Application of three-dimensional printing metal implants in orthopedics

doi:10.3969/j.issn.2095-4344.0566

Abstract

Abstract:

BACKGROUND: For the complicated bone defects caused by severe trauma, tumor resection and arthroplasty, conventional metal implants cannot achieve satisfactory results because of the large and irregular defect and limited ability of bone regeneration in pathological condition.
OBJECTIVE: To introduce the clinical application of three-dimensional (3D)-printed metal implants in orthopedics and to discuss how to further optimize the 3D-printed implant system in basic research, strengthen the bone regeneration at the defect region and the integrative effect in the host bone.
METHODS: A computer-based retrieval of PubMed, Web of Science, Springerlink, Medline, WanFang and CNKI databases was performed for relevant articles published from 2005 to 2018. The keywords were “3D printing, bone defect, metal implant, prosthesis” in English and Chinese, respectively. Initially, 401 articles were retrieved, and finally 67 eligible articles were included for result analysis.
RESULTS AND CONCLUSION: (1) 3D printing technology has been widely used in medicine, automobile manufacturing, aerospace and other fields. (2) 3D printing metal joints, acetabulum, vertebral body, pelvis and other implants have been applied in clinical practice. The follow-up results show that patients with 3D printing internal plants have early stability, the close implant-bone connection, and prosthesis loosening is rare, and the clinical results are satisfactory. (3) The further optimization of 3D printing metal plants in basic research, the application of optimizing the pore structure and material selection of 3D printing stents, hydroxyapatite, beta tricalcium phosphate, strontium salt and other biological coatings, including the local action of exogenous stem cells and growth factors, can promote the state of health or the pathological state. (4) The individualized design of 3D printed metal implant, good mechanical properties and the ability to induce bone growth significantly promote the integration effect of the prosthesis-host bone and provide a new direction for orthopedics.

中国组织工程研究杂志出版内容重点：人工关节；骨植入物；脊柱；骨折；内固定；数字化骨科；组织工程

Key words: Prostheses and Implants, Prosthesis Implantation, Bone Regeneration, Tissue Engineering

CLC Number:

R318

Zhao Min-chao, Huang Yan, Yuan Wei-jian, Chi Yu-fei, Li Zu-hao, Wu Han. Application of three-dimensional printing metal implants in orthopedics [J]. Chinese Journal of Tissue Engineering Research, 2018, 22(31): 5027-5033.

