Hydrogel for light delivery in biomedical applications.

Traditional optical waveguides or mediums are often silica-based materials, but their applications in biomedicine and healthcare are limited due to the poor biocompatibility and unsuitable mechanical properties. In term of the applications in human body, a biocompatible hydrogel system with excellent optical transparency and mechanical flexibility could be beneficial. In this review, we explore the different designs of hydrogel-based optical waveguides derived from natural and synthetic sources. We highlighted key developments such as light emitting contact lenses, implantable optical fibres, biosensing systems, luminating and fluorescent materials. Finally, we expand further on the challenges and perspectives for hydrogel waveguides to achieve clinical applications.

Chiral metal-organic frameworks incorporating nanozymes as neuroinflammation inhibitors for managing Parkinson's disease.

Nanomedicine-based anti-neuroinflammation strategy has become a promising dawn of Parkinson's disease (PD) treatment. However, there are significant gaps in our understanding of the therapeutic mechanisms of antioxidant nanomedicines concerning the pathways traversing the blood-brain barrier (BBB) and subsequent inflammation mitigation. Here, we report nanozyme-integrated metal-organic frameworks with excellent antioxidant activity and chiral-dependent BBB transendocytosis as anti-neuroinflammatory agents for the treatment of PD. These chiral nanozymes are synthesized by embedding ultra-small platinum nanozymes (Ptzymes) into L-chiral and D-chiral imidazolate zeolite frameworks (Ptzyme@L-ZIF and Ptzyme@D-ZIF). Compared to Ptzyme@L-ZIF, Ptzyme@D-ZIF shows higher accumulation in the brains of male PD mouse models due to longer plasma residence time and more pathways to traverse BBB, including clathrin-mediated and caveolae-mediated endocytosis. These factors contribute to the superior therapeutic efficacy of Ptzyme@D-ZIF in reducing behavioral disorders and pathological changes. Bioinformatics and biochemical analyses suggest that Ptzyme@D-ZIF inhibits neuroinflammation-induced apoptosis and ferroptosis in damaged neurons. The research uncovers the biodistribution, metabolic variances, and therapeutic outcomes of nanozymes-integrated chiral ZIF platforms, providing possibilities for devising anti-PD drugs.

MOF-Thermogel Composites for Differentiated and Sustained Dual Drug Delivery.

In recent years, multidrug therapy has gained increasing popularity due to the possibility of achieving synergistic drug action and sequential delivery of different medical payloads for enhanced treatment efficacy. While a number of composite material release platforms have been developed, few combine the bottom-up design versatility of metal-organic frameworks (MOFs) to tailor drug release behavior, with the convenience of temperature-responsive hydrogels (or thermogels) in their unique ease of administration and formulation. Yet, despite their potential, MOF-thermogel composites have been largely overlooked for simultaneous multidrug delivery. Herein, we report the first systematic study of common MOFs (UiO-66, MIL-53(Al), MIL-100(Fe), and MOF-808) with different pore sizes, geometries, and hydrophobicities for their ability to achieve simultaneous dual drug release when embedded within PEG-containing thermogel matrices. After establishing that MOFs exert small influences on the rheological properties of the thermogels despite the penetration of polymers into the MOF pores in solution, the release profiles of ibuprofen and caffeine as model hydrophobic and hydrophilic drugs, respectively, from MOF-thermogel composites were investigated. Through these studies, we elucidated the important role of hydrophobic matching between MOF pores and loaded drugs in order for the MOF component to distinctly influence drug release kinetics. These findings enabled us to identify a viable MOF-thermogel composite containing UiO-66 that showed vastly different release kinetics between ibuprofen and caffeine, enabling temporally differentiated yet sustained simultaneous drug release to be achieved. Finally, the MOF-thermogel composites were shown to be noncytotoxic in vitro, paving the way for these underexploited composite materials to find possible clinical applications for multidrug therapy.

Automatic analysis framework based on 3D-CT multi-scale features for accurate prediction of Ki67 expression levels in substantial renal cell carcinoma.

