Polyglycerol-Functionalized ß-Cyclodextrins as Crosslinkers in Thermoresponsive Nanogels for the Enhanced Dermal Penetration of Hydrophobic Drugs.

Thermoresponsive nanogels (tNGs) are promising candidates for dermal drug delivery. However, poor incorporation of hydrophobic drugs into hydrophilic tNGs limits the therapeutic efficiency. To address this challenge, ß-cyclodextrins (ß-CD) are functionalized by hyperbranched polyglycerol serving as crosslinkers (hPG-ßCD) to fabricate ßCD-tNGs. This novel construct exhibits augmented encapsulation of hydrophobic drugs, shows the appropriate thermal response to dermal administration, and enhances the dermal penetration of payloads. The structural influences on the encapsulation capacity of ßCD-tNGs for hydrophobic drugs are analyzed, while concurrently retaining their efficacy as skin penetration enhancers. Various synthetic parameters are considered, encompassing the acrylation degree and molecular weight of hPG-ßCD, as well as the monomer composition of ßCD-tNGs. The outcome reveals that ßCD-tNGs substantially enhance the aqueous solubility of Nile Red elevating to 120 µg mL-1 and augmenting its dermal penetration up to 3.33 µg cm-2. Notably, the acrylation degree of hPG-ßCD plays a significant role in dermal drug penetration, primarily attributed to the impact on the rigidity and hydrophilicity of ßCD-tNGs. Taken together, the introduction of the functionalized ß-CD as the crosslinker in tNGs presents a novel avenue to enhance the efficacy of hydrophobic drugs in dermatological applications, thereby offering promising opportunities for boosted therapeutic outcomes.

Nanogels: Smart tools to enlarge the therapeutic window of gene therapy.

Gene therapy can potentially treat a great number of diseases, from cancer to rare genetic disorders. Very recently, the development and emergency approval of nucleic acid-based COVID-19 vaccines confirmed its strength and versatility. However, gene therapy encounters limitations due to the lack of suitable carriers to vectorize therapeutic genetic material inside target cells. Nanogels are highly hydrated nano-size crosslinked polymeric networks that have been used in many biomedical applications, from drug delivery to tissue engineering and diagnostics. Due to their easy production, tunability, and swelling properties they have called the attention as promising vectors for gene delivery. In this review, nanogels are discussed as vectors for nucleic acid delivery aiming to enlarge gene therapy's therapeutic window. Recent works highlighting the optimization of inherent transfection efficiency and biocompatibility are reviewed here. The importance of the monomer choice, along with the internal structure, surface decoration, and responsive features are outlined for the different transfection modalities. The possible sources of toxicological endpoints in nanogels are analyzed, and the strategies to limit them are compared. Finally, perspectives are discussed to identify the remining challenges for the nanogels before their translation to the market as transfection agents.

Bringing innovative wound care polymer materials to the market: Challenges, developments, and new trends.

The development of innovative products for treating acute and chronic wounds has become a significant topic in healthcare, resulting in numerous products and innovations over time. The growing number of patients with comorbidities and chronic diseases, which may significantly alter, delay, or inhibit normal wound healing, has introduced considerable new challenges into the wound management scenario. Researchers in academia have quickly identified promising solutions, and many advanced wound healing materials have recently been designed; however, their successful translation to the market remains highly complex and unlikely without the contribution of industry experts. This review article condenses the main aspects of wound healing applications that will serve as a practical guide for researchers working in academia and industry devoted to designing, evaluating, validating, and translating polymer wound care materials to the market. The article highlights the current challenges in wound management, describes the state-of-the-art products already on the market and trending polymer materials, describes the regulation pathways for approval, discusses current wound healing models, and offers a perspective on new technologies that could soon reach consumers. We envision that this comprehensive review will significantly contribute to highlighting the importance of networking and exchanges between academia and healthcare companies. Only through the joint of these two actors, where innovation, manufacturing, regulatory insights, and financial resources act in harmony, can wound care products be developed efficiently to reach patients quickly and affordably.

Leveraging novel innovative thermoresponsive polymers in microneedles for targeted intradermal deposition.

