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\def\RunningAuthor{Kalpana Seelam and Daisy Rani A   }
\firstPage{2999}
\articleType{Original Article}
\receivedDate{10 Mar 2020}
\acceptedDate{01 May 2020}
\revisedDate{18 Apr 2020}
\journalVolume{2020, 11}
\journalIssue{3}
\journalDoi{ijrps.v11i3.2394}
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\def\journalTitle{International Journal of Research in Pharmaceutical Sciences}

\title{Microfluidic based Platform for drug screening-A review}
\author{Kalpana~Seelam\textsuperscript{*}\textsuperscript{1,2}, 
            Daisy~Rani~A\textsuperscript{1}~\\[5pt]{\textsuperscript{1}Department of Instrument Technology, Andhra University, Visakapatanam-530003, Andhra Pradesh, India}~\\{\textsuperscript{2}Department of Electronics and Instrumentation Engineering, V.R.Siddhartha Engineering College, Vijayawada-520007, Andhra Pradesh, India}}

\begin{abstract}
There is a lot of requirement to develop a preclinical rapid drug screening devices to treat the throat cancerous patients in effective manner. Very High cost models like animal based, 2d and 3d type models are static drug screening models and they are unable to mimic the human body dynamic condition. So microfluidic platform based drug screening devices will give predetermined and prominent result in rapid drug screening by mimic dynamic body conditions. Now it is required to review what are the developments from last five years in screening the drug for cancer. Recently research is going on microfluidic platforms to screen the efficacy of mixed drugs, drug tolerance, and drug susceptibility. So this study presents the review on what are the advancements in microfluidic platforms for rapid drug screening and for different cancer patients. This study also presents what are the different sensing methodologies of microfluidic devices exists to screen the drug for various cancerous tissues.  
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}chemotherapy,\newline microfluidic platform,\newline rapid drug screening,\newline throat cancer
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Kalpana~Seelam~\\ Phone:\ +91-9550117226~\\  Email:\ kalpanaseelam@gmail.com
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{Introduction}
According to GLOBOCAN 2018 data nearly 11, 57 294 new cancer cases were diagnosed in India in 2018. The total deaths due to cancer are 7, 84,821 and 22, 58,208 people living with cancer. In above mentioned statistics oral cancer can get second place in India (according to GLOBOCAN-2018). The number of deaths due to oral cancer is high in India then the other countries. New oral cancers registered for every year is nearly one lakh fifteen thousand  \unskip~\citep{769244:18295769}  and the number of deaths due to oral cancer in India is 70 thousand for year \unskip~\citep{769244:18295907}.

According to Siddhartha Mukherjee a famous writer and physician Cancer is `emperor of Maladies' [Siddhartha Mukherjee 2010]. So treating every cancer is not unique, treat every tumor in different way based on the patient body dynamic conditions. First stage of therapy in the cancer treatment is surgery followed by chemotherapy and radiation. 


\bgroup
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\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/490ee97b-3739-4526-b489-9acb4dce2017-upicture1.png}{\includegraphics{images/490ee97b-3739-4526-b489-9acb4dce2017-upicture1.png}}{}
\makeatother 
\caption{\boldmath {Conventional Vs 3D Drug Screening Methods}}
\label{f-2fe64c01cead}
\end{figure*}
\egroup
In chemotherapy the each patient required different drugs or combination of drugs to treat the tumor because the drug sensitivity depends on the genetic condition of the patients. Previously image based technologies such CT scan and MRI scan are used to evaluate response of tumor to ant1icancer drugs based on the tumor size. Later static models are used to screen the drug; it gives better results compared to imaging because the drug directly reacts with the tissue of the tumor. Currently the efficiency of the therapy gives results after weeks or months, it is the main challenges in timely management of cancer \unskip~\citep{769244:18295915}. So it the time to develop a rapid drug screening device to evaluate the efficacy of the drug on cancerous tumors that would help clinicians to separate the patients those who are respond to the treatment and non-responders to the treatment.


\bgroup
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\centering \makeatletter\IfFileExists{images/d609d65c-f0b9-43a1-be63-a5dd281f0063-upicture2.png}{\includegraphics{images/d609d65c-f0b9-43a1-be63-a5dd281f0063-upicture2.png}}{}
\makeatother 
\caption{\boldmath {Microfluidic channel fabrication materials }}
\label{f-7864d183a521}
\end{figure*}
\egroup
In recent years advances in micro fabrication technology provide bay to development of on chip organoids. Normally used conventional methods do not include anatomical processes that are normally faced by cells/tissues in the human body, such as micro perfusion, shear stress and drug diffusion rates \unskip~\citep{769244:18295773,769244:18295912,769244:18295765}. This is regularly reflected through the failure of many treatment methods, selected after in vitro screening, to perform in vivo in animal models \unskip~\citep{769244:18295909}. The microfluidic devices that can explore single cell and multi cell responses, multipara metrically on a large scale. By using microfluidic devices the small amount of sample consumption, reduced reaction time and ability to analyze small volume samples   \unskip~\citep{769244:18295768,769244:18295917,769244:18295911} (Beebe because of their small dimension channels. Microfluidic platforms also support organ on chip which allows innovative bays to simultaneously observe and analyze huge number of cells, where every cell position is tracked, analyzed and maintained for long period of time. 

