Accessing distributions of exchange and dipolar couplings in stiff molecular rulers with Cu(II) centres.

Determining distributed exchange couplings is important for understanding the properties of synthetic magnetic molecules. Such distributions can be determined from pulsed dipolar spectroscopy (PDS) data, but this is challenging due to the similar influence of both exchange and dipolar couplings on such data. In this work we introduce two models that aim to identify these two contributions to the spin-spin couplings from frequency-domain PDS data of shape-persistent molecules having either two Cu(ii) ions, or a Cu(ii) ion and a nitroxide radical as the paramagnetic moieties. The first model assumes correlated Lorentzian or Gaussian exchange and dipole-dipole coupling distributions whose parameters are the model's unknowns. The second model relies on prior knowledge of the distance distribution and by performing Tikhonov regularization along the exchange coupling dimension yields the latter distribution model-free. Both models were able to differentiate between the absence and the presence of exchange interaction, to determine the coupling regime (ferro- or antiferromagnetic) and to estimate the distribution shape. In contrast, calculations within the exchange resilient model of the neural network analysis implemented in DeerAnalysis2018 were not able for our data to identify exchange couplings and return correct distance distributions. However, the generic model was able to identify and separate the strongly curved intermolecular background in the relaxation-induced dipolar modulation enhancement (RIDME) experiments. Our analysis revealed that in such systems exchange coupling may be present up to at least 3.3 nm in π-conjugated systems involving Cu(ii)-PyMTA, while it is negligible for distances r ≥ 4.5 nm between Cu(ii) ions and r ≥ 3.8 nm between a Cu(ii) ion and an unpaired electron of a nitroxide radical. Disruption of the π-conjugation between the ligand of the Cu(ii) complex and the nitroxide leads to negligible exchange coupling at distances r ≥ 2.6 nm in the corresponding [Cu(ii)-TAHA]-nitroxide ruler. Overall, for cases with known distance distributions, the presented analysis techniques allow to determine distributions of exchange couplings from PDS data.

Magnetic excitation and readout of methyl group tunnel coherence.

Methyl groups are ubiquitous in synthetic materials and biomolecules. At sufficiently low temperature, they behave as quantum rotors and populate only the rotational ground state. In a symmetric potential, the three localized substates are degenerate and become mixed by the tunnel overlap to delocalized states separated by the tunnel splitting ν t . Although ν t can be inferred by several techniques, coherent superposition of the tunnel-split states and direct measurement of ν t have proven elusive. Here, we show that a nearby electron spin provides a handle on the tunnel transition, allowing for its excitation and readout. Unlike existing dynamical nuclear polarization techniques, our experiment transfers polarization from the electron spin to methyl proton spins with an efficiency that is independent of the magnetic field and does not rely on an unusually large tunnel splitting. Our results also demonstrate control of quantum states despite the lack of an associated transition dipole moment.

[Immunity against measles among healthcare personnel at the University Hospital Frankfurt, 2003-2013]. / Immunität gegen Masern beim medizinischen Personal des Universitätsklinikums Frankfurt, 2003-2013.

BACKGROUND: Despite aiming for the elimination of measles by 2015, the current epidemiological situation in Germany shows that there is still insufficient vaccination coverage among the population. During the present pre-elimination period, nosocomial measles are gaining in importance. AIM: The purpose of our study was to determine the immune status of measles among healthcare personnel and medical students at the University Hospital Frankfurt. Moreover, the knowledge of study participants regarding the WHO's goal of the elimination of measles and the general attitude towards vaccination recommendations were investigated. METHODS: A retrospective study of measles seroprevalence was conducted among healthcare personnel and students at the University Hospital Frankfurt with an observation period of 11 years. In spring 2014, medical students were asked to complete an anonymous questionnaire regarding vaccination status, knowledge of measles and acceptance of measles vaccination recommendations. RESULTS: In total, 9,933 serologies were evaluated and 85.7% of the participants had sufficient immunity against measles. Significant changes in immunity to measles over time were not observed. However, a significant difference in the immunity rate of participants born before 1970 and those born after1970 was found. Participants born before 1970 significantly more often showed sufficient immunity against measles compared to those born later (96.4 vs. 83.3 %, p < 0.0001). Almost 20 % of the medical students were not aware of their measles vaccination status and merely 70.7 % indicated that they had received two measles vaccinations. Furthermore, only 45.4 % of the medical students were familiar with the WHO's goal of eliminating measles by 2015; however 95 % could be classified as vaccination-supporters on the basis of the questionnaire. CONCLUSIONS: Overall, the immunity rate of measles determined by serology within the study population did not reach the WHO goal of ≥ 95 %, and this gap was even greater in group of medical students. Despite the medical students' positive attitude towards vaccination guidelines, the awareness in this field awaits improvement.

