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Bio-Design and Manufacturing

, Volume 1, Issue 4, pp 280–288 | Cite as

Research center of biomanufacturing in Xi’an Jiaotong University

  • Ling Wang
  • Dichen Li
  • Jiankang He
  • Bingheng Lu
Laboratory Report

Overview

Xi’an Jiaotong University (XJTU) has carried out the research of additive manufacturing (AM) since 1993, who is one of the earliest institutes majoring in AM. After 20 years of effort, XJTU has made great progress on the additive manufacturing of polymer, metals, ceramics, composite materials and intelligent materials. XJTU has established a research team that features the engineering application of rapid manufacturing system. A Ministry of Education’s innovative team, which is academically leaded by Prof. Bingheng Lu, was formed in the field of AM. The basic research was supported by the State Key Laboratory of Manufacturing System Engineering (XJTU). XJTU has won a second prize of the State Award for Scientific and Technological Progress, three second prizes of State Award for Technological Invention and four first prizes of ministerial and provincial science and technology award in the field of AM. XJTU has more than 300 invention patents about AM.

Supported by National Natural Science Foundation (NSFC) of China, XJTU took the lead in the development of biofabrication. The first customized mandibular substitute surgery in the world was carried out by XJTU in 2001. In the research of customized bone substitutes, the problem of personalized precise adaptation was solved, and an in situ design methodology was proposed for customized craniomaxillofacial substitutes to promote bone in-growth. XJTU developed an integrated technology of bionic design and manufacturing technology for craniomaxillofacial substitutes. Based on this technology, specialized 3D printing equipment has been developed and commercialized, thousands of clinical cases have been carried out, and good physiological functions of patients have been restored. The research achievement on ‘Design and Manufacturing Technology of Customized Craniomaxillofacial Implants’ has won the second prize of State Award for Technological Invention in 2014 and the golden prize of the first ‘Good Design in China’ in 2015.

XJTU has also carried out the research on 3D printing of polyetheretherketone (PEEK) orthopedic implants and implemented the world’s first clinical trial of 3D-printed PEEK rib and heart plate implants. Focusing on the controllable fabrication of the typical soft and hard tissue of the human body (liver, bone), the microvascular gradient structure of soft and hard tissue fixation interface (ligament/cartilage/bone), systematic research work was carried out at three levels: the theoretical basis of bionic design, the additive manufacturing method of macro-/microstructure and the mechanisms of microstructure promoting tissue regeneration. Moreover, the 4D printing technology has been developed for the biofabricate of degradable tracheal stent and breast scaffold implant and the first international clinical trial was implemented, which stimulated the development of biofabricating technology of biodegradable engineering tissue and organ develops from benchwork to clinical applications. The academic achievements were quoted and positively evaluated by many international scholars. Finally, XJTU has achieved the very first CFDA registration certificate of customized implant in China, which is a milestone in the industrialization of 3D bioprinting technology in China.

Research directions

Design and 3D printing technology of customized PEEK orthopedic implant

The 3D printing technology of PEEK is based on the biomaterials of polyetheretherketone and was used to manufacture the high-performance customized orthopedic implants. The team has developed a 3D printing technology of property-controlled cold deposition and the corresponding intelligent process, which can produce PEEK component with adjustable properties (stiffness and modulus). Based on that, the rapid manufacturing of high-performance, low-cost, high-precision PEEK orthopedic implants can be achieved. The relative techniques take the leading position world widely, and the clinical application was implemented in Xi’an in 2017, noted as the world’s first 3D-printed PEEK ribs. Moreover, the team has won the second prize at Solvay AM Cup for the best precision of printing [1].

Software developed for customized orthopedic implants (OrthoDesign)

To solve the existed problem of the current designing methodology for the design of customized prosthesis, lack of the ability of biomechanical analysis and the standard operational procedure (SOP), a software was developed by integrating five modulus of: reconstruction of the bone, implants, bone/prosthesis assembly, optimization analysis, and microstructural modeling, to realize the rapidly intelligent design in both of the macro-level (geometry) and the micro-level (microstructural design) of customized medical prosthesis. The CAD file of the designed prosthesis can be directly used for 3D printing manufacturing. Most importantly, the optimized microstructural design can improve the long-term stability of the implants with excellent bone in-growth [2, 3, 4, 5, 6].

