Search

Late-stage dry age-related macular degeneration (AMD) or geographic atrophy (GA) is an irreversible blinding condition characterized by degeneration of retinal pigment epithelium (RPE) and the associated photoreceptors. Clinical and genetic evidence supports a role for dysfunctional lipid processing and accumulation of harmful oxidized lipids in the pathogenesis of GA. Using an oxidized low-density lipoprotein (ox-LDL)-induced RPE death assay, we screened and identified sterically-hindered phenol compounds with potent protective activities for RPE. The phenol-containing PPARγ agonist, troglitazone, protected against ox-LDL–induced RPE cell death, whereas other more potent PPARγ agonists did not protect RPE cells. Knockdown of PPARγ did not affect the protective activity of troglitazone in RPE, confirming the protective function is not due to the thiazolidine (TZD) group of troglitazone. Prototypical hindered phenol trolox and its analogs potently protected against ox-LDL–induced RPE cell death whereas potent antioxidants without the phenol group failed to protect RPE. Hindered phenols preserved lysosomal integrity against ox-LDL–induced damage and FITC-labeled trolox was localized to the lysosomes in RPE cells. Analogs of trolox inhibited reactive oxygen species (ROS) formation induced by ox-LDL uptake in a dose-dependent fashion and were effective at sub-micromolar concentrations. Treatment with trolox analog 2,2,5,7,8-pentamethyl-6-chromanol (PMC) significantly induced the expression of the lysosomal protein NPC-1 and reduced intracellular cholesterol level upon ox-LDL uptake. Our data indicate that the lysosomal-localized hindered phenols are uniquely potent in protecting the RPE against the toxic effects of ox-LDL, and may represent a novel pharmacotherapy to preserve the vision in patients with GA.

To improve the quality of life for people living with chronic inflammatory skin diseases, we propose a new treatment strategy by exploring a stimuli-responsive drug delivery system. Formulations designed by exploiting smart materials can be programmed to perform a specific action upon exposure to disease-related stimuli. For instance, increased levels of reactive oxygen species (ROS), especially the accumulation of hydrogen peroxide, can be utilized to differentiate between healthy and inflamed tissues. In this concept-proofing study, the polymer poly(1,4 phenyleneacetone dimethylene thioketal) (PPADT) was investigated for its ROS-responsive properties and potential to treat inflammatory skin diseases. PPADT nanoparticles were formulated by oil-in-water emulsification followed by solvent evaporation and characterized by size, zeta-potential, and release kinetic profiles. Release profiles revealed that the PPADT nanoparticles were sensitive toward elevated levels of ROS in an ROS-stimulus concentration (0.1-10 mM) and time-dependent manner (flare-up mimicked). The safety assessment proved that the PPADT polymer and the monomers generated by oxidation do not show any sign of being cytotoxic to fibroblasts and no mutagenic liabilities were observed. In conclusion, the PPADT polymer demonstrated to be a promising material for stimuli-responsive delivery of hydrophobic small molecules in the treatment of inflammatory skin diseases.

Diseases of the retina cause vision loss and blindness, which have a profound impact on an individual's quality of life. The number of therapies available to treat retinal diseases is limited. Nanoparticle (NP)-based medicines represent one strategy to expand both the number of available therapies and the range of retinal diseases treated. Liposomes, phospholipid vesicles that frequently contain cholesterol and/or modified surface chemistries, have already had minor success in retinal disease treatment and hold significant promise. Here, we provide a snapshot of recent research developments in liposomal drug delivery systems for retinal diseases and discuss the challenges associated with liposomal systems in the context of recent developments.

The blood-brain barrier (BBB) is one of the main obstacles for therapies targeting brain diseases. Most macromolecules fail to pass the tight BBB, formed by brain endothelial cells interlinked by tight junctions. A wide range of small, lipid-soluble molecules can enter the brain parenchyma via diffusion, whereas macromolecules have to transcytose via vesicular transport. Vesicular transport can thus be utilized as a strategy to deliver brain therapies. By conjugating BBB targeting antibodies and peptides to therapeutic molecules or nanoparticles, it is possible to increase uptake into the brain. Previously, the synthetic peptide GYR and a peptide derived from melanotransferrin (MTfp) have been suggested as candidates for mediating transcytosis in brain endothelial cells (BECs). Here we study uptake, intracellular trafficking, and translocation of these two peptides in BECs. The peptides were synthesized, and binding studies to purified endocytic receptors were performed using surface plasmon resonance. Furthermore, the peptides were conjugated to a fluorophore allowing for live-cell imaging studies of their uptake into murine brain endothelial cells. Both peptides bound to low-density lipoprotein receptor-related protein 1 (LRP-1) and the human transferrin receptor, while lower affinity was observed against the murine transferrin receptor. The MTfp showed a higher binding affinity to all receptors when compared to the GYR peptide. The peptides were internalized by the bEnd.3 mouse endothelial cells within 30 min of incubation and frequently co-localized with endo-lysosomal vesicles. Moreover, our in vitro Transwell translocation experiments confirmed that GYR was able to cross the murine barrier and indicated the successful translocation of MTfp. Thus, despite binding to endocytic receptors with different affinities, both peptides are able to transcytose across the murine BECs.

