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Abstract TRPV6 calcium channel is a prospective target in prostate cancer (PCa) since it is not expressed in healthy prostate while its expression increases during cancer progression. Despite the role of TRPV6 in PCa cell survival and apoptotic resistance has been already established, no reliable tool to target TRPV6 channel in vivo and thus to reduce tumor burden is known to date. Here we report the generation of mouse monoclonal antibody mAb82 raised against extracellular epitope of the pore region of the channel. mAb82 inhibited TRPV6 currents by 90% at 24 µg/ml in a dose-dependent manner while decreasing store-operated calcium entry to 56% at only 2.4 µg/ml. mAb82 decreased PCa survival rate in vitro by 71% at 12 µg/ml via inducing cell death through the apoptosis cascade via activation of the protease calpain, following bax activation, mitochondria enlargement, and loss of cristae, Cyt C release, pro-caspase 9 cleavage with the subsequent activation of caspases 3/7. In vivo, mice bearing either PC3M trpv6+/+ or PC3M trpv6-/- +pTRPV6 tumors were successfully treated with mAb82 at the dose as low as 100 µg/kg resulting in a significant reduction tumor growth by 31% and 90%, respectively. The survival rate was markedly improved by 3.5 times in mice treated with mAb82 in PC3M trpv6+/+ tumor group and completely restored in PC3M trpv6-/- +pTRPV6 tumor group. mAb82 showed a TRPV6-expression dependent organ distribution and virtually no toxicity in the same way as mAbAU1, a control antibody of the same Ig2a isotype. Overall, our data demonstrate for the first time the use of an anti-TRPV6 monoclonal antibody in vitro and in vivo in the treatment of the TRPV6-expressing PCa tumors.

The slow healing process of diabetic wound due to persisting infections in wound bed, owing to hyperglycemia, makes the search for efficient treatments pending. While it is complicated to increase the wound closure rate in diabetic‐related wounds due to the complex pathology, the treatment of such wound with hydrogels is seen as a promising approach and pursued over the years. However, where is this research currently standing in terms of clinical translation of these different multifunctional and stimuli‐responsive hydrogel bandages to accelerate diabetic foot ulcer healing and help to improve the life of the patients and the future of diabetic wound management? This perspective article will review some of the most important advancements in the field and will conclude with some perspectives, considered as relevant in the clinical context.

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Abstract Impaired wound healing is a significant complication of diabetes. Platelet-derived extracellular vesicles (pEVs), rich in growth factors and cytokines, show promise as a powerful biotherapy to modulate cellular proliferation, angiogenesis, immunomodulation, and inflammation. For practical home-based wound therapy, however, pEVs should be incorporated into wound bandages with careful attention to delivery strategies. In this work, a gelatin-alginate hydrogel (GelAlg) loaded with reduced graphene oxide (rGO) was fabricated, and its potential as a diabetic wound dressing was investigated. The GelAlg@rGO-pEV gel exhibited excellent mechanical stability and biocompatibility in vitro, with promising macrophage polarization and reactive oxygen species (ROS)-scavenging capability. In vitro cell migration experiments were complemented by in vivo investigations using a streptozotocin-induced diabetic rat wound model. When exposed to near-infrared light at 2 W cm− 2, the GelAlg@rGO-pEV hydrogel effectively decreased the expression of inflammatory biomarkers, regulated immune response, promoted angiogenesis, and enhanced diabetic wound healing. Interestingly, the GelAlg@rGO-pEV hydrogel also increased the expression of heat shock proteins involved in cellular protective pathways. These findings suggest that the engineered GelAlg@rGO-pEV hydrogel has the potential to serve as a wound dressing that can modulate immune responses, inflammation, angiogenesis, and follicle regeneration in diabetic wounds, potentially leading to accelerated healing of chronic wounds.

Pagneux et al. developed a nanobody-functionalized electrochemical platform with smartphone readout to detect SARS-CoV-2 in clinical samples. They demonstrated that their device can rapidly and accurately detect SARS-CoV-2 in saliva and nasopharyngeal swab samples and discriminate between this virus and other respiratory viruses.