Measles outbreak spreading from the community to an anthroposophic school, Berlin, 2011.

Between April and July 2011 there was an outbreak of measles virus, genotype D4, in Berlin, Germany. We identified 73 case-patients from the community and among students of an anthroposophic school, who participated in a 4-day school trip, as well as their family and friends. Overall, 27% were aged ≥ 20 years, 57% were female and 15% were hospitalized. Of 39 community case-patients, 38% were aged ≥ 20 years, 67% were female and 63% required hospitalization. Unvaccinated students returning from the school trip were excluded from school, limiting transmission. Within the group of 55 school-trip participants, including 20 measles case-patients, a measles vaccine effectiveness of 97.1% (95% confidence interval 83.4-100) for two doses was estimated using exact Poisson regression. Our findings support school exclusions and the recommendation of one-dose catch-up vaccination for everyone born after 1970 with incomplete or unknown vaccination status, in addition to the two-dose routine childhood immunization recommendation.

[Hot spot: epidemiology of measles and rubella in Germany and the WHO European region]. / Hot Spot: Epidemiologie der Masern und Röteln in Deutschland und Europa.

The elimination of measles and rubella by 2015 is an important goal set by the World Health Organization European Region (WHO/Europa). Since 1991, the incidence of measles in WHO/Europa declined owing to routine childhood vaccination and supplementary immunization activities in the region. However, in many countries of Western Europe elimination of measles and rubella remains a challenge, and every year there are outbreaks with partly long-lasting transmission chains and dissemination of the virus internationally. In Germany, outbreaks occur because of the high proportion of susceptible individuals in specific population groups. In 2011, over 1,600 cases were reported (19.7 per 1,000,000 inhabitants, data from the Robert Koch Institute) whereas in 2012 only 167 cases were reported to the Robert Koch Institute (2 per 1,000,000 inhabitants). It is unclear whether the declining trend will continue in the following years due to improved vaccination coverage or whether number of cases will rise again because of the accumulation of susceptible groups. In Germany, there are currently no representative, country-wide data on rubella; however, data from the eastern federal states provide important epidemiological insights. Outbreaks are seldom reported, but statutory notification of rubella and congenital rubella syndrome was implemented in March 2013. As a result, it will be possible to better assess the epidemiology of rubella in Germany, although a considerable underreporting of rubella cases is anticipated.

[The German National Verification Committee for Measles and Rubella Elimination]. / Quo vadis Germania? Die Nationale Kommission zur Verifizierung der Elimination der Masern und Röteln.

BACKGROUND: Since 1984, the World Health Organization (WHO) European Region has pursued the goal of eliminating measles. In 2005, it was decided to also stop the endemic transmission of rubellavirus, thereby eliminating congenital rubella syndrome. Both infections are to be eliminated by 2015. To document the progress and verify the elimination at country level, national verification committees should be established in WHO EU memberstates. PROCEDURE: In December 2012, the German Ministry of Health appointed the German National Verification Committee for Measles and Rubella Elimination. The commission meets at least twice a year to compile and analyze data on the epidemiology of measles and rubella in Germany and on the vaccination coverage/ immunity of the German population against these infections to assess progress in the elimination goals. Furthermore, the commission indicates whether the available data are sufficient or contain inconsistencies, evaluates the success of key strategies implemented, and advises on activities related to the verification of the elimination process in the country. A scientific report on the commission's findings is to be submitted annually to the WHO regional office. FUTURE PROSPECTS: Germany is committed to the aim of eliminating measles and rubella. Thus, every possible effort should be made to reach this goal by the responsible players in the German immunization system. The commission - as an independent group of experts - will critically accompany and evaluate this process.

[Pertussis vaccination coverage among adults in Germany]. / Pertussis-impfquoten bei erwachsenen in Deutschland.

