3D打印骨组织工程支架的研究与应用

背景：虽然应用传统方法制作骨组织工程支架取得一定成就,但在支架的三维结构、力学强度、支架个性化方面不太满意,通过3D打印技术制作支架的方法有望改变这些不足。 目的：对3D打印技术制作骨组织工程支架作一综述,对支架的未来优化进行展望。 方法：应用计算机检索PubMed和谷歌学术数据库中,2008至2015年关于3D打印技术制作骨组织工程支架的文章。纳入包含骨组织工程支架结构设计、材料及通过不同3D打印技术制作的支架性能研究文章,排除观点重复和陈旧的文章,最后对37篇文献进行归纳总结。 结果与结论：目前可用作骨组织工程支架制作的3D打印技术有熔融层积成型、立体平版印刷、选区激光烧结及3DP技术。3D打印技术制作的骨组织工程支架在力学、结构、个性化方面有其独特优势,但该技术仍有很多问题需要解决,比如原材料的问题、不同3D打印技术的不足问题及3D打印机器的改进问题等。相信在未来多学科的共同合作下,可以制作出适合于临床的骨组织工程支架,造福于人类。  中国组织工程研究杂志出版内容重点：生物材料;骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性;组织工程     

3D打印骨组织工程支架的制备技术

近年来，随着3D打印技术的飞速发展，人们开始通过3D打印技术去不断完善适合不同需求的定制骨组织工程支架。由于组织工程制造的支架是需要植入生物体内的，这就对支架有着极为严苛的要求。3D打印技术作为一种新兴制备骨组织工程支架的技术，其最大的优点是可以依照需求来定制个性化形状、结构，良好的宏微观结构、润湿性、机械强度和细胞反应的新型骨组织工程支架。本文回顾了2014―2019年间对骨组织工程支架的研究，对3D打印骨组织工程支架进行了总结，并且介绍了在多功能骨组织工程支架设计与制作中的理念与研究。     

构建骨组织工程支架中应用的3D打印技术

背景：3D打印技术自20世纪末出现以来逐渐应用在医学领域已成为一种趋势。近年来3D打印技术被广泛用于骨组织工程支架材料的成型,并取得了一些令人惊喜的成果。 目的：文章从骨组织工程支架基本概念、3D打印的基本原理和流程、3D打印应用于构造支架的要求以及不同的粉末材料等方面进行阐述,分析其优势与目前存在的局限性,并对未来3D打印在骨组织工程支架中的应用进行展望。 方法：第一作者应用计算机检索1990年1月至2015年2月MEDLINE数据库、Science Direct全文数据库、中国期刊全文数据库、维普中文期刊网等有关3D打印技术在构建骨组织工程支架中应用的文章,检索词“3D打印,组织工程学,快速成型技术,支架,材料”,排除重复性研究。文章共检索到52篇相关文献,其中33篇文献符合纳入标准。 结果与结论：3D打印技术具有高精度、构建速度快、可按需制造实现个性化定制等优势。3D打印应用于骨组织工程支架构建时,所用的粉末或黏合剂需具备一定的条件,如流动性、稳定性与可湿性等。用于打印的粉末材料可分为人工合成多聚体、天然高分子聚合物、生物陶瓷及它们的混合物。不同粉末材料的粉末各自优缺点不同,且最终成型效果也不尽相同。3D打印技术也存在一些包括费用昂贵、不易大规模生产等方面的局限性。但尽管如此,3D打印的临床应用前景一片光明。 中国组织工程研究杂志出版内容重点：生物材料;骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性;组织工程     

3D打印技术制备器官芯片的研究现状

器官芯片是一种新兴的体外生物模型,在生物医学领域有重要的应用前景。但是,相关研究的开展通常受限于器官芯片繁琐和昂贵的制备过程。近年来,科研工作者借助3D打印技术,实现器官芯片制备的简易化、低成本化,以及芯片结构复杂化和成型一体化。这一技术的突破,有力推动器官芯片相关研究的发展,为其在生物医学领域的广泛应用提供有力支持。综述3D打印制备器官芯片的研究现状,主要包括器官芯片的发展背景、传统制造方法的局限性、 3D打印器官芯片的技术分类及其生物医学应用。列举5种基于不同成型原理的3D打印方法,归纳比较各方法的工艺特点以及制备器官芯片时的适用范围,探讨3D打印制备肝、肾、血管、心脏等器官芯片的具体实例和效果。最后分析该技术的不足之处, 并展望这一领域的发展趋势。     

