Showing papers in "Advanced Healthcare Materials in 2014"

Enhanced Tumor Accumulation of Sub-2 nm Gold Nanoclusters for Cancer Radiation Therapy

Abstract: A new type of metabolizable and efficient radiosensitizers for cancer radiotherapy is presented by combining ultrasmall Au nanoclusters (NCs, <2 nm) with biocompatible coating ligands (glutathione, GSH). The new nanoconstruct (GSH-coated Au25 NCs) inherits attractive features of both the Au core (strong radiosensitizing effect) and GSH shell (good biocompatibility). It can preferentially accumulate in tumor via the improved EPR effect, which leads to strong enhancement for cancer radiotherapy. After the treatment, the small-sized GSH-Au25 NCs can be efficiently cleared by the kidney, minimizing any potential side effects due to the accumulation of Au25 NCs in the body.

A Fast pH‐Switchable and Self‐Healing Supramolecular Hydrogel Carrier for Guided, Local Catheter Injection in the Infarcted Myocardium

Abstract: Minimally invasive intervention strategies after myocardial infarction use state-of-the-art catheter systems that are able to combine mapping of the infarcted area with precise, local injection of drugs. To this end, catheter delivery of drugs that are not immediately pumped out of the heart is still challenging, and requires a carrier matrix that in the solution state can be injected through a long catheter, and instantaneously gelates at the site of injection. To address this unmet need, a pH-switchable supramolecular hydrogel is developed. The supramolecular hydrogel is switched into a liquid at pH > 8.5, with a viscosity low enough to enable passage through a 1-m long catheter while rapidly forming a hydrogel in contact with tissue. The hydrogel has self-healing properties taking care of adjustment to the injection site. Growth factors are delivered from the hydrogel thereby clearly showing a reduction of infarct scar in a pig myocardial infarction model.

Capacitive Epidermal Electronics for Electrically Safe, Long-Term Electrophysiological Measurements

Abstract: Integration of capacitive sensing capabilities to epidermal electronic systems (EES) can enhance the robustness in operation for electrophysiological signal measurement. Capacitive EES designs are reusable, electrically safe, and minimally sensitive to motion artifacts. Experiments on human subjects illustrate levels of fidelity in ECG, EMG, and EOG recordings comparable to those of standard gel electrodes and of direct contact EES electrodes.

Multifunctional Skin-Like Electronics for Quantitative, Clinical Monitoring of Cutaneous Wound Healing

Abstract: Non-invasive, biomedical devices have the potential to provide important, quantitative data for the assessment of skin diseases and wound healing. Traditional methods either rely on qualitative visual and tactile judgments of a professional and/or data obtained using instrumentation with forms that do not readily allow intimate integration with sensitive skin near a wound site. Here, an electronic sensor platform that can softly and reversibly laminate perilesionally at wounds to provide highly accurate, quantitative data of relevance to the management of surgical wound healing is reported. Clinical studies on patients using thermal sensors and actuators in fractal layouts provide precise time-dependent mapping of temperature and thermal conductivity of the skin near the wounds. Analytical and simulation results establish the fundamentals of the sensing modalities, the mechanics of the system, and strategies for optimized design. The use of this type of "epidermal" electronics system in a realistic clinical setting with human subjects establishes a set of practical procedures in disinfection, reuse, and protocols for quantitative measurement. The results have the potential to address important unmet needs in chronic wound management.

A Size-Exclusion Nanocellulose Filter Paper for Virus Removal

Abstract: This is the first time a 100% natural, unmodified nanofibrous polymer-based membrane is demonstrated capable of removing viruses solely based on the size-exclusion principle, with a log10 reduction value (LRV) ≥ 6.3 as limited by the assay lower detection limit and the feed virus titre, thereby matching the performance of industrial synthetic polymer virus removal filters.

Synthesis and 3D printing of biodegradable polyurethane elastomer by a water-based process for cartilage tissue engineering applications.

