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Автор: Grafiati
Опубліковано: 7 липня 2024
Оновлено: 7 липня 2024

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1

Perenkov, Alexey D., Alena D. Sergeeva, Maria V. Vedunova, and Dmitri V. Krysko. "In Vitro Transcribed RNA-Based Platform Vaccines: Past, Present, and Future." Vaccines 11, no. 10 (October 16, 2023): 1600. http://dx.doi.org/10.3390/vaccines11101600.

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mRNA was discovered in 1961, but it was not used as a vaccine until after three decades. Recently, the development of mRNA vaccine technology gained great impetus from the pursuit of vaccines against COVID-19. To improve the properties of RNA vaccines, and primarily their circulation time, self-amplifying mRNA and trans-amplifying mRNA were developed. A separate branch of mRNA technology is circular RNA vaccines, which were developed with the discovery of the possibility of translation on their protein matrix. Circular RNA has several advantages over mRNA vaccines and is considered a fairly promising platform, as is trans-amplifying mRNA. This review presents an overview of the mRNA platform and a critical discussion of the more modern self-amplifying mRNA, trans-amplifying mRNA, and circular RNA platforms created on its basis. Finally, the main features, advantages, and disadvantages of each of the presented mRNA platforms are discussed. This discussion will facilitate the decision-making process in selecting the most appropriate platform for creating RNA vaccines against cancer or viral diseases.
2

Gupta, Priyanka, Aline Miller, Adedamola Olayanju, Thumuluru Kavitha Madhuri, and Eirini Velliou. "A Systematic Comparative Assessment of the Response of Ovarian Cancer Cells to the Chemotherapeutic Cisplatin in 3D Models of Various Structural and Biochemical Configurations—Does One Model Type Fit All?" Cancers 14, no. 5 (March 1, 2022): 1274. http://dx.doi.org/10.3390/cancers14051274.

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Epithelial Ovarian Cancer (EOC) is a silent, deadly and aggressive gynaecological disease with a relatively low survival rate. This has been attributed, to some extent, to EOC’s high recurrence rate and resistance to currently available platinum-based chemotherapeutic treatment methods. Multiple groups have studied and reported the effect of chemotherapeutic agents on various EOC 3D in vitro models. However, there are very few studies wherein a direct comparative study has been carried out between the different in vitro 3D models of EOC and the effect of chemotherapy within them. Herein, we report, for the first time, a direct comprehensive systematic comparative study of three different 3D in vitro platforms, namely (i) spheroids, (ii) synthetic PeptiGels/hydrogels of various chemical configurations and (iii) polymeric scaffolds with coatings of various extracellular matrices (ECMs) on the cell growth and response to the chemotherapeutic (Cisplatin) for ovary-derived (A2780) and metastatic (SK-OV-3) EOC cell lines. We report that all three 3D models are able to support the growth of EOC, but for different time periods (varying from 7 days to 4 weeks). We have also reported that chemoresistance to Cisplatin, in vitro, observed especially for metastatic EOC cells, is platform-dependent, in terms of both the structural and biochemical composition of the model/platform. Our study highlights the importance of selecting an appropriate 3D platform for in vitro tumour model development. We have demonstrated that the selection of the best platform for producing in vitro tumour models depends on the cancer/cell type, the experimental time period and the application for which the model is intended.
3

Gadde, Manasa, Melika Mehrabi-Dehdezi, Bisrat G. Debeb, Wendy A. Woodward, and Marissa Nichole Rylander. "Influence of Macrophages on Vascular Invasion of Inflammatory Breast Cancer Emboli Measured Using an In Vitro Microfluidic Multi-Cellular Platform." Cancers 15, no. 19 (October 8, 2023): 4883. http://dx.doi.org/10.3390/cancers15194883.

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Inflammatory breast cancer (IBC) is an aggressive disease with a poor prognosis and a lack of effective treatments. It is widely established that understanding the interactions between tumor-associated macrophages (TAMs) and the tumor microenvironment is essential for identifying distinct targeting markers that help with prognosis and subsequent development of effective treatments. In this study, we present a 3D in vitro microfluidic IBC platform consisting of THP1 M0, M1, or M2 macrophages, IBC cells, and endothelial cells. The platform comprises a collagen matrix that includes an endothelialized vessel, creating a physiologically relevant environment for cellular interactions. Through the utilization of this platform, it was discovered that the inclusion of tumor-associated macrophages (TAMs) led to an increase in the formation of new blood vessel sprouts and enhanced permeability of the endothelium, regardless of the macrophage phenotype. Interestingly, the platforms containing THP-1 M1 or M2 macrophages exhibited significantly greater porosity in the collagen extracellular matrix (ECM) compared to the platforms containing THP-1 M0 and the MDA-IBC3 cells alone. Cytokine analysis revealed that IL-8 and MMP9 showed selective increases when macrophages were cultured in the platforms. Notably, intravasation of tumor cells into the vessels was observed exclusively in the platform containing MDA-IBC3 and M0 macrophages.
4

McRae, Michael P., Kritika S. Rajsri, Timothy M. Alcorn, and John T. McDevitt. "Smart Diagnostics: Combining Artificial Intelligence and In Vitro Diagnostics." Sensors 22, no. 17 (August 24, 2022): 6355. http://dx.doi.org/10.3390/s22176355.

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We are beginning a new era of Smart Diagnostics—integrated biosensors powered by recent innovations in embedded electronics, cloud computing, and artificial intelligence (AI). Universal and AI-based in vitro diagnostics (IVDs) have the potential to exponentially improve healthcare decision making in the coming years. This perspective covers current trends and challenges in translating Smart Diagnostics. We identify essential elements of Smart Diagnostics platforms through the lens of a clinically validated platform for digitizing biology and its ability to learn disease signatures. This platform for biochemical analyses uses a compact instrument to perform multiclass and multiplex measurements using fully integrated microfluidic cartridges compatible with the point of care. Image analysis digitizes biology by transforming fluorescence signals into inputs for learning disease/health signatures. The result is an intuitive Score reported to the patients and/or providers. This AI-linked universal diagnostic system has been validated through a series of large clinical studies and used to identify signatures for early disease detection and disease severity in several applications, including cardiovascular diseases, COVID-19, and oral cancer. The utility of this Smart Diagnostics platform may extend to multiple cell-based oncology tests via cross-reactive biomarkers spanning oral, colorectal, lung, bladder, esophageal, and cervical cancers, and is well-positioned to improve patient care, management, and outcomes through deployment of this resilient and scalable technology. Lastly, we provide a future perspective on the direction and trajectory of Smart Diagnostics and the transformative effects they will have on health care.
5

Park, Seonghyuk, Youngtaek Kim, Jihoon Ko, Jiyoung Song, Jeeyun Lee, Young-Kwon Hong, and Noo Li Jeon. "One-step achievement of tumor spheroid-induced angiogenesis in a high-throughput microfluidic platform: one-step tumor angiogenesis platform." Organoid 3 (February 25, 2023): e3. http://dx.doi.org/10.51335/organoid.2023.3.e3.