PURPOSE: To investigate the effectiveness of an automatic analysis framework based on 3D-CT multi-scale features in predicting Ki67 expression levels in substantial renal cell carcinoma (RCC). METHODS: This retrospective study was conducted using multi-center cohorts consisting of 588 participants with pathologically confirmed RCC. The participants were divided into an internal training set (n = 485) and an external testing set (n = 103) from four and one local hospitals, respectively. The proposed automatic analytic framework comprised a 3D kidney and tumor segmentation model constructed by 3D UNet, a 3D-CT multi-scale features extractor based on the renal-tumor feature, and a low or high Ki67 prediction classifier using XGBoost. The framework was validated using a fivefold cross-validation strategy. The Shapley additive explanation (SHAP) method was used to determine the contribution of each feature. RESULTS: In the prediction of low or high Ki67, the combination of renal and tumor features achieved better performance than any single features. Internal validation using a fivefold cross-validation strategy yielded AUROC values of 0.75 ± 0.1, 0.75 ± 0.1, 0.83 ± 0.1, 0.77 ± 0.1, and 0.87 ± 0.1, respectively. The optimal model achieved an AUROC of 0.87 ± 0.1 and 0.82 ± 0.1 for low vs. high Ki67 prediction in the internal validation and external testing sets, respectively. Notably, the tumor first-order-10P was identified as the most influential feature in the model decision. CONCLUSIONS: Our study suggests that the proposed automatic analysis framework based on 3D-CT multi-scale features has great potential for accurately predicting Ki67 expression levels in substantial RCC. CRITICAL RELEVANCE STATEMENT: Automatic analysis framework based on 3D-CT multi-scale features provides reliable predictions for Ki67 expression levels in substantial RCC, indicating the potential usage of clinical applications.

Single-cell analysis reveals the multiple patterns of immune escape in the nasopharyngeal carcinoma microenvironment.

BACKGROUND: Single-cell transcriptomics has revolutionised our understanding of the cellular composition of the tumour microenvironment (TME) in nasopharyngeal carcinoma (NPC). Despite this progress, a key limitation of this technique has been its inability to capture epithelial/tumour cells, which has hindered further investigation of tumour heterogeneity and immune escape in NPC. METHODS: In this study, we aimed to address these limitations by analysing the transcriptomics and spatial characteristics of NPC tumour cells at single-cell resolution using scRNA/snRNA-seq and imaging mass cytometry techniques. RESULTS: Our findings demonstrate multiple patterns of immune escape mechanisms in NPC, including the loss of major histocompatibility complex (MHC) molecules in malignant cells, induction of epithelial-mesenchymal transition in fibroblast-like malignant cells and the use of hyperplastic cells in tumour nests to protect tumour cells from immune infiltration. Additionally, we identified, for the first time, a CD8+ natural killer (NK) cell cluster that is specific to the NPC TME. CONCLUSIONS: These findings provide new insights into the complexity of NPC immune landscape and may lead to novel therapeutic strategies for this disease.

Anticancer effect of involucrasin A on colorectal cancer cells by modulating the Akt/MDM2/p53 pathway.

Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide; however, there is still a lack of effective clinical anti-CRC agents. Naturally-occurring compounds have been considered a potentially valuable source of new antitumorigenic agents. Involucrasin A, a novel natural molecule, was isolated from Shuteria involucrata (Wall.) Wight & Arn by our team. In the present study, the anticancer activity of involucrasin A in HCT-116 CRC cells was evaluated. Firstly, the anti-proliferative effect of involucrasin A on HCT-116 cells was analyzed by sulforhodamine B and colony formation assays. The results revealed that involucrasin A exhibited a potent inhibitory effect on HCT-116 CRC cell proliferation in vitro. Subsequently, flow cytometry and western blotting indicated that involucrasin A induced apoptosis and upregulated the expression levels of apoptosis-related proteins, such as cleaved-caspase 6 and cleaved-caspase 9, in a dose-dependent manner. Mechanistically, involucrasin A significantly inhibited the phosphorylation of Akt and murine double minute 2 homologue (MDM2), which resulted in increased intracellular levels of p53. This was reversed by exogenous expression of the constitutively active form of Akt. Similarly, either knocking out p53 or knocking down Bax abrogated involucrasin A-induced proliferation inhibition and apoptosis. Together, the present study indicated that involucrasin A exerts antitumorigenic activities via modulating the Akt/MDM2/p53 pathway in HCT-116 CRC cells, and it is worthy of further exploration in preclinical and clinical trials.

Clinicopathological characteristics and associated factors of idiopathic membranous nephropathy with hyperuricemia: a single-centered cross-sectional study.

