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J. Stampfl:
"Bioprinter (3D-Drucker für Gewebe und Organe) in der Medizin - aktueller Stand";
Talk: Symposium Intensivmedizin und Intensivpflege, Bremen; 02-24-2016 - 02-26-2016.

Additive manufacturing technologies (AMT) have great potential for shaping 3D-structures with high shape complexity and high resolution. With the development of easy-to-use sys-tems exhibiting sufficiently fast build-speeds and decreased system prizes, AMT has moved from the arena of niche-manufacturing processes into the spotlight of a much larger audi-ence.
Additive Manufacturing Technologies is the currently used standardized term for all process-es (ASTM F2792), where 3D-structures are fabricated by adding material in form of thin lay-ers to finally obtain the targeted geometry. In literature, the terms Rapid Prototyping, Layered Manufacturing, Solid Freeform Fabrication 3D-Fabbing and 3D-printing are used synony-mously. In this work, the terms AMT and 3D-printing will be used to describe the general manufacturing principle.
AMT is capable of shaping individual geometries on demand, without the requirement of ex-pensive tooling. This makes AMT the ideal manufacturing process for applications in medi-cine and biomedical engineering, where customized, patient specific geometries are of high benefit. Fields of applications with current clinical use include the fabrication of drill guides for implantology and maxillo-facial surgery [1] as well as models [2] for digital dentistry. It is estimated that around 50 000 patients are treated every year using 3D-printed surgical plan-ning instruments [3]. For these applications, the required level regarding biocompatibility, bio-functional and structural (mechanical) properties of the used materials is achievable with currently available materials. The challenge is rather to provide structures with sufficient pre-cision and resolution at low cost.
From a commercial point of view, the probably most successful case of AMT in biomedical applications are invisible aligners [4] for orthodontics, where currently millions of parts are fabricated every year. In the case of invisible aligners, the 3D-printed geometry is moulded into a biocompatible thermoplastic material, which is then shipped to the patient. This means, again, that the requirements for this application are more on the side of geometrical and eco-nomic challenges.
A field of increasing clinical interest is the use of titanium implants made by selective laser sintering (SLS) or electron beam melting (EBM). SLS and EBM offer the possibility to use a clinically proven material (titanium) and provide implants with customized geometries [5]. Due to the use of titanium, even load-bearing applications can be targeted. AMT of titanium also simplifies the preparation of surfaces with mechanical retentions which potentially im-proves the in-growth of bone. Since more than 30 000 patients have been treated with EBM-implants alone, it can be claimed that titanium-based AMT implants are becoming an estab-lished method in orthopaedic surgery.
An even more attractive (but also more challenging) idea is to use AMT to fabricate cellular, biodegradable scaffolds for tissue engineering [6]. A significant number of research projects has been undertaken in this direction, with a focus on using material extrusion (e.g. fused deposition modelling, FDM) to fabricate cellular structures made of (degradable) thermo-plastic biopolymers like polylactic acid and polycaprolactone. An alternative route was to re-ly on binder jetting for manufacturing cellular scaffolds made of bioceramics (e.g. calcium phosphates). Both routes led to the development of commercial products, with a focus on hard-tissue regeneration. But the clinical impact of these developments did not meet the orig-inal very high expectations. A possible reason for this might be related to the limited defect size that can be treated with these initially rather simple scaffolds. Using classical, well estab-lished bone-replacement materials (e.g. bovine derived xenografts, bioceramic foams, colla-gen fleece, ...) very similar clinical outcome can be achieved. Therefore the motivation to es-tablish new, more complex repair systems based on AMT is rather low.
For the regeneration of larger defects or more complicated tissue constructs (e.g. osteochon-dral scaffolds for the treatment of osteoarthritis) it is obviously not sufficient, to just provide a 3D-printed cellular construct. Among other things, it will be necessary to incorporate 3D-functionalities to trigger sufficient vascularization. In order to better mimic the biological conditions in multi-tissue constructs (e.g. the zonal organization of cartilage-bone constructs) [7] it will also be necessary to have a closer look, how the micro- and nano-morphology of the scaffold material influences cell behaviour. AMT provides an excellent tool-set for de-veloping and systematically investigating these next-generation scaffold structures.