The blood-brain barrier (BBB) is a major obstacle to treating several brain disorders. Focused ultrasound (FUS) in combination with intravascular microbubbles increases BBB permeability by opening tight junctions, creating endothelial cell openings, improving endocytosis and increasing transcytosis. Here we investigated whether combining FUS and microbubbles with transferrin receptor-targeting liposomes would result in enhanced delivery to the brain of post-natal rats compared with liposomes lacking the BBB-targeting moiety. For all animals, increased BBB permeability was observed after FUS treatment. A 40% increase in accumulation of transferrin receptor-targeting liposomes was observed in the FUS-treated hemisphere, whereas the isotype immunoglobulin G liposomes showed no increased accumulation. Confocal laser scanning microscopy of brain sections revealed that both types of liposomes were mainly observed in endothelial cells in the FUS-treated hemisphere. The results demonstrate that FUS and microbubble treatment combined with BBB-targeting liposomes could be a promising approach to enhance drug delivery to the brain. (E-mail: marieke.olsman@ntnu. no) © 2021 The Author(s). Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Targeting nanocarrier drug delivery systems, that deliver drug payloads to the site of disease action, are frequently viewed as the future of nanocarrier based therapies but have struggled to breakthrough to the clinic in comparison to non-targeting counterparts. Using unilamellar liposomes as model nanocarriers, we show that cell targeting strategy (electrostatic, ligand and antigen) influences both the intracellular fate of the liposomes and the corresponding efficacy of the loaded drug, doxorubicin, in endothelial cells. We show that increased liposome uptake by cells does not translate to improved efficacy in this scenario but that liposome intracellular trafficking, particularly distribution between recycling endosomes and lysosomes, influences in vitro efficacy. Choosing targeting strategies that promote desired nanocarrier intracellular trafficking may be a viable strategy to enhance the in vivo efficacy of drug delivery systems.

This study details the structural characterization of glycolide-h4 as a function of pressure to 6 GPa using neutron powder diffraction on the PEARL instrument at ISIS Neutron and Muon source. Glycolide-h4, rather than its deuterated isotopologue, was used in this study due to the difficulty of deuteration. The low background afforded by zirconia-toughened alumina anvils nevertheless enabled the collection of data suitable for structural analysis to be obtained to a pressure of 5 GPa. Glycolide-h4 undergoes a reconstructive phase transition at 0.15 GPa to a previously identified form (II), which is stable to 6 GPa.

It is widely assumed that any unbalance between phase currents in 4-wire distribution circuits will equal the neutral current; that is that the sum of currents is zero. In practice, however, measurements made at distribution substations often show significant inconsistency. Several possible explanations for this are explored, showing that calculations of the voltage drop and losses are more accurate if harmonics are included. More generally, feeder configurations are described in which the currents may not sum to zero.

Distribution losses can be difficult to measure when the loss power has a similar proportion to monitoring equipment sensor tolerances. Measurements for the Western Power Distribution Losses Investigation project have addressed this problem by using high resolution demand measurements combined with loss calculations with an I2R method. This is combined with additional measurements to verify accuracy of the network database used to calculate losses in each network branch.

To improve therapeutic efficacy of nanocarrier drug delivery systems, it is essential to improve their uptake and penetration in tumour tissue, enhance cellular uptake and ensure efficient drug release at the tumour site. Here we introduce a tumour targeting drug delivery system based on the ultrasound-mediated delivery of enzyme sensitive liposomes. These enzyme sensitive liposomes are coated with cleavable poly(ethylene glycol) (PEG) which will be cleaved by two members of the enzyme matrix metalloproteinase family (MMP-2 and MMP-9). Cleavage of the PEG coat can increase cellular uptake and will destabilize the liposomal membrane which can result in accelerated drug release. The main aim of the work was to study the effect of focused ultrasound and microbubbles on the delivery and therapeutic efficacy of the MMP sensitive liposome. The performance of the MMP sensitive liposome was compared to a non-MMP sensitive version and Doxil-like liposomes. In vitro, the cellular uptake and cytotoxicity of the liposomes were studied, while in vivo the effect of ultrasound and microbubbles on the tumour accumulation, biodistribution, microdistribution, and therapeutic efficacy were investigated. For all tested liposomes, ultrasound and microbubble treatment resulted in an improved tumour accumulation, increased extravasation, and increased penetration of the liposomes from blood vessels into the extracellular matrix. Surprisingly, penetration depth was independent of the ultrasound intensity used. Ultrasound-mediated delivery of free doxorubicin and the Doxil-like and MMP sensitive liposome resulted in a significant reduction in tumour volume 28 days post the first treatment and increased median survival. The MMP sensitive liposome showed better therapeutic efficacy than the non-MMP sensitive version indicating that cleaving the PEG-layer is important. However, the Doxil-like liposome outcompeted the MMP and non-MMP sensitive liposome, both with and without the use of ultrasound and microbubbles. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Stem cells are known to differentiate in response to the chemical and mechanical properties of the substrates on which they are cultured. Thus, supramolecular biomaterials with tunable properties are well suited for the study of stem cell differentiation. In this report, we exploited this phenomenon by combining stem cell differentiation in hydrogels with variable stiffness and metabolomics analysis to identify specific bioactive lipids that are uniquely used up during differentiation. To achieve this, we cultured perivascular stem cells on supramolecular peptide gels of different stiffness, and metabolite depletion followed. On soft (1 kPa), stiff (13 kPa), and rigid (32 kPa) gels, we observed neuronal, chondrogenic, and osteogenic differentiation, respectively, showing that these stem cells undergo stiffness-directed fate selection. By analyzing concentration variances of >600 metabolites during differentiation on the stiff and rigid gels (and focusing on chondrogenesis and osteogenesis as regenerative targets, respectively), we identified that specific lipids (lysophosphatidic acid and cholesterol sulfate, respectively), were significantly depleted. We propose that these metabolites are therefore involved in the differentiation process. In order to unequivocally demonstrate that the lipid metabolites that we identified play key roles in driving differentiation, we subsequently demonstrated that these individual lipids can, when fed to standard stem cell cultures, induce differentiation toward chondrocyte and osteoblast phenotypes. Our concept exploits the design of supramolecular biomaterials as a strategy for discovering cell-directing bioactive metabolites of therapeutic relevance.

