Anterior-segment optical coherence tomography of filtering blebs in the early postoperative period of ab externo SIBS microshunt implantation with mitomycin C: Morphological analysis and correlation with intraocular pressure reduction.

PURPOSE: To analyse the morphological evolution of filtering blebs with anterior-segment OCT (AS-OCT) and its correlation with intraocular pressure after ab externo SIBS microshunt implantation with mitomycin C (MMC) during a 3-month follow-up period. METHODS: Twenty-eight filtering blebs of 28 patients with open-angle glaucoma were measured horizontally and vertically in the sub-Tenon space with AS-OCT after ab externo SIBS microshunt implantation with MMC. The intraocular pressure (IOP) was monitored simultaneously at each visit. Maturation of and morphological changes in the blebs and correlations with the IOP were recorded. RESULTS: The average median preoperative IOP of 20.7 (range, 12-30) mmHg decreased to 8.5 (range, 4-17), 8.9 (range, 5-17), 10.4 (range, 8-16) and 10.9 (range, 9-15) mmHg at 24 hr, 1 week, 1 month and 3 months, respectively (p < 0.001). A multiform morphology on AS-OCT prevailed at all time points, with a 3.5% rate of a uniform bleb morphology at the first week. The horizontal and vertical diameters of the blebs increased from baseline to the third month. The horizontal expansion (406 ± 127 µm on day 7, p = 0.04, 712 ± 211 µm on day 30, p = 0.02 and 952 ± 218 µm on day 90, p < 0.001) was greater than the vertical expansion (16 ± 18 µm, p = 0.3 on day 1, 63 ± 27 µm, p = 0.02 on day 30 and 137 ± 34 µm, p < 0.001 on day 90) without correlation with the IOP (r = -0.3, p = 0.2). CONCLUSION: Anterior-segment OCT (AS-OCT) of the filtering blebs formed after ab externo SIBS microshunt implantation showed progressive horizontal and vertical expansion of the blebs in the sub-Tenon space, with a significant peak at the first month not significantly correlated with the decrease in the IOP.

Injectable Hydrogel Capable of In Situ Covalent Crosslinking for Permanent Embolization.

Vascular embolization provides an effective approach for the treatment of hemorrhage, aneurysms, and other vascular abnormalities. However, current embolic materials, such as metallic coils and liquid embolic agents, are limited by their inability to provide safe, consistent, and controlled embolization. Here, we report an injectable hydrogel that can remain at the injection site and subsequently undergo in situ covalent crosslinking, leading to the formation of a dual-crosslinking network (DCN) hydrogel for endovascular embolization. The DCN hydrogel is simple to prepare, easy to deploy via needles and catheters, and mechanically stable at the target injection site, thereby avoiding embolization of nontarget vessels. It possesses efficient hemostatic activity and good biocompatibility. The DCN hydrogel is also clearly visible under X-ray imaging, thereby allowing for targeted embolization. In vivo tests in a rabbit artery model demonstrates that the DCN hydrogel is effective in achieving immediate embolization of the target artery with long-term occlusion by inducing luminal fibrosis. Collectively, the DCN hydrogel provides a viable, biocompatible, and cost-effective alternative to existing embolic materials with clinical translation potential for endovascular embolization.

Transepithelial versus epithelium-off corneal crosslinking for progressive keratoconus.

