The Effect of Co-Delivery of Oxygen and Anticancer Drugs on the Viability of Healthy and Cancer Cells under Normoxic and Hypoxic Conditions.

Hypoxia, cancer, tissue damage, and acidic pH conditions are interrelated, as chronic hypoxic conditions enhance the malignant phenotype of cancer cells, causing more aggressive tissue destruction, and hypoxic cells rely on anaerobic glycolysis, leading to the accumulation of lactic acid. Therefore, the administration of oxygen is necessary to support the functions of healthy cells until the formation of new blood vessels and to increase the oxygen supply to cancerous tissues to improve the efficacy of antitumor drugs on tumor cells. In addition to O2 supply, pH-dependent delivery of anticancer drugs is desired to target cancer cells and reduce drug side effects on healthy cells. However, the simultaneous delivery of O2 and pH-dependent anticancer drugs via nanomaterials and their effects on the viability of normal and cancer cells under hypoxic conditions have not been studied in sufficient numbers. This study describes the synthesis of a pH-responsive nanomaterial containing oxygen and anticancer drugs that exhibits sustained O2 release over a 14 d period under hypoxic conditions and pH-dependent sustained release of anticancer drugs over 30 d. The simultaneous administration of O2 and anticancer drugs results in higher cell survival of normal cells than that of cancer cells under hypoxic and normoxic conditions.

Oxygen Delivery Biomaterials in Wound Healing Applications.

Oxygen (O2 ) delivery biomaterials have attracted great interest in the treatment of chronic wounds due to their potential applications in local and continuous O2 generation and delivery, improving cell viability until vascularization occurs, promoting structural growth of new blood vessels, simulating collagen synthesis, killing bacteria and reducing hypoxia-induced tissue damage. Therefore, different types of O2 delivery biomaterials including thin polymer films, fibers, hydrogels, or nanocomposite hydrogels have been developed to provide controlled, sufficient and long-lasting O2 to prevent hypoxia and maintain cell viability until the engineered tissue is vascularized by the host system. These biomaterials are made by various approaches, such as encapsulating O2 releasing molecules into hydrogels, polymer microspheres and 3D printed hydrogel scaffolds and adsorbing O2 carrying reagents into polymer films of fibers. In this article, different O2 generating sources such as solid inorganic peroxides, liquid peroxides, and photosynthetic microalgae, and O2 carrying perfluorocarbons and hemoglobin are presented and the applications of O2 delivery biomaterials in promoting wound healing are discussed. Furthermore, challenges encountered and future perspectives are highlighted.

Roadmap on multifunctional materials for drug delivery.

This Roadmap on drug delivery aims to cover some of the most recent advances in the field of materials for drug delivery systems (DDSs) and emphasizes the role that multifunctional materials play in advancing the performance of modern DDSs in the context of the most current challenges presented. The Roadmap is comprised of multiple sections, each of which introduces the status of the field, the current and future challenges faced, and a perspective of the required advances necessary for biomaterial science to tackle these challenges. It is our hope that this collective vision will contribute to the initiation of conversation and collaboration across all areas of multifunctional materials for DDSs. We stress that this article is not meant to be a fully comprehensive review but rather an up-to-date snapshot of different areas of research, with a minimal number of references that focus upon the very latest research developments.

Salivary biomarkers: novel noninvasive tools to diagnose chronic inflammation.

Several chronic disorders including type 2 diabetes (T2D), obesity, heart disease and cancer are preceded by a state of chronic low-grade inflammation. Biomarkers for the early assessment of chronic disorders encompass acute phase proteins (APP), cytokines and chemokines, pro-inflammatory enzymes, lipids and oxidative stress mediators. These substances enter saliva through the blood flow and, in some cases, there is a close relation between their salivary and serum concentration. Saliva can be easily collected and stored with non-invasive and cost-saving procedures, and it is emerging the concept to use it for the detection of inflammatory biomarkers. To this purpose, the present review aims to discuss the advantages and challenges of using standard and cutting-edge techniques to discover salivary biomarkers which may be used in diagnosis/therapy of several chronic diseases with inflammatory consequences with the pursuit to possibly replace conventional paths with detectable soluble mediators in saliva. Specifically, the review describes the procedures used for saliva collection, the standard approaches for the measurement of salivary biomarkers and the novel methodological strategies such as biosensors to improve the quality of care for chronically affected patients.

Oxygen and Drug-Carrying Periodic Mesoporous Organosilicas for Enhanced Cell Viability under Normoxic and Hypoxic Conditions.

