材料

热敏性生物材料是一类物理或化学性质随外界温度变化而发生变化的材料[197‒198]。其中一种典型代表是热敏水凝胶，它已广泛应用于骨组织工程的微创治疗。热敏水凝胶通常具有临界相变温度，可以根据温度变化实现溶胶-凝胶状态的转变。随着温度的变化，它们的膨胀行为、网络结构和（或）力学性能会发生显著变化，这使得它们作为可注射支架具有一定的优势[199]。目前，PNIPAAm因其在环境温度和体温之间的相变，以及与不同类型单体共聚的能力而成为制备水凝胶最常用的热敏材料之一[200]。在室温下，PNIPAAm是一种自由流动的液体；当温度升高时，它会凝固形成弹性水凝胶[201]。此外，由于交联PNIPAAm的高度可膨胀性，它甚至可以通过小尺寸针头注射[136]。近年来，通过原子转移自由基聚合将热敏性PNIPAAm接枝到明胶上，发现这种热敏复合水凝胶是骨修复细胞的优良递送载体[185]。合成热敏水凝胶的一个缺点是其生物相容性不如天然材料，并且缺乏与细胞相容的基团。因此，人们尝试通过对天然水凝胶进行修饰，制备热敏性水凝胶。例如，琼脂糖是一种天然冷却型水凝胶，在一定浓度范围内冷却到37 ℃以下就会转变为凝胶状态。研究者发现HA/琼脂糖凝胶复合材料易于合成且能与周围组织紧密结合，将其植入兔股骨内侧髁后，发现其具有较好的成骨能力[202]。研究人员以壳聚糖和β-磷酸甘油为原料制备了壳聚糖基热敏水凝胶，作为体外培养大鼠骨髓干细胞的生物支架，发现细胞可在凝胶支架中存活28天[203]。一种新型的基于麦芽糊精与波斯胶（Persian gum, PG）混合的热敏水凝胶被发现可以增强水凝胶的力学和生物学特性[204]。负载万古霉素的PLGA-PEG-PLGA/HA热敏水凝胶可实现抗生素的持续释放和促进骨组织修复（图6）[205]。

3.2 pH响应生物材料

pH响应材料会随着碱度的变化而发生物理或化学变化[206‒207]。这些pH响应可特性可归因于材料中可电离基团的质子化或降解[208]。pH响应可注射材料主要包括有机/无机纳米粒子和水凝胶，这些材料主要用于癌症的治疗。由于健康组织和肿瘤细胞外环境之间的pH值存在差异，在骨组织工程中出现了许多有效的pH响应抗癌药物递送系统。例如，一种由I型胶原蛋白和碳酸钙负载二氧化铈纳米颗粒和抗癌药物阿霉素（doxorubicin, DOX）组成的pH响应递送系统被用于治疗骨肉瘤[209]。在另一项研究中，研究人员开发了一种多功能纳米粒子，负载DOX的介孔二氧化硅纳米颗粒通过感知pH响应性释放抗肿瘤药物，杀灭骨肉瘤细胞（图7）[210]。

骨是肿瘤转移的常见部位，其局部微环境非常有利于肿瘤生长[211]。硼替佐米已被证明是一种有效的抗癌药物。目前，研究人员已经开发了多种pH响应材料来递送硼替佐米用于癌症治疗[212‒213]。在一项研究中，硼替佐米通过与pH响应性的硼酸儿茶酚连锁，并被装载到RGD靶向的三肽树状大分子上，以治疗转移性骨肿瘤[212]。在另一项研究中，负载硼替佐米的具有骨靶向能力的胶束被用于治疗乳腺癌骨转移，这些胶束由阿仑膦酸修饰，并通过儿茶酚与硼替佐米偶联，在体内可以显著抑制癌细胞的生长[213]。

除了用于治疗骨肿瘤外，pH响应材料还可用于治疗其他骨疾病。例如，研究人员制备了一种可注射的包埋pH响应微球的CPC，能够控制药物释放并治疗骨髓炎[214]。在另一项研究中，由PLGA-PEG-叶酸、聚（环己烷-1,4-二基丙酮二亚甲基缩醛）和脂质组成的多功能受体靶向型pH响应纳米载体，被用于递送甲氨蝶呤以治疗类风湿性关节炎[215]。

此外，各种pH响应水凝胶已被开发作为潜在的骨修复和自体骨移植的骨替代物。壳聚糖水凝胶通过伯胺基团的质子化/去质子化使水凝胶能够响应外部pH的变化，因而具有相当大的骨重塑潜力[216]。最近，以壳聚糖和HA为基础，研究人员制备了一种负载Hep的pH响应热敏水凝胶[217]，结果表明，具有生物活性的壳聚糖/HA/Hep水凝胶具有诱导血管生成的作用。此外，阴离子水凝胶（如羧甲基壳聚糖）会因酸性基因的电离作用，可在较高的pH值下膨胀。研究者还研制了一种由羧甲基壳聚糖（carboxymethyl, CMCh）和ACP组成的复合纳米水凝胶[218]。该水凝胶具有骨诱导作用，显著提高了BMP9诱导的骨再生效率。

除了壳聚糖水凝胶，还有许多其他类型的可注射pH响应水凝胶。例如，一种基于甲基丙烯酸酯的可注射pH响应微凝胶，可以通过增强力学性能加速组织修复[219]。在另一项研究中，研究人员合成了一种新型可注射的pH值/热敏可生物降解嵌段共聚物水凝胶[220]，该水凝胶可促进矿化组织形成并提高ALP活性，其有很大的潜力成为骨组织工程的可注射材料。

3.3 应力响应生物材料

另一类重要的智能材料是应力响应材料，当施加机械力时，它可以通过物理或化学变化来感知和响应环境应力[221]。剪切稀化水凝胶是一种典型的应力响应材料，这种材料可以人工注入组织中，在适度的压力下流动，并在目标部位快速凝固；因此，可被广泛应用于骨修复。自组装是剪切稀化水凝胶交联的主要途径，自组装过程的机制是剪切稀化体系特有的（此处自组装过程指促进组装的竞争力和抵消组装的力之间的平衡），这些相互作用力单独而言通常相对较弱，但结合在一起可以形成稳定的网络结构[222]。由于这些弱物理关联具有动态性质，形成的网络可以被施加的剪切力解离。剪切稀化过程是高度非线性的，在去除剪切力后，这些网络重新组装成水凝胶[223]。

最近，研究人员将CaSO4和成纤维细胞GF-18掺入几丁质-PLGA复合水凝胶中，开发了一种具有Herschel-Bulkley流体性质的水凝胶。结果表明，复合水凝胶在体外具有优异的成骨分化能力；此外，体内实验结果也显示了明显的骨愈合，表明该水凝胶在颅面骨缺损再生方面具有巨大潜力[224]。

在另一项研究中，研究人员开发了一种含有n-HA的几丁质-PCL基可注射复合微凝胶，其具有相同的Herschel-Bulkley流动性。该研究证实，与对照凝胶相比，该凝胶可诱导早期成骨分化[225]。具有剪切稀化流变特性的水凝胶能够在受到力学破坏后进行自组装和黏弹性恢复。一项研究表明，中等分子量的GAGs可以用来修饰水凝胶的流变性能。GAG-HAp胶状混合物在颅骨缺损中表现出良好的成骨作用[226]。

剪切稀化和自愈水凝胶也可实现有效载荷的均匀封装，这类水凝胶可以通过针头注射而不会堵塞，还能恢复到原始状态，这使得它们非常适合控制蛋白质、药物和基因等小分子的释放[227]。例如，利用带相反电荷的PLGA纳米颗粒可制备具有内聚性的胶体凝胶。随着剪切力的增加，负载地塞米松的胶体凝胶表现出剪切稀化的行为。体外药物释放实验表明，包封的地塞米松在两个月内完全释放；而体内观察显示有大量骨形成[196]。此外，为获得一种具有快速自愈合能力和优异生物相容性、可促进复合组织再生的超分子水凝胶，研究人员通过在生物相容性聚合物上接枝大量多氢键单元，开发出一种新型可注射自愈合水凝胶；将该水凝胶植入小鼠体内后，可观察到软骨-骨组织再生（图8）[228]。为了治疗不愈合缺损，研究人员引入了一种含有PCL纳米颗粒的可注射硅酸盐剪切稀化水凝胶，该水凝胶可递送细胞和血管源性GFs。注射的水凝胶能够填充骨中任何不规则形状的缺损，是一种良好的骨修复材料[229]。

除了水凝胶，骨水泥等其他材料也具有剪切变稀的流体特性。通过稳定剪切测试，研究人员研究了原始CaCO3自凝膏体的流变特性和注射性，结果表明，膏体制备后在较长一段时间内表现出剪切稀化的行为。这种剪切稀化行为使得CaCO3自凝膏体易于注射，可以很好地应用于骨缺损的治疗[230]。在另一项研究中，研究人员通过三维（three dimensional, 3D）打印技术成功制备了硅酸钙浆料，该浆料也表现出剪切稀化特性，打印成型后具有相当于人类松质骨的抗压强度[231]。一系列具有可注射性和生物相容性的HA浆料被证明可被用作可注射的骨移植替代品[232]。在另一项研究中，研究人员制备了一种基于异山梨酯-脂环二醇的可注射生物材料，该材料由两种新型二甲基丙烯酸单体和具有生物活性的纳米HA组成。该生物材料表现出非牛顿剪切稀化行为，可以用作骨水泥的替代品，且克服了传统丙烯酸骨水泥的典型缺点[233]。为了修复复杂的骨缺损，研究人员制备了一种含有骨形成纳米HA和诺里卡汀（noricaritin）的聚碳酸三甲酯复合支架。该复合材料表现出了明显的结晶响应和剪切稀化特性，实现了诺里卡汀的持续释放，表明其在眶底缺损重建中具有应用前景[234]。

4 利用微创生物材料实现成骨的多种方法

天然骨骼由致密的皮质骨和小梁松质骨组成，它们分别由密集排列的圆柱形骨单元和多孔的小梁网络组成。骨单元和小梁分别由不同胶原纤维形态的片层组成。胶原纤维由成束的矿化胶原原纤维组成，HA纳米晶体沉积在胶原分子之间的间隙中[235]。骨缺损修复是一个涉及多种因素的复杂过程，改善生化功能（即生物矿化、血管生成和免疫调节）是促进成骨的主要途径。对于骨再生，需要基质的生物矿化来沉积HAP和胶原。此外，血管的生成也很重要，因为血管可以运输细胞、营养物质和氧气。免疫细胞在骨骼再生中也扮演着不可或缺的角色，特别是巨噬细胞表型的适当转化可以促进成骨。因此，我们将基质生物矿化、血管生成和免疫调节分类为促进骨再生的不同途径。基质生物矿化是骨修复的主要过程，需要得到适当的血管生成和免疫调节的支持（图9）。

4.1 靶向血管生成

血管生成对骨形成至关重要[236‒239]。生物材料可以通过传递促血管生成因子[240]或支持细胞增殖[241‒242]来促进血管生成。注射GFs有望作为一种医学方法在骨科中得到普及[243]。血管生成过程中的两个关键GFs分别是VEGF和成纤维细胞GF（fibroblas GF, FGF）-2 [244]。VEGF的使用与血管密度和组织保留相关[242]。FGF-2可以促进血管生成和骨修复[243]。血管生成素-1（angiopoietin-1, ANG-1）是血管发育和血管生成的重要蛋白[245]，VEGF与ANG-1在血管生成中的协同作用已被证实[246]。

在过去的几十年里，药物递送系统被广泛关注和研究[243]。由透明质酸组成的无定形非纤维水凝胶被发现可以作为VEGF递送系统[242]。另有研究表明，局部注射负载FGF-2的明胶水凝胶，可实现FGF-2的持续递送，保护GFs的生物活性，促进诱导生物组织再生[243]。不同GFs联合使用也可大大增强血管生成的效果[247]。

4.2 靶向免疫调节

骨再生是一个极其复杂的过程，需要不同系统和组织中的细胞相互配合，其中免疫细胞在骨修复中起着重要的作用。骨损伤后，最先进入骨微环境的炎症细胞是免疫细胞，如中性粒细胞、巨噬细胞、T细胞等。在早期炎症微环境中，免疫细胞释放各种细胞因子和趋化因子，以吸引各种细胞进入骨损伤区参与炎症反应，同时募集骨组织中的骨髓间充质干细胞，并调控其增殖、分化或凋亡。然而，过度的炎症反应会损伤细胞，促进巨噬细胞和成纤维细胞在植入生物材料表面形成纤维囊，这会使生物材料与组织分离，导致工程材料植入失败。近年来，骨免疫学的发展揭示了免疫细胞在调节骨再生、维持骨稳态、调节骨重塑等方面的重要作用，即免疫系统和骨骼系统有许多共同的调控分子。植入生物材料后，不可避免地会引发宿主反应，导致植入生物材料周围的正常组织遭到破坏，最终导致植入物无法与周围组织融合。此外，炎症的程度会影响植入生物材料的性能，尤其是成骨性能[248]。进一步增强骨生物材料的免疫调节功能，有助于调节骨修复过程中的免疫反应。

研究表明，巨噬细胞通过经典激活途径极化为M1型后，主要发挥促炎功能，从而驱动早期炎症反应的启动。巨噬细胞亦可通过替代激活途径极化为M2型，发挥抗炎作用，促进炎症消退，并有助于成骨与血管生成。一种可注射的可动态整合多种生物功能的骨ECM 水凝胶被发现可诱导巨噬细胞M2极化并进一步促进成熟骨形成[249]。白细胞介素-4（interleukin-4, IL-4）广泛应用于巨噬细胞调控骨组织工程的构建。负载IL-4的富钙结冷胶水凝胶也被发现能够调节巨噬细胞的极化[250]。负载IL-4和BMP-2的复合水凝胶可诱导巨噬细胞向M2型分化并增强骨形成[251]。也有报道[252]称，负载纳米鱼骨粉的水凝胶增强了杂交水凝胶的力学性能，并调节了免疫微环境。Zn2+、Ca2+、Li+和Mg2+等金属离子被认为是具有调节巨噬细胞极化能力的治疗性离子。负载锂修饰生物玻璃的GelMA水凝胶在高糖微环境中可调节巨噬细胞极化（图10）[253]。

4.3 靶向矿化

生物矿化是指将生物矿化机制与材料制备相结合来模拟生物环境的过程，具体是通过一定的手段将磷酸钙化合物、碳酸钙等无机颗粒引入生物材料的过程。通过这一过程，可以使材料的结构和组成更接近天然骨骼，从而使复合材料具有独特的微观结构特性及优异的生物学性能。研究表明，在材料表面制备生物矿化层可以提高材料的生物相容性和细胞亲和性。此外，在材料表面形成类骨磷灰石层可以促进直接成骨，即材料表面形成生物矿化层（如HA层）可显著改善材料原有的生物学特性[254]。

作为理想的微创植入式生物材料，矿化生物材料被广泛应用于骨重建，其中矿化水凝胶的应用尤为广泛。水凝胶矿化涉及通过不同的方法将钙、磷化合物、碳酸钙等无机颗粒加入到水凝胶基质中。通过这一过程，凝胶的结构和组成更接近于天然骨骼。由n-HA、聚丙烯酸和碳酸钠组成的仿生矿化水凝胶能够保持良好的力学性能，同时表现出良好的骨诱导性[255‒256]。一种常见的矿化策略是在水凝胶前体中添加预制的无机颗粒，这些颗粒可在凝胶形成过程被包裹在水凝胶网络中，这既保留了水凝胶的可注射特性，又促进了成骨细胞的生长和成骨分化。负载高浓度Ca2+的矿化水凝胶在模拟体液中浸泡后，可实现磷灰石的快速形成和高结晶[257]。

矿化HA纳米纤维也可被掺入GelMA水凝胶中，形成复合水凝胶，以提高骨修复效果[258]。将2,2,6,6-四甲基哌啶氧化物所氧化的纤维素纳米原纤维加入聚合物溶液中，可得到矿化水凝胶。研究优化了氯化钙反应引发的聚合物链交联反应，同时促进了磷酸钙的原位矿化[259]。也有报道称，负载rhBMP-2的原位矿化水凝胶支架可实现骨组织再生，由于电荷结构相反，两性离子组分在整个支架中促进了磷酸钙的致密矿化[260]。

5 微创植入式生物材料在骨科中的生物医学应用

一般来说，较大的骨缺损需要介入治疗才能恢复。然而，自体骨虽是骨移植材料的金标准，但受到供应的限制。因此，许多研究聚焦于通过组织工程策略来促进骨再生[261‒263]。支架被认为是组织工程的关键部分，为细胞黏附和增殖提供了3D环境。植入式生物材料的应用是促进新骨形成和骨再生的主要手段[264]。使用可注射的生物材料来负载活细胞和生物活性分子是一种理想的策略，其微创输送可以减少炎症，避免侵入性手术造成的骨质流失[265‒266]。基因、细胞和GFs可以通过可注射的生物材料有效地传递到目标组织中，这使得这类材料在骨组织工程中的应用非常广泛（图11）[267]。微创生物材料具有广阔的临床应用前景，可用于修复创伤后的骨缺损、骨髓炎所致的骨缺损、骨质疏松性压缩性骨折、骨肿瘤所致的骨破坏等。此外，微创生物材料还可辅助固定金属内固定物，如螺钉、矫形钛合金板[5]等。