Microneedles have garnered considerable attention over the years as a versatile pharmaceutical platform that could be leveraged to deliver drugs into and across the skin. In the current work, poly (N-isopropylacrylamide) (PNIPAm) is synthesized and characterized as a novel material for the development of a physiologically responsive microneedle-based drug delivery system. Typically, this polymer transitions reversibly between a swell state at lower temperatures and a more hydrophobic state at higher temperatures, enabling precise drug release. This study demonstrates that dissolving microneedles patches made from PNIPAm, incorporating BIS-PNIPAm, a crosslinked polymer variant, exhibit enhanced mechanical properties, evident from a smaller height reduction in microneedle (∼10 %). Although microneedles using PNIPAm alone were achievable, it displayed poor mechanical strength, requiring the inclusion of additional polymeric excipients like PVA to enhance mechanical properties. In addition, the incorporation of a thermoresponsive polymer did not have a significant (p > 0.05) impact on the insertion properties of the needles as all formulations inserted to a similar depth of 500 µm into ex vivo skin. Furthering this, the needles were loaded with a model payload, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate (DID) and the deposition of the cargo was monitored via multiphoton microscopy that showed that a deposit is formed at a depth of ≈200 µm. Also, it was revealed that crosslinked-PNIPAm (Bis-PNIPAm) formulations exhibited notable skin accumulationof the dye only after 4 h, independent of the excipient matrix used. This phenomenon was absent in non-crosslinked PNIPAm formulations, indicating a deposit formation in Bis-PNIPAm microneedle formulation. Collectively, this proof-of-concept study has advanced our understanding on the possibility to use PNIPAm for dissolving microneedle fabrication which could be harnessed for the deposition of nanoparticles into the dermis, for extended drug release within the skin.

Nano-in-nano enteric protein delivery system: coaxial Eudragit® L100-55 fibers containing poly(N-vinylcaprolactam) nanogels.

Oral protein delivery holds significant promise as an effective therapeutic strategy for treating a wide range of diseases. However, effective absorption of proteins faces challenges due to biological barriers such as harsh conditions of the stomach and the low permeability of mucous membranes. To address these challenges, this article presents a novel nano-in-nano platform designed for enteric protein delivery. This platform, obtained by electrospinning, involves a coaxial arrangement comprising poly(N-vinylcaprolactam) nanogels (NGs) enclosed within nanofibers of Eudragit® L100-55 (EU), a pH-responsive polymer. The pH-selective solubility of EU ensures the protection of NGs during their passage through the stomach, where the fibers remain intact at low pH, and releases them in the intestine where EU dissolves. The switchable characteristic of this nano-in-nano platform is confirmed by using NGs loaded with a model protein (ovalbumin), which is selectively released when the intestinal pH is achieved. The versatility of this nano-in-nano delivery platform is demonstrated by the ability to modify the fibers dissolution profile simply by adjusting the concentration of EU used in the electrospinning process. Furthermore, by tuning the properties of NGs, the potential applications of this platform can be further extended, paving the way for diverse therapeutic possibilities.

Antibiotic prophylaxis in flexible ureterorenoscopy with negative urine culture.

Objective: To improve susceptibility profiles of nosocomial bacteria, identifying the difference between infectious complications in patients undergoing endoscopic flexible ureterolithotomy (fURS) with negative urine culture (UC) that received extended antibiotic prophylaxis (EP) compared with standard antibiotic prophylaxis (SP). Methodology: This is a retrospective, observational, analytical cohort study, comparing infectious complications between patients undergoing fURS with negative UC who received EP versus SP. We include patients with susccessfull fURS, <20-mm stones and complete information. Results: Overall, 10.3% of patients had complications, 7.2% of patients had postoperative urinary infection, 1.8% had upper urinary tract infection (UTI) and 1.4% had urinary sepsis. Lower UTI were significantly more likely in the extended prophylaxis group with 6.8% versus 2.7% (RR = 2.8; 95% CI: 1.10-7.37, p = 0.030). The risk of upper UTI and sepsis did not show significant differences. A total of 69% patients with postoperative infection had isolated multidrug-resistant bacteria (MDRB) in the UC, with a higher risk in patients with extended prophylaxis (RR = 3.1; 95% CI: 1.33-7.59, p = 0.009). Conclusions: Patients with negative UC who underwent fURS using extended prophylaxis have two times higher risk of low UTI than patients with standard prophylaxis, without differences in the incidence of upper UTI or urinary sepsis. The risk of MDRB isolation in the postoperative UC is higher in the extended prophylaxis group, therefore we recommend the standard 60-min preoperative prophylaxis.

