Chirality of Copper-Amino Acid Nanoparticles Determines Chemodynamic Cancer Therapeutic Outcome.

Chirality is a prevalent characteristic in nature, where biological systems exhibit a significant preference for specific enantiomers of biomolecules. However, there is a limited exploration into utilizing nanomaterials' chirality to modulate their interactions with intracellular substances. In this study, self-assembled copper-cysteine chiral nanoparticles and explore the influence of their charity on cancer chemodynamic therapy (CDT) are fabricated. Experimental and molecular dynamics (MD) simulation results demonstrate that the copper-l-cysteine chiral nanoparticles (Cu-l-Cys NPs) exhibit a stronger affinity toward l-glutathione (l-GSH) that is overproduced in cancer cells, compared to the copper-d-cysteine enantiomer (Cu-d-Cys NPs). The interaction between Cu-l-Cys NPs and l-GSH triggers a redox reaction that depletes l-GSH and converts Cu2+ into Cu+ . Subsequently, Cu+ catalyzes a Fenton-like reaction, decomposing H2 O2 into highly cytotoxic hydroxyl radicals (•OH) for cancer CDT. In vivo, results confirm that Cu-l-Cys NPs with good biocompatibility elicit a pronounced cancer cell death and effectively inhibit tumor growth. This work proposes a new perspective on chirality-enhanced cancer therapy.

2D Materials and Primary Human Dendritic Cells: A Comparative Cytotoxicity Study.

Human health can be affected by materials indirectly through exposure to the environment or directly through close contact and uptake. With the ever-growing use of 2D materials in many applications such as electronics, medical therapeutics, molecular sensing, and energy storage, it has become more pertinent to investigate their impact on the immune system. Dendritic cells (DCs) are highly important, considering their role as the main link between the innate and the adaptive immune system. By using primary human DCs, it is shown that hexagonal boron nitride (hBN), graphene oxide (GO) and molybdenum disulphide have minimal effects on viability. In particular, it is evidenced that hBN and GO increase DC maturation, while GO leads to the release of reactive oxygen species and pro-inflammatory cytokines. hBN and MoS2 increase T cell proliferation with and without the presence of DCs. hBN in particular does not show any sign of downstream T cell polarization. The study allows ranking of the three materials in terms of inherent toxicity, providing the following trend: GO > hBN ≈ MoS2 , with GO the most cytotoxic.

Biomaterial Cues Regulated Differentiation of Neural Stem Cells into GABAergic Neurons through Ca2+/c-Jun/TLX3 Signaling Promoted by Hydroxyapatite Nanorods.

Directed differentiation enables the production of a specific cell type by manipulating signals in development. However, there is a lack of effective means to accelerate the regeneration of neurons of particular subtypes for pathogenesis and clinical therapy. In this study, we find that hydroxyapatite (HAp) nanorods promote neural differentiation of neural stem cells due to their chemical compositions. Lysosome-mediated degradation of HAp nanorods elevates intracellular calcium concentrations and accelerates GABAergic neurogenesis. As a mechanism, the enhanced activity of a Ca2+ peak initiated by HAp nanorods leads to the activation of c-Jun and thus suppresses the expression of GABAergic/glutamatergic selection gene TLX3. We demonstrate the capability of HAp nanorods in promoting the differentiation into GABAergic neurons at both molecular and cellular function levels. Given that GABAergic neurons are responsible for various physiological and pathological processes, our findings open up enormous opportunities in efficient and precise stem cell therapy of neurodegenerative diseases.

Recent Advances in 2D Material-Mediated Immuno-Combined Cancer Therapy.

In the last years, cancer immunotherapy has started to attract a lot of attention, becoming one of the alternatives in the clinical treatment of cancer. Indeed, one of the advantages of immunotherapy is that both primary and distant tumors can be efficiently eradicated through a triggered immune response. Due to their large specific surface area and unique physicochemical properties, 2D materials have become popular in cancer immunotherapy, especially as efficient drug carriers. They have been also exploited as photothermal platforms, chemodynamic agents, and photosensitizers to further enhance the efficacy of the therapy. In this review, the focus is on the recent development of 2D materials as new tools to combine immunotherapy with chemotherapy, photothermal therapy, photodynamic therapy, chemodynamic therapy, radiotherapy, and radiodynamic therapy. These innovative synergistic approaches intend to go beyond the classical strategies based on a simple delivery function of immune modulators by nanomaterials. Furthermore, the effects of the 2D materials themselves and their surface properties (e.g., chemical modification and protein corona formation) on the induction of an immune response will be also discussed.