Wound dressings based on graphene sheets are expected to play a crucial role in wound treatment. The good conductivity and charge mobility of graphene as an electronic material makes graphene-based field effect transistors well-adapted for sensing of wound biomarkers. In this work, an aptamer-based field effect transistor using graphene as sensing channel material was developed and evaluated for the selective and sensitive monitoring of matrix metalloproteinase 9 (MMP-9), a wound biomarker upregulated in non-healing wounds. Concentration-dependent measurements performed with wound fluid spiked with MMP-9 on GFET-MMP/PEG sensors exhibited real-time detection of MMP-9 with a detection limit of 97 pM in 1x MOPS/1 mM CaCl2. The sensor was tested on swab samples from non-healing wounds and compared to results of antibody-based ELISA analysis. In contrast to ELISA, the GFET sensor was only sensing the active MMP-9 form and not the mixture of active and inactive forms, as evidenced by the analysis performed in the presence of EDTA as inactivation medium.

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miRNAs, small non-coding RNAs that regulate gene expression, are involved in various pathological processes, including viral infections. Virus infections may interfere with the miRNA pathway through the inhibition of genes involved in miRNA biogenesis. A reduction in the number and the levels of miRNAs expressed in nasopharyngeal swabs of patients with severe COVID-19 was lately observed by us, pointing towards the potential of miRNAs as possible diagnostic or prognostic biomarkers for predicting outcomes among patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The objective of the present study was to investigate whether SARS-CoV-2 infection influences the expression levels of messenger RNAs (mRNAs) of key genes involved in miRNA biogenesis. mRNA levels of AGO2, DICER1, DGCR8, DROSHA, and Exportin-5 (XPO5) were measured by quantitative reverse-transcription polymerase chain reaction (RT-qPCR) in nasopharyngeal swab specimens from patients with COVID-19 and controls, as well as in cells infected with SARS-CoV-2 in vitro. Our data showed that the mRNA expression levels of AGO2, DICER1, DGCR8, DROSHA, and XPO5 were not significantly different in patients with severe COVID-19 when compared to patients with non-severe COVID-19 and controls. Similarly, the mRNA expression of these genes was not affected by SARS-CoV-2 infection in NHBE and Calu-3 cells. However, in Vero E6 cells, AGO2, DICER1, DGCR8, and XPO5 mRNA levels were slightly upregulated 24 h after infection with SARS-CoV-2. In conclusion, we did not find evidence for downregulation of mRNA levels of miRNA biogenesis genes during SARS-CoV-2 infection, neither ex vivo nor in vitro.

Diabetes poses major economic, social, and public health challenges in all countries worldwide. Besides cardiovascular disease and microangiopathy, diabetes is a leading cause of foot ulcers and lower limb amputations. With the continued rise of diabetes prevalence, it is expected that the future burden of diabetes complications, early mortality, and disabilities will increase. The diabetes epidemic is partly caused by the current lack of clinical imaging diagnostic tools, the timely monitoring of insulin secretion and insulin-expressing cell mass (beta (β)-cells), and the lack of patients’ adherence to treatment, because some drugs are not tolerated or invasively administrated. In addition to this, there is a lack of efficient topical treatment capable of stopping the progression of disabilities, in particular for treating foot ulcers. In this context, polymer-based nanostructures garnered significant interest due to their tunable physicochemical characteristics, rich diversity, and biocompatibility. This review article emphasizes the last advances and discusses the prospects in the use of polymeric materials as nanocarriers for β-cell imaging and non-invasive drug delivery of insulin and antidiabetic drugs in the management of blood glucose and foot ulcers.

Improvement of insulin secretion by pancreatic β-cells and preservation of their mass are the current challenges that future antidiabetic drugs should meet for achieving efficient and long-term glycemic control in patients with type 2 diabetes (T2D). The successful development of glucagon-like peptide 1 (GLP-1) analogues, derived from the saliva of a lizard from the Helodermatidae family, has provided the proof of concept that antidiabetic drugs directly targeting pancreatic β-cells can emerge from venomous animals. The literature reporting on the antidiabetic effects of medicinal plants suggests that they contain some promising active substances such as polyphenols and alkaloids, which could be active as insulin secretagogues and β-cell protectors. In this review, we discuss the potential of several polyphenols, alkaloids and venom peptides from snake, frogs, scorpions and cone snails. These molecules could contribute to the development of new efficient antidiabetic medicines targeting β-cells, which would tackle the progression of the disease.