5.1 用于骨折和骨缺损愈合的微创植入式生物材料

因意外事故、骨肿瘤、先天性骨异常和外伤引起的骨缺损或骨折的修复，一直是临床骨修复的难题。目前主要的修复材料有自体骨、异体骨和人工骨移植生物材料[268‒269]。移植的骨修复材料的具体选择主要基于固定物的力学稳定性、骨折部位的血供情况、骨缺损的范围、骨缺损的大小。合成骨移植物有望缓解因缺乏合适的自体移植物和同种异体移植物材料而造成的巨大需求压力[270‒272]。

通过微创注射的方式将骨替代物移植到骨缺损部位，是临床上一种非常理想的对患者损伤最小的骨移植方法[273‒275]。在临床应用中，一些常见的骨折，如跟骨骨折、桡骨远端骨折、椎体压缩性骨折、胫骨平台骨折等，往往只需要注射骨替代物即可进行治疗。对于桡骨远端新鲜骨折，经皮注射骨代用品可以充分填充骨折缺损，防止断骨骨折移位，促进骨折愈合[276]。此类注射也可用于骨肿瘤手术后的骨缺损治疗，因为它们可以有效地填充骨缺损并诱导新骨的产生[273]。通过负载GFs和药物，可注射骨替代物也可用于治疗感染性骨病变和修复大面积长骨缺损[277‒278]。

如前所述，可注射生物材料的应用已经成为新骨形成和骨再生治疗中不可或缺的一部分[279‒280]。大多数临床使用的可注射骨移植物分为三大类：丙烯酸骨移植物、CPC和硫酸钙骨移植物[274]。在临床实践中，为了促进骨形成和减少感染，GFs和抗生素越来越多地被纳入骨移植替代品的组成部分[281]。BMP已被证明具有成骨诱导特性，并在调节参与骨生理的靶基因表达方面发挥重要作用[282‒283]。有几个临床病例使用BMP-2进行唇腭裂患者的上颌重建[284‒285]。Hissnauer等[286]报道了装载有BMP-2的锁定钢板成功用于治疗股骨骨不连。为了抑制感染，抗生素也被用于预防和治疗骨和关节感染，如开放性骨折和骨髓炎[287]。局部使用抗生素是一种有意义的方法，因为它具有局部浓度高、全身浓度低的优势[288]。这不仅在活动性感染中取得了良好的结果[289]，而且在预防性使用抗生素时也取得了理想效果[290]。抗生素掺入PMMA已广泛应用于临床治疗[291]。

5.2 用于椎体增强的微创植入式生物材料

骨质疏松症在老年人中普遍存在，表现为骨质流失、骨微结构退化、骨强度降低[292‒293]。骨质疏松性椎体压缩性骨折（osteoporotic vertebral compression fracture, OVCF）是骨质疏松症的并发症之一。OVCF可引起严重疼痛，影响患者的整体健康和生活质量。而椎体强化术可以快速有效地缓解这种疼痛，恢复椎体的强度和硬度[294‒295]。在手术过程中，骨水泥通过针头输送到受伤部位。理想情况下，用于OVCF的注入材料应该是可降解的，并且具有足够的力学强度来承受载荷。目前，应用最广泛的椎体增强骨水泥是基于PMMA的骨水泥[296]，由固相和液相组成。将两相混合形成膏状，在手术过程中注射到体内。PMMA骨水泥的固相包含PMMA粉末、引发剂和放射增光剂，液相包含甲基丙烯酸甲酯（methyl methacrylate, MMA）单体、稳定剂和促进剂。在目前的OVCF治疗中，已发现仿生矿化胶原修饰PMMA骨水泥可实现良好的椎体高度恢复，还可以显著降低术后相邻椎体骨折的发生率[297]。虽然PMMA可以提供足够的支持并迅速恢复椎体的完整性和功能，但它不可降解且具备生物惰性；此外，它的高弹性模量会造成应力遮挡效应，从而导致骨质流失[298]。因此，研究人员开发磷酸钙基和硫酸钙基骨水泥等可降解材料，用于强化椎体。CPC也被广泛应用于临床，据报道，其在临床应用中表现出良好的生物相容性和骨整合性[299]。虽然CPC表现出较好的抗压强度，但其脆性仍然是临床应用的主要限制，其较差的力学性能和相对不可预测的降解行为仍然是需要进一步研究的重要问题[300]。

5.3 用于骨植入物固定的微创生物材料

金属螺钉、钢板、髓内针、钢丝或骨板常用于固定骨折部位。在临床上，骨-材料界面的脱黏往往是导致种植体失败的原因。例如，在内固定中，椎弓根螺钉比其他植入物更常用[301]，然而，椎弓根螺钉的固定强度可能不足，或者之后会发生脊柱的力学过载修复。特别是骨质疏松会导致螺钉松动或无效，导致骨不愈合，植入后需要手术翻修[302]。为了加强种植体稳定性并防止其脱落，通常需要使用黏接剂来增加假体与骨组织之间的黏接。目前临床上用于骨种植体固定的胶凝材料主要有PMMA [303]、硫酸钙水泥[304]、CPCs [305]等，这些材料能够以微创方式植入体内，稳定骨种植体，促进骨愈合。

PMMA是种植体固定中最常用的黏接剂材料，它能提供足够的力学支撑。虽然PMMA的应用已取得显著成效，但PMMA很难被吸收，因此，它的使用会导致骨折断端形成屏障，影响骨折愈合[306]。许多允许与骨组织直接结合的生物活性材料已经被开发出来，以取代PMMA作为黏合物。其中一种替代材料是硫酸钙水泥，作为黏合材料使用时，硫酸钙水泥可以显著强化螺钉与骨的界面，增强椎弓根螺钉的长期稳定性。硫酸钙水泥周围的弱酸性环境可以阻止纤维组织向内生长，同时促进成骨细胞的聚集和水泥周围类骨物质的形成[307]。另一项研究表明，注射硫酸钙水泥可以提高椎弓根螺钉固定的拔出强度，这意味着它可能是PMMA的良好替代品[308]。磷酸钙骨水泥可用作黏结剂填充裂缝和空腔，以增加螺钉的稳定性。研究表明，体内注射固定磷酸钙骨水泥可显著提高种植前后螺钉拔出强度[309]。采用磷酸四钙与磷酸二钙反应的HA水泥增强螺钉，可显著提高螺钉的初始拔出力[310]。此外，一种用磷酸化磷酸丝氨酸氨基酸单体修饰的新型CPC被开发为骨黏合剂[311]，实验表明，磷酸丝氨酸的加入提高了骨水泥与多种表面的黏合力，包括生物材料（金属、聚合物等）、钙化组织和软组织。

最近，基于有机-无机相互作用的骨胶黏剂受到越来越多的关注，有望彻底改变骨修复的临床治疗方式。人们发现了一种基于磷酸四钙和磷脂的新型骨黏合剂，它在水环境中几分钟就能固化，并具有很高的骨-骨黏合剂强度。这种新材料的黏合力是生物可吸收磷酸钙骨水泥的10倍，是不可吸收PMMA骨水泥的7.5倍[312]。在另一项研究中，研究人员通过单宁酸与丝素和HA的自发共聚制备了无机-有机杂化水凝胶。单宁酸与丝素之间的强亲和力，以及牺牲配位键的结合，通过增加纳米级的能量耗散，显著提高了水凝胶的韧性和黏接强度，这有助于在潮湿的生物环境中充分稳定地固定骨折[313]。

5.4 用于骨肿瘤治疗的可注射生物材料

一般情况下，骨肉瘤患者在肿瘤切除后通常通过静脉注射抗癌药物进行治疗。但由于肿瘤切除部位残留肿瘤细胞，癌症复发时有发生。此外，骨肉瘤手术后留下的较大骨缺损超过了骨组织的自愈能力，给患者带来长期的痛苦，甚至导致手术失败[314]。成功的骨再生和残留癌细胞的控制对组织工程提出了挑战[315]。

基于两种或多种治疗相互作用的协同改善作用，近年来肿瘤临床研究逐渐从单一治疗转向联合治疗，以提高治疗效果[316‒317]。近红外（near-infrared, NIR）激光光热治疗（photothermal therapy, PTT）具有穿透深度深、照射准确、消融效果好等优点[318]。可注射的AgBiS2纳米颗粒已被设计用于计算机断层扫描成像和肿瘤的光治疗。这些AgBiS2纳米颗粒可以在NIR激光照射下有效地将光转化为热，并显著增加细胞内活性氧的产生[319]。PTT/光动力疗法（photodynamic therapy, PDT）联合使用在体内成功抑制骨肉瘤的生长[320]。研究者制备了牛血清白蛋白-氧化铱（bovine serum albumin-iridium oride, BSA-IrO2）纳米颗粒，具有高DOX载药量、高光热转化能力和光稳定性，可实现骨肉瘤有效协同化疗-PTT（图12）[321]。使用可注射的磁性纳米颗粒（magnetic nanoparticles, MNPs），磁热疗法可以将电磁能转化为热能，从而实现靶向热疗，从内到外加热肿瘤，避免对周围正常组织的损伤[322]。除了直接导致骨肉瘤细胞死亡外，磁热疗法还可能诱导剩余的癌细胞分化为更成熟的细胞类型，从而抑制其自我更新能力[323]。

化疗药物的使用提高了骨肉瘤患者的生存率，但肿瘤仍会继续复发并发生转移。此外，这些药物有时会导致多药耐药（multidrug resistance, MDR）[324‒325]。当患者接受全身化疗时，非特异性蛋白结合作用常将血液中的抗癌药物快速清除，会导致治疗效果不佳和不良副作用[326]。因此，骨肉瘤的成功治疗需要新型先进的化疗方法[327]。为了提高联合化疗的效果，合理设计药物载体系统是必要的[328‒329]。一种基于局部给药系统的可注射水凝胶能够通过局部注射将抗癌药物输送到癌症组织，而无需在血液中进行治疗，并通过联合化疗将MDR降至最低[330]。此外，与全身化疗相比，局部给药可以克服全身给药带来的副作用和药物半衰期短的挑战[331‒332]。盐酸DOX（DOX∙HCl）/顺铂（cisplatin, CP）负载水凝胶/（2-羟丙基）-环糊精[DOX∙HCl/CP-loaded hydrogel/(2-hydroxypropyl)-beta cyclodextrin, GDHCP]给药系统可在7天内连续释放DOX∙HCl和CP。与DOX∙HCl、CP和乙二醇壳聚糖水凝胶相比，GDHCP具有更好的抗癌效果[333]。此外，可注射的基于水凝胶的给药系统在一定程度上提高了化疗药物的最大耐受剂量（maximum tolerated dose, MTD），降低了全身毒性[334]。

血管阻滞剂与细胞毒性药物联合使用可提高抗肿瘤效果，诱导肿瘤的大范围凋亡[335]。将含有康普瑞汀A-4（combretastatin A-4, CA-4）和多烯紫杉醇（docetaxel, DTX）的微球嵌入可注射的水凝胶中，形成水凝胶微球（hydrogel microspheres, Gel-MPs），可用于药物的控制释放，以配合骨肉瘤的治疗。更具体地说，CA-4优先从降解的水凝胶中释放出来，破坏肿瘤的血管结构，减少肿瘤与周围组织之间的营养交换，并产生间隙使DTX穿透组织，从而抑制肿瘤细胞的增殖[332]。

可注射颗粒是治疗骨肿瘤的另一种有前途的载药介质。例如，pH响应聚合物被合成为可注射颗粒，用于靶向递送硼替佐米到转移性骨肿瘤。载药颗粒在正常组织中保持稳定，并在酸性微环境中快速释放硼替佐米，有效抑制转移性骨肿瘤的进展，显著抑制肿瘤相关的骨溶解[212]。同样，使用阿仑膦酸钠作为骨靶向配体，并包埋硼替佐米-儿茶酚偶联物，可开发出可注射的pH响应胶束，这种胶束可显著抑制体内骨肿瘤的生长，减少骨破坏[213]。为了提高化疗药物的特异性，研究人员开发了骨/肿瘤靶向注射纳米颗粒作为紫杉醇载体，并有效递送药物。这些纳米颗粒在体内能够在骨转移瘤中积累，抑制4T1肿瘤生长和肺转移[336]。

5.5 治疗骨缺损相关感染的可注射生物材料

根据临床研究，如果在植入部位发生感染，那么治疗效果就不太好，在大中型骨科手术中尤为明显。当感染发生时，患者死亡率上升，且导致住院时间延长，住院费用明显增加[337]。由于抗生素的不合理使用，耐药菌逐渐增多[338]，因此，迫切需要开发出能够有效抵抗感染、促进骨再生的材料[339]。

5.5.1 含有抗生素的可注射生物材料

水凝胶因其生物相容性被广泛用于组织再生[340‒341]。从天然来源材料到合成材料，水凝胶在骨组织工程中前景广阔[342‒343]。许多可注射的水凝胶通过原位交联，可以递送抗菌剂/抗生素，因而被广泛应用于骨再生[344‒345]。最近，双功能可注射水凝胶被广泛采用，因为这些凝胶可以杀死细菌并将抗生素释放到周围环境中[346]。抗生素的选择取决于它们对革兰氏阳性菌和革兰氏阴性菌的杀菌效果。万古霉素、替考拉宁、奎奴普汀/达福普汀、𫫇唑烷酮类、达托霉素、特拉万星和头孢洛林是目前已知对革兰氏阳性细菌具有高活性的药物[347]。头孢菌素、氟喹诺酮类药物、氨基糖苷类药物、亚胺培南和广谱青霉素对多种革兰氏阴性菌有效[348]。例如，一种装载万古霉素的功能性可注射水凝胶能够局部递送抗生素，抗生素主要是通过在水凝胶中万古霉素和葡聚糖醛之间形成的可逆亚胺键来封装的，这实现了万古霉素的pH响应性缓释，并在体内实验中取得了良好的效果[346]。

近年来，国内外新型抗菌药物的研究热点开始包括具有独特杀菌活性的酶的生物工程改造，如葡萄球菌溶菌酶和溶菌酶[349]。这些酶可以切断金黄色葡萄球菌细胞壁肽聚糖中的五甘氨酸肽键桥结构，从而快速渗透、溶解并杀死目标细菌[350]。由于酶通常具有较高的蛋白质活性但稳定性较差，因此将其包裹入载体中以增强稳定性并提高蛋白质的释放率。在一项研究中，装载葡萄球菌溶菌酶的CPC控制了酶的释放，并对耐甲氧西林金黄色葡萄球菌表现出良好的抗菌活性，证明了其治疗骨缺损和感染的潜力。

5.5.2 含有杀菌颗粒的可注射生物材料

最近，纳米颗粒介导的药物递送方法作为一种递送药物治疗和响应生物膜相关感染的手段被广泛研究[351]。许多纳米粒子具有良好的抗菌性能，如纳米ZnO等纳米材料在各个领域受到了广泛的关注。纳米颗粒具有较大的表面体积比，其中一些（如Ag、TiO2、ZnO和壳聚糖）具有良好的抗菌活性[352‒355]。ZnO对革兰氏阳性菌（如金黄色葡萄球菌）和革兰氏阴性菌（如大肠杆菌）均有杀灭作用[356]。例如，研究人员通过溶胶-凝胶法合成ZnO颗粒，并将其添加到海藻酸盐基可注射水凝胶中，以治疗软骨再生过程中骨缺损相关感染[357]。最近的研究表明，ZnO颗粒的抗菌机制可能涉及Zn2+释放和氧化应激[358]。人们认为微生物携带负电荷，而金属氧化物带正电荷，这就在细菌感染部位和金属氧化物之间产生了“静电”相互作用。一旦发生接触，细菌就会被氧化并立即死亡。ZnO的抑菌活性主要来源于细菌在ZnO表面的黏附作用。从ZnO中释放的离子与细菌细胞表面的蛋白质的巯基（—SH）发生反应。之后，蛋白质被ZnO灭活，从而导致膜的通透性降低，最终导致细胞死亡[359]。

银基纳米颗粒是另一种重要的抗菌物质，它们可以用作可注射生物材料中的抗菌成分（图13）[360]。聚合物-银纳米复合材料因其易于改性和可生物降解的特性而被广泛应用[353]。

6 结论与展望

在骨科领域，用于微创治疗的植入式生物材料已取得显著成效，这些材料不仅简化了手术流程、减少了并发症，还在一定程度上革新了传统手术方式。随着可植入生物材料不断创新，未来微创治疗将拥有更多选择与可能。然而，理想的骨替代材料需与天然骨组织高度匹配，这仍是一大挑战。因此，下一代骨替代品仍需满足更高的性能与生物相容性要求。基于当前研究与实践，我们认为未来微创植入式生物材料的发展趋势可能包括以下几个方面：

