Cellular nanovesicles for therapeutic immunomodulation: A perspective on engineering strategies and new advances.

Cellular nanovesicles which are referred to as cell-derived, nanosized lipid bilayer structures, have emerged as a promising platform for regulating immune responses. Owing to their outstanding advantages such as high biocompatibility, prominent structural stability, and high loading capacity, cellular nanovesicles are suitable for delivering various immunomodulatory molecules, such as small molecules, nucleic acids, peptides, and proteins. Immunomodulation induced by cellular nanovesicles has been exploited to modulate immune cell behaviors, which is considered as a novel cell-free immunotherapeutic strategy for the prevention and treatment of diverse diseases. Here we review emerging concepts and new advances in leveraging cellular nanovesicles to activate or suppress immune responses, with the aim to explicate their applications for immunomodulation. We overview the general considerations and principles for the design of engineered cellular nanovesicles with tailored immunomodulatory activities. We also discuss new advances in engineering cellular nanovesicles as immunotherapies for treating major diseases.

Engineering cells for precision drug delivery: New advances, clinical translation, and emerging strategies.

Cells have emerged as a promising new form of drug delivery carriers owing to their distinguished advantages such as naturally bypassing immune recognition, intrinsic capability to navigate biological barriers, and access to hard-to-reach tissues via onboarding sensing and active motility. Over the past two decades, a large body of work has focused on understanding the ability of cell carriers to breach biological barriers and to modulate drug pharmacokinetics and pharmacodynamics. These efforts have led to the engineering of various cells for tissue-specific drug delivery. Despite exciting advances, clinical translation of cell-based drug carriers demands a thorough understanding of the pressing challenges and potential strategies to overcome them. Here, we summarize recent advances and new concepts in cell-based drug carriers and their clinical translation. We also discuss key considerations and emerging strategies to engineering the next-generation cell-based delivery technologies for more precise, targeted drug delivery.

Regional differences of the sclera in the ocular hypertensive rat model induced by circumlimbal suture.

PURPOSE: To describe the regional differences of the sclera in ocular hypertension (OHT) models with the inappropriate extension of the ocular axis. METHODS: To discover the regional differences of the sclera at the early stage, OHT models were established using circumlimbal suture (CS) or sclerosant injection (SI). Axial length (AL) was measured by ultrasound and magnetic resonance imaging. The glaucoma-associated distinction was determined by intraocular pressure (IOP) and retrograde tracing of retinal ganglion cells (RGCs). The central thickness of the ganglion cell complex (GCC) was measured by optical coherence tomography. RGCs and collagen fibrils were detected using a transmission electron microscope, furthermore, anti-alpha smooth muscle actin (αSMA) was determined in the early stage after the operation. RESULTS: Compared with the control group, the eyes in OHT models showed an increased IOP (P < 0.001 in the CS group, P = 0.001 in the SI group), growing AL (P = 0.026 in the CS group, P = 0.043 in the SI group), reduction of central RGCs (P < 0.001 in the CS group, P = 0.017 in the SI group), thinning central GCC (P < 0.001 in the CS group), and a distinctive expression of αSMA in the central sclera in the early 4-week stage after the operation (P = 0.002 in the CS group). Compared with the SI group, the eye in the CS group showed a significantly increased AL (7.1 ± 0.4 mm, P = 0.031), reduction of central RGCs (2121.1 ± 87.2 cells/mm2, P = 0.001), thinning central GCC (71.4 ± 0.8 pixels, P = 0.015), and a distinctive expression of αSMA (P = 0.005). Additionally, ultrastructural changes in RGCs, scleral collagen fibers, and collagen crimp were observed in the different regions. Increased collagen volume fraction in the posterior segment of the eyeball wall (30.2 ± 3.1%, P = 0.022) was observed by MASSON staining in the CS group. CONCLUSION: Regional differences of the sclera in the ocular hypertensive rat model induced by CS may provide a reference for further treatment of scleral-related eye disorders.

Pathologically high intraocular pressure disturbs normal iron homeostasis and leads to retinal ganglion cell ferroptosis in glaucoma.