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Research on the development of anti-cancer drugs has progressed, but the low reliability of animal experiments due to biological differences between animals and humans causes failures in the clinical process. To overcome this limitation, 3-dimensional (3D) in vitro models have been developed to mimic the human cellular microenvironment using polydimethylsiloxane (PDMS). However, due to the characteristics and limitations of PDMS, it has low efficiency and is not suitable to be applied in the preclinical testing of a drug. High-throughput microfluidic platforms fabricated by injection molding have been developed, but these platforms require a laborious process when handling spheroids. We recently developed an injection-molded plastic array 3D culture tissue platform that integrates the process from spheroid formation to reconstruction of an in vitro model with spheroids (All-in-One-IMPACT). In this study, we implemented a 3D tumor spheroid angiogenesis model in the developed platform. We analyzed the tendency for angiogenesis according to gel concentration and confirmed that angiogenesis occurred using cancer cell lines and patient-derived cancer cells (PDCs). We also administered an anti-cancer drug to the PDC tumor spheroid angiogenesis model to observe the drug’s effect on angiogenesis according to its concentration. We demonstrated that our platform can be used to study the tumor microenvironment (TME) and drug screening. We expect that this platform will contribute to further research on the complex mechanisms of the TME and predictive preclinical models.
6

Brocklehurst, Sean, Neda Ghousifam, Kameel Zuniga, Danielle Stolley, and Marissa Nichole Rylander. "Multilayer In Vitro Human Skin Tissue Platforms for Quantitative Burn Injury Investigation." Bioengineering 10, no. 2 (February 17, 2023): 265. http://dx.doi.org/10.3390/bioengineering10020265.

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This study presents a multilayer in vitro human skin platform to quantitatively relate predicted spatial time–temperature history with measured tissue injury response. This information is needed to elucidate high-temperature, short-duration burn injury kinetics and enables determination of relevant input parameters for computational models to facilitate treatment planning. Multilayer in vitro skin platforms were constructed using human dermal keratinocytes and fibroblasts embedded in collagen I hydrogels. After three seconds of contact with a 50–100 °C burn tip, ablation, cell death, apoptosis, and HSP70 expression were spatially measured using immunofluorescence confocal microscopy. Finite element modeling was performed using the measured thermal characteristics of skin platforms to determine the temperature distribution within platforms over time. The process coefficients for the Arrhenius thermal injury model describing tissue ablation and cell death were determined such that the predictions calculated from the time–temperature histories fit the experimental burn results. The activation energy for thermal collagen ablation and cell death was found to be significantly lower for short-duration, high-temperature burns than those found for long-duration, low-temperature burns. Analysis of results suggests that different injury mechanisms dominate at higher temperatures, necessitating burn research in the temperature ranges of interest and demonstrating the practicality of the proposed skin platform for this purpose.
7

Kim, Tae Hee, Ji-Jing Yan, Joon Young Jang, Gwang-Min Lee, Sun-Kyung Lee, Beom Seok Kim, Justin J. Chung, Soo Hyun Kim, Youngmee Jung, and Jaeseok Yang. "Tissue-engineered vascular microphysiological platform to study immune modulation of xenograft rejection." Science Advances 7, no. 22 (May 2021): eabg2237. http://dx.doi.org/10.1126/sciadv.abg2237.

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Most of the vascular platforms currently being studied are lab-on-a-chip types that mimic capillary networks and are applied for vascular response analysis in vitro. However, these platforms have a limitation in clearly assessing the physiological phenomena of native blood vessels compared to in vivo evaluation. Here, we developed a simply fabricable tissue-engineered vascular microphysiological platform (TEVMP) with a three-dimensional (3D) vascular structure similar to an artery that can be applied for ex vivo and in vivo evaluation. Furthermore, we applied the TEVMP as ex vivo and in vivo screening systems to evaluate the effect of human CD200 (hCD200) overexpression in porcine endothelial cells (PECs) on vascular xenogeneic immune responses. These screening systems, in contrast to 2D in vitro and cellular xenotransplantation in vivo models, clearly demonstrated that hCD200 overexpression effectively suppressed vascular xenograft rejection. The TEVMP has a high potential as a platform to assess various vascular-related responses.
8

Vasconez Martinez, Mateo Gabriel, Eva I. Reihs, Helene M. Stuetz, Astrid Hafner, Konstanze Brandauer, Florian Selinger, Patrick Schuller, et al. "Using Rapid Prototyping to Develop a Cell-Based Platform with Electrical Impedance Sensor Membranes for In Vitro RPMI2650 Nasal Nanotoxicology Monitoring." Biosensors 14, no. 2 (February 18, 2024): 107. http://dx.doi.org/10.3390/bios14020107.

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Due to advances in additive manufacturing and prototyping, affordable and rapid microfluidic sensor-integrated assays can be fabricated using additive manufacturing, xurography and electrode shadow masking to create versatile platform technologies aimed toward qualitative assessment of acute cytotoxic or cytolytic events using stand-alone biochip platforms in the context of environmental risk assessment. In the current study, we established a nasal mucosa biosensing platform using RPMI2650 mucosa cells inside a membrane-integrated impedance-sensing biochip using exclusively rapid prototyping technologies. In a final proof-of-concept, we applied this biosensing platform to create human cell models of nasal mucosa for monitoring the acute cytotoxic effect of zinc oxide reference nanoparticles. Our data generated with the biochip platform successfully monitored the acute toxicity and cytolytic activity of 6 mM zinc oxide nanoparticles, which was non-invasively monitored as a negative impedance slope on nasal epithelial models, demonstrating the feasibility of rapid prototyping technologies such as additive manufacturing and xurography for cell-based platform development.
9

Xu, Liangcheng, Xin Song, Gwennyth Carroll, and Lidan You. "Novel in vitro microfluidic platform for osteocyte mechanotransduction studies." Integrative Biology 12, no. 12 (December 2020): 303–10. http://dx.doi.org/10.1093/intbio/zyaa025.