（1）许多可生物降解材料，如磷酸钙和硫酸钙，已被提议作为PMMA的替代品。然而，迄今为止，PMMA仍是临床应用中最主要的合成骨替代材料，在椎体强化等承重领域中表现尤为突出。理想情况下，在此类应用中，植骨材料的降解速率应与新骨形成速率相匹配，同时具备足够的机械强度以在降解过程中支撑骨结构。目前，可植入材料的力学性能与生物降解性的协调控制仍是一项重大挑战。此外，大多数研究通常采用静态压缩和拉伸测试评估生物陶瓷的力学性能，但这类静态评价可能不足以全面反映材料在体内动态环境下的实际表现。因此，为了更准确地预测生物材料的体内力学行为，亟须引入断裂韧性、疲劳性能等更具针对性的测试方法。

（2）随着组织工程领域的不断发展，对能够促进骨再生的支架材料的需求日益增长。实现高效的组织工程不仅需要深入理解细胞与材料之间的相互作用，还需要通过合理的结构设计，最大限度地模拟细胞外基质（ECM）环境。近年来，3D打印技术为个性化和微创治疗提供了新的可能性，通过实现不同层次支架的精确设计，为组织工程的临床应用铺平了道路。此外，为了实现最佳的修复效果，支架在注射过程中应保护细胞免受破坏性剪切应力的损伤。因此，亟须进一步研究并开发新型支架，以提高细胞在注射和植入过程中的存活率。

（3）生物材料通过多种机制促进成骨，包括血管生成、免疫调节和矿化促进等。深入理解这些机制不仅对于优化新型骨折愈合疗法至关重要，也为开发适用于MISs的仿生骨替代材料提供了关键指导。这一过程相当复杂，需要化学家、生物学家与材料科学家密切合作，共同揭示其中的作用机制。

（4）除了关注可植入生物材料的生物相容性和生物活性外，人们对其抗感染、抗肿瘤等多种功能性能的需求也日益增长。因此，具备多功能性和生物响应性的材料受到了越来越多的关注。目前，可用于临床的此类材料仍然有限，且大多基于水凝胶或微球系统。为了更好地满足多样化的临床需求，仍需进一步推进微创植入式生物材料的开发与创新。

参考文献

原文顺序 | 出版日期 | 本文引用
[1]

Xue X, Hu Y, Deng Y, Su J. Recent advances in design of functional biocompatible hydrogels for bone tissue engineering. Adv Funct Mater 2021;31(19):2009432. . 10.1002/adfm.202009432
[2]

Tamimi F, Torres J, Lopez-Cabarcos E, Bassett DC, Habibovic P, Luceron E, et al. Minimally invasive maxillofacial vertical bone augmentation using brushite based cements. Biomaterials 2009;30(2):208‒16. . 10.1016/j.biomaterials.2008.09.032
[3]

Finkemeier CG. Bone-grafting and bone-graft substitutes. J Bone Joint Surg Am 2002;84(3):454‒64. . 10.2106/00004623-200203000-00020
[4]

Peters MC, McLean ME. Minimally invasive operative care. II. Contemporary techniques and materials: an overview. J Adhes Dent 2001;3(1):17‒31.
[5]

Raucci MG, D’Amora U, Ronca A, Ambrosio L. Injectable functional biomaterials for minimally invasive surgery. Adv Healthc Mater 2020;9(13):2000349. . 10.1002/adhm.202000349
[6]

Alamir HTA, Ismaeel GL, Jalil AT, Hadi WH, Jasim IK, Almulla AF, et al. Advanced injectable hydrogels for bone tissue regeneration. Biophys Rev 2023;15(2):223‒37. . 10.1007/s12551-023-01053-w
[7]

Ghandforoushan P, Alehosseini M, Golafshan N, Castilho M, Dolatshahi-Pirouz A, Hanaee J, et al. Injectable hydrogels for cartilage and bone tissue regeneration: a review. Int J Biol Macromol 2023;246:125674. . 10.1016/j.ijbiomac.2023.125674
[8]

Leach DG, Young S, Hartgerink JD. Advances in immunotherapy delivery from implantable and injectable biomaterials. Acta Biomater 2019;88:15‒31. . 10.1016/j.actbio.2019.02.016
[9]

Togawa D, Bauer TW, Lieberman IH, Takikawa S. Histologic evaluation of human vertebral bodies after vertebral augmentation with polymethyl methacrylate. Spine 2003;28(14):1521‒7. . 10.1097/01.brs.0000076825.12630.3c
[10]

Ying SH, Kao HC, Chang MC, Yu WK, Wang ST, Liu CL. Fixation strength of PMMA-augmented pedicle screws after depth adjustment in a synthetic bone model of osteoporosis. Orthopedics 2012;35(10):e1511‒6. . 10.3928/01477447-20120919-21
[11]

Galovich LA, Perez-Higueras A, Altonaga JR, Orden JM, Barba ML, Morillo MT. Biomechanical, histological and histomorphometric analyses of calcium phosphate cement compared to PMMA for vertebral augmentation in a validated animal model. Eur Spine J 2011;20:376‒82. . 10.1007/s00586-011-1905-4
[12]

Montazerian M, Dutra ZE. History and trends of bioactive glass-ceramics. J Biomed Mater Res A 2016;104(5):1231‒49. . 10.1002/jbm.a.35639
[13]

Daculsi G, Durand M, Fabre T, Vogt F, Uzel AP, Rouvillain JL. Development and clinical cases of injectable bone void filler used in orthopaedic. IRBM 2012;33(4):254‒62. . 10.1016/j.irbm.2012.06.001
[14]

Liu M, Zeng X, Ma C, Yi H, Ali Z, Mou X, et al. Injectable hydrogels for cartilage and bone tissue engineering. Bone Res 2017;5(1):17014. . 10.1038/boneres.2017.14
[15]

Vishnu Priya M, Sivshanmugam A, Boccaccini AR, Goudouri OM, Sun W, Hwang N, et al. Injectable osteogenic and angiogenic nanocomposite hydrogels for irregular bone defects. Biomed Mater 2016;11(3):035017. . 10.1088/1748-6041/11/3/035017
[16]

Bongio M, van den Beucken JJJP, Leeuwenburgh SCG, Jansen JA. Development of bone substitute materials: from ‘biocompatible’ to ‘instructive’. J Mater Chem 2010;20(40):8747. . 10.1039/c0jm00795a
[17]

Hayashi K, Matsuguchi N, Uenoyama K, Sugioka Y. Re-evaluation of the biocompatibility of bioinert ceramics in vivo . Biomaterials 1992;13(4):195‒200. . 10.1016/0142-9612(92)90184-p
[18]

Chowdhury S, Vohra YK, Lemons JE, Ueno M, Ikeda J. Accelerating aging of zirconia femoral head implants: change of surface structure and mechanical properties. J Biomed Mater Res 2007;81(2):486‒92. . 10.1002/jbm.b.30688
[19]

Piconi C, Maccauro G. Zirconia as a ceramic biomaterial. Biomaterials 1999;20(1):1‒25. . 10.1016/s0142-9612(98)00010-6
[20]

Hench LL. The story of bioglass. J Mater Sci Mater Med 2006;17(11):967‒78. . 10.1007/s10856-006-0432-z
[21]

Kokubo T. Bioactive glass ceramics: properties and applications. Biomaterials 1991;12(2):155‒63. . 10.1016/0142-9612(91)90194-f
[22]

Daculsi G. Smart scaffolds: the future of bioceramic. J Mater Sci Mater Med 2015;26(4):154. . 10.1007/s10856-015-5482-7
[23]

Mahlooji E, Atapour M, Labbaf S. Electrophoretic deposition of bioactive glass—chitosan nanocomposite coatings on Ti-6Al-4V for orthopedic applications. Carbohydr Polym 2019;226:115299. . 10.1016/j.carbpol.2019.115299
[24]

Gatti AM, Zaffe D, Poli GP. Behaviour of tricalcium phosphate and hydroxyapatite granules in sheep bone defects. Biomaterials 1990;11(7):513‒7. . 10.1016/0142-9612(90)90068-2
[25]

Wu Y, Yang L, Chen L, Geng M, Xing Z, Chen S, et al. Core-shell structured porous calcium phosphate bioceramic spheres for enhanced bone regeneration. ACS Appl Mater Interfaces 2022;14(42):47491‒506. . 10.1021/acsami.2c15614
[26]

Begley CT, Doherty MJ, Mollan RA, Wilson DJ. Comparative study of the osteoinductive properties of bioceramic, coral and processed bone graft substitutes. Biomaterials 1995;16(15):1181‒5. . 10.1016/0142-9612(95)93584-z
[27]

Carey LE, Xu HH, Simon CG Jr, Takagi S, Chow LC. Premixed rapid-setting calcium phosphate composites for bone repair. Biomaterials 2005;26(24):5002‒14. . 10.1016/j.biomaterials.2005.01.015
[28]

Koju N, Sikder P, Gaihre B, Bhaduri SB. Smart injectable self-setting monetite based bioceramics for orthopedic applications. Materials 2018;11(7):1258. . 10.3390/ma11071258
[29]

Bohner M, Baroud G. Injectability of calcium phosphate pastes. Biomaterials 2005;26(13):1553‒63. . 10.1016/j.biomaterials.2004.05.010
[30]

Ishikawa K, Matsuya S, Nakagawa M, Udoh K, Suzuki K. Basic properties of apatite cement containing spherical tetracalcium phosphate made with plasma melting method. J Mater Sci Mater Med 2004;15(1):13‒7. . 10.1023/b:jmsm.0000010092.01661.a8
[31]

Aberg J, Brisby H, Henriksson HB, Lindahl A, Thomsen P, Engqvist H. Premixed acidic calcium phosphate cement: characterization of strength and microstructure. J Biomed Mater Res 2010;93(2):436‒41. . 10.1002/jbm.b.31600
[32]

Han B, Ma PW, Zhang LL, Yin YJ, Yao KD, Zhang FJ, et al. β-TCP/MCPM-based premixed calcium phosphate cements. Acta Biomater 2009;5(8):3165‒77. . 10.1016/j.actbio.2009.04.024
[33]

Luo J, Engqvist H, Persson C. A ready-to-use acidic, brushite-forming calcium phosphate cement. Acta Biomater 2018;81:304‒14. . 10.1016/j.actbio.2018.10.001
[34]

Lundager Madsen HE, Christensson F. Precipitation of calcium phosphate at 40 ℃ from neutral solution. J Cryst Growth 1991;114(4):613‒8. . 10.1016/0022-0248(91)90407-v
[35]

Sakae T, Nagata H, Sudo T. The crystal structure of synthetic calcium phosphate-sulfate hydrate, Ca<2) HPO<4 SO< 4. 4H<2 O, and its relation to brushite and gypsum. Am Min 1978;63(5‒6:520‒7.
[36]

Sadat-Shojai M, Khorasani MT, Dinpanah-Khoshdargi E, Jamshidi A. Synthesis methods for nanosized hydroxyapatite with diverse structures. Acta Biomater 2013;9(8):7591‒621. . 10.1016/j.actbio.2013.04.012
[37]

Gallinetti S, Canal C, Ginebra MP. Development and characterization of biphasic hydroxyapatite/β-TCP cements. J Am Ceram Soc 2014;97(4):1065‒73. . 10.1111/jace.12861
[38]

Sariibrahimoglu K, Wolke JG, Leeuwenburgh SC, Yubao L, Jansen JA. Injectable biphasic calcium phosphate cements as a potential bone substitute. J Biomed Mater Res 2014;102(3):415‒22. . 10.1002/jbm.b.33018
[39]

Komlev VS, Barinov SM, Bozo II, Deev RV, Eremin II, Fedotov AY, et al. Bioceramics composed of octacalcium phosphate demonstrate enhanced biological behavior. ACS Appl Mater Interfaces 2014;6(19):16610‒20. . 10.1021/am502583p
[40]

Chen S, Wang S, Li H, Forsberg K. Eu3+ doped monetite and its use as fluorescent agent for dental restorations. Ceram Int 2018;44(9):10510‒6. . 10.1016/j.ceramint.2018.03.068
[41]

Yu T, Zeng S, Liu X, Shi H, Ye J, Zhou C. Application of Sr-doped octacalcium phosphate as a novel Sr carrier in the α-tricalcium phosphate bone cement. Ceram Int 2017;43(15):12579‒87. . 10.1016/j.ceramint.2017.06.135
[42]

Xu S, Lin K, Wang Z, Chang J, Wang L, Lu J, et al. Reconstruction of calvarial defect of rabbits using porous calcium silicate bioactive ceramics. Biomaterials 2008;29(17):2588‒96. . 10.1016/j.biomaterials.2008.03.013
[43]

Li H, Xue K, Kong N, Liu K, Chang J. Silicate bioceramics enhanced vascularization and osteogenesis through stimulating interactions between endothelia cells and bone marrow stromal cells. Biomaterials 2014;35(12):3803‒18. . 10.1016/j.biomaterials.2014.01.039
[44]

Chen S, Shi L, Luo J, Engqvist H. Novel fast-setting mineral trioxide aggregate: its formulation, chemical-physical properties, and cytocompatibility. ACS Appl Mater Interfaces 2018;10(24):20334‒41. . 10.1021/acsami.8b04946
[45]

Prati C, Gandolfi MG. Calcium silicate bioactive cements: biological perspectives and clinical applications. Dent Mater 2015;31(4):351‒70. . 10.1016/j.dental.2015.01.004
[46]

Setbon HM, Devaux J, Iserentant A, Leloup G, Leprince JG. Influence of composition on setting kinetics of new injectable and/or fast setting tricalcium silicate cements. Dent Mater 2014;30(12):1291‒303. . 10.1016/j.dental.2014.09.005
[47]

Charnley J. Anchorage of the femoral head prosthesis to the shaft of the femur. J Bone Joint Surg 1960;42-B(1):28‒30. . 10.1302/0301-620x.42b1.28
[48]

Tai CL, Lai PL, Lin WD, Tsai TT, Lee YC, Liu MY, et al. Modification of mechanical properties, polymerization temperature, and handling time of polymethylmethacrylate cement for enhancing applicability in vertebroplasty. BioMed Res Int 2016;2016:7901562. . 10.1155/2016/7901562
[49]

Kim SB, Kim YJ, Yoon TL, Park SA, Cho IH, Kim EJ, et al. The characteristics of a hydroxyapatite-chitosan-PMMA bone cement. Biomaterials 2004;25(26):5715‒23. . 10.1016/j.biomaterials.2004.01.022
[50]

Boger A, Bohner M, Heini P, Verrier S, Schneider E. Properties of an injectable low modulus PMMA bone cement for osteoporotic bone. J Biomed Mater Res 2008;86B:474‒82. . 10.1002/jbm.b.31044
[51]

Lopez A, Hoess A, Thersleff T, Ott M, Engqvist H, Persson C. Low-modulus PMMA bone cement modified with castor oil. Biomed Mater Eng 2011;21(5‒6):323‒32.
[52]

Tsukeoka T, Suzuki M, Ohtsuki C, Sugino A, Tsuneizumi Y, Miyagi J, et al. Mechanical and histological evaluation of a PMMA-based bone cement modified with gamma-methacryloxypropyltrimethoxysilane and calcium acetate. Biomaterials 2006;27(21):3897‒903. . 10.1016/j.biomaterials.2006.03.002
[53]

Liu Z, Tang Y, Kang T, Rao M, Li K, Wang Q, et al. Synergistic effect of HA and BMP-2 mimicking peptide on the bioactivity of HA/PMMA bone cement. Colloids Surf B 2015;131:39‒46. . 10.1016/j.colsurfb.2015.04.032
[54]

Chen L, Zhai D, Huan Z, Ma N, Zhu H, Wu C, et al. Silicate bioceramic/PMMA composite bone cement with distinctive physicochemical and bioactive properties. RSC Advances 2015;5(47):37314‒22. . 10.1039/c5ra04646g
[55]

Cui X, Huang C, Zhang M, Ruan C, Peng S, Li L, et al. Enhanced osteointegration of poly(methylmethacrylate) bone cements by incorporating strontium-containing borate bioactive glass. J R Soc Interface 2017;14(131):20161057. . 10.1098/rsif.2016.1057
[56]

Engstrand J, Persson C, Engqvist H. The effect of composition on mechanical properties of brushite cements. J Mech Behav Biomed Mater 2014;29:81‒90. . 10.1016/j.jmbbm.2013.08.024
[57]

O’Neill R, McCarthy HO, Montufar EB, Ginebra MP, Wilson DI, Lennon A, et al. Critical review: injectability of calcium phosphate pastes and cements. Acta Biomater 2017;50:1‒19. . 10.1016/j.actbio.2016.11.019
[58]

