Correction: Evaluation of a Novel Thermosensitive Heparin-Poloxamer Hydrogel for Improving Vascular Anastomosis Quality and Safety in a Rabbit Model
Ying‐Zheng ZhaoHaifeng LvCui‐Tao LuLijuan ChenMin LinMing ZhangXi JiangXiaotong ShenRongrong JinJun CaiXinqiao TianHo Lun Wong
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Despite progress in the design of advanced surgical techniques, stenosis recurs in a large percentage of vascular anastomosis.In this study, a novel heparin-poloxamer (HP) hydrogel was designed and its effects for improving the quality and safety of vascular anastomosis were studied.HP copolymer was synthesized and its structure was confirmed by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy ( 1 H-NMR).Hydrogels containing HP were prepared and their important characteristics related to the application in vascular anastomosis including gelation temperature, rheological behaviour and micromorphology were measured.Vascular anastomosis were performed on the right common carotid arteries of rabbits, and the in vivo efficiency and safety of HP hydrogel to achieve vascular anastomosis was verified and compared with Poloxamer 407 hydrogel and the conventional hand-sewn method using Doppler ultrasound, CT angiograms, scanning electron microscopy (SEM) and histological technique.Our results showed that HP copolymer displayed special gel-sol-gel phase transition behavior with increasing temperature from 5 to 60 °C.HP hydrogel prepared from 18 wt% HP solution had a porous sponge-like structure, with gelation temperature at approximately 38 °C and maximum elastic modulus at 10,000 Pa.In animal studies, imaging and histological examination of rabbit common jugular artery confirmed that HP hydrogel group had similar equivalent patency, flow and burst strength as Poloxamer 407 group.Moreover, HP hydrogel was superior to poloxamer 407 hydrogel and hand-sewn method for restoring the functions and epithelial structure of the broken vessel junctions after operation.By combining the advantages of heparin and poloxamer 407, HP hydrogel holds high promise for improving vascular anastomosis quality and safety.Keywords:
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Summary Poloxamer 188, N.F. (RheothRx®), a nonionic block copolymer composed of 2 hydrophilic polyoxyethylene chains connected by a hydrophobic polyoxypropylene chain, normalizes the viscosity of whole blood high in soluble fibrin(ogen) complexes. Normalization may be via a poloxamer 188-induced decrease in fibrin(ogen)-red cell interaction. Our study examined the influences of poloxamer 188 on fibrin assembly and structure. Studies were performed in both purified and plasma systems with a poloxamer 188 concentration range of 0.1-20 mg/ml and specific clotting conditions (fibrinogen 1 mg/ml, thrombin 1 NIH u/ml, pH 7.4 [Tris 0.05 M], ionic strength 0.15 and calcium 5 mM). Fibrin assembly was accelerated in the presence of poloxamer 188. As poloxamer 188 concentration was increased from 0 to 8 mg/ml in plasma: a) the lag phase prior to initial turbidity rise decreased from 25 to <5 s; b) the final gel optical density (OD) increased from 0.65 to 1.28 and c) fiber size (mass/length ratio [ε]) increased from 4.3 to 12.6 × 1013 daltons/cm. Similar results were seen in the purified system with a poloxamer 188 concentration range of 0-8 mg/ml. OD increased from 0.26 to 0.51, and ε increased from 2.3 to 5.3 × 1013 daltons/cm. Above 8 mg/ml, precipitation of fibrinogen was noted in this system. Since large fibrin fibers tend to be degraded more rapidly, possible poloxamer mediated enhancement of r-tPA-mediated clot lysis was investigated. With r-tPA (70 lu/ml) present at the time of clotting, clot lysis in the presence of ploxamer 188 (8 mg/ml) was 50% complete at 1,600 s compared to 2,540 s for the control. Thus, poloxamer 188-induced alterations in fibrin structure and fibrin-cell interactions may explain some of this agent's interesting hemorrheologic and antithrombotic properties.
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Abstract Pluronic polyols, especially Pluronic F‐68, are commonly added to cell culture media to protect insect and mammalian cells from the hydrodynamic stress resulting from sparging. This article describes the relevant properties of Pluronic polyols, the ability of Pluronic polyols to protect insect and mammalian cells from sparging and agitation, and the application of Pluronic polyols to cell culture.