Abstract: Biodegradable materials that can undergo degradation in vivo are commonly employed to manufacture tissue engineering scaffolds, by techniques including the customized 3D printing. Traditional 3D printing methods involve the use of heat, toxic organic solvents, or toxic photoinitiators for fabrication of synthetic scaffolds. So far, there is no investigation on water-based 3D printing for synthetic materials. In this study, the water dispersion of elastic and biodegradable polyurethane (PU) nanoparticles is synthesized, which is further employed to fabricate scaffolds by 3D printing using polyethylene oxide (PEO) as a viscosity enhancer. The surface morphology, degradation rate, and mechanical properties of the water-based 3D-printed PU scaffolds are evaluated and compared with those of polylactic-co-glycolic acid (PLGA) scaffolds made from the solution in organic solvent. These scaffolds are seeded with chondrocytes for evaluation of their potential as cartilage scaffolds. Chondrocytes in 3D-printed PU scaffolds have excellent seeding efficiency, proliferation, and matrix production. Since PU is a category of versatile materials, the aqueous 3D printing process developed in this study is a platform technology that can be used to fabricate devices for biomedical applications.

Silicon Quantum Dots for Biological Applications

Abstract: Semiconductor nanoparticles (or quantum dots, QDs) exhibit unique optical and electronic properties such as size-controlled fluorescence, high quantum yields, and stability against photobleaching. These properties allow QDs to be used as optical labels for multiplexed imaging and in drug delivery detection systems. Luminescent silicon QDs and surface-modified silicon QDs have also been developed as potential minimally toxic fluorescent probes for bioapplications. Silicon, a well-known power electronic semiconductor material, is considered an extremely biocompatible material, in particular with respect to blood. This review article summarizes existing knowledge related to and recent research progress made in the methods for synthesizing silicon QDs, as well as their optical properties and surface-modification processes. In addition, drug delivery systems and in vitro and in vivo imaging applications that use silicon QDs are also discussed.

Solution‐Gated Graphene Transistors for Chemical and Biological Sensors

Abstract: Graphene has attracted much attention in biomedical applications for its fascinating properties. Because of the well-known 2D structure, every atom of graphene is exposed to the environment, so the electronic properties of graphene are very sensitive to charged analytes (ions, DNA, cells, etc.) or an electric field around it, which renders graphene an ideal material for high-performance sensors. Solution-gated graphene transistors (SGGTs) can operate in electrolytes and are thus excellent candidates for chemical and biological sensors, which have been extensively studied in the recent 5 years. Here, the device physics, the sensing mechanisms, and the performance of the recently developed SGGT-based chemical and biological sensors, including pH, ion, cell, bacterial, DNA, protein, glucose sensors, etc., are introduced. Their advantages and shortcomings, in comparison with some conventional techniques, are discussed. Conclusions and challenges for the future development of the field are addressed in the end.

Smart pH-responsive nanocarriers based on nano-graphene oxide for combined chemo- and photothermal therapy overcoming drug resistance

Abstract: A pH-responsive nanocarrier is developed by coating nanoscale graphene oxide (NGO) with dual types of polymers, polyethylene glycol (PEG) and poly(allylamine hydrochloride) (PAH), the latter of which is then modified with 2,3-dimethylmaleic anhydride (DA) to acquire pH-dependent charge reversibility. After loading with doxorubicin (DOX), a chemotherapy drug, the obtained NGO-PEG-DA/DOX complex exhibits a dual pH-responsiveness, showing markedly enhanced cellular uptake under the tumor microenvironmental pH, and accelerated DOX release under a further lowered pH inside cell lysosomes. Combining such a unique behavior with subsequently slow efflux of DOX, NGO-PEG-DA/DOX offers remarkably improved cell killing for drug-resistant cancer cells under the tumor microenvironmental pH in comparison with free DOX. Exploiting its excellent photothermal conversion ability, combined chemo- and photothermal therapy is further demonstrated using NGO-PEG-DA/DOX, realizing a synergistic therapeutic effect. This work presents a novel design of surface chemistry on NGO for the development of smart drug delivery systems responding to the tumor microenvironment and external physical stimulus, with the potential to overcome drug resistance.

Highly conductive stretchable and biocompatible electrode-hydrogel hybrids for advanced tissue engineering.