BACKGROUND: Pertussis vaccination for risk-groups (e. g. healthcare workers, employees of communal facilities, or persons with close contact to infants) has been recommended in Germany since 2001. In 2009, single-dose acellular pertussis (ap) vaccination was recommended for all adults at the next tetanus-diphtheria (Td) booster. Study aims were to assess 1) pertussis vaccination coverage in adults, and 2) use of tetanus-containing combination vaccines in hospitals. METHODS: For 1) we analysed data from two population-based telephone surveys conducted among adults in Germany in 2009/2010 (GEDA09: n = 21,262; GEDA10: n = 22,050). Factors associated with vaccination were identified by logistic regression analyses. For 2) a questionnaire survey of 133 hospital pharmacies serving 454 German hospitals was undertaken for the year 2007. RESULTS: Overall, 5.9% (95% confidence interval [CI] 5.5-6.3%) of GEDA10 participants reported up-to-date pertussis vaccination (ap-vaccination in past 10 years). In risk-groups, vaccination coverage was 10.7% (95%-CI 9.8-11.7%). Residence in former East-Germany and younger age were independently associated with an adequate vaccination status. Contrary to prevailing recommendations, ~75% of tetanus vaccines were administered as monovalent rather than Td- (or Tdap-)combination vaccines in hospitals. CONCLUSIONS: In light of high pertussis-incidence and low vaccination coverage in German adults, improvement of pertussis vaccine uptake is vital, e. g. through awareness campaigns targeting both physicians in private practice and hospitals.

Circular dichroism spectral data and metadata in the Protein Circular Dichroism Data Bank (PCDDB): a tutorial guide to accession and deposition.

The Protein Circular Dichroism Data Bank (PCDDB) is a web-based resource containing circular dichroism (CD) and synchrotron radiation circular dichroism spectral and associated metadata located at http://pcddb.cryst.bbk.ac.uk. This resource provides a freely available, user-friendly means of accessing validated CD spectra and their associated experimental details and metadata, thereby enabling broad usage of this material and new developments across the structural biology, chemistry, and bioinformatics communities. The resource also enables researchers utilizing CD as an experimental technique to have a means of storing their data at a secure site from which it is easily retrievable, thereby making their results publicly accessible, a current requirement of many grant-funding agencies world-wide, as well as meeting the data-sharing requirements for journal publications. This tutorial provides extensive information on searching, accessing, and downloading procedures for those who wish to utilize the data available in the data bank, and detailed information on deposition procedures for creating and validating entries, including comprehensive explanations of their contents and formats, for those who wish to include their data in the data bank.

DichroMatch: a website for similarity searching of circular dichroism spectra.

Circular dichroism (CD) spectroscopy is a widely used method for examining the structure, folding and conformational changes of proteins. A new online CD analysis server (DichroMatch) has been developed for identifying proteins with similar spectral characteristics by detecting possible structurally and functionally related proteins and homologues. DichroMatch includes six different methods for determining the spectral nearest neighbours to a query protein spectrum and provides metrics of how similar these spectra are and, if corresponding crystal structures are available for the closest matched proteins, information on their secondary structures and fold classifications. By default, DichroMatch uses all the entries in the Protein Circular Dichroism Data Bank (PCDDB) for its comparison set, providing the broadest range of publicly available protein spectra to match with the unknown protein. Alternatively, users can download or create their own specialized data sets, thereby enabling comparisons between the structures of related proteins such as wild-type versus mutants or homologues or a series of spectra of the same protein under different conditions. The DichroMatch server is freely available at http://dichromatch.cryst.bbk.ac.uk.

Impact of the experimental conditions on drug release from parenteral depot systems: From negligible to significant.

The aim of this study was to evaluate the impact of the experimental conditions on drug release measurements from parenteral depot systems. Frequently applied setups were used, including agitated and "non-agitated" flasks and tubes, flow-though cells as well as agarose gels. The bulk fluid volumes and flow rates were varied. Lipid implants (prepared by direct compression or melting & casting) as well as PLGA-based microparticles (prepared by O/W or W/O/W or S/O/W solvent extraction/evaporation methods) were studied. Theophylline, lidocaine, prilocaine, propranolol HCl, dexamethasone and ibuprofen were used as model drugs at different initial loadings. In all cases, the release medium was phosphate buffer pH 7.4, kept constant at 37°C. Particle size analysis, SEM, X-ray diffraction, DSC analysis and mathematical modeling were applied to better understand the observed phenomena. Interestingly, the importance of the impact of the experimental conditions ranged from negligible to significant, depending on the specific type of drug delivery system and setup. Both, lipid implants as well as PLGA-based microparticles can exhibit more or less sensitive/robust drug release patterns. The observed differences in sensitivity could partially be explained in a mechanistic way, but in many cases they are not yet fully understood. A thorough understanding of the underlying drug release mechanisms can be very helpful. If the devices are poorly characterized and treated as "black boxes", great care must be taken when drawing conclusions from in vitro drug release measurements.