Radiotherapy and chemotherapy are the standard interventions for cancer patients, although cancer cells often develop radio- and/or chemoresistance. Hyperthermia reduces tumor resistance and induces immune responses resulting in a better prognosis. We have previously described a method to induce tumor cell death by local hyperthermia employing pegylated reduced graphene oxide nanosheets and near infrared light (graphene-induced hyperthermia, GIHT). The spatiotemporal exposure/release of heat shock proteins (HSP), high group mobility box 1 protein (HMGB1), and adenosine triphosphate (ATP) are reported key inducers of immunogenic cell death (ICD). We hypothesize that GIHT decisively contributes to induce ICD in irradiated melanoma B16F10 cells, especially in combination with radiotherapy. Therefore, we investigated the immunogenicity of GIHT alone or in combination with radiotherapy in melanoma B16F10 cells. Tumor cell death in vitro revealed features of apoptosis that is progressing fast into secondary necrosis. Both HSP70 and HMGB1/DNA complexes were detected 18 hours post GIHT treatment, whereas the simultaneous release of ATP and HMGB1/DNA was observed only 24 hours post combined treatment. We further confirmed the adjuvant potential of these released DAMPs by immunization/challenge experiments. The inoculation of supernatants of cells exposed to sole GIHT resulted in tumor growth at the site of inoculation. The immunization with cells exposed to sole radiotherapy rather fostered the growth of secondary tumors in vivo. Contrarily, a discreet reduction of secondary tumor volumes was observed in mice immunized with a single dose of cells and supernatants treated with the combination of GIHT and irradiation. We propose the simultaneous release of several DAMPs as a potential mechanism fostering anti-tumor immunity against previously irradiated cancer cells.

The ongoing highly contagious Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), underlines the fundamental position of diagnostic testing in outbreak control by allowing a distinction of the infected from the non-infected people. Diagnosis of COVID-19 remains largely based on reverse transcription PCR (RT-PCR), identifying the genetic material of the virus. Molecular testing approaches have been largely proposed in addition to infectivity testing of patients via sensing the presence of viral particles of SARS-CoV-2 specific structural proteins, such as the spike glycoproteins (S1, S2) and the nucleocapsid (N) protein. While the S1 protein remains the main target for neutralizing antibody treatment upon infection and the focus of vaccine and therapeutic design, it has also become a major target for the development of point-of care testing (POCT) devices. This review will focus on the possibility of surface plasmon resonance (SPR)-based sensing platforms to convert the receptor-binding event of SARS-CoV-2 viral particles into measurable signals. The state-of-the-art SPR-based SARS-CoV-2 sensing devices will be provided, and highlights about the applicability of plasmonic sensors as POCT for virus particle as well as viral protein sensing will be discussed.

Photoreduction of hexavalent chromium, Cr(VI), identified as carcinogenic and mutagenic element, to Cr(III), believed to be an essential element, using copper sulfide nanostructures (CuS NSs) as photocatalyst was investigated under visible light irradiation (λ > 420 nm). The CuS NSs were synthesized at low temperature using a wet chemical route and fully characterized using various techniques such as scanning electron microscopy, transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, Raman spectroscopy and UV–vis spectrophotometry. The photocatalytic reduction of Cr(VI) using visible light irradiation was assessed by UV–vis by following the decrease of the characteristic absorbance at ∼352 nm in the presence of CuS NSs. While CuS NSs promoted Cr(VI) full reduction within 60 min, addition of adipic acid or formic acid accelerated significantly the photocatalytic reduction process. Under optimized conditions, CuS NSs rapidly (12 min) reduced Cr(VI) in presence of 0.5 mM adipic acid. Similarly, Cu NSs were found to be efficient for Cr(VI) reduction dissolved in water from a local lake. Stability studies showed that the photocatalyst could be recycled up to four times without any apparent decrease of its catalytic performance. Keywords: CuS nanostructures, Cr(VI), Photoreduction, Visible light, Lake water

