Multifunkcionalni kompoziti na bazi alginatnih hidrogelova za potencijalnu primenu u oblogama za rane

Alginate hydrogels are widely used in wound dressings due to hydrophilicity, biocompatibility, flexibility, and high sorption capacity, providing effective moisture regulation in wounds and inducing rapid granulation and reepithelization of the damaged tissue. However, these dressings are not bioactive so that different methodologies have been investigated to extend functionality of alginate hydrogels. In the present work, we show several approaches to achieve this aim by addition of different biologically active components. These include incorporation of silver nanoparticles as potent antimicrobial agents (1), bioactive honey components (2), activated charcoal (AC) particles as carriers of therapeutically active agents (3) as well as the use of Zn-alginate hydrogels that release zinc ions (4). The obtained composites were comprehensively characterized regarding composition, cytotoxicity, antibacterial activity, release kinetics of active agents and wound treatment in a rat model. Ag/alginate nanocomposite hydrogels releasing silver ions and/or nanoparticles exhibited high bactericidal activity against a broad spectrum of standard and multi-drug resistant clinical bacterial strains (Escherichia coli, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus – MRSA, Acinetobacter baumannii and Pseudomonas aeruginosa). Especially interesting results were obtained against 13 clinical isolates of A. baumannii, which were completely extinguished over 48 h in 6 cases (2). However, in 3 clinical isolates, antibacterial effects were not noticed implying possibility for development of bacterial resistance to silver. In the treatment of 2nd degree burns in rats Ag/alginate nanocomposites exhibited the same efficiency as commercial medical products (5). Composite alginate hydrogels with immobilized AC particles impregnated with povidone iodine (PVP-I) as a model therapeutically active agent, were developed with the aim to provide controlled particle release in the wound without actually releasing the adsorbed substance, thus achieving the desired activity without adverse effects by systemic absorption. The composite Ca-alginate hydrogels induced strong bactericidal effects against two standard bacterial strains and clinical multi-resistant wound isolates (MRSA, E. coli, P. aeruginosa, Еnterococcus faecalis and Proteus mirabilis) without releasing PVP-I in the environment (3). Furthermore, composite Zn-alginate hydrogels released zinc ions in addition to AC particles with adsorbed PVP-I, which induced additional microbicidal effects on one wild yeast strain (Candida albicans). The obtained bactericidal effects were ascribed to effective adsorption of bacteria onto AC particles and further direct contact with the adsorbed iodine, while the antifungal activity against C. albicans was assigned to released Zn 2+. Overall, the developed composite alginate hydrogels have shown high potentials for utilization in variety of multifunctional wound dressings according to the specific needs.Alginatni hidrogelovi se široko koriste u oblogama za rane zbog svoje hidrofilnosti, biokompatibilnosti, fleksibilnosti i velikog sorpcionog kapaciteta čime obezbeđuju efikasnu regulaciju vlažnosti rane i podstiču brzu granulaciju i reepitelizaciju oštećenog tkiva. Međutim, ove obloge nisu bioaktivne tako da su istraživane različite metodologije kako bi se proširila funkcionalnost alginatnih hidrogelova. U ovom radu je prikazano nekoliko pristupa ostvarivanju tog cilja dodatkom različitih biološki aktivnih komponenata. Ovi pristupi uključuju inkorporaciju nanočestica srebra kao potentnog antimikrobnog agensa (1), bioaktivnih komponenata meda (2), čestica aktivnog uglja (AU) kao nosača terapeutski aktivnih agenasa (3), kao i primenu hidrogelova Zn-alginata koji otpuštaju jone cinka. Dobijeni kompoziti su sveobuhvatno karakterisani u pogledu sastava, citotoksičnosti, antibakterijske aktivnosti, kinetike otpuštanja aktivnih agenasa i tretmana rana u eksperimentalnom modelu opekotina na pacovima. Ag/alginatni nanokompozitni hydrogelovi su usled otpuštanja jona i/ili nanočestica srebra, pokazali izraženu baktericidnu aktivnost prema širokom spektru standardnih i kliničkih multi- rezistentnih bakterijskih sojeva (Escherichia coli, Staphylococcus aureus, meticilin-resistentni Staphylococcus aureus – MRSA, Acinetobacter baumannii i Pseudomonas aeruginosa). Posebno interesantni rezultati su dobijeni u kulturama 13 kliničkih izolata A. baumannii, gde je u 6 slučajeva postignut potpun baktericidan efekat u toku 48 h (2). Ipak, kod 3 klinička izolata nije postignuto antibakterijsko dejstvo što ukazuje na mogućnost razvoja bakterijske rezistencije na srebro. U tretmanu opekotina drugog stepena na pacovima, Ag/alginatni nanokompoziti su pokazali istu efikasnost kao komercijalni medicinski proizvodi. Kompozitni alginatni hidrogelovi sa imobilisanim česticama AU impregniranih povidon-jodom kao model terapeutski aktivnom komponentom, su razvijeni sa ciljem da obezbede kontrolisano otpuštanje čestica AU u rani bez otpuštanja adsorbovane supstance kako bi se na taj način postiglo željeno dejstvo bez neželjenih efekata sistemske apsorpcije. Kompozitni Ca-alginatni hidrogelovi su pokazali jake baktericidne efekte na dva standardna bakterijska soja i nekoliko kliničkih multi- rezistentnih izolata iz rana (MRSA, E. coli, P. aeruginosa, Еnterococcus faecalis i Proteus mirabilis) bez otpuštanja povidon-joda u okolinu (3). Isto tako, kompozitni Zn-alginatni hidrogelovi su otpuštali jone cinka uz otpuštanje AU čestica sa adsorbovanim povidon-jodom što je prouzrokovalo dodatno mikrobicidno dejstvo na jedan divlji soj gljivice Candida albicans. Dobijeni baktericidni efekti su pripisani efikasnoj adsorpciji bakterija na čestice AU i daljem direktnom kontaktu adsorbovanog joda sa ćelijskom membranom bakterija, dok je antifungalna aktivnost u odnosu na C. albicans pripisana otpuštenim Zn 2+ jonima. Može se zaključiti da su razvijeni kompozitni alginatni hdrogelovi pokazali veliki potencijal za primenu u raznovrsnim multifunkcionalnim oblogama za rane prilagođenim specifičnim potrebama.Drugi naučni simpozijum Saveza farmaceutskih udruženja Srbije sa međunarodnim učešćem, 28. 10. 2021. Beogra

