3D生物打印在软骨修复中的应用*

关节软骨损伤后的自我修复是医学界一直在研究和探讨的难题。3D生物打印技术可以精准的分配载细胞生物材料,构建复杂的三维活体组织,在优化软骨缺损修复组织的内部结构、机械性能以及生物相容性上有很大优势,因此近年来成为软骨修复组织工程领域的研究热点。重点介绍了软骨生物3D生物打印的最新进展,包括软骨生物打印“墨水”材料的选择、种子细胞的来源以及3D生物打印技术的发展。此外,还阐述了3D生物打印技术在组织工程学应用上的部分局限性,并对其在软骨修复领域的发展与应用进行了预测。     

3D打印的医用材料在组织修复与治疗中的应用

当前由于交通和运动事故频发、骨肿瘤等疾病导致骨缺损、皮肤创伤不断加重等情况使病例日益增多，临床对修复材料的需求也逐年增加。不同临床修复材料的特性不同，而3D打印技术作为一项新型数字化成型技术，可与临床计算机断层扫描、磁共振成像等结合，利用计算机辅助设计个性化植入物，实现对孔隙结构的精准控制，设计出与患者受损区域几乎完全相同的三维多孔高活性修复材料，以实现精准医疗和个性化医疗。文章综述了近年来运用3D打印技术制备生物医用材料在组织修复与治疗方面的研究进展，包括生物材料的配方、制备原理及制备方法，并总结了3D生物打印技术的局限性和面临的挑战。     

基于专利信息分析的中国3D生物打印技术发展与产业化研究*

目的:基于专利信息对我国3D生物打印技术的发展态势进行分析。方法:本文基于incopat和TDA两大专利分析平台对中国3D生物打印的专利发展态势从专利统计分析与专利计量分析两个维度进行了跨库组合分析,总结了我国3D生物打印技术的专利前沿动态特征。结果:研究发现,中国3D生物打印技术从2013年起进入专利激增态势,中国作为潜在技术市场的国际竞争日趋激烈,本文还从专利申请人、技术领域分布、专利文本关键词聚类、专利价值、专利合作等方面进行了深度挖掘分析。结论:最后,结合对中国3D生物打印专利申请人的专利产业化案例深度分析与专利特征总结,为中国3D生物打印技术发展与产业化提供参考建议。     

生物三维打印的研究进展

三维(3D)打印具有灵活性和精密性的特点,已在军工、航天等制造行业中发挥重要作用.随之兴起的生物3D打印在再生医学领域同样具有广泛的应用前景.生物3D打印是将打印的墨水改成含有活细胞的混合物,从而构建活体组织器官.目前生物3D打印更多的是应用于硬组织的仿生重建和新型给药装置的制备,但具有生物活性、更复杂的组织器官的重建还处于探索阶段.本文主要对3D打印在生物医学上的应用进行综述,讨论生物3D打印目前面临的问题,并探讨生物3D打印的未来发展方向.     

脱细胞基质生物墨水制备方法及应用进展

组织器官脱细胞后制备成的脱细胞基质 (Decellularized extracellular matrix,dECM) 含有许多蛋白质和生长因子,不仅能够为细胞提供三维支架还能够调控细胞再生,是目前最具有生物结构的生物材料。3D生物打印可以层层打印dECM和自体细胞的组合,构建载细胞组织结构。文中综述了不同来源的组织器官脱细胞基质生物墨水制备方法,包括脱细胞、交联等,以及脱细胞基质生物墨水在生物打印中的应用,并展望了其未来的应用前景。     

生物4D打印技术在心血管组织工程中的研究及应用进展

3D生物打印技术是应用包含生物材料与活细胞在内的生物墨水来构造生物医学产品的技术，近年来得到快速发展。3D打印的组织是静态的，而人体的组织则处于实时动态之中，并且随时能够发生形态及性能的变化，要提高体外环境与体内真实环境的吻合度，就需要一种能够模拟这种动态过程的体外组织构建技术。4D打印概念的提出，给实现这种复杂技术提供了一条新的思路。4D打印可理解为“3D打印+时间”，在3D打印基础上，4D打印应用一种或多种对刺激具有响应的智能材料，这种材料可以在相应的刺激下改变它们的形态、性能及功能，以满足多种需求。本文重点关注4D打印技术在心血管系统中的最新研究进展及其潜在应用领域，为该项技术的发展提供一些理论及应用参考价值。     

