Controlled Release of Salicylic Acid from Biodegradable Cross-Linked Polyesters

The purpose of this work was to develop a family of crosslinked poly(xylitol adipate salicylate)s with a wide range of tunable release properties for delivering pharmacologically active salicylic acid. The synthesis parameters and release conditions were varied to modulate polyester properties and to understand the mechanism of release. Varying release rates were obtained upon longer curing (35% in the noncured polymer to 10% in the cured polymer in 7 days). Differential salicylic acid loading led to the synthesis of polymers with variable cross-linking and the release could be tuned (100% release for the lowest loading to 30% in the highest loading). Controlled release was monitored by changing various factors, and the release profiles were dependent on the stoichiometric composition, pH, curing time, and presence of enzyme. The polymer released a combination of salicylic acid and disalicylic acid, and the released products were found to be nontoxic. Minimal hemolysis and platelet activation indicated good blood compatibility. These polymers qualify as ``bioactive'' and ``resorbable'' and can, therefore, find applications as immunomodulatory resorbable biomaterials with tunable release properties.

Glioblastoma-derived Macrophage Colony-stimulating Factor (MCSF) Induces Microglial Release of Insulin-like Growth Factor-binding Protein 1 (IGFBP1) to Promote Angiogenesis

Glioblastoma (grade IV glioma/GBM) is the most common primary adult malignant brain tumor with poor prognosis. To characterize molecular determinants of tumor-stroma interaction in GBM, we profiled 48 serum cytokines and identified macrophage colony-stimulating factor (MCSF) as one of the elevated cytokines in sera from GBM patients. Both MCSF transcript and protein were up-regulated in GBM tissue samples through a spleen tyrosine kinase (SYK)-dependent activation of the PI3K-NF kappa B pathway. Ectopic overexpression and silencing experiments revealed that glioma-secreted MCSF has no role in autocrine functions and M2 polarization of macrophages. In contrast, silencing expression of MCSF in glioma cells prevented tube formation of human umbilical vein endothelial cells elicited by the supernatant from monocytes/microglial cells treated with conditioned medium from glioma cells. Quantitative proteomics based on stable isotope labeling by amino acids in cell culture showed that glioma-derived MCSF induces changes in microglial secretome and identified insulin-like growth factor-binding protein 1 (IGFBP1) as one of the MCSF-regulated proteins secreted by microglia. Silencing IGFBP1 expression in microglial cells or its neutralization by an antibody reduced the ability of supernatants derived from microglial cells treated with glioma cell-conditioned medium to induce angiogenesis. In conclusion, this study shows up-regulation of MCSF in GBM via a SYK-PI3K-NF kappa B-dependent mechanism and identifies IGFBP1 released by microglial cells as a novel mediator of MCSF-induced angiogenesis, of potential interest for developing targeted therapy to prevent GBM progression.

Kinematic flow patterns in slow deformation of a dense granular material

The kinematic flow pattern in slow deformation of a model dense granular medium is studied at high resolution using in situ imaging, coupled with particle tracking. The deformation configuration is indentation by a flat punch under macroscopic plane-strain conditions. Using a general analysis method, velocity gradients and deformation fields are obtained from the disordered grain arrangement, enabling flow characteristics to be quantified. The key observations are the formation of a stagnation zone, as in dilute granular flow past obstacles; occurrence of vortices in the flow immediately underneath the punch; and formation of distinct shear bands adjoining the stagnation zone. The transient and steady state stagnation zone geometry, as well as the strength of the vortices and strain rates in the shear bands, are obtained from the experimental data. All of these results are well-reproduced in exact-scale non-smooth contact dynamics simulations. Full 3D numerical particle positions from the simulations allow extraction of flow features that are extremely difficult to obtain from experiments. Three examples of these, namely material free surface evolution, deformation of a grain column below the punch and resolution of velocities inside the primary shear band, are highlighted. The variety of flow features observed in this model problem also illustrates the difficulty involved in formulating a complete micromechanical analytical description of the deformation.

