ENH proofread conclusions
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@ -4522,7 +4522,7 @@ porcine-derived collagen, which itself is not \gls{gmp}-compliant due to its
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non-human animal origins. However, using any other source of collagen should
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non-human animal origins. However, using any other source of collagen should
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work so long as the structure of the microcarriers remains relatively similar
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work so long as the structure of the microcarriers remains relatively similar
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and it has lysine groups that can react with the \gls{snb} to attach \gls{stp}
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and it has lysine groups that can react with the \gls{snb} to attach \gls{stp}
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and \glspl{mab}. Obviously these would need to be tested and verified, but they
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and \glspl{mab}. Obviously these would need to be tested and verified, but these
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should not be insurmountable. Furthermore, the \gls{mab} binding step requires
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should not be insurmountable. Furthermore, the \gls{mab} binding step requires
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\gls{bsa} to prevent adsorption to the non-polar polymer walls of the reaction
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\gls{bsa} to prevent adsorption to the non-polar polymer walls of the reaction
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tubes. A human carrier protein such as \gls{hsa} could be used in its place to
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tubes. A human carrier protein such as \gls{hsa} could be used in its place to
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@ -4531,7 +4531,7 @@ expensive. Alternatively, the use of protein could be replaced altogether by a
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non-ionic detergent such as Tween-20 or Tween-80, which are already used for
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non-ionic detergent such as Tween-20 or Tween-80, which are already used for
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commercial \gls{mab} formulations for precisely this purpose\cite{Kerwin2008}.
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commercial \gls{mab} formulations for precisely this purpose\cite{Kerwin2008}.
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Validating the process with Tween would be the best next step to eliminate
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Validating the process with Tween would be the best next step to eliminate
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\gls{bsa} from the process. The \gls{stp} and \glspl{mab} in this process were
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\gls{bsa} from the process. The \gls{stp} and \glspl{mab} in this work were
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not \gls{gmp}-grade; however, they are commonly used in clinical technology such
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not \gls{gmp}-grade; however, they are commonly used in clinical technology such
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as dynabeads and thus the research-grade proteins used here could be easily
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as dynabeads and thus the research-grade proteins used here could be easily
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replaced. The \gls{snb} is a synthetic small molecule and thus does not have any
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replaced. The \gls{snb} is a synthetic small molecule and thus does not have any
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@ -4545,7 +4545,12 @@ as well as it does. Several broad areas remain to be investigated, including the
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role of the increased cytokine output (including \il{15} which was explored to
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role of the increased cytokine output (including \il{15} which was explored to
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some extent in this work), the role of cells on the interior of the \gls{dms}
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some extent in this work), the role of cells on the interior of the \gls{dms}
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relative to those outside the \gls{dms}, and the role of the physical surface
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relative to those outside the \gls{dms}, and the role of the physical surface
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properties of the \gls{dms} (including the morphology and the stiffness).
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properties of the \gls{dms} (including the morphology and the stiffness). One
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plausible hypothesis to be tested is that the bumpy microcarrier surface is more
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like that of an \gls{apc}, which enhances immunological synapse formation and
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thus activation. Another related hypothesis is that the signal strength is
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lower than the beads, which leads to increased proliferation, less exhaustion,
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and by extension more memory.
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\subsection{additional ligands and signals on the DMSs}
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\subsection{additional ligands and signals on the DMSs}
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@ -4553,22 +4558,23 @@ In this work we only explored the use of \acd{3} and \acd{28} \glspl{mab} coated
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on the surface of the \gls{dms}. The chemistry used for the \gls{dms} is very
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on the surface of the \gls{dms}. The chemistry used for the \gls{dms} is very
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general, and any molecule or protein that could be engineered with a biotin
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general, and any molecule or protein that could be engineered with a biotin
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ligand could be attached without any further modification. There are many other
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ligand could be attached without any further modification. There are many other
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ligands that could have profound effects on the expansion and quality of T cells
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ligands (in addition to integrin-binding domains and \il{15} complexes as
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which may be utilized. The simplest next step is to simply vary the ratio of
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described at the end of \cref{aim2b}) that could have profound effects on the
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\acd{3} and \acd{28} signal. Another obvious example is to attach
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expansion and quality of T cells which may be utilized. The simplest next step
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\il{15}/\il{15R$\upalpha$} complexes to the surface to mimic \textit{trans}
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is to simply vary the ratio of \acd{3} and \acd{28} signal. Another obvious
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presentation from other cell types\cite{Stonier2010}. Other adhesion ligands or
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example is to attach \il{15}/\il{15R$\upalpha$} complexes to the surface to
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peptides such as GFOGER could be used to stimulate T cells and provide more
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mimic \textit{trans} presentation from other cell types\cite{Stonier2010}. Other
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motility on the \glspl{dms}\cite{Stephan2014}. Finally, viral delivery systems
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adhesion ligands or peptides such as GFOGER could be used to stimulate T cells
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could theoretically be attached to the \gls{dms}, greatly simplifying the
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and provide more motility on the \glspl{dms}\cite{Stephan2014}. Finally, viral
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transduction step.
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delivery systems could theoretically be attached to the \gls{dms}, greatly
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simplifying the transduction step.
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\subsection{assessing performance using unhealthy donors}
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\subsection{assessing performance using unhealthy donors}
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All the work presented in this dissertation was performed using healthy donors.
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All the work presented in this dissertation was performed using healthy donors.
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This was mostly due to the fact that it was much easier to obtain healthy donor
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This was mostly due to the fact that it was much easier to obtain healthy donor
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cells and was much easier to control. However, it is indisputable that the most
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cells and was much easier to control. However, it is indisputable that the most
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relevant test cases of the \gls{dms} will be for unhealthy patient T cells, at
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relevant test cases of the \glspl{dms} will be for unhealthy patient T cells, at
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least in the case of autologous therapies. In particular, it will be interesting
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least in the case of autologous therapies. In particular, it will be interesting
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to see how the \gls{dms} performs when assessed head-to-head with bead-based
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to see how the \gls{dms} performs when assessed head-to-head with bead-based
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expansion technology given that even in healthy donors, we observed the
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expansion technology given that even in healthy donors, we observed the
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