A common event in optic neuropathies is the loss of axons and death of retinal ganglion cells (RGCs) resulting in irreversible blindness. Mammalian target of rapamycin (mTOR) signaling pathway agonists have been shown to foster axon regeneration and RGC survival in animal models of optic nerve damage. However, many challenges remain in developing therapies that exploit cell growth and tissue remodeling including (i) activating/inhibiting cell pathways synergistically, (ii) avoiding tumorigenesis, and (iii) ensuring appropriate physiological tissue function. These challenges are further exacerbated by the need to overcome ocular physiological barriers and clearance mechanisms. Here we present liposomes loaded with multiple mTOR pathway stimulating biologics designed to enhance neuroprotection after retina damage. Liposomes were loaded with ciliary neurotrophic factor, insulin-like growth factor 1, a lipopeptide N-fragment osteopontin mimic, and lipopeptide phosphatase tension homologue inhibitors for either the ATP domain or the c-terminal tail. In a mouse model of N-methyl-d-aspartic acid induced RGC death, a single intravitreal administration of liposomes reduced both RGC death and loss of retina electrophysiological function. Furthermore, combining liposomes with transplantation of induced pluripotent stem cell derived RGCs led to an improved electrophysiological outcome in mice. The results presented here show that liposomes carrying multiple signaling pathway modulators can facilitate neuroprotection and transplant electrophysiological outcome.

PURPOSE. To determine whether human retinal endothelial cells (HRECs) express the endothelial cell protein C receptor (EPCR) and to realize its potential as a targeting moiety by developing novel single and dual corticosteroid–loaded functionalized liposomes that exhibit both enhanced uptake by HRECs and superior biologic activity compared to nontargeting liposomes and free drug.METHODS. EPCR expression of HRECs was investigated through flow cytometry and Western blot assays. EPCR-targeting liposomes were developed by functionalizing EPCR-specific antibodies onto liposomes, and the uptake of liposomes was assessed with flow cytometry and confocal laser scanning microscopy. The therapeutic potential of EPCR-targeting liposomes was determined by loading them with prednisolone either through bilayer insertion and/or by remote loading into the aqueous core. The carrier efficacy was assessed in two ways through its ability to inhibit secretion of interleukins in cells stimulated with high glucose and angiogenesis in vitro by using an endothelial cell tube formation assay.RESULTS. HRECs express EPCR at a similar level in both human aortic and umbilic vein endothelial cells. The EPCR-targeting liposomes displayed at least a 3-fold higher uptake compared to nontargeting liposomes. This enhanced uptake was translated into superior antiinflammatory efficacy, as the corticosteroid-loaded EPCR-targeting liposomes significantly reduced the secretion of IL-8 and IL-6 and inhibited the development of cell tube formations in contrast to nontargeting liposomes.CONCLUSIONS. We show that HRECs express EPCR and this receptor could be a promising nanomedicine target in ocular diseases where the endothelial barrier of the retina is compromised.

The manuscript presents the first report of hair dyes of various colors formed by cocrystallization. Unlike the most popular oxidative hair dye (OHD) products, these dyes are NH3 free and do not require H2O2 as a color developer. The importance of these new hair dyes products is further enhanced by recent reports which indicate that some of the OHDs may be carcinogenic.

