In-drop thermal cycling of microcrystal assembly for senescence control (MASC) with minimal variation in efficacy.

The secretome from mesenchymal stem cells (MSCs) has recently gained attention for new therapeutics. However, clinical application requires in vitro cell manufacturing to attain enough cells. Unfortunately, this process often drives MSCs into a senescent state that drastically changes cellular secretion activities. Antioxidants are used to reverse and prevent the propagation of senescence; however, their activity is short-lived. Polymer-stabilized crystallization of antioxidants has been shown to improve bioactivity, but the broad crystal size distribution (CSD) significantly increases the efficacy variation. Efforts were made to crystalize drugs in microdroplets to narrow the CSD, but the fraction of drops containing at least one crystal can be as low as 20%. To this end, this study demonstrates that in-drop thermal cycling of hyaluronic acid-modified antioxidant crystals, named microcrystal assembly for senescence control (MASC), can drive the fraction of microdrops containing crystals to >86% while achieving significantly narrower CSDs (13±3µm) than in bulk (35±11µm). Therefore, this approach considerably improves the practicality of CSD-control in drops. In addition to exhibiting uniform release, MASC made with antioxidizing N-acetylcysteine extended the release time by 40%. MASC further improves the restoration of reactive oxygen species homeostasis in MSCs, thus minimizing cellular senescence and preserving desired secretion activities. We propose that MASC is broadly useful to controlling senescence of a wide array of therapeutic cells during biomanufacturing.

Stimulus-Responsive Anti-Oxidizing Drug Crystals and their Ecological Implication.

Various antioxidants are being used to neutralize the harmful effects of reactive oxygen species (ROS) overproduced in diseased tissues and contaminated environments. Polymer-directed crystallization of antioxidants has attracted attention as a way to control drug efficacy through molecular dissolution. However, most recrystallized antioxidants undertake continuous dissolution independent of the ROS level, thus causing side-effects. This study demonstrates a unique method to assemble antioxidant crystals that modulate their dissolution rate in response to the ROS level. We hypothesized that antioxidants recrystallized using a ROS-labile polymer would be triggered to dissolve when the ROS level increases. We examined this hypothesis by using catechin as a model antioxidant. Catechin was recrystallized using polyethylenimine cross-linked with ROS-labile diselanediylbis-(ethane-2,1-diyl)-diacrylate. Catechin crystallized with the ROS-labile polymer displays accelerated dissolution proportional to the H2 O2 concentration. The ROS-responsive catechin crystals protect vascular cells from oxidative insults by activating intracellular glutathione peroxidase expression and, in turn, inhibiting an increase in the intracellular oxidative stress. In addition, ROS-responsive catechin crystals alleviate changes in the heart rate of Daphnia magna in oxidative media. We propose that the results of this study would be broadly useful for improving the therapeutic efficacy of a broad array of drug compounds.

In Situ Incorporation of Pores and Nanoparticles into Polymer Surfaces Using Melt Crystallization.

Engineering the surface properties of a material without affecting its bulk properties is desirable for many applications, but it is often not readily achievable because it requires a complex series of processing steps. This study presents for the first time a simple and straightforward method that can convert regular flat polymer surfaces into various porous composite surfaces. The controlled dissolution of the polymer surface by a dispersion and subsequent melt crystallization allows for the successful embedding of dispersed inorganic or organic particles in the pore walls. The porous surface morphology is not significantly affected by the type of dispersed particle, but the contact and sliding angles and surface wettability are. Both superhydrophobic and oil/water separation surfaces can be conveniently fabricated from flat polymer surfaces. This novel and versatile technique could provide engineering freedom for the future development of various functional materials.

Spatial Organization of Superparamagnetic Iron Oxide Nanoparticles in/on Nano/Microsized Carriers Modulates the Magnetic Resonance Signal.

Superparamagnetic iron oxide nanoparticles (SPIONs) are often encapsulated into drug-carrying nano/microsized particles for simultaneous magnetic resonance (MR) imaging and treatment of diseased tissues. Unfortunately, encapsulated SPIONs may have a limited ability to modulate the T2-weighted relaxation of water protons, but this insight has not been examined systematically. This study demonstrates that SPIONs immobilized on 200 nm diameter poly(lactic- co-glycolic acid) (PLGA) nanoparticles using Pickering emulsification present 18-fold higher relaxivity than encapsulated SPIONs and 1.5-fold higher relaxivity than free SPIONs. In contrast, the SPIONs immobilized on 10 µm diameter PLGA particles exhibit a minor increase in MR relaxivity. This interesting finding will significantly impact current efforts to synthesize and assemble advanced MR contrast agents.

