Overcoming the Dilemma of In Vivo Stable Adhesion and Sustained Degradation by the Molecular Design of Polyurethane Adhesives for Bone Fracture Repair.

Bone adhesive is a promising candidate to revolutionize the clinical treatment of bone repairs. However, several drawbacks have limited its further clinical application, such as unreliable wet adhesive performance leading to fixation failure and poor biodegradability inhibiting bone tissue growth. By incorporating catechol groups and disulfide bonds into polyurethane (PU) molecules, an injectable and porous PU adhesive is developed with both superior wet adhesion and biodegradability to facilitate the reduction and fixation of comminuted fractures and the subsequent regeneration of bone tissue. The bone adhesive can be cured within a reasonable time acceptable to a surgeon, and then the wet bone adhesive strength is near 1.30 MPa in 1 h. Finally, the wet adhesive strength to the cortical bone will achieve about 1.70 MPa, which is also five times more than nonresorbable poly(methyl methacrylate) bone cement. Besides, the cell culture experiments also indicate that the adhesives show excellent biocompatibility and osteogenic ability in vitro. Especially, it can degrade in vivo gradually and promote fracture healing in the rabbit iliac fracture model. These results demonstrate that this ingenious bone adhesive exhibits great potential in the treatment of comminuted fractures, providing fresh insights into the development of clinically applicable bone adhesives.

Poly(lactic acid-co-glycolic acid)-based celecoxib extended-release microspheres for the local treatment of traumatic heterotopic ossification.

Traumatic heterotopic ossification (THO) is a serious and common clinical post-traumatic complication for which there is no effective and safe drug treatment. Routine administration of nonsteroidal anti-inflammatory drugs (NSAIDs) after injury is extensively used approach for THO. However, serious adverse events can occur in the event of an overdose of NSAIDs. In our study, we have developed a poly(lactic acid-co-glycolic acid) (PLGA) microsphere by emulsifying solvent volatilization for the prolonged slow delivery of celecoxib (CLX). Three groups of celecoxib-poly(lactic acid-co-glycolic acid) microspheres (CLX-PLGA MPs) were prepared with particle sizes of 3.75±1.28 µm, 49.56±17.15 µm, and 94.98±42.53 µm. Meanwhile, related parameters of microspheres in each group were studied: drug loading (DL), encapsulation rate (EE), and slow-release behavior. The DL and EE of the 3 CLX-PLGA MPs did not vary significantly, and subsequently, we selected the second drug loading microspheres with a retardation period of about 70 days for subsequent experiments. Moreover, cellular and animal experiments suggest that the microspheres are biocompatible and can be safely applied to localized trauma tissue. Finally, it is demonstrated that CLX-PLGA MPs have an effect on inhibiting the osteogenic differentiation of bone marrow mesenchymal stem cells and have the potential to inhibit ectopic bone formation of the THO model in Sprague-Dawley rat. Therefore, this study suggests that CLX-PLGA MPs are expected to be applied topically in the early post-traumatic period to prevent the development of THO.

A Rapid and Sensitive HPLC Method for Simultaneous Determination of Irinotecan Hydrochloride and Curcumin in Co-delivered Polymeric Nanoparticles.

In recent years, a great deal of attention has been paid to the combined use of multiple antitumor drugs for better cancer treatment. The aims of the study are to construct a nanoparticle drug delivery system for the co-delivery of irinotecan hydrochloride and curcumin and to develop an analytical method for simultaneously quantifying these molecules, which is essential for further studies of the co-delivered nano system. The irinotecan hydrochloride and curcumin co-delivered nanoparticle (ICN) were prepared by combinatorially entrapping them into polyethylene glycol-poly lactic acid-co-glycolic acid (PEG-PLGA) polymeric nanoparticles. A simple, sensitive and rapid high-performance liquid chromatography method was developed and validated to simultaneously quantify the compounds in the co-delivered nanoparticle system. Acetonitrile and ultrapure water containing sodium dodecyl sulfate (0.08 mol/L), disodium phosphate (Na2HPO4, 0.002 mol/L) and acetic acid (4%, v/v) were used as the mobile phase and their ratio was set at 50:50. The flow rate was set to 1.0 mL/min, and the temperature in the column oven was maintained at 40°C. The analysis was carried out at 256 and 424 nm to assess irinotecan hydrochloride and curcumin, respectively. Detectors with only one channel can also visualize both analytes in one chromatogram at 379 nm and still demonstrate acceptable sensitivity. The retention times for irinotecan hydrochloride and curium were 3.317 and 5.560 min, respectively. The method developed was confirmed to be sensitive, accurate (recovery, 100 ± 2%), precise (relative standard deviation, RSD ≤ 1%), robust and linear (R2 ≥ 0.9996) in the range from 2.05 to 1050 µg/mL. The presented method has been used to quantify irinotecan hydrochloride and curcumin in the co-delivered ICN nano system to assess the drug delivery quality of the nanoparticles and can also be used for routine analysis because of its simplicity and accuracy.

Nanosized-Ag-doped porous ß-tricalcium phosphate for biological applications.