MOLNUPIRAVIR COMPARED TO NIRMATRELVIR/RITONAVIR FOR COVID-19 IN HIGH-RISK PATIENTS WITH HAEMATOLOGICAL MALIGNANCY IN EUROPE. A MATCHED-PAIRED ANALYSIS FROM THE EPICOVIDEHA REGISTRY

Introduction: Molnupiravir and nirmatrelvir/ritonavir are antivirals used to prevent progression to severe SARS-CoV-2 infections, which reduce both hospitalization and mortality rates. Nirmatrelvir/ritonavir was authorised in Europe in December 2021, while molnupiravir is not yet licensed in Europe as of February 2022. Molnupiravir may be an alternative to nirmatrelvir/ritonavir, because it displays less frequent drug-drug interactions and contraindications. A caveat connected to molnupiravir derives from the mode of action inducing viral mutations. In clinical trials on patients without haematological malignancy, mortality rate reduction of molnupiravir appeared less pronounced than that of nirmatrelvir/ritonavir. Little is known about the comparative efficacy of the two drugs in patients with haematological malignancy at high-risk of severe COVID-19. Thus, we here assess the effectiveness of molnupiravir compared to nirmatrelvir/ritonavir in our cohort of patients with haematological malignancies. Methods: Clinical data of patients treated either with molnupiravir or nirmatrelvir/ritonavir monotherapy for COVID-19 were retrieved from the EPICOVIDEHA registry. Patients treated with molnupiravir were matched by sex, age (±10 years), and baseline haematological malignancy severity to controls treated with nirmatrelvir/ritonavir. Results: A total of 116 patients receiving molnupiravir for the clinical management of COVID-19 were matched to an equal number of controls receiving nirmatrelvir/ritonavir. In each of the groups, 68 (59%) patients were male; with a median age of 64 years (IQR 53-74) for molnupiravir recipients and 64 years (IQR 54-73) for nirmatrelvir/ritonavir recipients; 57% (n=66) of the patients had controlled baseline haematological malignancy, 13% (n=15) stable, and 30% (n=35) had active disease at COVID-19 onset in each of the groups. During COVID-19 infection, one third of patients from each group were admitted to hospital. Although a similar proportion of vaccinated patients was observed in both groups (molnupiravir n=77, 66% vs nirmatrelvir/ritonavir n=87, 75%), those treated with nirmatrelvir/ritonavir had more often received four doses (n=27, 23%) as compared to patients treated with molnupiravir (n=5, 4%, p<0.001). No differences were detected in COVID-19 severity (p=0.39) or hospitalization (p=1.0). No statistically significant differences were identified in overall mortality rate (p=0.78) or in survival probability (d30 p=0.19, d60 p=0.67, d90 p=0.68, last day of follow up p=0.68). In all patients, deaths were either attributed to COVID-19 or the infection contributed to death as per treating physician's judgement. Conclusions: In high-risk patients with haematological malignancies and COVID-19, molnupiravir showed rates of hospitalization and mortality comparable to those of nirmatrelvir/ritonavir in this matched-pair analysis. Molnupiravir appears to be a plausible alternative to nirmatrelvir/ritonavir for COVID-19 treatment in patients with haematological malignancy

Age, Successive Waves, Immunization, and Mortality in Elderly COVID-19 Haematological Patients: EPICOVIDEHA Findings

Introduction: elderly patients with haematologic malignancies face the highest risk of severe COVID-19 outcomes. The infection impact in different age groups remains unstudied in detail. Methods: We analysed elderly patients (age groups: 65-70, 71-75, 76-80 and >80 years old) with hematologic malignancies included in the EPICOVIDEHA registry between January 2020 and July 2022. Univariable and multivariable Cox regression models were conducted to identify factors influencing death in COVID-19 patients with haematological malignancy. results: the study included data from 3,603 elderly patients (aged 65 or older) with haematological malignancy, with a majority being male (58.1%) and a significant proportion having comorbidities. The patients were divided into four age groups, and the analysis assessed COVID-19 outcomes, vaccination status, and other variables in relation to age and pandemic waves.tThe 90-day survival rate for patients with COVID-19 was 71.2%, with significant differences between groups. The pandemic waves had varying impacts, with the first wave affecting patients over 80 years old, the second being more severe in 65-70, and the third being the least severe in all age groups. factors contributing to 90-day mortality included age, comorbidities, lymphopenia, active malignancy, acute leukaemia, less than three vaccine doses, severe COVID-19, and using only corticosteroids as treatment. Conclusions: These data underscore the heterogeneity of elderly haematological patients, highlight the different impact of COVID waves and the pivotal importance of vaccination, and may help in planning future healthcare efforts

Zaslužujemo više informacija o svijetu

Urednici medija koji su bili intervjuirani, različito, čak suprotno doživljavaju i organiziraju vanjsku politiku i vijesti iz svijeta. Zatim, usporednom analizom vijesti koje su tog dana1 objavile TVCG i IN televizija s vijestima koje su se pojavile na BBC-ju i CNN-u, zaključili smo da prosječni građanin Crne Gore zaslužuje više informacija o događajima u svijetu. I posljednjom analizom koju smo tog dana proveli, najtiražnijih dnevnih novina, postojećih internetskih portala i radijskih postaja potvrdili smo činjenicu da u Crnoj Gori ne postoji dovoljno jak utjecaj globalnih medija. Ono što je važno istaknuti jest da smo pratili informativni program, te da je zaključak izveden na osnovi tog istraživanja, a da je globalni utjecaj na kulturni i zabavni program mnogo veći

Functional bioreactor characterization to assess potentials of nanocomposites based on different alginate types and silver nanoparticles for use as cartilage tissue implants

In this work, functional characterization of biomaterials concerning potential application as articular cartilage implants was performed by using a biomimetic bioreactor with dynamic compression in the physiological regime (10% strain, 0.84 Hz frequency, 1 h on/1 h off). Specifically, two alginate types with low (LG) and high (HG) guluronic/mannuronic residue ratios with electrochemically synthesized silver nanoparticles (AgNPs) were evaluated. HG Ag/alginate hydrogels were clearly indicated as potential candidates due to better initial mechanical properties as compared to LG hydrogels (dynamic compression modulus of ~60 vs. ~40 kPa) as well as the mechanical stability displayed during 7 days of dynamic compression. Cytotoxicity studies in 3D bovine cartilage explant cultures under dynamic compression have shown negligible effects as compared to standard 2D monolayers of bovine chondrocytes where moderate cytotoxicity was observed. Finally, experimental and mathematical modeling studies revealed different mechanisms of AgNP release under physiological-like bioreactor conditions as compared to static conditions. Overall, the results clearly demonstrate bioreactor advantages in characterization and selection of candidate biomaterials as well as potentials to bridge the in vitro-in vivo gap.Published version [http://technorep.tmf.bg.ac.rs/handle/123456789/4191]This is the peer-reviewed version of the following article: Zvicer J, Mišković-Stanković V, Obradović B. Functional bioreactor characterization to assess potentials of nanocomposites based on different alginate types and silver nanoparticles for use as cartilage tissue implants. in Journal of Biomedical Materials Research Part A. 2019;107(4):755-768. [doi:10.1002/jbm.a.36590

Cytotoxicity studies of Ag/alginate nanocomposite hydrogels in 2D and 3D cultures

Alginate nanocomposite hydrogels with incorporated electrochemically synthesized silver nanoparticles were investigated regarding cytotoxicity in vitro. Direct contact test of Ag/alginate discs was applied in 2D monolayer cultures of bovine calf chondrocytes while a 3D culture of bovine articular cartilage explants pressed by the discs was established in a biomimetic bioreactor with dynamic compression in the physiological regime (10 % strain, 0.84 Hz frequency, 1 h on / 1 h off). Moderate cytotoxicity was observed in 2D cell cultures as opposed to findings in 3D explant cultures, which were not affected by the Ag/alginate discs despite the compression

Alginate hydrogel microbeads incorporated with Ag nanoparticles obtained by electrochemical method

An innovative method was developed for production of alginate hydrogel microbeads incorporated with silver nanoparticles (AgNPs) based on electrochemical synthesis followed by electrostatic extrusion. AgNPs were synthesized galvanostatically at different values of AgNO3 concentration in the initial solution (0.5-3.9 mM), current density (5-50 mA cm(-2)), and implementation time (0.5-10 min). Increase in all of these parameters increased the concentration of AgNPs in alginate solution and was confirmed by TEM analysis and UV-vis spectroscopy. Cyclic voltammetry studies and Fourier transform infrared spectroscopy proved the alginate to be a good capping agent for the electrochemical synthesis of silver nanoparticles, due to coordination bonding between hydroxyl and ether groups, as well as ring oxygen atoms in uronic acid residues of alginate molecules, and Ag nanoparticles. Ag/alginate colloid solution was used for production of uniform hydrogel microbeads (with diameter of 487.75 +/- 16.5 mu m) by electrostatic extrusion technique. UV-vis spectroscopy confirmed retention and entrapment of AgNPs in microbeads during the production process. Alginate microbeads incorporated with AgNPs are attractive as biocompatible carriers and/or efficient donors of AgNPs as active components especially for potential biomedical applications, which was demonstrated by the antibacterial activity against Staphylococcus aureus

Novel alginate based nanocomposite hydrogels with incorporated silver nanoparticles

Alginate colloid solution containing electrochemically synthesized silver nanoparticles (AgNPs) was investigated regarding the nanoparticle stabilization and possibilities for production of alginate based nanocomposite hydrogels in different forms. AgNPs were shown to continue to grow in alginate solutions for additional 3 days after the synthesis by aggregative mechanism and Ostwald ripening. Thereafter, the colloid solution remains stable for 30 days and could be used alone or in mixtures with aqueous solutions of poly(vinyl alcohol) (PVA) and poly(N-vinyl-2-pyrrolidone) (PVP) while preserving AgNPs as verified by UV-Vis spectroscopy studies. We have optimized techniques for production of Ag/alginate microbeads and Ag/alginate/PVA beads, which were shown to efficiently release AgNPs decreasing the Escherichia coli concentration in suspensions for 99.9% over 24 h. Furthermore, Ag/hydrogel discs based on alginate, PVA and PVP were produced by freezing-thawing technique allowing adjustments of hydrogel composition and mechanical properties as demonstrated in compression studies performed in a biomimetic bioreactor