Magnetic 3D bioprinting

Magnetic 3D bioprinting is a methodology that employs biocompatible magnetic nanoparticles to print cells into 3D structures or 3D cell cultures. In this process, cells are tagged with magnetic nanoparticles (nanoshuttle) that are used to render them magnetic.[1][2] Once magnetic, these cells can be rapidly printed into specific 3D patterns using external magnetic forces that mimic tissue structure and function.

General principle

There are several advantages to using magnetic 3D bioprinting over other 3D printing modalities such as extrusion, photolithography, and stereolithography. This includes the rapid bioprinting process (15 min – 1 h) compared to the days-long processes of others;[3][4] the endogenous synthesis of extracellular matrix (ECM) without the need of an artificial protein substrate and fine spatial control.[5][6][7] Using this system, 3D cell culture models can be rapidly printed from simple spheroids and rings to more complex organotypic models such as the lung,[5] aortic valve,[6] and white fat.[7]

History

The first commercially available 3D bioprinting system is being commercialized by Nano3D Biosciences, Inc. The first application of this system is for high-throughput and high-content drug screening.[8]

Process

The cells first need to be incubated in the presence of magnetic nanoparticles to make them more susceptible to manipulation through magnetic fields. The system developed by Nano3D Biosciences uses a "nanoshuttle" which is a nanoparticle assembly consisting of gold, magnetic iron oxide, and poly-L-lysine which assists in adhesion to the cell membrane via electrostatic interactions.[5] In this system, cells are magnetically printed into 3D patterns (rings or dots) using fields generated by permanent magnets. The cells within the printed construct interact with surrounding cells and the ECM to migrate, proliferate, and ultimately shrink the structure, typically within 24 hours.

When used as a toxicity assay, this shrinkage varies with drug concentration and is a label-free metric of cell function that can be easily captured and measured with brightfield imaging.[8] In the system developed by Nano3D Biosciences, the size of the pattern can be captured using an iPod-based system, which is programmed using a freely available app (Experimental Assistant) to image whole plates of up to 96 structures at small intervals (as small as one second) to efficiently capture pharmacodynamics.

Diamagnetophoresis

Cells can be assembled without using magnetic nanoparticles by employing diamagnetism. Some materials are strongly attracted, or susceptible, to magnets than others. Materials with higher magnetic susceptibility will experience stronger attraction to a magnet and move towards it. The weakly attracted material with lower susceptibility is displaced to lower magnetic field regions that lie away from the magnet. By designing magnetic fields and carefully arranged magnets, it is possible to use the differences in the magnetic susceptibilities of two materials to concentrate only one within a volume.

An example is to be found in the work where a bio-ink was formulated by suspending human breast cancer cells in a cell culture medium that contained the paramagnetic salt, diethylenetriaminepentaacetic acid gadolinium (III) dihydrogen salt hydrate (Gd-DTPA). Like most cells, these breast cancer cells are much more weakly attracted by magnets than Gd-DTPA, which is an FDA-approved MRI contrast agent for use in humans. Therefore, when a magnetic field was applied, the salt hydrate moved towards the magnets, displacing the cells to a predetermined area of minimum magnetic field strength, which seeded the formation of a 3D cell cluster.[9]

Application

Magnetic 3D bioprinting can be used to screen for cardiovascular toxicity, which accounts for 30% of drug withdrawals. [10] Vascular smooth muscle cells are magnetically printed into 3D rings to mimic blood vessels that can contract and dilate. This system could potentially replace experiments using ex vivo tissue, which are costly and yield few data per experiment. Furthermore, magnetic 3D bioprinting can use human cells to approximate a human in vivo response better than with an animal model. This has been demonstrated by the bioassay which combines the benefits of 3D bioprinting in building tissue-like structures for study with the speed of magnetic printing.

Users

The target users for magnetic 3D bioprinting are in the pharmaceutical and CRO industries, where this system can be integrated early in the drug discovery process as a compound screen for toxicity and efficacy. In the future, magnetic 3D bioprinting could be applied to the field of regenerative medicine and organogenesis.