Controlled release kinetics of p-aminosalicylic acid from biodegradable crosslinked polyesters for enhanced anti-mycobacterial activity

Unlike conventional polymeric drug delivery systems, where drugs are entrapped in polymers, this study focuses on the incorporation of the drug into the polymer backbone to achieve higher loading and sustained release. Crosslinked, biodegradable, xylitol based polyesters have been synthesized in this study. The bioactive drug moiety, p-aminosalicylic acid (PAS), was incorporated in xylitol based polyesters to impart its anti-mycobacterial activity. To understand the influence of the monomer chemistry on the incorporation of PAS and its subsequent release from the polymer, different diacids have been used. Controlled release profiles of the drug from these polyesters were studied under normal physiological conditions. The degradation of the polyesters varied from 48% to 76% and the release of PAS ranged from 54% to 65% of its initial loading in 7 days. A new model was developed to explain the release kinetics of PAS from the polymer that accounted for the polymer degradation and drug concentration. The thermal, mechanical, drug release and cytocompatibility properties of the polymers indicate their suitability in biomedical applications. The released products from these polymers were observed to be pharmacologically active against Mycobacteria. The high drug loading and sustained release also ensured enhanced efficacy. These polymers form biocompatible, biodegradable polyesters where the sustained release of PAS may be tailored for potential treatment of mycobacterial infections. Statement of significance In the present work, we report on novel polyesters with p-aminosalicylic acid (PAS) incorporated in the polymer backbone. The current work aims to achieve controlled release of PAS and ensures the delivered PAS is stable and pharmacologically active. The novelty of this work primarily involves the synthetic chemistry of polymerization and detailed analysis and efficacy of active PAS delivery. A new kinetic model has been developed to explain the PAS release profiles. These polymers are biodegradable, cytocompatible and anti-mycobacterial in nature. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Fast and slow climate responses to CO2 and solar forcing: A linear multivariate regression model characterizing transient climate change

Climate change in response to a change in external forcing can be understood in terms of fast response to the imposed forcing and slow feedback associated with surface temperature change. Previous studies have investigated the characteristics of fast response and slow feedback for different forcing agents. Here we examine to what extent that fast response and slow feedback derived from time-mean results of climate model simulations can be used to infer total climate change. To achieve this goal, we develop a multivariate regression model of climate change, in which the change in a climate variable is represented by a linear combination of its sensitivity to CO2 forcing, solar forcing, and change in global mean surface temperature. We derive the parameters of the regression model using time-mean results from a set of HadCM3L climate model step-forcing simulations, and then use the regression model to emulate HadCM3L-simulated transient climate change. Our results show that the regression model emulates well HadCM3L-simulated temporal evolution and spatial distribution of climate change, including surface temperature, precipitation, runoff, soil moisture, cloudiness, and radiative fluxes under transient CO2 and/or solar forcing scenarios. Our findings suggest that temporal and spatial patterns of total change for the climate variables considered here can be represented well by the sum of fast response and slow feedback. Furthermore, by using a simple 1-D heat-diffusion climate model, we show that the temporal and spatial characteristics of climate change under transient forcing scenarios can be emulated well using information from step-forcing simulations alone.

Physical insights into salicylic acid release from poly(anhydrides)