PURPOSE: This study was designed to investigate the clinicopathological features of idiopathic membranous nephropathy (IMN) with hyperuricemia (HUA), together with associated factors within 10 years in a single centre in Shandong Province. METHODS: In this cross-sectional study, we analysed the clinical and pathological data of 694 IMN patients in our hospital from January 2010 to December 2019. Based on serum uric acid (UA) level, the patients were divided into hyperuricemia (HUA) group (n = 213) and normal serum uric acid (NUA) group (n = 481). Multi-variate logistic regression analysis was conducted on to screen the associated factors of HUA. RESULTS: 213 (30.69%) IMN patient were complicated with HUA. Compared with the patients with NUA, significant increase was noticed in the proportion of patients showing edema, concurrent hypertensive disease or diabetes mellitus (DM), as well as the proportion of positive glomerular capillary loop IgM and positive C1q in the HUA group (P < 0.05). In addition, significant increase was noticed in the 24 h urine protein, serum creatinine, triglycerides, complement C3 and complement C4 in HUA group compared with those of NUA group (all P < 0.05). With gender as a control factor, multi-variate logistic regression analysis showed positive glomerular capillary loops C1q, serum albumin, serum phosphorus were associated with IMN combined with HUA in male, while triglycerides and serum creatinine were associated with IMN combined with HUA in female counterparts. CONCLUSION: About 30.69% of IMN patients had HUA, with a male predominance than female. In male patients with IMN, higher serum albumin level and serum phosphorus level were associated with higher incidence of HUA, while in female IMN patients, higher serum triglyceridemia and serum creatinine level were associated with higher incidence of HUA. Therefore, it can be targeted to prevent the occurrence of HUA in IMN.

Injectable PTHF-based thermogelling polyurethane implants for long-term intraocular application.

BACKGROUND: Hydrogels show great potential to be used for intraocular applications due to their high-water content and similarity to the native vitreous. Injectable thermosensitive hydrogels through a small-bore needle can be used as a delivery system for drugs or a tamponading substitute to treat posterior eye diseases with clear clinical potential. However, none of the currently available thermosensitive hydrogels can provide intraocular support for up to 3 months or more. METHOD: In this study, an injectable polytetrahydrofuran (PTHF)-based thermosensitive hydrogel was synthesized by polyurethane reaction. We examined the injectability, rheological properties, microstructure, cytotoxicity, and in vivo compatibility and stability of the hydrogels in rabbit eyes. RESULTS: We found that the PTHF block type and PTHF component ratio could modulate thermogelation properties of the polyurethane polymers. The PTHF-based hydrogel implants retained normal retinal structure and function. Incorporating bioinert PTHF generated highly biocompatible and more stable thermogels in the vitreous cavity, with gel networks and the presence of polymer still observed after 3 months when other thermogels would have been completely cleared. Moreover, despite lacking hydrolytically cleavable linkages, the polymers could be most naturally removed from the native vitreous by bio-erosion without additional surgical interventions. CONCLUSION: Our findings suggest the potential of incorporating hydrophobic bioinert blocks to enhance the in vivo stability of supramolecularly associated hydrogels for long-term intraocular applications.

Nanodiamond-Based Optical-Fiber Quantum Probe for Magnetic Field and Biological Sensing.

Owing to the unique electronic spin properties, nitrogen-vacancy (NV) centers hosted in diamond have emerged as a powerful quantum tool for detecting various physical parameters and biological species. In this work, an optical-fiber quantum probe, configured by chemically modifying nanodiamonds on the surface of a cone fiber tip, is developed. Based on the continuous-wave optically detected magnetic resonance method and lock-in amplification technique, it is found that the sensing performance of probes can be engineered by varying the nanodiamond dispersion concentration and modification duration during the chemical modification process. Combined with a pair of magnetic flux concentrators, the magnetic field detection sensitivity has reached 0.57 nT/Hz1/2@1 Hz, a new record among the fiber magnetometers based on nanodiamonds. Taking Gd3+ as the demo, the capability of probes in paramagnetic species detection is also demonstrated experimentally. Our work provides a new approach to develop NV centers as quantum probes featuring high integration, multifunction, high sensitivity, etc.

Mitochondrial toxicity evaluation of traditional Chinese medicine injections with a dual in vitro approach.

