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Hydroxyapatite undoubtedly has vital roles in tissue engineering applications. The fabrication methods and different treatments lead distinct properties in hydroxyapatite crystals, including particle, size, shape, and surface features. In this study, we applied sol-gel synthesis route for hydroxyapatite production which offers relatively cost available and high yield of product. The influence of initial pH parameter and various temperature treatments on properties of hydroxyapatite were investigated. The leading hydroxyapatite powders have been compared in terms of their morphological and chemical structures by XRD and SEM analyses. The incipient pH in which the precursor solutions introduced to one another had critical role in this synthesis reaction. This has determined major properties, such as the chemical composition, phase purity, product yield, and morphology. The reactions of precursor solutions with higher incipient pH contributed to high yield (86%) of pure HA possessing high thermal stability. On the other hand, in lower incipient pH (8) counterpart, β-TCP phase was detected upon treatment at 950 °C. We had used the acquired pure HA in dried form in chitosan based injectable hydrogel compositions with pro-angiogenic features designed for bone tissue regeneration and drug delivery applications.

Introduction: The objective of this study was to identify the possible effect of thiazide and thiazide-like diuretic use on the relationship between uric acid and cognitive function in geriatric patients with normal renal function. Method: Serum uric acid levels and Mini-Mental State Examination scores of 238 patients (age >= 65 years) treated in an outpatient geriatric clinic were evaluated in this observational, cross-sectional, retrospective study. The effect of thiazide diuretic use on Mini-Mental State Examination score was also assessed. Results: Compared to patients that are not currently taking thiazide diuretics (non-thiazide group) serum uric acid was significantly higher in patients using thiazide and thiazide-like diuretics (thiazide group) (5.27 +/- 0.12 vs 6.09 +/- 0.20; P< 0.001). Although the serum uric acid levels were higher in the thiazide group the Mini-Mental State Examination scores were similar to the non-thiazide group. There was a strong positive correlation between serum uric acid levels and Mini-Mental State Examination score in both groups (P< 0.001). The Mini-Mental State Examination score was significantly lower in the lowest serum uric acid quartile in both groups (P< 0.001). Conclusions: Low serum uric acid levels are associated with cognitive impairment; a slight but significant increase of serum uric acid due to thiazide diuretic use does not seem to enhance cognitive function in geriatric patients.

Hard and soft tissue repair and regeneration require multiple surgical interventions, as very often-repeated clinical procedures are required. In addition, insufficient vascularisation remains as the main challenge for bone repair and regeneration. Therefore, bone regeneration via minimal invasive biomaterials promoting angiogenesis by bioactive agents are very much considered at present. Hereof, among new generation biomaterials, in-situ forming stimuli responsive injectable hydrogels have been of interest both in clinical and non-clinical communities. In this study, novel pH and thermosensitive in-situ formed injectable hydrogel compositions were developed by a heparin (Hep) functionalised chitosan (CS) polymer matrix integrated with a nonsintered hydroxyapatite (HA) system neutralised with sodium bicarbonate (NaHCO3). Due to designed bioactive features, CS/HA/Hep hydrogels are desired to ensure strong chemical anchorage and biological bridging by promoting vascular network formation at bone tissue defects due to the potential binding capacity of Hep for endogenous angiogenic growth factors and proteins. The production and optimisation of hydrogel compositions and their modification for pre-sterile synthesis technique with glycerol additive for enhancing mechanical properties meanwhile were investigated. The versatile properties of hydrogels were investigated for many aspects, such as injectability, gelation, rheology, mechanical properties, degradability, bioactivity, biocompatibility and angiogenesis. Hydrogel compositions showed facile injectability allowing suitable manual injection by 21 gauge (G) minimum needle thickness, and fast gelation at average body temperature (37 °C). In modified hydrogels, slight pH increment at solutions above 6.4 provided interpenetrating cross-linked morphology starting gelation in 2-3 minutes with enhanced elasticity, and mechanical strength. Hydrogels showed great bioactivity confirmed in Simulated Body Fluid (SBF) by forming mineralised carbonated apatite layer. The gradual hydrogel degradation was confirmed over 6-weeks up to 60% and 70% in PBS and Lysozyme-PBS media respectively. All developed hydrogels were cytocompatible and ensured proliferation of osteoblast-like cells. Optimal CS/HA/Hephydrogel compositions showed excellent pro-angiogenic capacity in ex-ovo chick embryo’s CAM model. Novel tuneable injectable pH and thermosensitive hydrogels (CS/HA/Hep) have tremendous clinical potential for minimal invasive surgery for bone repair and regeneration and targeted drug delivery applications.