Glaucoma can result in retinal ganglion cell (RGC) death and permanently damaged vision. Pathologically high intraocular pressure (ph-IOP) is the leading cause of damaged vision during glaucoma; however, controlling ph-IOP alone does not entirely prevent the loss of glaucomatous RGCs, and the underlying mechanism remains elusive. In this study, we reported an increase in ferric iron in patients with acute primary angle-closure glaucoma (the most typical glaucoma with ph-IOP damage) compared with the average population by analyzing free iron levels in peripheral serum. Thus, iron metabolism might be involved in regulating the injury of RGCs under ph-IOP. In vitro and in vivo studies confirmed that ph-IOP led to abnormal accumulation of ferrous iron in cells and retinas at 1-8 h post-injury and elevation of ferric iron in serum at 8 h post-injury. Nuclear receptor coactivator 4 (NCOA4)-mediated degradation of ferritin heavy polypeptide 1(FTH1) is essential to disrupt iron metabolism in the retina after ph-IOP injury. Furthermore, knockdown of Ncoa4 in vivo inhibited FTH1 degradation and reduced the retinal ferrous iron level. Elevated ferrous iron induced by ph-IOP led to a marked accumulation of pro-ferroptotic factors (lipid peroxidation and acyl CoA synthetase long-chain family member 4) and a depletion of anti-ferroptotic factors (glutathione, glutathione peroxidase 4, and nicotinamide adenine dinucleotide phosphate). These biochemical changes resulted in RGC ferroptosis. Deferiprone can pass through the blood-retinal barrier after oral administration and chelated abnormally elevated ferrous iron in the retina after ph-IOP injury, thus inhibiting RGC ferroptosis and protecting visual function. In conclusion, this study revealed the role of NCOA4-FTH1-mediated disturbance of iron metabolism and ferroptosis in RGCs during glaucoma. We demonstrate the protective effect of Deferiprone on RGCs via inhibition of ferroptosis, providing a research direction to understand and treat glaucoma via the iron homeostasis and ferroptosis pathways.

Application of team-based learning to ophthalmology in China.

Objectives: The purpose of this study was to explore whether team-based learning (TBL) was more effective than traditional didactic lectures (TDLs) in improving medical students' problem-solving and study skills in the clinical course of ophthalmology. In addition, we were also concerned about Chinese students' satisfaction with TBL. Methods: Our study program involved 275 students of the 5-year clinical medicine program from Central South China University, of which 140 were enrolled in a modified TBL course. A questionnaire that included closed-ended and open-ended items was distributed to students immediately following the completion of the TBL session, and 108 valid questionnaires were collected. Descriptive statistics were used to analyze quantitative data. The effects of the TBL module on students' performance were measured between the groups using a one-way between-group analysis of variance (ANOVA) test by the individual readiness assurance test (IRAT), the group readiness assurance test (GRAT), and final examination scores (FESs), compared with a class without the TBL session. Results: With our modified TBL strategy, 140 students achieved a mean test score of 72.65 on test questions that assessed their knowledge of ophthalmology compared to 135 students who achieved a mean score of 70.8 using the TDL method (p = 0.3434). The performance in a pre-class quiz was significantly better in the GRAT compared to the IRAT. In comparison to the TDL session, the modified TBL was preferred and acceptable by most medical students. Conclusions: By applying the modified TBL to ophthalmology, students improved their performance, self-study, and teamwork, and their class engagement and satisfaction were enhanced. However, TBL should be further optimized and developed to enhance educational outcomes.

Red Blood Cell Inspired Strategies for Drug Delivery: Emerging Concepts and New Advances.

In the past five decades, red blood cells (RBCs) have been extensively explored as drug delivery systems due to their distinguishing potential in modulating the pharmacokinetic, pharmacodynamics, and biological activity of carried payloads. The extensive interests in RBC-mediated drug delivery technologies are in part derived from RBCs' unique biological features such as long circulation time, wide access to many tissues in the body, and low immunogenicity. Owing to these outstanding properties, a large body of efforts have led to the development of various RBC-inspired strategies to enable precise drug delivery with enhanced therapeutic efficacy and reduced off-target toxicity. In this review, we discuss emerging concepts and new advances in such RBC-inspired strategies, including native RBCs, ghost RBCs, RBC-mimetic nanoparticles, and RBC-derived extracellular vesicles, for drug delivery.