3D打印在医学领域的应用进展

三维(3D)打印出现于20世纪90年代,最初应用于模具制造、工业设计等领域。随着打印材料的研发和控制技术的完善,其应用越来越广泛。相较于传统制造技术,3D打印在小批次、设计复杂的物件制造上具有成本和效率优势,这也使得3D打印技术在医学领域中拥有极佳的应用前景。本文简述了3D打印技术的相关概念并综述了3D打印技术在医学领域中四个方面的应用:辅助外科手术,如打印3D模型辅助医生进行术前规划,打印手术导板等;打印个性化医疗器械,如打印助听器、义肢、义齿、新型给药系统和个性化内植入物等;应用于组织工程,如打印组织工程支架以及生物3D打印技术等;应用于医学教育和基础科研,如打印3D模型用于临床教学或者解剖教学,打印3D实体模型用于生物力学研究以及3D打印人工组织器官用于药物测试和肿瘤研究等。最后总结了现有3D打印技术的不足之处,并对其在医学领域的发展前景做出展望。     

壳聚糖/聚乳酸/羟基磷灰石/聚乙烯醇复合材料骨支架的制备及表征

背景:制备可降解材料骨组织工程支架,应用于修复骨肉瘤造成的骨缺损是当前骨组织工程研究热点.目的:确定壳聚糖/聚乳酸/羟基磷灰石/聚乙烯醇复合材料的配比,优化骨支架力学性能.方法:基于挤出式3D打印技术制备壳聚糖/聚乳酸/羟基磷灰石/聚乙烯醇骨支架,以最大抗压强度为评价指标,设计正交实验,以乙酸浓度(1.5％,2％,2....     

三维生物打印技术在泌尿系组织工程中的研究进展

针对泌尿系疾病导致的组织器官损伤和缺失,目前临床上的治疗方法存在局限性。组织工程通过对细胞、生物支架和生物相关分子的研究,提供了一种可替代或再生受损组织器官的治疗手段。三维（3D）生物打印技术作为新兴制造技术,能对载有细胞的生物材料精确控制,进一步推动着组织工程领域的发展。本文综述了3D生物打印技术在肾脏、输尿管、膀胱、尿道组织工程中的研究进展和应用,并讨论了目前面临的主要挑战和未来展望。     

骨组织工程多孔支架制备方法的研究进展

近年来,骨组织工程中人工合成骨移植物的出现为骨缺损病例的修复提供了新思路,在原料、性能及应用上得到了广泛的关注和研究,也在临床上取得了初步应用.文章从骨支架材料的传统制备方法和基于计算机技术的3D打印相关技术的原理和优缺点进行了综述,并对制备技术的未来改进方向和可行性提出展望,以期探索出更具有应用价值的方法.     

3D打印技术在生物学中的应用与进展

现代成像技术是生物医学领域中的一个重要组成部分。然而,由于传统的2D方法所具有的代表性,使得许多包含3D 重建的传统方法被限制。3D 打印,也被称作快速原形技术或者增材制造技术,它是通过电脑辅助,分层加工、逐层叠加的方式获得三维产品,曾经应用在工业与制造领域中。3D 成像分析会提供比2D 放射线照相技术更详细的信息,由于3D 打印的这些附加优点,因此它可以应用于术前计划以及再生治疗中。现如今,3D 打印技术已经被广泛的应用于医学领域。例如,3 D 打印技术的应用已经被延伸到组织或器官的生物细胞打印,组织工程中骨架的创造以及在多样的医学领域中的实际临床应用。本文就目前3D 打印技术在生物学中的应用及进展加以综述。     

三维打印技术在肝脏外科和肝毒性评价中的研究进展

三维(3D)打印作为一种新兴的快速成型技术,已广泛应用于生物医学领域。3D打印最初在医学中主要用于可视化模型、模具的构建,但随着生物医学领域3D打印技术的发展,该技术逐渐应用在复杂组织再生和器官重构等方面,通过生物3D打印获得的人工组织和器官,有望用于器官移植以及进行新药研发和药物毒性评价等医药学相关的研究。本文重点阐述了3D打印技术在肝脏外科中的个体化应用,并重点介绍了生物3D打印技术在肝移植、药物肝脏代谢和肝毒性评价中的研究进展,并进一步对其未来发展趋势进行了展望。     

