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=<span style="color:#009440">bio(t)</span><span style="color:#3070b3">INK</span> - a synthetic biology approach to bioprinting=
  
 
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While interactions of biomolecules make up the cellular system, the three-dimensional organization of cells makes up tissues and organs. For decades now, scientists have tried to reconstitute such functional tissues by assembling the cells they are made out of - especially for the field of regenerative medicine, where the acquisition of suitable transplants may mean life or death for the patient. The prospect of creating personalized transplants artificially has since motivated groups all around the world to take part in this endeavour.<ref>Murphy, S. V., & Atala, A. (2014). 3D bioprinting of tissues and organs. Nature biotechnology, 32(8), 773-785.</ref>
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While interactions between biomolecules make up cellular systems, the three-dimensional organization of cells makes up tissues and organs. For decades, scientists have tried to reconstitute such functional tissues by assembling the cells they are made of especially for the field of regenerative medicine, where acquiring – or failing to acquire – suitable transplants may mean life or death for the patient. The prospect of creating personalized transplants artificially has since motivated groups all around the world to take part in this endeavour.<ref>Murphy, S. V., & Atala, A. (2014). 3D bioprinting of tissues and organs. Nature biotechnology, 32(8), 773-785.</ref>
  
But not only could bioprinting prove fruitful in the field of personalized medicine - for pharmacological applications, three-dimensional cell culture systems often constitute the first step in testing a potential pharmacological agent. Systems that resemble the human system as much as possible are hereby especially desirable, as they allow a more faithful prediction of a drug's effect ''in vivo'' and may furthermore reduce the need for lab animals.<ref>Griffith, L. G., & Swartz, M. A. (2006). Capturing complex 3D tissue physiology in vitro. Nature reviews Molecular cell biology, 7(3), 211-224.</ref>
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Thus, not only could [https://2016.igem.org/Team:LMU-TUM_Munich/Demonstrate bioprinting] prove fruitful in the field of personalized medicine for pharmacological applications, three-dimensional cell culture systems often constitute the first step in testing a potential pharmacological agent. Systems that resemble the human system as much as possible are especially desirable as they allow for predicting a drug's effect ''in vivo'' more confidently and may furthermore reduce the need for lab animals.<ref>Griffith, L. G., & Swartz, M. A. (2006). Capturing complex 3D tissue physiology in vitro. Nature reviews Molecular cell biology, 7(3), 211-224.</ref>
[[File:Muc16 dafuture.jpeg|thumb|right|320px| '''Figure 1:''' A vision of bioprinting in the future: Designing and printing whole organs in the lab.]]
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<div class="imagelink float-right">[[Media:Muc16 dafuture.jpeg]][[Image:Muc16 dafuture.jpeg|320px|link=]]
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<div class="caption">'''Figure 1:''' A vision of bioprinting in the future: designing and printing whole organs in the lab.</div></div>
  
Bioprinting systems nowadays have not been able to have a distinct impact on either of these fields. Most of the current techniques here rely on a scaffold, on which cells are seeded. After a certain timespan of ''in vitro'' maturation, cells form intercellular contacts and start to grow into two-dimensional cell layers. For the reconstruction of the tissue, layers have to then be combined and the scaffold needs to be removed or degrade automatically within the recipient. The technical complexity of the printing process itself makes bioprinting as it exists now not only technically complex but also time-consuming and expensive. Furthermore, the growth of two-dimensional cellular layers does not resemble histogenesis ''in vivo'' and is limited to simple tissues that do not require exact positioning or multiple cell types.<ref>Derby, B. (2012). Printing and prototyping of tissues and scaffolds. Science, 338(6109), 921-926.</ref>
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So far, Bioprinting systems have not been able to distinctly impact either of these fields. Most of the current techniques rely on a scaffold on which cells are seeded. After a certain timespan of ''in vitro'' maturation, cells form intercellular contacts and start to grow into two-dimensional cell layers. To reconstruct the tissue, layers have then to be combined and the scaffold needs to be removed or degraded naturally within the recipient. The technical complexity of the printing process itself makes bioprinting, as it exists now, not only cumbersome but also time-consuming and expensive. Furthermore, the growth of two-dimensional cellular layers does not resemble histogenesis ''in vivo'' and is limited to simple tissues that do not require exact positioning or contain multiple cell types.<ref>Derby, B. (2012). Printing and prototyping of tissues and scaffolds. Science, 338(6109), 921-926.</ref>
  