Abstract: Hydrogel-based, molecular permeable electronic devices are considered to be promising for electrical stimulation and recording of living tissues, either in vivo or in vitro. This study reports the fabrication of the first hydrogel-based devices that remain highly electrically conductive under substantial stretch and bending. Using a simple technique involving a combination of chemical polymerization and electropolymerization of poly (3,4-ethylenedioxythiophene) (PEDOT), a tight bonding of a conductive composite of PEDOT and polyurethane (PU) to an elastic double-network hydrogel is achieved to make fully organic PEDOT/PU-hydrogel hybrids. Their response to repeated bending, mechanical stretching, hydration-dessication cycles, storage in aqueous condition for up to 6 months, and autoclaving is assessed, demonstrating excellent stability, without any mechanical or electrical damage. The hybrids exhibit a high electrical conductivity of up to 120 S cm(-1) at 100% elongation. The adhesion, proliferation, and differentiation of neural and muscle cells cultured on these hybrids are demonstrated, as well as the fabrication of 3D hybrids, advancing the field of tissue engineering with integrated electronics.

Graphene-based electroresponsive scaffolds as polymeric implants for on-demand drug delivery.

Abstract: Stimuli-responsive biomaterials have attracted significant attention in the field of polymeric implants designed as active scaffolds for on-demand drug delivery. Conventional porous scaffolds suffer from drawbacks such as molecular diffusion and material degradation, allowing in most cases only a zero-order drug release profile. The possibility of using external stimulation to trigger drug release is particularly enticing. In this paper, the fabrication of previously unreported graphene hydrogel hybrid electro-active scaffolds capable of controlled small molecule release is presented. Pristine ball-milled graphene sheets are incorporated into a three dimensional macroporous hydrogel matrix to obtain hybrid gels with enhanced mechanical, electrical, and thermal properties. These electroactive scaffolds demonstrate controlled drug release in a pulsatile fashion upon the ON/OFF application of low electrical voltages, at low graphene concentrations (0.2 mg mL(-1) ) and by maintaining their structural integrity. Moreover, the in vivo performance of these electroactive scaffolds to release drug molecules without any "resistive heating" is demonstrated. In this study, an illustration of how the heat dissipating properties of graphene can provide significant and previously unreported advantages in the design of electroresponsive hydrogels, able to maintain optimal functionality by overcoming adverse effects due to unwanted heating, is offered.

Graphene-regulated cardiomyogenic differentiation process of mesenchymal stem cells by enhancing the expression of extracellular matrix proteins and cell signaling molecules.

Abstract: The potential of graphene as a mesenchymal stem cell (MSC) culture substrate to promote cardiomyogenic differentiation is demonstrated. Graphene exhibits no sign of cytotoxicity for stem cell culture. MSCs are committed toward cardiomyogenic lineage by simply culturing them on graphene. This may be attributed, at least partially, to the regulation of expression levels of extracellular matrix and signaling molecules.

Implantable silk composite microneedles for programmable vaccine release kinetics and enhanced immunogenicity in transcutaneous immunization.

Abstract: Microneedle vaccines mimic several aspects of cutaneous pathogen invasion by targeting antigen to skin-resident dendritic cells and triggering local infl ammatory responses in the skin, which are correlated with enhanced immune responses. Here, we tested whether control over vaccine delivery kinetics can enhance immunity through further mimicry of kinetic profi les present during natural acute infections. An approach for the fabrication of silk/poly(acrylic acid) (PAA) composite microneedles composed of a silk tip supported on a PAA base is reported. On brief application of microneedle patches to skin, the PAA bases rapidly dissolved to deliver a protein subunit vaccine bolus, while also implanting persistent silk hydrogel depots into the skin for a low-level sustained cutaneous vaccine release over 1‐2 weeks. Use of this platform to deliver a model whole-protein vaccine with optimized release kinetics resulted in > 10-fold increases in antigen-specifi c T-cell and humoral immune responses relative to traditional parenteral needle-based immunization. compared with traditional parenteral immunization approaches targeting less immunogenic tissues such as muscle (reviewed elsewhere). [ 1 ] Microneedle vaccination has in many cases also outperformed hypodermic needle-based delivery to the skin, suggesting the importance of factors relating to microneedle delivery itself, such as the infl ammatory state generated by micrometer-scale wounding following microneedle insertion. [ 2 , 3 ] Unrelated studies have begun to reveal the importance of antigen and adjuvant delivery kinetics in the developing immune response, both within the context of vaccination and in natural responses to infection. [ 4‐7 ] For example, the magnitude, functionality, and phenotype of CD8 + T-cell responses can be shaped by immunizations where antigen or adjuvant delivery kinetics are controlled over multi-week periods, with persistent antigenic and infl ammatory signals eliciting stronger responses than transient bolus vaccine exposure. [ 4 , 5 ] These fi ndings are consistent with known differences in the natural immunity generated against transient versus persistent pathogens, indicating specifi c mechanisms of immunity that may be exploited through engineered kinetics to yield greater vaccine effi cacy. We have recently begun to explore the combination of these two approaches for enhancing immunogenicity, through the