\textbf{\space }


\begin{table*}[!htbp]
\caption{\boldmath {Advantages of tumor-on chip screening technologies over micro screening} }
\label{tw-4d22445c9457}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{LLL}
\tbltoprule \rowcolor{kwdboxcolor}Feature  & Micro screening technologies & Microfluidic (tumor-on-a-Chip) screening technologies\\
\tblmidrule 
Scaling  &
  Not scaled to cell dimension &
  Scaled to cell dimension\\
Size &
  bulky &
  Miniaturized\\
Availability &
  Centralized laboratories &
  Decentralized \\
Time &
  More time consumed &
  Short preparative process\\
Sample volume &
  large &
  Small\\
Biohazard waste &
  high &
  Less\\
Flow type &
  turbulent &
  laminar\\
Surface area to volume ratio &
  less &
  high\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Performance of different microfluidic platforms} }
\label{tw-fb6141731364}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.3123\linewidth-2\tabcolsep}p{\dimexpr.1849\linewidth-2\tabcolsep}p{\dimexpr.2017\linewidth-2\tabcolsep}p{\dimexpr.1195\linewidth-2\tabcolsep}p{\dimexpr.1816\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Microfluidic platform & Droplet microfluidics & Paper based microfluidics & Digital microfluidics & Continuous flow microfluidics\\
\tblmidrule 
Multi-step liquid handling &
  no &
  yes &
  yes &
  yes\\
High-throughput Screening &
  yes &
  yes &
  - &
  yes\\
Single cell drug screening &
  yes &
  no &
  - &
  no\\
3D cell-based drug screening &
  yes &
  no &
  yes &
  yes\\
Low cost &
  no &
  yes &
  no &
  no\\
Flexibility &
  no &
  yes &
  no &
  yes\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{- Represents no literature reported}
    
\item{}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {List of recently developed microfluidic tumour models} }
\label{tw-0ce273b29dd3}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1643\linewidth-2\tabcolsep}p{\dimexpr.23939999999999998\linewidth-2\tabcolsep}p{\dimexpr.28359999999999996\linewidth-2\tabcolsep}p{\dimexpr.31270000000000003\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Targeted object  & Microfluidic device type  & Sensing methodology & Outcome of the study \\
\tblmidrule 
Nematodes &
  3D &
  By applying electric field guide the motion of the nematodes &
  drug screening on a microfluidic device is improve the  \mbox{}\protect\newline Sensitivity and data throughput of in vivo testing.\\
Brain cancer &
  3D hydrogel based &
  Coloured Dye is used see the output &
  Different Drug screening for brain cancer\\
Breast cancer  &
  3D &
  Electrical sensing &
  Drug susceptible/drug resistance\\
Lung cancer &
  2D &
  Raman measurement of living cells and force distance measurement of each cell &
  Non-invasive drug response \\
Ovary  &
  3D spheroids &
  Mortality fraction &
  Drug resistance\\
pancreas &
  2D &
  Electrical sensing &
  Comparison of drug effectiveness in 2D, 3D and on chip\\
Prostate cancer &
  3D hydrogel based &
  Electrical sensing &
  Drug susceptible/drug resistance\\
Skin  &
  3D \mbox{}\protect\newline 2D &
  biophysical force  &
  Cell migration , drug combination \\
urinary &
  2D &
  fluorescence &
  drug combination\\
vascular &
  3d hydrogel based &
  biophysical force  &
  Anti-angiogenic drug comparison \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
The microfluidic based channel devices mimic the anatomical microenvironment which includes drug diffusion rate in human body or into tumor and shear stress. In the context of tumor biology, for example, and drug screening, microfluidic technologies are prominent technologies. Conventional methods and microfluidic platforms are shown in Figure~\ref{f-2fe64c01cead}. The advantages of microfluidic (tumor-on {\textendash}chip) screening technologies over micro screening technologies \unskip~\citep{769244:18295911} are explained in Table~\ref{tw-4d22445c9457}.

