Editing Tissue engineering (section)

=== Bioreactors ===

{{Main|Bioreactor}}

In tissue engineering, a bioreactor is a device that attempts to simulate a physiological environment in order to promote cell or tissue growth in vitro. A physiological environment can consist of many different parameters such as temperature, pressure, oxygen or carbon dioxide concentration, or osmolality of fluid environment, and it can extend to all kinds of biological, chemical or mechanical stimuli. Therefore, there are systems that may include the application of forces such as electromagnetic forces, mechanical pressures, or fluid pressures to the tissue. These systems can be two- or three-dimensional setups. Bioreactors can be used in both academic and industry applications. General-use and application-specific bioreactors are also commercially available, which may provide static chemical stimulation or a combination of chemical and mechanical stimulation.{{cn|date=April 2025}}

Cell [[Cell proliferation|proliferation]] and [[Cellular differentiation|differentiation]] are largely influenced by mechanical<ref>{{cite journal | vauthors = Maul TM, Chew DW, Nieponice A, Vorp DA | title = Mechanical stimuli differentially control stem cell behavior: morphology, proliferation, and differentiation | journal = Biomechanics and Modeling in Mechanobiology | volume = 10 | issue = 6 | pages = 939–53 | date = December 2011 | pmid = 21253809 | pmc = 3208754 | doi = 10.1007/s10237-010-0285-8 }}</ref> and biochemical<ref>{{cite journal | vauthors = Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR | display-authors = 6 | title = Multilineage potential of adult human mesenchymal stem cells | journal = Science | volume = 284 | issue = 5411 | pages = 143–47 | date = April 1999 | pmid = 10102814 | doi = 10.1126/science.284.5411.143 | bibcode = 1999Sci...284..143P }}</ref> cues in the surrounding [[extracellular matrix]] environment. Bioreactors are typically developed to replicate the specific physiological environment of the tissue being grown (e.g., flex and fluid shearing for heart tissue growth).<ref name="CM and PNIPAAm">{{cite journal | vauthors = Lee EL, von Recum HA | title = Cell culture platform with mechanical conditioning and nondamaging cellular detachment | journal = Journal of Biomedical Materials Research. Part A | volume = 93 | issue = 2 | pages = 411–18 | date = May 2010 | pmid = 20358641 | doi = 10.1002/jbm.a.32754 }}</ref> This can allow specialized cell lines to thrive in cultures replicating their native environments, but it also makes bioreactors attractive tools for culturing [[stem cell]]s. A successful stem-cell-based bioreactor is effective at expanding stem cells with uniform properties and/or promoting controlled, reproducible differentiation into selected mature cell types.<ref>{{cite journal | vauthors = King JA, Miller WM | title = Bioreactor development for stem cell expansion and controlled differentiation | journal = Current Opinion in Chemical Biology | volume = 11 | issue = 4 | pages = 394–98 | date = August 2007 | pmid = 17656148 | pmc = 2038982 | doi = 10.1016/j.cbpa.2007.05.034 }}</ref>

There are a variety of [[bioreactors]] designed for 3D cell cultures. There are small plastic cylindrical chambers, as well as glass chambers, with regulated internal humidity and moisture specifically engineered for the purpose of growing cells in three dimensions.<ref name="mc2biotek.com">{{cite web|url=http://www.mc2biotek.com/3d-tissue-culture/the-3d-prototissue-system/|archive-url=https://web.archive.org/web/20120528202009/http://www.mc2biotek.com/3d-tissue-culture/the-3d-prototissue-system/|url-status=dead|archive-date=28 May 2012|title=MC2 Biotek – 3D Tissue Culture – The 3D ProtoTissue System™}}</ref> The bioreactor uses [[Biological activity|bioactive]] synthetic materials such as [[polyethylene terephthalate]] membranes to surround the spheroid cells in an environment that maintains high levels of nutrients.<ref name="Prestwich, GD 2008 pp. 139">{{cite journal | vauthors = Prestwich GD | title = Evaluating drug efficacy and toxicology in three dimensions: using synthetic extracellular matrices in drug discovery | journal = Accounts of Chemical Research | volume = 41 | issue = 1 | pages = 139–48 | date = January 2008 | pmid = 17655274 | doi = 10.1021/ar7000827 }}</ref><ref>{{cite journal | vauthors = Friedrich J, Seidel C, Ebner R, Kunz-Schughart LA | title = Spheroid-based drug screen: considerations and practical approach | journal = Nature Protocols | volume = 4 | issue = 3 | pages = 309–24 | year = 2009 | pmid = 19214182 | doi = 10.1038/nprot.2008.226 | s2cid = 21783074 }}</ref> They are easy to open and close, so that cell spheroids can be removed for testing, yet the chamber is able to maintain 100% humidity throughout.<ref name="Marx, Vivien 2013">{{cite journal | vauthors = Marx V | title = Cell culture: a better brew | journal = Nature | volume = 496 | issue = 7444 | pages = 253–58 | date = April 2013 | pmid = 23579682 | doi = 10.1038/496253a | s2cid = 4399610 | bibcode = 2013Natur.496..253M | doi-access = free }}</ref> This humidity is important to achieve maximum cell growth and function. The bioreactor chamber is part of a larger device that rotates to ensure equal cell growth in each direction across three dimensions.<ref name="Marx, Vivien 2013"/>