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Abstract Osteocytes are the major mechanosensing cells in bone remodeling. Current in vitro bone mechanotransduction research use macroscale devices such as flow chambers; however, in vitro microfluidic devices provide an optimal tool to better understand this biological process with its flexible design, physiologically relevant dimensions and high-throughput capabilities. This project aims to design and fabricate a multi-shear stress, co-culture platform to study the interaction between osteocytes and other bone cells under varying flow conditions. Standard microfluidic design utilizing changing geometric parameters is used to induce different flow rates that are directly proportional to the levels of shear stress, with devices fabricated from standard polydimethylsiloxane (PDMS)-based softlithography processes. Each osteocyte channel (OCY) is connected to an adjacent osteoclast channel (OC) by 20-μm perfusion channels for cellular signaling molecule transport. Significant differences in RANKL levels are observed between channels with different shear stress levels, and we observed that pre-osteoclast differentiation was directly affected by adjacent flow-stimulated osteocytes. Significant decrease in the number of differentiating osteoclasts is observed in the OC channel adjacent to the 2-Pa shear stress OCY channel, while differentiation adjacent to the 0.5-Pa shear stress OCY channel is unaffected compared with no-flow controls. Addition of zoledronic acid showed a significant decrease in osteoclast differentiation, compounding to effect instigated by increasing fluid shear stress. Using this platform, we are able to mimic the interaction between osteocytes and osteoclasts in vitro under physiologically relevant bone interstitial fluid flow shear stress. Our novel microfluidic co-culture platform provides an optimal tool for bone cell mechanistic studies and provides a platform for the discovery of potential drug targets for clinical treatments of bone-related diseases.
10

Foong, Charlene Shu-Fen, Edwin Sandanaraj, Harold B. Brooks, Robert M. Campbell, Beng Ti Ang, Yuk Kien Chong, and Carol Tang. "Glioma-Propagating Cells as an In Vitro Screening Platform." Journal of Biomolecular Screening 17, no. 9 (August 27, 2012): 1136–50. http://dx.doi.org/10.1177/1087057112457820.

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Gliomas are the most devastating of primary adult malignant brain tumors. These tumors are highly infiltrative and can arise from cells with extensive self-renewal capability and chemoresistance, frequently termed glioma-propagating cells (GPCs). GPCs are thus the plausible culprits of tumor recurrence. Treatment strategies that eradicate GPCs will greatly improve disease outcome. Such findings support the use of GPCs as in vitro cellular systems for small-molecule screening. However, the nuances in using GPCs as a cellular screening platform are not trivial. These slow-growing cells are typically cultured as suspension, spheroid structures in serum-free condition supplemented with growth factors. Consequently, replenishment of growth factors throughout the screening period must occur to maintain cells in their undifferentiated state, as the more lineage-committed, differentiated cells are less tumorigenic. We present a case study of a small-molecule screen conducted with GPCs and explain how unique sphere activity assays were implemented to distinguish drug efficacies against the long-term, self-renewing fraction, as opposed to transient-amplifying progenitors, the latter of which are detected in conventional viability assays. We identified Polo-like kinase 1 as a regulator of GPC survival. Finally, we leveraged on public glioma databases to illustrate GPC contribution to disease progression and patient survival outcome.
11

Kamudzandu, M., M. Köse-Dunn, M. G. Evans, R. A. Fricker, and P. Roach. "A micro-fabricated in vitro complex neuronal circuit platform." Biomedical Physics & Engineering Express 5, no. 4 (June 3, 2019): 045016. http://dx.doi.org/10.1088/2057-1976/ab2307.

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12

Redaelli, Loredana, Giovanna Maresca, Sara Tremolada, Christina Kuhn, Matteo Brioschi, Dietmar Hess, Elke Guenther, and Lia Scarabottolo. "NeuroSafe: A human integrated in vitro Neurotoxicity Safety Platform." Journal of Pharmacological and Toxicological Methods 81 (September 2016): 376–77. http://dx.doi.org/10.1016/j.vascn.2016.02.137.

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13

Boos, Julia Alicia, Patrick Mark Misun, Astrid Michlmayr, Andreas Hierlemann, and Olivier Frey. "Microfluidic Multitissue Platform for Advanced Embryotoxicity Testing In Vitro." Advanced Science 6, no. 13 (April 29, 2019): 1900294. http://dx.doi.org/10.1002/advs.201900294.

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14

Butnarasu, Cosmin, Olga Valentina Garbero, Paola Petrini, Livia Visai, and Sonja Visentin. "Permeability Assessment of a High-Throughput Mucosal Platform." Pharmaceutics 15, no. 2 (January 22, 2023): 380. http://dx.doi.org/10.3390/pharmaceutics15020380.

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Permeability across cellular membranes is a key factor that influences absorption and distribution. Before absorption, many drugs must pass through the mucus barrier that covers all the wet surfaces of the human body. Cell-free in vitro tools currently used to evaluate permeability fail to effectively model the complexity of mucosal barriers. Here, we present an in vitro mucosal platform as a possible strategy for assessing permeability in a high-throughput setup. The PermeaPad 96-well plate was used as a permeability system and further coupled to a pathological, tridimensional mucus model. The physicochemical determinants predicting passive diffusion were determined by combining experimental and computational approaches. Drug solubility, size, and shape were found to be the critical properties governing permeability, while the charge of the drug was found to be influential on the interaction with mucus. Overall, the proposed mucosal platform could be a promising in vitro tool to model the complexity of mucosal tissues and could therefore be adopted for drug-permeability profiling.
15

Yang, Yangyang, Yufan Wang, Nan Zheng, Rongshan Cheng, Diyang Zou, Jie Zhao, and Tsung-Yuan Tsai. "Development and Validation of a Novel In Vitro Joint Testing System for Reproduction of In Vivo Dynamic Muscle Force." Bioengineering 10, no. 9 (August 25, 2023): 1006. http://dx.doi.org/10.3390/bioengineering10091006.

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In vitro biomechanical experiments utilizing cadaveric specimens are one of the most effective methods for rehearsing surgical procedures, testing implants, and guiding postoperative rehabilitation. Applying dynamic physiological muscle force to the specimens is a challenge to reconstructing the environment of bionic mechanics in vivo, which is often ignored in the in vitro experiment. The current work aims to establish a hardware platform and numerical computation methods to reproduce dynamic muscle forces that can be applied to mechanical testing on in vitro specimens. Dynamic muscle loading is simulated through numerical computation, and the inputs of the platform will be derived. Then, the accuracy and robustness of the platform will be evaluated through actual muscle loading tests in vitro. The tests were run on three muscles (gastrocnemius lateralis, the rectus femoris, and the semitendinosus) around the knee joint and the results showed that the platform can accurately reproduce the magnitude of muscle strength (errors range from −6.2% to 1.81%) and changing pattern (goodness-of-fit range coefficient ranges from 0.00 to 0.06) of target muscle forces. The robustness of the platform is mainly manifested in that the platform can still accurately reproduce muscle force after changing the hardware combination. Additionally, the standard deviation of repeated test results is very small (standard ranges of hardware combination 1: 0.34 N~2.79 N vs. hardware combination 2: 0.68 N~2.93 N). Thus, the platform can stably and accurately reproduce muscle forces in vitro, and it has great potential to be applied in the future musculoskeletal loading system.
16

Park, Kijun, Yeontaek Lee, and Jungmok Seo. "Recent Advances in High-throughput Platforms with Engineered Biomaterial Microarrays for Screening of Cell and Tissue Behavior." Current Pharmaceutical Design 24, no. 45 (April 16, 2019): 5458–70. http://dx.doi.org/10.2174/1381612825666190207093438.

