Microfluidic chip devices are preferably fabricated on transparent surfaces such as glass or transparent polymer to make them amenable for microscopic imaging [11,20]. It is desirable for chip devices to be disposable. This makes the use of polymers attractive because of their safe and eco-friendly characteristics [21,22]. Polydimethylsiloxane (PDMS) has gained widespread adoption in the fields of the microfluidic chip, tissue engineering, and cancer biology due to its biocompatibility and ease of fabrication [20,23]. PDMS is oxygen permeable, supporting the culture of cells involved in PDAC TME, thus appropriate for cancer studies [24,25]. A detailed technical review of the materials and design of microfluidic devices is out of the scope of this article and can be found elsewhere [11,20,22,26].

In contrast to static cell culture systems in culture flasks and plates, a chip enables the modeling of in vivo physical conditions by allowing a controlled flow of culture medium into the cell chambers. The flow rates can be tailored to mimic the shear stress of the respective organ [26,27]. Our ability to mimic such dynamic cues (i.e., mechanical forces, hypoxia, and matrix stiffness) on a chip is crucial in modeling cellular events in cancer. For example, epithelial to mesenchymal transition (EMT), a key event in cancer progression and invasion, responds to such dynamic forces in the tumor [28,29,30,31]. The phenotypic transition of the cancerous epithelium into mesenchymal faith enhances their pro-survival tone, migratory capacity, and metastasis [30,32]. Dynamic laminar microfluidic platforms could show how flow-based shear stress promotes EMT in cancer [33,34]. Lung tumoroids culture in such flow-based microfluidic chips express higher EMT markers compared with tumoroids in static conditions [28]. Thus, the maneuverable features of microfluidic platforms allow us to evaluate the impact of physical stressors such as changes in the flow and shear stress on the mechanism of cancer progression.

The culture of several cell types within such a dynamic system has made microfluidic chips a desirable in vitro platform towards building more complex organ mimics [23,35,36]. Integration of additional devices and biosensors in the platform has further advanced its translational application for on-chip analysis. For instance, dielectrophoresis-type devices or dynamic-ELISA on a chip allow the measurement of secreted proteins and molecules in real-time [35,36,37,38,39,40]. Together, microfluidic devices incorporating multiple cell types in a physiologically relevant microenvironment with physical, biochemical, and optical sensing capabilities could be instrumental in better modeling molecular and/or cellular characterizations of cancer biology towards an individualized OOC platform for ex vivo drug testing in cancer [41]. This is important, as the TME, including vasculature, immune cells, and non-cellular components surrounding the cancerous epithelium, play a major role in tumor growth and drug resistance [42]. Here we will briefly list some of the crucial cellular processes occurring in the TME that have been successfully recapitulated in microfluidic devices.

The TME has an active role in tumor progression, immune evasion, and drug response in PDAC [70,71]. Non-cellular components of TME of pancreas tumors are composed of ECM and dense fibrous tissue, regarded as “desmoplasia” (Figure 1) [72]. The dense ECM is mainly composed of matrix proteins such as collagen secreted by the cellular components of TME such as fibroblasts and pancreatic stellate cells (PSCs) [73]. PSCs can reduce cancer cell death upon chemotherapy induction by releasing soluble factors or activating stemness signaling pathways in cancer cells [15]. Several other immune cell types are present in the TME, among which macrophages are the most abundant that gauge both the innate and adaptive immune responses against the tumor [73]. Similar to PSCs, macrophages in interaction with cancer cells can shift towards a pro-tumorigenic phenotype, which leads to increased cancer cell stemness and growth [74]. Macrophages are also crucial in rendering chemoresistance to conventional chemotherapeutics for PDAC [75]. Pancreatic epithelial ducts secrete alkali in the epical side and create an alkaline pH in the microenvironment to prevent the breakdown of secreted pre-enzymes in the normal pancreas before reaching the small bowel lumen [76]. In PDAC, dysregulation of ion channel transporters (i.e., Ca²⁺ and K⁺ channels) and the tumor hypovascularization contribute to the acidification of the microenvironment, which further promotes cancerous characteristics in the epithelium (e.g., selection of EMT phenotypes) while shifting the stromal cells (i.e., PSC and macrophages) towards protumorigenic phenotypes [76,77]. While there are numerous other cell types in the TME (e.g., T cells, B cells, Dendritic cells), we focus on collagen-producing cells and macrophages as two major components of the TME in PDAC. In the following sections, we highlight the characteristics and plasticity of these cell types within the tumor area before discussing the opportunities provided by OOCs to model TME in PDAC.