Subconjunctivally implantable hydrogels with degradable and thermoresponsive properties for sustained release of insulin to the retina.

The objective of this work is to develop subconjunctivally implantable, biodegradable hydrogels for sustained release of intact insulin to the retina to prevent and treat retinal neurovascular degeneration such as diabetic retinopathy. The hydrogels are synthesized by UV photopolymerization of N-isopropylacrylamide (NIPAAm) monomer and a dextran macromer containing multiple hydrolytically degradable oligolactate-(2-hydroxyetheyl methacrylate) units (Dex-lactateHEMA) in 25:75 (v:v) ethanol:water mixture solvent. Insulin is loaded into the hydrogels during the synthesis process with loading efficiency up to 98%. The hydrogels can release biologically active insulin in vitro for at least one week and the release kinetics can be modulated by varying the ratio between NIPAAm and Dex-lactateHEMA and altering the physical size of the hydrogels. The hydrogels are not toxic to R28 retinal neuron cells in culture medium with 100% cell viability. The hydrogels can be implanted under the conjunctiva without causing adverse effects to the retina based on hematoxylin and eosin stain, immunostaining for microglial cell activation, and electroretinography. These subconjunctivally implantable hydrogels have potential for long-term periocular delivery of insulin or other drugs to treat diabetic retinopathy and other retinal diseases

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

New Experimental and Computational Results on the Radical-Controlled Oscillating Belousov-Zhabotinsky Reaction

New experimental results on the oscillatory dynamics of the radical-controlled Belousov−Zhabotinsky reaction (the Rácz system) in a batch reactor are reported. The system exhibits oscillations with no induction period, a typical feature of the radical-controlled mechanism. However, in the presence of acetylacetone (CH2(COCH3)2), an induction period is observed before oscillations start, which increases with increasing acetylacetone concentration. There is a critical concentration of acetylacetone at which no oscillations occur. Quenching of radical-controlled oscillations is also observed at low and high malonic acid concentrations as well as at low and high sulfuric acid concentrations. An induction period is observed before the onset of radical-controlled oscillations at sulfuric acid concentrations ≥5.5 M. The duration of radical-controlled oscillations reaches a maximum at an intermediate sulfuric acid concentration. Numerical simulations based on the Radicalator model predict limits of malonic acid and sulfuric acid concentration within which oscillations are observed. The Radicalator model with additional reactions involving (i) CH2(COCH3)2 + Ce4+ → •CH(COCH3)2, (ii) •CH(COCH3)2 + BrO2• → products, and (iii) •CH(COCH3)2 + •CH(COCH3)2 → products also predicts lengthening of induction period with the increase of acetylacetone concentration and suppression of oscillations at high acetylacetone concentration. Inclusion of the reaction between acetylacetone and HOBr had no effect

Polymerization coupled to oscillating reactions: (1) A mechanistic investigation of acrylonitrile polymerization in the Belousov - Zhabotinsky reaction in a batch reactor

When acrylonitrile is added to the Belousov - Zhabotinsky reaction, periodic polymerization is observed. (Pojman, J. A.; Leard, D.C.; West, W. W. J. Am. Chem. Soc. 1992, 114, 8298). The polymer\u27s structure and the amount of bromine in the polymer sample were determined by 13C NMR and elemental analysis, respectively. Carbon-13-labeled malonic acid indicates that polymerization of acrylonitrile is initiated by malonyl radical. The bromous radicals are believed to terminate the polymer leaving an alcohol group on the polymer end. Further analysis of the polymer sample confirms that the sample is partially brominated. Numerical simulations based on a modified FKN mechanism are found to be in good agreement with experimental findings. Simulations indicate that periodic termination of the polymer chain by bromine dioxide, not the periodic initiation by malonyl radical, is the dominant cause of the periodic polymerization. Similar results were found in the malonyl-controlled variant of the BZ reaction

Polymerization Coupled to Oscillating Reactions: (1) A Mechanistic Investigation of Acrylonitrile Polymerization in the Belousov-Zhabotinsky Reaction in a Batch Reactor

When acrylonitrile is added to the Belousov−Zhabotinsky reaction, periodic polymerization is observed. (Pojman, J. A.; Leard, D. C.; West, W. W. J. Am. Chem. Soc. 1992, 114, 8298). The polymer\u27s structure and the amount of bromine in the polymer sample were determined by 13C NMR and elemental analysis, respectively. Carbon-13-labeled malonic acid indicates that polymerization of acrylonitrile is initiated by malonyl radical. The bromous radicals are believed to terminate the polymer leaving an alcohol group on the polymer end. Further analysis of the polymer sample confirms that the sample is partially brominated. Numerical simulations based on a modified FKN mechanism are found to be in good agreement with experimental findings. Simulations indicate that periodic termination of the polymer chain by bromine dioxide, not the periodic initiation by malonyl radical, is the dominant cause of the periodic polymerization. Similar results were found in the malonyl-controlled variant of the BZ reaction

Subconjunctivally Implanted Hydrogels for Sustained Insulin Release to Reduce Retinal Cell Apoptosis in Diabetic Rats

PURPOSE. Diabetic retinopathy (DR) is a leading cause of blindness in diabetic patients that involves early-onset retinal cell loss. Here, we report our recent work using subconjunctivally implantable hydrogels for sustained insulin release to the retina to prevent retinal degeneration. METHODS. The hydrogels are synthesized by UV photopolymerization of N-isopropylacrylamide and a dextran macromer containing oligolactate-(2-hydroxyetheyl methacrylate) units. Insulin was loaded into the hydrogels during the synthesis. The ex vivo bioactivity of insulin released from the hydrogels was tested on fresh rat retinas using immunoprecipitation and immunoblotting to measure insulin receptor tyrosine and Akt phosphorylation. The biosafety and the effect on the blood glucose of the hydrogels were evaluated in rats 2 months after subconjunctival implantation. The release of insulin from the hydrogels was studied both in vitro in PBS (pH 7.4), and in vivo using confocal microscopy and RIA kit. The in vivo bioactivity of the released insulin was investigated in diabetic rats using DNA fragmentation method. RESULTS. The hydrogels could load insulin with approximately 98% encapsulation efficiency and continuously release FITC-insulin in PBS (pH ¼ 7.4) at 378C for at least 5 months depending on their composition. Insulin lispro released from the hydrogels was biologically active by increasing insulin receptor tyrosine and Akt serine phosphorylation of ex vivo retinas. In vivo studies showed normal retinal histology 2 months post subconjunctival implantation. Insulin released from subconjunctivally implanted hydrogels could be detected in the retina by using confocal microscopy and RIA kit for 1 week. The implanted hydrogels with insulin lispro did not change the blood glucose level of normal and diabetic rats, but significantly reduced the DNA fragmentation of diabetic retinas for 1 week. CONCLUSIONS. The developed hydrogels have great potential to sustain release of insulin to the retina via subconjunctival implantation to minimize DR without the risk of hypoglycemia