Enhanced Adhesion of Polydimethylsiloxane Using an Interlocked Finger Structure.

Silicone-based polymers have been widely used for many applications, but their extremely low surface energies and the resulting poor adhesion have been the cause for continuous problems. Herein, a novel adhesion improvement technique using an interlocked finger structure is demonstrated, which enables up to 24.8 and 7.3-fold increases in adhesion compared to the untreated and conventional plasma-treated cases, respectively. The interlocked finger structure is fabricated by surface-confined dissolution and subsequent directional melt crystallization of a solvent. After removing the solvent crystals, porous surfaces are prepared from polyurethane, polyvinyl alcohol, and polystyrene, and these are used to fabricate interfaces of interlocked finger structures with polydimethylsiloxane. The improvement in adhesion strength linearly depends on the pore depth of the prepared surfaces. This novel technique of surface adhesion could improve the performance of polymers with intrinsically poor adhesion in future applications.

Translational and rotational motion control of microgels enabling shoaling and schooling.

A technique for adequate flow control is important in the fields of science and engineering. In this study, we hypothesized that the unrestricted flow control inside a chamber containing 'schools of magnetic particles' might be possible through control of an external magnetic field, biomimicking the flow generated by schools of fish. Microgels based on superparamagnetic iron oxide nanoparticles (SPIONs) and poly(acrylic acid) hydrogels were employed. With an increase in the SPION content, the microgels responded more efficiently to the translational movement of the magnetic field. Rotational movement was more efficiently achieved with anisotropic distribution of SPIONs inside microgels, which was induced by applying a magnetic field immediately prior to crosslinking. The systems of the anisotropic microgels successfully provided microflow for effective mixing in a capillary. This biomimetic flow control may be useful for the control of fluid systems of any micro- or nano-size and any shape, regardless of the tortuosity.

In-Situ Formation of Polymer Particles Embedded in Electrospun Fibers via Multi-Nozzle Electrospinning in a Pulsating Instability Regime.

Engineering novel material structures has continually been pursued to further advance modern technologies. These advancements often rely on novel processing technologies. Although many processing parameters have been thoroughly examined in the field of electrospinning, the quasi-steady-state jetting modes are an exception. In this work, we examine the unique structures of polymer particles embedded in water-soluble electrospun fibers, which were successfully prepared via multi-nozzle electrospinning in a pulsating instability mode, without additional emulsifying steps. The aspect ratio of polymer particles can be tailored, based on the concentration of the inner solution, the size of the inner nozzle, and the conductivity of the solution. After dissolving the water-soluble sheath, the polymer particles can easily be dispersed in water and separated from the matrix. This novel electrospinning technology has the potential to open new areas of research such as electrohydrodynamic jetting for drug-delivery systems, sensors, scaffolds, and intelligent coatings.

Pectin Micro- and Nano-capsules of Retinyl Palmitate as Cosmeceutical Carriers for Stabilized Skin Transport.

Retinyl palmitate (RP)-loaded pectinate micro- and nano-particles (PMP and PNP) were designed for stabilization of RP that is widely used as an anti-wrinkle agent in anti-aging cosmeceuticals. PMP/PNP were prepared with an ionotropic gelation method, and anti-oxidative activity of the particles was measured with a DPPH assay. The stability of RP in the particles along with pectin gel and ethanolic solution was then evaluated. In vitro release and skin permeation studies were performed using Franz diffusion cells. Distribution of RP in each skin tissue (stratum corneum, epidermis, and dermis) was also determined. PMP and PNP could be prepared with mean particle size diameters of 593~843 µm (PMP) and 530 nm (i.e., 0.53 µm, PNP). Anti-oxidative activity of PNP was greater than PMP due largely to larger surface area available for PNP. The stability of RP in PMP and PNP was similar but much greater than RP in pectin bulk gels and ethanolic solution. PMP and PNP showed the abilities to constantly release RP and it could be permeated across the model artificial membrane and rat whole skin. RP was serially deposited throughout the skin layers. This study implies RP loaded PMP and PNP are expected to be advantageous for improved anti-wrinkle effects.

Encapsulated particles attached on electrospun fibers by in situ combination of electrospinning and coaxial electrospraying.