Healthcare is undergoing large transformations, and it is imperative to leverage new technologies to support the advent of personalized medicine and disease prevention. It is now well accepted that the levels of certain biological molecules found in blood and other bodily fluids, as well as in exhaled breath, are an indication of the onset of many human diseases and reflect the health status of the person. Blood, urine, sweat, or saliva biomarkers can therefore serve in early diagnosis of diseases such as cancer, but also in monitoring disease progression, detecting metabolic disfunctions, and predicting response to a given therapy. For most point-of-care sensors, the requirement that patients themselves can use and apply them is crucial not only regarding the diagnostic part, but also at the sample collection level. This has stimulated the development of such diagnostic approaches for the non-invasive analysis of disease-relevant analytes. Considering these timely efforts, this review article focuses on novel, sensitive, and selective sensing systems for the detection of different endogenous target biomarkers in bodily fluids as well as in exhaled breath, which are associated with human diseases.

Abstract Background Enterococcus faecalis, generally considered as a saprophytic bowel commensal, has recently emerged as an important nosocomial pathogen causing severe urinary tract infections, surgical wound infections, bacteremia, and bacterial endocarditis. This bacterium is capable of forming biofilms on various surfaces and its high level of antibiotic resistance contributes to its pathogenicity. The aim of this study was to evaluate the effect on E. faecalis, of Substance P (SP), an antimicrobial peptide that is produced in the gut and skin. Results We found that SP did not have antibacterial activity against E. faecalis V583 (MIC >1000 µg/ml). Conversely, SP stimulated aggregation, hydrophobicity, lactic acid and tyramine production in this bacterium. The cytotoxicity and bacterial translocation were also accelerated when E. faecalis V583 were pretreated with SP before infection of intestinal Caco-2/TC7 cells. Conclusion SP can modulate the physiology of E. faecalis. Extensive studies are now needed to screen within the human microbiota which bacteria are responsive to host molecules, and to identify their sensors.

The synthesis of multifunctional photothermal nanoagents for antibiotic loading and release remains a challenging task in nanomedicine. Herein, we investigated a simple, low-cost strategy for the preparation of CuS-BSA nanoparticles (NPs) loaded with a natural enzyme, lysozyme, as an antibacterial drug model under physiological conditions. The successful development of CuS-BSA NPs was confirmed by various characterization tools such as transmission electron microscopy (TEM), X-ray diffraction (XRD), Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS). Lysozyme loading onto CuS-BSA NPs was evaluated by UV/vis absorption spectroscopy, Fourier-transform infrared spectroscopy (FTIR), zeta potential, and dynamic light scattering measurements. The CuS-BSA/lysozyme nanocomposite was investigated as an effective means for bacterial elimination of B. subtilis (Gram-positive) and E. coli (Gram-negative), owing to the combined photothermal heating performance of CuS-BSA and lysozyme release under 980 nm (0.7 W cm−2) illumination, which enhances the antibiotic action of the enzyme. Besides the photothermal properties, CuS-BSA/lysozyme nanocomposite possesses photodynamic activity induced by NIR illumination, which further improves its bacterial killing efficiency. The biocompatibility of CuS-BSA and CuS-BSA/Lysozyme was elicited in vitro on HeLa and U-87 MG cancer cell lines, and immortalized human hepatocyte (IHH) cell line. Considering these advantages, CuS-BSA NPs can be used as a suitable drug carrier and hold promise to overcome the limitations of traditional antibiotic therapy.

