Project description:Adoptive cellular therapy with chimeric antigen receptor T cells (car-ts) has recently received approval from Health Canada and the U.S. Food and Drug Administration after remarkable and durable remissions were seen in children with recurrent or refractory leukemia and adults with non-Hodgkin lymphoma-responses that were so impressive that a shift in the paradigm of care has now occurred for children with acute lymphoblastic leukemia. The concept behind car-t immunotherapy is that modification of a patient's own T cells to facilitate their localization to the cancer cell, with subsequent activation of the T cell effector mechanism and proliferation, will result in targeted killing of cancer cells. The car-ts are a novel drug in that the starting material for the manufacture of the car-t product comes from the patient, whose viable T cells are then genetically modified. Thus, collaboration is needed between the pharmaceutical companies, which must meet good manufacturing standards for each patient's unique product, and the treating sites. For regulators and health authorities, this new class of drugs requires new paradigms for assessment and approval. Treatments with car-ts require that institutions address unique logistics requirements and management of novel toxicities. The Hospital for Sick Children has had early experience with both the licensing of clinical trials and the introduction of the first commercial product. Here, we provide an overview of basic concepts and treatment, with caveats drawn from what we have learned thus far in bringing this new therapy to the clinical front line.
Project description:Dynamic performance has long been critical for micro-electro-mechanical system (MEMS) devices and is significantly affected by damping. Different structural vibration conditions lead to different damping effects, including border and amplitude effects, which represent the effect of gas flowing around a complicated boundary of a moving plate and the effect of a large vibration amplitude, respectively. Conventional models still lack a complete understanding of damping and cannot offer a reasonably good estimate of the damping coefficient for a case with both effects. Expensive efforts have been undertaken to consider these two effects, yet a complete model has remained elusive. This paper investigates the dynamic performance of vibrated structures via theoretical and numerical methods simultaneously, establishing a complete model in consideration of both effects in which the analytical expression is given, and demonstrates a deviation of at least threefold lower than current studies by simulation and experimental results. This complete model is proven to successfully characterize the squeeze-film damping and dynamic performance of oscillators under comprehensive conditions. Moreover, a series of simulation models with different dimensions and vibration statuses are introduced to obtain a quick-calculating factor of the damping coefficient, thus offering a previously unattainable damping design guide for MEMS devices.
Project description:The extravasation of tumor cells is a key event in tumor metastasis. However, the mechanism underlying tumor cell extravasation remains unknown, mainly hindered by obstacles from the lack of complexity of biological tissues in conventional cell culture, and the costliness and ethical issues of in vivo experiments. Thus, a cheap, time and labor saving, and most of all, vascular microenvironment-mimicking research model is desirable. Herein, we report a microfluidic chip-based tumor extravasation research model which is capable of simultaneously simulating both mechanical and biochemical microenvironments of human vascular systems and analyzing their synergistic effects on the tumor extravasation. Under different mechanical conditions of the vascular system, the tumor cells (HeLa cells) had the highest viability and adhesion activity in the microenvironment of the capillary. The integrity of endothelial cells (ECs) monolayer was destroyed by tumor necrosis factor-α (TNF-α) in a hemodynamic background, which facilitated the tumor cell adhesion, this situation was recovered by the administration of platinum nanoparticles (Pt-NPs). This model bridges the gap between cell culture and animal experiments and is a promising platform for studying tumor behaviors in the vascular system.
Project description:The development of microelectromechanical systems has resulted in the rapid development of polydimethylpolysiloxane (PDMS) microfluidic devices for drug screening models. Various cell functions, such as the response of endothelial cells to fluids, have been elucidated using microfluidic devices. Additionally, organ-on-a-chip systems that include organs that are important for biological circulation, such as the heart, liver, pancreas, kidneys, and brain, have been developed. These organs realize the biological circulation system in a manner that cannot be reproduced by artificial organs; however, the flow channels between the organs are often artificially created by PDMS. In this study, we developed a microfluidic device consisting only of cells, by combining cell sheet technology with microtitanium wires. Microwires were placed between stacked fibroblast cell sheets, and the cell sheets adhered to each other, after which the microwires were removed leaving a luminal structure with a size approximately equal to the arteriolar size. The lumen structure was constructed using wires with diameters of 50, 100, 150, and 200 μm, which were approximations of the arteriole diameters. Furthermore, using a perfusion device, we successfully perfused the luminal structure created inside the cell sheets. The results revealed that a culture solution can be supplied to a cell sheet with a very high cell density. The biofabrication technology proposed in this study can contribute to the development of organ-on-a-chip systems.