Over the last decade, inorganic/organic hybrids have been exploited for oxygen-carrying materials and drug delivery. Its low-cost synthesis, controlled shape and size, and stability have made it a viable delivery strategy for therapeutic agents. Rutin (quercetin-3-O-rutinoside) is a bioflavonoid found in fruits and vegetables. Rutin has a variety of pharmaceutical applications, but its low water solubility reduces its stability and bioavailability. As a result, we introduce a new and stable nanosystem for loading a low-soluble drug (rutin) into oxygen-carrying periodic mesoporous organosilicas (PMO-PFCs). Over the course of 14 days, this nanosystem provided a sustained oxygen level to the cells in both normoxic and hypoxic conditions. At different pH values, the drug release (rutin) profile is also observed. Furthermore, the rutin-coated PMO-PFCs interacted with both healthy and malignant cells. The healthy cells have better cell viability on the rutin-coated oxygen-carrying PMO-PFCs, while the malignant cells have a lower cell viability.

3D-Printable Oxygen- and Drug-Carrying Nanocomposite Hydrogels for Enhanced Cell Viability.

Nanocomposite (NC) hydrogels have been widely studied due to their tunable biochemical/ physical properties for tissue engineering and biomedical applications. Nanoparticles (NPs) that can carry bioactive hydrophilic/hydrophobic molecules and provide sustained release within hydrogels are an ideal all-in-one-platform for local drug delivery applications. Dual delivery of different bioactive molecules is desired to achieve synergetic therapeutic effect in biomedical applications. For example, the co-administration of drug molecules and oxygen (O2) is an ideal choice to improve cell viability, while reducing the harmful effects of hypoxia. Therefore, we prepared drug-loaded O2-carrying periodic mesoporous organosilica (PMO-PFC) NPs and their 3D-printable hydrogel precursors based on gelatin methacryloyl (GelMa) to fabricate 3D-scaffolds to improve cell-viability under both normoxia (21% O2) and hypoxia (1% O2) conditions. We used rutin as the hydrophobic drug molecule to demonstrate that our O2-carrying PMO-PFC NPs can improve hydrophobic drug loading and their sustained delivery over 7 days, while supporting sustained O2-delivery for 14 days under hypoxia conditions. Furthermore, the fibroblast cells were interacted with NC hydrogel scaffolds to test their impact on cell-viability under both normoxia and hypoxia conditions. The improved rheological properties suggest the prepared NC hydrogels can be further tested or used as an injectable hydrogel. The improved mechanical properties and 3D printability of NC hydrogels indicate their potential use as artificial tissue constructs.

Recent Advances in Injectable Hydrogels for Controlled and Local Drug Delivery.

Injectable hydrogels have received considerable interest in the biomedical field due to their potential applications in minimally invasive local drug delivery, more precise implantation, and site-specific drug delivery into poorly reachable tissue sites and into interface tissues, where wound healing takes a long time. Injectable hydrogels, such as in situ forming and/or shear-thinning hydrogels, can be generated using chemically and/or physically crosslinked hydrogels. Yet, for controlled and local drug delivery applications, the ideal injectable hydrogel should be able to provide controlled and sustained release of drug molecules to the target site when needed and should limit nonspecific drug molecule distribution in healthy tissues. Thus, such hydrogels should sense the environmental changes that arise in disease states and be able to release the optimal amount of drug over the necessary time period to the target region. To address this, researchers have designed stimuli-responsive injectable hydrogels. Stimuli-responsive hydrogels change their shape or volume when they sense environmental stimuli, e.g., pH, temperature, light, electrical signals, or enzymatic changes, and deliver an optimal concentration of drugs to the target site without affecting healthy tissues.

Advances in Controlled Oxygen Generating Biomaterials for Tissue Engineering and Regenerative Therapy.

Oxygen (O2) generating biomaterials are emerging as important compositions to improve our capabilities in supporting tissue engineering and regenerative therapeutics. Several in vitro studies demonstrated the usefulness of O2 releasing biomaterials in enhancing cell survival and differentiation. However, more efforts are needed to develop materials that can provide sustained O2 release for the long-term. In this paper, we present different O2 generating sources, including hydrogen peroxide, sodium percarbonate, calcium peroxide and magnesium peroxide, and also cover types of carriers and relevant methods of fabricating O2 generating systems. Then, the applications of O2 generating materials in supporting engineered constructs, supplying high O2 demanding cell transplants, and supporting ischemic tissues are discussed. Moreover, the challenges and future perspectives are highlighted.

3D printing of step-gradient nanocomposite hydrogels for controlled cell migration.