Figures/Tables 3

2.1 临床应用近年来，3D打印技术在骨科中得到了广泛应用。对于一些特殊的患者，如骨肿瘤切除术后和严重骨缺损的翻修手术，外科医生必须延长切口或增加植骨量以保证植入物的稳定性和匹配性。延长切口会加重机体损伤，不利于恢复。自体移植是治疗骨缺损的金标准，但其应用受限于供区并发症、恢复时间长、成本高和手术造成的组织损伤大等诸多因素[15-17]。此外，异种移植物也有免疫排斥和感染的风险[18-19]。3D打印技术可以模拟手术前的情况，并设计个体化的假体用于植入。该部分总结了相关病例，探讨3D打印在临床的应用前景。在3D打印关节方面，由于近年来人工髋关节翻修术的增多，复杂的髋臼缺损甚至骨盆不连续变得更为常见，3D打印髋臼假体在翻修手术中得到了极大的关注，且3D打印髋臼假体已获准上市(图2A)。多个研究结果表明，3D打印髋臼假体可显著改善Harris髋关节评分，恢复髋关节中心，减少手术并发症，尤其是严重的缺损[20-22]。3D打印全肩关节假体尚未见报道，但肩关节周围部位，如关节盂、锁骨、肩胛骨等已有随访2年以上的病例。Stoffelen等[23]研制出一种3D打印关节盂用于肩关节置换术后严重的关节盂缺损。多孔结构良好地填充了骨缺损，并且部件的附加螺纹孔允许转换成反向构型。该病例在2.5年随访中获得了良好的功能评分(图2B)。Fan等[24]应用3D打印技术治疗位于锁骨尤文肉瘤(图2C)。多孔结构减少了弹性模量，相邻结构被不可吸收缝线固定到假体的小孔上，术后获得了良好的美国骨肿瘤学会评分，无术后并发症产生。吉林大学第二医院王金成教授团队报道了多例应用3D打印金属假体质量建肿瘤切除术的关节功能，具有仿生结构的Co-Cr-Mo合金假体完美填充了桡骨远端巨细胞瘤切除术后产生的骨缺损，关节面通过表面拟合，以确保腕关节运动轨迹的流畅(图2D)，平均11个月的随访提示结果满意[12]。此外该团队还为膝关节巨细胞瘤切除后的骨缺损制备了3D打印钛合金胫骨端微孔垫块，为侧副韧带、髌韧带和骨质提供附着点和长入点(图2E)，使非限制型膝关节假体替代限制型膝关节肿瘤假体、重建胫骨上端成为可能[13]。在脊柱方面，北医三院刘忠军教授团队与爱康宜城公司合力设计的3D打印椎体已获准上市。他们针对上颈椎(C2)尤文氏肉瘤进行了3D打印定制钛合金椎体的重建，并且优化了内植物的显微结构，获得了生物力学稳定性、骨愈合的孔隙率、支柱尺寸之间超微结构的平衡。术后CT提示骨性融合良好，未见植入物下沉或移位[25]。西安交通大学第二附属医院贺西京教授团队也已将3D打印的寰枢椎钢板及人工寰枢椎应用于临床。此外，澳大利亚Mobbs教授团队也证明3D打印金属内植物在脊柱肿瘤切除术后重建中获得满意效果(图2F，G)[26-27]。由于自身结构的复杂不规则、过大的承载负荷、病变缺损的广泛以及深部具有重要组织结构，使得骨盆肿瘤切除术后重建一直是巨大的挑战[28-29]，传统的重建方法无法达到满意的结果[30]。3D打印技术在骨盆肿瘤切除后的缺损重建中具有显著地优势，减少了手术创伤、实现了早期下地，精准的个体化匹配获得良好的功能恢复。3D打印金属假体在骶骨骨肉瘤半骶骨切除术后重建(图2H)[31]、骶骨脊索瘤术后重建(图2I)中均获得了满意结果[32]。总的来说，3D打印金属内植物临床应用的中短期随访表明该技术可使假体与骨缺损精确匹配，实现早期稳定性，内植物与宿主骨结合牢固，假体松动等并发症少见，获得了较满意的效果。 "

