Copyright © 2018 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited. Three Dimensional Printed Bone Implants in the Clinic Nazzar Tellisi, MBBCh, FRCS (Tr, Ortho),  Nureddin A. Ashammakhi, MD, PhD, yz§jj Fabrizio Billi, PhD, ô and Outi Kaarela, MD, PhD z Abstract: Implants are being continuously developed to achieve personalized therapy. With the advent of 3-dimensional (3D) printing, it is becoming possible to produce customized precisely fitting implants that can be derived from 3D images fed into 3D printers. In addition, it is possible to combine various materials, such as ceramics, to render these constructs osteoconductive or growth factors to make them osteoinductive. Constructs can be seeded with cells to engineer bone tissue. Alternatively, it is possible to load cells into the biomaterial to form so called bioink and print them together to from 3D bioprinted constructs that are characterized by having more homogenous cell distribution in their matrix. To date, 3D printing was applied in the clinic mostly for surgical training and for planning of surgery, with limited use in producing 3D implants for clinical application. Few examples exist so far, which include mostly the 3D printed implants applied in maxillofacial surgery and in orthopedic surgery, which are dis- cussed in this report. Wider clinical application of 3D printing will help the adoption of 3D printers as essential tools in the clinics in future and thus, contribute to realization of personalized medicine. Key Words: 3D printing, bioprinting, personalized medicine, tissue engineering (J Craniofac Surg 2018;00: 00–00) B one defects may result from congenital disorders, or they may follow trauma, disease, or surgical resection. They need recon- struction to resume function and restore shape. The gold standard of reconstructing bone defects has been the use of bone grafts. 1 However, these suffer from limited availability, donor-site morbid- ity, and associated risks. 2 Bone substitute materials were thus developed to reconstruct bone defects but they suffer from limited success due to failure to integrate and remodel, infection, 3 inflam- mation, and pain. 4 With the advent of tissue engineering, it was hoped that living grafts can be made in the laboratory by using cell- seeded scaffolds. 5 However, it was difficult to produce scaffolds with controlled structure and homogenous cell distribution. 6 The technique of three-dimensional (3D) printing was originally invented in 1986 7 and was later used to produce scaffolds with controlled structure. 8 Furthermore, cells mixed with a biomaterial to form bioink for 3D bioprinting in which cells can homogeneously be distributed in the resulting constructs. 9 In the reconstruction procedures of complex craniomaxillofacial (CMF) skeleton, with irregular defects, it is difficult to adapt available implants, and thus, the fabrication of patient-tailored devices is needed. With the use of 3D printing, the production of customized implants becomes achievable. Although the technology has been proved in many studies in vitro 10–16 and in vivo 17–19 employing various types of biomaterials, its translation to the clinic has not advanced with the same pace because of many reasons, including the lack of efficacy and complicated approval procedures. EVOLUTION OF 3D PRINTING 3D Printing For 3D printing, various types of biomaterials were used including metals and polymers. To render 3D constructs osteoconductive, 20 ceramics such as hydroxyapatite, 19,21–23 tricalcium phosphate (TCP), 17,24 biphasic calcium phosphate, 18,24,25 nano-silicate, 26 silica, and bioactive glass 27 were used. The use of biodegradable materials alleviated the problems and risks associated with the use of biostable materials such as infection, cold sensitivity, interference with imag- ing, risk of pseudomigration, problem in the growing skulls of children, and restriction of growth. 28,29 In addition, biodegradable materials can be combined with growth factors, 30 cells, and drugs. The 3D biodegradable materials may be produced at the point of care in future because it can be a less demanding fabrication process as compared to 3D printing of metals. 3D Bioprinting For bioprinting, gels are usually used to contain cells in a pregel liquid with subsequent gelation achieved by using crosslinking methods which can be chemical, 10,31–34 physical, 7,10,26,35 or com- bination of them, depending on the type of the material. However, using hydrogels 23,25,32,36,37 allows for fabricating of constructs with only limited number of layers, as the weight building up may lead to collapse of the structure. Thus, various support and reinforcement methods were employed such as the use of bioceramics, 32,38 nanofibers in the structure 39,40 (Fig. 1), struts, 42 or external poly- meric frames or other temporary support. 17 Most 3D bioprinted biodegradable constructs last for only few weeks which may limit their application in the clinic. For example, gelatine methacryloyl constructs last for a maximum of 3 weeks on average because they are degraded. 26 Cell-laden silk fibroin gelatin constructs were unstable after 21 days. When modified with methacrylic anhydride, hyaluronic acid was found to last for almost 38 days 43 (Fig. 2). When bone-marrow-derived stem-cell-laden TCP-containing From the  Chapel Allerton Hospital, Leeds Teaching Hospitals, Leeds, UK; y Department of Bioengineering, University of California at Los Angeles, Los Angeles, CA; z Division of Plastic Surgery, Department of Surgery, Oulu University Hospital, Oulu; § School of Technology and Innovations, University of Vaasa, Vaasa, Finland; jj Biotechnology Research Center, Authority for Natural Sciences Research and Technol- ogy, Tripoli, Libya; and ô Department of Orthopaedic Surgery, David Geffen School of Medicine, Orthopaedic Hospital Research Center, University of California at Los Angeles, Los Angeles, CA. Received May 20, 2018. Accepted for publication June 15, 2018. Address correspondence and reprint requests to Nureddin A. Ashammakhi, MD, PhD, Department of Biotechnology, Samueli School of En- gineering, University of California at Los Angeles, Los Angeles, CA; E-mail: n.ashammakhi@ucla.edu NT and NA contributed equally to this study and both are considered as first authors. The authors report no conflicts of interest. Copyright # 2018 by Mutaz B. Habal, MD ISSN: 1049-2275 DOI: 10.1097/SCS.0000000000004829 SCIENTIFIC FOUNDATION The Journal of Craniofacial Surgery  Volume 00, Number 00, Month 2018 1