BACKGROUND: Keratoconus is the most common corneal dystrophy. It can cause loss of uncorrected and best-corrected visual acuity through ectasia (thinning) of the central or paracentral cornea, irregular corneal scarring, or corneal perforation. Disease onset usually occurs in the second to fourth decade of life, periods of peak educational attainment or career development. The condition is lifelong and sight-threatening. Corneal collagen crosslinking (CXL) using ultraviolet A (UVA) light applied to the cornea is the only treatment that has been shown to slow progression of disease. The original, more widely known technique involves application of UVA light to de-epithelialized cornea, to which a photosensitizer (riboflavin) is added topically throughout the irradiation process. Transepithelial CXL is a recently advocated alternative to the standard CXL procedure, in that the epithelium is kept intact during CXL. Retention of the epithelium offers the putative advantages of faster healing, less patient discomfort, faster visual rehabilitation, and less risk of corneal haze. OBJECTIVES: To assess the short- and long-term effectiveness and safety of transepithelial CXL compared with epithelium-off CXL for progressive keratoconus. SEARCH METHODS: To identify potentially eligible studies, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature database (LILACS); ClinicalTrials.gov; and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not impose any date or language restrictions. We last searched the electronic databases on 15 January 2020. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in which transepithelial CXL had been compared with epithelium-off CXL in participants with progressive keratoconus. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. MAIN RESULTS: We included 13 studies with 723 eyes of 578 participants enrolled; 13 to 119 participants were enrolled per study. Seven studies were conducted in Europe, three in the Middle East, and one each in India, Russia, and Turkey. Seven studies were parallel-group RCTs, one study was an RCT with a paired-eyes design, and five studies were RCTs in which both eyes of some or all participants were assigned to the same intervention. Eleven studies compared transepithelial CXL with epithelium-off CXL in participants with progressive keratoconus. There was no evidence of an important difference between intervention groups in maximum keratometry (denoted 'maximum K' or 'Kmax'; also known as steepest keratometry measurement) at 12 months or later (mean difference (MD) 0.99 diopters (D), 95% CI -0.11 to 2.09; 5 studies; 177 eyes; I2 = 41%; very low certainty evidence). Few studies described other outcomes of interest. The evidence is very uncertain that epithelium-off CXL may have a small (data from two studies were not pooled due to considerable heterogeneity (I2 = 92%)) or no effect on stabilization of progressive keratoconus compared with transepithelial CXL; comparison of the estimated proportions of eyes with decreases or increases of 2 or more diopters in maximum K at 12 months from one study with 61 eyes was RR 0.32 (95% CI 0.09 to 1.12) and RR (non-event) 0.86 (95% CI 0.74 to 1.00), respectively (very low certainty). We did not estimate an overall effect on corrected-distance visual acuity (CDVA) because substantial heterogeneity was detected (I2 = 70%). No study evaluated CDVA gain or loss of 10 or more letters on a logarithm of the minimum angle of resolution (logMAR) chart. Transepithelial CXL may result in little to no difference in CDVA at 12 months or beyond. Four studies reported that either no adverse events or no serious adverse events had been observed. Another study noted no change in endothelial cell count after either procedure. Moderate certainty evidence from 4 studies (221 eyes) found that epithelium-off CXL resulted in a slight increase in corneal haze or scarring when compared to transepithelial CXL (RR (non-event) 1.07, 95% CI 1.01 to 1.14). Three studies, one of which had three arms, compared outcomes among participants assigned to transepithelial CXL using iontophoresis versus those assigned to epithelium-off CXL. No conclusive evidence was found for either keratometry or visual acuity outcomes at 12 months or later after surgery. Low certainty evidence suggests that transepithelial CXL using iontophoresis results in no difference in logMAR CDVA (MD 0.00 letter, 95% CI -0.04 to 0.04; 2 studies; 51 eyes). Only one study examined gain or loss of 10 or more logMAR letters. In terms of adverse events, one case of subepithelial infiltrate was reported after transepithelial CXL with iontophoresis, whereas two cases of faint corneal scars and four cases of permanent haze were observed after epithelium-off CXL. Vogt's striae were found in one eye after each intervention. The certainty of the evidence was low or very low for the outcomes in this comparison due to imprecision of estimates for all outcomes and risk of bias in the studies from which data have been reported. AUTHORS' CONCLUSIONS: Because of lack of precision, frequent indeterminate risk of bias due to inadequate reporting, and inconsistency in outcomes measured and reported among studies in this systematic review, it remains unknown whether transepithelial CXL, or any other approach, may confer an advantage over epithelium-off CXL for patients with progressive keratoconus with respect to further progression of keratoconus, visual acuity outcomes, and patient-reported outcomes (PROs). Arrest of the progression of keratoconus should be the primary outcome of interest in future trials of CXL, particularly when comparing the effectiveness of different approaches to CXL. Furthermore, methods of assessing and defining progressive keratoconus should be standardized. Trials with longer follow-up are required in order to assure that outcomes are measured after corneal wound-healing and stabilization of keratoconus. In addition, perioperative, intraoperative, and postoperative care should be standardized to permit meaningful comparisons of CXL methods. Methods to increase penetration of riboflavin through intact epithelium as well as delivery of increased dose of UVA may be needed to improve outcomes. PROs should be measured and reported. The visual significance of adverse outcomes, such as corneal haze, should be assessed and correlated with other outcomes, including PROs.

Single intratracheal administration of cross-linked water-soluble acrylic acid polymer causes acute alveolo-interstitial inflammation and the subsequent fibrotic formation possibly via the TGF-ß1 pathway in the lung of rats.

