Impact of Molecular Architecture and Adsorption Density on Adhesion of Mussel-Inspired Surface Primers with Catechol-Cation Synergy.

Marine mussels secrete proteins rich in residues containing catechols and cationic amines that displace hydration layers and adhere to charged surfaces under water via a cooperative binding effect known as catechol-cation synergy. Mussel-inspired adhesives containing paired catechol and cationic functionalities are a promising class of materials for biomedical applications, but few studies address the molecular adhesion mechanism(s) of these materials. To determine whether intramolecular adjacency of these functionalities is necessary for robust adhesion, a suite of siderophore analog surface primers was synthesized with systematic variations in intramolecular spacing between catechol and cationic functionalities. Adhesion measurements conducted with a surface forces apparatus (SFA) allow adhesive failure to be distinguished from cohesive failure and show that the failure mode depends critically on the siderophore analog adsorption density. The adhesion of these molecules to muscovite mica in an aqueous electrolyte solution demonstrates that direct intramolecular adjacency of catechol and cationic functionalities is not necessary for synergistic binding. However, we show that increasing the catechol-cation spacing by incorporating nonbinding domains results in decreased adhesion, which we attribute to a decrease in the density of catechol functionalities. A mechanism for catechol-cation synergy is proposed based on electrostatically driven adsorption and subsequent binding of catechol functionalities. This work should guide the design of new adhesives for binding to charged surfaces in saline environments

Sustained release of locally delivered celecoxib provides pain relief for osteoarthritis: a proof of concept in dog patients

OBJECTIVE: Drug delivery platforms that allow for gradual drug release after intra-articular administration have become of much interest as a treatment strategy for osteoarthritis (OA). The aim of this study was to investigate the safety and efficacy of an intra-articular sustained release formulation containing celecoxib (CXB), a cyclooxygenase-2 (COX-2) selective inhibitor. METHODS: Amino acid-based polyesteramide microspheres (PEAMs), a biodegradable and non-toxic platform, were loaded with CXB and employed in two in vivo models of arthritis: an acute inflammatory arthritis model in rats (n = 12), and a randomized controlled study in chronic OA dog patients (n = 30). In parallel, the bioactivity of sustained release of CXB was evaluated in monolayer cultures of primary dog chondrocytes under inflammatory conditions. RESULTS: Sustained release of CXB did not alleviate acute arthritis signs in the rat arthritis model, based on pain measurements and synovitis severity. However, in OA dog patients, sustained release of CXB improved limb function as objective parameter of pain and quality of life based on gait analysis and owner questionnaires. It also decreased pain medication dependency over a 2-month period and caused no adverse effects. Prostaglandin E 2 levels, a marker for inflammation, were lower in the synovial fluid of CXB-treated dog OA patients and in CXB-treated cultured dog chondrocytes. CONCLUSION: These results show that local sustained release of CXB is less suitable to treat acute inflammation in arthritic joints, while safe and effective in treating pain in chronic OA in dogs

Sustained release of locally delivered celecoxib provides pain relief for osteoarthritis: a proof of concept in dog patients

Objective: Drug delivery platforms that allow for gradual drug release after intra-articular administration have become of much interest as a treatment strategy for osteoarthritis (OA). The aim of this study was to investigate the safety and efficacy of an intra-articular sustained release formulation containing celecoxib (CXB), a cyclooxygenase-2 (COX-2) selective inhibitor. Methods: Amino acid-based polyesteramide microspheres (PEAMs), a biodegradable and non-toxic platform, were loaded with CXB and employed in two in vivo models of arthritis: an acute inflammatory arthritis model in rats (n = 12), and a randomized controlled study in chronic OA dog patients (n = 30). In parallel, the bioactivity of sustained release of CXB was evaluated in monolayer cultures of primary dog chondrocytes under inflammatory conditions. Results: Sustained release of CXB did not alleviate acute arthritis signs in the rat arthritis model, based on pain measurements and synovitis severity. However, in OA dog patients, sustained release of CXB improved limb function as objective parameter of pain and quality of life based on gait analysis and owner questionnaires. It also decreased pain medication dependency over a 2-month period and caused no adverse effects. Prostaglandin E2 levels, a marker for inflammation, were lower in the synovial fluid of CXB-treated dog OA patients and in CXB-treated cultured dog chondrocytes. Conclusion: These results show that local sustained release of CXB is less suitable to treat acute inflammation in arthritic joints, while safe and effective in treating pain in chronic OA in dogs

