In Vitro Models in Biocompatibility Assessment for Biomedical-Grade Chitosan Derivatives in Wound Management

One of the ultimate goals of wound healing research is to find effective healing techniques that utilize the regeneration of similar tissues. This involves the modification of various wound dressing biomaterials for proper wound management. The biopolymer chitosan (β-1,4-D-glucosamine) has natural biocompatibility and biodegradability that render it suitable for wound management. By definition, a biocompatible biomaterial does not have toxic or injurious effects on biological systems. Chemical and physical modifications of chitosan influence its biocompatibility and biodegradability to an uncertain degree. Hence, the modified biomedical-grade of chitosan derivatives should be pre-examined in vitro in order to produce high-quality, biocompatible dressings. In vitro toxicity examinations are more favorable than those performed in vivo, as the results are more reproducible and predictive. In this paper, basic in vitro tools were used to evaluate cellular and molecular responses with regard to the biocompatibility of biomedical-grade chitosan. Three paramount experimental parameters of biocompatibility in vitro namely cytocompatibility, genotoxicity and skin pro-inflammatory cytokine expression, were generally reviewed for biomedical-grade chitosan as wound dressing

Chitosan Modification and Pharmaceutical/Biomedical Applications

Chitosan has received much attention as a functional biopolymer for diverse applications, especially in pharmaceutics and medicine. Our recent efforts focused on the chemical and biological modification of chitosan in order to increase its solubility in aqueous solutions and absorbability in the in vivo system, thus for a better use of chitosan. This review summarizes chitosan modification and its pharmaceutical/biomedical applications based on our achievements as well as the domestic and overseas developments: (1) enzymatic preparation of low molecular weight chitosans/chitooligosaccharides with their hypocholesterolemic and immuno-modulating effects; (2) the effects of chitin, chitosan and their derivatives on blood hemostasis; and (3) synthesis of a non-toxic ion ligand—D-Glucosaminic acid from Oxidation of D-Glucosamine for cancer and diabetes therapy

Clinical study of chitosan-derivative-based hemostat in the treatment of split-thickness donor sites

The hemostatic efficacy of a chitosan-derivative-based prototype was clinically evaluated in the treatment of split-thickness skin-graft donor sites in 17 patients, in comparison with two commercial materials. The test materials were placed randomly on the wound sites for 8 min. to stop the bleeding; the treated wounds were uncovered afterwards for evaluation. The total amount of blood loss in each treated wound was determined by measuring the blood absorbed in each used dressing. The bleeding area in each treated wound after an 8-min. treatment, was determined by wound image analysis. The amounts of blood loss measured from the wound sites treated with each material for 8 min. were found insignificantly different. However, from the visual observation and wound image analysis, the amount of blood ooze and the bleeding area after being left uncovered for 30, 60 and 90 sec. were significantly detected to be at a miniumum in wounds treated with the chitosan-derivative-based prototype, implying that the prototype could stop the bleeding most effectively

Geranylgeraniol prevents zoledronic acid-mediated reduction of viable mesenchymal stem cells via induction of Rho-dependent YAP activation

Long-term use of zoledronic acid (ZA) increases the risk of medication-related osteonecrosis of the jaw (MRONJ). This may be attributed to ZA-mediated reduction of viable mesenchymal stem cells (MSCs). ZA inhibits protein geranylgeranylation, thus suppressing cell viability and proliferation. Geranylgeraniol (GGOH), which is a naturally found intermediate compound in the mevalonate pathway, has positive effects against ZA. However, precise mechanisms by which GGOH may help preserve stem cell viability against ZA are not fully understood. The objective of this study was to investigate the cytoprotective mechanisms of GGOH against ZA. The results showed that while ZA dramatically decreased the number of viable MSCs, GGOH prevented this negative effect. GGOH-rescued ZA-exposed MSCs formed mineralization comparable to that produced by normal MSCs. Mechanistically, GGOH preserved the number of viable MSCs by its reversal of ZA-mediated Ki67+ MSC number reduction, cell cycle arrest and apoptosis. Moreover, GGOH prevented ZA-suppressed RhoA activity and YAP activation. The results also established the involvement of Rho-dependent YAP and YAP-mediated CDK6 in the cytoprotective ability of GGOH against ZA. In conclusion, GGOH preserves a pool of viable MSCs with osteogenic potency against ZA by rescuing the activity of Rho-dependent YAP activation, suggesting GGOH as a promising agent and YAP as a potential therapeutic target for MRONJ

Effects of Surface Treatments of Polycaprolactone Scaffolds on their Properties

Polycaprolactone (PCL) was surface modified with alkaline hydrolysis by NaOH and/or low pressure oxygen (O2) plasma treatment. The hydrolysis was conducted in two different stages: one was performed prior to PCL scaffold fabrication by a high pressure supercritical CO2 technique; the other was carried out after the fabrication. The resulting hydrolyzed PCL scaffolds, with pore sizes in the range of 150-250 μm, were denoted as pre-HPCL and post-HPCL, respectively. Both non-hydrolyzed and hydrolyzed PCL scaffolds were subsequently subjected to the plasma treatment, to further enhance the hydrophilicity of the scaffolds. The surface morphology, wettability and chemical composition of all PCL scaffolds were analyzed by scanning electron microscopy (SEM), water contact angle measurement, and X-ray photoelectron spectroscopy (XPS), respectively. It was found that the surface of the scaffolds turned from fairly smooth to highly rough after the hydrolysis and plasma treatment, particularly when both treatments were in use. The post-hydrolysis induced more surface roughness, compared to the pre-hydrolysis. In addition, the water contact angles on the scaffolds enormously reduced after the treatments; plasma treatment, however, showed a more prominent effect than the alkaline hydrolysis. Although expressing a zero-degree contact angle, the plasma-treated pre-HPCL scaffold was wetted more readily than the plasma-treated post-HPCL. These were in good agreement with the XPS results; interestingly, the plasma-treated pre-HPCL scaffold exhibited the greatest O/C atomic ratio among the PCL scaffolds. This indicated its highest extent of PCL chain oxidation, a degradation of ester groups into-COOH and-OH groups.</jats:p

Geranylgeraniol prevents zoledronic acid-mediated reduction of viable mesenchymal stem cells via induction of Rho-dependent YAP activation

Long-term use of zoledronic acid (ZA) increases the risk of medication-related osteonecrosis of the jaw (MRONJ). This may be attributed to ZA-mediated reduction of viable mesenchymal stem cells (MSCs). ZA inhibits protein geranylgeranylation, thus suppressing cell viability and proliferation. Geranylgeraniol (GGOH), which is a naturally found intermediate compound in the mevalonate pathway, has positive effects against ZA. However, precise mechanisms by which GGOH may help preserve stem cell viability against ZA are not fully understood. The objective of this study was to investigate the cytoprotective mechanisms of GGOH against ZA. The results showed that while ZA dramatically decreased the number of viable MSCs, GGOH prevented this negative effect. GGOH-rescued ZA-exposed MSCs formed mineralization comparable to that produced by normal MSCs. Mechanistically, GGOH preserved the number of viable MSCs by its reversal of ZA-mediated Ki67+MSC number reduction, cell cycle arrest and apoptosis. Moreover, GGOH prevented ZA-suppressed RhoA activity and YAP activation. The results also established the involvement of Rho-dependent YAP and YAP-mediated CDK6 in the cytoprotective ability of GGOH against ZA. In conclusion, GGOH preserves a pool of viable MSCs with osteogenic potency against ZA by rescuing the activity of Rho-dependent YAP activation, suggesting GGOH as a promising agent and YAP as a potential therapeutic target for MRONJ.</jats:p