Salicylic acid (SA) based biodegradable polyanhydrides (PAHs) are of great interest for drug delivery in a variety of diseases and disorders owing to the multi-utility of SA. There is a need for the design of SA-based PAHs for tunable drug release, optimized for the treatment of different diseases. In this study, we devised a simple strategy for tuning the release properties and erosion kinetics of a family of PAHs. PAHs incorporating SA were derived from related aliphatic diacids, varying only in the chain length, and prepared by simple melt condensation polymerization. Upon hydrolysis induced erosion, the polymer degrades into cytocompatible products, including the incorporated bioactive SA and diacid. The degradation follows first order kinetics with the rate constant varying by nearly 25 times between the PAH obtained with adipic acid and that with dodecanedioic acid. The release profiles have been tailored from 100% to 50% SA release in 7 days across the different PAHs. The release rate constants of these semi-crystalline, surface eroding PAHs decreased almost linearly with an increase in the diacid chain length, and varied by nearly 40 times between adipic acid and dodecanedioic acid PAH. The degradation products with SA concentration in the range of 30-350 ppm were used to assess cytocompatibility and showed no cytotoxicity to HeLa cells. This particular strategy is expected to (a) enable synthesis of application specific PAHs with tunable erosion and release profiles; (b) encompass a large number of drugs that may be incorporated into the PAH matrix. Such a strategy can potentially be extended to the controlled release of other drugs that may be incorporated into the PAH backbone and has important implications for the rational design of drug eluting bioactive polymers.

Strength reliability and in vitro degradation of three-dimensional powder printed strontium-substituted magnesium phosphate scaffolds

Strontium ions (Sr2+) are known to prevent osteoporosis and also encourage bone formation. Such twin requirements have motivated researchers to develop Sr-substituted biomaterials for orthopaedic applications. The present study demonstrates a new concept of developing Sr-substituted Mg-3(PO4)(2) - based biodegradable scaffolds. In particular, this work reports the fabrication, mechanical properties with an emphasis on strength reliability as well as in vitro degradation of highly biodegradable strontium-incorporated magnesium phosphate cements. These implantable scaffolds were fabricated using three-dimensional powder printing, followed by high temperature sintering and/or chemical conversion, a technique adaptable to develop patient-specific implants. A moderate combination of strength properties of 36.7 MPa (compression), 242 MPa (bending) and 10.7 MPa (tension) were measured. A reasonably modest Weibull modulus of up to 8.8 was recorded after uniaxial compression or diametral tensile tests on 3D printed scaffolds. A comparison among scaffolds with varying compositions or among sintered or chemically hardened scaffolds reveals that the strength reliability is not compromised in Sr-substituted scaffolds compared to baseline Mg-3(PO4)(2). The micro-computed tomography analysis reveals the presence of highly interconnected porous architecture in three-dimension with lognormal pore size distribution having median in the range of 17.74-26.29 mu m for the investigated scaffolds. The results of extensive in vitro ion release study revealed passive degradation with a reduced Mg2+ release and slow but sustained release of Sr2+ from strontium-substituted magnesium phosphate scaffolds. Taken together, the present study unequivocally illustrates that the newly designed Sr-substituted magnesium phosphate scaffolds with good strength reliability could be used for biomedical applications requiring consistent Sr2+-release, while the scaffold degrades in physiological medium. Statement of significance The study investigates the additive manufacturing of scaffolds based on different strontium-substituted magnesium phosphate bone cements by means of three-dimensional powder printing technique (3DPP). Magnesium phosphates were chosen due to their higher biodegradability compared to calcium phosphates, which is due to both a higher solubility as well as the absence of phase changes (to low soluble hydroxyapatite) in vivo. Since strontium ions are known to promote bone formation by stimulating osteoblast growth, we aimed to establish such a highly degradable magnesium phosphate ceramic with an enhanced bioactivity for new bone ingrowth. After post-processing, mechanical strengths of up to 36.7 MPa (compression), 24.2 MPa (bending) and 10.7 MPa (tension) could be achieved. Simultaneously, the failure reliability of those bioceramic implant materials, measured by Weibull modulus calculations, were in the range of 4.3-8.8. Passive dissolution studies in vitro proved an ion release of Mg2+ and PO43- as well as Sr2+, which is fundamental for in vivo degradation and a bone growth promoting effect. In our opinion, this work broadens the range of bioceramic bone replacement materials suitable for additive manufacturing processing. The high biodegradability of MPC ceramics together with the anticipated promoting effect on osseointegration opens up the way for a patient-specific treatment with the prospect of a fast and complete healing of bone fractures. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.