3D printing technology for repairing articular cartilage defects

This technique aims for repairing the large-scale bone/cartilage defects, based on the intra-articular biomechanics and biological environment of the joint, to meet the demands of designing, manufacturing and functional evaluation for multi-material and multi-level bone/cartilage scaffold. The development of manufacturing technology and functional evaluation technique for bone/cartilage substitute has provided good scientific foundation and engineering implementation for the biofabrication of artificial living joint tissue with improved mechanical and biological properties [7, 8, 9, 10, 11, 12, 13, 14, 15, 16].
A precise stereolithography (SLA) additive manufacturing technology was developed in this group for the biofabrication of multi-material and multi-scale scaffold, and the experimental platform and equipment were built in-house for manufacturing of large-scale bionic scaffold. The equipment is developed with a new printing processing system of SLA ceramic slurry, to realize a continuous printing technique with no obvious layer structure. At present, this technology has an automatic feedback strategy to control the printing defects during the forming process, based on that two sets of complete 3D printing processes and the corresponding experimental prototypes were developed allowing the fast manufacturing of bionic scaffolds with high precision and complex geometry at the maximum printing size of 30 mm × 30 mm × 30 mm. An in vitro culture and functional evaluation system has been developed to adopt the biomechanical and physiological environment of joint. Animal studies (rabbits, dogs and sheep) were also carried out to validate the effectiveness of the design and manufacturing for osteochondral composite scaffolds.

Biofabrication and clinical application of biodegradable customize implant

The team also majored in the 3D printing of biodegradable materials for the application of breast tissue replacement and tracheal scaffold. The system of bionic design and 3D printing technology has been established for biofabrication of flexible biodegradable soft tissue scaffold, and collaborated with Xijing Hospital of the Fourth Military Medical University, the first international clinical trial of a customized biodegradable flexible breast stent was implemented. Up to date, 14 clinical cases have been implemented with good clinical outcome. The implanted stent has formed good match to the morphology and mechanical properties of the host tissue, additionally, good self-repair mechanisms has also been achieved through the process of host tissue regeneration and scaffold degradation. This technique provides a novel way for breast-conserving treatment of breast cancer [17, 18, 19, 20, 21, 22, 23, 24, 25].
The team has also proposed a tracheal suspension surgery based on the printed biodegradable tracheal stent and has the first clinical application in China. Up until now, 4 clinical trials have been implemented with good clinical performance. Clinical trials were reported by CCTV7, CCTV10, Xinhua News Agency, People’s Daily and other special reports, and have received good social responses.

Multi-nozzle 3D cell-printing technology

The project focuses on the multi-cell in situ 3D printing technology, aiming for the biofabrication of multi-tissue such as vascular muscle. By taking the ink-jetting and extrusion-based 3D printing technologies as the core, a multi-nozzle 3D cell-printing equipment was developed in-house, for precise fabrication of soft tissue such as blood vessel, muscle or skin from the hydrogel-based composition of cells and bioactives via cross-linking. This has provided a novel solution for the challenges faced by tissue engineering for complex vascularization tissue construct and regeneration. The maximum printing size of the bespoke equipment is 100 mm × 100 mm × 100 mm, providing sterile surgical condition for the in situ printing. In addition, the multi-nozzle system is adaptable for various forming mechanisms of multiple materials, providing coaxial nozzle, spray nozzle and single-tube nozzle, fulfilled the printing requirement of hollow tube gel and microfilament gel at the range of 400–1200 µm [26, 27, 28, 29, 30, 31, 32, 33, 34].

Facilities

The biofabrication laboratory has many facilities including cell and tissue culture facilities such as cell culture incubator and clean hood, many types of cell and tissue printing equipment such as ink-jetting cell printer, multi-material extrusion-based printer and laser printer, all printers are bespoke in-house by the members themselves, and the printing cell types cover skin, heart, muscle, ligament, cartilage and bone tissue. In addition, the laboratory has also many equipment for functional evaluation of the printed scaffolds and tissue such as Inverted fluorescence microscope, SEM, micro-CT, and mechanical testing equipment such as materials testing machine, fatigue testing machine, hip/knee joint simulator. Therefore, most of the functional evaluation work can be done within the laboratory conveniently and high efficiently with the help of many laboratory assistants.