In a Japanese chemical factory, a lung disease like pneumoconiosis appeared at a high rate among workers handling cross-linked water-soluble acrylic acid polymer (CWAAP). To our knowledge, no such case was known in the world until very recently. The present study was designed to elucidate the effect of single intratracheal CWAAP instillation on the lung of rats. The CWAAP group had a significant increase in relative lung weight accompanied by a significant elevation in the number of total cells, total protein concentrations, and myeloperoxidase concentrations in bronchoalveolar lavage fluid when compared to the control group. The histopathological study revealed acute lung inflammation with the destruction of alveoli. The factors promoting fibrosis, macrophages, TGF-ß1, collagen and fibronectin vs. the factors suppressing fibrosis, matrix metalloproteinases were more powerfully driven in the CWAAP group, resultantly leading to fibrotic formation. In turn, we examined if acute lung inflammation and the subsequent fibrotic formation seen in the CWAAP group appeared in the other water-soluble polymer groups. Their histopathological findings were observed only in the polyacrylic acid sodium (PAAS), a monomer of CWAAP, group. The degree of inflammation and fibrogenesis was stronger in the CWAAP group than in the PAAS group. In conclusion, the present study demonstrated the induction of acute lung inflammation and the subsequent fibrotic formation by single intratracheal CWAAP instillation. The structural features of CWAAP that contains many carboxyl groups and cross-linked chains may be responsible for enhanced inflammation and fibrogenesis in the lung.

Targeted delivery of mitomycin C-loaded and LDL-conjugated mesoporous silica nanoparticles for inhibiting the proliferation of pterygium subconjunctival fibroblasts.

Pterygium is a degenerative disease that characterized by excessive fibrovascular proliferation. To reduce the recurrence rate, surgery is the main strategy, in combination with adjacent procedures or adjunctive therapy. One of the most common adjunctive agents, mitomycin C (MMC), is known as an alkylating agent that inhibits fibroblast proliferation but is limitedly applied in pterygium due to various complications. A previous study demonstrated that activated pterygium subconjunctival fibroblasts overexpressed low-density lipoprotein (LDL) receptors. In this study, we designed and synthesized MMC-loaded mesoporous silica nanoparticles conjugated with LDL (MMC@MSNs-LDL) to deliver MMC into activated pterygium fibroblasts in a targeted manner. The MMC loading efficiency was approximately 6%. The cell viability test (CCK-8 assay) revealed no cytotoxicity for the empty carrier MSNs at a concentration of ≤1 mg/ml after administration for 48 h in subconjunctival fibroblasts. Primary pterygium and normal human subconjunctival fibroblasts with or without stimulation by vascular endothelial growth factor (VEGF) were treated as follows: 1) 10 µg/ml MMC@MSNs-LDL for 24 h (MMC concentration: 0.6 µg/ml); 2) 0.2 mg/ml MMC for 5 min then cultured for 24 h after MMC removal; and 3) normal culture without any drug treatment. At 24 h, the anti-proliferative effect of MMC@MSNs-LDL in activated pterygium fibroblasts was similar to that of MMC (cell viability: 46.2 ± 5.5% vs 40.5 ± 1.1%, respectively, P = 0.349). Furthermore, the cytotoxicity of MMC@MSNs-LDL to normal fibroblasts with or without VEGF stimulation was significantly lower than that of traditional MMC (cell viability: 75.6 ± 4.4% vs 36.0 ± 1.5%, respectively, P < 0.001; 84.7 ± 5.5% vs 35.7 ± 1.3%, P < 0.001). The binding of fluorescently labeled MMC@MSNs-LDL in fibroblasts was assessed using confocal fluorescence microscopy. The uptake of targeted nanoparticles in fibroblasts was time dependent and saturated at 6 h. VEGF-activated pterygium fibroblasts showed more uptake of MMC@MSNs-LDL than normal fibroblasts with or without VEGF activation (both P < 0.001). Our data strongly suggest that MMC@MSNs-LDL had an effective antiproliferative role in activated pterygium fibroblasts, with reduced toxicity to normal fibroblasts compared to traditional application of MMC. LDL-mediated drug delivery might have great potential in the management of pterygium recurrence.

A riboflavin-ultraviolet light A-crosslinked decellularized heart valve for improved biomechanical properties, stability, and biocompatibility.