Liposomes for medical applications are often administered by intravenous injection. Once in the bloodstream, the liposomes are covered with a "protein corona", which impacts the behavior and eventual fate of the liposomes. Currently, many aspects of the liposomal protein corona are not well understood. For example, there is generally a lack of knowledge about the liposome binding affinities and dynamics of common types of blood plasma proteins. Fluorescence correlation spectroscopy (FCS) is a powerful experimental technique that potentially can provide such knowledge. In this study, we have used FCS to investigate the binding of human serum albumin (HSA) to standard types of PEGylated fluid-phase liposomes (consisting of DOPC and DOPE-PEG2k) and PEGylated gel-phase liposomes (consisting of DSPC and DSPE-PEG2k) with various PEG chain surface densities. We detected no significant binding of HSA to the PEGylated fluid-phase liposomes. In contrast, we found that HSA bound tightly to the PEGylated gel-phase liposomes, although only a low number of HSA molecules could be accommodated per liposome. Overall, we believe that our data provides a useful benchmark for other researchers interested in studying the liposomal protein corona.

Copper losses in low voltage distribution circuits are a significant proportion of total energy losses and contribute to higher customer costs and carbon emissions. These losses can be evaluated using network models with customer demand data. This paper considers the under-estimation of copper losses when the spiky characteristics of real customer demands are smoothed by arithmetic mean averaging. This is investigated through simulation and by analysis of measured data. The mean losses in cables and equipment supplying a single dwelling estimated from half-hourly data were found to have significant errors of 40%, compared to calculations using high resolution data. Similar errors were found in estimates of peak thermal loading over a half-hour period, with significant variation between results for each customer. The errors reduce as the demand is aggregated, with mean losses for a group of 22 dwellings under-estimated by 7% using half-hourly data. This paper investigates the relationship between the demand data time resolution and errors in the estimated losses. Recommendations are then provided for the time resolution to be used in future measurements and simulation studies. A linear extrapolation technique is also presented whereby errors due to the use of averaged demand data can be reduced.

Silica nanoparticles have been shown to have great potential as drug delivery systems (DDS), however, their fabrication often involves harsh chemicals and energy intensive laborious methods. This work details the employment of a bioinspired "green" method for the controlled synthesis of silica, use of the products to entrap and release drug molecules and their cytotoxicity in order to develop novel DDS. Bioinspired silica synthesis occurs at pH 7, room temperature and in less than 5 minutes, resulting in a rapid, cheaper and greener route. Drugs were loaded into silica during the silica formation, thus allowing a one step and one pot method for simultaneous silica synthesis and drug loading. We established that the drug release profile can be modulated by synthetic parameters, which can allow design of tailored DDS. A systematic investigation using a two level factorial design was adopted in order to identify the key synthetic parameters and quantify their effects on silica formation, drug loading and drug release. The observation that these new DDS are considerably less cytotoxic than their current counterparts, and exhibit additional benefits such as green synthesis and ease of functionalization, strengthens the argument for their future use in DDS and other biomedical applications. © 2014 the Partner Organisations.

N-acryloylmorpholine (NAM) was photo-polymerized to produce the homopolymer poly(N-acryloylmorpholine) (PNAM). PNAM behaves as a physical hydrogel in aqueous solvents, doubling its dry weight over a 2 h period before undergoing dissolution following a second order exponential decay profile. In vitro cellular experiments using mouse myoblasts showed that PNAM acts as an effective spatial cell barrier for 38 h, with slow migration of cells into the PNAM area occurring between 45 and 73 h after cell seeding. At 80 h myoblasts fully occupied the area initially blocked by PNAM. Immunofluorescent staining of myoblasts adjacent to PNAM showed normal cytoskeletal structure and well developed focal adhesions indicating limited PNAM toxicity. This study shows that PNAM is an easy to synthesize physical hydrogel that acts as a temporal and spatial barrier to cell adhesion.

Compartmentalization is a key feature of biological cells which conduct their metabolic activity in individual steps isolated in distinct, separated compartments. The creation of architectures containing multiple compartments with a structure that resembles that of a biological cell has generated significant research attention and these assemblies are proposed as candidate materials for a range of biomedical applications. In this Review article, the recent successes of multicompartment architectures as carriers for the delivery of therapeutic cargo or the creation of micro- and nanoreactors that mimic metabolic activities, thus acting as artificial cells or organelles, are discussed. The developed technologies to assemble such complex architectures are outlined, the multicompartment carriers’ properties which contribute to their performance in diverse applications are discussed, and their successful applications are highlighted. Finally, future directions and developments in the field are suggested.

We report on a pronounced specific-ion effect on the intermolecular and chiral organization, supramolecular structure formation, and resulting materials properties for a series of low molecular weight peptide-based hydrogelators, observed in the presence of simple inorganic salts. This effect was demonstrated using aromatic short peptide amphiphiles, based on fluorenylmethoxycarbonyl (Fmoc). Gel-phase materials were formed due to molecular self-assembly, driven by a combination of hydrogen bonding and pi-stacking interactions. Pronounced morphological changes were observed by atomic force microscopy (AFM) for Fmoc-YL peptide, ranging from dense fibrous networks to spherical aggregates, depending on the type of anions present. The gels formed had variable mechanical properties, with G' values between 0.8 kPa and 2.4 kPa as determined by rheometry. Spectroscopic analysis provided insights into the differential mode of self-assembly, which was found to be dictated by the hydrophobic interactions of the fluorenyl component, with comparable H-bonding patterns observed in each case. The efficiency of the anions in promoting the hydrophobic interactions and thereby self-assembly was found to be consistent with the Hofmeister anion sequence. Similar effects were observed with other hydrophobic peptides, Fmoc-VL and Fmoc-LL. The effect was found to be less pronounced for a less hydrophobic peptide, Fmoc-AA. To get more insights into the molecular mechanism, the effect of anions on sol-gel equilibrium was investigated, which indicates the observed changes result from the specific-ion effects on gels structure, rather than on the sol-gel equilibrium. Thus, we demonstrate that, by simply changing the ionic environment, structurally diverse materials can be accessed providing an important design consideration in nanofabrication via molecular self-assembly.

Amorphous silica nanoparticles (a-SiNPs) with high surface area and small pore size have been synthesized using a zwitterionic surfactant in acid media. The produced nanoparticles displayed large specific surface area (-850 m2/g) with an average particles size of 45 nm. The loading efficiency was assessed by incorporating three model water insoluble active substances Carbamazepine (CBZ), Ibuprofen (IBU) and Cyclosporin (CyA) via passive loading and it was found to varying from 15-40%. The loaded silica nanoparticles were analyzed using X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) to investigate the state of the adsorbed active agents. CyA was found to be in amorphous state, IBU was partially crystalline while CBZ was transformed into form I. The dissolution profiles showed rapid release for CBZ while IBU and CyA demonstrated prolonged release for 24 hr. The viability of Caco-2 cells was not affected in the presence of a-SiNPs showing negligible cytotoxicity (85%) at high concentrations up to 15 mg/ml.

Solid lipid nanoparticles (SLNs) loaded with ibuprofen (IBU) were prepared by solvent-free high-pressure homogenization (HPH). The produced SLNs consisted of stearic acid, triluarin or tripalmitin as lipid matrixes and various stabilizers. The produced empty and IBU-loaded SLNs were characterized for particle size stability over 8 months. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were implemented to characterize the IBU state of freeze-dried SLNs. IBU was found to be in both amorphous and crystalline form within the lipid matrix. The lyophilized powders showed increased dissolution rates for IBU depending on the lipid nature. SLNs were incubated in Caco-2 cells for 24 h showing negligible cell cytotoxicity up to 15 mg/mL.

High throughput materials discovery using combinatorial polymer microarrays to screen for new biomaterials with new and improved function is established as a powerful strategy. Here we combine this screening approach with high throughput surface characterisation (HT-SC) to identify surface structure-function relationships. We explore how this combination can help to identify surface chemical moieties that control protein adsorption and subsequent cellular response. The adhesion of human embryoid body (hEB) cells to a large number (496) of different acrylate polymers synthesized in a microarray format is screened using a high throughput procedure. To determine the role of the polymer surface properties on hEB cell adhesion, detailed HT-SC of these acrylate polymers is carried out using time of flight secondary ion mass spectrometry (ToF SIMS), x-ray photoelectron spectroscopy (XPS), pico litre drop sessile water contact angle (WCA) measurement and atomic force microscopy (AFM). A structure-function relationship is identified between the ToF SIMS analysis of the surface chemistry after a fibronectin (Fn) pre-conditioning step and the cell adhesion to each spot using the multivariate analysis technique partial least squares (PLS) regression. Secondary ions indicative of the adsorbed Fn correlate with increased cell adhesion whereas glycol and other functionalities from the polymers are identified that reduce cell adhesion. Furthermore, a strong relationship between the ToF SIMS spectra of bare polymers and the cell adhesion to each spot is identified using PLS regression. This identifies a role for both the surface chemistry of the bare polymer and the pre-adsorbed Fn, as-represented in the ToF SIMS spectra, in controlling cellular adhesion. In contrast, no relationship is found between cell adhesion and wettability, surface roughness, elemental or functional surface composition. The correlation between ToF SIMS data of the surfaces and the cell adhesion demonstrates the ability of identifying surface moieties that control protein adsorption and subsequent cell adhesion using ToF SIMS and multivariate analysis.

Cyclosporine (CyA) solid lipid nanoparticles were prepared by using a solvent free high pressure homogenization process. CyA was incorporated into SLNs that consisted of stearic acid, trilaurin or tripalmitin lipid solid cores in order to enhance drug solubility. The process was conducted by varying lipid compositions, drug initial loading and applied homogenization pressure. The processing temperatures were above the lipid melting points for all formulations. The empty and CyA loaded SLN particles made were characterized for particle size stability over six months. Atomic force microscopy (AFM) and photon correlation spectroscopy (PCS) showed particle sizes ranging from 112-177 nm for empty and 181-215 nm for loaded SLNs each with narrow particle size distributions. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) techniques were used to characterize the CyA state, which was found to be amorphous, within the lipid cores of freeze-dried SLNs. The CyA metastable form showed a profound effect on the drug dissolution rates. SLNs were incubated in Caco-2 cells for 24 hr showing negligible cell cytotoxicity up to 15 mg/ml.

