Programmable biomaterials for dynamic and responsive drug delivery

Biomaterials are continually being designed that enable new methods for interacting dynamically with cell and tissues, in turn unlocking new capabilities in areas ranging from drug delivery to regenerative medicine. In this review, we explore some of the recent advances being made in regards to programming biomaterials for improved drug delivery, with a focus on cancer and infection. We begin by explaining several of the underlying concepts that are being used to design this new wave of drug delivery vehicles, followed by examining recent materials systems that are able to coordinate the temporal delivery of multiple therapeutics, dynamically respond to changing tissue environments, and reprogram their bioactivity over time

High order amplitude equation for steps on creep curve

We consider a model proposed by one of the authors for a type of plastic instability found in creep experiments which reproduces a number of experimentally observed features. The model consists of three coupled non-linear differential equations describing the evolution of three types of dislocations. The transition to the instability has been shown to be via Hopf bifurcation leading to limit cycle solutions with respect to physically relevant drive parameters. Here we use reductive perturbative method to extract an amplitude equation of up to seventh order to obtain an approximate analytic expression for the order parameter. The analysis also enables us to obtain the bifurcation (phase) diagram of the instability. We find that while supercritical bifurcation dominates the major part of the instability region, subcritical bifurcation gradually takes over at one end of the region. These results are compared with the known experimental results. Approximate analytic expressions for the limit cycles for different types of bifurcations are shown to agree with their corresponding numerical solutions of the equations describing the model. The analysis also shows that high order nonlinearities are important in the problem. This approach further allows us to map the theoretical parameters to the experimentally observed macroscopic quantities.Comment: LaTex file and eps figures; Communicated to Phys. Rev.

Biophysical and electrochemical studies of protein-nucleic acid interactions

This review is devoted to biophysical and electrochemical methods used for studying protein-nucleic acid (NA) interactions. The importance of NA structure and protein-NA recognition for essential cellular processes, such as replication or transcription, is discussed to provide background for description of a range of biophysical chemistry methods that are applied to study a wide scope of protein-DNA and protein-RNA complexes. These techniques employ different detection principles with specific advantages and limitations and are often combined as mutually complementary approaches to provide a complete description of the interactions. Electrochemical methods have proven to be of great utility in such studies because they provide sensitive measurements and can be combined with other approaches that facilitate the protein-NA interactions. Recent applications of electrochemical methods in studies of protein-NA interactions are discussed in detail

Dectin-1 isoforms contribute to distinct Th1/Th17 cell activation in mucosal candidiasis

We thank Dr. Cristina Massi Benedetti for digital art and editingRecognition of β-glucans by dectin-1 has been shown to mediate cell activation, cytokine production and a variety of antifungal responses. Here, we report that the functional activity of dectin-1 in mucosal immunity to Candida albicans is influenced by the genetic background of the host. Dectin-1 was required for the proper control of gastrointestinal and vaginal candidiasis in C57BL/6 but not BALB/c mice, the latter actually showing increased resistance in the absence of dectin-1. Susceptibility of dectin-1-deficient C57BL/6 mice to infection was associated with defective IL-17A, aryl hydrocarbon receptor-dependent IL-22 production as well as adaptive Th1 responses. In contrast, resistance of dectin-1-deficient BALB/c mice was associated with increased IL-17A and IL-22 production, and the skewing towards Th1/Treg immune responses that provide immunological memory. Disparate canonical/noncanonical NF-κB signaling pathways downstream dectin-1were activated in the two different mouse strains. Thus, the net activity of dectin-1 in antifungal mucosal immunity is dependent on the host’s genetic background that affects both the innate cytokine production as well as the adaptive Th1/Th17 cell activation upon dectin-1 signaling.The studies were supported by the Specific Targeted Research Project “ALLFUN” (FP7−HEALTH−2009 contract number 260338 to LR) and the Italian Project AIDS 2010 by ISS (Istituto Superiore di Sanità - contract number 40H40 to LR) and Fondazione Cassa di Risparmio di Perugia Project n. 2011.0124.021. AC and CC were financially supported by fellowships from Fundação para a Ciência e Tecnologia, Portugal (contracts SFRH/BPD/46292/2008 and SFRH/BD/65962/2009, respectively)