Targeting-Triggered Porphysome Nanostructure Disruption for Activatable Photodynamic Therapy

Abstract: Photodynamic therapy (PDT) and photothermal therapy (PTT) possess advantages over the conventional therapies with additional treatment selectivity achieved with local laser irradiation. Comparing to PTT that ablates target tissue via thermal necrosis, PDT induces target cell death via singlet oxygen without damaging the underling connective tissue, thus preserving its biological function. Activatable photosensitizers provide an additional level of treatment selectivity via the disease-associated activation mechanism. In this study, folate-conjugated porphysomes are introduced as targeting-triggered activatable nano-sized beacons for PDT. Porphysomes are reported previously as the most stable and efficient delivery system of porphyrin, but their nanostructure converts the singlet oxygen generation mechanism to thermal ablation mechanism. By folate-receptor-mediated endocytosis, folate-porphysomes are internalized into cells rapidly and resulted in efficient disruption of nanostructures, thus switching back on the photodynamic activity of the densely packed porphyrins for effective PDT. In both in vitro and in vivo studies, folate-porphysomes can achieve folate receptor-selective PDT efficacy, which proves the robustness of targeting-triggered PDT activation of porphysome nanostructure for highly selective tumor ablation. The formulation of porphysomes can be modified with other targeting ligands as activatable photosensitizers for personalized treatment in future.

Peptide dendrimer-Doxorubicin conjugate-based nanoparticles as an enzyme-responsive drug delivery system for cancer therapy.

Abstract: Peptide dendrimers have shown promise as an attractive platform for drug delivery In this study, mPEGylated peptide dendrimer-doxorubicin (dendrimer-DOX) conjugate-based nanoparticle is prepared and characterized as an enzyme-responsive drug delivery vehicle The drug DOX is conjugated to the periphery of dendrimer via an enzyme-responsive tetra-peptide linker Gly-Phe-Leu-Gly (GFLG) The dendrimer-DOX conjugate can self-assemble into nanoparticle, which is confirmed by dynamic light scattering, scanning electron microscopy, and transmission electron microscopy studies At equal dose, mPEGylated dendrimer-DOX conjugate-based nanoparticle results in significantly high antitumor activity, and induces apoptosis on the 4T1 breast tumor model due to the evidences from tumor growth curves, an immunohistochemical analysis, and a histological assessment The in vivo toxicity evaluation demonstrates that nanoparticle substantially avoids DOX-related toxicities and presents good biosafety without obvious side effects to normal organs of both tumor-bearing and healthy mice as measured by body weight shift, blood routine test, and a histological analysis Thus, the mPEGylated peptide dendrimer-DOX conjugate-based nanoparticle may be a potential nanoscale drug delivery vehicle for the breast cancer therapy

Three-Dimensional Paper-Based Model for Cardiac Ischemia

Abstract: In vitro models of ischemia have not historically recapitulated the cellular interactions and gradients of molecules that occur in a 3D tissue. This work demonstrates a paper-based 3D culture system that mimics some of the interactions that occur among populations of cells in the heart during ischemia. Multiple layers of paper containing cells, suspended in hydrogels, are stacked to form a layered 3D model of a tissue. Mass transport of oxygen and glucose into this 3D system can be modulated to induce an ischemic environment in the bottom layers of the stack. This ischemic stress induces cardiomyocytes at the bottom of the stack to secrete chemokines which subsequently trigger fi broblasts residing in adjacent layers to migrate toward the ischemic region. This work demonstrates the usefulness of patterned, stacked paper for performing in vitro mechanistic studies of cellular motility and viability within a model of the laminar ventricle tissue of the heart. the blood vessel into the tissue, and ii) the consumption of these nutrients by cellular metabolism. Most tissues in the body have capillaries every ≈200 µm to ensure suffi cient delivery of oxygen to all cells. [ 2 ] Cardi

