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Danielle Dinunzio
Overall, these results validate the utility of our TIME-on-Chip to recreate and analyze the locomotion behavior of 3D tumor cultures, and carry out integrated labeling and post-assay analyses directly on chip.
The integration of tumor-on-a-chip technology with mini-tissues or organoids has emerged as a powerful approach in cancer research and drug development. This review provides an extensive examination of the diverse biofabrication methods employed to create mini-tissues, including 3D bioprinting, spheroids, microfluidic systems, and self-assembly techniques using cell-laden hydrogels. Furthermore, it explores various approaches for fabricating organ-on-a-chip platforms. This paper highlights the synergistic potential of combining these technologies to create tumor-on-a-chip models that mimic the complex tumor microenvironment and offer unique insights into cancer biology and therapeutic responses.
Subsequently, we will explore the various techniques employed in fabricating organ-on-a-chip platforms. These platforms offer dynamic and controlled microenvironments that enable researchers to mimic the essential functions of specific organs, making them powerful tools for studying normal physiology and disease progression. Additionally, we will examine microfluidics-based organ-on-a-chip models, biomaterial-based approaches employing biologically relevant scaffolds, and hybrid systems that integrate both technologies [13, 17].
Building on this foundation, we will investigate the exciting area of tumor-on-a-chip models, where mini-tissues or organoids are merged with advanced microfluidic systems to create physiologically relevant tumor microenvironments (TMEs). These innovative platforms can provide new insights into cancer biology, including tumor heterogeneity, invasion, metastasis, and responses to therapeutic agents [18, 19]. By examining various tumor-on-a-chip models, we demonstrate the unique advantages of each biofabrication method and their potential applications in the context of cancer research.
This review aims to shed light on promising developments in the integration of tumor-on-a-chip technology with mini-tissues or organoids through diverse biofabrication methods. The synergy between these cutting-edge technologies can bridge the gap between traditional 2D cell culture and in vivo studies, providing researchers with more reliable and representative in vitro models to explore the complexities of cancer biology and therapeutic interventions. Through an improved understanding of tumor behavior and drug responses, these advanced models may pave the way for personalized medical approaches and propel us closer to more effective and targeted cancer treatments.
From the perspective of cancer research, 3D bioprinted mini-tissues provide valuable insights into tumor growth, invasion, and drug responses. By incorporating different cell types, including several stem cells and ECM components, researchers can create tumorlike structures that closely mimic the TME, allowing the study of tumor-stromal interactions, angiogenesis, and immune cell infiltration [38, 39]. Among various types of tumor models, the 3D bioprinting of glioblastoma tumors has been well studied, as it is an aggressive form of cancer that affects the central nervous system [40]. For instance, Dai et al. fabricated glioma stem cell-laden bioconstructs composed of gelatin, alginate, and fibrinogen [41]. The cells proliferated well and showed high differentiation potential (glial fibrillary acidic protein and β-tubulin III). Moreover, the 3D tumor model showed higher drug resistance to temozolomide than the 2D model. Additionally, inkjet bioprinting was used to obtain copatterned hepatoma and glioma constructs to evaluate the efficacy of chemotherapeutics (in this case tegafur) against cells [42]. Researchers have concluded that the developed approach allows precise patterning (at the microscale) of various cells onto microchips for accurate analysis of drug efficacy. In addition, Wang et al. developed a 3D mini-tissue composed of human lung cancer cells (A549/95-D) using a 3D bioprinting process [43]. The cancer cells were combined with a gelatin-alginate-based bioink and extruded to form 3D constructs, which were subsequently crosslinked in a sodium alginate solution. To investigate cancer invasion, the authors assessed matrix metalloproteinases 2 (MMP2) and matrix metalloproteinases 9 (MMP9) using qPCR. The results revealed a significant upregulation of these genes in cells cultured within 3D constructs compared to those in 2D culture. Based on these examples, 3D bioprinting can enable the creation of patient-specific tumor models, paving the way for personalized medical approaches. However, the absence of adequate cell-cell interactions is a significant limitation in the realm of 3D bioprinted tissues. Research has demonstrated that robust cell-cell interactions, which affect intricate intracellular signaling, can substantially enhance the bioactivities of the cells within a tissue. To address this concern, researchers have explored cellular aggregates called cell spheroids, which can bolster the lacking cell-cell interactions in 3D bioprinted tissues. The subsequent sections delve into the fabrication and applications of cell-spheroids as mini-tissues.
