New achievements in the realm of nanoscience and innovative techniques of nanomedicine have moved micro/nanoparticles (MNPs) to the point of becoming actually useful for practical applications in the near future. Various differences between the extracellular and intracellular environments of cancerous and normal cells and the particular characteristics of tumors such as physicochemical properties, neovasculature, elasticity, surface electrical charge, and pH have motivated the design and fabrication of inventive “smart” MNPs for stimulus-responsive controlled drug release. These novel MNPs can be tailored to be responsive to pH variations, redox potential, enzymatic activation, thermal gradients, magnetic fields, light, and ultrasound (US), or can even be responsive to dual or multi-combinations of different stimuli. This unparalleled capability has increased their importance as site-specific controlled drug delivery systems (DDSs) and has encouraged their rapid development in recent years. An in-depth understanding of the underlying mechanisms of these DDS approaches is expected to further contribute to this groundbreaking field of nanomedicine. Smart nanocarriers in the form of MNPs that can be triggered by internal or external stimulus are summarized and discussed in the present review, including pH-sensitive peptides and polymers, redox-responsive micelles and nanogels, thermo- or magnetic-responsive nanoparticles (NPs), mechanical- or electrical-responsive MNPs, light or ultrasound-sensitive particles, and multi-responsive MNPs including dual stimuli-sensitive nanosheets of graphene. This review highlights the recent advances of smart MNPs categorized according to their activation stimulus (physical, chemical, or biological) and looks forward to future pharmaceutical applications.

/pdf/smart-micro-nanoparticles-in-stimulus-responsive-drug-gene-1duzknz8dr.pdf

Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems

https://escholarship.org/content/qt50r1b9sg/qt50r1b9sg.pdf?t=ok16ag

Engineered nanomaterials for water treatment and remediation: Costs, benefits, and applicability

Progressive cerebral deposition of the amyloid β-protein (Aβ) in brain regions serving memory and cognition is an invariant and defining feature of Alzheimer disease. A highly similar but less robust process accompanies brain aging in many nondemented humans, lower primates, and some other mammals. The discovery of Aβ as the subunit of the amyloid fibrils in meningocerebral blood vessels and parenchymal plaques has led to innumerable studies of its biochemistry and potential cytotoxic properties. Here we will review the discovery of Aβ, numerous aspects of its complex biochemistry, and current attempts to understand how a range of Aβ assemblies, including soluble oligomers and insoluble fibrils, may precipitate and promote neuronal and glial alterations that underlie the development of dementia. Although the role of Aβ as a key molecular factor in the etiology of Alzheimer disease remains controversial, clinical trials of amyloid-lowering agents, reviewed elsewhere in this book, are poised to resolve the question of its pathogenic primacy.

/pdf/biochemistry-of-amyloid-b-protein-and-amyloid-deposits-in-1yqaziru91.pdf

Biochemistry of Amyloid β-Protein and Amyloid Deposits in Alzheimer Disease

Nanotechnology has begun to play a remarkable role in various fields of science and technology. In biomedical applications, nanoparticles have opened new horizons, especially for biosensing, targeted delivery of therapeutics, and so forth. Among drug delivery systems (DDSs), smart nanocarriers that respond to specific stimuli in their environment represent a growing field. Nanoplatforms that can be activated by an external application of light can be used for a wide variety of photoactivated therapies, especially light-triggered DDSs, relying on photoisomerization, photo-cross-linking/un-cross-linking, photoreduction, and so forth. In addition, light activation has potential in photodynamic therapy, photothermal therapy, radiotherapy, protected delivery of bioactive moieties, anticancer drug delivery systems, and theranostics (i.e., real-time monitoring and tracking combined with a therapeutic action to different diseases sites and organs). Combinations of these approaches can lead to enhanced and synergi...

Smart Nanostructures for Cargo Delivery: Uncaging and Activating by Light

Biological cells are well known to respond to a multitude of chemical signals. In the nervous system, chemical signaling has been shown to be crucially involved in development, normal functioning, and disorders of neurons and glial cells. However, there are an increasing number of studies showing that these cells also respond to mechanical cues. Here, we summarize current knowledge about the mechanical properties of nervous tissue and its building blocks, review recent progress in methodology and understanding of cellular mechanosensitivity in the nervous system, and provide an outlook on the implications of neuromechanics for future developments in biomedical engineering to aid overcoming some of the most devastating and currently incurable CNS pathologies such as spinal cord injuries and multiple sclerosis.

https://www.annualreviews.org/doi/pdf/10.1146/annurev-bioeng-071811-150045

Mechanics in neuronal development and repair.

By using a highly sensitive technique of atomic force microscopy-based single-cell compression, the rigidity of cultured N2a and HT22 neuronal cells was measured as a function of amyloid-β42 (Aβ42) protein treatment. Aβ42 oligomers led to significant cellular stiffening; for example, 90–360% higher force was required to reach 80% deformation for N2a cells. Disaggregated or fibrillar forms of Aβ42 showed much less change. These observations were explained by a combination of two factors: (i) incorporation of oligomer into cellular membrane, which resulted in an increase in the Young's modulus of the membrane from 0.9 ± 0.4 to 1.85 ± 0.75 MPa for N2a cells and from 1.73 ± 0.90 to 5.5 ± 1.4 MPa for HT22 cells, and (ii) an increase in intracellular osmotic pressure (e.g., from 7 to 40 Pa for N2a cells) through unregulated ion influx. These findings and measurements provide a deeper, more characteristic, and quantitative insight into interactions between cells and Aβ42 oligomers, which have been considered the prime suspect for initiating neuronal dysfunction in Alzheimer's disease.