Tissue-engineered heart valves are a promising alternative to current valve substitutes. As the main scaffold of tissue-engineered heart valves, the decellularized heart valve (DHV) has problems such as biomechanical property damage and rapid degradation. In this study, we applied a photo-crosslinking reaction induced by riboflavin and ultraviolet light A (UVA) in the DHV for improving its biomechanical properties and stability. The results showed that the biomechanical properties of the DHV significantly improved following riboflavin-UVA (R-UVA) crosslinking. Moreover, the R-UVA-crosslinked DHV (R-UV-DHV) showed better resistance to enzymatic degradation in vitro, with significantly higher thermal denaturation temperature compared to that of the untreated DHV, indicating that the stability of the R-UV-DHV improved. Histological staining and scanning electron microscopy showed that the leaflet ultrastructure was preserved better after R-UVA crosslinking compared to a glutaraldehyde-crosslinked DHV. In addition, we found that the R-UV-DHV exhibited excellent human umbilical vein endothelial cell adhesion and cells could readily grow on its surface. In an in vitro anti-calcification experiment, the R-UV-DHV demonstrated non-calcifying properties in a simulated body fluid. Furthermore, the R-UV-DHV showed characteristics of slow degradation, non-calcification, and reduced pro-inflammatory response through a rat subcutaneous implantation model. As a result, R-UVA can effectively crosslink the DHV and the R-UV-DHV possessed satisfactory biocompatibility. R-UVA crosslinking can be a new approach for improving the performance of the DHV to prepare a better scaffold for tissue-engineered valves.

A designed supramolecular cross-linking hydrogel for the direct, convenient, and efficient administration of hydrophobic drugs.

Hydrogels formed through reversible supramolecular interactions may attain self-healing in the in situ environment. However, the low grafting degree of functional groups and steric hindrance effect of polymer backbones significantly reduced the self-healing efficacy and kinetics. To overcome these deficiencies, we designed a novel hydrogel via non-covalent host-guest interaction between ß-cyclodextrin modified hyaluronic acid (HA-CD) and adamantane modified 4-arm-PEG (4-arm-PEG-Ad). The multi-armed monomer enabled to increase the number of functional groups and avoid steric hindrance effects, offering more efficient host-guest interaction. The insoluble dexamethasone could be loaded in the ß-CDs' hydrophobic cavities. The designed hydrogels exhibited excellent self-healing properties. The mechanical strengths, swelling rate and release of dexamethasone could be adjusted by adding 4-arm-PEG-Ad. The novel hydrogels significantly improved the therapeutic effect of the dexamethasone in burn wound healing. Herein, these hydrogels had great potential for direct, convenient, and efficient delivery of hydrophobic drugs and improved their therapeutic effects.

Adventitial Collagen Crosslink Reduces Intimal Hyperplasia in a Rabbit Arteriovenous Graft Model.

BACKGROUND: Intimal hyperplasia (IH) is the initial lesion of vein graft failure after coronary artery bypass grafting. The weak venous wall is likely one of the primary reasons for IH after exposure to the arterial environment. We investigate whether adventitial collagen cross-link by glutaraldehyde (GA) reinforces the venous wall and then reduces IH. MATERIALS AND METHODS: Adventitial collagen cross-link by 0.3% GA was performed on the rabbit jugular veins. The degree of cross-link was accessed by tensile test. The jugular vein with or without cross-link was implanted into the carotid artery of rabbit. Vein dilatation at the immediate anastomosis and pathological remodeling of vein graft after 4 wk was assessed. RESULTS: Tensile test indicated that the mechanical property of 3-min cross-linked veins more closely resembled that of the carotid artery. In rabbit arteriovenous graft models, 3-min adventitial collagen cross-link limited overdistension (diameter: 3.24 mm versus 4.65 mm, P < 0.01) at the immediate anastomosis and reduced IH (intima thickness: 78.83 µm versus 140.19 µm, P < 0.01) of vein grafts 4 wk after implantation in the cross-link group as compared with the graft group (without cross-link). Compared with the cross-link group, the expression of proliferating cell nuclear antigen and vascular cell adhesion molecule-1 increased significantly at both the mRNA and protein levels within the graft group (P < 0.01), but the expression of smooth muscle-22α decreased significantly (P < 0.01). CONCLUSIONS: Adventitial collagen cross-link by GA increased the vessel stiffness and remarkably reduced IH in a rabbit arteriovenous graft model.

Apolipoprotein E Peptide-Guided Disulfide-Cross-Linked Micelles for Targeted Delivery of Sorafenib to Hepatocellular Carcinoma.