In this study, we report the step-gradient nanocomposite (NC) hydrogel generated easily by spatial connection of different nanocomposite hydrogel pastes varying in the concentrations of nanomaterials with the aid of a 3D printing technique. The prepared 3D printed gradient NC hydrogel has self-adhesive properties and is used to direct the migration of fibroblast cells towards the higher concentration of biopolymer-coated silica-based nanomaterials (NMs) within the 3D network of the hydrogel. Furthermore, we demonstrate the potential application of our gradient NC hydrogel in migration and subsequent enhanced osteogenic differentiation of human bone marrow derived mesenchymal stem cells (hBM MSC). The osteogenic differentiation of hBM MSC is achieved in the absence of osteogenic differentiation medium due to the silica-based NMs. The increase in the NM content in the gradient construct promotes hBM MSC migration and results in higher Ca2+ deposition.

Self-assembled monolayers of chiral periodic mesoporous organosilica as a stimuli responsive local drug delivery system.

We present the preparation of self-assembled monolayers (SAMs) of pH responsive chiral periodic mesoporous organosilicas (PMOs) as model implants with drug delivery ability. SAMs of pH responsive PMOs were prepared by layer-by-layer coating of PMOs with polyelectrolytes (e.g. the enantiomers of a polycation biopolymer), for delivering organic molecules and anticancer drug molecules locally in a controlled manner to the adhered cells. We demonstrate that the amount of primary fibroblast, immortal NIH 3T3, and malignant Colo 818 cells adhered to the SAM of the d-enantiomer of polycation-functionalized PMOs was higher in comparison to that of the l-enantiomer of the polycation-functionalized PMO monolayer. In addition, we observe that the 3T3 and Colo cells internalized more of the organic and anticancer drug molecules (released from pH responsive PMOs) than the primary cells did due to the local acidic environment of them. Therefore, as the chirality of the PMOs influenced the amount of cells that adhered, the released molecules interacted with different amounts of cells which allowed us to tune the extent of local drug delivery.

A highly fluorescent water soluble spirobifluorene dye with a large Stokes shift: synthesis, characterization and bio-applications.

The first water-soluble spirobifluorene derivative has been synthesized, which exhibits high fluorescence quantum yield and a large Stokes shift (>100 nm). Proteins induce changes in the emission color, allowing to reach the nanomolar detection limit. Cellular uptake and cytotoxicity studies in living cells revealed its biocompatibility, indicating potential application for live cell imaging.

Chirality-dependent cell adhesion and enrichment in Janus nanocomposite hydrogels.

To assess chirality-dependent cell adhesion and cell enrichment in an extracellular matrix (ECM)-like model, in this study we created 3D nanocomposite (NC) hydrogels composed of periodic mesoporous organosilica (PMO) functionalized with chiral molecules [NC "homo-hydrogels" (NC hydrogels with one kind of functionalized PMO)]. Additionally, we prepared Janus NC hydrogel by connecting two enantiomorphous NC hydrogels, producing an advanced material that can be used to investigate the effect of opposite enantiomers on the behaviors of healthy and cancer cells in a single biomaterial at the same time and under the same reaction conditions. We found that the surface chirality of the functionalized PMO particles strongly influenced cell affinity to the NC hydrogels, especially in serum-containing media. Additionally, chirality was also successfully used to enrich healthy cells within the Janus NC hydrogel from a mixture of healthy cells and cancer cells.

Nanocomposite Hydrogels and Their Applications in Tissue Engineering.

Nanocomposite (NC) hydrogels, organic-inorganic hybrid materials, are of great interest as artificial three-dimensional (3D) biomaterials for biomedical applications. NC hydrogels are prepared in water by chemically or physically cross-linking organic polymers with nanomaterials (NMs). The incorporation of hard inorganic NMs into the soft organic polymer matrix enhances the physical, chemical, and biological properties of NC hydrogels. Therefore, NC hydrogels are excellent candidates for artificial 3D biomaterials, particularly in tissue engineering applications, where they can mimic the chemical, mechanical, electrical, and biological properties of native tissues. A wide range of functional NMs and synthetic or natural organic polymers have been used to design new NC hydrogels with novel properties and tailored functionalities for biomedical uses. Each of these approaches can improve the development of NC hydrogels and, thus, provide advanced 3D biomaterials for biomedical applications.

Cell Growth on ("Janus") Density Gradients of Bifunctional Zeolite L Crystals.