Poly(ethylene oxide)-block-Polyphosphoester-graft-Paclitaxel Conjugates with Acid-Labile Linkages as a pH-Sensitive and Functional Nanoscopic Platform for Paclitaxel Delivery

Abstract: There has been an increasing interest to develop new types of stimuli-responsive drug delivery vehicles with high drug loading and controlled release properties for chemotherapeutics. An acid-labile poly(ethylene oxide)-block-polyphosphoester-graft-PTX drug conjugate (PEO-b-PPE-g-PTX G2) degradable, polymeric paclitaxel (PTX) conjugate containing ultra-high levels of PTX loading is improved significantly, in this second-generation development, which involves connection of each PTX molecule to the polymer backbone via a pH-sensitive β-thiopropionate linkage. The PEO-b-PPE-g-PTX G2 forms well-defined nanoparticles in an aqueous solution, by direct dissolution into water, with a number-averaged hydrodynamic diameter of 114 ± 31 nm, and exhibits a PTX loading capacity as high as 53 wt%, with a maximum PTX concentration of 0.68 mg mL(-1) in water (vs 1.7 μg mL(-1) for free PTX). The PEO-b-PPE-g-PTX G2 shows accelerated drug release under acidic conditions (≈50 wt% PTX released in 8 d) compared with neutral conditions (≈20 wt% PTX released in 8 d). Compared to previously reported polyphosphoester-based PTX drug conjugates, PEO-b-PPE-g-PTX G1 without the β-thiopropionate linker, the PEO-b-PPE-g-PTX G2 shows pH-triggered drug release property and 5- to 8-fold enhanced in vitro cytotoxicity against two cancer cell lines.

Microneedle-based transdermal sensor for on-chip potentiometric determination of K(+).

Abstract: The determination of electrolytes is invaluable for point of care diagnostic applications An ion selective transdermal microneedle sensor is demonstrated for potassium by integrating a hollow microneedle with a microfluidic chip to extract fluid through a channel towards a downstream solid-state ion-selective-electrode (ISE) 3D porous carbon and 3D porous graphene electrodes, made via interference lithography, are compared as solid-state transducers for ISE's and evaluated for electrochemical performance, stability, and selectivity The porous carbon K(+) ISE's show better performance than the porous graphene K(+) ISE's, capable of measuring potassium across normal physiological concentrations in the presence of interfering ions with greater stability This new microfluidic/microneedle platform shows promise for medical applications

Poly(N-vinylcaprolactam): a thermoresponsive macromolecule with promising future in biomedical field.

Abstract: Poly(N-vinylcaprolactam) (PNVCL) is a thermoresponsive and biocompatible polymer that raises an increasing interest in the biomedical area, especially in drug delivery systems (DDS) that include micelles, hydrogels, and hybrid particles. The thermoresponsiveness of PNVCL, used alone or in combination with other stimuli- responsive polymers or particles (pH, magnetic field, or chemicals), is often key in the loading and/or release process in these DDS. The renewed focus on this polymer, which is known for decades, is to a large extent due to recent progress in synthetic strategies. Especially, the advent of efficient controlled radical polymerization (CRP) methods for NVCL monomer gives now access to unprecedented well-defined NVCL-based copolymers with unique properties. This Review article addresses up-to-date synthetic aspects, biological features, and biomedical applications of the latest NVCL-containing systems.

Biphasic ferrogels for triggered drug and cell delivery.

Abstract: Ferrogels are an attractive material for many biomedical applications due to their ability to deliver a wide variety of therapeutic drugs on-demand. However, typical ferrogels have yet to be optimized for use in cell-based therapies, as they possess limited ability to harbor and release viable cells. Previously, an active porous scaffold that exhibits large deformations and enhanced biological agent release under moderate magnetic fields has been demonstrated. Unfortunately, at small device sizes optimal for implantation (e.g., 2 mm thickness), these monophasic ferrogels no longer achieve significant deformation due to a reduced body force. A new biphasic ferrogel, containing an iron oxide gradient, capable of large deformations and triggered release even at small gel dimensions, is presented in this study. Biphasic ferrogels demonstrate increased porosity, enhanced mechanical properties, and potentially increased biocompatibility due to their reduced iron oxide content. With their ability to deliver drugs and cells on-demand, it is expected that these ferrogels will have wide utility in the fields of tissue engineering and regenerative medicine.