Performance assessment of bubbles barriers for microplastic remediation.

We report the results of experiments designed to evaluate the performance of a bubble barrier device for microplastics collection in natural and artificial streams. Bubble barrier is an innovative device based on the principle that pumping air to produce a vertical curtain of small air bubbles along the depth of a waterway creates a sufficient current to direct floating and non-floating particle towards a catchment device. The bubble barrier has been designed and already tested in rivers. Despite its use, there is a lack of information on the fluid mechanical functioning and performance, i.e., its ability to catch the largest number of microplastic particles. The aim of the present study is to test different bubble barriers configurations (length of the bubble generator, alignment with the main current) in different hydraulic conditions. We used a laboratory channel to produce a scaled river flow and we performed velocity measurements, and particle tracking visualization to understand how the bubble curtain could influence the water flow. The catchment performance of the different barriers has been tested using two types of particles, lighter and heavier than water. The results show that the system performance is strongly linked to a combination of the bubble generator configuration and the main properties of the flow. This study is the first attempt to provide scientific data on the bubble barrier and future design strategies depending on its application.

Evaluation of Macular and Peripapillary Blood Flow in Response to Intraocular Pressure Reduction in Patients With Posner-Schlossman Syndrome.

Purpose: The study aimed to evaluate the effect of intraocular pressure (IOP) reduction on macular and peripapillary microcirculation in patients with Posner-Schlossman syndrome (PSS) by optical coherence tomography angiography (OCTA). Methods: A prospective comparative study was conducted. Patients diagnosed with PSS at the Eye Center of Xiangya Hospital, Central South University, from February 2020 to November 2021 were consecutively included. OCTA was used for the macular and peripapillary microcirculation measurements, and optical coherence tomography (OCT) was employed for the retinal nerve fiber layer (RNFL) and lamina cribrosa depth (LCD) measurements. The patients received OCT and OCTA examinations at baseline and 1 week post-treatment when the IOP was under control. Changes in macular and peripapillary microcirculation, RNFL, and LCD were calculated for all the analyzed areas. Results: Twenty-one eyes from 21 patients were included in the study. Pre-treatment and post-treatment IOP were 43.17 ± 10.36 mm Hg (range, 30-60 mm Hg) and 17.17 ± 2.85 mm Hg (range, 13-23 mm Hg), respectively. No statistically significant changes were detected in RNFL, LCD, or macular and peripapillary microcirculation after significant IOP reduction. Conclusion: The results suggested that a large IOP reduction may not result in a significant increase in peripapillary and macular capillary perfusion in patients with PSS.

Bacteria-Mediated Intracellular Click Reaction for Drug Enrichment and Selective Apoptosis of Drug-Resistant Tumor Cells.

Functionalized biocarriers that can perform bio-orthogonal reactions in tumor cells may provide solutions to overcome the efflux of the chemotherapeutic agent from drug-resistant tumor cells. Herein, we report the enrichment of therapeutic drugs in tumor cells through intracellular click reaction with functionalized bacteria. Specifically, an intracellular bioactive drug enrichment template (OPV@Escherichia coli) is constructed by combining positively charged oligo(phenylene-vinylene)-alkyne (OPV-C≡CH) with E. coli via electrostatic interaction. After the cell uptake of OPV@E. coli and Cu(II)-based complex, Cu(I) generated in situ can catalyze the bio-orthogonal click reaction to covalently anchor the azide-bearing molecules of cyanine 5 (Cy5-N3) and paclitaxel (PTX-N3) on OPV@E. coli. These molecules and their functions were retained and enriched inside the drug-resistant tumor cells A549T, which can label cells with fluorescent probes and selectively induce the apoptosis of drug-resistant tumor cells.

Selective Fluorescence Imaging of Cancer Cells Based on ROS-Triggered Intracellular Cross-Linking of Artificial Enzyme.