QuinXell Technologies now under [http://www.quintechlifesciences.com Quintech Life Sciences] from [[Singapore]] has developed a bioreactor known as the [https://www.quintechlifesciences.com/home/tisxell/ TisXell Biaxial Bioreactor] which is specially designed for the purpose of tissue engineering. It is the first bioreactor in the world to have a spherical glass chamber with [[biaxial]] rotation; specifically to mimic the rotation of the fetus in the womb; which provides a conducive environment for the growth of tissues.<ref>{{cite journal | vauthors = Zhang ZY, Teoh SH, Chong WS, Foo TT, Chng YC, Choolani M, Chan J | title = A biaxial rotating bioreactor for the culture of fetal mesenchymal stem cells for bone tissue engineering | journal = Biomaterials | volume = 30 | issue = 14 | pages = 2694–704 | date = May 2009 | pmid = 19223070 | doi = 10.1016/j.biomaterials.2009.01.028 }}</ref>

Multiple forms of mechanical stimulation have also been combined into a single bioreactor. Using gene expression analysis, one academic study found that applying a combination of cyclic strain and ultrasound stimulation to pre-osteoblast cells in a bioreactor accelerated matrix maturation and differentiation.<ref>{{cite journal | vauthors = Kang KS, Lee SJ, Lee HS, Moon W, Cho DW | title = Effects of combined mechanical stimulation on the proliferation and differentiation of pre-osteoblasts | journal = Experimental & Molecular Medicine | volume = 43 | issue = 6 | pages = 367–73 | date = June 2011 | pmid = 21532314 | pmc = 3128915 | doi = 10.3858/emm.2011.43.6.040 }}</ref> The technology of this combined stimulation bioreactor could be used to grow bone cells more quickly and effectively in future clinical stem cell therapies.<ref>{{cite book| vauthors = Rosser J, Thomas DJ | chapter = 10 – Bioreactor processes for maturation of 3D bioprinted tissue|date= January 2018 | title = 3D Bioprinting for Reconstructive Surgery|pages=191–215| veditors = Thomas DJ, Jessop ZM, Whitaker IS |publisher=Woodhead Publishing|language=en|isbn=978-0-08-101103-4 }}</ref>

[[MC2 Biotek]] has also developed a bioreactor known as ProtoTissue<ref name="mc2biotek.com"/> that uses [[gas exchange]] to maintain high oxygen levels within the cell chamber; improving upon previous bioreactors, since the higher oxygen levels help the cell grow and undergo normal [[cell respiration]].<ref>{{cite journal | vauthors = Griffith LG, Swartz MA | title = Capturing complex 3D tissue physiology in vitro | journal = Nature Reviews. Molecular Cell Biology | volume = 7 | issue = 3 | pages = 211–24 | date = March 2006 | pmid = 16496023 | doi = 10.1038/nrm1858 | s2cid = 34783641 }}</ref>

Active areas of research on bioreactors includes increasing production scale and refining the physiological environment, both of which could improve the efficiency and efficacy of bioreactors in research or clinical use. Bioreactors are currently used to study, among other things, cell and tissue level therapies, cell and tissue response to specific physiological environment changes, and development of disease and injury.{{cn|date=April 2025}}