The application of high throughput surface characterization (HTSC) to the analysis of polymeric biomaterial libraries is an important advancement for the discovery and development of new biomedical materials and is the focus of this review. The potential for HTSC to identify structure/activity relationships for large libraries of materials can be utilized to accelerate materials discovery as well as providing insight into the underlying biological-material interactions. Furthermore, the correlations identified between surface chemical structure and cellular behavior could not have been predicted by a rational design approach based simply on review of bulk structure, which demonstrates the importance of HTSC in the assessment of cell-material and cell-biomolecular interactions that are dependent on surface properties.

Scanning tunneling microscopy (STM) has become a staple surface microscopy technique for a number of research fields ranging from semiconductor research to heterogeneous catalysis. Pharmaceutical compounds, however, remain largely unstudied. Here we report the first STM study of carbamazepine (CBZ), an anti-epileptic drug, on Au(111) and Cu(111) surfaces. The analysis reveals that CBZ adopts unusual chiral molecular architectures on both metals. These previously unreported structures, which are strikingly different from CBZ packing arrangements observed in 3D crystal structures, indicate that the main molecular architecture is driven by a combination of CBZ intermolecular hydrogen bonding and metal-CBZ interactions. Comparison of the 2D molecular structures reveals large differences in local geometry and packing density that are dependent on the nature of the metal surface. These results have implications for the potential role of metal surfaces as heteronuclei or templating agents for controlling polymorph formation, which continues to be a problem for many compounds in the pharmaceutical industry including CBZ.

Plasma species that form plasma polymer deposits readily penetrate through small openings and are therefore well suited to coat the interior of porous objects. Here, we show how the size of the cross section of square channels influences the penetration of active species from a hexane plasma and how it affects the formation of surface chemical gradients in the interior of these model pores. WCA mapping and ToF-SIMS imaging are used to visualize the plasma polymer deposit in the interior of the model pores and demonstrate that a strong dependence of the wettability gradient profile only exists up to a channel cross section of about 1 mm. XPS data allow us to calculate a deposition rate of plasma polymerized hexane (ppHex) at discrete positions on the surface and show that the deposition rate of ppHex is reduced by the presence of the mask up to a distance of 16 mm in advance of the channel opening. A strong dependence of the ppHex deposition rate on the cross-section of the channels is found within the first 2 mm in front of the pore opening. An estimation of the sheath thickness suggests that this effect can be attributed to the plasma sheath that perturbs the plasma in front of the pores. Plasma mass spectrometry allows us to identify the nature of the plasma species penetrating from the plasma through the pores and shows that no negatively charged ions are able to penetrate through the small channels. Neutral and positively charged species penetrate several millimeters down the channels and both species are therefore likely to contribute to the formation of the deposit on the sample. In addition, the formation of positively charged higher molecular mass hexane fragments is observed in the gas phase, demonstrating the likelihood of neutral-positive reactions in the plasma.

An integrated high-throughput polymer synthesis and rapid material/protein/cell interaction assays were developed to optimize stem cell microenvironments. Microarrayed polymers were synthesized and studied for the ability to support the growth of partially differentiated human embryonic stem cells. In parallel, a programmed laser scanning cytometry system was developed to allow for rapid quantification of cell material interaction.

Here, we report the use of fluorescently labelled proteins to study protein adsorption to microarrayed synthetic polymers for the first time, indicating that this method is appropriate for the study of protein adsorption on these arrays. To investigate protein adhesion directly we use atomic force microscopy (AFM) to measure the force of adhesion between a protein-coated probe and the arrayed polymers. Both approaches show promise as methods for screening protein interactions with polymers in a microarray format. Comparison of these very different measures of protein-surface interactions indicate a good correlation.

Development of drug delivery systems (DDS) is essential in many cases to remedy the limitations of free drug molecules. Silica has been of great interest as a DDS due to being more robust and versatile than other types of DDS (e.g., liposomes). Using ibuprofen as a model drug, we investigated bioinspired silica (BIS) as a new DDS and compared it to mesoporous silica (MS); the latter has received much attention for drug delivery applications. BIS is synthesized under benign conditions without the use of hazardous chemicals, which enables controllable in situ loading of drugs by carefully designing the DDS formulation conditions. Here, we systematically studied these conditions (e.g., chemistry, concentration, and pH) to understand BIS as a DDS and further achieve high loading and release of ibuprofen. Drug loading into BIS could be enhanced (up to 70%) by increasing the concentration of the bioinspired additive. Increasing the silicate concentration increased the release to 50%. Finally, acidic synthesis conditions could raise loading efficiency to 62% while also increasing the total mass of drug released. By identifying ideal formulation conditions for BIS, we produced a DDS that was able to release fivefold more drug per weight of silica when compared with MCM-41. Biocompatibility of BIS was also investigated, and it was found that, although ∼20% of BIS was able to pass through the gut wall into the bloodstream, it was nonhemolytic (∼2% hemolysis at 500 μg mL-1) when compared to MS (10% hemolysis at the same concentration). Overall, for DDS, it is clear that BIS has several advantages over MS (ease of synthesis, controllability, and lack of hazardous chemicals) as well as being less toxic, making BIS a real potentially viable green alternative to DDS.