光固化3D打印软组织材料的性能研究进展

光固化3D打印技术具有成型速度快、精度高的特点,可以精确控制需打印软组织的大小、形状和强度等,完成所需替代软组织支架的高匹配定制,有效解决软组织替代物的巨大缺口。目前该技术的应用范围取决于光敏材料的性能,首先,需具备适当的黏度、固化时间和固化收缩率等,以执行光固化打印并能控制打印组织的精度;其次,打印组织还需满足机体使用的机械性能(如强度、硬度、韧性)和良好的生物相容性(如促细胞黏附、增殖及分化),而降解性质、孔隙率、血管化等直接影响打印组织的机械性能或生物相容性。综述软组织支架打印所需光敏材料的基本性能和特殊性能要求及目前改良材料性能的方法,并展望光敏材料的发展趋势,对软组织工程光敏打印材料的开发具有指导意义。     

3D bioprinting in orthopedics translational research

Abstract

The repair of critical-size bone defect remains a challenge for orthopedic surgeons. With the advent of an aging society and their accompanying chronic diseases, it is becoming more difficult to treat bone defects, especially large segmental bone defects that are caused by trauma, tumors, infections, and congenital malformations. New materials and technologies need to be developed to address these conditions. 3D bioprinting is a novel technology that bridges the biomaterial and living cells and is an important method in tissue engineering projects. 3D bioprinting has the advantages of replacing or repairing damaged tissue and organs. The progress in material science and 3D printing devices make 3D bioprinting a technology which can be used to create various scaffolds with a large range of advanced material and cell types. However, in regard to the widespread use of bioprinting, biosafety, immunogenicity and rising costs are rising to be concerned. This article reviews the developments and applications of 3D bioprinting and highlights newly applied techniques and materials and the recent achievements in the orthopedic field. This paper also briefly reviews the difference between the methods of 3D bioprinting. The challenges are also elaborated with the aim to research materials, manufacture scaffolds, promote vascularization and maintain cell viability.     

生物支架材料修复感染性骨缺损的研究进展

骨髓炎所致的感染性骨缺损复发频繁，难以治愈。各种生物支架材料作为极具潜力的新型骨植入材料，有效弥补了现今感染性骨缺损修复材料的缺陷。其中天然生物衍生材料具有良好生物相容性，人工合成无机材料和有机高分子材料抗感染能力显著，复合材料结合3D打印和表面涂层技术，改善了常规植入物机械性能差、抗菌能力差、缺乏骨诱导功能等缺点。生物支架材料已在修复感染性骨缺损、促进骨再生等方面展现出良好前景。本文就生物支架材料修复感染性骨缺损的研究进展作一综述。     

Structural and material approaches to bone tissue engineering in powder-based three-dimensional printing

This article reviews the current state of knowledge concerning the use of powder-based three-dimensional printing (3DP) for the synthesis of bone tissue engineering scaffolds. 3DP is a solid free-form fabrication (SFF) technique building up complex open porous 3D structures layer by layer (a bottom-up approach). In contrast to traditional fabrication techniques generally subtracting material step by step (a top-down approach), SFF approaches allow nearly unlimited designs and a large variety of materials to be used for scaffold engineering. Today's state of the art materials, as well as the mechanical and structural requirements for bone scaffolds, are summarized and discussed in relation to the technical feasibility of their use in 3DP. Advances in the field of 3DP are presented and compared with other SFF methods. Existing strategies on material and design control of scaffolds are reviewed. Finally, the possibilities and limiting factors are addressed and potential strategies to improve 3DP for scaffold engineering are proposed.     

