ADD a bunch of background on microcarriers

tex/thesis.tex

@@ -569,6 +569,68 @@ present our final conclusions in Chapter~\ref{conclusions}.
 % TODO consider adding a separate section on microcarriers and their use in
 % bioprocess
 % TODO add stuff about T cell licensing
+
+\subsection{microcarriers in bioprocessing}
+
+% https://www.sciencedirect.com/science/article/pii/S0928493118338001#bb0010
+
+Microcarriers have historically been used to grow a number of adherent cell
+types for a variety of applications. They were introduced in 1967 as a means to
+grow adherent cells `in suspension', effectively turning a 2D flask system into
+a 3D culture system (https://www.nature.com/articles/216064a0.pdf).
+Microcarriers are generally spherical and are several hundred \si{\um} in
+diameter, which means they collectively have a much higher surface area than a
+traditional flask when matched for volume. Consequently, this means that
+microcarrier-based cultures can operate with much lower footprints than
+flask-like systems. Microcarriers also allow cell culture to operate more like a
+traditional chemical engineering process, wherein a stirred tank bioreactor may
+be employed to enhance oxygen transfer, maintain pH, and continuously supply
+nutrients ().
+
+A variety of microcarriers have been designed, primarily differing in their
+choice of material and macroporous structure. Key concerns have been cell
+attachment at the beginning of culture and cell detachment at the harvesting
+step; these have largely driven the nature of the material and structures
+employed. Many microcarriers simply use polystyrene (the material used for
+tissue culture flasks and dishes in general) with no modification (SoloHill
+Plastic, Nunc Biosilon), with a cationic surface charge (SoloHill Hillex) or
+coated with an \gls{ecm} protein such as collagen (SoloHill Fact III). Other
+base materials have been used such as dextran (GE Healthcare Cytodex), cellulose
+(GE Healthcare Cytopore), and glass (Sigma Aldrich G2767), all with none or
+similar surface modifications. Additionally, some microcarriers such as
+\gls{cus} and \gls{cug} are composed entirely out of protein (in these cases,
+porcine collagen) which also allows the microcarriers to be enzymatically
+degraded. In the case of non-protein materials, cells may still be detached
+using enzymes but these require similar methods to those currently used in
+flasks such as trypsin which target the cellular \gls{ecm} directly. Since
+trypsin and related enzymes tends to be harsh on cells, an advantage of using
+entirely protein-based microcarriers is that they can be degraded using a much
+safer enzyme such as collagenase, at the cost of being more expensive and also
+being harder to make \gls{gmp}-compliant. Going one step further, some
+microcarriers are composed of a naturally degrading scaffold such as alginate,
+which do not need an enzyme for degradation but are limited in that the
+degradation process is less controllable. Finally, microcarriers can differ in
+their overall structure. \gls{cug} and \gls{cus} microcarriers as well as the
+Cytopore microcarriers are macroporous, meaning they have a porous network in
+which cells can attach throughout their interior. This drastically increases the
+effective surface area and consequently the number of cells which may be grown
+per unit volume. Other microcarriers are microporous (eg only to small
+molecules) or not porous at all (eg polystyrene) in which case the cells can
+only grow on the surface.
+
+% https://www.sciencedirect.com/science/article/pii/S0734975013000657
+% https://link.springer.com/article/10.1023/A:1008038609967
+% https://onlinelibrary.wiley.com/doi/full/10.1002/bit.23289
+Microcarriers have seen the most use in growing \gls{cho} cells and hybridomas
+in the case of protein manufacturing (eg \gls{igg} production) as well as
+pluripotent stem cells and mesenchymal stromal cells more recently in the case
+of cell manufacturing\cite{Heathman2015, Sart2011}. Interestingly, some groups
+have even explored using biodegradable microcarriers \invivo{} as a delivery
+vehicle for stem cell therapies in the context of regenerative medicine.
+However, the characteristic shared by all the cell types in this application is
+the fact that they are adherent. In this work, we explore the use of
+microcarrier for T cells, which are naturally non-adherent.
+
 \subsection*{current T cell manufacturing technologies}
 
 \Gls{car} T cell therapy has received great interest from both academia and
@@ -621,20 +683,6 @@ cytokine release properties and ability to resist exhaustion\cite{Wang2018,
   Yang2017}, and no method exists to preferentially expand the CD4 population
 compared to state-of-the-art systems.
 
-Here we propose a method using microcarriers functionalized with \acd{3} and
-\acd{28} \glspl{mab} for use in T cell expansion cultures. Microcarriers have
-historically been used throughout the bioprocess industry for adherent cultures
-such as stem cells and \gls{cho} cells, but not with suspension cells such as T
-cells\cite{Heathman2015, Sart2011}. The carriers have a macroporous structure
-that allows T cells to grow inside and along the surface, providing ample
-cell-cell contact for enhanced autocrine and paracrine signaling. Furthermore,
-the carriers are composed of gelatin, which is a collagen derivative and
-therefore has adhesion domains that are also present within the lymph nodes.
-Finally, the 3D surface of the carriers provides a larger contact area for T
-cells to interact with the \glspl{mab} relative to beads; this may better
-emulate the large contact surface area that occurs between T cells and
-\glspl{dc}.
-
 \subsection*{integrins and T cell signaling}
 
 Because the microcarriers used in this work are derived from collagen, one key