Time-of-flight secondary ion mass spectrometry (TOF-SIMS) was used in a high-throughput fashion to obtain mass spectra from the surfaces of 576 novel acrylate-based polymers, synthesized using a combinatorial approach and in a micropatterned format. To identify variations in surface chemistry within the library, principal component analysis (PCA) was used. PCA clearly identified surface chemical commonality and differences within the library. The TOF-SIMS spectra were also used to determine the relationship between water contact angle (WCA) and the surface chemistry of the polymer library using partial least-squares regression (PLS). A good correlation between the TOF-SIMS data from the novel polymers and water contact angle was obtained. Examination of the PLS regression vector allowed surface moieties that correlate with high and low WCA to be identified. This in turn provided an insight into molecular structures that significantly influence wettability. This study demonstrates that multivariate analysis can be successfully applied to TOF-SIMS data from a large library of samples and highlights the potential of these techniques for building complex surface property/chemistry models.

This article shows that pressure can be a low-intensity route to the synthesis of polymethacrylic acid. The exploration of perdeuterated methacrylic acid at high pressure using neutron diffraction reveals that methacrylic acid exhibits two polymorphic phase transformations at relatively low pressures. The first is observed at 0.39 GPa, where both phases were observed simultaneously and confirm our previous observations. This transition is followed by a second transition at 1.2 GPa to a new polymorph that is characterized for the first time. On increasing pressure, the diffraction pattern of phase III deteriorates significantly. On decompression phase III persists to 0.54 GPa before transformation to the ambient pressure phase. There is significant loss of signal after decompression, signifying that there has been a loss of material through polymerization. The orientation of the molecules in phase III provides insight into the possible polymerization reaction.

Rh-catalysed Fischer–Tropsch synthesis at high pressures exhibits reversible electrochemical promotion by potassium. At 473 K and 14 bar, 43 products were detected, comprising alkanes, alkenes and primary alcohols. Potassium increased selectivity towards alkenes and primary alcohols as a result of actual increases in the rates of formation of these products – an apparently unprecedented observation. Alkane formation was progressively suppressed by added alkali. These findings are discussed in terms of K-induced acceleration and retardation of possible rate limiting steps for alkene and alkane formation, respectively. Plausible mechanisms are discussed.

trans -Methyl styrene, an alkene that contains readily abstractable allylic H atoms, adsorbs with very similar conformations on oxygenated single crystal surfaces of Cu and Ag. Strikingly, however, subsequent reaction on silver leads merely to combustion of the organic molecule, whereas copper is extremely effective in catalyzing the epoxidation of this “difficult” alkene.

The catalytic behavior, chemical state, and morphology of a Rh thin film catalyst electrochemically promoted by alkali have been investigated by reactor studies, XPS, and SEM. At 1 bar pressure and 473 K, electro-pumped alkali decreases overall activity toward the production of hydrocarbons from CO and H2 while increasing selectivity toward higher hydrocarbons, especially alkenes. On the active surface, rhodium is in a partially oxidized state; however, the catalytic activity is assigned to the metallic (Rh0) component. The promoter phase is an alkali compound other than carbonate, although at high alkali loadings large amounts of crystalline alkali carbonate are deposited on the surface. The heavily carbonated system nevertheless retains most of its catalytic activity, with continued increase in selectivity toward higher hydrocarbons as the alkali loading is increased. Fully reversible behavior is found in every respect, including recovery of the initial state by electrochemical decomposition of the crys...

A novel polymorph of glycolide, the precursor to polyglycolic acid, has been observed at 0.6 GPa. Large scale high-pressure production has been performed and the seeds successfully used to aid crystallisation of the polymorph at ambient pressure. PIXEL calculations confirm the metastable nature of the polymorph. Subsequent experiments show that, whilst initially stable for 12 days, this may be a case of disappearing polymorphism.

Partial Least Squares (PLS) regression is an established analytical tool in surface science, particularly for relating multivariate ToF-SIMS data to a univariate surface property. Herein we construct a PLS model using ToF-SIMS and surface energy data from a 496 copolymer micro-patterned library. Using this 496 copolymer library we investigate how changing the number of samples used to construct the PLS model affects the identity of the most influential ions identified in the regression vector. The regression coefficients vary in magnitude, but the general relationship between ion structure and surface energy is maintained. As expected, if copolymers containing monomers with unique chemistries are removed from the training set, secondary ions specific to these copolymers are not present in the regression vector. The use of PLS to obtain quantitative predictions has not been actively explored in the surface analytical field. We investigate whether the PLS model obtained can be used to predict the surface energies of polymers within and outside of the training set. The model systematically underestimated the surface energy of a group of acrylate copolymers synthesised using monomers common to the training set, but in different compositions. The predictions for a group of acrylate copolymers that were synthesised from monomers not used in the training set were very poor. When the model was used to obtain predictions for six commercially available polymers the values obtained were all close to the mean surface energy of the training set. This exercise suggests that PLS may be able to predict the surface energy of polymers synthesised from monomers common to the training set, confirming the importance that the training set reflects the chemistry of the samples to be predicted.