Sorafenib (SF) is an FDA-approved molecular-targeted drug for treating hepatocellular carcinoma (HCC). SF, however, suffers from poor water solubility, low bioavailability, dose-limiting side effects, and possible drug resistance. Here, we report on apolipoprotein E peptide-decorated disulfide-cross-linked micellar SF (ApoE-Ms-SF) as a targeted and intelligent formulation for HCC therapy. ApoE-Ms-SF was prepared with a good SF loading of 7.0 wt %, small size (37 nm), high stability, and reduction-triggered drug release from poly(ethylene glycol)-b-poly(ε-caprolactone-co-dithiolane trimethylene carbonate)-mefenamate (PEG-P(CL-DTC)-MA) and ApoE-modified ApoE-PEG-P(CL-DTC) block copolymers. MTT assays in low-density lipoprotein receptors (LDLRs) overexpressing SMMC-7721 human liver cancer cells showed ApoE density-dependent antitumor potency of ApoE-Ms-SF, in which 7.5% ApoE led to the best antitumor effect (IC50: 8.5 vs 23.3 µg/mL for free SF). Confocal studies, flow cytometry, western blot, and apoptotic assays illustrated clearly a more efficient uptake of ApoE-Ms than nontargeted Ms by SMMC-7721 cells as well as lower phosphorylated extracellular signal-regulated kinase protein level and better cell apoptosis caused by ApoE-Ms-SF compared with Ms-SF and free SF. ApoE-Ms-SF revealed a long circulation time (elimination half-life = 6.8 h). DiR-loaded ApoE-Ms showed a significantly higher accumulation in SMMC-7721 tumor than the nontargeted counterpart. The therapeutic outcomes in the orthotopic SMMC-7721 tumor models demonstrated that ApoE-Ms-SF reduced SF-associated side effects and brought about enhanced angiogenesis inhibition and tumor apoptosis compared to free SF and Ms-SF controls, leading to a better treatment of HCC.

Carboplatin-related acute interstitial nephritis in a patient with pancreatic neuroendocrine tumor.

Carboplatin is characterized by low nephrotoxicity, including acute tubular necrosis (ATN), compared to a conventional platinum complex due to its low accumulative property in the renal tubules. Therefore, there are extremely few reports of carboplatin-induced kidney injury and only one case has been histologically examined. Herein, we describe the case of a 53-year-old man who presented with acute kidney injury (AKI) that occurred after carboplatin administration and was diagnosed with biopsy-proven acute interstitial nephritis (AIN). To our knowledge, this is the second case report of carboplatin-related AIN. The patient was diagnosed with a pancreatic neuroendocrine tumor, and chemotherapy consisting of cisplatin and irinotecan was initiated. However, 1 week later, he was admitted to our institution with fever, fatigue and an increase in C-reactive protein (CRP) level. The chemotherapy regimen was altered to carboplatin and etoposide, but high fever occurred on the first day, and CRP re-elevation and AKI became apparent 9 days later. Renal biopsy revealed prominent inflammatory cell infiltration into the interstitium, which lead to the pathological diagnosis of AIN. On immunostaining for surface markers, CD3- and CD68-positive cells were found to be predominant, and CD20-positive cells were relatively few. Although the serum creatinine level increased to 6.81 mg/dL, it decreased to 1.43 mg/dL 15 days after steroid therapy. This case demonstrated that carboplatin-related kidney injury includes not only ATN but also AIN. Appropriate pathological diagnosis including renal biopsy and indications for steroid treatment should be carefully considered.

Cross-Linked Hyaluronic Acid as Tear Film Substitute.

Purpose: The aim of this review is to clarify the role of cross-linked Hyaluronic acid (HA) molecule as a tear supplement and to define its possible applications in dry eye disease. Methods: Current Literature about HA and its cross-linked derivatives has been examined. Results: HA is superior in increasing the viscosity and stability of the tear film compared with other tear supplements such as polyvinyl alcohol, hydroxypropyl methylcellulose, carboximethyl cellulose and polyethylene glycol. Moreover, HA can be modified in different ways to improve its properties such as molecular weight, viscosity, and hydrophobicity to adapt the new artificial molecule to different aims. Conclusions: The current pharmacological trend is to improve the properties of HA by cross-linking parts of the molecule to achieve better bioavailability and resistence to degradation. In dry eye disease, cross-linked HA as tear supplement seems to provide better ocular comfort than linear HA and is therefore subjected to growing interest and diffusion.

Pain Management in Corneal Collagen Crosslinking for Keratoconus: A Comparative Case Series.