Cohort profile: the German ClinSurv HIV project--a multicentre open clinical cohort study supplementing national HIV surveillance.

BACKGROUND: New forms of HIV/AIDS therapy require new surveillance instruments to meet shifting public health demands. The Clinical Surveillance of HIV Disease (ClinSurv HIV) project was established in 1999 as a collaboration between major HIV treatment centres in Germany and the Robert Koch Institute (RKI). The project contributes to national HIV surveillance and focuses on the changing epidemiology of HIV/AIDS after the introduction of new therapies in 1995. METHODS: ClinSurv HIV is designed as an open multicentre observational cohort study of HIV-infected patients. Anonymized data on diagnoses, treatment and laboratory parameters are collected in a standardized format. Data are currently sampled biannually via 11 centres specializing in HIV diagnosis and care within the legal framework of the German Protection against Infection Act [Infektionsschutzgesetz (IfSG)]. RESULTS: A total of 14874 patients were enrolled in the study by 30 June 2009. Of these, 10221 patients (68.7%) were enrolled after 1 January 1999 and 6006 patients (40.4%) were known to have been diagnosed as positive for HIV before 1999. Evaluation indicators, such as the number of newly enrolled patients per half-year period, loss to follow-up, completeness of data per case, availability of data per possible clinical contact, and internal quality control parameters, show a very stable evolution in the cohort, which although open, can be observed. Comparison with the national HIV surveillance data suggests a high degree of representativeness according to major demographic variables. CONCLUSION: Bearing in mind the obvious strengths and weaknesses discussed, the German ClinSurv HIV cohort provides a broad range of research opportunities in the field of HIV/AIDS both within Germany and in international collaborative research.

Unintended potential impact of perfect sink conditions on PLGA degradation in microparticles.

Yet, no standardized test method for drug release measurements from PLGA-based microparticles has been generally agreed on, or described by the regulatory authorities. Often, perfect sink conditions are provided in vitro to avoid artificial drug saturation effects. However, the maintenance of such conditions might strongly affect PLGA degradation. The involved physicochemical processes are complex and the potential impact of perfect sink conditions is not yet well understood. Differently sized, highly porous, carbamazepine- and ibuprofen-loaded PLGA microparticles were prepared by a W/O/W emulsion solvent extraction/evaporation technique. The initial drug loading was intentionally low (3-4%) so that the two drugs were molecularly dispersed within the polymeric matrices (monolithic solutions). This was important to be able to exclude potential limited drug solubility effects on the resulting release kinetics. Drug release into phosphate buffer pH 7.4 was measured under perfect sink conditions. SEC, DSC and SEM were used to characterize polymer degradation. The decrease in the average polymer molecular weight, glass transition temperature as well as changes in the inner and outer morphology of the PLGA microparticles were strongly affected by the bulk fluid's volume. In the case of the poorly water-soluble drug carbamazepine, much lower "microparticle mass:phosphate buffer volume" ratios were required to maintain perfect sink conditions, resulting in stable pH values within the bulk fluid, slower PLGA degradation and, thus, lower drug release rates. Thus, great care has to be taken when defining the conditions for in vitro drug release measurements from PLGA-based microparticles, avoiding potentially artificial conditions for polymer degradation.

PCDDB: the Protein Circular Dichroism Data Bank, a repository for circular dichroism spectral and metadata.

The Protein Circular Dichroism Data Bank (PCDDB) is a public repository that archives and freely distributes circular dichroism (CD) and synchrotron radiation CD (SRCD) spectral data and their associated experimental metadata. All entries undergo validation and curation procedures to ensure completeness, consistency and quality of the data included. A web-based interface enables users to browse and query sample types, sample conditions, experimental parameters and provides spectra in both graphical display format and as downloadable text files. The entries are linked, when appropriate, to primary sequence (UniProt) and structural (PDB) databases, as well as to secondary databases such as the Enzyme Commission functional classification database and the CATH fold classification database, as well as to literature citations. The PCDDB is available at: http://pcddb.cryst.bbk.ac.uk.

2Struc: the secondary structure server.

SUMMARY: The defined secondary structure of proteins method is often considered the gold standard for assignment of secondary structure from three-dimensional coordinates. However, there are alternative methods. '2Struc: The Secondary Structure Server' has been created as a single point of access for eight different secondary structure assignment methods. It has been designed to enable comparisons between methods for analyzing the secondary structure content for a single protein. It also includes a second functionality, 'Compare-the-Protein' to enable comparisons of the secondary structure features from any one method to be made within a collection of nuclear magnetic resonance models, or between the crystal structures of two different proteins. AVAILABILITY: http://2struc.cryst.bbk.ac.uk CONTACT: r.w.janes@qmul.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Drug release from PLGA-based microparticles: effects of the "microparticle:bulk fluid" ratio.