See also

References
  1. Souza GR, Molina JR, Raphael RM, Ozawa MG, Stark DJ, Levin CS, Bronk LF, Ananta JS, Mandelin J, Georgescu MM, Bankson JA, Gelovani JG, Killian TC, Arap W, Pasqualini R (April 2010). "Three-dimensional tissue culture based on magnetic cell levitation". Nature Nanotechnology. 5 (4): 291–6. Bibcode:2010NatNa...5..291S. doi:10.1038/nnano.2010.23. PMC 4487889. PMID 20228788.
  2. Haisler WL, Timm DM, Gage JA, Tseng H, Killian TC, Souza GR (October 2013). "Three-dimensional cell culturing by magnetic levitation". Nature Protocols. 8 (10): 1940–9. doi:10.1038/nprot.2013.125. PMID 24030442. S2CID 24247462.
  3. Friedrich J, Seidel C, Ebner R, Kunz-Schughart LA (2009). "Spheroid-based drug screen: considerations and practical approach". Nature Protocols. 4 (3): 309–24. doi:10.1038/nprot.2008.226. PMID 19214182. S2CID 21783074.
  4. Seiler AE, Spielmann H (June 2011). "The validated embryonic stem cell test to predict embryotoxicity in vitro". Nature Protocols. 6 (7): 961–78. doi:10.1038/nprot.2011.348. PMID 21720311. S2CID 5643556.
  5. Tseng H, Gage JA, Raphael RM, Moore RH, Killian TC, Grande-Allen KJ, Souza GR (September 2013). "Assembly of a three-dimensional multitype bronchiole coculture model using magnetic levitation" (PDF). Tissue Engineering. Part C, Methods. 19 (9): 665–75. doi:10.1089/ten.tec.2012.0157. hdl:1911/70947. PMID 23301612. Archived from the original (PDF) on 2014-01-11. Retrieved 2014-01-10.
  6. Tseng H, Balaoing LR, Grigoryan B, Raphael RM, Killian TC, Souza GR, Grande-Allen KJ (January 2014). "A three-dimensional co-culture model of the aortic valve using magnetic levitation". Acta Biomaterialia. 10 (1): 173–82. doi:10.1016/j.actbio.2013.09.003. PMID 24036238.
  7. Daquinag AC, Souza GR, Kolonin MG (May 2013). "Adipose tissue engineering in three-dimensional levitation tissue culture system based on magnetic nanoparticles" (PDF). Tissue Engineering. Part C, Methods. 19 (5): 336–44. doi:10.1089/ten.tec.2012.0198. PMC 3603558. PMID 23017116. Archived from the original (PDF) on 2014-01-11. Retrieved 2014-01-11.
  8. Timm DM, Chen J, Sing D, Gage JA, Haisler WL, Neeley SK, et al. (October 2013). "A high-throughput three-dimensional cell migration assay for toxicity screening with mobile device-based macroscopic image analysis". Scientific Reports. 3: 3000. Bibcode:2013NatSR...3E3000T. doi:10.1038/srep03000. PMC 3801146. PMID 24141454.
  9. Mishriki S, Abdel Fattah AR, Kammann T, Sahu RP, Geng F, Puri IK (2019). "Rapid Magnetic 3D Printing of Cellular Structures with MCF-7 Cell Inks". Research. 2019: 9854593. doi:10.34133/2019/9854593. PMC 6750075. PMID 31549098.
  10. Gwathmey JK, Tsaioun K, Hajjar RJ (June 2009). "Cardionomics: a new integrative approach for screening cardiotoxicity of drug candidates". Expert Opinion on Drug Metabolism & Toxicology. 5 (6): 647–60. doi:10.1517/17425250902932915. PMID 19442031. S2CID 37441896.

Further reading
  • Tran J (2015). "To Bioprint or Not to Bioprint". North Carolina Journal of Law and Technology. 17: 123–78. SSRN 2562952.
  • Tran J (2015). "Patenting Bioprinting". Harvard Journal of Law and Technology Digest. SSRN 2603693.
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