Electrohydrodynamic jetting has been widely used as a promising strategy for the development of functionalized scaffolds to mimic natural extracellular matrix. The current electrospun scaffolds achieve functionality through additional mechanical or chemical treatments, and their life-time depends on fiber degradation. An innovative in situ approach used to attach core-shell poly(D,L-lactide-co-glycolide) (PLGA) particles on fibrous mats is described here. This particle/fiber composite was prepared by electrohydrodynamic jetting of countercharged nozzles (EJC) based on neutralization between electrospun nanofibers and coaxial electrosprayed droplets. The PLGA particles were successfully attached onto both water-soluble polyvinylpyrrolidone and hydrophobic poly(L-lactide-co-D,L-lactide). The resulting release rates of encapsulated model compounds were independently controlled by fiber degradation. Encapsulation efficiency and the dimensions of particles and fibers were easily engineered by changing solvents. The particle/fiber composite prepared by EJC could be a superior material for developing future biomaterials with architectured biological and mechanical properties.

Pore size reduction in directional crystallization processing of porous polymeric membranes.

Although various prep technologies of porous polymeric materials have evolved, the versatile control of pore morphology still remains as the most demanding subject. Herein, we applied the engineering principles of crystal habit by directional crystallization to the fabrication of porous PVDF (polyvinylidene fluoride) membranes. Pores of low tortuosity and relatively high porosity (80-90%) were successfully fabricated by the directional crystallization of DMSO (dimethyl sulfoxide) under a temperature gradient imposed by the controlled movement of a sample toward a liquid nitrogen reservoir followed by subsequent solvent removal. Pore size was controlled across a wide range by mixing DMSO with dioxane. Notably, nanoporous structures could be prepared at a 1:1 mixing ratio, in which the multi-step crystallization of solvents restricted by highly concentrated solutes enabled the preparation of nanomembranes. The homogeneous dispersion of TiO2 nanoparticles into PVDF, which are often used to improve hydrophilicity and antifouling performance, was easily achieved by this method. This novel prep technology based on the directional crystallization of solvent mixtures is a potentially viable solution to the limitations of current porous materials research.

Redispersible drug nanoparticles prepared without dispersant by electro-spray drying.

The redispersibility of drug nanoparticles is critical in the formulation development of oral solid dosage forms from drug nanosuspensions. To address this issue, various drying techniques such as, spray drying, fluidized bed drying, etc. have been developed based on freeze drying. In this work, redispersible dried powders were successfully prepared from drug nanosuspensions without the use of dispersant by applying an electrical potential to the nozzle during the spray drying process. The applied voltage, not the concentration of the nanosuspension, was critical in determining the redispersibility. Despite the high electric field, the particle morphology and crystallinity were not dependent on the applied voltage, which suggests that the drug crystals were not damaged. This novel technique could broaden the applicability of spray drying technology and allow for novel formulations of drug nanoparticles.

Extending the Bioavailability of Hydrophilic Antioxidants for Metal Ion Detoxification via Crystallization with Polysaccharide Dopamine.

Although metal ions, such as silver and gold, have been shown to have strong antimicrobial properties, their potential to have toxic effects on human and environmental health has gained interest with an improved understanding of their mechanisms to promote oxidative stress. Redox control is a major focus of many drug delivery systems and often incorporates an antioxidant as the active pharmaceutical ingredient (API) to neutralize overproduced reactive oxygen species (ROS). Nevertheless, there are still limitations with bioavailability and extended redox control with regard to antioxidant drug delivery. Herein, this study develops a colloidal antioxidant crystal system that dissolves sustainably through polymer stabilization using sodium hyaluronate conjugated with dopamine (HA-dopa). We explore the role of dopamine incorporation into crystal-stabilizing polymers and quantify the balance between drug-polymer interactions and competing polymer-polymer interactions. We propose that this type of analysis is useful in the engineering of and provides insight into the release behavior of polymer-crystal complexes. In developing our crystal complex, N-acetylcysteine (NAC) was used as the model antioxidant to protect against silver ion toxicity. We found that our optimized HA-dopa-stabilized NAC crystals prolong the release time of NAC 5-fold compared to a polymer-free NAC crystal. Therefore, following sublethal exposure to AgNO3, the extended lifetime of NAC was able to maintain normal intracellular ROS levels, modulate metabolic function, mitigate fluctuations in ATP levels and ATP synthase activity, and preserve contraction frequency in engineered cardiac muscle tissue. Furthermore, the protective effects of the HA-dopa-stabilized NAC crystals were extended to a Daphnia magna model where silver-ion-induced change to both cell-level biochemistry and organ function was alleviated. As such, we propose that the packaging of hydrophilic antioxidants as colloidal crystals drastically extends the lifetime of the API, better maintains ROS homeostasis post metal ion exposure, and therefore preserves both intracellular biochemistry and tissue functionality.