The aim of this study was to better understand the importance of the "microparticle mass:bulk fluid volume" ratio during in vitro drug release measurements from PLGA microparticles. Initially porous/non-porous, ibuprofen/lidocaine/propranolol HCl-loaded systems were exposed to phosphate buffer pH 7.4 in agitated test tubes, varying the microparticle concentration from 5:1 to 20:1mg:mL. Interestingly, drug release was virtually unaffected by the "microparticle mass:bulk fluid volume" ratio in the case of initially porous, ibuprofen-loaded microparticles, exhibiting complete drug release within about 1 week. Optical microscopy, SEM, DSC and pH measurements of the bulk fluid revealed no major impact of the microparticle concentration on the systems' properties within the first couple of days. However, a more rapid and pronounced decrease in the pH of the release medium occurred after 10-14 d at elevated "microparticle mass:bulk fluid volume" ratios. This resulted in an accelerated: (i) decrease in the glass transition temperature, (ii) microparticle agglomeration, and (iii) increase in the internal and external microparticle porosity. Importantly, this phenomenon did not significantly affect drug release from initially porous, lidocaine-loaded microparticles, exhibiting complete release within about 18 d. In contrast, drug release became significantly faster at higher "microparticle mass:bulk fluid volume" ratios in the case of initially non-porous, lidocaine-loaded microparticles and initially porous, propranolol HCl-loaded systems, exhibiting complete release after 1 and 2 months, respectively. Thus, depending on the type of system, the "microparticle mass:bulk fluid volume" ratio may or may not affect the observed release kinetics in vitro. This should be carefully taken into account when defining the experimental conditions for drug release measurements from this type of advanced drug delivery systems.

Comparative varicella vaccine effectiveness during outbreaks in day-care centres.

BACKGROUND: Routine varicella vaccination for children >11 months was introduced in Germany in 2004 with three different vaccine brands available. In 2008 and 2009, we investigated seven varicella outbreaks in day-care centres (DCC). METHODS: Varicella disease and vaccination status of 1084 children was reviewed to evaluate vaccination coverage (VC), brand-specific varicella vaccine effectiveness (VE), and risk factors of breakthrough varicella (BV, >42 days after vaccination). A case was defined as a child with acute onset of varicella attending one of the respective DCC at the time of outbreak. Children with a previous history of varicella, age<11 months, vaccinated at age<11 months or <42 days before disease onset or during the outbreak were excluded from VE and BV risk factors analyses (adjusted for gender, age and DCC). FINDINGS: Of 631 children with available vaccination information, 392 (62%) were vaccinated at least once. Overall VE among 352 children eligible was 71% (95% confidence interval (CI) 57-81, p<0.001) and differed significantly by disease severity and number of doses administered. Risk for BV was higher for 1 dose of Varilrix (RR=2.8, 95%CI 1.0-7.8, p=0.05) or Priorix-Tetra (RR=2.4, 95%CI 0.7-8.3, p=0.18) but lower for 2 doses of Priorix-Tetra (RR=0.5, 95%CI 0.1-2.7, p=0.41) than for 1 dose of Varivax. INTERPRETATION: Enhanced efforts to increase VC in Germany and 2 doses varicella vaccine might be successful to reduce the risk for BV. The evidence that VE and risk of BV are associated with vaccine brand needs further investigation.

Fenofibrate-loaded PLGA microparticles: effects on ischemic stroke.

Many drugs are not able to cross the Blood Brain Barrier (BBB) and, thus, cannot reach a target site within the Central Nervous System (CNS). Local controlled drug delivery can help to overcome this restriction. However, this is a highly challenging approach and only one product is yet available on the market: Gliadel, which is used to reduce the risk of local tumor recurrence upon resection of malignant glioma. The aim of this study was to evaluate the potential of local controlled drug delivery to the CNS to reduce the consequences of ischemic stroke. Fenofibrate as well as its active metabolite fenofibric acid were encapsulated within PLGA microparticles. Importantly, fenofibrate-loaded microparticles effectively reduced the consequences of ischemic stroke in Wistar rats: the total, cortical and striatal infarct volumes decreased from 257 to 197, 193 to 139, and 64 to 58 mm(3), respectively. Interestingly, fenofibric acid-loaded microparticles did not show significant in vivo efficacy, which might be attributable to a potentially limited distribution pattern within the brain and/or limited cell uptake. Thus, local controlled drug delivery to the CNS also has a significant potential for the treatment/prevention of other types of diseases than cancer. Furthermore, this approach can help to provide proof of concept in vivo in the early drug discovery phase, if the drug candidate cannot cross the BBB.