多环芳烃污染土壤生物修复研究进展

多环芳烃 (Polycyclic aromatic hydrocarbons,PAHs) 是一类广泛分布于环境中的持久性污染物,结构稳定、难以降解,对生态环境和生物具有“三致”毒害性,其环境去除和修复备受关注。绿色、安全、经济的生物修复技术被广泛应用于PAHs污染土壤的修复。本文从土壤中PAHs的来源、迁移、归趋和污染水平总结了目前我国土壤多环芳烃污染的基本状况;归纳了具有PAHs降解作用的微生物、植物种类及机理;比较了微生物修复、植物修复和联合修复3类主要的生物修复技术。指出植物与微生物的互作机理的解析,抗逆菌株、植株的筛选与培育,实际应用的安全和效能评估应成为多环芳烃污染土壤修复领域未来的研究方向。     

基于专利分析的3D生物打印产业发展态势研究

目的:揭示3D生物打印产业技术研发态势和专利布局,以期为相关机构提供竞争情报,为行业发展提供数据支撑。方法:基于3D生物打印领域产业调研和技术分解,构造检索式获取数据,多维度量化分析领域专利。结果:3D生物打印产业发展可分为孕育期、萌芽期和高速发展期;该产业集中度较低,处于分散竞争阶段;申请人多依据地缘因素选择合作对象,合作方之间多为不同类型的机构;中国申请人的专利申请量占全球的比重已接近50%,但美国申请人的专利篇均被引频次仍远超中国;美国申请人更关注海外市场。结论:3D生物打印产业尚未形成规模效应,有必要整合业内资源,打造产业集群;中、美两国在该产业都具有优势地位,中国亟待加强海外专利布局;综合权衡专利数量和质量,美国申请人的专利竞争力仍高于中国,中国需培育更多核心专利。     

微生物表面展示技术及其在环境污染治理中的应用

微生物表面展示技术是通过基因工程手段,将短的外源肽或蛋白质表达在微生物细胞表面,该技术可以应用于开发活的细菌疫苗、筛选抗体库、生产生物细胞吸附剂以及制备整细胞生物催化剂。通过金属高效结合肽的肽库筛选和微生物展示技术,将金属结合肽直接展示在微生物的表面,用于处理环境中的重金属污染,为环境中重金属污染的防治提供了一条崭新的途径。利用微生物表面展示技术制备整细胞催化剂,用于有毒有机污染物的处理,可以极大地加快污染物的降解速率。简要介绍了微生物表面展示技术及其在重金属污染治理和毒性有机污染物的脱毒等环境生物修复方面的最新研究进展。     

微生物菌剂在难降解有机污染治理的研究进展

大量的难降解有机污染物被排放到环境中,因其蓄积性、持久性和生物毒性,对人类健康和生态环境造成严重危害。近年来,利用微生物菌剂治理难降解有机污染物的研究已取得较好的进展。综述微生物菌剂在国内外的发展历程,介绍微生物菌剂制备中常用的固定化技术及载体材料,并分析总结微生物菌剂在酚类物质、多环芳烃和多氯联苯等有机污染物治理中的研究进展。在此基础上,提出治理难降解有机污染物的微生物菌剂研发所存在的主要问题及其展望。     

Enthusiastic portrayal of 3D bioprinting in the media: Ethical side effects

There has been a surge in mass media reports extolling the potential for using three‐dimensional printing of biomaterials (3D bioprinting) to treat a wide range of clinical conditions. Given that mass media is recognized as one of the most important sources of health and medical information for the general public, especially prospective patients, we report and discuss the ethical consequences of coverage of 3D bioprinting in the media. First, we illustrate how positive mass media narratives of a similar biofabricated technology, namely the Macchiarini scaffold tracheas, which was involved in lethal experimental human trials, influenced potential patient perceptions. Second, we report and analyze the positively biased and enthusiastic portrayal of 3D bioprinting in mass media. Third, we examine the lack of regulation and absence of discussion about risks associated with bioprinting technology. Fourth, we explore how media misunderstanding is dangerously misleading the narrative about the technology.     