Vaccination remains one of the most effective tools to prevent infectious diseases. To ensure that the best possible antigenic components are chosen to stimulate a cognitive immune response, boosting antigen presentation using adjuvants is common practice. Nanodiamond-based adjuvants are proposed here as a rapid and versatile platform for antigen conjugation, utilizing peptides common to different pathogenic strains and making this strategy a good candidate for a “ready-to-use” vaccine. Initiation of an inflammatory reaction with a resulting immune response is based on the ability of living organisms to entrap nanostructures such as nanodiamonds with neutrophil extracellular traps (NETs) formation. In this work, coronavirus peptide homological for MERS-CoV, fusion inhibitor, was conjugated to nanodiamonds and used to induce neutrophilic-driven self-limiting inflammation. The resulting adjuvant was safe and did not induce any tissue damage at the site of injection. Mice immunization resulted in IgG titers of ¼,000 within 28 days. Immunization of rabbits resulted in the formation of a high level of antibodies persistently present for up to 120 days after the first immunization (animal lifespan ~3 years). The peptide used for immunization proved to be reactive with sera of convalescent COVID patients, demonstrating the possibility of developing pancoronaviral vaccine candidates.

The eradication of viral infections is an ongoing challenge in the medical field, as currently evidenced with the newly emerged Coronavirus disease 2019 (COVID-19) associated with severe respiratory distress. As treatments are often not available, early detection of an eventual infection and its level becomes of outmost importance. Nanomaterials and nanotechnological approaches are increasingly used in the field of viral sensing to address issues related to signal-to-noise ratio, limiting the sensitivity of the sensor. Superparamagnetic nanoparticles (MPs) present one of the most exciting prospects for magnetic bead-based viral aggregation assays and their integration into different biosensing strategies as they can be easily separated from a complex matrix containing the virus through the application of an external magnetic field. Despite the enormous potential of MPs as capture/pre-concentrating elements, they are not ideal with regard of being active elements in sensing applications as they are not the sensor element itself. Even though engineering of magneto-plasmonic nanostructures as promising hybrid materials directly applicable for sensing due to their plasmonic properties are often used in sensing, to our surprise, the literature of magneto-plasmonic nanostructures for viral sensing is limited to some examples. Considering the wide interest this topic is evoking at present, the different approaches will be discussed in more detail and put into wider perspectives for sensing of viral disease markers.

Background: The main goals of cancer treatment are not only to eradicate the tumor itself but also to elicit a specific immune response that overcomes the resistance of tumor cells against chemo- and radiotherapies. Hyperthermia was demonstrated to chemo- and radio-sensitize cancerous cells. Many reports have confirmed the immunostimulatory effect of such multi-modal routines. Methods: We evaluated the interaction of graphene oxide (GO) nanosheets; its derivatives reduced GO and PEGylated rGO, with components of peripheral blood and evaluated its thermal conductivity to induce cell death by localized hyperthermia. Results: We confirmed the sterility and biocompatibility of the graphene nanomaterials and demonstrated that hyperthermia applied alone or in the combination with radiotherapy induced much more cell death in tumor cells than irradiation alone. Cell death was confirmed by the release of lactate dehydrogenase from dead and dying tumor cells. Conclusion: Biocompatible GO and its derivatives can be successfully used in graphene-induced hyperthermia to elicit tumor cell death.

Pediococcus pentosaceus MZF16 has been isolated from artisanal Tunisian meat so called “Dried Ossban,” an original ecological niche, and identified by MALDI-TOF mass spectrometry and 16S rDNA sequencing. This bacterium showed a high tolerance to gastric stress conditions, and toward bile salts. P. pentosaceus MZF16 also demonstrated a hydrophobic surface profile (high adhesion to xylene), autoaggregation, and adhesive abilities to the human intestinal Caco-2/TC7 cell line. These properties may help the bacterium colonizing the gut. Furthermore, MZF16 was found to be resistant to gentamycin and chloramphenicol but did not harbor any transferable resistance determinants and/or virulence genes. The data also demonstrated absence of cytotoxicity of this strain. Conversely, P. pentosaceus MZF16 can slightly stimulate the immune system and enhance the intestinal epithelial barrier function. Moreover, this bacterium has been shown to be highly active against Listeria spp. due to bacteriocin production. Characterization of the bacteriocin by PCR amplification, sequencing and bioinformatic analyses revealed that MZF16 produces a bacteriocin 100% identical to coagulin, a pediocin-like inhibitory substance produced by Bacillus coagulans. To our knowledge, this is the first report that highlights the production of a pediocin 100% identical to coagulin in a Pediococcus strain. As coagulin, pediocin MZF16 has the consensus sequence YYGNGVXCXXXXCXVXXXXA (X denotes any amino acid), which confirms its belonging to class IIa bacteriocins, and its suitability to preserve foods from Listeria monocytogenes development. According to these results, P. pentosaceus MZF16 can be proposed as a probiotic and bioprotective agent for fermented foods, including Tunisian dry meat and sausages. Further investigations will aim to study the behavior of this strain in meat products as a component of functional food.