Biologically inspired, cell-selective release of aptamer-trapped growth factors by traction forces

Biomaterial scaffolds that are designed to incorporate dynamic, spatiotemporal information have the potential to interface with cells and tissues to direct behavior. Here we describe a bioinspired, programmable nanotechnology-based platform that harnesses cellular traction forces to activate growth factors, eliminating the need for exogenous triggers (e.g. light), spatially diffuse triggers (e.g. enzymes, pH changes) or passive activation (e.g. hydrolysis). We use flexible aptamer technology to create modular, synthetic mimics of the Large Latent Complex that restrains TGF-β1. This flexible nanotechnology-based approach is shown here to work with both platelet-derived growth factor-BB (PDGF-BB) and vascular endothelial growth factor (VEGF-165), integrate with glass coverslips, polyacrylamide gels, and collagen scaffolds, enable activation by various cells (e.g. primary human dermal fibroblasts, HMEC-1 endothelial cells) and unlock fundamentally new capabilities such as selective activation of growth factors by differing cell types (e.g. activation by smooth muscle cells but not fibroblasts) within clinically relevant collagen sponges

Using biomaterials to rewire the process of wound repair

Wound healing is one of the most complex processes that our bodies must perform. While our ability to repair wounds is often taken for granted, conditions such as diabetes, obesity, or simply old age can significantly impair this process. With the incidence of all three predicted to continue growing into the foreseeable future, there is an increasing push to develop strategies that facilitate healing. Biomaterials are an attractive approach for modulating all aspects of repair, and have the potential to steer the healing process towards regeneration. In this review, we will cover recent advances developing biomaterials that actively modulate the process of wound healing, and will provide insight into how biomaterials can be used to simultaneously rewire multiple phases of the repair process

In vitro modelling of the physiological and diseased female reproductive system

The maladies affecting the female reproductive tract (FRT) range from infections to endometriosis to carcinomas. In vitro models of the FRT play an increasingly important role in both basic and translational research, since the anatomy and physiology of the FRT of humans and other primates differ significantly from most of the commonly used animal models, including rodents. Using organoid culture to study the FRT has overcome the longstanding hurdle of maintaining epithelial phenotype in culture. Both ECM-derived and engineered materials have proved critical for maintaining a physiological phenotype of FRT cells in vitro by providing the requisite 3D environment, ligands, and architecture. Advanced materials have also enabled the systematic study of factors contributing to the invasive metastatic processes. Meanwhile, microphysiological devices make it possible to incorporate physical signals such as flow and cyclic exposure to hormones. Going forward, advanced materials compatible with hormones and optimised to support FRT-derived cells' long-term growth, will play a key role in addressing the diverse array of FRT pathologies and lead to impactful new treatments that support the improvement of women's health

Distribution of aluminium fractions in acid forest soils: influence of vegetation changes

This study examines aluminium as a potentially phytotoxic element in acidic forest soils. Concentrations of Al forms in soils are generally controlled by soil chemical conditions, such as pH, organic matter, base cation contents, etc. Moreover, soil conditions are influenced by the vegetation cover. This study analyzed the distribution of Al forms in soils after changes in vegetation. HPLC/IC was used for the separation of three Al fractions in two soil extracts according to their charge. An aqueous extract (AlH2O) simulated the natural soil conditions and bioavailable Al fractions. Potentially available Al form was represented by a 0.5 M KCl extract (AlKCl). We demonstrated that the vegetation type influences the concentrations of different Al fractions, mainly in the surface organic horizons. Differences were more common in the KCl extract. The trivalent fraction was less influenced by vegetation changes than the mono- and divalent fractions. Afforestation increased the concentrations of AlKCl and AlH2O. In contrast, grass expansion after deforestation led to significantly decreased concentrations of AlKCl and AlH2O. Concentrations of AlH2O in organic horizons were higher in spruce forest than in beech forest. A long-term effect of liming on soil pH and concentrations of potentially toxic Al fractions was not apparent. The results provide information on the variations of Al fractions distributions following vegetation type changes and indicate the existence of some natural mechanisms controlling Al toxicity. Furthermore, the results can be used in the management of forested areas endangered by soil acidification

miR-142-3p Reduces the Size, Migration, and Contractility of Endometrial and Endometriotic Stromal Cells by Targeting Integrin- and Rho GTPase-Related Pathways That Regulate Cytoskeletal Function