Materials which undergo self-assembly to form supermolecular structures can provide alternative strategies to drug loading problems in controlled release application. RADA 16 is a simple and versatile self-assembling peptide with a designed structure formed of two distinct surfaces, one hydrophilic and one hydrophobic that are positioned such a well-ordered fashion allowing precise assembly into a predetermined organization. A “smart” architecture in nanostructures can represent a good opportunity to use RADA16 as a carrier system for hydrophobic drugs solving problems of drugs delivery. In this work, we have investigated the diffusion properties of Pindolol, Quinine and Timolol Maleate from RADA16 in PBS and in BSS-PLUS at 37 °C. A sustained, controlled, reproducible and efficient drug release has been detected for all the systems, which has allow to understand the dependence of release kinetics on the physicochemical characteristics of RADA16 structural and chemical properties of the selected drugs and the nature of solvents used. For the analysis various physicochemical characterization techniques were used in order to investigate the state of the peptide before and after the drugs were added. Not only does RADA16 optimise drug performance, but it can also provide a solution for drug delivery issues associated with lipophilic drugs.

Amphiphilic self-assembling peptides are functional materials, which, depending on the amino acid sequence, the peptide length, and the physicochemical conditions, form a variety of nanostructures including nanovesicles, nanotubes, and nanovalves. We designed lipidlike peptides with an aspartic acid or lysine hydrophilic head and a hydrophobic tail composed of six alanines (i.e., ac-A6KCONH2, KA6-CONH2, ac-A6D-COOH, and DA6-COOH). The resulting novel peptides have a length similar to biological lipids and form nanovesicles at physiological conditions. AFM microscopy and light scattering analyses of the positively charged lipid-like ac-A6K-CONH2, KA6-CONH2 peptide formulations showed individual nanovesicles. The negatively charged ac-A6DCOOH and DA6-COOH peptides self-assembled into nanovesicles that formed clusters that upon drying were organized into necklace-like formations of nanovesicles. Encapsulation of probe molecules and release studies through the peptide bilayer suggest that peptide nanovesicles may be good candidates for sustained release of pharmaceutically active hydrophilic and\ud hydrophobic compounds. Lipid-like peptide nanovesicles represent a paradigm shifting system that may complement liposomes for the delivery of diagnostic and therapeutic agents.

This article details the exploration of perdeuterated acrylic acid at high pressure using neutron diffraction. The structural changes that occur in acrylic acid-d4 are followed via diffraction and rationalized using the Pixel method. Acrylic acid undergoes a reconstructive phase transition to a new phase at ∼0.8 GPa and remains molecular to 7.2 GPa before polymerizing on decompression to ambient pressure. The resulting product is analyzed via Raman and FT-IR spectroscopy and differential scanning calorimetry and found to possess a different molecular structure compared with polymers produced via traditional routes.

Beta-adrenocepetor antagonists (beta-blockers) alter the nanostructure of lysozyme amyloids, resulting in different drug release profiles.

N-acryloylmorpholine (NAM) was photo-polymerized to produce the homopolymer poly(N-acryloylmorpholine) (PNAM). PNAM behaves as a physical hydrogel in aqueous solvents, doubling its dry weight over a 2 h period before undergoing dissolution following a second order exponential decay profile. In vitro cellular experiments using mouse myoblasts showed that PNAM acts as an effective spatial cell barrier for 38 h, with slow migration of cells into the PNAM area occurring between 45 and 73 h after cell seeding. At 80 h myoblasts fully occupied the area initially blocked by PNAM. Immunofluorescent staining of myoblasts adjacent to PNAM showed normal cytoskeletal structure and well developed focal adhesions indicating limited PNAM toxicity. This study shows that PNAM is an easy to synthesize physical hydrogel that acts as a temporal and spatial barrier to cell adhesion.

Mesoporous silica nanoparticles MCM – 41 were synthesized with two dimensional hexagonal p6mm symmetry, high specific surface area(~ 980m2/g) narrow pore size and an average particle size of 186 nm. The produced nanoparticles were used to encapsulate carbamazepine through a supercritical carbon dioxide process combined with various organic solvents. Supercritical processing was found to provide increased drug encapsulation. The loaded MCM - 41 nanoparticles were analyzed using X–ray diffraction and differential scanning calorimetry (DSC) to investigate the crystalline state of the encapsulated carbamazepine and it was found to be dependent on the nature of the organic solvent. Carbamazepine showed increased dissolution rates under sink conditions. Viability studies of Caco – 2 cells demonstrated negligible cytotoxicity for the MCM–41 nanoparticles.