Inside living cells, regulation of catalytic activity of artificial enzymes remains challenging due to issues such as biocompatibility, efficiency, and stability of the catalyst, by which the practical applications of artificial enzymes have been severely hindered. Here, an artificial enzyme, PTT-SGH, with responsiveness to reactive oxygen species (ROS), was obtained by introducing a catalytic histidine residue to pentaerythritol tetra(3-mercaptopropionate) (PTT). The artificial enzyme formed large aggregates in cells via the intracellular ROS-mediated oxidation of thiol groups. The process was significantly facilitated in tumor cells because of the higher ROS concentration in the tumor microenvironment. The catalytic activity of this artificial enzyme was intensively enhanced through deprotonation of cross-linked PTT-SGH, which showed typical esterase activities. Selective fluorescence imaging of tumor cells was achieved using the artificial enzyme to trigger the cleavage of the ester bond of the caged fluorophore inside living cells.

3D printing of artificial skin patches with bioactive and optically active polymer materials for anti-infection and augmenting wound repair.

A printable ink composed of a photoactive cationic conjugated poly(phenylene vinylene) derivative (PPV) and gelatin/alginate/hyaluronic acid is developed for 3D printing artificial skin patches. This patch shows excellent photodynamic therapy-based anti-infection superiority and outstanding bioactivity to facilitate wound repair. This study contributes to design new conjugated polymer inks for manufacturing functional skin patches.

Near-Infrared-Light Remote-Controlled Activation of Cancer Immunotherapy Using Photothermal Conjugated Polymer Nanoparticles.

Remote control of the therapeutic process is an ideal strategy for maximizing efficacy and avoiding side effects, especially for cancer immunotherapy. Herein, a conjugated polymer nanoparticles (CPNs)-mediated optogenetic system for in situ activation of immunotherapy under near-infrared laser irradiation is reported. This system is composed of photothermal CPNs and interferon-gamma (IFN-γ) plasmid driven by heat shock promoter HSP70. The photothermally responsive CPNs serve as a photo-heat nanotransducer to trigger the gene transcription of IFN-γ cytokine. The secreted IFN-γ from cancer cells can sufficiently elicit surrounding tumor-associated macrophages activation through IFN-γ-JAK-STAT1 transcription-factor signaling pathway and finally induce cancer cell killing by immunotherapy. Therefore, this synergetic optogenetic system provides a promising approach to remotely control the process of cancer immunotherapy.

Self-luminescent photodynamic therapy and pathogen detection for infectious diseases.

The importance of detection and treatments of infectious diseases has been stressed to the world by the ongoing COVID-19 pandemic. As a substitution of an external light source, self-luminescent therapeutics featuring in situ light emission aims to address the lack of tissue penetration in conventional photodynamic therapy (PDT). Luminol-based self-luminescent systems are successfully incorporated in PDT and detection of pathogens in infectious diseases. In these systems, luminol/hydrogen peroxide is served as luminescence source which can be activated by horseradish peroxidase (HRP). As a supplement strategy to the HRP-based bioluminescence, electrochemiluminescence (ECL) provided an electric-driven therapeutic solution and demonstrated potential capabilities of wearable healthcare devices with properly constructed transparent flexible hydrogels. Besides the diagnosis of infection and detection of bacteria, fungi and virus in solution or powder samples have been achieved by ATP-derived self-luminescence as the light source. In this inspirational note, we provide an overview on latest progress in the PDT and microbial detection by self-luminescent systems with an emphasis on the bioluminescence and ECL.

3D Bioprinting of Polythiophene Materials for Promoting Stem Cell Proliferation in a Nutritionally Deficient Environment.