Downregulated microRNA-142-3p signaling contributes to the pathogenesis of endometriosis, an invasive disease where the lining of the uterus grows at ectopic locations, by yet incompletely understood mechanisms. Using bioinformatics and in vitro assays, this study identifies cytoskeletal regulation and integrin signaling as two relevant categories of miR-142-3p targets. qPCR revealed that miR-142-3p upregulation in St-T1b cells downregulates Rho-associated protein kinase 2 (ROCK2), cofilin 2 (CFL2), Ras-related C3 botulinum toxin substrate 1 (RAC1), neural Wiskott-Aldrich syndrome protein (WASL), and integrin α-V (ITGAV). qPCR and Western-blotting showed miR-142-3p effect on WASL and ITGAV was significant also in primary endometriotic stroma cells. Luciferase reporter assays in ST-T1b cells then confirmed direct regulation of ITGAV and WASL. On the functional side, miR-142-3p upregulation significantly reduced ST-T1b cell size, the size of vinculin plaques, migration through fibronectin-coated transwell filters, and the ability of ST-T1b and primary endometriotic stroma cells to contract collagen I gels. These results suggest that miR-142-3p has a strong mechanoregulatory effect on endometrial stroma cells and its external administration reduces the invasive endometrial phenotype. Within the limits of an in vitro investigation, our study provides new mechanistic insights into the pathogenesis of endometriosis and provides a perspective for the development of miR-142-3p based drugs for inhibiting invasive growth of endometriotic cells

The ellagic acid metabolites urolithin A and B differentially affect growth, adhesion, motility, and invasion of endometriotic cells in vitro