Purpose: To compare management of postoperative pain after corneal collagen crosslinking (CXL) with oral gabapentin or ketorolac. Methods: Prospective interventional comparative case series in a single center. Patients undergoing epithelium-off (epi-off) or epithelium-on (epi-on) techniques performed by a single surgeon for progressive keratoconus were enrolled and randomly assigned to the ketorolac (10-mg tablets every 8 h) or the gabapentin (300-mg capsules every 8 h) group and instructed to take the medication for the first 3 postoperative days. Using a numeric scale of pain, scores were assessed for current pain (at the time of applying the questionnaire), and average pain over the preceding 24 h. Eye symptoms and systemic adverse events related to oral medication were also assessed. Results: Thirty-seven patients were included, with 22 (10 epi-on and 12 epi-off) assigned to the ketorolac group and 15 (7 epi-on and 8 epi-off) to the gabapentin group. No statistically significant differences were noted on the pain scale between groups at any point of the study, in the median pain scores of patients at the time of applying the questionnaire, nor in the severity of pain during the 24-h period before the assessment. Also, no differences were found among groups for the eye symptoms and the systemic adverse events. The median regression analysis showed no effect of the type of surgery or gender in the severity of pain. Conclusions: Both oral ketorolac and oral gabapentin can be used with similar results for pain and symptomatic control after epi-on or epi-off CXL procedures.

Transepithelial versus epithelium-off corneal collagen cross-linking for corneal ectasia: protocol for a systematic review, meta-analysis and trial sequential analysis of randomised controlled trials.

INTRODUCTION: Corneal ectasias are progressive, degenerative ocular diseases defined by abnormal structural changes in the cornea, leading to distortion of vision and substantial reduction in quality of life. Corneal collagen cross-linking (CXL) increases the biomechanical rigidity of the cornea and has been shown to halt ectatic processes. The established CXL protocol requires removal of the corneal epithelium. However, some surgeons have proposed transepithelial approaches to enhance patient recovery and minimise adverse events. Whether novel transepithelial approaches are as effective in arresting ectasia as the established epithelium-off protocol remains unclear. This study will systematically review the evidence on transepithelial CXL approaches and compare it to the epithelium-off protocol. METHODS AND ANALYSIS: We will include randomised controlled trials (RCTs) comparing transepithelial and epithelium-off CXL for any corneal ectasia. We will search 16 electronic databases including MEDLINE and Embase, as well as the grey literature. Two reviewers will independently screen search results to identify eligible studies, complete data abstraction and conduct quality assessment. We will assess the quality of individual RCTs using the Cochrane risk of bias assessment tool. Our primary outcome will be the change in maximal keratometry at 12 months after treatment, and we will examine 11 additional outcomes. We will summarise our analyses by measures of association (relative risk or odds ratio) and corresponding 95% confidence intervals (CIs) for dichotomous outcomes and weighted mean differences with 95% CIs for continuous outcomes. Prespecified subgroup analyses will be conducted to explore heterogeneity. The overall quality of evidence will be rated using the Grading of Recommendations Assessment, Development and Evaluation approach. ETHICS AND DISSEMINATION: Ethics approval is not required for this systematic review as it draws from previously published data. Results of the study will be submitted to a peer-reviewed journal for publication and discussed at conferences and seminars. PROSPERO REGISTRATION NUMBER: CRD42018102069.

Two-year outcomes of a randomized controlled trial of transepithelial corneal crosslinking with iontophoresis for keratoconus.

PURPOSE: To evaluate the 2-year clinical outcomes of corneal crosslinking (CXL) using transepithelial iontophoresis CXL (T-ionto CXL) in comparison with standard CXL for the treatment of progressive keratoconus. SETTING: Single-site study. DESIGN: Randomized controlled clinical trial with identifier code NCT02117999. METHODS: The eyes of the participants were randomized to have either T-ionto CXL and/or standard CXL. Assessments of uncorrected (UDVA) and corrected (CDVA) distance visual acuities (logarithm of the minimum angle of resolution [logMAR]), manifest refraction spherical equivalent, maximum simulated keratometry (K) (diopters [D]), corneal higher-order aberrations (HOAs), central corneal thickness (CCT), and endothelial cell density (ECD) were performed at 3 days, 7 days, and 1, 3, 6, 12, and 24 months postoperatively. RESULTS: The study comprised 34 eyes (25 patients). There were 22 eyes in the T-ionto CXL group and 12 eyes in the standard CXL group. Two years after T-ionto CXL and standard CXL, the mean maximum K flattened by -1.05 ± 1.20 D (P = .07) (20 eyes) and -1.51 ± .89 D (P < .001) (11 eyes), respectively. Two study cases (10%) and no control showed maximum K steepening of more than 1.0 D at 24 months postoperatively. The mean change in CDVA was -0.08 ± 0.15 logMAR (P = .04) and -0.02 ± 0.06 logMAR (P = .34) after T-ionto CXL and standard CXL, respectively. A significant average decrease in the myopic defocus (+0.81 D; P < .05) was found in both groups. No significant differences in the outcome measures between treatments were found at 24 months. The corneal HOAs, CCT, and ECD values did not change significantly in any group at 2 years postoperatively. CONCLUSIONS: Clinically significant topographic, visual, and refractive improvements were found 2 years after T-ionto CXL; standard CXL showed more significant corneal apex flattening than the transepithelial iontophoresis protocol.