3D printing of stem cells provides a tremendous opportunity to tissue engineering in regenerative medicine. However, developing new bioactive materials to rationally augment stem cell viability is still an enormous challenge owing to the nutritionally deficient environment caused by the limited-penetration distance of nutrition when cells are encapsulated within biomaterials. In this work, a cationic conjugated polythiophene derivative, poly[3-(3'-N,N,N-triethylamino-1'-propyloxy)-4-methyl-2,5-thiophene hydrochloride] (PMNT), is designed and integrated into an anionic gelatin/alginate matrix to develop a new 3D bioprintable conjugated polymer ink Gel/Alg/PMNT, while the electrostatic interaction can assist PMNT to anchor inside ink without severe diffusional loss. In principle, PMNT is confirmed to promote human umbilical cord-derived mesenchymal stem cell (hMSC) proliferation in a serum-free medium by driving cell cycles and up-regulating gene expression in the pathways of biosynthesis and the metabolism. By employing the 3D bioprinting strategy together with hMSCs, the accelerated healing of full-thickness excisional wounds is further realized through the augmented-stem cell therapeutics utilizing Gel/Alg/PMNT ink, in which hMSC proliferation can be effectively promoted upon inductive stimulation of PMNT. The inherent highly bioactive and robust proliferation-promoted nature of the developed conjugated polymer ink Gel/Alg/PMNT significantly overcomes the nutritionally deficient environment, especially in 3D-printed large-scale architectures. The bioactive polythiophene material exhibits a unique capacity to promote stem cell proliferation without the need of serum, providing a new bioink for 3D bioprinting in tissue reconstructions.

In Situ Synthesis of Photoactive Polymers on a Living Cell Surface via Bio-Palladium Catalysis for Modulating Biological Functions.

Cell surface engineering with functional polymers is an effective strategy to modulate cell activity. Here, a bio-palladium catalyzed polymerization strategy was developed for in situ synthesis of conjugated polymers on living cell surfaces. Through Sonagashira polymerization, photoactive polyphenyleneethynylene (PPE) is synthesized on the cell surface via cell-generated bio-Pd catalyst. The in situ formed PPE is identified by excellent light-harvest capacity and blue fluorescence on the surfaces of E. coli and C. pyrenoidosa. Besides imaging microbes for tracing the polymerization process, PPE also exhibits enhanced antibacterial activity against E. coli. It can also augment the ATP synthesis of C. pyrenoidosa through enlarging the light absorption and accelerating the cyclic electron transport of the algae. With this bio-metal catalyzed polymerization method, functional polymers can be synthesized in situ on the living cell surface.

Photocontrolled RAFT Polymerization Catalyzed by Conjugated Polymers under Aerobic Aqueous Conditions.

Photocontrolled polymerization offers a convenient way to direct the reaction progress and tailor the polymer structures. Nevertheless, conjugated polymers are yet to be utilized as the photocatalyst in associated reactions. Herein, we employed poly(boron dipyrromethene-alt-fluorene) (PBF), a conjugated polymer with better photostability than eosin Y, as the photocatalyst for photo-RAFT polymerizations of acrylic monomers, and the polymers were obtained with moderately narrow molecular weight distributions. The reaction progress was effectively controlled by switching irradiation conditions, and the block copolymers were prepared from chain extension of a macroinitiator. As electron spin resonance (ESR) and optical spectra results suggested, the reductive quenching of PBF* by ascorbate was the key step leading to the reduction of a chain transfer agent (CTA), whereas the hydroxyl radical derived from superoxide was considered as a byproduct of deoxygenation.

Management of the Temporal Bone Fibrous Dysplasia With External Auditory Canal Stenosis and Secondary Cholesteatoma in an Asian Population: A 11-Case Series.

OBJECTIVE: This article summarizes the experience of diagnosis and treatment of temporal bone fibrous dysplasia (FD) with external auditory canal (EAC) stenosis and secondary cholesteatoma in the Chinese population, in order to improve the quality of life of patients in the future. METHODS: Eleven patients with FD of the temporal bone who underwent surgery were retrospectively reviewed. RESULTS: All lesions originated from the temporal bone, and all involved of the EAC. There were 11 cases of cholesteatoma in the EAC, 4 cases of cholesteatoma in the middle ear. The most common symptoms were hearing loss (100%), tinnitus (36.4%), and otorrhea (36.4%). Two patients were severe-profound sensorineural hearing loss, and one patient was complicated with subperiosteal abscesses. All 11 patients underwent surgery. There were no perioperative complications in this series and median follow-up time was 4.2 years. CONCLUSION: Temporal bone FD remains a rare diagnosis, especially in the Asian population. The lesions mainly lead to stenosis of the EAC, especially at the osteochondral junction. Cholesteatoma is the main complication of this disease, which is secondary to occlusion of the EAC with the growth of the lesion. Canaloplasty of EAC combined with wide meatoplasty can provide excellent prognosis in most cases.