With the recently gained knowledge about the importance of the influence of the 3D-micro-environment [8] surrounding the cells, the relevance of manufacturing systems being capable of providing such a defined 3D-environment will certainly grow in the coming years.
An even more visionary strategy, compared to providing functional scaffolds for tissue re-generation, is the printing of whole organs. With the development of inkjet-based systems ca-pable of depositing living cells [9] a completely new route for engineering living tissue was opened. Initially systems based on household inkjetting devices [10] with a focus on increas-ing throughput were used. In recent years, a whole industry has emerged around the devel-opment of dedicated bio-inkjetting and bioplotting systems. Despite the fact that amazing re-sults have been achieved in this field, it has to be noted that alternative approaches (e.g. by utilizing decellularized biological matrices [11]) have also shown astonishing results, and are probably even closer to clinical applications compared to 3D-bioplotted constructs.
References
[1] D´haese J, Van De Velde T, Komiyama A, Hultin M, De Bruyn H. Accuracy and Com-plications Using Computer-Designed Stereolithographic Surgical Guides for Oral Reha-bilitation by Means of Dental Implants: A Review of the Literature. Clin Implant Dent Relat Res 2012;14:321-35. doi:10.1111/j.1708-8208.2010.00275.x.
[2] Kasparova M, Grafova L, Dvorak P, Dostalova T, Prochazka A, Eliasova H, et al. Pos-sibility of reconstruction of dental plaster cast from 3D digital study models. Biomed Eng Online 2013;12. doi:10.1186/1475-925X-12-49.
[3] Wohlers T, Caffrey T. Wohlers Report- Additive Manufacturing and 3D printing state of the industry. 2013.
[4] Kravitz ND, Kusnoto B, BeGole E, Obrez A, Agran B. How well does Invisalign work? A prospective clinical study evaluating the efficacy of tooth movement with Invisalign. Am J Orthod Dentofacial Orthop 2009;135:27-35. doi:10.1016/j.ajodo.2007.05.018.
[5] Moin DA, Hassan B, Mercelis P, Wismeijer D. Designing a novel dental root analogue implant using cone beam computed tomography and CAD/CAM technology. Clin Oral Implants Res 2013;24:25-7. doi:10.1111/j.1600-0501.2011.02359.x.
[6] Hutmacher DW, Sittinger M, Risbud MV. Scaffold-based tissue engineering: rationale for computer-aided design and solid free-form fabrication systems. Trends Biotechnol 2004;22:354-62. doi:10.1016/j.tibtech.2004.05.006.
[7] Woodfield TBF, Blitterswijk CAV, Wijn JD, Sims TJ, Hollander AP, Riesle J. Polymer Scaffolds Fabricated with Pore-Size Gradients as a Model for Studying the Zonal Organ-ization within Tissue-Engineered Cartilage Constructs. Tissue Eng 2005;11:1297-311. doi:10.1089/ten.2005.11.1297.
[8] Lutolf MP, Hubbell JA. Synthetic biomaterials as instructive extracellular microenvi-ronments for morphogenesis in tissue engineering. Nat Biotechnol 2005;23:47-55. doi:10.1038/nbt1055.
[9] Mironov V, Boland T, Trusk T, Forgacs G, Markwald RR. Organ printing: computer-aided jet-based 3D tissue engineering. Trends Biotechnol 2003;21:157-61. doi:10.1016/S0167-7799(03)00033-7.
[10] Xu T, Jin J, Gregory C, Hickman JJ, Boland T. Inkjet printing of viable mammalian cells. Biomaterials 2005;26:93-9. doi:10.1016/j.biomaterials.2004.04.011.
[11] Ott HC, Matthiesen TS, Goh S-K, Black LD, Kren SM, Netoff TI, et al. Perfusion-decellularized matrix: using nature´s platform to engineer a bioartificial heart. Nat Med 2008;14:213-21. doi:10.1038/nm1684.