Regeneration of injured nerve tissues requires intricate interplay of complex processes like axon elongation, remyelination, and synaptic formation in a tissue‐specific manner. A decellularized nerve ...matrix‐gel (DNM‐G) and a decellularized spinal cord matrix‐gel (DSCM‐G) are prepared from porcine sciatic nerves and spinal cord tissue, respectively, to recapitulate the microenvironment cues unique to the native tissue functions. Using an in vitro dorsal root ganglion–Schwann cells coculture model and proteomics analysis, it is confirmed that DNM‐G promotes far stronger remyelination activity and reduces synapse formation of the regenerating axons in contrast to DSCM‐G, Matrigel, and collagen I, consistent with its tissue‐specific function. Bioinformatics analysis indicates that the lack of neurotrophic factors and presence of some axon inhibitory molecules may contribute to moderate axonal elongation activity, while laminin β2, Laminin γ1, collagens, and fibronectin in DNM‐G promote remyelination. These results confirm that DNM‐G is a promising matrix material for peripheral nerve repair. This study provides more insights into tissue‐specific extracellular matrix components correlating to biological functions supporting functional regeneration.
Decellularized nerve matrix‐gel (DNM‐G) and decellularized spinal cord matrix‐gel (DSCM‐G) can recapitulate the microenvironment cues unique to the native tissue functions. In vitro study shows that DNM‐G promotes far stronger remyelination activity and reduces synapse formation of the regenerating axons in contrast to DSCM‐G; tissue‐specific extracellular matrix components correlating biological functions' supporting functional regeneration are investigated.
Cell‐free deoxyribonucleic acid (cfDNA) released from either dead or damaged cells serves as a key autoantigen in rheumatoid arthritis (RA). They can be recognized by nucleic acid (NA) sensors such ...as the toll‐like receptor (TLR), leading to activation of the innate immune system and chronic inflammation. Developed here is a cationic molecular scavenger, by screening cationic dendronized polymers, which eliminates cfDNA and inhibits TLR recognition and nucleic‐acid‐induced inflammation. The structure–property study demonstrates that toxicity, NA binding capacity, and biodistribution could be balanced to achieve maximum therapeutic effect by exquisite control of the molecular structure. In addition, the optimized cationic polymer effectively inhibited joint swelling, synovial hyperplasia, and bone destruction in collagen‐induced arthritis (CIA) rat models. The results offer support for synthetic polymers offering new paradigm in autoimmune disease treatment.
Scavenger hunt: Screening of cationic dendronized polymers led to scavengers that could eliminate cell‐free DNAs and inhibit Toll‐like receptor recognition and nucleic‐acid‐induced inflammation. The scavengers having longer backbones and higher charge densities were preferentially accumulated in the inflammatory joints of arthritis rats. As a result, joint swelling, synovial hyperplasia, and bone destruction were inhibited.
Abstract Controlled delivery of protein would find diverse therapeutic applications. Formulation of protein nanoparticles by polyelectrolyte complexation between the protein and a natural polymer ...such as chitosan (CS) is a popular approach. However, the current method of batch-mode mixing faces significant challenges in scaling up while maintaining size control, high uniformity, and high encapsulation efficiency. Here we report a new method, termed flash nanocomplexation (FNC), to fabricate insulin nanoparticles by infusing aqueous solutions of CS, tripolyphosphate (TPP), and insulin under rapid mixing condition ( Re > 1600) in a multi-inlet vortex mixer. In comparison with the bulk-mixing method, the optimized FNC process produces CS/TPP/insulin nanoparticles with a smaller size (down to 45 nm) and narrower size distribution, higher encapsulation efficiency (up to 90%), and pH-dependent nanoparticle dissolution and insulin release. The CS/TPP/insulin nanoparticles can be lyophilized and reconstituted without loss of activity, and produced at a throughput of 5.25 g h−1 when a flow rate of 50 mL min−1 is used. Evaluated in a Type I diabetes rat model, the smaller nanoparticles (45 nm and 115 nm) control the blood glucose level through oral administration more effectively than the larger particles (240 nm). This efficient, reproducible and continuous FNC technique is amenable to scale-up in order to address the critical barrier of manufacturing for the translation of protein nanoparticles.