Folate-targeted drug-delivery systems prepared by nano-comminution.

BACKGROUND: The size reduction ability of conventional wet comminution has been improved by proper polymeric stabilizer systems, and the resulting nano-comminution methods have led to the commercialization of many poorly water-soluble drugs after improving their bioavailability. During nano-comminution, polymer steric stabilizers physically adsorb onto the surface of drug particles. METHOD: In this study, the cross-linking and subsequent functionalization methods of the physically adsorbed polymers were used to widen the applicability of the nano-comminution. Chitosan was used as a steric stabilizer for two hydrophobic drugs, naproxen and paclitaxel. RESULTS: Chitosan was successfully cross-linked (immobilized) by tripolyphosphate. The cross-linked stable polymer layer on drug nanoparticles was conjugated with folic acid, a model targeting moiety. The chemical reactions were performed without destroying the stabilities of drug nanosuspensions. The cross-linking and conjugation reactions significantly modified the release profiles of drug nanoparticles. CONCLUSION: This simple preparation method can be utilized to prepare novel drug encapsulations and folate-targeted delivery systems.

Novel polymorphic form of adefovir dipivoxil derived from polymer-directed crystallization.

Crystallization is an essential step in pharmaceutical processing. The discovery of a non-classical crystallization pathway would be a promising strategy to engineer the properties of drug crystalline particles for specific delivery conditions. Herein, polymer-directed crystallization was successfully employed to modify the characteristics of a model drug, adefovir dipivoxil (AD). Polyacrylic acid (PAA), ethyl cellulose (EC), and hydroxypropyl cellulose were added as active polymers to control the crystallization pathway of AD. Changes in crystal habit were observed in all cases. A novel polymorph was found after the addition of PAA and EC, and was confirmed by XRD and DSC results. In FTIR investigations, the crystals derived from PAA-directed crystallization showed strong interactions between PAA and AD. The polymer content in polymer-directed crystallization-derived powders varied from 7 to 24 wt%, and the presence of polymers lead to sustained release of AD. These results make polymer-directed crystallization a simple and efficient technique to engineer the physical and chemical properties of drug crystals.

Temperature-Responsive On-Off Control over Water Evaporation Achieved via Sweat-Gland-Mimetic Composites.

Responsive cooling materials that mimic sweat glands have gained popularity because they are efficient and do not require artificial energy sources. Temperature-responsive hydrogels sweat above their volume transition temperature through the release of water and exhibit excellent cooling ability. However, thus far, practical applications have not been possible because the water in these materials cannot be preserved in cool environments. To address this issue, this paper presents a simple composite of poly(N-isopropylacrylamide) and polydimethylsiloxane that offers excellent on-off control over water evaporation and can be used repeatedly; the proposed composite features an evaporation rate of 2.97 g/h above the lower critical solution temperature (LCST) and 0.08 g/h below the LCST. This 35.7-fold change in the water evaporation rate is comparable to that in mammalian sweat glands. The responsive on-off control relies on the structures of the composite and the dry layers formed on the surface of the composite in cool environments. The proposed material effectively regulates water evaporation and offers a novel, low-cost cooling strategy suitable for numerous applications.

Highly spherical and deformable chitosan microspheres for arterial embolization.

The aim of this study was to fabricate deformable chitosan (CS) microspheres for arterial embolization. CS microspheres containing poly(ethylene glycol) (PEG) were prepared by ionotropic gelation; PEG was then removed from the CS microspheres to produce the highly porous structure to allow deformability. The porosity was controlled by blending ratios of CS/PEG polymers (CS/PEG=from 100/0 to 15/85) and the effect of porosity on microcatheter delivery was examined. The size range of porous microspheres was 500-600 mum with sphericity between 1.012-1.041. Scanning electron microscope observation confirmed that microporous networks were effectively obtained by PEG extraction proportional to the initial amount of PEG. Water retention capacities, indicative of internal porosities of microspheres, increased with increasing initial amounts of blended PEG. CS microspheres with water retention values of greater than 28% exhibited noticeable deformation and smooth passage through the microcatheter tip. Novel deformable microspheres are, therefore, expected to be clinically applicable for arterial embolization.

Lipoic acid nanoparticles: effect of polymeric stabilizer on appetite suppression.

Alpha-lipoic acid (ALA), which is common in the human body, is efficacious in appetite suppression. However, its typical formulations of salt or micronized crystals cannot satisfy the desired bioavailability requirements for appetite suppression due to low absorption and a short plasma half-life. Herein, we describe a new ALA nanoparticulate formulation produced by nano-comminution using polymeric stabilizers, such as hydroxypropyl cellulose, Pluronic F127, and polyvinylpyrrolidone. Nanoparticles of similar sizes did not show any remarkable differences in the in vitro release profiles. However, the in vivo results from food intake studies in mice demonstrated that the hydroxypropyl cellulose case had the largest improved efficacy among the three polymeric stabilizer cases. Compared to the nanosuspension formulations, the powder formulations of nanoparticles had improved efficacy in reducing food intake for six hours, possibly because of the delayed release kinetics. Therefore, the ALA powder formulation of nanoparticles is a candidate to replace the current formulations to achieve proper appetite suppression.

Stretchable Lithium-Ion Battery Based on Re-entrant Micro-honeycomb Electrodes and Cross-Linked Gel Electrolyte.

Stretchable energy storage devices are of great interest because of their potential applications in body-friendly, skin-like, wearable devices. However, stretchable batteries are very challenging to fabricate. The electrodes must have a degree of stretchability because the active materials occupy most of the volume, and the separator and packaging should also be stretchable. Here, an all-component stretchable lithium-ion battery was realized by leveraging the structural stretchability of re-entrant micro-honeycomb graphene-carbon nanotube (CNT)/active material composite electrodes and a physically cross-linked gel electrolyte, without using an inactive elastomeric substrate or matrix. Active materials interconnected via the entangled CNT and graphene sheets provided a mechanically stable porous network framework, and the inwardly protruding framework in the re-entrant honeycomb structure allowed for structural stretching during deformation. The composite network consisting solely of binder-free, highly conductive materials provided superior electron transfer, and vertically aligned microchannels enabled facile ion transport. Additionally, the physically cross-linked gel electrolyte increased the mechanical stability upon deformation of the electrodes and was effective as a stretchable separator. The resulting stretchable battery showed a high areal capacity of 5.05 mAh·cm-2, superior electrochemical performance up to 50% strain under repeated (up to 500) stretch-release cycles, and long-term stability of 95.7% after 100 cycles in air conditions.

Electrothermal soft manipulator enabling safe transport and handling of thin cell/tissue sheets and bioelectronic devices.

"Living" cell sheets or bioelectronic chips have great potentials to improve the quality of diagnostics and therapies. However, handling these thin and delicate materials remains a grand challenge because the external force applied for gripping and releasing can easily deform or damage the materials. This study presents a soft manipulator that can manipulate and transport cell/tissue sheets and ultrathin wearable biosensing devices seamlessly by recapitulating how a cephalopod's suction cup works. The soft manipulator consists of an ultrafast thermo-responsive, microchanneled hydrogel layer with tissue-like softness and an electric heater layer. The electric current to the manipulator drives microchannels of the gel to shrink/expand and results in a pressure change through the microchannels. The manipulator can lift/detach an object within 10 s and can be used repeatedly over 50 times. This soft manipulator would be highly useful for safe and reliable assembly and implantation of therapeutic cell/tissue sheets and biosensing devices.

Improved efficacy of appetite suppression by lipoic acid particles prepared by nanocomminution.

PURPOSE: This article was intended to improve the efficacy of alpha-lipoic acid (ALA) for appetite suppression by controlling the particle size and self-polymerization of ALA. METHODS: ALA was fabricated into micro- and nanoparticles, and the efficacy and in vitro release were investigated. Because of the self-polymerization of ALA into poly[3-(n-butane carboxylic acid)propyl]disulfide (PBCPD) by processing heat, low-speed rotation comminution was used to control PBCPD content. RESULTS: The ALA particle size initially decreased and then increased after 10 hours of nanocomminution, indicating aggregation related to PBCPD formation. The in vitro release of ALA was significantly reduced by the existence of PBCPD. Interestingly, the reduction was not followed by a decrease in efficacy. Alternatively, the food intake was significantly reduced by ALA particles containing more than 30 mol% PBCPD. CONCLUSIONS: When the particle size and self-polymerization of ALA were carefully controlled, the efficacy on appetite suppression could be superior to water-soluble ALA salt. The ALA particles might have a composite nanostructure of ALA and PBCPD.