Degradation-by-design: how chemical functionalization enhances the biodegradability and safety of 2D materials.

A large number of graphene and other 2D materials are currently used for the development of new technologies, increasingly entering different industrial sectors. Interrogating the impact of such 2D materials on health and environment is crucial for both modulating their potential toxicity in living organisms and eliminating them from the environment. In this context, understanding if 2D materials are bio-persistent is mandatory. In this review we describe the importance of biodegradability and decomposition of 2D materials. We initially cover the biodegradation of graphene family materials, followed by other emerging classes of 2D materials including transition metal dichalcogenides and oxides, Xenes, Mxenes and other non-metallic 2D materials. We explain the role of defects and functional groups, introduced onto the surface of the materials during their preparation, and the consequences of chemical functionalization on biodegradability. In strong relation to the chemistry on 2D materials, we describe the concept of "degradation-by-design" that we contributed to develop, and which concerns the covalent modification with appropriate molecules to enhance the biodegradability of 2D materials. Finally, we cover the importance of designing new biodegradable 2D conjugates and devices for biomedical applications as drug delivery carriers, in bioelectronics, and tissue engineering. We would like to highlight that the biodegradation of 2D materials mainly depends on the type of material, the chemical functionalization, the aqueous dispersibility and the redox potentials of the different oxidative environments. Biodegradation is one of the necessary conditions for the safe application of 2D materials. Therefore, we hope that this review will help to better understand their biodegradation processes, and will stimulate the chemists to explore new chemical strategies to design safer products, composites and devices containing 2D materials.

[Advances in the Application of Hydroxyapatite Composite Materials in Bone Tissue Engineering].

Hydroxyapatite (HAp) is the main inorganic component of the bones and teeth, and it possesses bioactivity and biocompatibility. However, due to its poor mechanical performance, slow degradation speed, and lack of diversity in its function, it is difficult to apply HAp alone as a scaffold material for bone tissue engineering. By combining HAp with other types of materials, composite materials with specific properties can be prepared, and the scopes of HAp applications can be expanded. Firstly, we elaborated on the importance, and strengths and weaknesses of HAp for bone tissue engineering biomaterials and then reviewed the research status of HAp composite materials used in bone regeneration. Secondly, about hot research topics in the field of applying HAp composite materials in bone repair, we summarized the representative findings in the field, and discussions and analysis were made accordingly. Finally, we also examined the future development prospects of HAp composite bone repair materials.

One-pot synthesis of BiOCl nanosheets with dual functional carbon for ultra-highly efficient photocatalytic degradation of RhB.

Water pollution from Rhodamine B (RhB) has become a challenging problem which human beings are urgent to confront. A high-efficiency photocatalysis system is required for the industrial application. A novel carbon doped bismuth oxychloride (C-BiOCl) composite photocatalyst with dual functional carbon was synthesized by one-pot hydrothermal process. The introduction of the carbon in the synthesis modified the morphology of BiOCl by suppressing the growing-up of the layered structures, which resulted in more active catalytic sites and shorter path of charge transfer. Moreover, the doped carbon would improve the utilization of light, and shift the band structures of the BiOCl. The as-synthesized C-BiOCl possesses a significant improvement (around 400%) on the photocatalytic degradation of RhB. Therefore, this efficient photocatalyst with dual functional carbon has been synthesized and would be regarded as a novel strategy for the design of high-performance photocatalysts.

Self-Assembled Copper-Amino Acid Nanoparticles for in Situ Glutathione "AND" H2O2 Sequentially Triggered Chemodynamic Therapy.