Oral delivery of protein drugs is an attractive route of administration due to its convenience for repeated dosing and good patient compliance. However, currently oral protein therapeutics show very ...low bioavailability mainly due to the existence of hostile gastrointestinal (GI) environments, including mucus layers and intestinal epithelial barriers. Herein, using insulin as a model protein therapeutic, the core–shell nanoparticles with thiolated hyaluronic acid (HA‐SH) coating (NPHA‐SH) are produced utilizing a two‐step flash nanocomplexation process to enhance oral delivery efficiency of insulin. A positively charged nanoparticle core is first generated by electrostatic complexation between insulin and N‐(2‐hydroxypropyl)‐3‐trimethyl ammonium chloride modified chitosan (HTCC), followed by surface coating with HA‐SH. The optimized NPHA‐SH shows an average size of 100 nm with high encapsulation efficiency (91.1%) and loading capacity (38%). In vitro and ex vivo results confirm that NPHA‐SH shows high mucus‐penetration ability, improved intestinal retention and transepithelial transport property due to its thiolated surface and the ability of HA‐SH coating to dissociate from the nanoparticle surface when across the mucosal layer. Oral administration of NPHA‐SH to Type 1 diabetic rats yields high efficacy and an average relative bioavailability of 11.3%. These results demonstrate that the HA‐SH coated core–shell nanoparticles are a promising oral delivery vehicle for protein therapeutics.
Uniform core–shell nanoparticles with a positively charged HTCC/insulin nanocomplex core and a thiolated hyaluronic acid (HA‐SH) coating are engineered with a two‐step flash nanocomplexation (FNC) process to improve intestinal retention, mucus‐penetration ability, and transepithelial transport efficiency, thus collectively enhancing the efficacy and bioavailability of the encapsulated insulin after oral administration.
Cell-free DNA (cfDNA) released from damaged or dead cells can activate DNA sensors that exacerbate the pathogenesis of rheumatoid arthritis (RA). Here we show that ~40 nm cationic nanoparticles (cNP) ...can scavenge cfDNA derived from RA patients and inhibit the activation of primary synovial fluid monocytes and fibroblast-like synoviocytes. Using clinical scoring, micro-CT images, MRI, and histology, we show that intravenous injection of cNP into a CpG-induced mouse model or collagen-induced arthritis rat model can relieve RA symptoms including ankle and tissue swelling, and bone and cartilage damage. This culminates in the manifestation of partial mobility recovery of the treated rats in a rotational cage test. Mechanistic studies on intracellular trafficking and biodistribution of cNP, as well as measurement of cytokine expression in the joints and cfDNA levels in systemic circulation and inflamed joints also correlate with therapeutic outcomes. This work suggests a new direction of nanomedicine in treating inflammatory diseases.
The Early Permian magmatism in Tarim, NW China comprises diamondiferous kimberlites, lamprophyres, flood basalts, Fe–Ti oxide ore-bearing layered mafic–ultramafic intrusions, bi-modal dyke swarms, ...alkaline igneous complexes (including syenites and A-type granites), rhyolites and pyroclastic rocks. The extent of this intraplate magmatism exceeds 250,000km2, making it comparable to Large Igneous Provinces (LIPs). Screening of available radiometric ages reveals three main magmatic episodes in the Tarim LIP, with the first being marked by ~300Ma small-volume kimberlites, followed by two phases of bimodal magmatism at ~290Ma and at ~280Ma, respectively. This relatively long time interval of the Early Permian magmatism is consistent with a low eruption rate of the Tarim LIP and is supported by the intercalation of volcanic rocks with sediments in outcrops and drill holes. Although the spatial distribution of each magmatic episode in the Tarim LIP is far from assessed, it seems that the ~290Ma flood basalts are widespread across the province, whereas ~300Ma kimberlites and ~280Ma ultramafic–mafic–felsic intrusions and dyke swarms only occur in the Bachu Uplift and around the margins of the Tarim craton.
We propose that the ~300Ma kimberlites were derived from deep part of the metasomatized sub-continental lithospheric mantle (SCLM), while the ~290Ma flood basalts were likely formed as a result of mixing of plume-derived melts with SCLM-derived melts (e.g., lamproitic melt) as they rose through the SCLM. In contrast, the ~280Ma magmas were most likely derived from the convecting mantle. A plume incubation model is proposed to account for the temporo-spatial distribution of the Tarim LIP, in which different styles of plume–lithosphere interaction are recognized. In the first two episodes, the mantle plume incubating the base of the craton provides the heat that triggered melting of the enriched components in the SCLM. In contrast, adiabatic decompression melting within the plume produced the ~280Ma magmatic phase. Thermal modeling suggests that lithospheric thinning by thermal erosion might have been associated with the upwelling mantle plume, with the greatest thinning occurring in the Bachu area. Thinned spots and weak zones at the margins of cratons and mobile belts caused preferential channeling of plume flow and subsequent decompression melting. This explains the localized distribution of ~280Ma magmas in the Tarim LIP.
