# Anti-Cancer Drug Screening with Microfluidic Technology
## 1 Introduction  
Microfluidic technology has various potential applications in cancer research, including drug screening, drug discovery, immunotherapy, and clinical oncology [1, 2]. In this review, we focus on the recent advances in cancer drug screening using microfluidic technology. The 2D cell culture cannot mimic the native 3D physiological environment and cellular response in vivo [3]. On the other side, animal models cannot detect the side effects of drugs well because of the biological differences between humans and animals. There is evidence that in vitro 3D tumor models can improve the preclinical predictions for cancer therapies due to their physiological relevance [4]. Hence, 3D cell tumor models are increasingly interesting to study the cell response to various stimuli. However, there are concerns with the reproducibility of the results achieved by 3D models due to large variabilities among these models [5]. So, these models still do not meet the required standards for preclinical trials. The 3D tumor models can be classified into scaffold-free systems, scaffold-based systems, hydrogel-based models, bioreactor-based models, microcarrier-based models, cancer-on-a-chip, and bioprinted models [6, 7, 8]. Organoids and patient-derived tumor xenografts are advanced strategies desirable for mimicking 3D tumor architecture and the in vivo microenvironment, respectively. Despite the great efforts in drug screening on 3D models, enormous challenges still exist for personalized drug screening for clinical trials [9]. The establishment of standardized methodologies can bring these 3D models to preclinical tests [6, 10]. More details on the tumor microenvironment in terms of its physical, chemical, and biological composition can be obtained from the excellent review paper by [10]. Different microfluidics technologies in cell-based high-throughput drug screening, including perfusion flow, droplet, and microarray modes are reviewed by [11]. Microfluidic concentration gradient generators, cell co-culture models, organ-on-chips, and combinations of microfluidic with other high-throughput systems can be found in the detailed review by [12]. Combinatorial drug treatment has shown its superiority over monodrug therapy for many diseases, especially for cancers, due to intra-tumor heterogeneity [13; 14]. Although different anti-cancer drugs have been developed for cancer, mono-drug treatments typically fail in the war against cancer [15]. Compared to mono-drugs, drug combinations can simultaneously inhibit multiple excessive pathways of tumor cells and have better efficacy [16; 17]. In this context, microfluidics could overcome the expensive and time-consuming process of combinatorial drug screening with high-throughput screening (HTS) of more compound candidates [18]. Microfluidics is a promising science and technology that can be used in various industrial [19] as well as biological and biomedical applications, including cell culture [20], cell separation [21], cryopreservation [22], and drug delivery [23]. The recent progress in microfluidic platforms for anti-cancer drug screening is well-reviewed in [24], in which current microfluidic devices are categorized as 2D, 3D, and droplet-based. Moreover, new research to address drug resistance, combinatorial drug therapy, cancer metastasis, and cancer heterogeneity is also discussed. [PERSON] et al. also reviewed anti-cancer drug development with the application of microfluidic technology with a focus on the modeling of the tumor microenvironment, high-throughput assays, and microfluidic-integrated biosensors [25]. Since the sample size is different for each type of cancer, the developed microfluidic systems should be tuned based on the sample size [26]. For example, liquid, tissue, or surgical biopsy can be used to capture the circulating tumor cells (CTCs) [27; 28], a small piece of cancer tissue or a large sample of cancer tissue, respectively. This review guides the reader to the appropriate microfluidic drug screening chips developed for their available sample size.