2.2.1 正常状态下骨缺损 3D打印金属支架孔径是影响骨长入的一个重要因素，通过优化孔径可以促进骨整合。以往研究表明，骨长入的最佳孔径范围为100-500 μm[34]。另外有研究推荐孔径大于300 μm的支架可以更好地促进新骨形成和毛细血管生成[35]。Li等[36]利用3D打印技术制备了3种不同孔径的钛合金支架(300-400，400-500，500-700 μm)，体外与骨髓间充质干细胞共培养发现孔径300-400 μm的支架更利于骨髓间充质干细胞增殖和成骨分化，在山羊体内3 cm长的节段性缺损中植入不同规格孔径的支架，可见孔径为300-400 μm的支架有明显的骨长入。除了孔径直径，孔隙形状的改变也可以改善微孔支架的力学和成骨性能。Pobloth等[37]采用蜂窝状结构的设计使应力屏蔽最小化，同时确保避免了机械失效，这种优化了孔隙形状的钛网很好的促进了羊胫骨中段骨缺损的愈合。同时通过计算机有限元设计与优化也应用于改善支架性能[38]。在孔隙支架中封装有利于骨再生的药物，并使其在局部组织中缓释，是促进骨生长愈合一种有潜力的研究方向。辛伐他汀作为一种常见的血酯调节剂，局部给药可促进骨形成和骨缺损愈合[39-40]。水凝胶作为细胞载体或者药物缓释体系都可以明显促进缺损组织再生[41]。3D打印多孔Ti6Al4V支架填充负载辛伐他汀的泊洛沙姆407水凝胶植入家兔胫骨近端骨缺损，术后第8周0.1 mg和0.5 mg辛伐他丁组支架内骨体积对比对照组分别为16.09% 和31.35%，且有显著的骨密度提高，结果证明该复合支架可显著改善骨整合、促进骨长入与新生血管形成[42]。复合明胶凝胶和纳米羟基磷灰石的多孔钛合金支架可明显促进成骨细胞前体MC3TC-E1细胞的增殖黏附和成骨分化，在骨缺损模型中明胶与羟基磷灰石按1∶1混合的支架可以明显加速颅骨缺损的愈合，成骨相关基因和蛋白的表达也明显增加[43]。与此相似Kumar等[44]制备了一种由海藻酸钠、明胶和纳米羟基磷灰石组成的水凝胶搭载成骨细胞，在3D打印的多孔结构中观察到存在细胞外基质样水凝胶有利于成骨细胞的黏附、增殖、成骨能力，相关研究结果见图3。 2.2.2 病理状态下骨缺损在一些病理状态下，如骨质疏松、糖尿病、感染等，假体植入通常会导致骨愈合时间延长、再生骨质量差、易发生再骨折、植入物下沉或松动，以及长期卧床导致的一些并发症，如坠积性肺炎和压疮等[45-48]。尽管3D打印金属支架较传统支架更易促进骨长入，但是对3D打印金属内植物的优化，将进一步促进支架-宿主骨整合，获得最佳效果。骨质疏松症是一种以低骨量为特征的疾病，最常见的是由于骨吸收速度增加与骨形成速度不相匹配。骨质疏松性骨缺损中不平衡骨重建是造成内植物失败的主要原因，骨质与内植物结合不牢固易造成植入物松动，导致假体周围骨折[49]。乙基-2，5-二羟基苯甲酸酯作为一种促进骨形成和抑制骨吸收的药物，被聚乳酸-乙醇酸嵌段共聚物封装后以涂层形式存在于钛合金空隙支架表面。复合支架植入骨质疏松大鼠股骨缺损后第4，8和12周微CT检测显示支架周围骨吸收减少，骨形成增加。因此，证实在骨质疏松模型中，这种具有药物缓释作用的3D打印钛合金支架可使骨愈合增加，内植物稳定性增强[50]。一些抗骨质疏松药物常被添加到支架材料中以促进骨质疏松性骨缺损的愈合。掺杂锶(Sr)和双磷酸盐的泡沫铁支架可以促进骨质疏松性骨折的愈合[51]。低水平激光治疗对骨丢失严重、骨代谢紊乱影响骨重建的患者可以有效刺激骨生长[52]。此外，低水平激光治疗能够加速新骨形成，从而增加成骨细胞活性，加快血管化和胶原纤维的分布，提高抗菌和免疫效果[53]。低水平激光治疗的其他积极作用还包括在内植物周围进行的血流刺激、改善植入物与骨表面之间的接触以及促进更快的骨成熟[54]。在骨质疏松大鼠股骨缺损处植入钛合金支架之后体外给予低水平激光治疗可以明显加速钛合金支架内的骨修复，且在非骨质疏松大鼠缺损中也得到了相似结果[55]。糖尿病相关的骨内植入物有较高的失败风险，需要有效的方法来改善骨植入物界面的骨整合[56]。具有聚乳酸-乙醇酸嵌段共聚物涂层的3D打印钛合金支架对糖尿病坏境中的成骨细胞具有保护作用，其降解产物乳酸促进糖尿病骨缺损中的血管形成[57]。糖尿病的存在与骨质疏松的发生关系密切[58]，外加脉冲电磁场的特异性波形抑制骨质疏松动物的骨丢失，并促进成骨细胞的活性和功能[59-60]。在健康家兔股骨缺损处植入3D打印的多孔Ti6Al4V支架后给予脉冲电磁场治疗对促进骨再生的能力已被证明(图4A)[61]。但脉冲电磁场能否促进病理状态下的骨缺损修复还有待进一步研究。Cai等[62]在1型糖尿病家兔股骨缺损处植入钛合金支架后1周开始进行为期8周的体外脉冲电磁场治疗。与对照组相比，脉冲电磁场治疗通过激活成功相关的Wnt/β-catenin信号通路而不影响破骨相关的RANKL/RANK通路，明显促进了糖尿病骨缺损的骨整合。此外，对同样是股骨缺损处植入相同成分钛合金支架的糖尿病家兔给以全身振动治疗同样可以激活Wnt/β-catenin通路，从而促进1型糖尿病兔骨代谢、骨组织学和多孔钛种植体骨整合(图4B)[63]。假体感染仍然是骨科术后的一个严重并发症，感染的骨缺损中由于系统性抗生素治疗没有达到特定的作用位点而迁延不愈[64]。研究者用许多方法改良内植物表面从而达到抑制细菌黏附和生长的目的。纳米银可有效预防细菌黏附、生物膜形成和后续的假体感染[65-66]。将纳米银涂层的3D打印钛合金支架植入大鼠胫骨缺损中，骨-内植物界面的纳米级元素图谱和透射电子显微镜显示银主要存在于骨组织中，并与硫共定位，很好的验证了纳米银在体内缓释，在不影响成骨的同时具有抗菌的潜力[67]。"

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