There are technical obstacles in the safety evaluation of traditional Chinese medicine (TCM) injections due to their complex chemical nature and the lack of rapid and accurate in vitro methods. Here, we established a dual in vitro mitochondrial toxicity approach combing the conventional "glucose/galactose" assay in HepG2 cells with the cytotoxic assay in mitochondrial respiration deficient cells. Using this dual in vitro approach, for the first time, we systematically assessed the mitochondrial toxicity of TCM injections. Four of the 35 TCM injections, including Xiyanping, Dengzhanhuasu, Shuanghuanglian, and Yinzhihuang, significantly reduced cellular ATP production in galactose medium in the first assay, and presented less cytotoxic in the respiration deficient cells in the second assay, indicating that they have mitochondrial toxicity. Furthermore, we identified scutellarin, rutin, phillyrin, and baicalin could be the potential mitochondrial toxic ingredients in the 4 TCM injections by combining molecular docking analysis with experimental validation. Collectively, the dual in vitro approach is worth applying to the safety evaluation of more TCM products, and mitochondrial toxic TCM injections and ingredients found in this study deserve more attention.

Bottom-up design of hydrogels for programmable drug release.

Hydrogels are a promising drug delivery system for biomedical applications due to their biocompatibility and similarity to native tissue. Programming the release rate from hydrogels is critical to ensure release of desired dosage over specified durations, particularly with the advent of more complicated medical regimens such as combinatorial drug therapy. While it is known how hydrogel structure affects release, the parameters that can be explicitly controlled to modulate release ab initio could be useful for hydrogel design. In this review, we first survey common physical models of hydrogel release. We then extensively go through the various input parameters that we can exercise direct control over, at the levels of synthesis, formulation, fabrication and environment. We also illustrate some examples where hydrogels can be programmed with the input parameters for temporally and spatially defined release. Finally, we discuss the exciting potential and challenges for programming release, and potential implications with the advent of machine learning.

A Polyanionic Tartrate-containing Temperature-responsive Hydrogel.

Thermogels, a class of hydrogels which show spontaneous sol-gel phase transition when warmed, are an important class of soft biomaterials. To date, however, most amphiphilic polymers that are able to form thermogels in aqueous solution are uncharged, and the influence of ionisable groups on thermogelation are largely unknown. Herein, we report the first example of a polyanionic amphiphilic multi-block copolymer, containing multiple pendant carboxylate groups, that can form transparent thermogels spontaneously when warmed up to physiological temperature. We demonstrate that introducing negative charges onto thermogelling polymers could significantly alter the properties of the micelles and thermogels formed. Furthermore, the polymer's polyanionic character provides new options for modulating the gel rheological properties, such as stiffness and gelation temperatures, through electrostatic interactions with different cations. We also demonstrated that the polyanionic thermogel allowed slower sustained release of a cationic model drug compound compared to an anionic one over 2 weeks. The findings from our study demonstrate exciting new possibilities for advanced biomedical applications using charged polyelectrolyte thermogel materials.

Injectable Hybrid-Crosslinked Hydrogels as Fatigue-Resistant and Shape-Stable Skin Depots.

Injectable hydrogels have gained considerable attention, but they are typically mechanically weak and subject to repeated physiological stresses in the body. Herein, we prepared polyurethane diacrylate (EPC-DA) hydrogels, which are injectable and can be photocrosslinked into fatigue-resistant implants. The mechanical properties can be tuned by changing photocrosslinking conditions, and the hybrid-crosslinked EPC-DA hydrogels exhibited high stability and sustained release properties. In contrast to common injectable hydrogels, EPC-DA hydrogels exhibited excellent antifatigue properties with >90% recovery during cyclic compression tests and showed shape stability after application of force and immersion in an aqueous buffer for 35 days. The EPC-DA hydrogel formed a shape-stable hydrogel depot in an ex vivo porcine skin model, with establishment of a temporary soft gel before in situ fixing by UV crosslinking. Hybrid crosslinking using injectable polymeric micelles or nanoparticles may be a general strategy for producing hydrogel implants resistant to physiological stresses.

Platinum-Decorated Gold Nanoparticle-Based Microfluidic Chip Immunoassay for Ultrasensitive Colorimetric Detection of SARS-CoV-2 Nucleocapsid Protein.