Special Symposium - Biomaterials for tissue engineering applications- Oral ONLY Symposium: Vascularisation Strategies in Tissue Engineering Introduction: Bone treatment methods comprising transplantation techniques and solid scaffold biomaterial strategies suffer from multiple invasive surgical procedures. Recently, in-situ formed injectable hydrogels have drawn attentions since they can be introduced into tissue defects via minimally invasive methods. Thermosensitive (sol-gel) hydrogels are produced as a solution, and form gel at complex tissue defects by stimuli of the natural body temperature.The lack of sufficient blood supply to tissues due to the insufficient vascularity, the ultimate bone healing in major defects remain very challenging. Therefore, there is a huge demand of development of alternative pro-angiogenic biomaterials.The main aim of this project is to develop novel chitosan based thermosensitive injectable hydrogel composites to stimulate bone angiogenesis during bone regeneration. Experimental methods: Biodegradable chitosan (CS) matrix has been integrated with hydroxyapatite (HA) due to its inherited bioactivity. Heparin (Hep), which is a glycosaminoglycan was impregnated in CS/HA hydrogels and its angiogenesis potential investigated due to its highly anionic nature that can lead anchorage of physiologically present angiogenic growth factors.Chitosan based pH-dependent, thermoresponsive injectable solutions were produced with solgel technique at 4ºC by neutralizing with sodium bicarbonate (NaHCO3) and hydrogels were obtained upon incubation at 37ºC. Hydrogels were evaluated for their injectability and gelation properties. In addition, rheology measurements, chemical analyses and biological analyses involving angiogenesis via Chick Chorioallantoic Membrane (CAM) assay, bioactivity studies via Simulated Body Fluid (SBF) and in-vitro degradation studies were also carried out. Results and discussions: The solution injectability forces was under than the maximum manual injection force and allowing easy injection via 21 G and ticker sized needles which is suitable for orthopaedic and most dental administrations [1],[2]. Thermosetting gelation has occurred at the vicinity of body temperature and gelation was initiated from surface in 5-10 min at 37ºC. Interconnected porous hydrogels have exhibited pro-angiogenic response evaluated through CAM confirmed that the hydrogels with minimal heparin concentrations performed the best. Bioactivity studies with Simulated Body Fluid (SBF) showed needle-like carbonated apatite mineral deposition on hydrogels. In a six-weeks of in-vitro degradation study, hydrogels incubated in PBS and Lysozyme-PBS media had substantial weigh loss reaching up to 60 % and 70 %, respectively. Conclusions: Bioactive and biodegradable CS/HA/Hep injectable hydrogels can find potential application to stimulate bone angiogenesis for the repair and regeneration of non-load bearing bones.

OBJECTIVES The lack of sufficient blood supply to tissues due to the insufficient vascularity, the ultimate bone healing remains very challenging. Current clinical treatments often cause further blood loss due to multiple surgical interventions. Therefore, there is a significant need to develop minimally invasive injectable materials to promote bone angiogenesis. Stimuli responsive injectable hydrogels allow simple injection and in-situ gelation at targeted tissues, also offering therapeutic agents delivery e.g. drugs and cells. We aim to develop hybrid thermosensitive injectable hydrogels by incorporating biodegradable chitosan (CS), bioactive hydroxyapatite and heparin (Hep) to investigate its potential for angiogenesis due to its highly anionic nature that can anchorage physiological angiogenic growth factors. METHODS Injectable hydrogel solutions were produced via sol-gel technique after neutralization with sodium bicarbonate at 4°C, and hydrogels were formed upon incubation at 37°C. Sol injectability, rheological, gelation and chemical features and biological analyses involving cell cytotoxicity, angiogenesis via an ex-ovo Chick Chorioallantoic Membrane (CAM) assay, bioactivity and in-vitro degradation studies performed for characterisation of hydrogels. RESULTS AND CONCLUSIONS The thermosensitive liquid formulations allowing easy injection transferred to thermosetting gels instinctively at body temperature starting in 5-10 min. Hydrogels exhibited pro-angiogenic response in certain compositions achieved with minimal heparin concentrations. Bioactivity studies demonstrated needle-like carbonated apatite deposition on hydrogels. In-vitro degradation study of hydrogels showed substantial weight loss up to 60-70% at six-weeks. Bioactive and biodegradable CS/HA/Hep injectable hydrogels may be considered for clinical applications to stimulate bone angiogenesis in non-load bearing bone repair and regeneration.

