Recent Advances in Nanomedicine for Ocular Fundus Neovascularization Disease Management.

As an indispensable part of the human sensory system, visual acuity may be impaired and even develop into irreversible blindness due to various ocular pathologies. Among ocular diseases, fundus neovascularization diseases (FNDs) are prominent etiologies of visual impairment worldwide. Intravitreal injection of anti-vascular endothelial growth factor drugs remains the primary therapy but is hurdled by common complications and incomplete potency. To renovate the current therapeutic modalities, nanomedicine emerged as the times required, which is endowed with advanced capabilities, able to fulfill the effective ocular fundus drug delivery and achieve precise drug release control, thus further improving the therapeutic effect. This review provides a comprehensive summary of advances in nanomedicine for FND management from state-of-the-art studies. First, the current therapeutic modalities for FNDs are thoroughly introduced, focusing on the key challenges of ocular fundus drug delivery. Second, nanocarriers are comprehensively reviewed for ocular posterior drug delivery based on the nanostructures: polymer-based nanocarriers, lipid-based nanocarriers, and inorganic nanoparticles. Thirdly, the characteristics of the fundus microenvironment, their pathological changes during FNDs, and corresponding strategies for constructing smart nanocarriers are elaborated. Furthermore, the challenges and prospects of nanomedicine for FND management are thoroughly discussed.

A novel injectable thermo/photo dual-crosslinking hydrogel based on modified chitosan for fast sealing open globe injury.

Open globe injuries (OGIs) demand immediate attention to prevent further complications and improve vision prognosis. Herein, we developed a thermo/photo dual-crosslinking injectable hydrogel, HBC_m_Arg, for rapidly sealing OGIs in emergency ophthalmic cases. HBC_m_Arg was prepared with arginine and methacrylic anhydride modified hydroxybutyl chitosan (HBC). HBC_m_Arg was initially in liquid form at 25 °C, enabling easy injection at the injury site. After reaching the ocular surface temperature, it underwent reversible heat-induced gelation to achieve in situ transformation. Further, HBC_m_Arg was capable of rapid photocrosslinking under UV light, forming a dual network structure to bolster mechanical strength, thereby facilitating effective OGI closure. Biocompatibility assessments, including in vitro studies with three ocular cell types and in vivo experiments on rabbit eyes, confirmed the safety profile of HBC_m_Arg. Ex vivo and in vivo burst pressure tests demonstrated the hydrogel's ability to promptly restore intraocular pressure and withstand elevated pressures, underscoring its potential for OGI stabilization. Additionally, the suitable degradation of HBC_m_Arg within ocular tissues, coupled with its stability in ex vivo assessments, presented a delicate balance between stability and biodegradability. In conclusion, HBC_m_Arg holds promise for improving emergency ophthalmic care by providing a rapid, effective, and safe way to seal OGIs in critical situations.

Artificial Intelligence in Ophthalmic Surgery: Current Applications and Expectations.

Artificial Intelligence (AI) has found rapidly growing applications in ophthalmology, achieving robust recognition and classification in most kind of ocular diseases. Ophthalmic surgery is one of the most delicate microsurgery, requiring high fineness and stability of surgeons. The massive demand of the AI assist ophthalmic surgery will constitute an important factor in boosting accelerate precision medicine. In clinical practice, it is instrumental to update and review the considerable evidence of the current AI technologies utilized in the investigation of ophthalmic surgery involved in both the progression and innovation of precision medicine. Bibliographic databases including PubMed and Google Scholar were searched using keywords such as "ophthalmic surgery", "surgical selection", "candidate screening", and "robot-assisted surgery" to find articles about AI technology published from 2018 to 2023. In addition to the Editorials and letters to the editor, all types of approaches are considered. In this paper, we will provide an up-to-date review of artificial intelligence in eye surgery, with a specific focus on its application to candidate screening, surgery selection, postoperative prediction, and real-time intraoperative guidance.

Azithromycin-carrying and microtubule-orientated biomimetic poly (lactic-co-glycolic acid) scaffolds for eyelid reconstruction.

Introduction: Tarsal plate repair is the major challenge of eyelid reconstruction for the oculoplastic surgeon. The ideal synthetic tarsal plate substitute should imitate the microstructure and mechanical strength of the natural eyelid. The aim of this work was to develop a novel bionic substitute for eyelid reconstruction. Methods: Three types of poly(lactic-co-glycolic acid) (PLGA) scaffolds (random, oriented, and azithromycin-loaded oriented scaffolds) were prepared using an improved thermal-induced phase separation technique. The microstructure of the scaffolds was examined by scanning electron microscopy. In vitro cytotoxicity was assessed using scaffold extracts. Fibroblast and primary rat meibomian gland epithelial cells (rMGCs) were cultured within the scaffolds, and their behavior was observed using fluorescence staining. Three types of PLGA scaffolds were implanted into rabbit eyelid defect in vivo to evaluate their inductive tissue repair function. Results: We successfully fabricated three types of PLGA scaffolds with varying pore architectures, and the axially aligned scaffold demonstrated interconnected and vertically parallel channels. In vitro cytotoxicity tests using scaffold extracts revealed no apparent cytotoxicity. Fluorescence staining showed that both Fibroblast and rMGCs could adhere well onto the pore walls, with fibroblast elongating along the axially aligned porous structure. At 8 weeks post-implantation, all scaffolds were well integrated by fibrovascular tissue. The axially aligned scaffold groups exhibited faster degradation compared to the random scaffold group, with smaller fragments surrounded by mature collagen fibers. Conclusion: The study found that the axially aligned scaffolds could well support and guide cellular activities in vitro and in vivo. Moreover, the axially aligned scaffold group showed a faster degradation rate with a matched integration rate compared to the random scaffold group. The findings suggest that the oriented scaffold is a promising alternative for eyelid tarsal plate substitutes.

Automatic Diagnosis of Infectious Keratitis Based on Slit Lamp Images Analysis.

Infectious keratitis (IK) is a common ophthalmic emergency that requires prompt and accurate treatment. This study aimed to propose a deep learning (DL) system based on slit lamp images to automatically screen and diagnose infectious keratitis. This study established a dataset of 2757 slit lamp images from 744 patients, including normal cornea, viral keratitis (VK), fungal keratitis (FK), and bacterial keratitis (BK). Six different DL algorithms were developed and evaluated for the classification of infectious keratitis. Among all the models, the EffecientNetV2-M showed the best classification ability, with an accuracy of 0.735, a recall of 0.680, and a specificity of 0.904, which was also superior to two ophthalmologists. The area under the receiver operating characteristics curve (AUC) of the EffecientNetV2-M was 0.85; correspondingly, 1.00 for normal cornea, 0.87 for VK, 0.87 for FK, and 0.64 for BK. The findings suggested that the proposed DL system could perform well in the classification of normal corneas and different types of infectious keratitis, based on slit lamp images. This study proves the potential of the DL model to help ophthalmologists to identify infectious keratitis and improve the accuracy and efficiency of diagnosis.

An electrospun scaffold functionalized with a ROS-scavenging hydrogel stimulates ocular wound healing.

Ocular alkali burn is a serious ophthalmic emergency. Highly penetrative alkalis cause strong inflammatory responses leading to persistent epithelial defects, acute corneal perforation and severe scarring, and thereby persistent pain, loss of vision and cicatricial sequelae. Early and effective anti-inflammation management is vital in reducing the severity of injury. In this study, a double network biomaterial was prepared by compounding electrospinning nanofibres of thioketal-containing polyurethane (PUTK) with a reactive oxygen species (ROS)-scavenging hydrogel (RH) fabricated by crosslinking poly(poly(ethylene glycol) methyl ether methacrylate-co-glycidyl methacrylate) with thioketal diamine and 3,3'-dithiobis(propionohydrazide). The developed PUTK/RH patch exhibited good transparency, high tensile strength and increased hydrophilicity. Most importantly, it demonstrated strong antioxidant activity against H2O2 and 2,2-di(4-tert-octylphenyl)-1-picryl-hydrazyl (DPPH). Next, a rat corneal alkali burn model was established, and the PUTK/RH patch was transplanted on the injured cornea. Reduced inflammatory cell infiltration was revealed by confocal microscopy, and lower expression levels of genes relative to inflammation, vascularization and scarring were identified by qRT-PCR and western blot. Fluorescein sodium dyeing, hematoxylin and eosin (H&E) staining and immunohistochemical staining confirmed that the PUTK/RH patch could accelerate corneal wound healing by inhibiting inflammation, promoting epithelial regeneration and decreasing scar formation. STATEMENT OF SIGNIFICANCE: Ocular alkali burn is a serious ophthalmic emergency, characterized with persistent inflammation and irreversible vision loss. Oxidative stress is the main pathological process at the acute inflammatory stage, during which combined use of glucocorticoids and amniotic membrane transplantation is the most widely accepted treatment. In this study, we fabricated a polyurethane electrospun nanofiber membrane functionalized with a ROS-scavenging hydrogel. This composite patch could be a promising amniotic membrane substitute, possessing with a transparent appearance, elasticity and anti-inflammation effect. It could be easily transplanted onto the alkali-burned corneas, resulting in a significant inhibition of stromal inflammation and accelerating the recovery of corneal transparency. The conception of ROS-scavenging wound patch may offer a new way for ocular alkali burn.

Class-Aware Attention Network for infectious keratitis diagnosis using corneal photographs.

Infectious keratitis is one of the common ophthalmic diseases and also one of the main blinding eye diseases in China, hence rapid and accurate diagnosis and treatment for infectious keratitis are urgent to prevent the progression of the disease and limit the degree of corneal injury. Unfortunately, the traditional manual diagnosis accuracy is usually unsatisfactory due to the indistinguishable visual features. In this paper, we propose a novel end-to-end fully convolutional network, named Class-Aware Attention Network (CAA-Net), for automatically diagnosing infectious keratitis (normal, viral keratitis, fungal keratitis, and bacterial keratitis) using corneal photographs. In CAA-Net, a class-aware classification module is first trained to learn class-related discriminative features using separate branches for each class. Then, the learned class-aware discriminative features are fed into the main branch and fused with other feature maps using two attention strategies to assist the final multi-class classification performance. For the experiments, we have built a new corneal photograph dataset with 1886 images from 519 patients and conducted comprehensive experiments to verify the effectiveness of our proposed method. The code is available at https://github.com/SWF-hao/CAA-Net_Pytorch.

A cascade eye diseases screening system with interpretability and expandability in ultra-wide field fundus images: A multicentre diagnostic accuracy study.

Background: Clinical application of artificial intelligence is limited due to the lack of interpretability and expandability in complex clinical settings. We aimed to develop an eye diseases screening system with improved interpretability and expandability based on a lesion-level dissection and tested the clinical expandability and auxiliary ability of the system. Methods: The four-hierarchical interpretable eye diseases screening system (IEDSS) based on a novel structural pattern named lesion atlas was developed to identify 30 eye diseases and conditions using a total of 32,026 ultra-wide field images collected from the Second Affiliated Hospital of Zhejiang University, School of Medicine (SAHZU), the First Affiliated Hospital of University of Science and Technology of China (FAHUSTC), and the Affiliated People's Hospital of Ningbo University (APHNU) in China between November 1, 2016 to February 28, 2022. The performance of IEDSS was compared with ophthalmologists and classic models trained with image-level labels. We further evaluated IEDSS in two external datasets, and tested it in a real-world scenario and an extended dataset with new phenotypes beyond the training categories. The accuracy (ACC), F1 score and confusion matrix were calculated to assess the performance of IEDSS. Findings: IEDSS reached average ACCs (aACC) of 0·9781 (95%CI 0·9739-0·9824), 0·9660 (95%CI 0·9591-0·9730) and 0·9709 (95%CI 0·9655-0·9763), frequency-weighted average F1 scores of 0·9042 (95%CI 0·8957-0·9127), 0·8837 (95%CI 0·8714-0·8960) and 0·8874 (95%CI 0·8772-0·8972) in datasets of SAHZU, APHNU and FAHUSTC, respectively. IEDSS reached a higher aACC (0·9781, 95%CI 0·9739-0·9824) compared with a multi-class image-level model (0·9398, 95%CI 0·9329-0·9467), a classic multi-label image-level model (0·9278, 95%CI 0·9189-0·9366), a novel multi-label image-level model (0·9241, 95%CI 0·9151-0·9331) and a lesion-level model without Adaboost (0·9381, 95%CI 0·9299-0·9463). In the real-world scenario, the aACC of IEDSS (0·9872, 95%CI 0·9828-0·9915) was higher than that of the senior ophthalmologist (SO) (0·9413, 95%CI 0·9321-0·9504, p = 0·000) and the junior ophthalmologist (JO) (0·8846, 95%CI 0·8722-0·8971, p = 0·000). IEDSS remained strong performance (ACC = 0·8560, 95%CI 0·8252-0·8868) compared with JO (ACC = 0·784, 95%CI 0·7479-0·8201, p= 0·003) and SO (ACC = 0·8500, 95%CI 0·8187-0·8813, p = 0·789) in the extended dataset. Interpretation: IEDSS showed excellent and stable performance in identifying common eye conditions and conditions beyond the training categories. The transparency and expandability of IEDSS could tremendously increase the clinical application range and the practical clinical value of it. It would enhance the efficiency and reliability of clinical practice, especially in remote areas with a lack of experienced specialists. Funding: National Natural Science Foundation Regional Innovation and Development Joint Fund (U20A20386), Key research and development program of Zhejiang Province (2019C03020), Clinical Medical Research Centre for Eye Diseases of Zhejiang Province (2021E50007).