The role of Eudragit® as a component of hydrogel formulations for medical devices.

Over the last decade, significant progress has been made in developing hydrogels as medical devices. By physically cross-linking pharmaceutically approved polymers into three-dimensional matrices, we can ensure their biocompatibility and facilitate their seamless transition from the laboratory to clinical applications. Moreover, the reversible nature of their physical cross-links allows hydrogels to dissolve in the presence of external stimuli. Particularly, their high degree of hydration, high molecular weight, and superior flexibility of the polymer chains facilitate their interaction with complex biological barriers (e.g., mucus layer), making them ideal candidates for mucosal drug delivery. However, fine-tuning the composition of the hydrogel formulations is of great importance to optimize the performance of the medical device and its therapeutic cargo. Herein, we investigated the influence of different Eudragits® on the properties of hydrogels based on polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and polyethylene glycol (PEG), which were originally proposed as ocular inserts in previous reports. Our research aims to determine the effects that including different Eudragits® have on the structure and protein ocular delivery ability of various hydrogel formulations. Properties such as matrix stability, protein encapsulation, release kinetics, mucoadhesion, and biocompatibility have been analyzed in detail. Our study represents a guideline of the features that Eudragits® have to exhibit to endow hydrogels with good adhesion to the eye's conjunctiva, biocompatibility, and structural strength to cope with the ocular biointerface and allow sustained protein release. This work has important implications for the design of new hydrogel materials containing Eudragits® in their composition, particularly in mucosal drug delivery.

Polymer Colloids: Current Challenges, Emerging Applications, and New Developments.

Polymer colloids are complex materials that have the potential to be used in a vast array of applications. One of the main reasons for their continued growth in commercial use is the water-based emulsion polymerization process through which they are generally synthesized. This technique is not only highly efficient from an industrial point of view but also extremely versatile and permits the large-scale production of colloidal particles with controllable properties. In this perspective, we seek to highlight the central challenges in the synthesis and use of polymer colloids, with respect to both existing and emerging applications. We first address the challenges in the current production and application of polymer colloids, with a particular focus on the transition toward sustainable feedstocks and reduced environmental impact in their primary commercial applications. Later, we highlight the features that allow novel polymer colloids to be designed and applied in emerging application areas. Finally, we present recent approaches that have used the unique colloidal nature in unconventional processing techniques.

Bioadhesive eutectogels supporting drug nanocrystals for long-acting delivery to mucosal tissues.

Eutectogels (Egels) are an emerging class of soft ionic materials outperforming traditional temperature-intolerant hydrogels and costly ionogels. Due to their excellent elasticity, non-volatile nature, and adhesion properties, Egels are attracting a great deal of interest in the biomedical space. Herein, we report the first example of adhesive Egels loading drug nanocrystals (Egel-NCs) for controlled delivery to mucosal tissues. These soft materials were prepared using gelatin, glycerine, a deep eutectic solvent (DES) based on choline hydrochloride and glycerol, and nanocrystallised curcumin, a model drug with potent antimicrobial and anti-inflammatory activities. We first explored the impact of the biopolymer concentration on the viscoelastic and mechanical properties of the networks. Thanks to the dynamic interactions between gelatin and the DES, the Egel showed excellent stretchability and elasticity (up to ≈160%), reversible gel-sol phase transition at mild temperature (≈50 â€‹°C), 3D-printing ability, and good adhesion to mucin protein (stickiness ≈40 â€‹kPa). In vitro release profiles demonstrated the ability of the NCs-based Egel to deliver curcumin for up to four weeks and deposit significantly higher drug amounts in excised porcine mucosa compared to the control cohort. All in all, this study opens new prospects in designing soft adhesive materials for long-acting drug delivery and paves the way to explore novel eutectic systems with multiple therapeutic applications.