Microfluidic systems have emerged as powerful tools for creating mini-tissues owing to their ability to control fluid flow, cell seeding, and culture conditions in microscale environments. Microfluidic devices are typically manufactured from biocompatible materials, such as poly(dimethyl siloxane) (PDMS), poly(methyl methacrylate) (PMMA), and cyclic olefin polymer (COP). In this context, silicone-based elastomer (PDMS) is the most commonly used material owing to its diverse characteristics, including optical transparency, low cost, easy fabrication of intricate structures, bioinertness, and gas permeability [51, 52]. Similarly, PMMA has been extensively studied for use in microfluidic devices using various methods including milling, hot embossing, micromachining, laser ablation, and microinjection molding [53]. Furthermore, PMMA is a notably more rigid polymer compared to PDMS, rendering it more suitable for mass production [54, 55]. However, owing to its rigidity, PMMA is not suitable for valve applications in microfluidic devices. In addition, COPs have demonstrated high resistance to both chemical and biological factors while maintaining optical transparency [56-58]. This makes them an excellent choice of polymer for microfluidic applications. Various fabrication methods, such as laser ablation, micromilling, injection molding, hot embossing, and nanoimprint lithography, can be employed in the production of microfluidic devices. The chips were designed to accommodate multiple channels, reservoirs, and chambers to regulate fluid flow and cell culture. These platforms enable the generation of precise tissue architectures and dynamic microenvironments [13, 59].
Consequently, the diameter of the core fiber can be reduced and crosslinked simultaneously. Similarly, Dickman et al. utilized a microfluidic chip with a calcium chloride solution in the side channels to crosslink the alginate hydrogel in the core simultaneously during the extrusion process. Consequently, the printability of the proposed system was significantly increased [66].
Diverse biofabrication methods for mini-tissues offer unique capabilities to generate tissue-like structures with cellular complexity and physiological relevance. By connecting the potential of 3D bioprinting, spheroids, microfluidic systems, and hybrid fabrication approaches, researchers have paved the way for more advanced and sophisticated tumor-on-a-chip models [40, 68-70]. In the subsequent sections, we explore the integration of these mini-tissues with organ-on-a-chip (OOC) platforms to create comprehensive tumor-on-a-chip models, offering unprecedented opportunities to unravel the complexities of cancer biology and advance personalized medicine.
Microfluidics-based approaches offer precise fluid control and cellular integration, whereas biomaterial-based strategies provide a more native-like microenvironment. Hybrid systems combine these technologies to create comprehensive and functional organ models. For instance, Urbaczek et al. investigated OOC integrated with microfluidic channels containing endothelial cells. To enhance the bioactivities of the endothelial cells, the channel was treated with oxygen plasma followed by fibronectin coating [90]. As a result of these treatments, a notable increase in vascular endothelial growth factor (VEGF) secreted from the cells was observed. These OOC platforms have tremendous potential for advancing disease modeling, drug screening, and personalized medicine, contributing significantly to the fields of tissue engineering and regenerative medicine. In the following section, we explore the integration of mini-tissues or organoids with these OOC platforms to create tumor-on-a-chip models, presenting a powerful approach to cancer research and therapeutic development.
Applications of 3D bioprinted tissue-constructs incorporated in TOC. (A) (i) Schematic illustrations of the bioprinting process for the organ-on-a-chip (OOC), and (ii) optical images of the perfusion of OOC and flurescent images of DAPI (blue)/CD31 (green) demonstrating vascularization of perfuable OOC. Adapted with permission from [93], copyright Wiley 2021. (B) Schematic showing (i) native and (ii) designed lymphatic-blood system of tumor microenvironment. (iii-vi) Schematic diagram of the fabrication process of the OOC demontrating perfusable blood (red) and flymphatic (yellow) hollow tubes. Adapted with permission from [94], copyright Wiley 2019. (C) (i) schematical diagram illustrating 3D bioprinting of multistage microfluidic OOC and (ii) confocal imaging demonstrating HUVEC (red) and pericyte cells (blue) within the OOC. Adapted with permission from [95], copyright AAAS 2021.
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