Gold‐Nanorod‐Assisted Near‐Infrared Stimulation of Primary Auditory Neurons

Abstract: Infrared stimulation offers an alternative to electrical stimulation of neuronal tissue, with potential for direct, non-contact activation at high spatial resolution. Conventional methods of infrared neural stimulation (INS) rely on transient heating due to the absorption of relatively intense laser beams by water in the tissue. However, the water absorption also limits the depth of penetration of light in tissue. Therefore, the use of a near-infrared laser at 780 nm to stimulate cultured rat primary auditory neurons that are incubated with silica-coated gold nanorods (Au NRs) as an extrinsic absorber is investigated. The laser-induced electrical behavior of the neurons is observed using whole-cell patch clamp electrophysiology. The nanorod-treated auditory neurons (NR-ANs) show a significant increase in electrical activity compared with neurons that are incubated with non-absorbing silica-coated gold nanospheres and control neurons with no gold nanoparticles. The laser-induced heating by the nanorods is confirmed by measuring the transient temperature increase near the surface of the NR-ANs with an open pipette electrode. These findings demonstrate the potential to improve the efficiency and increase the penetration depth of INS by labeling nerves with Au NRs and then exposing them to infrared wavelengths in the water window of tissue.

Enzyme-responsive cell-penetrating peptide conjugated mesoporous silica quantum dot nanocarriers for controlled release of nucleus-targeted drug molecules and real-time intracellular fluorescence imaging of tumor cells

Abstract: Here, a set of novel and personalized nanocarriers are presented for controlled nucleus-targeted antitumor drug delivery and real-time imaging of intracellular drug molecule trafficking by integrating an enzyme activatable cell penetrating peptide (CPP) with mesoporous silica coated quantum dots nanoparticles. Upon loading of antitumor drug, doxorubicin (DOX) and further exposure to proteases in tumor cell environment, the enzymatic cleavage of peptide sequence activates oligocationic TAT residues on the QDs@mSiO2 surface and direct the DOX delivery into cellular nucleus. The systematic cell imaging and cytotoxicity studies confirm that the enzyme responsive DOX-loaded CPP-QDs@mSiO2 nanoparticles can selectively release DOX in the tumor cells with high cathepsin B enzyme expression and greatly facilitate DOX accumulation in targeted nucleus, thus exhibiting enhanced antitumor activity in these cells. As contrast, there is limited nuclear-targeted drug accumulation and lower tumor cytotoxicity observed in the cells without enzyme expression. More importantly, significant antitumor DOX accumulation and higher tumor inactivation is also found in the drug resistant tumor cells with targeted enzyme expression. Such simple and specific enzyme responsive mesoporous silica-QDs nanoconjugates provide great promise for rational design of targeted drug delivery into biological system, and may thus greatly facilitate the medical theranostics in the near future.

Biodegradable thermogelling polymers: working towards clinical applications.

Abstract: As society ages, aging medical problems such as organ damage or failure among senior citizens increases, raising the demand for organ repair technologies. Synthetic materials have been developed and applied in various parts of human body to meet the biomedical needs. Hydrogels, in particular, have found extensive applications as wound healing, drug delivery and controlled release, and scaffold materials in the human body. The development of the next generation of soft hydrogel biomaterials focuses on facile synthetic methods, efficacy of treatment, and tunable multi-functionalities for applications. Supramolecular 3D entities are highly attractive materials for biomedical application. They are assembled by modules via various non-covalent bonds (hydrogen bonds, p-p stacking and/or van der Waals interactions). Biodegradable thermogels are a class of such supramolecular assembled materials. Their use as soft biomaterials and their related applications are described in this Review.