/pdf/single-cell-mechanics-provides-a-sensitive-and-quantitative-1scr8dgzbz.pdf

Single-cell mechanics provides a sensitive and quantitative means for probing amyloid-β peptide and neuronal cell interactions

Protein microarrays are rapidly emerging as valuable tools in creating combinatorial cell culture systems where inducers of cellular differentiation can be identified in a rapid and multiplexed fashion. In the present study, protein microarraying was combined with photoresist lithography to enable printing of extracellular matrix (ECM) protein arrays while precisely controlling "on-the-spot" cell-cell interactions. In this surface engineering approach, the micropatterned photoresist layer formed on a glass substrate served as a temporary stencil during the microarray printing, defining the micrometer-scale dimensions and the geometry of the cell-adhesion domains within the printed protein spots. After removal of the photoresist, the glass substrates contained micrometer-scale cell-adhesive regions that were encoded within 300 or 500 microm diameter protein domains. Fluorescence microscopy and atomic force microscopy (AFM) were employed to characterize protein micropatterns. When incubated with micropatterned surfaces, hepatic (HepG2) cells attached on 300 or 500 mum diameter protein spots; however, the extent of cell-cell contacts within each spot varied in accordance with dimensions of the photoresist stencil, from single cells attaching on 30 microm diameter features to multicell clusters residing on 100 or 200 microm diameter regions. Importantly, the photoresist removal process was shown to have no detrimental effects on the ability of several ECM proteins (collagens I, II, and IV and laminin) to support functional hepatic cultures. The micropatterning approach described here allows for a small cell population seeded onto a single cell culture substrate to be exposed to multiple scenarios of cell-cell and cell-surface interactions in parallel. This technology will be particularly useful for high-throughput screening of biological stimuli required for tissue specification of stem cells or for maintenance of differentiated phenotype in scarce primary cells.

Use of photolithography to encode cell adhesive domains into protein microarrays

Current in vitro methods to assess nanomaterial cytotoxicity involve various assays to monitor specific cellular dysfunction, such as metabolic imbalance or inflammation. Although high throughput, fast, and animal-free, these in vitro methods suffer from unreliability and lack of relevance to in vivo situations. New approaches, especially with the potential to reliably relate to in vivo studies directly, are in critical need. This work introduces a new approach, single cell mechanics, derived from atomic force microscopy-based single cell compression. The single cell based approach is intrinsically advantageous in terms of being able to directly correlate to in vivo investigations. Its reliability and potential to measure cytotoxicity is evaluated using known systems: zinc oxide (ZnO) and silicon dioxide (SiO2) nanoparticles (NP) on human aortic endothelial cells (HAECs). This investigation clearly indicates the reliability of single cell compression. For example, ZnO NPs cause significant changes in force vs relative deformation profiles, whereas SiO2 NPs do not. New insights into NPs-cell interactions pertaining to cytotoxicity are also revealed from this single cell mechanics approach, in addition to a qualitative cytotoxicity conclusion. The advantages and disadvantages of this approach are also compared with conventional cytotoxicity assays.

/pdf/new-approach-to-investigate-the-cytotoxicity-of-43c3r4sp61.pdf

New approach to investigate the cytotoxicity of nanomaterials using single cell mechanics.

Focal adhesions play an important role in cell spreading, migration, and overall mechanical integrity. The relationship of cell structural and mechanical properties was investigated in the context of focal adhesion processes. Combined atomic force microscopy (AFM) and laser scanning confocal microscopy (LSCM) was utilized to measure single cell mechanics, in correlation with cellular morphology and membrane structures at a nanometer scale. Characteristic stages of focal adhesion were verified via confocal fluorescent studies, which confirmed three representative F-actin assemblies, actin dot, filaments network, and long and aligned fibrous bundles at cytoskeleton. Force-deformation profiles of living cells were measured at the single cell level, and displayed as a function of height deformation, relative height deformation and relative volume deformation. As focal adhesion progresses, single cell compression profiles indicate that both membrane and cytoskeleton stiffen, while spreading increases especially from focal complex to focal adhesion. Correspondingly, AFM imaging reveals morphological geometries of spherical cap, spreading with polygon boundaries, and elongated or polarized spreading. Membrane features are dominated by protrusions of 41–207 nm tall, short rods with 1–6 μm in length and 10.2–80.0 nm in height, and long fibrous features of 31–246 nm tall, respectively. The protrusion is attributed to local membrane folding, and the rod and fibrous features are consistent with bilayer decorating over the F-actin assemblies. Taken collectively, the reassembly of F-actin during focal adhesion formation is most likely responsible for the changes in cellular mechanics, spreading morphology, and membrane structural features.

F-Actin reassembly during focal adhesion impacts single cell mechanics and nanoscale membrane structure

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Single-cell mechanics provides a sensitive and quantitative means for probing amyloid-β peptide and neuronal cell interactions

Use of photolithography to encode cell adhesive domains into protein microarrays

New approach to investigate the cytotoxicity of nanomaterials using single cell mechanics.

F-Actin reassembly during focal adhesion impacts single cell mechanics and nanoscale membrane structure