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We prepared a series of alginate and Pluronic-based solutions as the in situ gelling vehicles for ophthalmic delivery of pilocarpine. The rheological properties, in vitro release as well as in vivo pharmacological response of polymer solutions, including alginate, Pluronic solution, and alginate/Pluronic solution, were evaluated. The optimum concentration of alginate solution for the in situ gel-forming delivery systems was 2% (w/w) and that for Pluronic solution was 14% (w/w). The mixture of 0.1% alginate and 14% Pluronic solutions showed a significant increase in gel strength in the physiological condition; this gel mixture was also found to be free flowing at pH 4.0 and 25 °C. Both in vitro release and in vivo pharmacological studies indicated that the alginate/Pluronic solution retained pilocarpine better than the alginate or Pluronic solutions alone. The results demonstrated that the alginate/Pluronic mixture can be used as an in situ gelling vehicle to increase ocular bioavailability.
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Poloxamers are negatively temperature-sensitive hydrogels and their hydrophilic groups interact with water molecules at lower temperatures (liquid phase) while their hydrophobic groups interact more strongly with increases in temperature causing gelation. To investigate the factors affecting the rheological properties of poloxamers, various parameters including different poloxamer P407 concentrations, poloxamers P407/P188 blending ratios and additives were examined. The results presented a clear trend of decreasing gelling temperature/time when P407 was at higher concentrations. Moreover, the addition of P188 enhanced the gelling temperature regardless of poloxamer concentration. Polysaccharides and their derivatives have been widely used as components of hydrogel and we found that alginic acid (AA) or carboxymethyl cellulose (CMC) reduced the gelling temperature of poloxamers. In addition, AA-containing poloxamer promoted cell proliferation and both AA -and CMC-containing poloxamer hydrogels reduced cell migration. This study investigated the intriguing characteristics of poloxamer-based hydrogel, providing useful information to compounding an ideal and desired thermo-sensitive hydrogel for further potential clinical applications such as development of sprayable anti-adhesive barrier, wound-healing dressings or injectable drug-delivery system for cartilage repair.
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The properties of poloxamer surfactants were investigated by a number of techniques. The adsorption of P188, P338 and P407, was studied on range of solids. The solids used were hydrophobic and poorly water soluble. An effect of temperature on the adsorption behaviour of the three surfactants was noticed. Poloxamers undergo a transition at a temperature which is dependent on their poly(oxypropylene) content, resulting in the amount of poloxamer adsorbing increasing. The transition can be attributed to a dehydration of the poly(oxypropylene) core of the poloxamer molecule, corresponding to changes in the micellar behaviour of the surfactants. The CMC is highly dependent on temperature. The nature of the adsorbate was found to affect poloxamer adsorption. The surface nature of the solids was investigated using contact angles. The poloxamers were investigated for their surface energy using different methods, and considered as both complete molecules and the sum of their individual components. Poloxamers do not adsorb readily to solids which have higher surface energies or which are more polar, suggesting that knowledge of surface nature could be useful in predicting adsorption behaviour. A model surface was created using chlorotrimethylsilane coated glass. It was possible to produce an artificial surface with known repeatable surface energy. Poloxamers adsorb to the coated slides. Slides with poloxamer adsorbed were shown to have altered surface nature. The hydrophobicity of the plates decreased as poloxamer adsorbed. The effect of temperature on the poly(oxyethylene) component of the poloxamer molecule was investigated by two techniques. Hydrophobic Interaction Chromatography and Photon Correlation Spectroscopy. It was shown that the poly(oxyethylene) reduced in size with increasing temperature. The hydrophobicity does not alter significantly with changes in temperature. These two techniques were also shown to substantiate the effects of temperature on the poly(oxypropylene) shown through adsorption studies.
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To determine the impact of delivery vehicles in photosensitizing efficacy of HPPH, a hydrophobic photosensitizer was dissolved in various formulations: 1% Tween 80/5% dextrose, Pluronic P-123 and Pluronic F-127 in 0.5%, 1% and 2% phosphate buffer solutions (PBS). HPPH was also conjugated to Pluronic F-127, and the resulting conjugate (PL-20) was formulated in PBS. Among the different delivery vehicles, only Pluronic P-123 displayed significant vehicle cytotoxicity, whereas Pluronic F127 was nontoxic. Compared to PL-20, HPPH formulated in Tween80 and Pluronic F-127 showed higher cell-uptake, but lower long-term retention in Colon26 cell compared to PL-20. The higher retention of PL-20 was similarly observed during in vivo uptake with BALB/c mice baring Ct26 tumors. In contrast to the in vitro uptake experiments, PL-20 showed slightly higher uptake compared to HPPH formulated in Tween or Pluronic-F127. A significant difference in pharmacokinetic profile was also observed between the HPPH-Pluronic formulation and PL-20. Under similar in vivo treatment parameters (drug dose 0.47 µmol kg-1 , light dose: 135 J cm-2 at 24 h post-injection of PS), HPPH formulated either in Tween or Pluronic F-127 formulation showed similar in vivo PDT efficacy (20-30% tumor cure on day 60), whereas PL-20 showed 40% tumor cure (day 60).
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