Three-dimensional printing of porous ceramic scaffolds for bone tissue engineering

This article reports a new process chain for custom-made three-dimensional (3D) porous ceramic scaffolds for bone replacement with fully interconnected channel network for the repair of osseous defects from trauma or disease. Rapid prototyping and especially 3D printing is well suited to generate complex-shaped porous ceramic matrices directly from powder materials. Anatomical information obtained from a patient can be used to design the implant for a target defect. In the 3D printing technique, a box filled with ceramic powder is printed with a polymer-based binder solution layer by layer. Powder is bonded in wetted regions. Unglued powder can be removed and a ceramic green body remains. We use a modified hydroxyapatite (HA) powder for the fabrication of 3D printed scaffolds due to the safety of HA as biocompatible implantable material and efficacy for bone regeneration. The printed ceramic green bodies are consolidated at a temperature of 1250 degrees C in a high temperature furnace in ambient air. The polymeric binder is pyrolysed during sintering. The resulting scaffolds can be used in tissue engineering of bone implants using patient-derived cells that are seeded onto the scaffolds.This article describes the process chain, beginning from data preparation to 3D printing tests and finally sintering of the scaffold. Prototypes were successfully manufactured and characterized. It was demonstrated that it is possible to manufacture parts with inner channels with a dimension down to 450 microm and wall structures with a thickness down to 330 microm. The mechanical strength of dense test parts is up to 22 MPa.     

3D打印羊椎骨粉/聚乙烯醇支架、纳米级羟基磷灰石/聚乙烯醇支架、羊椎骨粉/聚乙烯醇无孔骨板的性能比较

BACKGROUND: With the promotion of 3D printing technology, 3D printing scaffolds for bone tissue engineering have become the new ideas for jaw bone repair. OBJECTIVE: To compare the physical and biological properties of sheep vertebral bone meal/polyvinyl alcohol (PVA) scaffold, nano-hydroxyapatite (nHA)/PVA scaffold, and sheep vertebral bone meal/PVA nonporous bone plate. METHODS: 3D printing technology was used to print sheep vertebral bone meal/PVA scaffold, nHA/PVA scaffold, and sheep vertebral bone meal/PVA nonporous bone plate. Porosity, morphology, water absorption rate and mechanical properties of different scaffolds were detected. Three kinds of scaffolds were all used to culture bone marrow mesenchymal stem cells, and cell proliferation ability was detected using cell counting kit-8 at 1, 4, 7 days of culture. RESULTS AND CONCLUSION: Under scanning electron microscope, the sheep vertebral bone meal/PVA scaffold and nHA/PVA scaffold exhibited regular and interconnected pores with good continuity and clear network structure; the sheep vertebral bone meal/PVA nonporous bone plate had no obvious pores; however, it had dense and evenly distributed micropores with different sizes on its surface. The porosity of nHA/PVA scaffold was lower than that of the sheep vertebral bone meal/PVA scaffold (P < 0.05). The water absorption rate was highest for the nHA/PVA scaffold followed by the sheep vertebral bone meal/PVA scaffold and the sheep vertebral bone meal/PVA nonporous bone plate (P < 0.05). In contrast, the scaffold toughness was highest for the sheep vertebral bone meal/PVA nonporous bone plate, followed by the sheep vertebral bone meal/PVA scaffold and nHA/PVA scaffold. In addition, the cell proliferation activity of cells cultured on the sheep vertebral bone meal/PVA scaffold was significantly higher than that cultured on the other two kinds of scaffolds. Taken together, the 3D printing sheep vertebral bone/PVA scaffold has good physical and chemical performance.     

Fabrication and characterization of poly(propylene fumarate) scaffolds with controlled pore structures using 3-dimensional printing and injection molding

Poly(propylene fumarate) (PPF) is an injectable, biodegradable polymer that has been used for fabricating preformed scaffolds in tissue engineering applications because of in situ crosslinking characteristics. Aiming for understanding the effects of pore structure parameters on bone tissue ingrowth, 3-dimensional (3D) PPF scaffolds with controlled pore architecture have been produced in this study from computer-aided design (CAD) models. We have created original scaffold models with 3 pore sizes (300, 600, and 900 microm) and randomly closed 0%, 10%, 20%, or 30% of total pores from the original models in 3 planes. PPF scaffolds were fabricated by a series steps involving 3D printing of support/build constructs, dissolving build materials, injecting PPF, and dissolving support materials. To investigate the effects of controlled pore size and interconnectivity on scaffolds, we compared the porosities between the models and PPF scaffolds fabricated thereby, examined pore morphologies in surface and cross-section using scanning electron microscopy, and measured permeability using the falling head conductivity test. The thermal properties of the resulting scaffolds as well as uncrosslinked PPF were determined by differential scanning calorimetry and thermogravimetric analysis. Average pore sizes and pore shapes of PPF scaffolds with 600- and 900-microm pores were similar to those of CAD models, but they depended on directions in those with 300-microm pores. Porosity and permeability of PPF scaffolds decreased as the number of closed pores in original models increased, particularly when the pore size was 300 microm as the result of low porosity and pore occlusion. These results show that 3D printing and injection molding technique can be applied to crosslinkable polymers to fabricate 3D porous scaffolds with controlled pore structures, porosity, and permeability using their CAD models.     