Nanoformulations that can respond to the specific tumor microenvironment (TME), such as a weakly acidic pH, low oxygen, and high glutathione (GSH), show promise for killing cancer cells with minimal invasiveness and high specificity. In this study, we demonstrate self-assembled copper-amino acid mercaptide nanoparticles (Cu-Cys NPs) for in situ glutathione-activated and H2O2-reinforced chemodynamic therapy for drug-resistant breast cancer. After endocytosis into tumor cells, the Cu-Cys NPs could first react with local GSH, induce GSH depletion, and reduce Cu2+ to Cu+. Subsequently, the generated Cu+ would react with local H2O2 to generate toxic hydroxyl radicals (·OH) via a Fenton-like reaction, which has a fast reaction rate in the weakly acidic TME, that are responsible for tumor-cell apoptosis. Due to the high GSH and H2O2 concentration in tumor cells, which sequentially triggers the redox reactions, Cu-Cys NPs exhibited relatively high cytotoxicity to cancer cells, whereas normal cells were left alive. The in vivo results also proved that Cu-Cys NPs efficiently inhibited drug-resistant breast cancer without causing obvious systemic toxicity. As a novel copper mercaptide nanoformulation responsive to the TME, these Cu-Cys NPs may have great potential in chemodynamic cancer therapy.

Cellular Stemness Maintenance of Human Adipose-Derived Stem Cells on ZnO Nanorod Arrays.

Ever-growing tissue regeneration and other stem cell therapies cause pressing need for large population of self-renewable stem cells. However, stem cells gradually lose their stemness after long-term in vitro cultivation. In this study, a ZnO nanorod (ZnO NR) array is used to maintain the stemness of human adipose-derived stem cells (hADSCs). The results prove that after culturing hADSCs on ZnO NRs for 3 weeks, the stemness genes and protein expression level are higher than that on culture plates and ZnO film. ZnO NRs can maintain stemness of hADSCs without inhibiting the cell proliferation and oriented differentiation capabilities. KLF4 (Kruppel-like factor 4) is a Zn2+ -binding gene that plays a vital role in cell proliferation and differentiation. Sustained Zn2+ release and the increased expression of KLF4 can be detected, suggesting that ZnO NRs have efficiently released Zn2+ for stemness maintenance. Taken together, the nanotopography of ZnO NRs and the Zn2+ release synergistically facilitate stemness maintenance. This study has provided a powerful tool for directing cell fate, maintaining stemness, and realizing the expansion of stem cells in vitro, which will open a new route for the manufacture of large populations of stem cells and fulfilling the growing demand for the cell therapy market.

Effect of Hydroxyapatite Nanorods on the Fate of Human Adipose-Derived Stem Cells Assessed In Situ at the Single Cell Level with a High-Throughput, Real-Time Microfluidic Chip.

The fate of stem cells at the single cell level with limited communication with other cells is still unknown due to the lack of an efficient tool for highly accurate molecular detection. Moreover, the conditional sensitivity of biological experiments requires a sufficient number of parallel experiments to support a conclusion. In this work, a microfluidic single cell chip is designed for use with a protein chip to investigate the effect of hydroxyapatite (HAp) on the osteogenic differentiation of human adipose-derived stem cells (hADSCs) in situ at the single cell level. By successfully detecting secretory proteins in situ, it is found that the HAp nanorods enhance osteogenic differentiation at the single cell level. In the chip, the single cell seeding approach confirms the osteogenic differentiation of the hADSCs, which endocytoses HAp, by reducing the influence of the factors secreted by neighboring differentiating cells. Most importantly, more than 7000 microchambers provide a sufficient number of parallel experiments for statistical analysis, which ensure a high level of repeatability of the HAp nanorod-induced osteogenic differentiation. The microfluidic chip comprising single cell culture microchambers with in situ detection capability is a promising tool for research on cell behavior or cell fate at the single cell level.

Piezoelectric Microchip for Cell Lysis through Cell-Microparticle Collision within a Microdroplet Driven by Surface Acoustic Wave Oscillation.