•Spatial distribution of igneous rocks in the Tarim large igneous province•Three magmatic episodes possess distinct rock association and geochemistry.•Lithospheric thinning in association with thermal erosion by upwelling mantle•Plume–lithosphere interaction in the formation of the Tarim LIP
Scalable manufacturing continues to present a major barrier for clinical translation of nanotherapeutics. Methods available for fabricating protein-encapsulating nanoparticles in a scalable fashion ...are scarce. Protein delivery often requires multiple functionalities to be incorporated into the same vehicle. Specifically for nanoparticle-mediated oral delivery of protein therapeutics, protection in GI tract, site-specific release, facilitating transmucosal permeation, and enhancing epithelial transport are a few desirable features to be engineered into a nanoparticle system. Here we devised a sequential flash nanocomplexation (FNC) technique for the scalable production of a core-shell structured nanoparticle system by combining materials choice and particle size and structure to fulfill these functions, therefore enhancing the delivery efficiency of insulin. This method is highly effective in controlling the size, generating core-shell structure with high encapsulation efficiency (97%) and payload capacity (67%) using insulin/l-penetratin complex nanoparticles as a core coated with hyaluronic acid (HA). Both the in vitro and in vivo models confirmed that the HA coating on these core-shell nanoparticles enhanced the permeation of nanoparticles through the intestinal mucus layer and improved trans-epithelial absorption of insulin nanoparticles; and the enhancement effect was most prominent using HA with the highest average molecular weight. The insulin-loaded nanoparticles were then encapsulated into enteric microcapsules (MCs) in an FNC process to provide additional protection against the acidic environment in the stomach while allowing rapid release of insulin nanoparticles when they reach small intestine. The optimized multifunctional MCs delivered an effective glucose reduction in a Type I diabetes rat model following a single oral administration, yielding a relative bioavailability of 11% in comparison with subcutaneous injection of free-form insulin. This FNC technique is highly effective in controlling particle size and structure to improve delivery properties and function. It can be easily extended to oral delivery for other protein therapeutics.
Abstract Stem cells display sensitivity to substrate presentation of topographical cues via changes in cell morphology. These biomechanical responses may be transmitted to the nucleus through ...cytoskeletal-linked signaling pathways. Here we investigate the influence of aligned substratum topography on the cell morphology and subsequently, the neuronal differentiation capabilities of adult neural stem cells (ANSCs). ANSCs that were cultured on aligned fibers elongated along the major fiber axis. Upon induction of differentiation with retinoic acid, a higher fraction of cells on aligned fibers exhibited markers of neuronal differentiation as compared with cells on random fiber or unpatterned surfaces. This effect was in part due to substrate selectivity, whereby aligned fiber substrates were less receptive to the attachment and continued survival of oligodendrocytes than random fiber or unpatterned substrates. Substrate-induced elongation alone was also effective in upregulating canonical Wnt signaling in ANSCs, which was further potentiated by retinoic acid treatment. These findings suggest a mechanism by which morphological control of stem cells operates in concert with biochemical cues for cell fate determination.
In this paper, ZnO, MoS2 and ZnO-time/MoS2 films with excellent nonlinear absorption (NA) properties were successfully prepared by single/two-step magnetron sputtering. The morphology, structure and ...NA property of the samples were studied. The scanning electron microscope results show that cluster-like MoS2 have different morphology. This phenomenon can be attributed to the fact that the multi-directional growth of the ZnO base films causes the original growth orientation of MoS2 to be changed. The NA characteristics under different excitation intensities are studied by Z-Scan technology. The material exhibits the reverse saturation absorption characteristic caused by two-photon absorption. Furthermore, the order of magnitude of NA coefficient for samples was determined to be 10−6 cm/W. The ZnO-time/MoS2 films display excellent NA characteristics, which are desirable for field of optical switch, optical limiting, optical communication and integrated optics.
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•The ZnO-time/MoS2 films with different conditions have been synthesized.•The ultrafast nonlinear optical properties of ZnO-time/MoS2 films were analyzed.•The mechanism of growth and nonlinear absorption for ZnO-time/MoS2 films is analyzed.
In this paper, the exponential synchronization problem of two different discrete-time chaotic neural networks with time delays and stochastic disturbances is investigated. In addition, the unreliable ...communication links are taken into account between the master system and its slave system, which are modelled as stochastic data dropouts satisfying Bernoulli distributions. By utilizing the Lyapunov functional approach and the stochastic analysis theory, a sufficient condition for the error dynamic system to be mean-square exponentially stable is first obtained. Then based on such sufficient condition, a reliable controller is designed to guarantee that two different discrete-time delayed neural networks with stochastic disturbances are exponentially synchronized in the mean square. The parameters of a desired state feedback controller can be achieved by solving in terms of linear matrix inequality. Finally, a numerical example is presented to validate the feasibility and effectiveness of the proposed synchronization approaches.
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