A hybrid thermoresponsive plasmonic nanogel designed for NIR-mediated chemotherapy.

Temperature-trigger chemotherapy is one of the state-of-the-art anti-tumoral strategies in nanomedicine. However, this strategy is in close relationship with the effect of the temperature in the tumor tissue. With high temperatures, the ablation of the tumor tissue can hinder a correct chemotherapy approximation. On the other hand, with moderate temperatures a negative vascularization that promotes the tumor growing is produced and competes with the chemotherapeutic effects. We have constructed one nanogel system composed of a thermoresponsive polymer cross-linked by plasmonic gold nanoparticles (AuNPs) for temperature-trigger chemotherapy. Doxorubicin loaded in the porous interior of the nanogel is released when the thermoresponsive network of the nanogel collapses due to the heat generated by the AuNPs upon near infra-red light irradiation. The hybrid nanogel system has been tested in vitro and in vivo, where it was observed that the temperatures reached in the in vivo NIR irradiation have an undesired effect on the inhibition of the tumor growth while the drug loaded systems considerably reduced the tumor sizes. This study shows the importance of design in temperature triggered antitumoral systems, where lower temperatures usually reached in practical situations due to light attenuation produced by the tissue can be positively utilized for enhancing the antitumoral effect of loaded drugs in the system.

One stone, many birds: Recent advances in functional nanogels for cancer nanotheranostics.

Inspired by the development of nanomedicine and nanotechnology, more and more possibilities in cancer theranostic have been provided in the last few years. Emerging therapeutic modalities like starvation therapy, chemodynamic therapy, and tumor oxygenation have been integrated with diagnosis, giving a plethora of theranostic nanoagents. Among all of them, nanogels (NGs) show superiority benefiting from their unique attributes: high stability, high water-absorption, large specific surface area, mechanical strength, controlled responsiveness, and high encapsulation capacity. There have been a vast number of investigations supporting various NGs combining drug delivery and multiple bioimaging techniques, encompassing photothermal imaging, photoacoustic imaging, fluorescent imaging, ultrasound imaging, magnetic resonance imaging, and computed tomography. This review summarizes recent advances in functional NGs for theranostic nanomedicine and discusses the challenges and future perspectives of this fast-growing field. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

Nanocarriers for Skin Applications: Where Do We Stand?

Skin penetration of active molecules for treatment of diverse diseases is a major field of research owing to the advantages associated with the skin like easy accessibility, reduced systemic-derived side effects, and increased therapeutic efficacy. Despite these advantages, dermal drug delivery is generally challenging due to the low skin permeability of therapeutics. Although various methods have been developed to improve skin penetration and permeation of therapeutics, they are usually aggressive and could lead to irreversible damage to the stratum corneum. Nanosized carrier systems represent an alternative approach for current technologies, with minimal damage to the natural barrier function of skin. In this Review, the use of nanoparticles to deliver drug molecules, genetic material, and vaccines into the skin is discussed. In addition, nanotoxicology studies and the recent clinical development of nanoparticles are highlighted to shed light on their potential to undergo market translation.

The Delivery Challenge of Genome Editing in Human Epithelia.

Despite exciting advances in gene editing, their clinical translation is still hampered by the lack of delivery systems that can encapsulate and deliver gene editing tools like CRISPR-Cas9 or prime editors to the target side. This is particularly challenging in human epithelia, such as the skin and the lung; the latter of which being a mucosal surface that is covered by a mucus layer. In this perspective, the design and biological assessment of delivery systems for gene editing tools like CRISPR in skin and mucosal surfaces are discussed. The current state-of-the-art, current knowledge, and translational gaps, and guide toward improved translation are highlighted.

SANDBLASTING INFLUENCE ON BOND STRENGTH OF CoCr ALLOY AND ONE ADHESIVE 10 MDP BASED / INFLUENCIA DEL ARENADO EN LA RESISTENCIA DE UNIÓN DE UNA ALEACIÓN DE CoCr Y UN ADHESIVO A BASE DE 10 MDP

Traditionally, fixed prostheses based on base metal alloys were retained on their abutments with powder-liquid cement (zinc phosphate, polycarboxylate, glass ionomer). Currently, with the development of CAD-CAM, there is a tendency to make conservative dental preparations. Undoubtedly it is a very good technique, concerning healthy dental tissue. But the resulting restorations would already need cement and adhesives that capable of chemically bonding to the different substrates, so as not to peel off. Manufacturers indicate that molecules such as 10 MDP, VBDATDT, 4-META can bind to metals. METHOD. 30 CoCr cylinders were divided into 3 groups. With the first, sandblasting was carried out and an adhesive agent based on 10 MDP was immediately placed to cement 4 resin microtubes using a resinous cement. The remaining groups were sandblasted in the same way, but in them, it was decided to wait for 24 and 48 hours to perform the adhesive procedure. RESULTS. The immediate group reached the highest values of bond strength. When more time was waited after sandblasting, the lowest values were obtained, even after aging. CONCLUSIONS. CoCr alloys can be cemented with resinous cement, as long as a correct mechanical and chemical surface treatment is carried out.

Tradicionalmente las prótesis fijas a base de aleaciones de metal base se retenían sobre sus pilares con cementos polvo-líquido (fosfato de zinc, policarboxilato, ionómero de vidrio). Actualmente con el desarrollo del CAD CAM, existe la tendencia a realizar preparaciones dentales conservadoras. Indudablemente es una muy buena técnica, por el respeto del tejido dental sano. Pero las restauraciones resultantes ya necesitarían de cementos y adhesivos que sean capaces de adherirse químicamente a los diferentes sustratos, para no despegarse. Fabricantes indican que, moléculas como el 10 MDP, el VBDATDT, 4-META pueden unirse a los metales. MÉTODO. 30 cilindros de CoCr fueron divididos en 3 grupos. Con el primero, se procedió a arenar e inmediatamente se colocó un agente adhesivo a base de 10 MDP para cementar 4 microtubos de resina por medio de un cemento resinoso. Con los grupos restantes de igual manera se arenó, pero en ellos se decidió esperar 24 y 48 horas para realizar el procedimiento adhesivo. RESULTADOS. El grupo inmediato alcanzó los mas altos valores de resistencia de unión. Cuando se esperó mas tiempo después de arenar se obtuvieron los más bajos valores, incluso después de envejecidos. CONCLUSIONES. Las aleaciones de CoCr pueden ser cementadas con cementos resinosos, siempre y cuando se realice un correcto tratamiento mecánico y químico de su superficie.

Exploiting cyanine dye J-aggregates/monomer equilibrium in hydrophobic protein pockets for efficient multi-step phototherapy: an innovative concept for smart nanotheranostics.

After several decades of development in the field of near-infrared (NIR) dyes for photothermal therapy (PTT), indocyanine green (ICG) still remains the only FDA-approved NIR contrast agent. However, upon NIR light irradiation ICG can react with molecular oxygen to form reactive oxygen species and degrade the ICG core, losing the convenient dye properties. In this work, we introduce a new approach for expanding the application of ICG in nanotheranostics, which relies on the confinement of self-organized J-type aggregates in hydrophobic protein domains acting as monomer depots. Upon the fast photobleaching, while the dye is irradiated, this strategy permits the equilibrium-driven monomer replacement after each irradiation cycle that radically increases the systems' effectivity and applicability. Gadolinium-doped casein micelles were designed to prove this novel concept at the same time as endowing the nanosystems with further magnetic resonance imaging (MRI) ability for dual-modal imaging-guided PTT. By teaching a new trick to a very old dog, the clinical prospect of ICG will undoubtedly be boosted laying the foundation for novel therapeutics. It is anticipated that future research could be expanded to other relevant J-aggregates-forming cyanine dyes or nanocrystal formulations of poorly water-soluble photosensitizers.