Improved curcumin loading, release, solubility and toxicity by tuning the molar ratio of cross-linker to ß-cyclodextrin.

A novel ß-cyclodextrin-based nanosponge (CDNS) was proposed as curcumin (CUR) delivery system improving pharmacokinetics and anticancer activity of CUR. The effect of molar ratio of Epiclon (EPI) as cross-linker and ß-cyclodextrin (ßCD) on the porosity, surface area, swelling ratio, CUR solubility and loading capacity, rate of drug release and selective toxicity of the CDNSs was fully investigated. The high degree of cross-linking led to the formation of mesoporous CDNS having high specific surface area and high loading capacity. All CUR-free CDNSs showed no toxicity against MCF 10A and 4T1 cells as normal and cancerous cells, respectively. While CDNSs-CUR exhibited selective toxicity against cancerous cells. In sum, high CUR aqueous solubility, significant loading and controllable release of the CUR, outstanding and selective toxicity against cancerous cells make CDNS8-CUR (EPI/ßCD = 8) as promising candidate for further study in the cancer therapy.

pH/Thermo-Dual Responsive Tunable In Situ Cross-Linkable Depot Injectable Hydrogels Based on Poly(N-Isopropylacrylamide)/Carboxymethyl Chitosan with Potential of Controlled Localized and Systemic Drug Delivery.

In the current study, cytocompatible in situ cross-linkable pH/thermo-dual responsive injectable hydrogels were prepared based on poly(N-isopropylacrylamide) and carboxymethyl chitosan, i.e., poly(CMCS-g-NIPAAm). The prepared formulations were aimed to be used as drug depot of 5-fluorouracil (5-FU) after subcutaneous administration in vivo. The phase transition from sol-gel state under physiologic temperature range was analyzed and confirmed by tube titling and optical transmittance measurements. The viscoelastic properties of gel formulations were confirmed by rheology determination via time sweep, temperature, and continuous ramp test. Oscillatory swelling cycles confirmed temperature effect and structural changes. pH and temperature sensitivity of dual responsive gels were analyzed at different pH and temperature programs. In vitro drug release profile displayed that developed formulations have the highest release in acidic pH at 25°C. The safety of blank gel formulations was evaluated against L929 cell lines via MTT assay and confirmed cytocompatibility with no detectable toxicity. In vitro cytotoxic potential of drug-loaded gels against HeLa and MCF-7 cancer cell lines confirmed that 5-FU has controlled cytotoxic potential in depot form in comparison to free 5-FU solution. The IC50 values for free 5-FU (21 ± 05 µg/ml and 18 ± 66 µg/ml) were found higher in comparison to the loaded form. The copolymer structure formation was confirmed by NMR and FTIR spectroscopic analysis. TG and DSC analysis proved the thermal stability and phase transition temperatures of pure and copolymer samples, while SEM analysis showed the porous nature of in situ formed hydrogels. It was concluded from the results that the developed formulations have pH/temperature sensitivity with potential of systemic and intratumoral controlled drug delivery properties.

In Vitro Bovine Liver Experiment of Cisplatin-Infused and Normal Saline-Infused Radiofrequency Ablation with an Internally Cooled Perfusion Electrode.