El-Fiqi A, Kim JH, Perez RA, Kim HW. Novel bioactive nanocomposite cement formulations with potential properties: incorporation of the nanoparticle form of mesoporous bioactive glass into calcium phosphate cements. J Mater Chem B 2015;3(7):1321‒34. . 10.1039/c4tb01634c
[59]

Gbureck U, Spatz K, Thull R, Barralet JE. Rheological enhancement of mechanically activated alpha-tricalcium phosphate cements. J Biomed Mater Res 2005;73B(1):1‒6. . 10.1002/jbm.b.30148
[60]

Mohammadi M, Hesaraki S, Hafezi-Ardakani M. Investigation of biocompatible nanosized materials for development of strong calcium phosphate bone cement: comparison of nano-titania, nano-silicon carbide and amorphous nano-silica. Ceram Int 2014;40(6):8377‒87. . 10.1016/j.ceramint.2014.01.044
[61]

Kruger R, Groll J. Fiber reinforced calcium phosphate cements—on the way to degradable load bearing bone substitutes? Biomaterials 2012;33(25):5887‒900. . 10.1016/j.biomaterials.2012.04.053
[62]

Canal C, Ginebra MP. Fibre-reinforced calcium phosphate cements: a review. J Mech Behav Biomed Mater 2011;4(8):1658‒71. . 10.1016/j.jmbbm.2011.06.023
[63]

Kucko NW, de Lacerda SS, Sobral Marques T, Herber RP, van den Beuken JJJP, Zuo Y, et al. Tough and osteocompatible calcium phosphate cements reinforced with poly(vinyl alcohol) fibers. ACS Biomater Sci Eng 2019;5(5):2491‒505. . 10.1021/acsbiomaterials.9b00226
[64]

Motisuke M, Santos VR, Bazanini NC, Bertran CA. Apatite bone cement reinforced with calcium silicate fibers. J Mater Sci Mater Med 2014;25(10):2357‒63. . 10.1007/s10856-014-5280-7
[65]

Gallinetti S, Mestres G, Canal C, Persson C, Ginebra MP. A novel strategy to enhance interfacial adhesion in fiber-reinforced calcium phosphate cement. J Mech Behav Biomed Mater 2017;75:495‒503. . 10.1016/j.jmbbm.2017.08.017
[66]

Liu C, Shao H, Chen F, Zheng H. Effects of the granularity of raw materials on the hydration and hardening process of calcium phosphate cement. Biomaterials 2003;24(23):4103‒13. . 10.1016/s0142-9612(03)00238-2
[67]

Montufar EB, Maazouz Y, Ginebra MP. Relevance of the setting reaction to the injectability of tricalcium phosphate pastes. Acta Biomater 2013;9(4):6188‒98. . 10.1016/j.actbio.2012.11.028
[68]

Jahandideh R, Behnamghader A, Hesaraki S. The effect of carboxylic acids and phosphate salts additives on the properties of chondroitin sulfate calcium phosphate cements. Ceram Int 2023;49(6):9219‒30. . 10.1016/j.ceramint.2022.11.086
[69]

Gbureck U, Barralet JE, Spatz K, Grover LM, Thull R. Ionic modification of calcium phosphate cement viscosity. Part I: hypodermic injection and strength improvement of apatite cement. Biomaterials 2004;25(11):2187‒95. . 10.1016/j.biomaterials.2003.08.066
[70]

Fernandez E, Sarda S, Hamcerencu M, Vlad MD, Gel M, Valls S, et al. High-strength apatitic cement by modification with superplasticizers. Biomaterials 2005;26(15):2289‒96. . 10.1016/j.biomaterials.2004.07.043
[71]

Chen WC, Ju CP, Wang JC, Hung CC, Lin JHC. Brittle and ductile adjustable cement derived from calcium phosphate cement/polyacrylic acid composites. Dent Mater 2008;24(12):1616‒22. . 10.1016/j.dental.2008.03.032
[72]

Gao C, Liu H, Luo ZP, Sajilafu YH, Yang L. Modification of calcium phosphate cement with poly(gamma-glutamic acid) and its strontium salt for kyphoplasty application. Mater Sci Eng C 2017;80:352‒61. . 10.1016/j.msec.2017.05.070
[73]

Wang J, Liu C, Liu Y, Zhang S. Double-network interpenetrating bone cement via in situ hybridization protocol. Adv Funct Mater 2010;20(22):3997‒4011. . 10.1002/adfm.201000995
[74]

Rodel M, Tessmar J, Groll J, Gbureck U. Highly flexible and degradable dual setting systems based on PEG-hydrogels and brushite cement. Acta Biomater 2018;79:182‒201. . 10.1016/j.actbio.2018.08.028
[75]

Unosson J, Engqvist H. Development of a resorbable calcium phosphate cement with load bearing capacity. Bioceram Dev Appl 2014;4:74.
[76]

Bahn SL. Plaster: a bone substitute. Oral Surg Oral Med Oral Pathol 1966;21(5):672‒81. . 10.1016/0030-4220(66)90045-4
[77]

Coetzee AS. Regeneration of bone in the presence of calcium sulfate. Arch Otolaryngol 1980;106(7):405‒9. . 10.1001/archotol.1980.00790310029007
[78]

Jung HM, Song GA, Lee YK, Baek JH, Ryoo HM, Kim GS, et al. Modulation of the resorption and osteoconductivity of alpha-calcium sulfate by histone deacetylase inhibitors. Biomaterials 2010;31(1):29‒37. . 10.1016/j.biomaterials.2009.09.019
[79]

Ruan Z, Yao D, Xu Q, Liu L, Tian Z, Zhu Y. Effects of mesoporous bioglass on physicochemical and biological properties of calcium sulfate bone cements. Appl Mater Today 2017;9:612‒21. . 10.1016/j.apmt.2017.10.006
[80]

Khatua C, Sengupta S, Kundu B, Bhattacharya D, Balla VK. Enhanced strength, in vitro bone cell differentiation and mineralization of injectable bone cement reinforced with multiferroic particles. Mater Des 2019;167:107628. . 10.1016/j.matdes.2019.107628
[81]

Hu NM, Chen Z, Liu X, Liu H, Lian X, Wang X, et al. Mechanical properties and in vitro bioactivity of injectable and self-setting calcium sulfate/nano-HA/ collagen bone graft substitute. J Mech Behav Biomed Mater 2012;12:119‒28. . 10.1016/j.jmbbm.2011.12.007
[82]

Huan Z, Chang J. Self-setting properties and in vitro bioactivity of calcium sulfate hemihydrate-tricalcium silicate composite bone cements. Acta Biomater 2007;3(6):952‒60. . 10.1016/j.actbio.2007.05.003
[83]

Bohner M. New hydraulic cements based on α-tricalcium phosphate-calcium sulfate dihydrate mixtures. Biomaterials 2004;25(4):741‒9. . 10.1016/s0142-9612(03)00573-8
[84]

Yang G, Liu J, Li F, Pan Z, Ni X, Shen Y, et al. Bioactive calcium sulfate/magnesium phosphate cement for bone substitute applications. Mater Sci Eng C 2014;35:70‒6. . 10.1016/j.msec.2013.10.016
[85]

Ding SJ, Shie MY, Hoshiba T, Kawazoe N, Chen G, Chang HC. Osteogenic differentiation and immune response of human bone-marrow-derived mesenchymal stem cells on injectable calcium-silicate-based bone grafts. Tissue Eng Part A 2010;16(7):2343‒54. . 10.1089/ten.tea.2009.0749
[86]

Chen CC, Lai MH, Wang WC, Ding SJ. Properties of anti-washout-type calcium silicate bone cements containing gelatin. J Mater Sci Mater Med 2010;21(4):1057‒68. . 10.1007/s10856-009-3948-1
[87]

Xu C, Wang X, Zhou J, Huan Z, Chang J. Bioactive tricalcium silicate/alginate composite bone cements with enhanced physicochemical properties. J Biomed Mater Res 2018;106(1):237‒44. . 10.1002/jbm.b.33848
[88]

Ding SJ, Shie MY, Wang CY. Novel fast-setting calcium silicate bone cements with high bioactivity and enhanced osteogenesis in vitro . J Mater Chem 2009;19(8):1183. . 10.1039/b819033j
[89]

Mestres G, Ginebra MP. Novel magnesium phosphate cements with high early strength and antibacterial properties. Acta Biomater 2011;7(4):1853‒61. . 10.1016/j.actbio.2010.12.008
[90]

Moseke C, Saratsis V, Gbureck U. Injectability and mechanical properties of magnesium phosphate cements. J Mater Sci Mater Med 2011;22(12):2591‒8. . 10.1007/s10856-011-4442-0
[91]

Liao J, Lu S, Duan X, Xie Y, Zhang Y, Li Y, et al. Affecting mechanism of chitosan on water resistance of magnesium phosphate cement. Int J Appl Ceram Technol 2018;15(2):514‒21. . 10.1111/ijac.12795
[92]

Lu X, Chen B. Experimental study of magnesium phosphate cements modified by metakaolin. Constr Build Mater 2016;123:719‒26. . 10.1016/j.conbuildmat.2016.07.092
[93]

Wang S, Xu C, Yu S, Wu X, Jie Z, Dai H. Citric acid enhances the physical properties, cytocompatibility and osteogenesis of magnesium calcium phosphate cement. J Mech Behav Biomed Mater 2019;94:42‒50. . 10.1016/j.jmbbm.2019.02.026
[94]

Liu W, Zhai D, Huan Z, Wu C, Chang J. Novel tricalcium silicate/magnesium phosphate composite bone cement having high compressive strength, in vitro bioactivity and cytocompatibility. Acta Biomater 2015;21:217‒27. . 10.1016/j.actbio.2015.04.012
[95]

Utech S, Boccaccini AR. A review of hydrogel-based composites for biomedical applications: enhancement of hydrogel properties by addition of rigid inorganic fillers. J Mater Sci 2015;51(1):271‒310. . 10.1007/s10853-015-9382-5
[96]

Nejadnik MR, Yang X, Bongio M, Alghamdi HS, van den Beucken JJ, Huysmans MC, et al. Self-healing hybrid nanocomposites consisting of bisphosphonated hyaluronan and calcium phosphate nanoparticles. Biomaterials 2014;35(25):6918‒29. . 10.1016/j.biomaterials.2014.05.003
[97]

Wang H, Bongio M, Farbod K, Nijhuis AW, van den Beucken J, Boerman OC, et al. Development of injectable organic/inorganic colloidal composite gels made of self-assembling gelatin nanospheres and calcium phosphate nanocrystals. Acta Biomater 2014;10(1):508‒19. . 10.1016/j.actbio.2013.08.036
[98]

Boyer C, Figueiredo L, Pace R, Lesoeur J, Rouillon T, Visage CL, et al. Laponite nanoparticle-associated silated hydroxypropylmethyl cellulose as an injectable reinforced interpenetrating network hydrogel for cartilage tissue engineering. Acta Biomater 2018;65:112‒22. . 10.1016/j.actbio.2017.11.027
[99]

Zhao Y, Cui Z, Liu B, Xiang J, Qiu D, Tian Y, et al. An injectable strong hydrogel for bone reconstruction. Adv Healthc Mater 2019;8(17):e1900709. . 10.1002/adhm.201900709
[100]

Cui X, Zhang Y, Wang H, Gu Y, Li L, Zhou J, et al. An injectable borate bioactive glass cement for bone repair: preparation, bioactivity and setting mechanism. J Non-Cryst Solids 2016;432:150‒7. . 10.1016/j.jnoncrysol.2015.06.001
[101]

Gaharwar AK, Dammu SA, Canter JM, Wu CJ, Schmidt G. Highly extensible, tough, and elastomeric nanocomposite hydrogels from poly(ethylene glycol) and hydroxyapatite nanoparticles. Biomacromolecules 2011;12(5):1641‒50. . 10.1021/bm200027z
[102]

Kretlow JD, Klouda L, Mikos AG. Injectable matrices and scaffolds for drug delivery in tissue engineering. Adv Drug Deliv Rev 2007;59(4‒5):263‒73.
[103]

Ifkovits JL, Burdick JA. Review: photopolymerizable and degradable biomaterials for tissue engineering applications. Tissue Eng 2007;13(10):2369‒85. . 10.1089/ten.2007.0093
[104]

Zhang M, Yang Y, Li M, Shang Q, Xie R, Yu J, et al. Toughening double-network hydrogels by polyelectrolytes. Adv Mater 2023;35(26):e2301551. . 10.1002/adma.202301551
[105]

Ullah F, Othman MB, Javed F, Ahmad Z, Md AH. Classification, processing and application of hydrogels: a review. Mater Sci Eng C 2015;57:414‒33. . 10.1016/j.msec.2015.07.053
[106]

Cui ZK, Kim S, Baljon JJ, Wu BM, Aghaloo T, Lee M. Microporous methacrylated glycol chitosan-montmorillonite nanocomposite hydrogel for bone tissue engineering. Nat Commun 2019;10(1):3523. . 10.1038/s41467-019-11511-3
[107]

Wu J, Zheng K, Huang X, Liu J, Liu H, Boccaccini AR, et al. Thermally triggered injectable chitosan/silk fibroin/bioactive glass nanoparticle hydrogels for in situ bone formation in rat calvarial bone defects. Acta Biomater 2019;91:60‒71. . 10.1016/j.actbio.2019.04.023
[108]

Mao AS, Shin JW, Mooney DJ. Effects of substrate stiffness and cell-cell contact on mesenchymal stem cell differentiation. Biomaterials 2016;98:184‒91. . 10.1016/j.biomaterials.2016.05.004
[109]

Ingavle GC, Gionet-Gonzales M, Vorwald CE, Bohannon LK, Clark K, Galuppo LD, et al. Injectable mineralized microsphere-loaded composite hydrogels for bone repair in a sheep bone defect model. Biomaterials 2019;197:119‒28. . 10.1016/j.biomaterials.2019.01.005
[110]

Hasani-Sadrabadi MM, Sarrion P, Pouraghaei S, Chau Y, Ansari S, Li S, et al. An engineered cell-laden adhesive hydrogel promotes craniofacial bone tissue regeneration in rats. Sci Transl Med 2020;12(534):eaay6853. . 10.1126/scitranslmed.aay6853
[111]

Liu C, Wu J, Gan D, Li Z, Shen J, Tang P, et al. The characteristics of mussel-inspired nHA/OSA injectable hydrogel and repaired bone defect in rabbit. J Biomed Mater Res 2019;108(5):1814‒25. . 10.1002/jbm.b.34524
[112]

Mayol L, Quaglia F, Borzacchiello A, Ambrosio L, La Rotonda MI. A novel poloxamers/hyaluronic acid in situ forming hydrogel for drug delivery: rheological, mucoadhesive and in vitro release properties. Eur J Pharm Biopharm 2008;70(1):199‒206. . 10.1016/j.ejpb.2008.04.025
[113]

Jung HH, Park K, Han DK. Preparation of TGF-beta1-conjugated biodegradable pluronic F127 hydrogel and its application with adipose-derived stem cells. J Control Release 2010;147(1):84‒91. . 10.1016/j.jconrel.2010.06.020
[114]

Tan H, Ramirez CM, Miljkovic N, Li H, Rubin JP, Marra KG. Thermosensitive injectable hyaluronic acid hydrogel for adipose tissue engineering. Biomaterials 2009;30(36):6844‒53. . 10.1016/j.biomaterials.2009.08.058
[115]

Bulpitt P, Aeschlimann D. New strategy for chemical modification of hyaluronic acid: preparation of functionalized derivatives and their use in the formation of novel biocompatible hydrogels. J Biomed Mater Res 1999;47(2):152‒69. . 10.1002/(sici)1097-4636(199911)47:2<152::aid-jbm5>3.3.co;2-9
[116]

Martinez-Sanz E, Ossipov DA, Hilborn J, Larsson S, Jonsson KB, Varghese OP. Bone reservoir: injectable hyaluronic acid hydrogel for minimal invasive bone augmentation. J Control Release 2011;152(2):232‒40. . 10.1016/j.jconrel.2011.02.003
[117]

Lei Y, Gojgini S, Lam J, Segura T. The spreading, migration and proliferation of mouse mesenchymal stem cells cultured inside hyaluronic acid hydrogels. Biomaterials 2011;32(1):39‒47. . 10.1016/j.biomaterials.2010.08.103
[118]

Jin R, Teixeira LS, Dijkstra PJ, van Blitterswijk CA, Karperien M, Feijen J. Enzymatically-crosslinked injectable hydrogels based on biomimetic dextran-hyaluronic acid conjugates for cartilage tissue engineering. Biomaterials 2010;31(11):3103‒13. . 10.1016/j.biomaterials.2010.01.013
[119]

Pek YS, Kurisawa M, Gao S, Chung JE, Ying JY. The development of a nanocrystalline apatite reinforced crosslinked hyaluronic acid-tyramine composite as an injectable bone cement. Biomaterials 2009;30(5):822‒8. . 10.1016/j.biomaterials.2008.10.053
[120]