A hyaluronic acid/platelet-rich plasma hydrogel containing MnO2 nanozymes efficiently alleviates osteoarthritis in vivo.

The osteoarthritis (OA) symptoms cannot be fully remedied by using only a single functional component because of its complex pathogenesis. Herein, a MnO2 nanozyme-encapsulated hydrogel was fabricated via dispersing bovine serum albumin (BSA)-MnO2 (BM) nanoparticles (NPs) into a hyaluronic acid (HA)/platelet-rich plasma (PRP) gel network crosslinked by Schiff base reaction. Due to the self-healing and pH-responsive properties of Schiff base bonds, the hydrogel not only functioned as viscosupplementation but also exhibited pH-responsive release of BM NPs and growth factors in PRP. The BM NPs could attenuate the severe oxidative stress, and the PRP could promote chondrocyte proliferation. In a rat OA model, the HA/PRP/BM hydrogel markedly suppressed cartilage matrix degradation. Both the in vitro and in vivo studies showed that this novel hydrogel platform could inhibit the development of osteoarthritis through a synergetic effect of mechanical dissipation, depressing inflammation, facilitating cartilage repair, and thus has essential application prospects in OA treatment.

A novel lncRNA lnc-PPRL promotes pterygium development by activating PI3K/PDK1 signaling pathway.

A sight threatening, pterygium is a common proliferative and degenerative disease of the ocular surface. LncRNAs have been widely studied in the occurrence and development of various diseases, however, the study of lncRNAs in pterygium has just relatively lacking. In the present study, we performed the high-throughput RNA sequencing (HTS) technology to identify differentially expressed lncRNAs in pterygium. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out to forecast the regulatory and functional role of lncRNAs in pterygium. Notably, we identified a novel lncRNA, LOC102724238, which we named pterygium positively-related lncRNA (lnc-PPRL), was up-regulated in pterygium. Lnc-PPRL showed to be preferentially accumulated in cytoplasm, and it can promote cell proliferation, migration and invasion of human pterygium epithelium cells (hPECs). Further study of underlying mechanisms demonstrated that lnc-PPRL may exert its biological effect by activating canonical PI3K/PDK1 pathway, and subsequently promoting the activation of Akt/mTOR signaling pathway and its downstream effectors. Interestingly, lnc-PPRL was also proved to influence YAP nuclear localization. Taken together, our study firstly suggested that the "big molecule" lnc-PPRL have potential as a novel therapeutic target for the prevention and treatment of pterygium.

The micro-structure and biomechanics of eyelid tarsus.