[[File:Muc16 mahprinter.png|thumb|left|320px|Our modified 3D-printer for printing of genetically engineered cells, enabling the creation of stable cellular matrices.]]
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Our ambitious project intends to eliminate these disadvantages: We are able to [https://2016.igem.org/Team:LMU-TUM_Munich/Proof create three-dimensional cellular structures] easily, quickly and at low cost by immediately cross-linking cells into a protein/cell-matrix upon printing. The interactions of cells with each other and the [https://2016.igem.org/Team:LMU-TUM_Munich/Proteins protein matrix] are mediated by the strongest non-covalent force found in nature the biotin-streptavidin interaction. In using a two-component system of genetically engineered cells and proteins, we create a "molecular superglue" that allows precise positioning of cells via bioprinting and locking them in position, allowing the formation of three-dimensional intercellular contacts and physiological microenvironments.
Our ambitious project intends to eliminate these distinct disadvantages: We are able to create three-dimensional cellular structures easily, quickly and at low cost by immediately cross-linking cells into a protein-cell-matrix upon printing. The interactions between cells with each other and the protein matrix are hereby mediated by the strongest non-covalent interaction found in nature - the biotin-streptavidin interaction. By using a two-component system of genetically engineered cells and proteins, we create a kind of molecular superglue that allows precise positioning of cells via bioprinting while locking them in position, allowing the formation of three-dimensional intercellular contacts and physiological microenvironments.
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<div class="imagelink float-left">[[Media:Muc16 mahprinter.png]][[Image:Muc16 mahprinter.png|320px|link=]]
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<div class="caption">'''Figure 2:''' Our modified 3D-printer to printing genetically engineered cells, enabling the creation of stable cellular matrices.</div></div>
  
For delivery of cells, we hijacked a conventional 3D-printer that can be programmed to inject cells with a millimeter precision. Due to the quick nature of the polymerization of cells, we achieve a very high spatial resolution. But that's not everything: The printing system we created can easily be created by any lab around the world as long as they have a conventional 3D-printer, allowing to print cellular structures as required with only little initial investment.
 
  
Apart from the more medically orientated aspects of regenerative medicine and pharmacology, cellular systems are also of great interest for basic and applied research. While much on the molecular interactions within cells is known, comparatively little is known about the complex interactions of cells with each other. Thus, by providing a tool to make research on a supracellular scale more accessible, we are convinced that our system is able to noticeably advance science in many areas.
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For cell delivery, we [https://2016.igem.org/Team:LMU-TUM_Munich/Hardware hijacked a conventional 3D printer] that can be programmed to inject cells with sub-millimeter precision. Since the cells rapidly polymerize, we achieve a very high spatial resolution. But that's not all: The printing system we created can easily reproduced by any lab around the world provided they have a conventional 3D printer to start with, allowing to print cellular structures as required with only little initial investment.  
  
In addition to establishing the biotINK system itself, we have also worked on several ways to functionalize tissue: For the creation of  synthetic organs, we modified cells to secrete insulin in response to external stimuli with infrared light. Also, we have worked on inducing vascularization in printed tissue in response to hypoxia. Furthermore, we have also modified our system to work in bacterial cells as well.
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Apart from the more medically oriented aspects of regenerative medicine and pharmacology, cellular systems are also of great interest for basic and applied research. While much on the molecular interactions within cells is known, comparatively little is known about the complex interactions of cells with each other. Therefore, by providing a tool to render research on a supercellular scale more accessible, we are convinced that our system is able to noticeably advance science in many areas.
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In addition to establishing the <span style="color:#009440">biot</span><span style="color:#3070b3">INK</span> system itself, we have also worked on several ways to functionalize tissue: To create synthetic organs, we modified cells to secrete insulin in response to external stimuli with infrared light. Also, we have worked on inducing vascularization in printed tissue in response to hypoxia. Furthermore, we have also modified our system to work in bacterial cells.
 