International collaboration

The team has built solid foundation with many international research centers in the past decade, including Ph.D. student exchange, visiting scholars and international program. Research centers include the Federal Materials Testing Center of Germany (BAM) in Berlin, UCL Orthopaedic Bioengineering Research Group within the Division of Surgery and Interventional Science, University College London, Biomaterials and Biomechanics Research Group, University of Las Palmas de Gran Canaria (ULPGC), University of Minho in Porto, and Russian Academy of Science. Agreements of collaboration have been signed with each individual partner, and in total of 18 co-publications were achieved on the basis of the collaboration.

References

  1. 1.
    Kang J, Wang L*, Yang C et al (2018) Custom design and biomechanical analysis of 3D printed PEEK rib prostheses. Biomech Model Mechanobiol 17(4):1083–1092CrossRefGoogle Scholar
  2. 2.
    Qin M, Liu Y, Wang L et al (2015) Design and optimization of the fixing plate for customized mandible implants. J Cranio-Maxillofac Surg 43(7):1296–1302CrossRefGoogle Scholar
  3. 3.
    Wang L, Yang W, Peng X et al (2015) Effect of progressive wear on the contact mechanics of hip replacements—does the realistic surface profile matter? J Biomech 48(6):1112–1118CrossRefGoogle Scholar
  4. 4.
    Sun C, Wang L, Wang Z et al (2015) Finite element analysis of a retrieved custom-made knee prosthesis. J Mech Med Biol 15(03):458–472CrossRefGoogle Scholar
  5. 5.
    Dong LL, Guo PN, Liu R et al (2017) Three-dimensional printing technology facilitates customized pelvic prosthesis implantation in malignant tumor surgery: a case report. Int J Clin Exp Med 10(7):11020–11025Google Scholar
  6. 6.
    Wang L, Kang J, Sun C et al (2017) Mapping porous microstructures to yield desired mechanical properties for application in 3D printed bone scaffolds and orthopaedic implants. Mater Des 133(Supplement C):62–68CrossRefGoogle Scholar
  7. 7.
    Bian W, Li D, Lian Q et al (2012) Fabrication of a bio-inspired beta-Tricalcium phosphate/collagen scaffold based on ceramic stereolithography and gel casting for osteochondral tissue engineering. Rapid Prototyp J 18(1):68–80CrossRefGoogle Scholar
  8. 8.
    Yi C, Li D, Jing W (2013) Using variable beam spot scanning to improve the efficiency of stereolithography process. Rapid Prototyp J 19(2):100–110CrossRefGoogle Scholar
  9. 9.
    Zhang W, Lian Q, Li D et al (2014) Cartilage repair and subchondral bone migration using 3D printing osteochondral composites: a one-year-period study in rabbit trochlea. Biomed Res Int 5:746138Google Scholar
  10. 10.
    Zhang W, Qin L, Li D et al (2015) The effect of interface microstructure on interfacial shear strength for osteochondral scaffolds based on biomimetic design and 3D printing. Mater Sci Eng, C 46:10–15CrossRefGoogle Scholar
  11. 11.
    Lan PH, Li XK, Fan XL et al (2016) Ceramic coating of a titanium alloy implant prevents cartilage damage due to localized cartilage defects. J Biomater Tissue Eng 6(8):602–612CrossRefGoogle Scholar
  12. 12.
    Wu X, Lian Q, Li D et al (2017) Tilting separation analysis of bottom-up mask projection stereolithography based on cohesive zone model. J Mater Process Technol 243:184–196CrossRefGoogle Scholar
  13. 13.
    Qin L, Yang F, Xin H et al (2017) Oxygen-controlled bottom-up mask-projection stereolithography for ceramic 3D printing. Ceram Int 43(17):14956–14961CrossRefGoogle Scholar
  14. 14.
    Chen X, Zhao G, Wu Y et al (2017) Cellular carbon microstructures developed by using stereolithography. Carbon 123:34–44CrossRefGoogle Scholar
  15. 15.
    He J, Jiang N, Qin T et al (2017) Microfiber-reinforced nanofibrous scaffolds with structure and material gradients to mimic ligament-to-bone interface. J Mater Chem B 5(43):8579–8590CrossRefGoogle Scholar
  16. 16.
    Blunn G, Tamaddon M, Liu C et al (2017) Intrinsic osteoinductivity of porous titanium scaffold for bone tissue engineering. Int J Biomater 2017:5093063Google Scholar