Eyelid tarsus is a fibrocartilagenous extracellular matrix around meibomian glands providing structural support to eyelids and play important roles in the integrity of the ocular surface. There are no previous studies investigating the relationship between micro-structure and function of eyelid tarsus. To investigate the structure of extracellular matrix and the biomechanical properties of tarsus, rabbit tarsus were stained with hematoxylin and eosin (H&E), MASSON and Verhoeff's Van Gieson (EVG), distribution of collagen and elastin fibers in tarsus extracellular matrix were analyzed with scanning electron microscopy. Tarsus strips were collected and went through uniaxial tensile test with an Instron Universal Testing Machine. Data from 15 tarsus samples were included in the study. The initial tensile modulus was 2.554 ± 1.453 Mpa, and the final tensile modulus was 23.554 ± 3.657 Mpa, with an extensibility of 35.47 ± 7.46%. Collagen fibers formed peripheral layers of lamellae around meibomian glands, while the elastin fibres were organized in a parallel arrangement in horizontal and sagittal section, and in a crossed arrangement around meibomian glands. After tensile test, elastin fibres were stretched and arranged perpendicular to the direction of the collagen fibril lamellae. The findings of this study suggest that the extracellular matrix structure formed by collagen-elastin network contributes to a nonlinear mechanical characteristic of eyelid tarsus.

A cell-free ROS-responsive hydrogel/oriented poly(lactide-co-glycolide) hybrid scaffold for reducing inflammation and restoring full-thickness cartilage defectsin vivo.

The modulation of inflammation in tissue microenvironment takes an important role in cartilage repair and regeneration. In this study, a novel hybrid scaffold was designed and fabricated by filling a reactive oxygen species (ROS)-scavenging hydrogel (RS Gel) into a radially oriented poly(lactide-co-glycolide) (PLGA) scaffold. The radially oriented PLGA scaffolds were fabricated through a temperature gradient-guided phase separation and freeze-drying method. The RS Gel was formed by crosslinking the mixture of ROS-responsive hyperbranched polymers and biocompatible methacrylated hyaluronic acid (HA-MA). The hybrid scaffolds exhibited a proper compressive modulus, good ROS-scavenging capability, and cell compatibility.In vivotests showed that the hybrid scaffolds significantly regulated inflammation and promoted regeneration of hyaline cartilage after they were implanted into full-thickness cartilage defects in rabbits for 12 w. In comparison with the PLGA scaffolds, the neo-cartilage in the hybrid scaffolds group possessed more deposition of glycosaminoglycans and collagen type II, and were well integrated with the surrounding tissue.

Large fuzzy biodegradable polyester microspheres with dopamine deposition enhance cell adhesion and bone regeneration in vivo.

The biodegradable polymer microparticles with different surface morphology and chemical compositions may influence significantly the behaviors of cells, and thereby further the performance of tissue regeneration in vivo. In this study, multi-stage hierarchical textures of poly(D,L-lactic-co-glycolide) (PLGA)/PLGA-b-PEG (poly(ethylene glycol)) microspheres with a diameter as large as 50-100 µm are fabricated based on interfacial instability of an emulsion. The obtained fuzzy structures on the microspheres are sensitive to annealing, which are changed gradually to a smooth one after treatment at 37 °C for 6 d or 80 °C for 1 h. The surface microstructures that are chemically dominated by PEG can be stabilized against annealing by dopamine deposition. By the combination use of annealing and dopamine deposition, a series of microspheres with robust surface topologies are facilely prepared. The fuzzy microstructures and dopamine deposition show a synergetic role to enhance cell-material interaction, leading to a larger number of adherent bone marrow-derived mesenchymal stem cells (BMSCs), A549 and MC 3T3 cells. The fuzzy microspheres with dopamine deposition can significantly promote bone regeneration 12 w post surgery in vivo, as revealed by micro-CT, histological, western blotting and RT-PCR analyses.

Facile fabrication of elastic, macro-porous, and fast vascularized silicone orbital implant.