Synthesis of ZnO nanoparticles by flame spray pyrolysis and characterisation protocol

There is uncertainty concerning the potential toxicity of zinc oxide (ZnO) nanoparticles, which may be attributed in part to a lack of understanding with regard to the physiochemical properties of the nanoparticles used in toxicological investigations. This paper reports the synthesis of a ZnO nanopowder by flame spray pyrolysis and demonstrates that the typically employed characterisation techniques such as specific surface area measurement and X-ray diffraction provide insufficient information on the sample, especially if it is intended for use in toxicity studies. Instead, a more elaborate characterisation protocol is proposed that includes particle morphology as well as detailed compositional analysis of the nanoparticle surface. Detailed transmission electron microscopy analysis illustrated the polydispersity within the sample: particles were elongated in the c-crystallographic direction, with average Ferret length ∼23 nm and Ferret width ∼14 nm. Dynamic light scattering (0.1 w/v% in deionised water, pH 7.4) revealed the particles were agglomerated with a modal secondary particle size of ∼1.5 μm. Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy indicated the presence of carbonate and hydroxide impurities on the surface of the ZnO nanoparticles and an increase of such impurities was observed as the sample was aged, which might influence the nanoparticle dissolution and/or cellular uptake behaviour. These data will be utilised, in order to facilitate the interpretation and understanding of results from toxicological investigations using in vitro cell lines

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Mechanical properties of confined mussel-inspired materials

There is currently a need for improved adhesives for medical and marine applications, primarily because the presence of water severely undermines adhesion. Due to their robust adhesion under water, marine mussels have been widely studied as inspirations for the design of wet adhesives. However, development of mussel-inspired materials has historically overemphasized the importance of the catechol functionality in mussel adhesion. This thesis demonstrates that the mechanical properties of mussel-inspired materials, including adhesion, cohesion, and stiffness, result from a range of factors beyond the presence of catechols. By investigating model systems spanning multiple length scales, this work reveals the importance of failure mode, binding group density, and electrostatic interactions on interfacial adhesion of mussel-inspired surface primers and peptides at the atomic scale. Interactions between thin films of pressure sensitive adhesives and polymers are shown to depend on film composition which is influenced by solvent-induced structural rearrangement and contact-induced damage. The mechanical properties of micro-scale hydrogel films are shown to be dictated by fluid flow through the polymer network. By providing a better understanding of mussel adhesion, this work seeks to guide the design of new mussel-inspired materials for diverse applications

Mechanical properties of confined mussel-inspired materials

There is currently a need for improved adhesives for medical and marine applications, primarily because the presence of water severely undermines adhesion. Due to their robust adhesion under water, marine mussels have been widely studied as inspirations for the design of wet adhesives. However, development of mussel-inspired materials has historically overemphasized the importance of the catechol functionality in mussel adhesion. This thesis demonstrates that the mechanical properties of mussel-inspired materials, including adhesion, cohesion, and stiffness, result from a range of factors beyond the presence of catechols. By investigating model systems spanning multiple length scales, this work reveals the importance of failure mode, binding group density, and electrostatic interactions on interfacial adhesion of mussel-inspired surface primers and peptides at the atomic scale. Interactions between thin films of pressure sensitive adhesives and polymers are shown to depend on film composition which is influenced by solvent-induced structural rearrangement and contact-induced damage. The mechanical properties of micro-scale hydrogel films are shown to be dictated by fluid flow through the polymer network. By providing a better understanding of mussel adhesion, this work seeks to guide the design of new mussel-inspired materials for diverse applications

St. Louis

Bird's-eye view of Saint Louis, Missouri as seen from above the Mississippi River.Copyright by Geo. Degen.LC Panoramic maps (2nd ed.), 438.