  17. 17.
    Mao M, He J, Liu Y et al (2012) Ice-template-induced silk fibroin–chitosan scaffolds with predefined microfluidic channels and fully porous structures. Acta Biomater 8(6):2175–2184CrossRefGoogle Scholar
  18. 18.
    He J, Wang Y, Liu Y et al (2013) Layer-by-layer micromolding of natural biopolymer scaffolds with intrinsic microfluidic networks. Biofabrication 5(2):025002CrossRefGoogle Scholar
  19. 19.
    Li X, He J, Bian W et al (2014) A novel silk-based artificial ligament and tricalcium phosphate/polyether ether ketone anchor for anterior cruciate ligament reconstruction - safety and efficacy in a porcine model. Acta Biomater 10(8):3696–3704CrossRefGoogle Scholar
  20. 20.
    He J, Qin T, Liu Y et al (2014) Electrospinning of nanofibrous scaffolds with continuous structure and material gradients. Mater Lett 137:393–397CrossRefGoogle Scholar
  21. 21.
    He J, Zhang W, Liu Y et al (2015) Design and fabrication of biomimetic multiphased scaffolds for ligament-to-bone fixation. Mater Sci Eng, C 50:12–18CrossRefGoogle Scholar
  22. 22.
    He J, Liu Y, Hao X et al (2012) Bottom-up generation of 3D silk fibroin–gelatin microfluidic scaffolds with improved structural and biological properties. Mater Lett 78(7):102–105CrossRefGoogle Scholar
  23. 23.
    He J, Xia P, Li D (2015) Development of melt electrohydrodynamic 3D printing for complex microscale poly (ε-caprolactone) scaffolds. Biofabrication 8(3):035008CrossRefGoogle Scholar
  24. 24.
    Li X, He J, Zhang W et al (2016) Additive manufacturing of biomedical constructs with biomimetic structural organizations. Materials 9(11):909CrossRefGoogle Scholar
  25. 25.
    Huang L, Wang L, He J et al (2016) Tracheal suspension by using 3-dimensional printed personalized scaffold in a patient with tracheomalacia. J Thorac Dis 8(11):3323–3328CrossRefGoogle Scholar
  26. 26.
    Liu Y, Li X, Qu X et al (2012) The fabrication and cell culture of three-dimensional rolled scaffolds with complex micro-architectures. Biofabrication 4(1):015004CrossRefGoogle Scholar
  27. 27.
    Zhao X, He J, Xu F et al (2016) Electrohydrodynamic printing: a potential tool for high-resolution hydrogel/cell patterning. Virtual Phys Prototyp 11(1):57–63CrossRefGoogle Scholar
  28. 28.
    He J, Xu F, Cao Y et al (2016) Towards microscale electrohydrodynamic three-dimensional printing. J Phys D Appl Phys 49(5):055504CrossRefGoogle Scholar
  29. 29.
    He J, Chen R, Lu Y et al (2016) Fabrication of circular microfluidic network in enzymatically-crosslinked gelatin hydrogel. Mater Sci Eng, C 59:53–60CrossRefGoogle Scholar
  30. 30.
    Zhang B, He J, Li X et al (2016) Micro/nanoscale electrohydrodynamic printing: from 2D to 3D. Nanoscale 8(34):15376–15388CrossRefGoogle Scholar
  31. 31.
    Qu XL, Xia P, He JK et al (2016) Microscale electrohydrodynamic printing of biomimetic PCL/nHA composite scaffolds for bone tissue engineering. Mater Lett 185:554–557CrossRefGoogle Scholar
  32. 32.
    Li X, Lian Q, Li DC et al (2017) Development of a robotic arm based hydrogel additive manufacturing system for in situ printing. Appl Sci Basel 7(1):73CrossRefGoogle Scholar
  33. 33.
    Mao M, He JK, Li X et al (2017) The emerging frontiers and applications of high-resolution 3D printing. Micromachines 8(4):113CrossRefGoogle Scholar
  34. 34.
    He J, Xu F, Dong R et al (2017) Electrohydrodynamic 3D printing of microscale poly (ε-caprolactone) scaffolds with multi-walled carbon nanotubes. Biofabrication 9(1):015007CrossRefGoogle Scholar

Copyright information

© Zhejiang University Press 2018

Authors and Affiliations

  • Ling Wang
    • 1
    • 2
  • Dichen Li
    • 1
    • 2
  • Jiankang He
    • 1
    • 2
  • Bingheng Lu
    • 1
    • 2
  1. 1.State Key Lab for Manufacturing System EngineeringXi’an Jiaotong UniversityXi’anChina
  2. 2.School of Mechanical EngineeringXi’an Jiaotong UniversityXi’anChina

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