A novel mechanism is revealed by which clinical isolates of adherent-invasive Escherichia coli (AIEC) penetrate into the epithelial cell layer, replicate, and establish biofilms in Crohn's disease. AIEC uses the FimH fimbrial adhesin to bind to oligomannose glycans on the surface of host cells. Oligomannose glycans exposed on early apoptotic cells are the preferred binding targets of AIEC, so apoptotic cells serve as potential entry points for bacteria into the epithelial cell layer. Thereafter, the bacteria propagate laterally in the epithelial intercellular spaces. We demonstrate oligomannosylation at two distinct sites of a glycoprotein receptor for AIEC, carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6 or CD66c), on human intestinal epithelia. After bacterial binding, FimH interacts with CEACAM6, which then clusters. The presence of the highest-affinity epitope for FimH, oligomannose-5, on CEACAM6 is demonstrated using LC-MS/MS. As mannose-dependent infections are abundant, this mechanism might also be used by other adherent-invasive pathogens.

Multivalent interactions are omnipresent in biology and confer biological systems with dramatically enhanced affinities towards different receptors. Such multivalent binding interactions have lately been considered for the development of new therapeutic strategies against bacterial and viral infections. Multivalent polymers, dendrimers, and liposomes have successfully targeted pathogenic interactions. While a high synthetic effort was often needed for the development of such therapeutics, the integration of multiple ligands onto nanostructures turned to be a viable alternative. Particles modified with multiple ligands have the additional advantage of creating a high local concentration of binding molecules. This review article will summarize the different nanoparticle-based approaches currently available for the treatment of viral infections.

The colonization of Escherichia coli (E. coli) to host cell surfaces is known to be a glycan-specific process that can be modulated by shear stress. In this work we investigate whether flow rate changes in microchannels integrated on surface plasmon resonance (SPR) surfaces would allow for investigating such processes in an easy and high-throughput manner. We demonstrate that adhesion of uropathogenic E. coli UTI89 on heptyl α-d-mannopyranoside-modified gold SPR substrates is minimal under almost static conditions (flow rates of 10 µL·min−1), and reaches a maximum at flow rates of 30 µL·min−1 (≈30 mPa). This concept is applicable to the investigation of any ligand-pathogen interactions, offering a robust, easy, and fast method for screening adhesion characteristics of pathogens to ligand-modified interfaces.

Over the last decades, carbon-based nanostructures have generated a huge interest from both fundamental and technological viewpoints owing to their physicochemical characteristics, markedly different from their corresponding bulk states. Among these nanostructured materials, carbon nanotubes (CNTs), and more recently graphene and its derivatives, hold a central position. The large amount of work devoted to these materials is driven not only by their unique mechanical and electrical properties, but also by the advances made in synthetic methods to produce these materials in large quantities with reasonably controllable morphologies. While much less studied than CNTs and graphene, diamond nanowires, the diamond analogue of CNTs, hold promise for several important applications. Diamond nanowires display several advantages such as chemical inertness, high mechanical strength, high thermal and electrical conductivity, together with proven biocompatibility and existence of various strategies to functionalize their surface. The unique physicochemical properties of diamond nanowires have generated wide interest for their use as fillers in nanocomposites, as light detectors and emitters, as substrates for nanoelectronic devices, as tips for scanning probe microscopy as well as for sensing applications. In the past few years, studies on boron-doped diamond nanowires (BDD NWs) focused on increasing their electrochemical active surface area to achieve higher sensitivity and selectivity compared to planar diamond interfaces. The first part of the present review article will cover the promising applications of BDD NWS for label-free sensing. Then, the potential use of diamond nanowires as inorganic substrates for matrix-free laser desorption/ionization mass spectrometry, a powerful label-free approach for quantification and identification of small compounds, will be discussed.