Cell lysis is an important and crucial step for the detection of intracellular secrets. Usually, cell lysis is based on strong ultrasonic waves or toxic chemical regents, which require a large amount of cell suspension. To obtain high efficiency cell lysis for a small amount of sample, a mechanical cell lysis method based on a surface acoustic wave (SAW) microchip is proposed. The microchip simply consists of a piece of LiNbO3 crystal substrate, interdigitated transducers (IDTs) with 80 pairs of parallel electrodes and 3M Magic Tapes. The modulated input electrical signal is coupled into the substrate through IDTs, which produces an acoustic stream in the droplet on the surface of a substrate. When a biofluid droplet containing cells and microparticles is dropped on the surface of the microchip, the cells and microparticles are accelerated and collide with each other. The fluorescence staining results illustrate that the cell membrane is efficiently destroyed and that proteins as well as nucleic acids inside the cell are released. The experimental results show that this method has a high efficiency and low sample consumption. The potential application is the pretreatment of a small amount of tested sample in a hospital or biolab.

Polylactic Acid Nanopillar Array-Driven Osteogenic Differentiation of Human Adipose-Derived Stem Cells Determined by Pillar Diameter.

Numerous studies have determined that physical cues, especially the nanotopography of materials, play key roles in directing stem cell differentiation. However, most research on nanoarrays for stem cell fate regulation is based on nonbiodegradable materials, such as silicon wafers, TiO2, and poly(methyl methacrylate), which are rarely used as tissue engineering biomaterials. In this study, we prepared biodegradable polylactic acid (PLA) nanopillar arrays with different diameters but the same center-to-center distance using a series of anodic aluminum oxide nanowell arrays as templates. Human adipose-derived stem cells (hADSCs) were selected to investigate the effect of the diameter of PLA nanopillar arrays on stem cell differentiation. By culturing hADSCs without the assistance of any growth factors or osteogenic-induced media, the differentiation tendencies of hADSCs on the nanopillar arrays were assessed at the gene and protein levels. The assessment results suggested that the osteogenic differentiation of hADSCs can be driven by nanopillar arrays, especially by nanopillar arrays with a diameter of 200 nm. Moreover, an in vivo animal model of the samples demonstrated that PLA film with the 200 nm pillar array exhibits an improved ectopic osteogenic ability compared with the planar PLA film after 4 weeks of ectopic implantation. This study has provided a new variable to investigate in the interaction between stem cells and nanoarray structures, which will guide the bone regeneration clinical research field. This work paves the way for the utility of degradable biopolymer nanoarrays with specific geometrical and mechanical signals in biomedical applications, such as patches and strips for spine fusion, bone crack repair, and restoration of tooth enamel.

TiO2 Nanorod Array Constructed Nanotopography for Regulation of Mesenchymal Stem Cells Fate and the Realization of Location-Committed Stem Cell Differentiation.

As a physical cue for controlling the fate of stem cells, surface nanotopography has attracted much attention to improve the integration between implants and local host tissues and cells. A biocompatible surface TiO2 nanorod array is proposed to regulate the fate of bone marrow derived mesenchymal stem cells (MSCs). TiO2 substrates with different surface nanotopographies: a TiO2 nanorod array and a polished TiO2 ceramic are built by hydrothermal and sintering processes, respectively. The assessment of morphology, viability, gene expression, and protein characterization of the MSCs cultured on the different TiO2 substrates proves that a TiO2 nanorod array promotes the osteogenic differentiation of MSCs, while a TiO2 ceramic with a smooth surface suppresses it. Periodically assembled TiO2 nanorod array stripes on the smooth TiO2 ceramic are constructed by a combination of microfabrication and a chemical synthesis process, which realizes the location-committed osteogenic differentiation of MSCs. A route to control the differentiation of MSCs by a nanostructured surface, which can also control the location and direction of MSCs on the surface of biomaterials with micro-nano scale surface engineering, is demonstrated.

Loss of angiotensin-converting enzyme 2 promotes growth of gallbladder cancer.

The aim of this study is to investigate the role of angiotensin-converting enzyme 2 (ACE2) in gallbladder cancer (GBC) and the therapeutic potential of angiotensin receptor blocker in GBC. Human gallbladder epithelial cells (HGBEC) together with GBC cells and tissue samples were used. In vitro studies were carried out to investigate the role of ACE2 in GBC cells. ACE2 levels were studied in in vivo GBC mouse models subject to ARB treatment. ACE2 level was decreased in GBC cells compared with that in normal gallbladder cells. Replenishment of angiotensin II (A2) promoted tumour cell growth, which could be mitigated by ACE2 supplement. ARB blocked A2-induced GBC cell growth and activated ERK. Activity of mTOR was not altered with different ACE2 status. ARB inhibited tumour growth in xenograft mouse models. In vivo study also showed that decreased expression of ACE2 was associated with enlarged tumour size. By genetic replenishment of ACE2 and pharmaceutical use of ARB, restored ACE2 level mitigated GBC growth. Our results supported the rationale for the use of ARB in GBC patients for potential therapeutic benefit.