Orbital implants with interconnected porous architecture had gained prominence, as they were capable of being colonized by fibrovascular tissue and minimizing complications. However, mechanical properties of orbital implant had received little attention among existing design philosophy. Herein, a compliant porous silicone scaffold was developed by gelatin porogen-leaching method and used as the orbital implant in this study. The silicone scaffolds exhibited desired microstructure and simulated mechanical properties, including high porosity of ~90%, suitable pore size of 280-450 µm, reduced modulus of 50.1 ± 11.7 KPa, and excellent elasticity. in vitro results showed that the porous silicone scaffolds did not exhibit noticeable cytotoxicity and were favorable for both adhesion and proliferation of human vascular ECs. The porous silicone scaffold was easy to be manipulated when implanted into the anophthalmic sockets of rabbits. The implanted scaffolds provided satisfactory volume replacement and induced extensive fibro-vascularization, showing desirable orbital reconstruction effects. Therefore, our novel porous silicone scaffolds may be promising substitutes for current orbital implants.

A tarsus construct of a novel branched polyethylene with good elasticity for eyelid reconstruction in vivo.

Branched polyethylene (B-PE) elastomer was investigated for its potential medical application as a tarsus construct. The in vitro results showed that the B-PE and processed B-PE films or scaffolds did not exhibit noticeable cytotoxicity to the NIH3T3 fibroblasts and human vascular endothelial cells (ECs). The B-PE scaffolds with a pore size of 280-480 µm were prepared by using a gelatin porogen-leaching method. The porous scaffolds implanted subcutaneously in rats exhibited mild inflammatory response, collagen deposition and fast fibrovascularization, suggesting their good biocompatibility. Quantitative real-time PCR analysis showed low expression of pro-inflammatory genes and up-regulated expressions of collagen deposition and vascularization-related genes, validating the results of historical evaluation in a molecular level. The B-PE scaffolds and Medpor controls were transplanted in rabbits with eyelid defects. The B-PE scaffolds exhibited a similar elastic modulus and provided desirable repair effects with mild fibrous capsulation, less eyelid deformities, and were well integrated with the fibrovascular tissue compared with the Medpor controls.

Age-Related Regeneration of Osteochondral and Tibial Defects by a Fibrin-Based Construct in vivo.

Tissue-biomaterial interactions in different microenvironments influence significantly the repair and regeneration outcomes when a scaffold or construct is implanted. In order to elucidate this issue, a fibrin gel filled macroporous fibrin scaffold (fibrin-based scaffold) was fabricated by loading fibrinogen via a negative pressure method, following with thrombin crosslinking. The macroporous fibrin scaffold exhibited a porous structure with porosity of (88.1 ± 1.3)%, and achieved a modulus of 19.8 ± 0.4 kPa at a wet state after fibrin gel filling, providing a suitable microenvironment for bone marrow-derived mesenchymal stem cells (BMSCs). The in vitro cellular culture revealed that the fibrin-based scaffold could support the adhesion, spreading, and proliferation of BMSCs in appropriate cell encapsulation concentrations. The fibrin-based scaffolds were then combined with BMSCs and lipofectamine/plasmid deoxyribonucleic acid (DNA) encoding mouse-transforming growth factor ß1 (pDNA-TGF-ß1) complexes to obtain the fibrin-based constructs, which were implanted into osteochondral and tibial defects at young adult rabbits (3 months old) and aged adult rabbits (12 months old) to evaluate their respective repair effects. Partial repair of osteochondral defects and perfect restoration of tibial defects were realized at 18 weeks post-surgery for the young adult rabbits, whereas only partial repair of subchondral bone and tibial bone defects were found at the same time for the aged adult rabbits, confirming the adaptability of the fibrin-based constructs to the different tissue microenvironments by tissue-biomaterial interplays.

Enhanced regeneration of osteochondral defects by using an aggrecanase-1 responsively degradable and N-cadherin mimetic peptide-conjugated hydrogel loaded with BMSCs.