Gold nanoparticle-based point-of-care tests (POCT) are one of the most widely used diagnostic tools for SARS-CoV-2 screening. However, the limitation of their insufficient sensitivity often leads to false negative results in early disease diagnostics. The ongoing pandemic of COVID-19 makes diagnostic tools that are more accurate, sensitive, simple, and affordable in high demand. In this work, we develop a platinum-decorated gold nanoparticle (Au@Pt NP)-based microfluidic chip immunoassay with a sensitivity surpassing that of paper-based detection of nucleocapsid (N) protein, one of the most conserved biomarkers of COVID-19. The synthesized Au@Pt NPs show high stability and catalytic activity in complex environments. The catalytic amplification of Au@Pt NPs enables naked-eye detection of N protein in the low femtogram range (ca. 0.1 pg/mL) and the detection of throat swab samples in under 40 min. This microfluidic chip immunoassay is easy for operation and readout without instrument assistance, making it more suitable for on-site detection and future pathogen surveillance.

A bio-functional polymer that prevents retinal scarring through modulation of NRF2 signalling pathway.

One common cause of vision loss after retinal detachment surgery is the formation of proliferative and contractile fibrocellular membranes. This aberrant wound healing process is mediated by epithelial-mesenchymal transition (EMT) and hyper-proliferation of retinal pigment epithelial (RPE) cells. Current treatment relies primarily on surgical removal of these membranes. Here, we demonstrate that a bio-functional polymer by itself is able to prevent retinal scarring in an experimental rabbit model of proliferative vitreoretinopathy. This is mediated primarily via clathrin-dependent internalisation of polymeric micelles, downstream suppression of canonical EMT transcription factors, reduction of RPE cell hyper-proliferation and migration. Nuclear factor erythroid 2-related factor 2 signalling pathway was identified in a genome-wide transcriptomic profiling as a key sensor and effector. This study highlights the potential of using synthetic bio-functional polymer to modulate RPE cellular behaviour and offers a potential therapy for retinal scarring prevention.

Piceatannol Prevents Colon Cancer Progression via Dual-Targeting to M2-Polarized Tumor-Associated Macrophages and the TGF-ß1 Positive Feedback Signaling Pathway.

SCOPE: M2 phenotype tumor-associated macrophages (M2-TAMs) play a key role in distant metastasis and poor clinical outcomes. Herein, a specific molecular mechanism that contributes to malignant progression is illuminated and investigates whether piceatannol (PIC) can target the crosstalk between M2-TAMs and cancer cells for potential colorectal cancer (CRC) therapy. METHODS AND RESULTS: To mimic the tumor microenvironment (TME), direct and indirect coculture systems in vitro and in vivo mouse xenograft models are established. The results demonstrate that post-treatment with PIC in TME more effectively prevented the aggressive features and stemness of SW480 cells by restricting the polarization of M2-like macrophages and blocking the transforming growth factor ß1 (TGF-ß1) positive feedback autocrine/paracrine loop that exists between M2-like polarized macrophages and cancer cells. Furthermore, xenograft assays also observe significant repression in tumor growth and lung metastases with the administration of PIC. The key mechanism underlying the antimetastasis effects of PIC may include its directly inhibitory activity against TGF-ß receptor type-1 (TGF-ßR1) in the M2-like TAMs-created TME. CONCLUSION: These novel findings demonstrate that PIC is a potent TGF-ß1/TGF-ßR1 pathway inhibitor and TME modulator for preventing tumor progression and metastasis in CRC by reeducating TAMs.

Branched PCL-Based Thermogelling Copolymers: Controlling Polymer Architecture to Tune Drug Release Profiles.

Temperature-responsive hydrogels, or thermogels, are a unique class of biomaterials that show facile and spontaneous transition from solution to gel when warmed. Their high biocompatibility, and ease of formulation with both small molecule drugs and biologics have made these materials prime candidates as injectable gel depots for sustained local drug delivery. At present, controlling the kinetics and profile of drug release from thermogels is achieved mainly by varying the ratio of hydrophobic: hydrophilic composition and the polymer molecular weight. Herein, we introduce polymer branching as a hitherto-overlooked polymer design parameter that exhibits profound influences on the rate and profile of drug release. Through a family of amphiphilic thermogelling polymers with systematic variations in degree of branching, we demonstrate that more highly-branched polymers are able to pack less efficiently with each other during thermogel formation, with implications on their physical properties and stability towards gel erosion. This in turn resulted in faster rates of release for both encapsulated small molecule hydrophobic drug and protein. Our results demonstrate the possibility of exploiting polymer branching as a hitherto-overlooked design parameter for tailoring the kinetics and profile of drug release in injectable thermogel depots.