Hydrogels being similar to extracellular matrix (ECM) of tissues have very attractive features mitigating surgical treatments, and improving sustainable delivery of drugs and growth factors. Thermosensitive polymer solutions show excellent phase transition capacity from sol to gel when cooled or heated. Once low temperature processed polymer solutions are injected into the body, gelation formation occurs in-situ at tissue defects under the stimuli of body heat. In this project, we investigate thermosensitive chitosan matrixed hydrogel compositions in which hydroxyapatite and heparin are impregnated for bone repair and regeneration. Having similar properties to collagen, chitosan has a unique natural polysaccharide structure possessing good biocompatibility, biodegradability combined with the gelation capability makes it an ideal material to be used in tailor-making scaffolds for Tissue Engineering applications. Although chitosan-based thermoresponsive hydrogels have been clinically used for cartilage regeneration, there is limited research on their use in bone regeneration. The chitosan hydrogels with the impregnation of hydroxyapatite increase bioactivity and mechanical strength, and heparin inclusion induces vascularisation, ultimately helping bone regeneration. In this study, chitosanbased gels have been prepared with the varying amount of hydroxyapatite and heparin. These homogeneous composite gels have presented irreversible gelation behavior nearly at the body temperature accordingly the rheology tests (Tinitial gelation = ~31 °C). The initial gelation time of the solutions have been determined as ~ 10 min via test tube invert method. Injection performance of prepared solutions have been tested through the syringes with a range of scaled needles. The finest needle size in which the solutions could have a proper flow was a 21-gauge needle. The chemical structural properties of gels formed at 37 °C have been studied by Infrared and Raman spectroscopies. Morphological properties have also been fully evaluated. Biological properties to assess their biocompatibility and vascularisation potential have also been carried out. Results obtained to date are excellent confirming the great potential of thermosensitive gels to induce bone vascularisation Turkish Ministry of National Education

Non-alcoholic fatty liver disease is a progressive inflammatory disease that ultimately results in cirrhosis and liver failure. It is assosiciated with two step hit scenario; the first step is fat accumulationin liver and in the second step inflammation and fibrosis are the major compenents. The incidence of this disease is increasing worldwide, following rising incidences of obesity and diabetes mellitus.The aim of this study is to analyze the relationship between non-alcoholic fatty liver disease andseverity and neutrophil-to-lymphocyte ratio among the patients having type 2 diabetes mellitus.This study involved 143 patients with type 2 diabetes who were placed into four groups (grade 0, 1, 2, 3) based on steatosis level due to blinded ultrasonographic evaluation. Biochemical parameters and counts of total white blood cells, neutrophils, and lymphocytes were determined. Neutrophil-to-lymphocyte ratio was compared across the four patient groups.Levels of hemoglobin A1c, creatinine, alanine aminotransferase, high-density lipoprotein cholesterol and triglycerides were significantly different between the four patient groups (ANOVA p-values: p0.001, p=0.011, p=0.002, p=0.034, p=0.002, respectively). Counts of white blood cells, neutrophils, lymphocytes, and neutrophil-to-lymphocyte ratio significantly differed between the groups (p0.001). Neutrophil-to-lymphocyte ratio was positively correlated with steatosis grade (p0.001).Neutrophil-to-lymphocyte ratio increases with increasing grade of non-alcoholic fatty liver disease in patients with type 2 diabetes, and may be a convenient marker to follow progression of non-alcoholic fatty liver disease. (Acta gastro-enterol. belg., 2016, 79, 295-300).

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WOS: 000391778300004, PubMed: 27830671, INTRODUCTION: Oxidative stress plays an important role in the pathogenesis of malign diseases. Prolidase is a member of the matrix metalloproteinase family, plays a major role in collagen metabolism, cell growth, and matrix remodeling. Elevated serum prolidase activity have beendemonstrated in several types of carcinoma. The aim of this study is to investigate the serum prolidase activity, total oxidant status (TOS), total antioxidant status (TAS) and to evaluate their relationship with tumor stage, lymph node metastasis, and tumor size in patients with breast carcinoma. METHODS: Thirty-five patients with breast carcinoma and forty healthy controls were enrolled to this study. Serum TAS, TOS levels, and prolidase activities were measured and oxidative stress indices (OSI) were calculated. RESULTS: TOS, OSI levels and prolidase activities were significantly higher in the patients with breast carcinoma compared to the control group (P < 0.001, P < 0.001, P = 0.002, respectively). TAS levels were significantly lower in the in the patients with breast carcinoma compared to the control group (P = 0.016). Positive correlations were found between prolidase activity, TOS, OSI levels and tumor stage, lymph node metastasis, and tumor size. A negative correlation was found between TAS levels and tumor size, hovewer there were no correlations between tas levels and stage of the tumor,as well as lymph node infiltration. CONCLUSION: We conclude that elevatedserum prolidase activity and oxidative stress may be associated with breast carcinoma. Increased serum prolidase activity may be related to stage and prognosis of breast carcinoma.

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