Engineering Interconnected Open-Porous Particles via Microfluidics Using Bijel Droplets as Structural Templates.

Designing porous structures is key in materials science, particularly for separation, catalysis, and cell culture systems. Bicontinuous interfacially jammed emulsion gels represent a unique class of soft matter formed by kinetically arresting the separation of the spinodal decomposition phase, which is stabilized by colloidal particles with neutral wetting. This study introduces a microfluidic technique to create highly interconnected open-porous particles using bijel droplets stabilized with hexadecyltrimethylammonium bromide (CTAB)-modified silica particles. Monodisperse droplets comprising a hydrophobic monomer, water, ethanol, silica particles, and CTAB were initially formed in the microfluidic device. The diffusion of ethanol from these droplets into the continuous cyclohexane phase triggered spinodal decomposition within the droplets. The phase-separated structure within the droplets was stabilized by the CTAB-modified silica particles, and subsequent photopolymerization yielded microparticles with highly interconnected, open pores. Moreover, the influence of the ratio of the CTAB and silica particles, fluid composition, and microchannel direction on the final structure of the microparticles was explored. Our findings indicated that the phase-separated structure of the particles transitioned from oil-in-water to water-in-oil as the CTAB/silica ratio was increased. At intermediate CTAB/silica ratios, microparticles with bicontinuous structures were formed. Regardless of the fluid composition, the pore size of the particles increased with time after phase separation. However, this coarsening was arrested 15 s after droplet formation in the CTAB-modified silica particles, accompanied by a change in the particle shape from spherical to ellipsoidal. In situ observations of the bijel droplet formation revealed that the particle shape deformation is caused by the rolling of elastic bijel droplets at the bottom of the microchannel. As such, the channel setup was altered from horizontal to vertical to prevent the deformation of bijel droplets, resulting in spherical particles with open pores.

Controlled mechanical properties of poly(ionic liquid)-based hydrophobic ion gels by the introduction of alumina nanoparticles with different shapes.

Ionic-liquid gels, also known as ion gels, have gained considerable attention due to their high ionic conductivity and CO2 absorption capacity. However, their low mechanical strength has hindered their practical applications. A potential solution to this challenge is the incorporation of particles, such as silica nanoparticles, TiO2 nanoparticles, and metal-organic frameworks (MOFs) into ion gels. Comparative studies on the effect of particles with different shapes are still in progress. This study investigated the effect of the shape of particles introduced into ion gels on their mechanical properties. Consequently, alumina/poly(ionic liquid) (PIL) double-network (DN) ion gels consisting of clustered alumina nanoparticles with various shapes (either spherical or rod-shaped) and a chemically crosslinked poly[1-ethyl-3-vinylimidazolium bis(trifluoromethanesulfonyl)imide] (PC2im-TFSI, PIL) network were prepared. The results revealed that the mechanical strengths of the alumina/PIL DN ion gels were superior to those of PIL single-network ion gels without particles. Notably, the fracture energies of the rod-shaped alumina/PIL DN ion gels were approximately 2.6 times higher than those of the spherical alumina/PIL DN ion gels. Cyclic tensile tests were performed, and the results indicate that the loading energy on the ion gel was dissipated through the fracture of the alumina network. TEM observation suggests that the variation in the mechanical strength depending on the shape can be attributed to differences in the aggregation structure of the alumina particles, thus indicating the possibility of tuning the mechanical strength of ion gels by altering not only particle kinds but its shape.

Toughening of poly(ionic liquid)-based ion gels with cellulose nanofibers as a sacrificial network.