Smart Layer-by-Layer Polymeric Microreactors: pH-Triggered Drug Release and Attenuation of Cellular Oxidative Stress as Prospective Combination Therapy.

Polymer capsules fabricated via the layer-by-layer (LbL) approach have emerged as promising biomedical systems for the release of a wide variety of therapeutic agents, owing to their tunable and controllable structure and the possibility to include several functionalities in the polymeric membrane during the fabrication process. However, the limitation of the capsules with a single functionality to overcome the challenges involved in the treatment of complex pathologies denotes the need to develop multifunctional capsules capable of targeting several mediators and/or mechanisms. Oxidative stress is caused by the accumulation of reactive oxygen species [e.g., hydrogen peroxide (H2O2), hydroxyl radicals (•OH), and superoxide anion radicals (•O2-)] in the cellular microenvironment and is a key modulator in the pathology of a broad range of inflammatory diseases. The disease microenvironment is also characterized by the presence of proinflammatory cytokines, increased levels of matrix metalloproteinases, and acidic pH, all of which could be exploited to trigger the release of therapeutic agents. In the present work, multifunctional capsules were fabricated via the LbL approach. Capsules were loaded with an antioxidant enzyme (catalase) and functionalized with a model drug (doxorubicin), which was conjugated to an amine-containing dendritic polyglycerol through a pH-responsive linker. These capsules efficiently scavenge H2O2 from solution, protecting cells from oxidative stress, and release the model drug in acidic microenvironments. Accordingly, in this work, a polymeric microplatform is presented as an unexplored combinatorial approach applicable for multiple targets of inflammatory diseases, in order to perform controlled spatiotemporal enzymatic reactions and drug release in response to biologically relevant stimuli.

Design and Testing of Efficient Mucus-Penetrating Nanogels-Pitfalls of Preclinical Testing and Lessons Learned.

Mucosal surfaces pose a challenging environment for efficient drug delivery. Various delivery strategies such as nanoparticles have been employed so far; yet, still yielding limited success. To address the need of efficient transmucosal drug delivery, this report presents the synthesis of novel disulfide-containing dendritic polyglycerol (dPG)-based nanogels and their preclinical testing. A bifunctional disulfide-containing linker is coupled to dPG to act as a macromolecular crosslinker for poly-N-isopropylacrylamide (PNIPAM) and poly-N-isopropylmethacrylamide (PNIPMAM) in a precipitation polymerization process. A systematic analysis of the polymerization reveals the importance of a careful polymer choice to yield mucus-degradable nanogels with diameters between 100 and 200 nm, low polydispersity, and intact disulfide linkers. Absorption studies in porcine intestinal tissue and human bronchial epithelial models demonstrate that disulfide-containing nanogels are highly efficient in overcoming mucosal barriers. The nanogels efficiently degrade and deliver the anti-inflammatory biomacromolecule etanercept into epithelial tissues yielding local anti-inflammatory effects. Over the course of this work, several problems are encountered due to a limited availability of valid test systems for mucosal drug-delivery systems. Hence, this study also emphasizes how critical a combined and multifaceted approach is for the preclinical testing of mucosal drug-delivery systems, discusses potential pitfalls, and provides suggestions for solutions.

A Dual Fluorescence-Spin Label Probe for Visualization and Quantification of Target Molecules in Tissue by Multiplexed FLIM-EPR Spectroscopy.

Simultaneous visualization and concentration quantification of molecules in biological tissue is an important though challenging goal. The advantages of fluorescence lifetime imaging microscopy (FLIM) for visualization, and electron paramagnetic resonance (EPR) spectroscopy for quantification are complementary. Their combination in a multiplexed approach promises a successful but ambitious strategy because of spin label-mediated fluorescence quenching. Here, we solved this problem and present the molecular design of a dual label (DL) compound comprising a highly fluorescent dye together with an EPR spin probe, which also renders the fluorescence lifetime to be concentration sensitive. The DL can easily be coupled to the biomolecule of choice, enabling in vivo and in vitro applications. This novel approach paves the way for elegant studies ranging from fundamental biological investigations to preclinical drug research, as shown in proof-of-principle penetration experiments in human skin ex vivo.