Three-dimensional printing biotechnology for the regeneration of the tooth and tooth-supporting tissues

The tooth and its supporting tissues are organized with complex three-dimensional (3D) architecture, including the dental pulp with a blood supply and nerve tissues, complex multilayer periodontium, and highly aligned periodontal ligament (PDL). Mimicking such 3D complexity and the multicellular interactions naturally existing in dental structures represents great challenges in dental regeneration. Attempts to construct the complex system of the tooth and tooth-supporting apparatus (i.e., the PDL, alveolar bone, and cementum) have made certain progress owing to 3D printing biotechnology. Recent advances have enabled the 3D printing of biocompatible materials, seed cells, and supporting components into complex 3D functional living tissue. Furthermore, 3D bioprinting is driving major innovations in regenerative medicine, giving the field of regenerative dentistry a boost. The fabrication of scaffolds via 3D printing is already being performed extensively at the laboratory bench and in clinical trials; however, printing living cells and matrix materials together to produce tissue constructs by 3D bioprinting remains limited to the regeneration of dental pulp and the tooth germ. This review summarizes the application of scaffolds for cell seeding and biofabricated tissues via 3D printing and bioprinting, respectively, in the tooth and its supporting tissues. Additionally, the key advantages and prospects of 3D bioprinting in regenerative dentistry are highlighted, providing new ideas for dental regeneration.     

Three-dimensional bioprinting of stem cell-derived central nervous system cells enables astrocyte growth,vasculogenesis, and enhances neural differentiation/function

Current research tools for preclinical drug development such as rodent models and two-dimensional immortalized monocultures have failed to serve as effective translational models for human central nervous system (CNS) disorders. Recent advancements in the development of induced pluripotent stem cells (iPSCs) and three-dimensional (3D) culturing can improve the in vivo-relevance of preclinical models, while generating 3D cultures though novel bioprinting technologies can offer increased scalability and replicability. As such, there is a need to develop platforms that combine iPSC-derived cells with 3D bioprinting to produce scalable, tunable, and biomimetic cultures for preclinical drug discovery applications. We report a biocompatible poly(ethylene glycol)-based matrix which incorporates Arg-Gly-Asp and Tyr-Ile-Gly-Ser-Arg peptide motifs and full-length collagen IV at a stiffness similar to the human brain (1.5 kPa). Using a high-throughput commercial bioprinter we report the viable culture and morphological development of monocultured iPSC-derived astrocytes, brain microvascular endothelial-like cells, neural progenitors, and neurons in our novel matrix. We also show that this system supports endothelial-like vasculogenesis and enhances neural differentiation and spontaneous activity. This platform forms a foundation for more complex, multicellular models to facilitate high-throughput translational drug discovery for CNS disorders.     

细胞打印技术及应用

细胞打印技术是一种在体外构造具有生物活性的三维多细胞体系的先进技术。近年来,有关细胞打印技术的研究引起广泛的关注,其原因在于该领域具有明显的学科交叉与渗透融合的特点,它处于生命科学与快速成型技术、生物制造技术、生物科学和材料科学的交汇点。更加值得关注的是它为组织工程学突破二维研究的局限性,在三维尺度上精确控制与人体组织或器官相似的三维构造体方面的研究提供了一种新的思路。基于这一技术不仅在三维组织工程,还对细胞生物学、高通量药物筛选及细胞传感器等方面的前沿问题均有广阔的研究应用前景,介绍了近年来开发用于细胞打印的技术及其潜在的应用。     