De Souza R, Zahedi P, Allen CJ, Piquette-Miller M. Biocompatibility of injectable chitosan-phospholipid implant systems. Biomaterials 2009;30(23‒24):3818‒24.
[121]

Cho J, Heuzey MC, Begin A, Carreau PJ. Physical gelation of chitosan in the presence of beta-glycerophosphate: the effect of temperature. Biomacromolecules 2005;6(6):3267‒75. . 10.1021/bm050313s
[122]

Ta HT, Dass CR, Larson I, Choong PF, Dunstan DE. A chitosan-dipotassium orthophosphate hydrogel for the delivery of Doxorubicin in the treatment of osteosarcoma. Biomaterials 2009;30(21):3605‒13. . 10.1016/j.biomaterials.2009.03.022
[123]

Chiu YL, Chen SC, Su CJ, Hsiao CW, Chen YM, Chen HL, et al. pH-triggered injectable hydrogels prepared from aqueous N-palmitoyl chitosan: in vitro characteristics and in vivo biocompatibility. Biomaterials 2009;30(28):4877‒88. . 10.1016/j.biomaterials.2009.05.052
[124]

Bhattarai N, Gunn J, Zhang M. Chitosan-based hydrogels for controlled, localized drug delivery. Adv Drug Deliv Rev 2010;62(1):83‒99. . 10.1016/j.addr.2009.07.019
[125]

Grellier M, Granja PL, Fricain JC, Bidarra SJ, Renard M, Bareille R, et al. The effect of the co-immobilization of human osteoprogenitors and endothelial cells within alginate microspheres on mineralization in a bone defect. Biomaterials 2009;30(19):3271‒8. . 10.1016/j.biomaterials.2009.02.033
[126]

Lee KY, Bouhadir KH, Mooney DJ. Controlled degradation of hydrogels using multi-functional cross-linking molecules. Biomaterials 2004;25(13):2461‒6. . 10.1016/j.biomaterials.2003.09.030
[127]

LeRoux MA, Guilak F, Setton LA. Compressive and shear properties of alginate gel: effects of sodium ions and alginate concentration. J Biomed Mater Res 1999;47(1):46‒53. . 10.1002/(sici)1097-4636(199910)47:1<46::aid-jbm6>3.0.co;2-n
[128]

Sakai S, Hirose K, Moriyama K, Kawakami K. Control of cellular adhesiveness in an alginate-based hydrogel by varying peroxidase and H2O2 concentrations during gelation. Acta Biomater 2010;6(4):1446‒52. . 10.1016/j.actbio.2009.10.004
[129]

Sakai S, Kawakami K. Synthesis and characterization of both ionically and enzymatically cross-linkable alginate. Acta Biomater 2007;3(4):495‒501. . 10.1016/j.actbio.2006.12.002
[130]

O’Cearbhaill ED, Murphy M, Barry F, McHugh PE, Barron V. Behavior of human mesenchymal stem cells in fibrin-based vascular tissue engineering constructs. Ann Biomed Eng 2010;38(3):649‒57. . 10.1007/s10439-010-9912-x
[131]

Ohta M, Suzuki Y, Chou H, Ishikawa N, Suzuki S, Tanihara M, et al. Novel heparin/alginate gel combined with basic fibroblast growth factor promotes nerve regeneration in rat sciatic nerve. J Biomed Mater Res 2004;71(4):661‒8. . 10.1002/jbm.a.30194
[132]

Jin R, Moreira Teixeira LS, Dijkstra PJ, van Blitterswijk CA, Karperien M, Feijen J. Chondrogenesis in injectable enzymatically crosslinked heparin/dextran hydrogels. J Control Release 2011;152(1):186‒95. . 10.1016/j.jconrel.2011.01.031
[133]

Kim M, Kim SE, Kang SS, Kim YH, Tae G. The use of de-differentiated chondrocytes delivered by a heparin-based hydrogel to regenerate cartilage in partial-thickness defects. Biomaterials 2011;32(31):7883‒96. . 10.1016/j.biomaterials.2011.07.015
[134]

Nie T, Baldwin A, Yamaguchi N, Kiick KL. Production of heparin-functionalized hydrogels for the development of responsive and controlled growth factor delivery systems. J Control Release 2007;122(3):287‒96. . 10.1016/j.jconrel.2007.04.019
[135]

Fujita M, Ishihara M, Simizu M, Obara K, Ishizuka T, Saito Y, et al. Vascularization in vivo caused by the controlled release of fibroblast growth factor-2 from an injectable chitosan/non-anticoagulant heparin hydrogel. Biomaterials 2004;25(4):699‒706. . 10.1016/s0142-9612(03)00557-x
[136]

Lee KY, Mooney DJ. Hydrogels for tissue engineering. Chem Rev 2001;101(7):1869‒79. . 10.1021/cr000108x
[137]

Chen T, Small DA, McDermott MK, Bentley WE, Payne GF. Enzymatic methods for in situ cell entrapment and cell release. Biomacromolecules 2003;4(6):1558‒63. . 10.1021/bm034145k
[138]

Wang LS, Chung JE, Chan PP, Kurisawa M. Injectable biodegradable hydrogels with tunable mechanical properties for the stimulation of neurogenesic differentiation of human mesenchymal stem cells in 3D culture. Biomaterials 2010;31(6):1148‒57. . 10.1016/j.biomaterials.2009.10.042
[139]

Liu Y, Chan-Park MB. Hydrogel based on interpenetrating polymer networks of dextran and gelatin for vascular tissue engineering. Biomaterials 2009;30(2):196‒207. . 10.1016/j.biomaterials.2008.09.041
[140]

Zhao Y, Han L, Yan J, Li Z, Wang F, Xia Y, et al. Irradiation sterilized gelatin-water-glycerol ternary gel as an injectable carrier for bone tissue engineering. Adv Healthc Mater 2017;6(2):201600749. . 10.1002/adhm.201600749
[141]

Arnold MP, Daniels AU, Ronken S, García HA, Friederich NF, Kurokawa T, et al. Acrylamide polymer double-network hydrogels: candidate cartilage repair materials with cartilage-like dynamic stiffness and attractive surgery-related attachment mechanics. Cartilage 2011;2(4):374‒83. . 10.1177/1947603511402320
[142]

Yang Y, Wang X, Yang F, Shen H, Wu D. A universal soaking strategy to convert composite hydrogels into extremely tough and rapidly recoverable double-network hydrogels. Adv Mater 2016;28(33):7178‒84. . 10.1002/adma.201601742
[143]

Sun JY, Zhao X, Illeperuma WR, Chaudhuri O, Oh KH, Mooney DJ, et al. Highly stretchable and tough hydrogels. Nature 2012;489(7414):133‒6. . 10.1038/nature11409
[144]

Cui N, Qian J, Xu W, Xu M, Zhao N, Liu T, et al. Preparation, characterization, and biocompatibility evaluation of poly(Nvarepsilon-acryloyl-L-lysine)/hyaluronic acid interpenetrating network hydrogels. Carbohydr Polym 2016;136:1017‒26. . 10.1016/j.carbpol.2015.09.095
[145]

Jaiswal MK, Xavier JR, Carrow JK, Desai P, Alge D, Gaharwar AK. Mechanically stiff nanocomposite hydrogels at ultralow nanoparticle content. ACS Nano 2016;10(1):246‒56. . 10.1021/acsnano.5b03918
[146]

Si Y, Wang L, Wang X, Tang N, Yu J, Ding B. Ultrahigh-water-content, superelastic, and shape-memory nanofiber-assembled hydrogels exhibiting pressure-responsive conductivity. Adv Mater 2017;29(24):1700339. . 10.1002/adma.201700339
[147]

Navaei A, Saini H, Christenson W, Sullivan RT, Ros R, Nikkhah M. Gold nanorod-incorporated gelatin-based conductive hydrogels for engineering cardiac tissue constructs. Acta Biomater 2016;41:133‒46. . 10.1016/j.actbio.2016.05.027
[148]

Konwar A, Kalita S, Kotoky J, Chowdhury D. Chitosan-iron oxide coated graphene oxide nanocomposite hydrogel: a robust and soft antimicrobial biofilm. ACS Appl Mater Interfaces 2016;8(32):20625‒34. . 10.1021/acsami.6b07510
[149]

Desai RM, Koshy ST, Hilderbrand SA, Mooney DJ, Joshi NS. Versatile click alginate hydrogels crosslinked via tetrazine-norbornene chemistry. Biomaterials 2015;50:30‒7. . 10.1016/j.biomaterials.2015.01.048
[150]

Yu F, Cao X, Zeng L, Zhang Q, Chen X. An interpenetrating HA/G/CS biomimic hydrogel via Diels-Alder click chemistry for cartilage tissue engineering. Carbohydr Polym 2013;97(1):188‒95. . 10.1016/j.carbpol.2013.04.046
[151]

Feng Q, Wei K, Lin S, Xu Z, Sun Y, Shi P, et al. Mechanically resilient, injectable, and bioadhesive supramolecular gelatin hydrogels crosslinked by weak host-guest interactions assist cell infiltration and in situ tissue regeneration. Biomaterials 2016;101:217‒28. . 10.1016/j.biomaterials.2016.05.043
[152]

Bai X, Gao M, Syed S, Zhuang J, Xu X, Zhang XQ. Bioactive hydrogels for bone regeneration. Bioact Mater 2018;3(4):401‒17. . 10.1016/j.bioactmat.2018.05.006
[153]

Dethe MR, Prabakaran A, Ahmed H, Agrawal M, Roy U, Alexander A. PCL-PEG copolymer based injectable thermosensitive hydrogels. J Control Release 2022;343:217‒36. . 10.1016/j.jconrel.2022.01.035
[154]

Collins MN, Ren G, Young K, Pina S, Reis RL, Oliveira JM. Scaffold fabrication technologies and structure/function properties in bone tissue engineering. Adv Funct Mater 2021;31(21):2010609. . 10.1002/adfm.202010609
[155]

Johnson CT, Wroe JA, Agarwal R, Martin KE, Guldberg RE, Donlan RM, et al. Hydrogel delivery of lysostaphin eliminates orthopedic implant infection by Staphylococcus aureus and supports fracture healing. Proc Natl Acad Sci USA 2018;115(22):E4960‒9. . 10.1073/pnas.1801013115
[156]

Chauhan N, Gupta P, Arora L, Pal D, Singh Y. Dexamethasone-loaded, injectable pullulan-poly(ethylene glycol) hydrogels for bone tissue regeneration in chronic inflammatory conditions. Mater Sci Eng C 2021;130:112463. . 10.1016/j.msec.2021.112463
[157]

Wu YL, Chen X, Wang W, Loh XJ. Engineering bioresponsive hydrogels toward healthcare applications. Macromol Chem Phys 2016;217(2):175‒88. . 10.1002/macp.201500172
[158]

He C, Kim SW, Lee DS. In situ gelling stimuli-sensitive block copolymer hydrogels for drug delivery. J Control Release 2008;127(3):189‒207. . 10.1016/j.jconrel.2008.01.005
[159]

Fu S, Ni P, Wang B, Chu B, Zheng L, Luo F, et al. Injectable and thermo-sensitive PEG-PCL-PEG copolymer/collagen/n-HA hydrogel composite for guided bone regeneration. Biomaterials 2012;33(19):4801‒9. . 10.1016/j.biomaterials.2012.03.040
[160]

Zhao X, Olsen I, Li H, Gellynck K, Buxton PG, Knowles JC, et al. Reactive calcium-phosphate-containing poly(ester-co-ether) methacrylate bone adhesives: chemical, mechanical and biological considerations. Acta Biomater 2010;6(3):845‒55. . 10.1016/j.actbio.2009.09.020
[161]

Xu T, Yang Y, Yeung EHL, Chen Q, Bei HP, Yang Q, et al. Injectable, self-contained, subaqueously cross-linking laminous adhesives for biophysical-chemical modulation of osteochondral microenvironment. Adv Funct Mater 2023;33(23):2213428. . 10.1002/adfm.202213428
[162]

Dawson E, Mapili G, Erickson K, Taqvi S, Roy K. Biomaterials for stem cell differentiation. Adv Drug Deliv Rev 2008;60(2):215‒28. . 10.1016/j.addr.2007.08.037
[163]

Pierschbacher MD, Ruoslahti E. Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule. Nature 1984;309(5963):30‒3. . 10.1038/309030a0
[164]

Hersel U, Dahmen C, Kessler H. RGD modified polymers: biomaterials for stimulated cell adhesion and beyond. Biomaterials 2003;24(24):4385‒415. . 10.1016/s0142-9612(03)00343-0
[165]

Shin H, Temenoff JS, Bowden GC, Zygourakis K, Farach-Carson MC, Yaszemski MJ, et al. Osteogenic differentiation of rat bone marrow stromal cells cultured on Arg-Gly-Asp modified hydrogels without dexamethasone and beta-glycerol phosphate. Biomaterials 2005;26(17):3645‒54. . 10.1016/j.biomaterials.2004.09.050
[166]

Wang DA, Williams CG, Yang F, Cher N, Lee H, Elisseeff JH. Bioresponsive phosphoester hydrogels for bone tissue engineering. Tissue Eng 2005;11(1‒2):201‒13.
[167]

Wang J, Mao HQ, Leong KW. A novel biodegradable gene carrier based on polyphosphoester. J Am Chem Soc 2001;123(38):9480‒1. . 10.1021/ja016062m
[168]

Morrison SJ, Kimble J. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 2006;441(7097):1068‒74. . 10.1038/nature04956
[169]

Lu D, Mahmood A, Wang L, Li Y, Lu M, Chopp M. Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome. Neuroreport 2001;12(3):559‒63. . 10.1097/00001756-200103050-00025
[170]

James S, Fox J, Afsari F, Lee J, Clough S, Knight C, et al. Multiparameter analysis of human bone marrow stromal cells identifies distinct immunomodulatory and differentiation-competent subtypes. Stem Cell Reports 2015;4(6):1004‒15. . 10.1016/j.stemcr.2015.05.005
[171]

Zhou M, Xi J, Cheng Y, Sun D, Shu P, Chi S, et al. Reprogrammed mesenchymal stem cells derived from iPSCs promote bone repair in steroid-associated osteonecrosis of the femoral head. Stem Cell Res Ther 2021;12(1):175. . 10.1186/s13287-021-02249-1
[172]

Huang Z, Gu H, Yin X, Gao L, Zhang K, Zhang Y, et al. Bone regeneration using injectable poly(γ-benzyl-L-glutamate) microspheres loaded with adipose-derived stem cells in a mouse femoral non-union model. Am J Transl Res 2019;11(5):2641‒56.
[173]

Shokrolahi F, Khodabakhshi K, Shokrollahi P, Badiani R, Moghadam ZM. Atorvastatin loaded PLGA microspheres: preparation, HAp coating, drug release and effect on osteogenic differentiation of ADMSCs. Int J Pharm 2019;565:95‒107. . 10.1016/j.ijpharm.2019.05.005
[174]

Yuan Z, Yuan X, Zhao Y, Cai Q, Wang Y, Luo R, et al. Injectable GelMA cryogel microspheres for modularized cell delivery and potential vascularized bone regeneration. Small 2021;17(11):e2006596. . 10.1002/smll.202006596
[175]

An C, Liu W, Zhang Y, Pang B, Liu H, Zhang Y, et al. Continuous microfluidic encapsulation of single mesenchymal stem cells using alginate microgels as injectable fillers for bone regeneration. Acta Biomater 2020;111:181‒96. . 10.1016/j.actbio.2020.05.024
[176]

Hou Y, Xie W, Achazi K, Cuellar-Camacho JL, Melzig MF, Chen W, et al. Injectable degradable PVA microgels prepared by microfluidic technology for controlled osteogenic differentiation of mesenchymal stem cells. Acta Biomater 2018;77:28‒37. . 10.1016/j.actbio.2018.07.003
[177]

Diniz IMA, Carreira ACO, Sipert CR, Uehara CM, Moreira MSN, Freire L, et al. Photobiomodulation of mesenchymal stem cells encapsulated in an injectable rhBMP4-loaded hydrogel directs hard tissue bioengineering. J Cell Physiol 2018;233(6):4907‒18. . 10.1002/jcp.26309
[178]

Kumar A, Nune KC, Misra RDK. Design and biological functionality of a novel hybrid Ti-6Al-4V/hydrogel system for reconstruction of bone defects. J Tissue Eng Regen Med 2018;12(4):1133‒44. . 10.1002/term.2614
[179]

Yuan S, Han Y, Xiang D, Wang B, Chen Y, Hao Y. An injectable hydroxypropyl-β-cyclodextrin cross-linked gelatin-based hydrogel loaded bone mesenchymal stem cell for osteogenic and in vivo bone regeneration of femoral head necrosis. Nanomedicine 2022;41:102521. . 10.1016/j.nano.2022.102521
[180]

Chai S, Huang J, Mahmut A, Wang B, Yao Y, Zhang X, et al. Injectable photo-crosslinked bioactive BMSCs-BMP2-GelMA scaffolds for bone defect repair. Front Bioeng Biotechnol 2022;10:875363. . 10.3389/fbioe.2022.875363
[181]