Advances in materials science and bionanotechnology have allowed the refinements of current drug delivery systems, expected to facilitate the development of personalized medicine. While dermatological topical pharmaceutical formulations such as foams, creams, lotions, gels, etc., have been proposed for decades, these systems target mainly skin-based diseases. To treat systemic medical conditions as well as localized problems such as joint or muscle concerns, transdermal delivery systems (TDDSs), which use the skin as the main route of drug delivery, are very appealing. Over the years, these systems have shown to offer important advantages over oral as well as intravenous drug delivery routes. Besides being non-invasive and painless, TDDSs are able to deliver drugs with a short-half-life time more easily and are well adapted to eliminate frequent administrations to maintain constant drug delivery. The possibility of self-administration of a predetermined drug dose at defined time intervals makes it also the most convenient personalized point-of-care approach. The transdermal market still remains limited to a narrow range of drugs. While small and lipophilic drugs have been successfully delivered using TDDSs, this approach fails to deliver therapeutic macromolecules due to size-limited transport across the stratum corneum, the outermost layer of the epidermis. The low permeability of the stratum corneum to water-soluble drugs as well as macromolecules poses important challenges to transdermal administration. To widen the scope of drugs for transdermal delivery, new procedures to enhance skin permeation to hydrophilic drugs and macromolecules are under development. Next to iontophoresis and microneedle-based concepts, thermal-based approaches have shown great promise to enhance transdermal drug delivery of different therapeutics. In this inaugural article for the section “Frontiers in Bioengineering and Biotechnology,” the advances in this field and the handful of examples of thermal technologies for local and systemic transdermal drug delivery will be discussed and put into perspective.

Impaired penetration of antibiotics through bacterial biofilms is one of the reasons for failure of antimicrobial therapy. Hindered drug diffusion is caused on the one hand by interactions with the sticky biofilm matrix and on the other hand by the fact that bacterial cells are organized in densely packed clusters of cells. Binding interactions with the biofilm matrix can be avoided by encapsulating the antibiotics into nanocarriers, while interfering with the integrity of the dense cell clusters can enhance drug transport deep into the biofilm. Vapor nanobubbles (VNB), generated from laser irradiated nanoparticles, are a recently reported effective way to loosen up the biofilm structure in order to enhance drug transport and efficacy. In the present study, we explored if the disruptive force of VNB can be used simultaneously to interfere with the biofilm structure and trigger antibiotic release from light-responsive nanocarriers. The antibiotic tobramycin was incorporated in two types of light-responsive nanocarriers—liposomes functionalized with gold nanoparticles (Lip-AuNP) and graphene quantum dots (GQD)—and their efficacy was evaluated on Pseudomonas aeruginosa biofilms. Even though the anti-biofilm efficacy of tobramycin was improved by liposomal encapsulation, electrostatic functionalization with 70 nm AuNP unfortunately resulted in premature leakage of tobramycin in a matter of hours. Laser-irradiation consequently did not further improve P. aeruginosa biofilm eradication. Adsorption of tobramycin to GQD, on the other hand, did result in a stable formulation with high encapsulation efficiency, without burst release of tobramycin from the nanocarriers. However, even though laser-induced VNB formation from GQD resulted in biofilm disruption, an enhanced anti-biofilm effect was not achieved due to tobramycin not being efficiently released from GQD. Even though this study was unsuccessful in designing suitable nanocarriers for simultaneous biofilm disruption and light-triggered release of tobramycin, it provides insights into the difficulties and challenges that need to be considered for future developments in this regard.