\textbf{Microfluidic-channel based drug screenig devices design }

The primary goal of drug screening using a microfluidic platform is to design and fabricate microfluidic devices based on the required target's function. The first liquid chromatograph was introduced in 1991\unskip~\citep{769244:18295764}, after the field has subsequently undergone a vast transformation such as introducing micromixtures, microreactors, separation systems. Microfluidic plat forms are categorized into two types one is 2D and 3D depending on the type of cell culture. 

\textbf{Cell culture environments using microfluidics}

The human body cells requires vascularized network system and oxygen exchange process to survive, so which is mimic by 3d cell culture which means cell are immersed in hydrogel material such as matrigel, collagen, fibrin and synthetic hydrogels like polyacrylamide, polyethylene glycol. The interaction between cells and the matrix is mimic by hydrogel. So by busing microfluidic platform we have to create a well chamber type structure to hold the matrigel and cells in order to mimic biological conditions of cells in body. Microfluidic channel are fabricated with different materials \unskip~\citep{769244:18295906}  which are presented in Figure~\ref{f-7864d183a521} . 

\textbf{Drug screening devices based on microfluidic platform}

In last 10 years microfluidic platforms for drug screening are rapidly growing. The latest designs for Microfluidic platforms include droplet based \unskip~\citep{769244:18295817} , continues flow based \unskip~\citep{769244:18295819} , digital microfluidics \unskip~\citep{769244:18295914,769244:18295767}, paper based \unskip~\citep{769244:18295908} and electro wetting based chip. Detailed summery is presented in Table~\ref{tw-fb6141731364}.

\textbf{Current challenges in drug screening using microfluidic platforms}

The major issues that presently face cancer chemotherapy are: tumour metastases, combinatorial drug treatment optimization cancer drug resistance, and designing personalized cancer therapies \unskip~\citep{769244:18295818,769244:18295816} . These challenges are not mutually exclusive and some of the microfluidic channel based models have tried to solve one or more challenges. The method used to screen the drug for nematodes is 3d microfluidic platform \unskip~\citep{769244:18295905} which improves throughput and sensitivity\unskip~\citep{769244:18295904}.

At a time different types of drugs are screening for brain cancer by using 3D hydrogel based microfluidic platform \unskip~\citep{769244:18295913}. Drug susceptibility and drug resistance for breast and prostate cancer is find out by microfluidic platform using electric sensing method \unskip~\citep{769244:18295821}. 2D microfluidic platform is used to screen the drug for lung cancer by using Raman measurement of living cells and force distance measurement of each cell \unskip~\citep{769244:18295916}. 3D spheroids microfluidic platform is used to find the drug resistance for ovary cancer \unskip~\citep{769244:18295770}. Comparison of drug effectiveness in 2D, 3D and on chip microfluidic platforms for pancreas is developed \unskip~\citep{769244:18295771}. For skin cancer cell migration and drug combination is developed by using 2d and 3d microfluidic platform of sensing method biophysical sensing method\unskip~\citep{769244:18295816}. Drug combination screening is done by 2D model microfluidic platform for urinary cancer by using fluorescence method\unskip~\citep{769244:18295766}. 3D hydrogel based microfluidic platform is developed for anti-angiogenic drug comparison for vascular cancer\unskip~\citep{769244:18295918}. Advantages of above mention methods are presented in Table~\ref{tw-0ce273b29dd3}. 
    
\section{\textbf{Conclusions}}
In last 5-6 years there is a huge demand for microfluidic platform based devices to screen the anticancer drug. Based on the number of drugs screened in given time and speed anticancer drug screening devices are of two types: low throughput and high throughput . We have already good models to screen the drugs such as complex in nature, so it is required to reduce the complexity to screen the anti-throat cancer drug effectively. The major issue here to present is every patient condition is different so it is required to design patient centric platform to screen the drug. This study presents review of different types of microfluidic platforms to screen anticancer drugs for different tumours. However what's the cancer and drug is doesn't matter here.it is required to design rapid drug screening methods, so that we can provide better therapy for the cancerous patients by knowing the tumour is resist to drug or not. Most microfluidic platforms are available only in laboratories to demonstrate, but it is the time to produce them in market with different types of sensing microfluidic patient centric devices so that we can reduce the number of deaths caused by cancer and individual will be able to receive personalized treatment. Our aim here is to design rapid drug screening device for throat cancer patients with good sensitivity.
\section*{Acknowledgement}The authors express their gratitude to the Dept. of EIE in V. R. Siddhatha Engineering college, Vijayawada and Dept.of Instrument Technology in Andhra University, Visakhapatnam, Andhra Pradesh for providing necessary support in due course of the work.

\textbf{Conflict of Interest}

The author confirms that this article content has no conflicts of interest.\textbf{\space }

\textbf{Funding Support}

None.
    

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