Due to the poor self-repair capabilities of articular cartilage, chondral or osteochondral injuries are difficult to be recovered. In this study, an N-cadherin mimetic peptide sequence HAVDIGGGC (HAV) was conjugated to direct cell-cell interactions, and an aggrecanase-1 cleavable peptide sequence CRDTEGE-ARGSVIDRC (ACpep) was used to crosslink hyperbranched PEG-based multi-acrylate polymer (HBPEG) with cysteamine-modified chondroitin sulfate (Cys-CS), obtaining an aggrecanase-1 responsively degradable and HAV-conjugated hydrogel ((HAV-HBPEG)-CS-ACpep). A HBPEG-CS-ACpep hydrogel without the HAV motif was also prepared. The two hydrogels exhibited similar equilibrium swelling ratios, elastic moduli and pore sizes after lyophilization, indicating the negligible influence of conjugated HAV on the crosslinking networks and mechanical properties of the hydrogels. After being degraded in PBS, aggrecanase-1 (ADAMTS4) and trypsin, the HBPEG-CS-ACpep hydrogel exhibited significantly decreased elastic moduli with a much lower value when incubated in enzyme solutions. The two hydrogels could maintain the viability of encapsulated bone marrow-derived mesenchymal stem cells (BMSCs), and the (HAV-HBPEG)-CS-ACpep hydrogel better promoted the cell-cell interactions. After being implanted into osteochondral defects in rabbits for 18 weeks, the two cell-laden hydrogel groups achieved better repair effects than the blank control group. Moreover, hyaline cartilage was formed in the (HAV-HBPEG)-CS-ACpep/BMSCs hydrogel group, while a hybrid of hyaline cartilage and fibrocartilage was found in the HBPEG-CS-ACpep/BMSCs hydrogel group.

PAQR4 promotes chemoresistance in non-small cell lung cancer through inhibiting Nrf2 protein degradation.

Purpose: Lung cancer is the leading cause of cancer related deaths worldwide. We have previously identified many differentially expressed genes (DEGs) from large scale pan-cancer dataset using the Cross-Value Association Analysis (CVAA) method. Here we focus on Progestin and AdipoQ Receptor 4 (PAQR4), a member of the progestin and adipoQ receptor (PAQR) family localized in the Golgi apparatus, to determine their clinical role and mechanism in the development of non-small cell lung cancer (NSCLC). Methods: The protein expression profile of PAQR4 was examined by IHC using tissue microarrays, and the effects of PAQR4 on cell proliferation, colony formation and xenograft tumor formation were tested in NSCLC cells. Real-time RT-PCR, co-immunoprecipitation (co-IP) and GST-pulldown assays were used to explore the mechanism of action of PAQR4. Results: We provided evidence showing that PAQR4 is increased in NSCLC cancer cell lines (A549, H1299, H1650, H1975, H358, GLC-82 and SPC-A1), and identified many mutations in PAQR4 in non-small cell lung cancer (NSCLC) tissues. We demonstrated that PAQR4 high expression correlates with a worse clinical outcome, and that its knockdown suppresses cell proliferation by inducing apoptosis. Importantly, overexpressed PAQR4 physically interacts with Nrf2 in NSCLC cells, blocking the interaction between Nrf2 and Keap1. Conclusion: Our results suggest that PAQR4 depletion enhances the sensitivity of cancerous cell to chemotherapy both in vitro and xenograft tumor formation in vivo, by promoting Nrf2 protein degradation through a Keap1-mediated ubiquitination process.

Influence of pore architectures of silk fibroin/collagen composite scaffolds on the regeneration of osteochondral defects in vivo.

The regeneration of osteochondral defects faces great challenges because of the limited self-regenerative capabilities of cartilage tissues. In situ inductive regeneration can be realized using bioactive scaffolds combined with endogenous reparative cells. Cell migration could be significantly facilitated by scaffolds with oriented channels. For this purpose, silk fibroin (SF) was composited with collagen (Col) to fabricate extracellular matrix (ECM)-mimetic SF/Col composite scaffolds with random pores, radially aligned pores or axially aligned pores by ice-templated assembly and temperature gradient-guided thermally-induced phase separation. Scanning electron microscopy (SEM) observation confirmed the random and aligned architectures in the respective scaffolds. The three kinds of SF/Col composite scaffolds exhibited a porous structure with a porosity of ∼85%, an appropriate elastic modulus with mechanical anisotropy in the aligned scaffolds, and good biocompatibility. The oriented channels could improve in vivo cell migration and infiltration. During the tissue remodeling processes, the regeneration of osteochondral tissues particularly cartilage was obviously faster in the radially aligned scaffold group than in the other two groups. Nevertheless, satisfactory regeneration was achieved in the two aligned scaffold groups with hyaline cartilage formation at 18 weeks post-surgery, while a hybrid of hyaline cartilage and fibrocartilage was formed in the random scaffold group.