Project description:At present, point-of-care (POC) diagnostics typically provide a binary indication of health status (e.g., home pregnancy test strip). Before anticipatory use of diagnostics for assessment of complex diseases becomes widespread, development of sophisticated bioassays capable of quantitatively measuring disease biomarkers is necessary. Successful translation of new bioassays into clinical settings demands the ability to monitor both the onset and progression of disease. Here we report on a clinical POC diagnostic that enables rapid quantitation of an oral disease biomarker in human saliva by using a monolithic disposable cartridge designed to operate in a compact analytical instrument. Our microfluidic method facilitates hands-free saliva analysis by integrating sample pretreatment (filtering, enrichment, mixing) with electrophoretic immunoassays to quickly measure analyte concentrations in minimally pretreated saliva samples. Using 20 microl of saliva, we demonstrate rapid (<10 min) measurement of the collagen-cleaving enzyme matrix metalloproteinase-8 (MMP-8) in saliva from healthy and periodontally diseased subjects. In addition to physiologically measurable indicators of periodontal disease, conventional measurements of salivary MMP-8 were used to validate the microfluidic assays described in this proof-of-principle study. The microchip-based POC diagnostic demonstrated is applicable to rapid, reliable measurement of proteinaceous disease biomarkers in biological fluids.
Project description:Microfluidic devices provide a low-input and efficient platform for single-cell RNA-seq (scRNA-Seq). Here we present microfluidic diffusion-based RNA-seq (MID-RNA-seq) for conducting scRNA-seq with a diffusion-based reagent swapping scheme. This device incorporates cell trapping, lysis, reverse transcription and PCR amplification all in one microfluidic chamber. MID-RNA-Seq provides high data quality that is comparable to existing scRNA-seq methods while implementing a simple device design that permits multiplexing. The robustness and scalability of MID-RNA-Seq device will be important for transcriptomic studies of scarce cell samples.
Project description:The search for next-generation biomarkers has enabled cell-based diagnostics in a number of disciplines ranging from oncology to pharmacogenetics. However, cell-based diagnostics are still far from clinical reality due to the complex assays and associated protocols which typically require cell isolation, lysis, DNA extraction, amplification, and detection steps. Leveraging recent advances in microfluidics, many biochemical assays have been translated onto microfluidic platforms. We have compared and summarized recent advances in modular approaches toward the realization of fully-integrated, cell-based molecular diagnostics for clinical and point-of-care applications.
Project description:The generator, which combines convolutional neural network (CNN) and Transformer as its core modules, serves as the primary model for the handwriting font generation network and demonstrates effective performance. However, there are still problems with insufficient feature extraction in the overall structure of the font, the thickness of strokes, and the curvature of strokes, resulting in subpar detail in the generated fonts. To solve the problems, we propose a method for constructing a handwritten font generation model based on Pyramid Squeeze Attention, called PSA-HWT. The PSA-HWT model is divided into two parts: an encoder and a decoder. In the encoder, a multi-branch structure is used to extract spatial information at different scales from the input feature map, achieving multi-scale feature extraction. This helps better capture the semantic information and global structure of the font, aiding the generation model in understanding fine-grained features such as the shape, thickness, and curvature of the font. In the decoder, it uses a self-attention mechanism to capture dependencies across various positions in the input sequence. This helps to better understand the relationship between the generated strokes or characters and the handwritten font being generated, ensuring the overall coherence of the generated handwritten text. The experimental results on the IAM dataset demonstrate that PSA-HWT achieves a 16.35% decrease in Fréchet inception distance (FID) score and a 13.09% decrease in Geometry Score (GS) compared to the current advanced methods. This indicates that PSA-HWT generates handwritten fonts of higher quality, making it more practically valuable.