Towards more realistic in vitro release measurement techniques for biodegradable microparticles.

PURPOSE: To better understand the importance of the environmental conditions for drug release from biodegradable microparticles allowing for the development of more appropriate in vitro release measurement techniques. METHODS: Propranolol HCl diffusion in various agarose gels was characterized by NMR and UV analysis. Fick's law was used to theoretically predict the mass transport kinetics. Drug release from PLGA-based microparticles in such agarose gels was compared to that measured in agitated bulk fluids ("standard" method). RESULTS: NMR analysis revealed that the drug diffusivity was almost independent of the hydrogel concentration, despite of the significant differences in the systems' mechanical properties. This is due to the small size of the drug molecules/ions with respect to the hydrogel mesh size. Interestingly, the theoretically predicted drug concentration-distance-profiles could be confirmed by independent experiments. Most important from a practical point of view, significant differences in the release rates from the same batch of PLGA-based microparticles into a well agitated bulk fluid versus a semi-solid agarose gel were observed. CONCLUSION: Great care must be taken when defining the in vitro conditions for drug release measurements from biodegradable microparticles. The obtained new insight can help facilitating the development of more appropriate in vitro release testing procedures.

PLGA-based drug delivery systems: importance of the type of drug and device geometry.

Different types of ibuprofen- and lidocaine-loaded, poly(lactic-co-glycolic acid) (PLGA)-based microparticles and thin, free films of various dimensions were prepared and physico-chemically characterized in vitro. The obtained experimental results were analyzed using mathematical theories based on Fick's second law of diffusion. Importantly, the initial drug loadings were low in all cases (4%, w/w), simplifying the mathematical treatment and minimizing potential effects of the acidic/basic nature of the two model drugs on polymer degradation. Interestingly, the type of drug and device geometry strongly affected the resulting release kinetics and relative importance of the involved mass transport mechanisms. For instance, the relative release rate was almost unaffected by the system size in the case of spherical microparticles, but strongly depended on the thickness of thin, free films, irrespective of the type of drug. Ibuprofen and lidocaine release was found to be primarily diffusion controlled from the investigated PLGA-based microparticles for all system sizes, whereas diffusion was only dominant in the case of the thinnest free films. Interestingly, the type of drug did not significantly affect the resulting polymer degradation kinetics. However, ibuprofen release was always much faster than lidocaine release for all system geometries and sizes. This can probably be attributed to attractive ionic interactions between protonated, positively charged lidocaine ions and negatively charged, deprotonated carboxylic end groups of PLGA, hindering drug diffusion. The determined apparent diffusion coefficients of the drugs clearly point out that the mobility of an active agent in PLGA-based delivery systems does not only depend on its own physico-chemical properties and the type of PLGA used, but also to a large extent on the size and shape of the device. This has to be carefully taken into account when developing/optimizing this type of advanced drug delivery systems.

How porosity and size affect the drug release mechanisms from PLGA-based microparticles.

Porous, poly(lactic-co-glycolic acid) (PLGA)-based microparticles were prepared using a water-in-oil-in-water (W/O/W) solvent extraction/evaporation technique. Lidocaine was used as a model drug and different-sized particle fractions were obtained by sieving. The physicochemical properties of the devices and changes thereof upon exposure to phosphate buffer pH 7.4 were studied using optical and scanning electron microscopy, size exclusion chromatography (SEC), differential scanning calorimetry (DSC), gravimetric analysis and in vitro drug release measurements. In contrast to non-porous microparticles of identical composition, the relative drug release rate was found to decrease with increasing system size. SEC, DSC and gravimetric analysis showed that the degradation rate of the polymer increased with increasing microparticle dimension, indicating that autocatalytic effects play an important role even in small and highly porous PLGA-based microparticles. However, these effects were much less pronounced than in non-porous devices. Importantly, they were overcompensated by the effects of the increasing diffusion pathway lengths with increasing system dimension. Thus, high initial microparticle porosities do not only lead to increased drug mobilities, but can also fundamentally alter the underlying mass transport mechanisms.