The treatment of infectious or potentially infective bone defects remains a major problem in clinical practice. Silver has the ability to potentiate antibiotics against resistant bacterial strains. In order to reduce the risk of long-term infections, it is necessary for the biomaterial scaffold to release Ag+ in a controlled manner during the entire healing process. In this study, given the antimicrobial characteristics of nanosized Ag (NSAg), we synthesized ß-tricalcium phosphate (ß-TCP) doped with 5 and 10 wt% NSAg (5 wt% NSAgTCP and 10 wt% NSAgTCP, respectively). The NSAgTCP composites exhibited similar macroporous structures to pure ß-TCP. The NSAgTCP samples were examined by scanning electron microscopy at 10,000-times magnification, which revealed that silver was still present at the nanometer scale. X-ray diffraction revealed that silver does not change the crystalline properties of ß-TCP. In addition, we observed that the mechanical strength of NSAgTCP increased with increasing amounts of added Ag. The antibacterial, physical, and chemical properties of NSAgTCP were investigated in vitro. We found that NSAgTCP is effective at inhibiting the growth of Staphylococcus aureus and Escherichia coli and is not cytotoxic to human bone marrow mesenchymal stem cells. Moreover, it does not hinder liver or kidney function when tested in vivo. As the bioceramic degrades, Ag ions are slowly released and new bone is formed. No significant cytotoxic effects were observed even when 10 wt% NSAgTCP was used. NSAgTCP has the ability to simultaneously repair bone defects and act as an anti-infective agent; hence, we expect that this material, with its good bone-repairing and anti-infective properties, will find wide spread use as a novel bone substitute.

Effects of X-shaped reduction-sensitive amphiphilic block copolymer on drug delivery.

To study the effects of X-shaped amphiphilic block copolymers on delivery of docetaxel (DTX) and the reduction-sensitive property on drug release, a novel reduction-sensitive amphiphilic copolymer, (PLGA)2-SS-4-arm-PEG2000 with a Gemini-like X-shape, was successfully synthesized. The formation of nanomicelles was proved with respect to the blue shift of the emission fluorescence as well as the fluorescent intensity increase of coumarin 6-loaded particles. The X-shaped polymers exhibited a smaller critical micelle concentration value and possessed higher micellar stability in comparison with those of linear ones. The size of X-shaped (PLGA)2-SS-4-arm-PEG2000 polymer nanomicelles (XNMs) was much smaller than that of nanomicelles prepared with linear polymers. The reduction sensitivity of polymers was confirmed by the increase of micellar sizes as well as the in vitro drug release profile of DTX-loaded XNMs (DTX/XNMs). Cytotoxicity assays in vitro revealed that the blank XNMs were nontoxic against A2780 cells up to a concentration of 50 µg/mL, displaying good biocompatibility. DTX/XNMs were more toxic against A2780 cells than other formulations in both dose- and time-dependent manners. Cellular uptake assay displayed a higher intracellular drug delivery efficiency of XNMs than that of nanomicelles prepared with linear polymers. Besides, the promotion of tubulin polymerization induced by DTX was visualized by immunofluorescence analysis, and the acceleration of apoptotic process against A2780 cells was also imaged using a fluorescent staining method. Therefore, this X-shaped reduction-sensitive (PLGA)2-SS-4-arm-PEG2000 copolymer could effectively improve the micellar stability and significantly enhance the therapeutic efficacy of DTX by increasing the cellular uptake and selectively accelerating the drug release inside cancer cells.

[Effect of carboxymethylchitosan-carboxymethylcellulose film on colonic anastomosis healing].

OBJECTIVE: To investigate the effects of carboxymethylchitosan-carboxymethylcellulose (CMCH-CMC) film on the adhesion and healing of colonic anastomosis. METHODS: Sixty-four healthy adult male SD rats was randomly divided into control group and experimental group (n=32). The model of colonic anastomosis was made according to Buckenmaier's method in all rats. The experimental group was treated by wrapping anastomosis with CMCH-CMC film (3 cm x 2 cm) and the control group was not treated. At 7 days and 14 days after operation, the adhesion formation of colonic anastomosis was observed, the tensile strength of the anastomosis was assessed and compared with 6 normal rats, and the hydroxyproline (HP) content of the anastomosis was detected. RESULTS: There were 3 deaths in the experimental group and 2 deaths in the control group. The adhesive scores of the experimental group on the 7th and 14th postoperative day [(0.50 +/- 0.16) points and (0.45 +/- 0.14) points, (P < 0.05)] were significantly lower than those of the control group [(1.67 +/- 0.15) points and (2.29 +/- 0.18) points, (P < 0.05)], (P < 0.01). Tensile strength were more marked on the 14th postoperative day than on the 7th postoperative day in the control group (P < 0.05), but there was no significant difference between the 7th day and the 14th day in the experimental group. The tensile strength of the control group and the experimental group on the 14th postoperative day [(178.36 +/- 20.10) and (172.74 +/- 22.18) mmHg] were respectively higher than those on the 7th postoperative day [(138.67 +/- 16.65) and (130.81 +/- 18.38) mmHg] (P < 0.01). The tensile strength of the control group and the experimental group on the 7th postoperative day were respectively significantly lower than that of the normal rats (P < 0.01). The level of HP in the anastomosis was significantly higher on the 7th postoperative day in the experimental group [(84.47 +/- 11.87) microg/mg dried weight] than that of the control group [(55.47 +/- 12.89) microg/mg dried weight), (P < 0.05)], but there was no significant difference between the experimental group and the control group on the 14th postoperative day [(146.07 +/- 14.81) microg/mg dried weight, (137.14 +/- 16.81) microg/mg dried weight, (P> 0.05)]. CONCLUSION: The CMCH-CMC film can decrease adhesion the formation of colonic anastomosis, but does not interfere with the healing of colonic anastomosis.