MicroRNA-135a acts as a putative tumor suppressor by directly targeting very low density lipoprotein receptor in human gallbladder cancer.

The precise functions and mechanisms of microRNAs (miR) in gallbladder cancer (GBC) remain elusive. In this study, we found that miR-135a-5p expression is often dampened and correlated with neoplasm histologic grade in GBC. MicroRNA-135a-5p introduction clearly inhibited GBC cell proliferation in vitro and in vivo. Moreover, very low density lipoprotein receptor (VLDLR), which is often upregulated in GBC tissues, was identified as a direct functional target of miR-135a-5p. Furthermore, the p38 MAPK pathway was proven to be involved in miR-135a-VLDLR downstream signaling. Together, these results suggested that the miR-135a-VLDLR-p38 axis may contribute to GBC cell proliferation.

Inhibition of mTOR pathway attenuates migration and invasion of gallbladder cancer via EMT inhibition.

Gallbladder cancer (GBC) is an aggressive disease in which epithelial-mesenchymal transition (EMT) plays a critical role. Whether inhibition of mTOR effects via EMT reversal in GBC remains unclear. Using genetic and pharmacologic inhibitions of mTOR, we investigated the changes of EMT levels in GBC cells. Expressions of EMT related genes were also studied. Migration and invasion assays were carried out and in vivo tumour metastasis mouse models were established. Circulating tumour DNA was quantified. We used EMT index (ratio of Vimentin/Ecadherin expression) to profile EMT levels. We found that inhibition of mTOR using shRNAs and rapamycin inhibited EMT in GBC-SD gallbladder cancer cells. Inhibition of mTOR inhibited EMT in GBC-SD cells in TGF-ß-dependent manner, which was contributed majorly by mTORC2 inhibition. Rapamycin decreased invasiveness and migration of GBC-SD cells in vitro and in vivo. We have in the current study shown that rapamycin diminishes the ability of invasion and migration of GBC via inhibition of TGF-ß-dependent EMT. Our findings contribute to the understanding of the carcinogenesis of GBC.

Hydro-Sensitive, In Situ Ultrafast Physical Self-Gelatinizing, and Red Blood Cells Strengthened Hemostatic Adhesive Powder with Antibiosis and Immunoregulation for Wound Repair.

Immediate and effective hemostatic treatments for complex bleeding wounds are an urgent clinical demand. Hemostatic materials with characteristics of adhesion, sealing, anti-infection, and concrescence promotion have drawn growing concerns. However, pure natural multifunctional hemostatic materials with in situ ultrafast self-gelation are rarely reported. In this study, a hydro-sensitive collagen/tannic acid (ColTA) natural hemostatic powder is developed that can in situ self-gel to form adhesive by the non-covalent crosslinking between tannic acid (TA) and collagen (Col) in liquids. The physical interactions endow ColTA adhesive with the characteristics of instantaneous formation and high adhesion at various substrate surfaces. Crucially, ColTA powder adhesive shows an enhanced adhesion performance in the presence of blood due to the electrostatic interactions between ColTA adhesive and red blood cells, conducive to effective in situ sealing and rapid hemostasis. The biocompatible and hemocompatible ColTA adhesive can effectively control bleeding and seal the wounds of the caudal vein, liver, heart, and femoral arteries in rats. Furthermore, the low-cost and ready-to-use ColTA adhesive powder also possesses good antibacterial and inhibiting biofilm formation ability, and can efficiently regulate immune response by the NF-κB pathway to promote wound repair, making it a highly promising hemostatic material with great potential for biomedical applications.

A multifunctional chitosan-based hydrogel with self-healing, antibacterial, and immunomodulatory effects as wound dressing.