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Latest revision as of 15:39, 2 December 2016

bio(t)INK - a synthetic biology approach to bioprinting

While interactions between biomolecules make up cellular systems, the three-dimensional organization of cells makes up tissues and organs. For decades, scientists have tried to reconstitute such functional tissues by assembling the cells they are made of – especially for the field of regenerative medicine, where acquiring – or failing to acquire – suitable transplants may mean life or death for the patient. The prospect of creating personalized transplants artificially has since motivated groups all around the world to take part in this endeavour.[1]

Thus, not only could bioprinting prove fruitful in the field of personalized medicine – for pharmacological applications, three-dimensional cell culture systems often constitute the first step in testing a potential pharmacological agent. Systems that resemble the human system as much as possible are especially desirable as they allow for predicting a drug's effect in vivo more confidently and may furthermore reduce the need for lab animals.[2]

So far, Bioprinting systems have not been able to distinctly impact either of these fields. Most of the current techniques rely on a scaffold on which cells are seeded. After a certain timespan of in vitro maturation, cells form intercellular contacts and start to grow into two-dimensional cell layers. To reconstruct the tissue, layers have then to be combined and the scaffold needs to be removed or degraded naturally within the recipient. The technical complexity of the printing process itself makes bioprinting, as it exists now, not only cumbersome but also time-consuming and expensive. Furthermore, the growth of two-dimensional cellular layers does not resemble histogenesis in vivo and is limited to simple tissues that do not require exact positioning or contain multiple cell types.[3]

Our ambitious project intends to eliminate these disadvantages: We are able to create three-dimensional cellular structures easily, quickly and at low cost by immediately cross-linking cells into a protein/cell-matrix upon printing. The interactions of cells with each other and the protein matrix are mediated by the strongest non-covalent force found in nature – the biotin-streptavidin interaction. In using a two-component system of genetically engineered cells and proteins, we create a "molecular superglue" that allows precise positioning of cells via bioprinting and locking them in position, allowing the formation of three-dimensional intercellular contacts and physiological microenvironments.


For cell delivery, we hijacked a conventional 3D printer that can be programmed to inject cells with sub-millimeter precision. Since the cells rapidly polymerize, we achieve a very high spatial resolution. But that's not all: The printing system we created can easily reproduced by any lab around the world provided they have a conventional 3D printer to start with, allowing to print cellular structures as required with only little initial investment.

Apart from the more medically oriented aspects of regenerative medicine and pharmacology, cellular systems are also of great interest for basic and applied research. While much on the molecular interactions within cells is known, comparatively little is known about the complex interactions of cells with each other. Therefore, by providing a tool to render research on a supercellular scale more accessible, we are convinced that our system is able to noticeably advance science in many areas.

In addition to establishing the biotINK system itself, we have also worked on several ways to functionalize tissue: To create synthetic organs, we modified cells to secrete insulin in response to external stimuli with infrared light. Also, we have worked on inducing vascularization in printed tissue in response to hypoxia. Furthermore, we have also modified our system to work in bacterial cells.

References

  1. Murphy, S. V., & Atala, A. (2014). 3D bioprinting of tissues and organs. Nature biotechnology, 32(8), 773-785.
  2. Griffith, L. G., & Swartz, M. A. (2006). Capturing complex 3D tissue physiology in vitro. Nature reviews Molecular cell biology, 7(3), 211-224.
  3. Derby, B. (2012). Printing and prototyping of tissues and scaffolds. Science, 338(6109), 921-926.

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LMU & TUM Munich

Technische Universität MünchenLudwig-Maximilians-Universität München

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