Microfluidic Generation of Gradient Hydrogels to Modulate Hematopoietic Stem Cell Culture Environment

Abstract: The bone marrow provides spatially and temporally variable signals that impact the behavior of hematopoietic stem cells (HSCs). While multiple biomolecular signals and bone marrow cell populations have been proposed as key regulators of HSC fate, new tools are required to probe their importance and mechanisms of action. Here, a novel method based on a microfluidic mixing platform to create small volume, 3D hydrogel constructs containing overlapping patterns of cell and matrix constituents inspired by the HSC niche is described. This approach is used to generate hydrogels containing opposing gradients of fluorescent microspheres, MC3T3-E1 osteoblasts, primary murine hematopoietic stem and progenitor cells (HSPCs), and combinations thereof in a manner independent of hydrogel density and cell/particle size. Three different analytical methods are described to characterize local properties of these hydrogels at multiple scales: 1) whole construct fluorescent analysis; 2) multi-photon imaging of individual cells within the construct; 3) retrieval of discrete sub-regions from the hydrogel post-culture. The approach reported here allows the creation of stable gradients of cell and material cues within a single, optically translucent 3D biomaterial to enable a range of investigations regarding how microenvironmental signals impact cell fate.

Monodispersed bioactive glass submicron particles and their effect on bone marrow and adipose tissue-derived stem cells.

Abstract: Spherical monodispersed bioactive particles are potential candidates for nanocomposite synthesis or as injectable particles that could be internalized by cells for the local sustained delivery of inorganic therapeutic ions (e.g., calcium or strontium). Particles are also likely to be released from porous bioactive glass and sol-gel hybrid scaffolds as they degrade; thus, it is vital to investigate their interaction with cells. Spherical monodispersed bioactive glass particles (mono-SMBG), with diameters of 215 ± 20 nm are synthesized using a modified Stober process. Confocal and transmission electron microscopy demonstrate that mono-SMBGs are internalized by human bone marrow (MSCs) and adipose-derived stem cells (ADSCs) and located within cell vesicles and in the cytoplasm. Particle dissolution inside the cells is observed. Alamar Blue, MTT and Cyquant assays demonstrate that 50 μg mL(-1) of mono-SMBGs did not inhibit significantly MSC or ADSC metabolic activity. However, at higher concentrations (100 and 200 μg mL(-1)) small decrease in metabolic activity and total DNA is observed. Mono-SMBG did not induce ALPase activity, an early marker of osteogenic differentiation, without osteogenic supplements; however, in their presence osteogenic differentiation is achieved. Additionally, large numbers of particles are internalized by the cells but have little effect on cell behavior.

Highly fluorescent and photostable probe for long-term bacterial viability assay based on aggregation-induced emission.

Abstract: Long-term tracking of bacterial viability is of great importance for monitoring the viability change of bacteria under storage, evaluating disinfection efficiency, as well as for studying the pharmacokinetic and pharmacodynamic properties of antibacterials. Most of the conventional viability dyes, however, suffer from high toxicity and/or poor photostability, making them unsuitable for long-term studies. In this work, an aggregation-induced emission molecule, TPE-2BA, which can differentiate dead and living bacteria and serve as a highly fluorescent and photostable probe for long-term viability assay. TPE-2BA is a cell-impermeable DNA stain that binds to the groove of double-stranded DNA. Bacteria with compromised membrane open the access for TPE-2BA to reach DNA, endowing it with strong emission. The feasibility of using TPE-2BA for screening effective bactericides is also demonstrated. Plate count experiment reveals that TPE-2BA poses negligible toxicity to bacteria, indicating that it is an excellent probe for long-term bacterial viability assay.

Stretchable, Multiplexed pH Sensors With Demonstrations on Rabbit and Human Hearts Undergoing Ischemia

Abstract: Stable pH is an established biomarker of health, relevant to all tissues of the body, including the heart. Clinical monitoring of pH in a practical manner, with high spatiotemporal resolution, is particularly difficult in organs such as the heart due to its soft mechanics, curvilinear geometry, heterogeneous surfaces, and continuous, complex rhythmic motion. The results presented here illustrate that advanced strategies in materials assembly and electrochemical growth can yield interconnected arrays of miniaturized IrOx pH sensors encapsulated in thin, low-modulus elastomers to yield conformal monitoring systems capable of noninvasive measurements on the surface of the beating heart. A thirty channel custom data acquisition system enables spatiotemporal pH mapping with a single potentiostat. In vitro testing reveals super-Nernstian sensitivity with excellent uniformity (69.9 ± 2.2 mV/pH), linear response to temperature (-1.6 mV °C(-1) ), and minimal influence of extracellular ions (<3.5 mV). Device examples include sensor arrays on balloon catheters and on skin-like stretchable membranes. Real-time measurement of pH on the surfaces of explanted rabbit hearts and a donated human heart during protocols of ischemia-reperfusion illustrate some of the capabilities. Envisioned applications range from devices for biological research, to surgical tools and long-term implants.