Extrusion-based 3D printing of poly(propylene fumarate) scaffolds with hydroxyapatite gradients

The primary focus of this work is to present the current challenges of printing scaffolds with concentration gradients of nanoparticles with an aim to improve the processing of these scaffolds. Furthermore, we address how print fidelity is related to material composition and emphasize the importance of considering this relationship when developing complex scaffolds for bone implants. The ability to create complex tissues is becoming increasingly relevant in the tissue engineering community. For bone tissue engineering applications, this work demonstrates the ability to use extrusion-based printing techniques to control the spatial deposition of hydroxyapatite (HA) nanoparticles in a 3D composite scaffold. In doing so, we combined the benefits of synthetic, degradable polymers, such as poly(propylene fumarate) (PPF), with osteoconductive HA nanoparticles that provide robust compressive mechanical properties. Furthermore, the final 3D printed scaffolds consisted of well-defined layers with interconnected pores, two critical features for a successful bone implant. To demonstrate a controlled gradient of HA, thermogravimetric analysis was carried out to quantify HA on a per-layer basis. Moreover, we non-destructively evaluated the tendency of HA particles to aggregate within PPF using micro-computed tomography (μCT). This work provides insight for proper fabrication and characterization of composite scaffolds containing particle gradients and has broad applicability for future efforts in fabricating complex scaffolds for tissue engineering applications.     

3D打印β-TCP/HA/PLA骨移植支架材料的研究

目的 制备个性化的3D打印骨移植支架修复材料,以满足骨缺损患者的需求.方法 运用计算机软件CAD设计出三维木堆结构的模型图,通过三维气浮运动平台,使用3D打印方法模拟出三维木堆结构的复合β-磷酸三钙(β-TCP)、羟基磷灰石(HA)和聚乳酸(PLA)材料的支架.再对支架材料进行抽真空热处理,X射线能谱仪检测其氯仿残留量,扫描电镜观察支架材料的表面形貌,最后用噻唑蓝(MTT)法检测支架材料对人SV40转染成骨细胞hFOB1.19的毒性.结果 当打印浆料的挤出气压在137.9～413.7kPa内,可打印出β-TCP/HA/PLA三维骨移植支架材料.成型后的三维骨移植支架材料经90℃保温抽真空处理及150℃热处理后能消除其中的氯仿;材料表面粗糙,拥有表面细孔和内部连通的微孔;其同hFOB1.19细胞共培养7d,细胞毒性等级为0级.结论 本研究制备的3D打印β-TCP/HA/PLA骨移植支架材料表面粗糙而具有通孔,利于成骨细胞的培养,且骨诱导作用明显,体现出3D打印在制备骨移植多孔材料上拥有很大的优势和发展前景.     

颅骨修补材料研究现状及3D打印技术应用前景

BACKGROUND: Skull repair materials cannot only restore the normal shape of the skull, but also play an important role in brain functional recovery. OBJECTIVE: To summarize the research status of polyetheretherketone (PEEK), titanium alloy and tissue engineering technique in cranioplasty and the prospect of three-dimensional (3D) printing technology. METHODS: Literatures related to skull repair materials were retrieved in databases of CNKI and PubMed published from 1995 to 2016, using the keywords of “bone regeneration material in calvarial, 3d printing bone scaffold” in Chinese and English, respectively.  RESULTS AND CONCLUSION: Although titanium and PEEK have been used in clinic, titanium holds conductivity, thermal conductivity, while PEEK that may be displaced or lost is not involved in osseointegration. Tissue engineering technology participates in the skull tissue reconstruction, achieving satisfactory repair outcomes, but the problems of scaffold selection and preparation, seed cell obtainment, and growth factor release need to be overcomed. 3D printing technology can print personalized shape, fit the defect precisely, but the raw materials should have good biocompatibility and biomechanical property. Combination of tissue engineering technology with 3D printing technology shows a broad prospect in cranioplasty.