PURPOSE: To evaluate the efficacy of cisplatin-infused and normal saline-infused radiofrequency ablation (RFA) with internally cooled perfusion (ICP) electrode. MATERIALS AND METHODS: Using a 200 W generator, thirty ablation zones were created and divided into three groups of 10 each as follows: group A, RFA alone with 16 gauge monopolar internally cooled (IC) electrode; group B, cisplatin-infused RFA with 16 gauge ICP electrode; and group C, normal saline-infused RFA with 16 gauge ICP electrode. Radiofrequency was applied to the explanted bovine liver for 12 min. During RFA, cisplatin and normal saline were injected into tissue at a rate of 0.5 mL/min through the ICP electrode by injection pump. Dimensions of the ablation zone and technical parameters were compared between the three groups. RESULT: In the cisplatin-infused RFA group, the ablation zone size was significantly larger than that of the RFA-alone group but significantly smaller than normal saline-infused RFA group. The width of longitudinal section and volume were 3.39 ± 0.22 cm2 and 26.55 ± 4.62 cm3 in RFA-alone group, 3.88 ± 0.32 cm2 and 36.45 ± 5.46 cm3 in cisplatin-infused RFA group, and 4.52 ± 0.50 cm2 and 49.44 ± 7.55 cm3 in normal saline-infused RFA group, respectively (p < 0.05 between any two groups). The mean impedance in group A, B, and C were 60.0 ± 7.2, 50.3 ± 2.5, and 40.3 ± 4.0 Ω, respectively (p < 0.05 between any two groups). CONCLUSION: Cisplatin-infused RFA with ICP electrode created the larger size of ablation zone than that of monopolar RFA with an IC electrode, but created the smaller size of ablation zone than that of normal saline-infused RFA.

Comparative analysis and properties evaluation of gelatin microspheres crosslinked with glutaraldehyde and 3-glycidoxypropyltrimethoxysilane as drug delivery systems for the antibiotic vancomycin.

In the present comparative study, gelatin microspheres (GMs) were prepared by emulsification-solvent-extraction method using well-known crosslinker: glutaraldehyde (GA) and biocompatible silane-coupling agent: glycidoxypropyltrimethoxysilane (GPTMS). Crosslinking with GA was done by a definite and common procedure, while GPTMS crosslinking potency was investigated after 5, 10, 24, and 48 h synthesis periods and the fabrication method was adjusted in order for preparation of GMs with optimized morphological and compositional characteristics. The prepared GMs were then evaluated and compared as drug delivery systems for the antibiotic vancomycin (Vm). Morphological observations, FTIR, ninhydrin assay, swelling behavior evaluation and Hydrolytic degradation analysis proved successful modification of GMs and revealed that increasing synthesis time from 5 h to 24 h and 48 h, when using GPTMS as crosslinker, led to formation of morphologically-optimized GMs with highest crosslinking degree (∼50%) and the slowest hydrolytic degradation rate. Such GMs also exhibited most sustained release period of Vm. The antibacterial test results against gram-positive bacterium Staphylococcus aureus, were in accordance with the release profiles of Vm, as well. Together, GPTMS-crosslinked GMs with their preferable characteristics and known as biocompatible gelatin-siloxane hybrids, could act as proper drug delivery systems for the sustained release of the antibiotic vancomycin.

Covalently crosslinked organophosphorous derivatives-chitosan hydrogel as a drug delivery system for oral administration of camptothecin.

Hydrogels are widely studied as drug delivery system. In this work we propose the employment of tetrakis(hydroxymethyl)phosphonium chloride as crosslinking agent to obtain covalent hydrogels based on chitosan. These hydrogels are obtained by Mannich reaction between the amino groups of chitosan with the hydroxymethyl groups of the crosslinker molecule. They show a pH sensitive second order swelling kinetic, have low toxicity, are biocompatible, mucoadhesive and allow a modified release of the encapsulated drug, camptothecin, for 48 h. This antitumor drug has been studied as a drug of interest to develop oral chemotherapy administration strategies. According to the obtained results, oral administration of camptothecin through hydrogels would provide low concentrations of drug at the absorption site, avoiding carrier saturation and reducing its intestinal toxicity.

Trans-epithelial corneal collagen cross-linking with iontophoresis for progressive keratoconus.

PURPOSE: To evaluate the efficacy of trans-epithelial corneal collagen cross-linking (CXL) with Iontophoresis among patients with progressive keratoconus. METHODS: It is a prospective interventional study, which is based on 41 eyes of 23 patients, suffering from progressive keratoconus and treated with trans-epithelial corneal cross-linking, using iontophoresis with ETDA and trometamol-enriched riboflavin 5 phosphates 0.1% hypotonic solution (Ricrolin+, Soot Italia SpA, Italy). RESULTS: The mean of uncorrected distance visual acuity and best corrected distant visual acuity was improved at 6 months with statistically significant differences from baseline (p < 0.05). There was no statistically significant difference in keratometric values, including K1, K2, Km, topographic astigmatism, and central corneal thickness. Patients, who had completed 1 year (21 eyes of 12 patients) of the treatment, showed similar results. CONCLUSION: The data indicated that corneal collagens cross-linking with iontophoresis using Ricroli+ may be an effective method in halting the progression of keratoconus without the side effects of epithelial removal, which may be encountered in the standard epi-off CXL procedure.