Engineering inkjet bioprinting processes toward translational therapies

Bioprinting is the assembly of three-dimensional (3D) tissue constructs by layering cell-laden biomaterials using additive manufacturing techniques, offering great potential for tissue engineering and regenerative medicine. Such a process can be performed with high resolution and control by personalized or commercially available inkjet printers. However, bioprinting's clinical translation is significantly limited due to process engineering challenges. Upstream challenges include synthesis, cellular incorporation, and functionalization of “bioinks,” and extrusion of print geometries. Downstream challenges address sterilization, culture, implantation, and degradation. In the long run, bioinks must provide a microenvironment to support cell growth, development, and maturation and must interact and integrate with the surrounding tissues after implantation. Additionally, a robust, scaleable manufacturing process must pass regulatory scrutiny from regulatory bodies such as U.S. Food and Drug Administration, European Medicines Agency, or Australian Therapeutic Goods Administration for bioprinting to have a real clinical impact. In this review, recent advances in inkjet-based 3D bioprinting will be presented, emphasizing on biomaterials available, their properties, and the process to generate bioprinted constructs with application in medicine. Current challenges and the future path of bioprinting and bioinks will be addressed, with emphasis in mass production aspects and the regulatory framework bioink-based products must comply to translate this technology from the bench to the clinic.     

Essential steps in bioprinting: From pre- to post-bioprinting

An increasing demand for directed assembly of biomaterials has inspired the development of bioprinting, which facilitates the assembling of both cellular and acellular inks into well-arranged three-dimensional (3D) structures for tissue fabrication. Although great advances have been achieved in the recent decade, there still exist issues to be addressed. Herein, a review has been systematically performed to discuss the considerations in the entire procedure of bioprinting. Though bioprinting is advancing at a rapid pace, it is seen that the whole process of obtaining tissue constructs from this technique involves multiple-stages, cutting across various technology domains. These stages can be divided into three broad categories: pre-bioprinting, bioprinting and post-bioprinting. Each stage can influence others and has a bearing on the performance of fabricated constructs. For example, in pre-bioprinting, tissue biopsy and cell expansion techniques are essential to ensure a large number of cells are available for mass organ production. Similarly, medical imaging is needed to provide high resolution designs, which can be faithfully bioprinted. In the bioprinting stage, compatibility of biomaterials is needed to be matched with solidification kinetics to ensure constructs with high cell viability and fidelity are obtained. On the other hand, there is a need to develop bioprinters, which have high degrees of freedom of movement, perform without failure concerns for several hours and are compact, and affordable. Finally, maturation of bioprinted cells are governed by conditions provided during the post-bioprinting process. This review, for the first time, puts all the bioprinting stages in perspective of the whole process of bioprinting, and analyzes their current state-of-the art. It is concluded that bioprinting community will recognize the relative importance and optimize the parameter of each stage to obtain the desired outcomes.     

Scaffold‐free inkjet printing of three‐dimensional zigzag cellular tubes

The capability to print three‐dimensional (3D) cellular tubes is not only a logical first step towards successful organ printing but also a critical indicator of the feasibility of the envisioned organ printing technology. A platform‐assisted 3D inkjet bioprinting system has been proposed to fabricate 3D complex constructs such as zigzag tubes. Fibroblast (3T3 cell)‐based tubes with an overhang structure have been successfully fabricated using the proposed bioprinting system. The post‐printing 3T3 cell viability of printed cellular tubes has been found above 82% (or 93% with the control effect considered) even after a 72‐h incubation period using the identified printing conditions for good droplet formation, indicating the promising application of the proposed bioprinting system. Particularly, it is proved that the tubular overhang structure can be scaffold‐free fabricated using inkjetting, and the maximum achievable height depends on the inclination angle of the overhang structure. As a proof‐of‐concept study, the resulting fabrication knowledge helps print tissue‐engineered blood vessels with complex geometry. Biotechnol. Bioeng. 2012; 109: 3152–3160. © 2012 Wiley Periodicals, Inc.