Ocular vs. Cervical Vestibular Evoked Myogenic Potentials in Benign Paroxysmal Positional Vertigo: A Systematic Review and Meta-Analysis.

Objective: To compare utricular dysfunction with saccular dysfunction in benign paroxysmal positional vertigo (BPPV), based on ocular vestibular evoked myogenic potentials (oVEMP) and cervical VEMP (cVEMP), respectively. Materials and Methods: We performed a literature search exploring utricular and saccular dysfunction in BPPV patients through June 2020 using oVEMP and cVEMP, respectively. The databases included Pubmed, Embase, CENTRAL, CNKI, Wan Fang Data, and CBM. The literatures were limited to Chinese and English. Inclusion criteria and exclusion criteria were defined. We adopted abnormal rate as the outcome. All statistical processes were conducted through software Review Manager. Considering the air-conducted sound (ACS) and bone conducted vibration (BCV) may have different mechanisms, and three types of diagnostic criteria for abnormal VEMP were available, sub-group analysis was performed simultaneously according to the sound stimuli and the diagnostic criteria of abnormal VEMP. Results: We retrieved 828 potentially relevant literatures, and finally 12 studies were included for meta-analysis of abnormal rate after duplication removal, titles and abstracts screening, and full-text reading. The abnormal rate of oVEMP was not significantly different from cVEMP (OR = 1.59, 95% CI = 0.99-2.57). But the abnormal rate was obviously different between the subgroups adopting ACS oVEMP and BCV oVEMP. In studies adopting ACS oVEMP, the abnormal rate of oVEMP was higher than cVEMP (OR = 1.85, 95% CI = 1.38-2.49). The abnormal rate of oVEMP was also higher than cVEMP when adopting asymmetry ratio (AR) and no response (NR) as diagnostic criteria (OR = 2.16, 95% CI = 1.61-2.89). Conclusion: The meta-analysis reveals that utricular dysfunction may be more predominant in BPPV compared with saccular dysfunction.

Supramolecular Nanofibers for Encapsulation and In Situ Differentiation of Neural Stem Cells.

Design and fabrication of fibrous materials by natural biological macromolecules in light of biomimetics to achieve spatially cellular arrangements are highly desirable in tissue engineering. Herein, chromatin-inspired supramolecular fibers formed through the interfacial polyelectrolyte complexation (IPC) process by DNA and histone proteins for encapsulation and in situ differentiation of murine brain-derived neural stem cells (NSCs) are reported. High cell viability of encapsulated NSCs demonstrates the excellent biocompatibility of fibers as 3D scaffolds. Moreover, a cell-adhesive peptide (K6 -PEG-RGD) is introduced into fibers by electrostatic interaction to improve NSCs encapsulation efficiency and prevent them from migrating out of fibers for enhanced spatially cellular arrangement. In situ differentiation of NSCs into oligodendrocytes within fibers is revealed by immunocytochemical staining assay. Due to the robust abilities to encapsulate and in situ differentiate NSCs, these chromatin-inspired supramolecular fibers show great potential in neural system-related tissue.

Primary temporal bone chondrosarcoma: experience with 10 cases.

Background: Temporal bone chondrosarcoma (TBC) are uncommon primary temporal bone malignancies, and clinicians lack experience in its diagnosis and treatment. The optimal management of patients with tumor of TBC also remains a topic of debate and controversy. Objectives: This article summarizes the experience of diagnosis and treatment of TBC, in order to improve the quality of life of cancer patients in the future. Material and methods: We conducted a retrospective analysis of 10 patients who were referred to our hospital from June 2009 to June 2018 for the treatment of TBC. Results: There were 3 males and 7 females. The most common presenting symptoms were facial paresis (50%) and hearing loss (40%), whereas otalgia (10%), vertigo (10%) and headache (10%) were less common. All tumors originated from the temporal bone, and 80% involved the jugular foramen area. All patients survived without evidence of disease at a median time of follow up of 28.8 months. Conclusions and significance: TBC mostly originated in the middle ear mastoid area, and easily extended to the jugular foramen area. An individualized surgical procedure that removes tumors integrally with minimal nerve and blood vessel damage provides long-term cancer control and minimal morbidity in most cases.