Bacterial infection often leads to inflammatory responses and delays wound healing. Chitosan (CS)-based composite hydrogels can hold desirable mechanical properties and maintain excellent antibacterial abilities, and thus may be promising as wound dressings. Although CS-based hydrogels have been widely studied on the antibacterial and wound-healing abilities, their immunomodulatory abilities were rarely evaluated. Herein, we developed a multifunctional CS/Poly[2-(methacryloyloxy)ethyl] trimethyl ammonium chloride (PMETAC) hydrogel. In vitro, this hydrogel exhibited self-healing ability and excellent biocompatibility, promoted macrophage polarization towards M2 phenotype, and showed desirable antibacterial activity. In vivo, this hydrogel accelerated the wound regeneration process by reducing bacterial burden, increasing collagen deposition, stimulating angiogenesis, promoting macrophage polarization to M2 direction, and shifting the balance of T helper type 17 (Th17) cells towards anti-inflammatory regulatory T (Treg) cells. This work revealed the potential immunomodulatory effect of CS-based wound dressings and thus may provide a novel target for developing efficient wound healing tools.

Janus porous polylactic acid membranes with versatile metal-phenolic interface for biomimetic periodontal bone regeneration.

Conventional treatment to periodontal and many other bone defects requires the use of barrier membranes to guided tissue regeneration (GTR) and guided bone regeneration (GBR). However, current barrier membranes normally lack of the ability to actively regulate the bone repairing process. Herein, we proposed a biomimetic bone tissue engineering strategy enabled by a new type of Janus porous polylactic acid membrane (PLAM), which was fabricated by combining unidirectional evaporation-induced pore formation with subsequent self-assembly of a bioactive metal-phenolic network (MPN) nanointerface. The prepared PLAM-MPN simultaneously possesses barrier function on the dense side and bone-forming function on the porous side. In vitro, the presence of MPN nanointerface potently alleviated the proinflammatory polarization of mice bone marrow-derived macrophages (BMDMs), induced angiogenesis of human umbilical vein endothelial cells (HUVECs), and enhanced the attachment, migration and osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs). The implantation of PLAM-MPN into rat periodontal bone defects remarkably enhanced bone regeneration. This bioactive MPN nanointerface within a Janus porous membrane possesses versatile capacities to regulate cell physiology favoring bone regeneration, demonstrating great potential as GTR and GBR membranes for clinical applications.

Cartilage-Inspired Inhomogeneous Salt-Hydrogel for Hydrated Drag-Reducing and Strain Sensing.

Articular cartilages exhibit load-bearing capacity and durability due to their inhomogeneous structure. Inspired by this unique structure, a tough and inhomogeneous salt-hydrogel was developed by trapping sodium acetate (NaAc) crystals in polyacrylamide (PAM) polymer networks and then partially redissolving the NaAc crystals. The compressive and tensile stresses of the salt-hydrogel increase significantly by more than 20 times when oversaturated Ac- and Na+ are introduced into the gel network. Such an enhancement in mechanical strength is primarily attributed to the formation of NaAc crystals within the gel network. Further investigations reveal that the mechanical strength of the salt-hydrogel is temperature-dependent as the NaAc crystals gradually redissolve in the gel network with increasing temperature. Furthermore, redissolving NaAc crystals in an aqueous solution can yield an inhomogeneous salt-hydrogel. The topmost soft surface of the salt-hydrogel offers hydration lubrication, while the inhomogeneous network confers load-bearing capacity and durability. Compared to regular hydrogels, the inhomogeneous salt-hydrogel surface can realize drag reduction and remain smooth without damage after the friction tests. Moreover, a salt-hydrogel coating is also fabricated to visually demonstrate its drag-reducing property. In addition, this salt-hydrogel possesses conductivity and can be utilized in the development of inhomogeneous salt-hydrogel fibers (diameter = 438 ± 7 µm) for strain detection. The produced salt-hydrogel fiber exhibits excellent durability and reproducibility as a strain sensor, capable of detecting both small strains (e.g., 1%) and large strains (e.g., 40%). This work provides fundamental insights into developing hydrogels with an inhomogeneous network and explores their potential applications (e.g., hydrated drag-reducing, strain sensing).