Dashtimoghadam E, Fahimipour F, Tongas N, Tayebi L. Microfluidic fabrication of microcarriers with sequential delivery of VEGF and BMP-2 for bone regeneration. Sci Rep 2020;10(1):11764. . 10.1038/s41598-020-68221-w
[182]

Datta S, Rameshbabu AP, Bankoti K, Roy M, Gupta C, Jana S, et al. Decellularized bone matrix/oleoyl chitosan derived supramolecular injectable hydrogel promotes efficient bone integration. Mater Sci Eng C 2021;119:111604. . 10.1016/j.msec.2020.111604
[183]

Feng Q, Xu J, Zhang K, Yao H, Zheng N, Zheng L, et al. Dynamic and cell-infiltratable hydrogels as injectable carrier of therapeutic cells and drugs for treating challenging bone defects. ACS Cent Sci 2019;5(3):440‒50. . 10.1021/acscentsci.8b00764
[184]

Zhang K, Jia Z, Yang B, Feng Q, Xu X, Yuan W, et al. Adaptable hydrogels mediate cofactor-assisted activation of biomarker-responsive drug delivery via positive feedback for enhanced tissue regeneration. Adv Sci 2018;5(12):1800875. . 10.1002/advs.201800875
[185]

Ren Z, Wang Y, Ma S, Duan S, Yang X, Gao P, et al. Effective bone regeneration using thermosensitive poly(N-isopropylacrylamide) grafted gelatin as injectable carrier for bone mesenchymal stem cells. ACS Appl Mater Interfaces 2015;7(34):19006‒15. . 10.1021/acsami.5b02821
[186]

Si M, Xia Y, Cong M, Wang D, Hou Y, Ma H. In situ co-delivery of doxorubicin and cisplatin by injectable thermosensitive hydrogels for enhanced osteosarcoma treatment. Int J Nanomedicine 2022;17:1309‒22. . 10.2147/ijn.s356453
[187]

Wu D, Qin H, Wang Z, Yu M, Liu Z, Peng H, et al. Bone mesenchymal stem cell-derived sEV-encapsulated thermosensitive hydrogels accelerate osteogenesis and angiogenesis by release of exosomal miR-21. Front Bioeng Biotechnol 2021;9:829136. . 10.3389/fbioe.2021.829136
[188]

Huang Z, Zhao Z, Lang J, Wang W, Fu Y, Wang W. Therapeutic study of thermosensitive hydrogel loaded with super-activated platelet lysate combined with core decompression technology for the treatment of femoral head necrosis. Stem Cells Int 2021;2021:7951616. . 10.1155/2021/7951616
[189]

Tao J, Zhang Y, Shen A, Yang Y, Diao L, Wang L, et al. Injectable chitosan-based thermosensitive hydrogel/nanoparticle-loaded system for local delivery of vancomycin in the treatment of osteomyelitis. Int J Nanomedicine 2020;15:5855‒71. . 10.2147/ijn.s247088
[190]

Ventura R, Padalhin A, Kim B, Park M, Lee B. Evaluation of bone regeneration potential of injectable extracellular matrix (ECM) from porcine dermis loaded with biphasic calcium phosphate (BCP) powder. Mater Sci Eng C 2020;110:110663. . 10.1016/j.msec.2020.110663
[191]

Yao Q, Liu Y, Pan Y, Li Y, Xu L, Zhong Y, et al. Long-term induction of endogenous BMPs growth factor from antibacterial dual network hydrogels for fast large bone defect repair. J Colloid Interface Sci 2022;607:1500‒15. . 10.1016/j.jcis.2021.09.089
[192]

Dos Santos FD, de Oliveira J, Pinto B, Kumar V, Cardoso V, Fernandes S, et al. Evaluation of antitumor activity and cardiac toxicity of a bone-targeted ph-sensitive liposomal formulation in a bone metastasis tumor model in mice. Nanomedicine 2017;13(5):1693‒701. . 10.1016/j.nano.2017.03.005
[193]

Hu J, Jiang Y, Tan S, Zhu K, Cai T, Zhan T, et al. Selenium-doped calcium phosphate biomineral reverses multidrug resistance to enhance bone tumor chemotherapy. Nanomedicine 2021;32:102322. . 10.1016/j.nano.2020.102322
[194]

Bai S, Cheng Y, Liu D, Ji Q, Liu M, Zhang B, et al. Bone-targeted PAMAM nanoparticle to treat bone metastases of lung cancer. Nanomedicine 2020;15(9):833‒49. . 10.2217/nnm-2020-0024
[195]

Sivashanmugam A, Charoenlarp P, Deepthi S, Rajendran A, Nair S, Iseki S, et al. Injectable shear-thinning CaSO4/FGF-18-incorporated chitin-PLGA hydrogel enhances bone regeneration in mice cranial bone defect model. ACS Appl Mater Interfaces 2017;9(49):42639‒52. . 10.1021/acsami.7b15845
[196]

Wang Q, Wang J, Lu Q, Detamore MS, Berkland C. Injectable PLGA based colloidal gels for zero-order dexamethasone release in cranial defects. Biomaterials 2010;31(18):4980‒6. . 10.1016/j.biomaterials.2010.02.052
[197]

Wang Y. Bio-resorbable thermal sensitive hydrogel (BioGel) for minimally invasive therapy. N Biotechnol 2016;33:S11. . 10.1016/j.nbt.2016.06.764
[198]

Li Q, Ning Z, Ren J, Liao W. Structural design and physicochemical foundations of hydrogels for biomedical applications. Curr Med Chem 2018;25(8):963‒81. . 10.2174/0929867324666170818111630
[199]

Sood N, Bhardwaj A, Mehta S, Mehta A. Stimuli-responsive hydrogels in drug delivery and tissue engineering. Drug Deliv 2016;23(3):758‒80. . 10.3109/10717544.2014.940091
[200]

Yoshioka H, Mori Y, Tsukikawa S, Kubota S. Thermoreversible gelation on cooling and on heating of an aqueous gelatin-poly(N-isopropylacrylamide) conjugate. Polym Adv Technol 1998;9(2):155‒8. . 10.1002/(sici)1099-1581(199802)9:2<155::aid-pat750>3.3.co;2-7
[201]

Vernengo J, Fussell GW, Smith NG, Lowman AM. Evaluation of novel injectable hydrogels for nucleus pulposus replacement. J Biomed Mater Res 2008;84(1):64‒9. . 10.1002/jbm.b.30844
[202]

Watanabe J, Kashii M, Hirao M, Oka K, Sugamoto K, Yoshikawa H, et al. Quick-forming hydroxyapatite/agarose gel composites induce bone regeneration. J Biomed Mater Res 2007;83A(3):845‒52. . 10.1002/jbm.a.31435
[203]

Huang Z, Yu B, Feng QL, Li SJ, Chen Y, Luo LQ. In situ-forming chitosan/nano-hydroxyapatite/collagen gel for the delivery of bone marrow mesenchymal stem cells. Carbohydr Polym 2011;85(1):261‒7. . 10.1016/j.carbpol.2011.02.029
[204]

Sajadi-Javan ZS, Varshosaz J, Mirian M, Manshaei M, Aminzadeh A. Thermo-responsive hydrogels based on methylcellulose/Persian gum loaded with taxifolin enhance bone regeneration: an in vitro/in vivo study. Cellulose 2022;29(4):2413‒33. . 10.1007/s10570-021-04383-8
[205]

Yuan B, Zhang Y, Wang Q, Ren G, Wang Y, Zhou S, et al. Thermosensitive vancomycin@PLGA-PEG-PLGA/HA hydrogel as an all-in-one treatment for osteomyelitis. Int J Pharm 2022;627:122225. . 10.1016/j.ijpharm.2022.122225
[206]

Lu Y, Sun W, Gu Z. Stimuli-responsive nanomaterials for therapeutic protein delivery. J Control Release 2014;194:1‒19. . 10.1016/j.jconrel.2014.08.015
[207]

Mura S, Nicolas J, Couvreur P. Stimuli-responsive nanocarriers for drug delivery. Nat Mater 2013;12(11):991‒1003. . 10.1038/nmat3776
[208]

Hoffman AS. Stimuli-responsive polymers: biomedical applications and challenges for clinical translation. Adv Drug Deliv Rev 2013;65(1):10‒6. . 10.1016/j.addr.2012.11.004
[209]

Tapeinos C, Battaglini M, Prato M, La Rosa G, Scarpellini A, Ciofani G. CeO2 nanoparticles-loaded pH-responsive microparticles with antitumoral properties as therapeutic modulators for osteosarcoma. ACS Omega 2018;3(8):8952‒62. . 10.1021/acsomega.8b01060
[210]

Martínez-Carmona M, Lozano D, Colilla M, Vallet-Regí M. Lectin-conjugated pH-responsive mesoporous silica nanoparticles for targeted bone cancer treatment. Acta Biomater 2018;65:393‒404. . 10.1016/j.actbio.2017.11.007
[211]

Mendoza-Reinoso V, McCauley LK, Fournier PGJ. Contribution of macrophages and T cells in skeletal metastasis. Cancers 2020;12(4): 1014. . 10.3390/cancers12041014
[212]

Wang M, Cai X, Yang J, Wang C, Tong L, Xiao J, et al. A targeted and pH-responsive bortezomib nanomedicine in the treatment of metastatic bone tumors. ACS Appl Mater Interfaces 2018;10(48):41003‒11. . 10.1021/acsami.8b07527
[213]

Zhu J, Huo Q, Xu M, Yang F, Li Y, Shi H, et al. Bortezomib-catechol conjugated prodrug micelles: combining bone targeting and aryl boronate-based pH-responsive drug release for cancer bone-metastasis therapy. Nanoscale 2018;10(38):18387‒97. . 10.1039/c8nr03899f
[214]

Chung MF, Chia WT, Liu HY, Hsiao CW, Hsiao HC, Yang CM, et al. Inflammation-induced drug release by using a pH-responsive gas-generating hollow-microsphere system for the treatment of osteomyelitis. Adv Healthc Mater 2014;3(11):1854‒61. . 10.1002/adhm.201400158
[215]

Zhao J, Zhao M, Yu C, Zhang X, Liu J, Cheng X, et al. Multifunctional folate receptor-targeting and pH-responsive nanocarriers loaded with methotrexate for treatment of rheumatoid arthritis. Int J Nanomedicine 2017;12:6735‒46. . 10.2147/ijn.s140992
[216]

Xu H, Matysiak S. Effect of pH on chitosan hydrogel polymer network structure. Chem Commun 2017;53:7373‒6. . 10.1039/c7cc01826f
[217]

Kocak FZ, Talari ACS, Yar M, Rehman IU. In-situ forming pH and thermosensitive injectable hydrogels to stimulate angiogenesis: potential candidates for fast bone regeneration applications. Int J Mol Sci 2020;21(5):1633. . 10.3390/ijms21051633
[218]

Zhao C, Qazvini NT, Sadati M, Zeng Z, Huang S, De La Lastra AL, et al. A pH-triggered, self-assembled, and bioprintable hybrid hydrogel scaffold for mesenchymal stem cell based bone tissue engineering. ACS Appl Mater Interfaces 2019;11(9):8749‒62. . 10.1021/acsami.8b19094
[219]

Milani AH, Freemont AJ, Hoyland JA, Adlam DJ, Saunders BR. Injectable doubly cross-linked microgels for improving the mechanical properties of degenerated intervertebral discs. Biomacromolecules 2012;13(9): 2793‒801. . 10.1021/bm3007727
[220]

Kim HK, Shim WS, Kim SE, Lee KH, Kang E, Kim JH, et al. Injectable in situ-forming pH/thermo-sensitive hydrogel for bone tissue engineering. Tissue Eng Part A 2009;15(4):923‒33. . 10.1089/ten.tea.2007.0407
[221]

Lu Y, Aimetti AA, Langer R, Gu Z. Bioresponsive materials. Nat Rev Mater 2017;2(1):16075. . 10.1038/natrevmats.2016.75
[222]

Aulisa L, Dong H, Hartgerink JD. Self-assembly of multidomain peptides: sequence variation allows control over cross-linking and viscoelasticity. Biomacromolecules 2009;10(9):2694‒8. . 10.1021/bm900634x
[223]

Guvendiren M, Lu HD, Burdick JA. Shear-thinning hydrogels for biomedical applications. Soft Matter 2012;8(2):260‒72. . 10.1039/c1sm06513k
[224]

Sivashanmugam A, Charoenlarp P, Deepthi S, Rajendran A, Nair SV, Iseki S, et al. Injectable shear-thinning CaSO4/FGF-18-incorporated chitin-PLGA hydrogel enhances bone regeneration in mice cranial bone defect model. ACS Appl Mater Interfaces 2017;9(49):42639‒52. . 10.1021/acsami.7b15845
[225]

Arun Kumar R, Sivashanmugam A, Deepthi S, Iseki S, Chennazhi KP, Nair SV, et al. Injectable chitin-poly(epsilon-caprolactone)/nanohydroxyapatite composite microgels prepared by simple regeneration technique for bone tissue engineering. ACS Appl Mater Interfaces 2015;7(18):9399‒409. . 10.1021/acsami.5b02685
[226]

Dennis SC, Detamore MS, Kieweg SL, Berkland CJ. Mapping glycosaminoglycan-hydroxyapatite colloidal gels as potential tissue defect fillers. Langmuir 2014;30(12):3528‒37. . 10.1021/la4041985
[227]

Uman S, Dhand A, Burdick JA. Recent advances in shear-thinning and self-healing hydrogels for biomedical applications. J Appl Polym Sci 2019;137(25):48668. . 10.1002/app.48668
[228]

Hou S, Wang X, Park S, Jin X, Ma PX. Rapid self-integrating, injectable hydrogel for tissue complex regeneration. Adv Healthc Mater 2015;4(10):1491‒5. . 10.1002/adhm.201500093
[229]

Alarcin E, Lee TY, Karuthedom S, Mohammadi M, Brennan MA, Lee DH, et al. Injectable shear-thinning hydrogels for delivering osteogenic and angiogenic cells and growth factors. Biomater Sci 2018;6(6):1604‒15. . 10.1039/c8bm00293b
[230]

Combes C, Tadier S, Galliard H, Girod-Fullana S, Charvillat C, Rey C, et al. Rheological properties of calcium carbonate self-setting injectable paste. Acta Biomater 2010;6(3):920‒7. . 10.1016/j.actbio.2009.08.032
[231]

Zhang ZN, Shao HP, Lin T, Zhang YM, He JZ, Wang LH. 3D gel printing of porous calcium silicate scaffold for bone tissue engineering. J Mater Sci 2019;54(14):10430‒6. . 10.1007/s10853-019-03626-1
[232]

Ryabenkova Y, Pinnock A, Quadros PA, Goodchild RL, Mobus G, Crawford A, et al. The relationship between particle morphology and rheological properties in injectable nano-hydroxyapatite bone graft substitutes. Mater Sci Eng C 2017;75:1083‒90. . 10.1016/j.msec.2017.02.170
[233]

Lukaszczyk J, Janicki B, Lopez A, Skolucka K, Wojdyla H, Persson C, et al. Novel injectable biomaterials for bone augmentation based on isosorbide dimethacrylic monomers. Mater Sci Eng C 2014;40:76‒84. . 10.1016/j.msec.2014.03.046
[234]

Geven MA, Sprecher C, Guillaume O, Eglin D, Grijpma DW. Micro-porous composite scaffolds of photo-crosslinked poly(trimethylene carbonate) and nano-hydroxyapatite prepared by low-temperature extrusion-based additive manufacturing. Polym Adv Technol 2017;28(10):1226‒32. . 10.1002/pat.3890
[235]

Du Y, Guo JL, Wang J, Mikos AG, Zhang S. Hierarchically designed bone scaffolds: from internal cues to external stimuli. Biomaterials 2019;218:119334. . 10.1016/j.biomaterials.2019.119334
[236]

Gurel Pekozer G, Torun Kose G, Hasirci V. Influence of co-culture on osteogenesis and angiogenesis of bone marrow mesenchymal stem cells and aortic endothelial cells. Microvasc Res 2016;108:1‒9. . 10.1016/j.mvr.2016.06.005
[237]

Yegappan R, Selvaprithiviraj V, Amirthalingam S, Mohandas A, Hwang NS, Jayakumar R. Injectable angiogenic and osteogenic carrageenan nanocomposite hydrogel for bone tissue engineering. Int J Biol Macromol 2019;122:320‒8. . 10.1016/j.ijbiomac.2018.10.182
[238]

Liu Y, Zhu Z, Pei X, Zhang X, Cheng X, Hu S, et al. ZIF-8-modified multifunctional bone-adhesive hydrogels promoting angiogenesis and osteogenesis for bone regeneration. ACS Appl Mater Interfaces 2020;12(33):36978‒95. . 10.1021/acsami.0c12090
[239]