STUDY QUESTION: What are the effects of plant-derived antioxidant compounds urolithin A (UA) and B (UB) on the growth and pathogenetic properties of an in vitro endometriosis model? SUMMARY ANSWER: Both urolithins showed inhibitory effects on cell behavior related to the development of endometriosis by differentially affecting growth, adhesion, motility, and invasion of endometriotic cells in vitro. WHAT IS KNOWN ALREADY: Endometriosis is one of the most common benign gynecological diseases in women of reproductive age and is defined by the presence of endometrial tissue outside the uterine cavity. As current pharmacological therapies are associated with side effects interfering with fertility, we aimed at finding alternative therapeutics using natural compounds that can be administered for prolonged periods with a favorable side effects profile. STUDY DESIGN, SIZE, DURATION: In vitro cultures of primary endometriotic stromal cells from 6 patients subjected to laparoscopy for benign pathologies with histologically confirmed endometriosis; and immortalized endometrial stromal (St-T1b) and endometriotic epithelial cells (12Z) were utilized to assess the effects of UA and UB on endometriotic cell properties. Results were validated in three-dimensional (3D) in vitro co-culture spheroids of 12Z and primary endometriotic stroma cells of one patient, and organoids from 3 independent donors with endometriosis. PARTICIPANTS/MATERIALS, SETTING, METHODS: The effects on cell growth were measured by non-radioactive colorimetric assay to measure cellular metabolic activity as an indicator of cell viability (MTT assay) and flow cytometric cell cycle assay on primary cultures, St-T1b, and 12Z. Apoptosis analyses, the impact on in vitro adhesion, migration, and invasion were evaluated in the cell lines. Moreover, Real-Time Quantitative Reverse Transcription polymerase chain reaction (RT-qPCR) assays were performed on primary cultures, St- T1b and 12Z to evaluate a plausible mechanistic contribution by factors related to proteolysis (matrix metalloproteinase 2, 3 and 9 -MMP2, MMP3, MMP9-, and tissue inhibitor of metalloproteinases -TIMP-1-), cytoskeletal regulators (Ras-related C3 botulinum toxin substrate 1 -RAC1-, Rho-associated coiled-coil containing protein kinase 2 -ROCK2-), and cell adhesion molecules (Syndecan 1 -SDC1-, Integrin alpha V–ITGAV-). Finally, the urolithins effects were evaluated on spheroids and organoids by formation, viability, and drug screen assays. MAIN RESULTS AND THE ROLE OF CHANCE: 40 mM UA and 20 mM UB produced a significant decrease in cell proliferation in the primary endometriotic cell cultures (P < 0.001 and P < 0.01, respectively) and in the St-T1b cell line (P < 0.001 and P < 0.05, respectively). In St-T1b, UA exhibited a mean half-maximum inhibitory concentration (IC50) of 39.88 mM, while UB exhibited a mean IC50 of 79.92 mM. Both 40 mM UA and 20 mM UB produced an increase in cells in the S phase of the cell cycle (P < 0.01 and P < 0.05, respectively). The same concentration of UA also increased the percentage of apoptotic ST-t1b cells (P < 0.05), while both urolithins decreased cell migration after 24 h (P < 0.001 both). Only the addition of 5 mM UB decreased the number of St-T1b adherent cells. TIMP-1 expression was upregulated in response to treating the cells with 40 mM UA (P < 0.05). Regarding the 12Z endometriotic cell line, only 40 mM UA decreased proliferation (P < 0.01); while both 40 mM UA and 20 mM UB produced an increase in cells in the G2/M phase (P < 0.05 and P < 0.01, respectively). In this cell line, UA exhibited a mean IC50 of 40.46 mM, while UB exhibited a mean IC50 of 54.79 mM. UB decreased cell migration (P < 0.05), and decreased the number of adherent cells (P < 0.05). Both 40 mM UA and 20 mM UB significantly decreased the cellular invasion of these cells; and several genes were altered when treating the cells with 40 mM UA and 10 mM UB. The expression of MMP2 was downregulated by UA (P < 0.001), and expression of MMP3 (UA P < 0.001 and UB P < 0.05) and MMP9 (P < 0.05, both) were downregulated by both urolithins. Moreover, UA significantly downregulated ROCK2 (P < 0.05), whereas UB treatment was associated with RAC1 downregulation (P < 0.05). Finally, the matrix adhesion receptors and signaling (co)receptors SDC1 and ITGAV were downregulated upon treatment with either UA or UB (P < 0.01 and P < 0.05, respectively in both cases). Regarding the effects of urolithins on 3D models, we have seen that they significantly decrease the viability of endometriosis spheroids (80 mM UA and UB: P < 0.05 both) as well as affecting their area (40 mM UA: P < 0.05, and 80 mM UA: P < 0.01) and integrity (40 mM UA and UB: P < 0.05, 80 mM UA and UB: P < 0.01). On the other hand, UA and UB significantly inhibited organoid development/outgrowth (40 and 80 mM UA: P < 0.0001 both; 40 mM UB: P < ns-0.05-0.001, and 80 mM UB: P < 0.01–0.001–0.001), and all organoid lines show urolithins sensitivity resulting in decreasing viability (UA exhibited a mean IC50 of 33.93 mM, while UB exhibited a mean IC50 of 52.60 mM). LARGE-SCALE DATA: N/A LIMITATIONS, REASONS FOR CAUTION: This study was performed on in vitro endometriosis models. WIDER IMPLICATIONS OF THE FINDINGS: These in vitro results provide new insights into the pathogenetic pathways affected by these compounds and mark their use as a potential new therapeutic strategy for the treatment of endometriosis. STUDY FUNDING/COMPETING INTEREST(S): This study was funded EU MSCA-RISE-2015 project MOMENDO (691058). The authors have no conflicts of interest to declare.Fil: Mc Cormack, Bárbara Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Maenhoudt, N.. Katholikie Universiteit Leuven; BélgicaFil: Fincke, V.. Munster University Hospital; AlemaniaFil: Stejskalova, A.. Munster University Hospital; AlemaniaFil: Greve, B.. Munster University Hospital; AlemaniaFil: Kiesel, L.. Munster University Hospital; AlemaniaFil: Meresman, Gabriela Fabiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Vankelecom, H.. Katholikie Universiteit Leuven; BélgicaFil: Götte, M.. Munster University Hospital; AlemaniaFil: Barañao, Rosa Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin