microfluidics, [9] centrifugation, [10] electrohydrodynamics, [11] and two-photon lithography [6] have been developed to fabricate microparticles with selected physical traits. However, the combination of all of these physical traits and further customization of properties in a single microparticle to augment the functionality, are hindered by the limitations to combining complementary physical anisotropies. In parallel, research has also focused on chemical anisotropy. Extended anisotropy can be implemented with the addition of subdivisions during fabrication, albeit limited by the process, or with posterior functionalization which may be obstructed by the stochastic nature of suspended microparticles in a reactive solution or limited by the available orthogonal chemical reaction sites present on the surface of the microparticles. [12] Imaginative solutions have been used to fabricate multiple subdivided microparticles or chips, offering an attractive approach in the encoding [4,5] and anticounterfeiting [13] fields, yet their main utilization has centered on biomedical and bioengineering. [9,14] Nevertheless, the combination of different customized properties to increase functionality in a single microparticle is limited by the availability of reactive pathways that would otherwise allow the incorporation of complementary chemical anisotropies. Consolidation of these technologies has advanced considerably in the microparticle field, yet the constant trade-off between physical anisotropies, chemical anisotropies and their combination limits the library of possible customized microparticles, a problem that is aggravated by miniaturization. In this work, we aim to remove constraints placed by entangled physical and chemical anisotropies to fabricate polymeric microparticles with customized traits. We achieve this by combining physical attributes and surface chemical functionalization to obtain SU-8 microparticles with specific anisotropic signatures at coordinates established in selected dimensions or domains, [3,15] which collectively define the multidimensional anisotropic space. To do so, we exploit standard SU-8 photolithography to invest the required physical anisotropies on the resulting wafer-bound microparticles. We then incorporate chemical anisotropy with soft lithography on the top, bottom or both surfaces of the microparticles with multiple patterned molecular inks. This collective approach guarantees a highthroughput and low polydispersity fabrication protocol without the need for excessively specialized facilities. Furthermore, the Next generation life science technologies will require the integration of building blocks with tunable physical and chemical architectures at the microscale. A central issue is to govern the multidimensional anisotropic space that defines these microparticle attributes. However, this control is limited to one or few dimensions due to profound fabrication tradeoffs, a problem that is exacerbated by miniaturization. Here, a vast number of anisotropic dimensions are integrate...
physical terms, the combination of cell membrane-cortex system and cytoskeleton constitutes a mechanical system whose stability is based on a force balance between compression and tensileload-bearing components. [1] Any physical perturbation of this cellular mechanical system elicits a redistribution of forces and rearrangement of mechanical elements that can be disruptive. [3] Thus, it is not surprising that multiple chemical drugs for research and therapeutics target to alter the cellular mechanical performance. Anticancer drugs such as paclitaxel or colchicine affect the microtubules, provoking mitotic catastrophe to cause cell death. [4,5] Other compounds, including cytochalasin B, cytochalasin D, and latrunculin A disrupt actin filaments, also disturbing cell function and growth. [6] Intracellular mechanical cues induced by physiological internalization of large objects can also alter the redistribution of forces and the rearrangement of mechanical elements. Indeed, during entosis (the engulfment of one living cell by another), cytokinesis in the engulfing cell is perturbed, which can cause aneuploidy. [7,8] This has parallels to cell division perturbation when cells are exposed to natural or artificial "long" fibrous material such as asbestos fibers that can induce genomic changes and cancer by sterically blocking cytokinesis. [9] Current advances in materials science have demonstrated that extracellular mechanical cues can define cell function and cell fate. However, a fundamental understanding of the manner in which intracellular mechanical cues affect cell mechanics remains elusive. How intracellular mechanical hindrance, reinforcement, and supports interfere with the cell cycle and promote cell death is described here. Reproducible devices with highly controlled size, shape, and with a broad range of stiffness are internalized in HeLa cells. Once inside, they induce characteristic cell-cycle deviations and promote cell death. Device shape and stiffness are the dominant determinants of mechanical impairment. Device structural support to the cell membrane and centering during mitosis maximize their effects, preventing spindle centering, and correct chromosome alignment. Nanodevices reveal that the spindle generates forces larger than 114 nN which overcomes intracellular confinement by relocating the device to a less damaging position. By using intracellular mechanical drugs, this work provides a foundation to defining the role of intracellular constraints on cell function and fate, with relevance to fundamental cell mechanics and nanomedicine.
Current microtechnologies have shown plenty of room inside a living cell for silicon chips. Microchips as barcodes, biochemical sensors, mechanical sensors and even electrical devices have been internalized into living cells without interfering their cell viability. However, these technologies lack from the ability to trap and preconcentrate cells in a specific region, which are prerequisites for cell separation, purification and posterior studies with enhanced sensitivity. Magnetic manipulation of microobjects, which allows a non-contacting method, has become an attractive and promising technique at small scales. Here, we show intracellular Ni-based chips with magnetic capabilities to allow cell enrichment. As a proof of concept of the potential to integrate multiple functionalities on a single device of this technique, we combine coding and magnetic manipulation capabilities in a single device. Devices were found to be internalized by HeLa cells without interfering in their viability. We demonstrated the tagging of a subpopulation of cells and their subsequent magnetic trapping with internalized barcodes subjected to a force up to 2.57 pN (for magnet-cells distance of 4.9 mm). The work opens the venue for future intracellular chips that integrate multiple functionalities with the magnetic manipulation of cells.
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