Chen S, Wang H, Liu D, Bai J, Haugen HJ, Li B, et al. Early osteoimmunomodulation by mucin hydrogels augments the healing and revascularization of rat critical-size calvarial bone defects. Bioact Mater 2023;25:176‒88. . 10.1016/j.bioactmat.2023.01.022
[240]

Yu S, Yao S, Wen Y, Wang Y, Wang H, Xu Q. Angiogenic microspheres promote neural regeneration and motor function recovery after spinal cord injury in rats. Sci Rep 2016;6(1):1‒13. . 10.1038/srep33428
[241]

Rauch MF, Hynes SR, Bertram J, Redmond A, Robinson R, Williams C, et al. Engineering angiogenesis following spinal cord injury: a coculture of neural progenitor and endothelial cells in a degradable polymer implant leads to an increase in vessel density and formation of the blood-spinal cord barrier. Eur J Neurosci 2009;29(1):132‒45. . 10.1111/j.1460-9568.2008.06567.x
[242]

Nih LR, Gojgini S, Carmichael ST, Segura T. Dual-function injectable angiogenic biomaterial for the repair of brain tissue following stroke. Nat Mater 2018;17(7):642‒51. . 10.1038/s41563-018-0083-8
[243]

Kuroda Y, Kawai T, Goto K, Matsuda S. Clinical application of injectable growth factor for bone regeneration: a systematic review. Inflamm Regen 2019;39(1):20. . 10.1186/s41232-019-0109-x
[244]

Li D, Xie K, Zhang L, Yao X, Li H, Xu Q, et al. Dual blockade of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) exhibits potent anti-angiogenic effects. Cancer Lett 2016;377(2):164‒73. . 10.1016/j.canlet.2016.04.036
[245]

Wong AL, Haroon ZA, Werner S, Dewhirst MW, Greenberg CS, Peters KG. Tie2 expression and phosphorylation in angiogenic and quiescent adult tissues. Circ Res 1997;81(4):567‒74. . 10.1161/01.res.81.4.567
[246]

Herrera JJ, Sundberg LM, Zentilin L, Giacca M, Narayana PA. Sustained expression of vascular endothelial growth factor and angiopoietin-1 improves blood-spinal cord barrier integrity and functional recovery after spinal cord injury. J Neurotrauma 2010;27(11):2067‒76. . 10.1089/neu.2010.1403
[247]

Han S, Arnold SA, Sithu SD, Mahoney ET, Geralds JT, Tran P, et al. Rescuing vasculature with intravenous angiopoietin-1 and αvβ3 integrin peptide is protective after spinal cord injury. Brain 2010;133(4):1026‒42. . 10.1093/brain/awq034
[248]

Chen X, Wang M, Chen F, Wang J, Li X, Liang J, et al. Correlations between macrophage polarization and osteoinduction of porous calcium phosphate ceramics. Acta Biomater 2020;103:318‒32. . 10.1016/j.actbio.2019.12.019
[249]

Qiu P, Li M, Chen K, Fang B, Chen P, Tang Z, et al. Periosteal matrix-derived hydrogel promotes bone repair through an early immune regulation coupled with enhanced angio- and osteogenesis. Biomaterials 2020;227:119552. . 10.1016/j.biomaterials.2019.119552
[250]

Zhang J, Shi H, Zhang N, Hu L, Jing W, Pan J. Interleukin-4-loaded hydrogel scaffold regulates macrophages polarization to promote bone mesenchymal stem cells osteogenic differentiation via TGF-β1/Smad pathway for repair of bone defect. Cell Prolif 2020;53(10):e12907. . 10.1111/cpr.12907
[251]

Zou M, Sun J, Xiang Z. Induction of M2-type macrophage differentiation for bone defect repair via an interpenetration network hydrogel with a GO-based controlled release system. Adv Healthc Mater 2021;10(6):2001502. . 10.1002/adhm.202001502
[252]

Huang L, Zhang J, Hu J, Zhao T, Gu Z. Biomimetic gelatin methacrylate/nano fish bone hybrid hydrogel for bone regeneration via osteoimmunomodulation. ACS Biomater Sci Eng 2020;6(6):3270‒4. . 10.1021/acsbiomaterials.0c00443
[253]

Wu Z, Bai J, Ge G, Wang T, Feng S, Ma Q, et al. Regulating macrophage polarization in high glucose microenvironment using lithium-modified bioglass-hydrogel for diabetic bone regeneration. Adv Healthc Mater 2022;11(13):2200298. . 10.1002/adhm.202270079
[254]

De Melo PD, Habibovic P. Biomineralization-inspired material design for bone regeneration. Adv Healthc Mater 2018;7(22):1800700. . 10.1002/adhm.201800700
[255]

Zhao Y, Li Z, Jiang Y, Liu H, Feng Y, Wang Z, et al. Bioinspired mineral hydrogels as nanocomposite scaffolds for the promotion of osteogenic marker expression and the induction of bone regeneration in osteoporosis. Acta Biomater 2020;113:614‒26. . 10.1016/j.actbio.2020.06.024
[256]

Xu TG, Liu DC, Wang Y, Chen S, Li B, Zhang F, et al. Tungsten carbide-enhanced radiopaque and biocompatible PMMA bone cement and its application in vertebroplasty. Compos Commun 2023;40:101615. . 10.1016/j.coco.2023.101615
[257]

Wei M, Hsu YI, Asoh TA, Sung MH, Uyama H. Design of injectable poly(γ-glutamic acid)/chondroitin sulfate hydrogels with mineralization ability. ACS Appl Bio Mater 2022;5(4):1508‒18. . 10.1021/acsabm.1c01269
[258]

Wang H, Hu B, Li H, Feng G, Pan S, Chen Z, et al. Biomimetic mineralized hydroxyapatite nanofiber-incorporated methacrylated gelatin hydrogel with improved mechanical and osteoinductive performances for bone regeneration. Int J Nanomed 2022;17:1511‒29. . 10.2147/ijn.s354127
[259]

Abouzeid RE, Salama A, El-Fakharany EM, Guarino V. Mineralized polyvinyl alcohol/sodium alginate hydrogels incorporating cellulose nanofibrils for bone and wound healing. Molecules 2022;27(3):697. . 10.3390/molecules27030697
[260]

Liu P, Bao T, Sun L, Wang Z, Sun J, Peng W, et al. In situ mineralized PLGA/ zwitterionic hydrogel composite scaffold enables high-efficiency rhBMP-2 release for critical-sized bone healing. Biomater Sci 2022;10(3):781‒93. . 10.1039/d1bm01521d
[261]

Lin K, Sheikh R, Romanazzo S, Roohani I. 3D printing of bioceramic scaffolds-barriers to the clinical translation: from promise to reality, and future perspectives. Materials 2019;12(17):2660. . 10.3390/ma12172660
[262]

Fu Z, Cui J, Zhao B, Shen SGF, Lin K. An overview of polyester/hydroxyapatite composites for bone tissue repairing. J Orthop Translat 2021;28:118‒30. . 10.1016/j.jot.2021.02.005
[263]

Ding L, Wang H, Li J, Liu D, Bai J, Yuan Z, et al. Preparation and characterizations of an injectable and biodegradable high-strength iron-bearing brushite cement for bone repair and vertebral augmentation applications. Biomater Sci 2022;11(1):96‒107. . 10.1039/d2bm01535h
[264]

Zhao Z, Zhao Q, Gu B, Yin C, Shen K, Tang H, et al. Minimally invasive implantation and decreased inflammation reduce osteoinduction of biomaterial. Theranostics 2020;10(8):3533‒45. . 10.7150/thno.39507
[265]

Ghosh M, Halperin-Sternfeld M, Grinberg I, Adler-Abramovich L. Injectable alginate-peptide composite hydrogel as a scaffold for bone tissue regeneration. Nanomaterials 2019;9(4):3533‒45. . 10.3390/nano9040497
[266]

Li Y, Pan Q, Xu J, He X, Li HA, Oldridge DA, et al. Overview of methods for enhancing bone regeneration in distraction osteogenesis: potential roles of biometals. J Orthop Translat 2021;27:110‒8. . 10.1016/j.jot.2020.11.008
[267]

Chen M, Zhang Y, Zhang W, Li J. Polyhedral oligomeric silsesquioxane-incorporated gelatin hydrogel promotes angiogenesis during vascularized bone regeneration. ACS Appl Mater Interfaces 2020;12(20):22410‒25. . 10.1021/acsami.0c00714
[268]

Cypher TJ, Grossman JP. Biological principles of bone graft healing. J Foot Ankle Surg 1996;35(5):413‒7. . 10.1016/s1067-2516(96)80061-5
[269]

Yuan J, Maturavongsadit P, Zhou Z, Lv B, Lin Y, Yang J, et al. Hyaluronic acid-based hydrogels with tobacco mosaic virus containing cell adhesive peptide induce bone repair in normal and osteoporotic rats. Biomater Transl 2020;1(1):89‒98.
[270]

Giannoudis PV, Dinopoulos H, Tsiridis E. Bone substitutes: an update. Injury 2005;36():S20‒7. . 10.1016/j.injury.2005.07.029
[271]

Steijvers E, Ghei A, Xia Z. Manufacturing artificial bone allografts: a perspective. Biomater Transl 2022;3(1):65‒80.
[272]

Ding L, Wang H, Zhang W, Li J, Liu D, Han F, et al. Calcium phosphate bone cement with enhanced physicochemical properties via in situ formation of an interpenetrating network. J Mater Chem B 2021;9(34):6802‒10. . 10.1039/d1tb00867f
[273]

Pacelli S, Basu S, Whitlow J, Chakravarti A, Acosta F, Varshney A, et al. Strategies to develop endogenous stem cell-recruiting bioactive materials for tissue repair and regeneration. Adv Drug Deliv Rev 2017;120:50‒70. . 10.1016/j.addr.2017.07.011
[274]

Lewis G. Viscoelastic properties of injectable bone cements for orthopaedic applications: state-of-the-art review. J Biomed Mater Res 2011;98(1):171‒91. . 10.1002/jbm.b.31835
[275]

Lai PL, Chen LH, Chen WJ, Chu IM. Chemical and physical properties of bone cement for vertebroplasty. Biomed J 2013;36(4):162‒7. . 10.4103/2319-4170.112750
[276]

Jensen ME, Evans AJ, Mathis JM, Kallmes DF, Cloft HJ, Dion JE. Percutaneous polymethylmethacrylate vertebroplasty in the treatment of osteoporotic vertebral body compression fractures: technical aspects. AJNR Am J Neuroradiol 1997;18(10):1897‒904.
[277]

Edidin AA, Ong KL, Lau E, Kurtz SM. Mortality risk for operated and nonoperated vertebral fracture patients in the medicare population. J Bone Miner Res 2011;26(7):1617‒26. . 10.1002/jbmr.353
[278]

Webb JC, Spencer RF. The role of polymethylmethacrylate bone cement in modern orthopaedic surgery. J Bone Joint Surg 2007;89(7):851‒7. . 10.1302/0301-620x.89b7.19148
[279]

Chen S, Grandfield K, Yu S, Engqvist H, Xia W. Synthesis of calcium phosphate crystals with thin nacreous structure. CrystEngComm 2016;18(6):1064‒9. . 10.1039/c5ce02078f
[280]

Chen S, Liu D, Fu L, Ni B, Chen Z, Knaus J, et al. Formation of amorphous iron-calcium phosphate with high stability. Adv Mater 2023;35(33):2301422. . 10.1002/adma.202370238
[281]

Ramly E, Alfonso A, Kantar R, Wang M, Siso J, Ibrahim A, et al. Safety and efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2) in craniofacial surgery. Plast Reconstr Surg Glob Open 2019;7(8):e2347. . 10.1097/gox.0000000000002347
[282]

Riley EH, Lane JM, Urist MR, Lyons KM, Lieberman JR. Bone morphogenetic protein-2: biology and applications. Clin Orthop Relat Res 1996;324:39‒46. . 10.1097/00003086-199603000-00006
[283]

Wang G, Yuan Z, Yu L, Yu Y, Zhou P, Chu G, et al. Mechanically conditioned cell sheets cultured on thermo-responsive surfaces promote bone regeneration. Biomater Transl 2023;4(1):27‒40.
[284]

Alonso N, Tanikawa D, Freitas Rda S, Canan L, Ozawa T, Rocha D. Evaluation of maxillary alveolar reconstruction using a resorbable collagen sponge with recombinant human bone morphogenetic protein-2 in cleft lip and palate patients. Tissue Eng Part C 2010;16(5):1183‒9. . 10.1089/ten.tec.2009.0824
[285]

Canan Jr L, da Silva FR, Alonso N, Tanikawa D, Rocha D, Coelho J. Human bone morphogenetic protein-2 use for maxillary reconstruction in cleft lip and palate patients. J Craniofac Surg 2012;23(6):1627‒33. . 10.1097/scs.0b013e31825c75ba
[286]

Hissnauer T, Stiel N, Babin K, Rupprecht M, Ridderbusch K, Rueger J, et al. Recombinant human bone morphogenetic protein-2 (rhBMP-2) for the treatment of nonunion of the femur in children and adolescents: a retrospective analysis. BioMed Res Int 2017;2017:3046842. . 10.1155/2017/3046842
[287]

Zalavras CG, Patzakis MJ, Holtom P. Local antibiotic therapy in the treatment of open fractures and osteomyelitis. Clin Orthop Relat Res 2004;427:86‒93. . 10.1097/01.blo.0000143571.18892.8d
[288]

Cancienne JM, Burrus MT, Weiss DB, Yarboro SR. Applications of local antibiotics in orthopedic trauma. Orthop Clin North Am 2015;46(4):495‒510. . 10.1016/j.ocl.2015.06.010
[289]

Ostermann P, Henry S, Seligson D. The role of local antibiotic therapy in the management of compound fractures. Clin Orthop Relat Res 1993;295:102‒11. . 10.1097/00003086-199310000-00015
[290]

Wininger D, Fass R. Antibiotic-impregnated cement and beads for orthopedic infections. Antimicrob Agents Chemother 1996;40(12):2675‒9. . 10.1128/aac.40.12.2675
[291]

Hake M, Young H, Hak D, Stahel P, Hammerberg E, Mauffrey C. Local antibiotic therapy strategies in orthopaedic trauma: practical tips and tricks and review of the literature. Injury 2015;46(8):1447‒56. . 10.1016/j.injury.2015.05.008
[292]

Mitchell BD, Streeten EA. Clinical impact of recent genetic discoveries in osteoporosis. Appl Clin Genet 2013;6:75‒85. . 10.2147/tacg.s52047
[293]

Chen S, Pujari-Palmer S, Rubino S, Westlund V, Ott M, Engqvist H, et al. Highly repeatable synthesis of nHA with high aspect ratio. Mater Lett 2015;159:163‒7. . 10.1016/j.matlet.2015.06.086
[294]

Polikeit A, Nolte LP, Ferguson SJ. The effect of cement augmentation on the load transfer in an osteoporotic functional spinal unit: finite-element analysis. Spine 2003;28(10):991‒6. . 10.1097/01.brs.0000061987.71624.17
[295]

Xu X, Song J. Segmental long bone regeneration guided by degradable synthetic polymeric scaffolds. Biomater Transl 2020;1(1):33‒45.
[296]

Bistolfi A, Ferracini R, Albanese C, Verne E, Miola M. PMMA-based bone cements and the problem of joint arthroplasty infections: status and new perspectives. Materials 2019;12(23):4002. . 10.3390/ma12234002
[297]

Wang X, Kou JM, Yue Y, Weng XS, Qiu ZY, Zhang XF. Clinical outcome comparison of polymethylmethacrylate bone cement with and without mineralized collagen modification for osteoporotic vertebral compression fractures. Medicine 2018;97(37):e12204. . 10.1097/md.0000000000012204
[298]

Sun X, Wu Z, He D, Shen K, Liu X, Li H, et al. Bioactive injectable polymethylmethacrylate/silicate bioceramic hybrid cements for percutaneous vertebroplasty and kyphoplasty. J Mech Behav Biomed Mater 2019;96:125‒35. . 10.1016/j.jmbbm.2019.04.044
[299]

Gumpert R, Bodo K, Spuller E, Poglitsch T, Bindl R, Ignatius A, et al. Demineralization after balloon kyphoplasty with calcium phosphate cement: a histological evaluation in ten patients. Eur Spine J 2014;23(6):1361‒8. . 10.1007/s00586-014-3239-5
[300]

Schröter L, Kaiser F, Stein S, Gbureck U, Ignatius A. Biological and mechanical performance and degradation characteristics of calcium phosphate cements in large animals and humans. Acta Biomater 2020;117:1‒20. . 10.1016/j.actbio.2020.09.031
[301]

Makvandi P, Ghaemy M, Mohseni M. Synthesis and characterization of photo-curable bis-quaternary ammonium dimethacrylate with antimicrobial activity for dental restoration materials. Eur Polym J 2016;74:81‒90. . 10.1016/j.eurpolymj.2015.11.011
[302]