Nanoparticle density gradients on surfaces have attracted interest as two-dimensional material surfaces that can mimic the complex nano-/microstructure of the native extracellular matrix, including its chemical and physical gradients, and can therefore be used to systematically study cell-material interactions. In this respect, we report the preparation of density gradients made of bifunctional zeolite L crystals on glass surfaces and the effects of the density gradient and biopolymer functionalization of zeolite L crystals on cell adhesion. We also describe how we created "Janus" density gradient surfaces by gradually depositing two different types of zeolite L crystals that were functionalized and loaded with different chemical groups and guest molecules onto the two distinct sides of the same glass substrate. Our results show that more cells adhered on the density gradient of biopolymer-coated zeolites than on uncoated ones. The number of adhered cells increased up to a certain surface coverage of the glass by the zeolite L crystals, but then it decreased beyond the zeolite density at which a higher surface coverage decreased fibroblast cell adhesion and spreading. Additionally, cell experiments showed that cells gradually internalized the guest-molecule-loaded zeolite L crystals from the underlying density gradient containing bifunctional zeolite L crystals.

Surface-Mediated Stimuli Responsive Delivery of Organic Molecules from Porous Carriers to Adhered Cells.

The alternating layer-by-layer deposition of oppositely charged polyelectrolytes on fluorescence-dye-(Hst)-loaded zeolites L ((Hst) Zeo-PSS/PLL) is described. The arrays and nanocomposite (NC) hydrogels of (Hst) Zeo-PSS/PLL are prepared. The subsequent cell experiments show the potential application of arrays and NC hydrogels of (Hst) Zeo-PSS/PLL as alternative 2D- and 3D-surfaces, respectively, for 2D- and 3D-surface-mediated controlled organic molecules delivery applications.

Enantiomorphous Periodic Mesoporous Organosilica-Based Nanocomposite Hydrogel Scaffolds for Cell Adhesion and Cell Enrichment.

The chemical functionalization of nanomaterials with bioactive molecules has been used as an effective tool to mimic extracellular matrix (ECM) and to study the cell-material interaction in tissue engineering applications. In this respect, this study demonstrates the use of enantiomerically functionalized periodic mesoporous organosilicas (PMO) for the generation of new multifunctional 3D nanocomposite (NC) hydrogels to control the affinity of cells to the hydrogel surfaces and so to control the enrichment of cells and simultaneous drug delivery in 3D network. The functionalization of PMO with enantiomers of bioactive molecules, preparation of their nanocomposite hydrogels, and the stereoselective interaction of them with selected cell types are described. The results show that the affinity of cells to the respective NC hydrogel scaffolds is affected by the nature of the biomolecule and its enantiomers, which is more pronounced in serum containing media. The differentiation of enantiomorphous NC hydrogels by cells is used to enrich one cell type from a mixture of two cells. Finally, PMO are utilized as nanocontainers to release two different dye molecules as a proof of principle for multidrug delivery in 3D NC hydrogel scaffolds.

Self-assembled monolayers and nanocomposite hydrogels of functional nanomaterials for tissue engineering applications.

In biotechnology, SAMs and NC hydrogels of functional nanomaterials are of high interest as 2D and 3D cell culture systems, respectively, to mimic natural ECM and to control cell behaviors. Advanced biotechnological approaches often use nanoscale topography together with suitable surface functionalization, as a model of ECM, to control cell behaviors and tissue formation. SAMs of NMs are effective ECM models as 2D surfaces due to their larger nanostructured surface areas which provide higher molecular density by functionalization on a planar substrate than molecular SAMs. Additionally, NC hydrogels, produced by cross-linking of organic polymers with NMs, are excellent candidates as 3D cell culture systems owing to their optical, cell-compatibility and the extraordinary mechanical properties.

When self-assembly meets biology: luminescent platinum complexes for imaging applications.

Luminescent platinum complexes have attractive chemical and photophysical properties such as high stability, emission in the visible region, high emission quantum yields and long excited state lifetimes. However the absorption spectrum of the compounds in the UV region, preventing their excitation in the harmless visible/red region, as well as the strong quenching of the luminescent triplet state, caused by dioxygen in water and biological fluids, reduces their possible applications for imaging. Therefore a possible solution to these drawbacks is to take advantage of the high tendency of such square planar compounds to self-assemble in supramolecular structures. The assemblies can be considered new chemical species with enhanced and tunable properties. Furthermore the assembly and disassembly process can be explored as a tool to obtain dynamic labels that can be applied in biomedicine. The change in color, the turn on and off of luminescence but also of the reactivity, the protection from quenching and environmental degradation are some of the attractive properties connected to the aggregation of the complexes.

Spatially controlled channel entrances functionalization of zeolites L.

The spatially controlled channel entrances functionalization of disk shaped zeolite L crystals is described. Fluorescent dye or bioactive molecules are immobilized at one end of the channels of zeolite crystals and subsequently the other side of the crystals is derivatized with magnetic iron oxide nanoparticles. The asymmetrically functionalized crystals were used for the control of the movement of bacteria in solution.