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In the last decades, bioengineers have developed myriad biomaterials for regenerative medicine. Development of screening techniques is essential for understanding complex behavior of cells in the biological microenvironments. Conventional approaches to the screening of cellular behavior in vitro have limitations in terms of accuracy, reusability, labor-intensive screening, and versatility. Thus, drug screening and toxicology test through in vitro screening platforms have been underwhelming. Recent advances in the high-throughput screening platforms somewhat overcome the limitations of in vitro screening platforms via repopulating human tissues’ biophysical and biomchemical microenvironments with the ability to continuous monitoring of miniaturized human tissue behavior. Herein, we review current trends in the screening platform in which a high-throughput system composed of engineered microarray devices is developed to investigate cell-biomaterial interaction. Furthermore, diverse methods to achieve continuous monitoring of cell behavior via developments of biosensor integrated high-throughput platforms, and future perspectives on high-throughput screening will be provided.
17

Korolj, Anastasia, Carol Laschinger, Chris James, Erding Hu, Claire Velikonja, Nathaniel Smith, Irene Gu, et al. "Curvature facilitates podocyte culture in a biomimetic platform." Lab on a Chip 18, no. 20 (2018): 3112–28. http://dx.doi.org/10.1039/c8lc00495a.

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18

Jiang, B., M. Schmitt, and G. Gargiulo. "P02.24.B A DRUG DISCOVERY PLATFORM FOR COMBINATORIAL TARGETING OF CELL STATES AND ENTITIES." Neuro-Oncology 25, Supplement_2 (September 1, 2023): ii35. http://dx.doi.org/10.1093/neuonc/noad137.109.

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Abstract Glioblastoma (GBM) is a lethal brain tumor with limited therapeutic options. Therapeutic resistance arises from the collaboration among heterogeneous and highly plastic cellular entities and states conserved across GBM patients and the tumor microenvironment.Tumor cells adapt in response to the current standard of care and infiltration of innate immune cells, recurrently acquiring a mesenchymal state that drives therapeutic resistance.Moreover, the blood-brain barrier (BBB) poses challenges to the effectiveness and bioavailability of approved therapeutics, as well as the discovery of new ones.Our lab has developed synthetic locus control regions (sLCRs) as transcriptional reporters for glioblastoma subtypes, enabling the study of cell identity and state transitions in vitro and in vivo. We have combined this tool with validated cellular models for glioblastoma mesenchymal transition and therapeutic resistance to establish an in vitro phenotypic screening platform. Currently, we are utilizing this platform to identify treatment combinations and dosing schemes that aim to overcome innate immunity-driven resistance and synergize with the standard of care. As a proof-of-concept for a new generation of brain tumor target discovery platforms, we will present the setup of our platform and preliminary results for a class of BBB-penetrant drugs.
19

Bazylevich, Andrii, Helena Tuchinsky, Eti Zigman-Hoffman, Ran Weissman, Ofer Shpilberg, Oshrat Hershkovitz-Rokah, Leonid Patsenker, and Gary Gellerman. "Synthesis and Biological Studies of New Multifunctional Curcumin Platforms for Anticancer Drug Delivery." Medicinal Chemistry 15, no. 5 (July 2, 2019): 537–49. http://dx.doi.org/10.2174/1573406415666181203112220.

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Background: Scientists have extensively investigated curcumin, yielding many publications on treatments of cancer. Numerous derivatives of curcumin were synthesized, evaluated for their anti-oxidant and free-radical scavenging, SAR, ADME properties and tested in anticancer applications. Objective: We decided to exploit curcumin as a bioactive core platform for carrying anticancer drugs, which likely possesses a carboxyl moiety for potential linkage to the carrier for drug delivery. Methods: The goal of this work is to develop biolabile multifunctional curcumin platforms towards anticancer drug delivery, including determination of drug release profiling in hydrolytic media, in vitro cytotoxicity, antioxidant properties and blockage of relevant cell survival pathways. Results: We report on a facile synthesis of the bioactive multifunctional curcumin-based platforms linked to a variety of anticancer drugs like amonafide and chlorambucil, and release of the drugs in a hydrolytic environment. The leading curcumin-based platform has presented antioxidant activity similar to curcumin, but with much more potent cytotoxicity in vitro in agreement with the augmented blockage of the NF-kB cell survival pathway. Conclusion: The approach presented here may prove beneficial for bioactive curcumin-based delivery applications where multiple drug delivery is required in a consecutive and controlled mode.
20

Yao, Xuerui, Ji Hyun Kang, Kee-Pyo Kim, Hyogeun Shin, Zhe-Long Jin, Hao Guo, Yong-Nan Xu, et al. "Production of Highly Uniform Midbrain Organoids from Human Pluripotent Stem Cells." Stem Cells International 2023 (September 29, 2023): 1–21. http://dx.doi.org/10.1155/2023/3320211.

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Brain organoids have been considered as an advanced platform for in vitro disease modeling and drug screening, but numerous roadblocks exist, such as lack of large-scale production technology and lengthy protocols with multiple manipulation steps, impeding the industrial translation of brain organoid technology. Here, we describe the high-speed and large-scale production of midbrain organoids using a high-throughput screening-compatible platform within 30 days. Micro midbrain organoids (µMOs) exhibit a highly uniform morphology and gene expression pattern with minimal variability. Notably, µMOs show dramatically accelerated maturation, resulting in the generation of functional µMOs within only 30 days of differentiation. Furthermore, individual µMOs display highly consistent responsiveness to neurotoxin, suggesting their usefulness as an in vitro high-throughput drug toxicity screening platform. Collectively, our data indicate that µMO technology could represent an advanced and robust platform for in vitro disease modeling and drug screening for human neuronal diseases.
21

Zhang, Ning, Vincent Milleret, Greta Thompson-Steckel, Ning-Ping Huang, János Vörös, Benjamin R. Simona, and Martin Ehrbar. "Soft Hydrogels Featuring In-Depth Surface Density Gradients for the Simple Establishment of 3D Tissue Models for Screening Applications." SLAS DISCOVERY: Advancing the Science of Drug Discovery 22, no. 5 (March 9, 2017): 635–44. http://dx.doi.org/10.1177/2472555217693191.

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Three-dimensional (3D) cell culture models are gaining increasing interest for use in drug development pipelines due to their closer resemblance to human tissues. Hydrogels are the first-choice class of materials to recreate in vitro the 3D extra-cellular matrix (ECM) environment, important in studying cell-ECM interactions and 3D cellular organization and leading to physiologically relevant in vitro tissue models. Here we propose a novel hydrogel platform consisting of a 96-well plate containing pre-cast synthetic PEG-based hydrogels for the simple establishment of 3D (co-)culture systems without the need for the standard encapsulation method. The in-depth density gradient at the surface of the hydrogel promotes the infiltration of cells deposited on top of it. The ability to decouple hydrogel production and cell seeding is intended to simplify the use of hydrogel-based platforms and thus increase their accessibility. Using this platform, we established 3D cultures relevant for studying stem cell differentiation, angiogenesis, and neural and cancer models.
22

Hirsch, C., J. P. Kaiser, F. Wessling, K. Fischer, M. Roesslein, P. Wick, and H. F. Krug. "A novel comprehensive evaluation platform to assess nanoparticle toxicityin vitro." Journal of Physics: Conference Series 304 (July 6, 2011): 012053. http://dx.doi.org/10.1088/1742-6596/304/1/012053.

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Hirsch, Cordula, Tina Buerki-Thurnherr, Lisong Xiao, Osman Arslan, Bruno Wampfler, Sanjay Mathur, Matthias Roesslein, Peter Wick, and Harald F. Krug. "A comprehensive evaluation platform to assess nanoparticle toxicity in vitro." Toxicology Letters 211 (June 2012): S41. http://dx.doi.org/10.1016/j.toxlet.2012.03.172.

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Kornuta, Jeffrey A., Matthew E. Nipper, and J. Brandon Dixon. "Low-cost microcontroller platform for studying lymphatic biomechanics in vitro." Journal of Biomechanics 46, no. 1 (January 2013): 183–86. http://dx.doi.org/10.1016/j.jbiomech.2012.09.031.

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25

Chan, Ki, and Tzi Bun Ng. "In-vitro nanodiagnostic platform through nanoparticles and DNA-RNA nanotechnology." Applied Microbiology and Biotechnology 99, no. 8 (March 13, 2015): 3359–74. http://dx.doi.org/10.1007/s00253-015-6506-4.

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DiCicco, Matthew, and Suresh Neethirajan. "An in vitro microfluidic gradient generator platform for antimicrobial testing." BioChip Journal 8, no. 4 (December 2014): 282–88. http://dx.doi.org/10.1007/s13206-014-8406-6.

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27

Pitoulis, Fotios, Samuel A. Watson, Eef Dries, Ifigeneia Bardi, Raquel Nunez-Toldra, Filippo Perbellini, and Cesare M. Terracciano. "Myocardial Slices - A Novel Platform for In Vitro Biomechanical Studies." Biophysical Journal 116, no. 3 (February 2019): 30a. http://dx.doi.org/10.1016/j.bpj.2018.11.203.

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28

Y Wong, Gabriel K., Kevin D. Costa, Bernard Fermini, and Ronald A. Li. "Modeling the heart with Novoheart’s MyHeart™ platform." Future Drug Discovery 2, no. 2 (April 1, 2020): FDD32. http://dx.doi.org/10.4155/fdd-2020-0003.

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Reliable and predictive human-specific in vitro heart models can revolutionize drug discovery and development. With the advent of pluripotent stem cell technologies, human cardiomyocytes can now be readily produced in large quantities. Using tissue engineering techniques, they can be further assembled into cardiac tissues of specific 2D and 3D configurations, to create models that behave and function like the native human heart. Novoheart (BC, Canada) uniquely offers the MyHeartTM Platform of bioengineered human heart constructs, designed to provide researchers with effective models of either healthy or diseased human hearts. As in vitro, human-based assays become more widely accepted, the next decade could witness a shift away from animal testing towards more accurate and scalable human assays like the MyHeartTM Platform.
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Laternser, Sandra, Chiara Cianciolo Cosentino, Justyna M. Przystal, Susanne Dettwiler, Elisabeth Jane Rushing, Nicolas U. Gerber, Ana Guerreiro Stücklin, et al. "MODL-22. DEVELOPING A REAL-TIME PERSONALIZED DRUG TESTING PLATFORM FOR PEDIATRIC CNS CANCERS." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii415. http://dx.doi.org/10.1093/neuonc/noaa222.595.

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Abstract INTRODUCTION The relatively small size of biopsied CNS tumors has presented a historical challenge for real-time drug screens. Moreover, in vivo assessment of drug response does not often benefit patients with aggressive gliomas given the relatively long time (>8 months) of tumor engraftment in the classic mouse PDX models. Here, we aimed to develop an innovative real-time in vivo and in vitro drug screening platform capable of analyzing a minimal number (<1E6) of cells obtained at biopsy. METHODS Existing primary cells were used to test 6 different culture platforms. The top platform was selected and used to expand tumor cells obtained of DMG biopsy. Tumor cells were validated using the minION sequencing platform. Single and combination drug (n=7) screens were performed. Effective drugs were further evaluated in zebrafish PDX and non-tumor bearing models to assess efficacy and toxicity, respectively. RESULTS A total of 8 biopsies were obtained. Successful cell expansion was achieved in 6/8 (75%) and a limited drug screen in 3/6 (50%) of cases. Single and combination drug (n=7) assays identified responder and non-responders to candidate drugs. Systemic toxicity of effective drugs was tested in non-tumor bearing zebrafish. Tumor cells were engrafted in zebrafish providing the opportunity for an in vivo screen. The entire process was completed within 21 days on average. CONCLUSIONS A novel platform was developed for rapid in vitro and in vivo drug screens of tumor cells obtained at biopsy. This platform will provide the opportunity to establish personalized therapy for heterogeneous cancers including DMGs.
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Morgan, Molly M., Linda A. Schuler, Jordan C. Ciciliano, Brian P. Johnson, Elaine T. Alarid, and David J. Beebe. "Modeling chemical effects on breast cancer: the importance of the microenvironment in vitro." Integrative Biology 12, no. 2 (February 2020): 21–33. http://dx.doi.org/10.1093/intbio/zyaa002.

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Abstract Accumulating evidence suggests that our ability to predict chemical effects on breast cancer is limited by a lack of physiologically relevant in vitro models; the typical in vitro breast cancer model consists of the cancer cell and excludes the mammary microenvironment. As the effects of the microenvironment on cancer cell behavior becomes more understood, researchers have called for the integration of the microenvironment into in vitro chemical testing systems. However, given the complexity of the microenvironment and the variety of platforms to choose from, identifying the essential parameters to include in a chemical testing platform is challenging. This review discusses the need for more complex in vitro breast cancer models and outlines different approaches used to model breast cancer in vitro. We provide examples of the microenvironment modulating breast cancer cell responses to chemicals and discuss strategies to help pinpoint what components should be included in a model.
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Tognarelli, Selene, Gastone Ciuti, Alessandro Diodato, Andrea Cafarelli, and Arianna Menciassi. "Robotic Platform for High-Intensity Focused Ultrasound Surgery Under Ultrasound Tracking: The FUTURA Platform." Journal of Medical Robotics Research 02, no. 03 (March 27, 2017): 1740010. http://dx.doi.org/10.1142/s2424905x17400104.

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Focused Ultrasound Therapy Using Robotic Approaches (FUTURA) is a European seventh research framework programme project aimed at creating an innovative platform for Focused Ultrasound Surgery (FUS). Merging robotics together with noninvasive ultrasound monitoring and therapy has the goal to improve flexibility, precision and accuracy of the intervention, thus enabling a large use of FUS for the treatment of different pathologies. The FUTURA platform, based on FUS therapy under US tracking, has been set up with the first clinical target of kidney cancer treatment. Experiments for assessing the accuracy of the FUS delivery with the FUTURA platform have been carried out under in vitro static conditions and presented here as preliminary outcomes of this study.
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Marrero-Berrios, Ileana, Anil Shrirao, Charles P. Rabolli, Rishabh Hirday, Rene S. Schloss, and Martin L. Yarmush. "Multi-layer stackable tissue culture platform for 3D co-culture." TECHNOLOGY 08, no. 01n02 (March 2020): 37–49. http://dx.doi.org/10.1142/s233954782050003x.

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In vitro tools, which can enable development of models that replicate the cell microenvironment associated with complex diseases such as osteoarthritis (OA), are critically needed. In OA, catabolic and inflammatory processes orchestrated by multiple cell types lead to the eventual destruction of articular cartilage. To address this need, our group developed a device that will enable investigation of complex cell systems. Our stackable tissue culture insert was fabricated and characterized with respect to biocompatibility, ease of use, and potential for tissue culture applications. The stackable tissue culture inserts can be easily modified, fabricated, and assembled into commercially available multi-well plates. In vitro studies conducted with three different cell types demonstrated high cell viability and functional secretion when cultured in the stackable inserts. Furthermore, synergistic effects when the three cell types were cultured together were observed. This demonstrates the need to more fully interrogate in vitro culture systems, and this stackable insert can provide a tool to fill the current technological void to do so.
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Rodriguez-Garcia, Aida, Jacqueline Oliva-Ramirez, Claudia Bautista-Flores, and Samira Hosseini. "3D In Vitro Human Organ Mimicry Devices for Drug Discovery, Development, and Assessment." Advances in Polymer Technology 2020 (August 10, 2020): 1–41. http://dx.doi.org/10.1155/2020/6187048.

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The past few decades have shown significant advancement as complex in vitro humanized systems have substituted animal trials and 2D in vitro studies. 3D humanized platforms mimic the organs of interest with their stimulations (physical, electrical, chemical, and mechanical). Organ-on-chip devices, including in vitro modelling of 3D organoids, 3D microfabrication, and 3D bioprinted platforms, play an essential role in drug discovery, testing, and assessment. In this article, a thorough review is provided of the latest advancements in the area of organ-on-chip devices targeting liver, kidney, lung, gut, heart, skin, and brain mimicry devices for drug discovery, development, and/or assessment. The current strategies, fabrication methods, and the specific application of each device, as well as the advantages and disadvantages, are presented for each reported platform. This comprehensive review also provides some insights on the challenges and future perspectives for the further advancement of each organ-on-chip device.
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Verdile, Nicole, Federica Camin, Radmila Pavlovic, Rolando Pasquariello, Milda Stuknytė, Ivano De Noni, Tiziana A. L. Brevini, and Fulvio Gandolfi. "Distinct Organotypic Platforms Modulate Rainbow Trout (Oncorhynchus mykiss) Intestinal Cell Differentiation In Vitro." Cells 12, no. 14 (July 13, 2023): 1843. http://dx.doi.org/10.3390/cells12141843.

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In vitro organotypic cell-based intestinal platforms, able to faithfully recapitulate the complex functions of the organ in vivo, would be a great support to search for more sustainable feed ingredients in aquaculture. We previously demonstrated that proliferation or differentiation of rainbow trout intestinal cell lines is dictated by the culture environment. The aim of the present work was to develop a culture platform that can efficiently promote cell differentiation into mature enterocytes. We compared four options, seeding the RTpiMI cell line derived from the proximal intestine on (1) polyethylene terephthalate (PET) culture inserts ThinCert™ (TC), (2) TC coated with the solubilized basement membrane matrix Matrigel® (MM), (3) TC with the rainbow trout fibroblast cell line RTskin01 embedded within the Matrigel® matrix (MMfb), or (4) the highly porous polystyrene scaffold Alvetex® populated with the abovementioned fibroblast cell line (AV). We evaluated the presence of columnar cells with a clear polarization of brush border enzymes, the formation of an efficient barrier with a significant increase in transepithelial electrical resistance (TEER), and its ability to prevent the paracellular flux of large molecules but allow the transit of small compounds (proline and glucose) from the apical to the basolateral compartment. All parameters improved moving from the simplest (TC) through the more complex platforms. The presence of fibroblasts was particularly effective in enhancing epithelial cell differentiation within the AV platform recreating more closely the complexity of the intestinal mucosa, including the presence of extracellular vesicles between fibroblasts and epithelial cells.
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Harrill, Joshua A., Logan J. Everett, Derik E. Haggard, Thomas Sheffield, Joseph L. Bundy, Clinton M. Willis, Russell S. Thomas, Imran Shah, and Richard S. Judson. "High-Throughput Transcriptomics Platform for Screening Environmental Chemicals." Toxicological Sciences 181, no. 1 (February 4, 2021): 68–89. http://dx.doi.org/10.1093/toxsci/kfab009.

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Abstract New approach methodologies (NAMs) that efficiently provide information about chemical hazard without using whole animals are needed to accelerate the pace of chemical risk assessments. Technological advancements in gene expression assays have made in vitro high-throughput transcriptomics (HTTr) a feasible option for NAMs-based hazard characterization of environmental chemicals. In this study, we evaluated the Templated Oligo with Sequencing Readout (TempO-Seq) assay for HTTr concentration-response screening of a small set of chemicals in the human-derived MCF7 cell model. Our experimental design included a variety of reference samples and reference chemical treatments in order to objectively evaluate TempO-Seq assay performance. To facilitate analysis of these data, we developed a robust and scalable bioinformatics pipeline using open-source tools. We also developed a novel gene expression signature-based concentration-response modeling approach and compared the results to a previously implemented workflow for concentration-response analysis of transcriptomics data using BMDExpress. Analysis of reference samples and reference chemical treatments demonstrated highly reproducible differential gene expression signatures. In addition, we found that aggregating signals from individual genes into gene signatures prior to concentration-response modeling yielded in vitro transcriptional biological pathway altering concentrations (BPACs) that were closely aligned with previous ToxCast high-throughput screening assays. Often these identified signatures were associated with the known molecular target of the chemicals in our test set as the most sensitive components of the overall transcriptional response. This work has resulted in a novel and scalable in vitro HTTr workflow that is suitable for high-throughput hazard evaluation of environmental chemicals.
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Lee, Boeun, Woo Kyeom Yang, Sarang Kim, Hee-Ra Lee, Donghyeon Kim, and Jongman Yoo. "Abstract LB099: Organoid-based drug efficacy evaluation model for immunotherapy." Cancer Research 83, no. 8_Supplement (April 14, 2023): LB099. http://dx.doi.org/10.1158/1538-7445.am2023-lb099.

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Abstract The endogenous immune system of patients are known to be activated through immuno-oncology drug, which activates the patient’s own immune system to target and attack tumors. Due to the relatively low occurrence of side effects and sustained success, these therapeutic techniques have gradually replaced the traditional cancer treatment regimen. The creation of an in-vitro screening platform for pre-evaluating the efficacy of immunotherapeutic drug candidates was highly essential despite the fact that many of the new emerging therapies had failed clinical trials.An in-vitro platform mirroring the interaction between a patient's unique Major Histocompatibility Complex (MHC) and T-cell receptor (TCR) is necessary for predicting the precise efficacy of immunotherapies. The tumor cells' MHC antigen molecule attaches to the T-cell receptor (TCR), allowing T-cells to manifest their tumor-killing activities as a result. The link between immunological checkpoint (ICP) in tumor cells and their receptors in T cells allows tumor cells to evade the effects of T-cell-mediated tumor death.We would like to introduce our "ODISEI" platform, a robust efficacy evaluation tool that enables the recapitulation of a patient's unique immune system, utilizing tumor organoids and PBMC from the same donors. Using PD-1/PD-L1 inhibiting antibodies, the enhanced functionality of our ODISEI platform as an effective evaluation platform for immunotherapy drugs was thoroughly examined. Additionally, we created several ODISEI platforms in order to recreate the precise interactions between tumor organoids and various immune sub-populations (T-cells, macrophages, regulatory T-cells, and dendritic cells). Our ODISEI platforms were validated by utilizing a variety of different drug candidates and evaluating their ability to eradicate tumors upon interaction with various reactive immune cells and tumors. As a result, our highly innovative ODISEI platform can be used to screen a variety of different immunotherapeutic drug candidates and distinguish their precise efficacy. Citation Format: Boeun Lee, Woo Kyeom Yang, Sarang Kim, Hee-Ra Lee, Donghyeon Kim, Jongman Yoo. Organoid-based drug efficacy evaluation model for immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB099.
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Abaci, Hasan Erbil, Karl Gledhill, Zongyou Guo, Angela M. Christiano, and Michael L. Shuler. "Pumpless microfluidic platform for drug testing on human skin equivalents." Lab on a Chip 15, no. 3 (2015): 882–88. http://dx.doi.org/10.1039/c4lc00999a.

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38

Zhang, Shun, Zhengpeng Wan, and Roger D. Kamm. "Vascularized organoids on a chip: strategies for engineering organoids with functional vasculature." Lab on a Chip 21, no. 3 (2021): 473–88. http://dx.doi.org/10.1039/d0lc01186j.

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39

Matre, Polina R., Byung-Kwon Choi, Oliver Delgado, and John K. Westwick. "Abstract 3440: Novel in vitro TME platform for rapid cancer therapeutic and target discovery." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3440. http://dx.doi.org/10.1158/1538-7445.am2022-3440.

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Abstract The tumor microenvironment (TME) plays an important role in malignances as tumors react with a multitude of changes and microenvironmental cues. TME components modulate tumor profiles and treatment responses, thereby affecting sensitivity to anti-cancer agents. The limited clinical success of therapeutics, including immunotherapies, emphasizes an unmet need to identify new targets and develop preclinical platforms to accelerate anti-cancer drug discovery. Although in vitro methods are essential in early drug development, standard approaches, which do not capture the complexity of TME, have been historically favored for both discovery and evaluation of potential therapeutics. Resonant's IMPACT TME platform couples proprietary high-fidelity TME models with deep data-driven analytics for rapid and cost-effective discovery of novel targets and antibody-based therapeutics. Target and candidate selection is based upon a biology-forward approach driven by live animal immune systems and functional screening prior to target identification. Identified candidates are then prioritized via integration of publicly available information with internal functional and multi-omic data. Resultant targets display attributes, such as tumor selectivity and immune-modulatory capabilities, that are amenable to several therapeutic modalities, including antibody-drug conjugates (ADCs) and bispecifics. To date, Resonant has interrogated a variety of solid tumor types and thousands of candidates resulting in an expanding library of actionable antibodies and targets. Representative examples of in vitro and in vivo efficacy of selected candidates derived from the IMPACT TME platform are presented, highlighting their individual potential and validating the Resonant approach. As technological advances transform the landscape of therapeutics, the need for novel targets is burgeoning, and Resonant’s TME-driven platform provides a valuable tool to meet these demands. Citation Format: Polina R. Matre, Byung-Kwon Choi, Oliver Delgado, John K. Westwick. Novel in vitro TME platform for rapid cancer therapeutic and target discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3440.
40

Muñoz, Victor F., Isabel Garcia-Morales, Juan Carlos Fraile-Marinero, Javier Perez-Turiel, Alvaro Muñoz-Garcia, Enrique Bauzano, Irene Rivas-Blanco, Jose María Sabater-Navarro, and Eusebio de la Fuente. "Collaborative Robotic Assistant Platform for Endonasal Surgery: Preliminary In-Vitro Trials." Sensors 21, no. 7 (March 26, 2021): 2320. http://dx.doi.org/10.3390/s21072320.

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Endonasal surgery is a minimally invasive approach for the removal of pituitary tumors (sarcomas). In this type of procedure, the surgeon has to complete the surgical maneuvers for sarcoma resection with extreme precision, as there are many vital structures in this area. Therefore, the use of robots for this type of intervention could increase the success of the intervention by providing accurate movements. Research has focused on the development of teleoperated robots to handle a surgical instrument, including the use of virtual fixtures to delimit the working area. This paper aims to go a step further with a platform that includes a teleoperated robot and an autonomous robot dedicated to secondary tasks. In this way, the aim is to reduce the surgeon’s workload so that he can concentrate on his main task. Thus, the article focuses on the description and implementation of a navigator that coordinates both robots via a force/position control. Finally, both the navigation and control scheme were validated by in-vitro tests.
41

Wilson, Brice A. P., Donna Voeller, Emily A. Smith, Antony Wamiru, Ekaterina I. Goncharova, Gang Liu, Stanley Lipkowitz, and Barry R. O’Keefe. "In Vitro Ubiquitination Platform Identifies Methyl Ellipticiniums as Ubiquitin Ligase Inhibitors." SLAS DISCOVERY: Advancing the Science of Drug Discovery 26, no. 7 (April 21, 2021): 870–84. http://dx.doi.org/10.1177/24725552211000675.

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The transfer of the small protein ubiquitin to a target protein is an intricately orchestrated process called ubiquitination that results in modulation of protein function or stability. Proper regulation of ubiquitination is essential, and dysregulation of this process is implicated in several human diseases. An example of a ubiquitination cascade that is a central signaling node in important disease-associated pathways is that of CBLB [a human homolog of a viral oncogene Casitas B-lineage lymphoma (CBL) from the Cas NS-1 murine retrovirus], a RING finger ubiquitin ligase (E3) whose substrates include a number of important cell-signaling kinases. These include kinases important in immune function that act in the T cell receptor and costimulatory pathways, the Tyro/Axl/MerTK (TAM) receptor family in natural killer (NK) cells, as well as growth factor receptor kinases like epidermal growth factor receptor (EGFR). Loss of CBLB has been shown to increase innate and adaptive antitumor immunity. This suggests that small-molecule modulation of CBLB E3 activity could enhance antitumor immunity in patients. To explore the hypothesis that enzymatic inhibition of E3s may result in modulation of disease-related signaling pathways, we established a high-throughput screen of >70,000 chemical entities for inhibition of CBLB activity. Although CBLB was chosen as a proof-of-principle target for inhibitor discovery, we demonstrate that our assay is generalizable to monitoring the activity of other ubiquitin ligases. We further extended our observed in vitro inhibition with additional cell-based models of CBLB activity. From these studies, we demonstrate that a class of natural product–based alkaloids, known as methyl ellipticiniums (MEs), is capable of inhibiting ubiquitin ligases intracellularly.
42

Boylan, Brian, Olivia McDermott, and Niall T. Kinahan. "Manufacturing Control System Development for an In Vitro Diagnostic Product Platform." Processes 9, no. 6 (May 31, 2021): 975. http://dx.doi.org/10.3390/pr9060975.

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The current in vitro diagnostic design process is a combination of methods from engineering disciplines and from government regulatory agencies. The goal of design processes that have been developed is to ensure that a new product meets the user’s expectations and is safe and effective in providing its claimed benefits and proper functioning, otherwise known as the essential design outputs. In order to improve the ability of designers and auditors to ascertain the safety and efficacy of a product, the use of design controls has been adopted that specify a method of evaluating the design process at several key stages. The main objective of this research was to examine the resolution and architectural details necessary to build an adequate manufacturing control system to assure the EDO outputs in large IVD instruments in the company under study. The control system is the defined inspections and test processes to delineate between acceptable and unacceptable product before release for sale. The authors reviewed current design control regulatory requirements within the IVD industry, as well as design controls in other regulated industries. This research was completed to determine what opportunities could be transferred to large in-vitro IVD instruments using an IVD manufacturer as a case study. In conclusion, the research identified three areas where a properly configured EDO can add value within IVD instrument design and manufacture, namely: (1) development of a control system which is fit for purpose; (2) a mechanism to manage and proliferate key design knowledge within the organisation and thereby manage outsourced services; and (3) implementing a scaled engineering change process because changes impacting EDO naturally require extra regulatory and engineering oversight.
43

Choi, Jin-Ha, Hyeon-Yeol Cho, and Jeong-Woo Choi. "Microdevice Platform for In Vitro Nervous System and Its Disease Model." Bioengineering 4, no. 4 (September 13, 2017): 77. http://dx.doi.org/10.3390/bioengineering4030077.

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44

Nguyen, Duong Thanh, Yantao Fan, Yasemin M. Akay, and Metin Akay. "Investigating Glioblastoma Angiogenesis Using A 3D in Vitro GelMA Microwell Platform." IEEE Transactions on NanoBioscience 15, no. 3 (April 2016): 289–93. http://dx.doi.org/10.1109/tnb.2016.2528170.

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45

Kumaria, Ashwin. "In Vitro Models as a Platform to Investigate Traumatic Brain Injury." Alternatives to Laboratory Animals 45, no. 4 (September 2017): 201–11. http://dx.doi.org/10.1177/026119291704500405.

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46

Weber, Thomas J., Jordan N. Smith, Zana A. Carver, and Charles Timchalk. "Non-invasive saliva human biomonitoring: development of an in vitro platform." Journal of Exposure Science & Environmental Epidemiology 27, no. 1 (November 11, 2015): 72–77. http://dx.doi.org/10.1038/jes.2015.74.

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47

HAGIWARA, Masaya, Rina NOBATA, and Tomohiro KAWAHARA. "In vitro 3D culture platform for elucidation of branching pattern formations." Proceedings of the Bioengineering Conference Annual Meeting of BED/JSME 2017.29 (2017): 2A41. http://dx.doi.org/10.1299/jsmebio.2017.29.2a41.

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Jusoh, Norhana, Jihoon Ko, and Noo Li Jeon. "Microfluidics-based skin irritation test using in vitro 3D angiogenesis platform." APL Bioengineering 3, no. 3 (September 2019): 036101. http://dx.doi.org/10.1063/1.5093975.

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49

York, S. L., P. Sethu, and M. M. Saunders. "In vitro osteocytic microdamage and viability quantification using a microloading platform." Medical Engineering & Physics 38, no. 10 (October 2016): 1115–22. http://dx.doi.org/10.1016/j.medengphy.2016.06.002.

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50

Symosko, Krista Maye, Katherine A. Watkins, E. Rose Lawson, In Ki Cho, Anthony W. S. Chan, and Charles A. Easley. "A novel in vitro fluorescent reporter platform for identifying male contraceptives." Fertility and Sterility 112, no. 3 (September 2019): e305. http://dx.doi.org/10.1016/j.fertnstert.2019.07.889.

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