Necrosis is associated with a profound inflammatory response. The regulation of necrosis-associated inflammation, particularly the mechanisms responsible for resolution of inflammation are incompletely characterized. Nanoparticles are known to induce plasma membrane damage and necrosis followed by sterile inflammation. We observed that injection of metabolically inert nanodiamonds resulted in paw edema in WT and Ncf1** mice. However, while inflammation quickly resolved in WT mice, it persisted over several weeks in Ncf1** mice indicating failure of resolution of inflammation. Mechanistically, NOX2-dependent reactive oxygen species (ROS) production and formation of neutrophil extracellular traps (NETs) were essential for the resolution of necrosis-induced inflammation: Hence, by evaluating the fate of the particles at the site of inflammation, we observed that Ncf1** mice deficient in NADPH-dependent ROS failed to generate granulation tissue therefore being unable to trap the nanodiamonds. These data suggest that NOX2-dependent NETosis is crucial for preventing the chronification of the inflammatory response to tissue necrosis by forming NETosis-dependent barriers between the necrotic and healthy surrounding tissue.

The fimbrial lectin FimH from uro- and enteropathogenic Escherichia coli binds with nanomolar affinity to oligomannose glycans exposing Manα1,3Man dimannosides at their non-reducing end, but only with micromolar affinities to Manα1,2Man dimannosides. These two dimannoses play a significantly distinct role in infection by E. coli. Manα1,2Man has been described early on as shielding the (Manα1,3Man) glycan that is more relevant to strong bacterial adhesion and invasion. We quantified the binding of the two dimannoses (Manα1,2Man and Manα1,3Man to FimH using ELLSA and isothermal microcalorimetry and calculated probabilities of binding modes using molecular dynamics simulations. Our experimentally and computationally determined binding energies confirm a higher affinity of FimH towards the dimannose Manα1,3Man. Manα1,2Man displays a much lower binding enthalpy combined with a high entropic gain. Most remarkably, our molecular dynamics simulations indicate that Manα1,2Man cannot easily take its major conformer from water into the FimH binding site and that FimH is interacting with two very different conformers of Manα1,2Man that occupy 42% and 28% respectively of conformational space. The finding that Manα1,2Man binding to FimH is unstable agrees with the earlier suggestion that E. coli may use the Manα1,2Man epitope for transient tethering along cell surfaces in order to enhance dispersion of the infection.

Perturbations in glucose homeostasis is critical for human health, as hyperglycemia (defining diabetes) leads to premature death caused by macrovascular and microvascular complications. However, the simple and accurate detection of glucose in the blood at low cost remains a challenging task, although it is of great importance for the diagnosis and therapy of diabetic patients. In this work, carbon quantum dots decorated with copper oxide nanostructures (CQDs/Cu2O) are prepared by a simple hydrothermal approach, and their potential for electrochemical non-enzymatic glucose sensing is evaluated. The proposed sensor exhibits excellent electrocatalytic activity towards glucose oxidation in alkaline solutions. The glucose sensor is characterized by a wide concentration range from 6 µM to 6 mM, a sensitivity of 2.9 ± 0.2 µA·µM−1·cm−2, and a detection limit of 6 µM at a signal-to-noise ratio S/N = 3. The sensors are successfully applied for glucose determination in human serum samples, demonstrating that the CQDs/Cu2O-based glucose sensor satisfies the requirements of complex sample detection with adapted potential for therapeutic diagnostics.

Protein analysis and quantification are required daily by thousands of laboratories worldwide for activities ranging from protein characterization to clinical diagnostics. Multiple factors have to be considered when selecting the best detection and quantification assay, including the amount of protein available, its concentration, the presence of interfering molecules, as well as costs and rapidity. This is also the case for lysozyme, a 14.3-kDa protein ubiquitously present in many organisms, that has been identified with a variety of functions: antibacterial activity, a biomarker of several serious medical conditions, a potential allergen in foods or a model of amyloid-type protein aggregation. Since the design of the first lysozyme aptamer in 2001, lysozyme became one of the most intensively-investigated biological target analytes for the design of novel biosensing concepts, particularly with regards to electrochemical aptasensors. In this review, we discuss the state of the art of aptamer-based electrochemical sensing of lysozyme, with emphasis on sensing in serum and real samples.