Graphene Oxide Triggers Toll-Like Receptors/Autophagy Responses In Vitro and Inhibits Tumor Growth In Vivo

Abstract: Graphene oxide (GO) is a nanomaterial with burgeoning bioapplications, while autophagy is implicated in cancer therapy. Although induction of autophagy by nanomaterials is reported, the underlying signaling mechanism in cancer cells and how this implicates the potential of GO in cancer therapy remain obscure. Here, it is shown that GO itself can induce the toll-like receptors (TLRs) responses and autophagy in cancer cells and confer antitumor effects in mice. GO can be phagocytosed by CT26 colon cancer cells, simultaneously triggering autophagy as well as TLR-4 and TLR-9 signaling cascades. By dissecting the crosstalk between the TLRs and autophagy pathways, it is uncovered that the GO-activated autophagy is regulated through the myeloid differentiation primary response gene 88 (MyD88)- and TNF receptor-associated factor 6 (TRAF6)-associated TLR-4/9 signaling pathways. Injection of GO alone into immunocompetent mice bearing the CT26 colon tumors not only suppresses the tumor progression but also enhances cell death, autophagy, and immune responses within the tumor bed. These data altogether implicate the potential of GO as an effective nanomaterial for autophagy induction and cancer therapy.

Disulfide Cross-Linked Polyurethane Micelles as a Reduction-Triggered Drug Delivery System for Cancer Therapy

Abstract: Nanoscale carriers that stably load drugs in blood circulation and release the payloads in desirable sites in response to a specific trigger are of great interest for smart drug delivery systems. For this purpose, a novel type of disulfide core cross-linked micelles, which are facilely fabricated by cross-linking of poly(ethylene glycol)/polyurethane block copolymers containing cyclic disulfide moieties via a thiol-disulfide exchange reaction, are developed. A broad-spectrum anti-cancer drug, doxorubicin (DOX), is loaded into the micelles as a model drug. The drug release from the core cross-linked polyurethane micelles (CCL-PUMs) loaded with DOX is suppressed in normal phosphate buffer saline (PBS), whereas it is markedly accelerated with addition of an intracellular reducing agent, glutathione (GSH). Notably, although DOX-loaded CCL-PUMs display lower cytotoxicity in vitro compared to either free DOX or DOX-loaded uncross-linked polyurethane micelles, the drug-loaded CCL-PUMs show the highest anti-tumor efficacy with reduced toxicity in vivo. Since enhanced anti-tumor efficacy and reduced toxic side effects are key aspects of efficient cancer therapy, the novel reduction-responsive CCL-PUMs may hold great potential as a bio-triggered drug delivery system for cancer therapy.

Titrating T-cell epitopes within self-assembled vaccines optimizes CD4+ helper T cell and antibody outputs.

Abstract: Epitope content plays a critical role in determining T-cell and antibody responses to vaccines, biomaterials, and protein therapeutics, but its effects are nonlinear and difficult to isolate. Here, molecular self-assembly is used to build a vaccine with precise control over epitope content, in order to finely tune the magnitude and phenotype of T helper and antibody responses. Self-adjuvanting peptide nanofibers are formed by co-assembling a high-affinity universal CD4+ T-cell epitope (PADRE) and a B-cell epitope from Staphylococcus aureus at specifiable concentrations. Increasing the PADRE concentration from micromolar to millimolar elicited bell-shaped dose-responses that are unique to different T-cell populations. Notably, the epitope ratios that maximize T follicular helper and antibody responses differed by an order of magnitude from those that maximized Th1 or Th2 responses. Thus, modular materials assembly provides a means of controlling epitope content and efficiently skewing the adaptive immune response in the absence of exogenous adjuvant; this approach may contribute to the development of improved vaccines and immunotherapies.