Ramos A, Duarte RJ, Mesnard M. Prediction at long-term condyle screw fixation of temporomandibular joint implant: a numerical study. J Craniomaxillofac Surg 2015;43(4):469‒74. . 10.1016/j.jcms.2015.02.013
[303]

Walsh WR, Svehla MJ, Russell J, Saito M, Nakashima T, Gillies RM, et al. Cemented fixation with PMMA or Bis-GMA resin hydroxyapatite cement: effect of implant surface roughness. Biomaterials 2004;25(20):4929‒34. . 10.1016/j.biomaterials.2003.12.020
[304]

Hu G, Xiao L, Fu H, Bi D, Ma H, Tong P. Study on injectable and degradable cement of calcium sulphate and calcium phosphate for bone repair. J Mater Sci Mater Med 2010;21(2):627‒34. . 10.1007/s10856-009-3885-z
[305]

Renner SM, Lim TH, Kim WJ, Katolik L, An HS, Andersson GB. Augmentation of pedicle screw fixation strength using an injectable calcium phosphate cement as a function of injection timing and method. Spine 2004;29(11): E212‒6. . 10.1097/00007632-200406010-00020
[306]

Farrar DF. Bone adhesives for trauma surgery: a review of challenges and developments. Int J Adhes Adhes 2012;33:89‒97. . 10.1016/j.ijadhadh.2011.11.009
[307]

Rauschmann MA, Wichelhaus TA, Stirnal V, Dingeldein E, Zichner L, Schnettler R, et al. Nanocrystalline hydroxyapatite and calcium sulphate as biodegradable composite carrier material for local delivery of antibiotics in bone infections. Biomaterials 2005;26(15):2677‒84. . 10.1016/j.biomaterials.2004.06.045
[308]

Yi X, Wang Y, Lu H, Li C, Zhu T. Augmentation of pedicle screw fixation strength using an injectable calcium sulfate cement: an in vivo study. Spine 2008;33(23):2503‒9. . 10.1097/brs.0b013e318184e750
[309]

Sun H, Liu C, Li X, Liu H, Zhang W, Yang H, et al. A novel calcium phosphate-based nanocomposite for the augmentation of cement-injectable cannulated pedicle screws fixation: a cadaver and biomechanical study. J Orthop Translat 2020;20:56‒66. . 10.1016/j.jot.2019.08.001
[310]

Leung KS, Siu WS, Li SF, Qin L, Cheung WH, Tam KF, et al. An in vitro optimized injectable calcium phosphate cement for augmenting screw fixation in osteopenic goats. J Biomed Mater Res 2006;78(1):153‒60. . 10.1002/jbm.b.30467
[311]

Pujari-Palmer M, Guo H, Wenner D, Autefage H, Spicer CD, Stevens MM, et al. A novel class of injectable bioceramics that glue tissues and biomaterials. Materials 2018;11(12):2492. . 10.3390/ma11122492
[312]

Kirillova A, Kelly C, von Windheim N, Gall K. Bioinspired mineral-organic bioresorbable bone adhesive. Adv Healthc Mater 2018;7(17):1800467. . 10.1002/adhm.201870070
[313]

Bai S, Zhang X, Lv X, Zhang M, Huang X, Shi Y, et al. Bioinspired mineral-organic bone adhesives for stable fracture fixation and accelerated bone regeneration. Adv Funct Mater 2019;30(5):1908381. . 10.1002/adfm.201908381
[314]

Pan S, Yin J, Yu L, Zhang C, Zhu Y, Gao Y, et al. 2D MXene-integrated 3D-printing scaffolds for augmented osteosarcoma phototherapy and accelerated tissue reconstruction. Adv Sci 2020;7(2):1901511. . 10.1002/advs.201901511
[315]

Bischoff I, Tsaryk R, Chai F, Furst R, Kirkpatrick CJ, Unger RE. In vitro evaluation of a biomaterial-based anticancer drug delivery system as an alternative to conventional post-surgery bone cancer treatment. Mater Sci Eng C 2018;93:115‒24. . 10.1016/j.msec.2018.07.057
[316]

Kim J, Kim J, Jeong C, Kim WJ. Synergistic nanomedicine by combined gene and photothermal therapy. Adv Drug Deliv Rev 2016;98:99‒112. . 10.1016/j.addr.2015.12.018
[317]

Fan W, Yung B, Huang P, Chen X. Nanotechnology for multimodal synergistic cancer therapy. Chem Rev 2017;117(22):13566‒638. . 10.1021/acs.chemrev.7b00258
[318]

Liu Y, Bhattarai P, Dai Z, Chen X. Photothermal therapy and photoacoustic imaging via nanotheranostics in fighting cancer. Chem Soc Rev 2019;48(7):2053‒108. . 10.1039/c8cs00618k
[319]

Zhou B, Guo Z, Lin Z, Zhang L, Jiang BP, Shen XC. Recent insights into near-infrared light-responsive carbon dots for bioimaging and cancer phototherapy. Inorg Chem Front 2019;6(5):1116‒28. . 10.1039/c9qi00201d
[320]

Cheng J, Wang W, Xu X, Lin Z, Xie C, Zhang Y, et al. AgBiS2 nanoparticles with synergistic photodynamic and bioimaging properties for enhanced malignant tumor phototherapy. Mater Sci Eng C 2020;107:110324. . 10.1016/j.msec.2019.110324
[321]

Gu W, Zhang T, Gao J, Wang Y, Li D, Zhao Z, et al. Albumin-bioinspired iridium oxide nanoplatform with high photothermal conversion efficiency for synergistic chemo-photothermal of osteosarcoma. Drug Deliv 2019;26(1):918‒27. . 10.1080/10717544.2019.1662513
[322]

Kaur P, Aliru ML, Chadha AS, Asea A, Krishnan S. Hyperthermia using nanoparticles-promises and pitfalls. Int J Hyperther 2016;32(1):76‒88. . 10.3109/02656736.2015.1120889
[323]

Moise S, Byrne JM, El Haj AJ, Telling ND. The potential of magnetic hyperthermia for triggering the differentiation of cancer cells. Nanoscale 2018;10(44):20519‒25. . 10.1039/c8nr05946b
[324]

Au KM, Satterlee A, Min Y, Tian X, Kim YS, Caster JM, et al. Folate-targeted pH-responsive calcium zoledronate nanoscale metal-organic frameworks: turning a bone antiresorptive agent into an anticancer therapeutic. Biomaterials 2016;82:178‒93. . 10.1016/j.biomaterials.2015.12.018
[325]

Wachtel M, Schafer BW. Targets for cancer therapy in childhood sarcomas. Cancer Treat Rev 2010;36(4):318‒27. . 10.1016/j.ctrv.2010.02.007
[326]

van Leeuwen BL, Kamps WA, Jansen HW, Hoekstra HJ. The effect of chemotherapy on the growing skeleton. Cancer Treat Rev 2000;26(5):363‒76. . 10.1053/ctrv.2000.0180
[327]

Rainusso N, Wang LL, Yustein JT. The adolescent and young adult with cancer: state of the art-bone tumors. Curr Oncol Rep 2013;15(4): 296‒307. . 10.1007/s11912-013-0321-9
[328]

Chun R, Kurzman ID, Couto CG, Klausner J, Henry C, MacEwen EG. Cisplatin and doxorubicin combination chemotherapy for the treatment of canine osteosarcoma: a pilot study. J Vet Intern Med 2000;14(5):495‒8. . 10.1892/0891-6640(2000)014<0495:cadccf>2.3.co;2
[329]

Hyun H, Park MH, Lim W, Kim SY, Jo D, Jung JS, et al. Injectable visible light-cured glycol chitosan hydrogels with controlled release of anticancer drugs for local cancer therapy in vivo: a feasible study. Artif Cells Nanomed Biotechnol 2018;46(sup2):874‒82. . 10.1080/21691401.2018.1470529
[330]

Yoo Y, Yoon SJ, Kim SY, Lee DW, Um S, Hyun H, et al. A local drug delivery system based on visible light-cured glycol chitosan and doxorubicinhydrochloride for thyroid cancer treatment in vitro and in vivo . Drug Deliv 2018;25(1):1664‒71. . 10.1080/10717544.2018.1507058
[331]

Wu W, Dai Y, Liu H, Cheng R, Ni Q, Ye T, et al. Local release of gemcitabine via in situ UV-crosslinked lipid-strengthened hydrogel for inhibiting osteosarcoma. Drug Deliv 2018;25(1):1642‒51. . 10.1080/10717544.2018.1497105
[332]

Zheng Y, Cheng Y, Chen J, Ding J, Li M, Li C, et al. Injectable hydrogel-microsphere construct with sequential degradation for locally synergistic chemotherapy. ACS Appl Mater Interfaces 2017;9(4):3487‒96. . 10.1021/acsami.6b15245
[333]

Yoon SJ, Moon YJ, Chun HJ, Yang DH. Doxorubicin.hydrochloride/cisplatin-loaded hydrogel/nanosized (2-hydroxypropyl)-beta-cyclodextrin local drug-delivery system for osteosarcoma treatment in vivo. Nanomaterials 2019;9(12):1652. . 10.3390/nano9121652
[334]

Yang Z, Yu S, Li D, Gong Y, Zang J, Liu J, et al. The effect of PLGA-based hydrogel scaffold for improving the drug maximum-tolerated dose for in situ osteosarcoma treatment. Colloids Surf B 2018;172:387‒94. . 10.1016/j.colsurfb.2018.08.048
[335]

Song W, Tang Z, Zhang D, Yu H, Chen X. Coadministration of vascular disrupting agents and nanomedicines to eradicate tumors from peripheral and central regions. Small 2015;11(31):3755‒61. . 10.1002/smll.201500324
[336]

Chen SH, Liu TI, Chuang CL, Chen HH, Chiang WH, Chiu HC. Alendronate/folic acid-decorated polymeric nanoparticles for hierarchically targetable chemotherapy against bone metastatic breast cancer. J Mater Chem B 2020;8(17):3789‒800. . 10.1039/d0tb00046a
[337]

Li J, Liu X, Zhou Z, Tan L, Wang X, Zheng Y, et al. Lysozyme-assisted photothermal eradication of methicillin-resistant staphylococcus aureus infection and accelerated tissue repair with natural melanosome nanostructures. ACS Nano 2019;13(10):11153‒67.
[338]

Reding-Roman C, Hewlett M, Duxbury S, Gori F, Gudelj I, Beardmore R. The unconstrained evolution of fast and efficient antibiotic-resistant bacterial genomes. Nat Ecol Evol 2017;1(3):1‒11. . 10.1038/s41559-016-0050
[339]

Zhang K, Wang S, Zhou C, Cheng L, Gao X, Xie X, et al. Advanced smart biomaterials and constructs for hard tissue engineering and regeneration. Bone Res 2018;6(1):1‒15. . 10.1038/s41413-018-0032-9
[340]

Leijten J, Seo J, Yue K, Trujillo-de Santiago G, Tamayol A, Ruiz-Esparza GU, et al. Spatially and temporally controlled hydrogels for tissue engineering. Mater Sci Eng Rep 2017;119:1‒35. . 10.1016/j.mser.2017.07.001
[341]

Sun Y, Nan D, Jin H, Qu X. Recent advances of injectable hydrogels for drug delivery and tissue engineering applications. Polym Test 2020;81:106283. . 10.1016/j.polymertesting.2019.106283
[342]

Sheikh Z, Najeeb S, Khurshid Z, Verma V, Rashid H, Glogauer M. Biodegradable materials for bone repair and tissue engineering applications. Materials 2015;8(9):5744‒94. . 10.3390/ma8095273
[343]

Tong X, Xu Y, Zhang T, Deng C, Xun J, Sun D, et al. Exosomes from CD133+ human urine-derived stem cells combined adhesive hydrogel facilitate rotator cuff healing by mediating bone marrow mesenchymal stem cells. J Orthop Translat 2023;39:100‒12. . 10.1016/j.jot.2023.02.002
[344]

Stefanov I, Perez-Rafael S, Hoyo J, Cailloux J, Santana Pérez OO, Hinojosa-Caballero D, et al. Multifunctional enzymatically generated hydrogels for chronic wound application. Biomacromolecules 2017;18(5):1544‒55. . 10.1021/acs.biomac.7b00111
[345]

Zhang Y, Zhang J, Chen M, Gong H, Thamphiwatana S, Eckmann L, et al. A bioadhesive nanoparticle-hydrogel hybrid system for localized antimicrobial drug delivery. ACS Appl Mater Interfaces 2016;8(28):18367‒74. . 10.1021/acsami.6b04858
[346]

Hoque J, Bhattacharjee B, Prakash R, Paramanandham K, Haldar J. Dual function injectable hydrogel for controlled release of antibiotic and local antibacterial therapy. Biomacromolecules 2017;19(2):267‒78. . 10.1021/acs.biomac.7b00979
[347]

Nailor MD, Sobel JD. Antibiotics for Gram-positive bacterial infection: vancomycin, teicoplanin, quinupristin/dalfopristin, oxazolidinones, daptomycin, telavancin, and ceftaroline. Med Clin North Am 2011;95(4):723‒42. . 10.1016/j.mcna.2011.03.011
[348]

Nordmann P, Poirel L, Toleman MA, Walsh TR. Does broad-spectrum β-lactam resistance due to NDM-1 herald the end of the antibiotic era for treatment of infections caused by Gram-negative bacteria? J Antimicrob Chemother 2011;66(4):689‒92. . 10.1093/jac/dkq520
[349]

Hukić M, Seljmo D, Ramovic A, Ibrišimović MA, Dogan S, Hukic J, et al. The effect of lysozyme on reducing biofilms by Staphylococcus aureus, Pseudomonas aeruginosa, and Gardnerella vaginalis: an in vitro examination. Microb Drug Resist 2018;24(4):353‒8. . 10.1089/mdr.2016.0303
[350]

Kawai Y, Mickiewicz K, Errington J. Lysozyme counteracts β-lactam antibiotics by promoting the emergence of L-form bacteria. Cell 2018;172(5):1038‒1049.e10. . 10.1016/j.cell.2018.01.021
[351]

Chen FM, Zhang J, Zhang M, An Y, Chen F, Wu ZF. A review on endogenous regenerative technology in periodontal regenerative medicine. Biomaterials 2010;31(31):7892‒927. . 10.1016/j.biomaterials.2010.07.019
[352]

Rashki S, Asgarpour K, Tarrahimofrad H, Hashemipour M, Ebrahimi MS, Fathizadeh H, et al. Chitosan-based nanoparticles against bacterial infections. Carbohydr Polym 2021;251:117108. . 10.1016/j.carbpol.2020.117108
[353]

Li Y, Miao Y, Yang L, Zhao Y, Wu K, Lu Z, et al. Recent advances in the development and antimicrobial applications of metal-phenolic networks. Adv Sci 2022;9(27):2202684. . 10.1002/advs.202202684
[354]

Levchuk I, Kralova M, Rueda-Márquez JJ, Moreno-Andrés J, Gutiérrez-Alfaro S, Dzik P, et al. Antimicrobial activity of printed composite TiO2/SiO2 and TiO2/SiO2/Au thin films under UVA-LED and natural solar radiation. Appl Catal B 2018;239:609‒18. . 10.1016/j.apcatb.2018.08.051
[355]

Dar GN, Umar A, Zaidi SA, Baskoutas S, Hwang SW, Abaker M, et al. Ultra-high sensitive ammonia chemical sensor based on ZnO nanopencils. Talanta 2012;89:155‒61. . 10.1016/j.talanta.2011.12.006
[356]

Alves MM, Bouchami O, Tavares A, Córdoba L, Santos CF, Miragaia M, et al. New insights into antibiofilm effect of a nanosized ZnO coating against the pathogenic methicillin resistant Staphylococcus aureus. ACS Appl Mater Interfaces 2017;9(34):28157‒67. . 10.1021/acsami.7b02320
[357]

Martínez-Carmona M, Gun’ko Y, Vallet-Regí M. ZnO nanostructures for drug delivery and theranostic applications. Nanomaterials 2018;8(4):268. . 10.3390/nano8040268
[358]

Yang T, Oliver S, Chen Y, Boyer C, Chandrawati R. Tuning crystallization and morphology of zinc oxide with polyvinylpyrrolidone: formation mechanisms and antimicrobial activity. J Colloid Interface Sci 2019;546:43‒52. . 10.1016/j.jcis.2019.03.051
[359]

Zhang F, Li X, He N, Lin Q. Antibacterial properties of ZnO/calcium alginate composite and its application in wastewater treatment. J Nanosci Nanotechnol 2015;15(5):3839‒45. . 10.1166/jnn.2015.9496
[360]

Makvandi P, Ali GW, Della Sala F, Abdel-Fattah WI, Borzacchiello A. Hyaluronic acid/corn silk extract based injectable nanocomposite: a biomimetic antibacterial scaffold for bone tissue regeneration. Mater Sci Eng C 2020;107:110195. . 10.1016/j.msec.2019.110195
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