Ion gels have the potential to be used in a broad range of applications, such as in carbon dioxide separation membranes and soft electronics. However, their low mechanical strength limits their practical applications. In this study, we developed double-network (DN) ion gels composed of TEMPO-oxidized cellulose nanofibers with hydrophobic groups (TOCNF) and cross-linked poly[1-ethyl-3-vinylimidazolium bis(trifluoromethanesulfonyl)imide] (PC2im-TFSI) networks. The mechanical strength of the gel increased as the amount of TOCNF in the gels increased up to 6 wt%. Moreover, the fracture energy of the DN ion gels with 6 wt% TOCNF was found to be 19 times higher than that of the PC2im-TFSI single network (SN) ion gels. Cyclic stress-strain measurements of the DN gels showed that the loading energy on the gels dissipates owing to the destruction of the physically cross-linked TOCNF network in the gels. The DN ion gels also exhibited a high decomposition temperature of approximately 400 °C because of the thermal stability of all components. Additionally, the fracture energy of the TOCNF/poly(ionic liquid) (PIL) DN ion gel was two times higher than that of the silica nanoparticles/PIL DN ion gel developed in our previous study [Watanabe et al., Soft Matter, 2020, 16, 1572-1581]. This suggests that fiber-shaped nanomaterials are more effective than spherical nanomaterials in enhancing the mechanical properties of ion gels. These results show that TOCNF can be used to toughen PIL-based ion gels and hence broaden their applications.

Microfluidic Production of Monodisperse Biopolymer Microcapsules for Latent Heat Storage.

Microencapsulation of phase change materials in a polymer shell is a promising technology to prevent them from leakage and to use them as a handleable powder state. However, the microencapsulation process is a time-consuming process because the typical shell-forming step requires polymerization or evaporation of the solvent. In this study, we report a simple and rapid flow process to prepare monodisperse biocompatible cellulose acetate (CA) microcapsules encapsulating n-hexadecane (HD) for latent heat storage applications. The microcapsules were prepared by combining microfluidic droplet formation and subsequent rapid solvent removal from the droplets by solvent diffusion. The diameter and shell thickness of the microcapsules could be controlled by adjusting the flow rate and the HD-to-CA weight ratio in the dispersed phase. We found that 1-hexadecanol added to the microcapsules played the role of a nucleation agent and mitigated the supercooling phenomenon during crystallization. Furthermore, cross-linking of the CA shell with poly(propylene glycol), tolylene 2,4-diisocyanate terminated, resulted in the formation of a thin and dense shell. The microcapsules exhibited a 66 wt % encapsulation efficiency and a 176 J g-1 latent heat storage capacity, with negligible supercooling. We believe that this microflow process can contribute to the preparation of environmentally friendly microcapsules for heat storage applications.

Design of Clickable Ionic Liquid Monomers to Enhance Ionic Conductivity for Main-Chain 1,2,3-Triazolium-Based Poly(Ionic Liquid)s.

A series of clickable α-azide-ω-alkyne ionic liquid (IL) monomers with an ethylene oxide spacer were developed and applied to the synthesis of 1,2,3-triazolium-based poly(ionic liquid)s (TPILs) with high ionic conductivities via one-step thermal azide-alkyne cycloaddition click chemistry. Subsequently, the number of IL moieties in the resultant TPILs was further increased by N-alkylation of the 1,2,3-triazole-based backbones of the TPILs with a quarternizing reagent. This strategy affords the preparation of TPILs having either one or two 1,2,3-triazolium cations with bis(trifluoromethylsulfonyl)imide anions in a monomer unit. Synthesis of the TPILs was confirmed by 1H and 13C NMR spectroscopy and gel permeation chromatography. The effects of the length of the ethylene oxide spacer and the number of IL moieties in the IL monomer unit on the physicochemical properties of the TPILs were characterized by differential scanning calorimetry, thermogravimetric analysis, and impedance spectroscopy. The introduction of a longer ethylene oxide spacer or an increase in the number of IL moieties in the monomer unit resulted in TPILs with lower glass-transition temperatures and higher ionic conductivities. The highest ionic conductivity achieved in this study was 2.0 × 10-5 S cm-1 at 30 °C. These results suggest that the design of the IL monomer provides the resultant polymer with high chain flexibility and a high IL density, and so it is effective for preparing TPILs with high ionic conductivities.

Millimeter-thick xenoislet-laden fibers as retrievable transplants mitigate foreign body reactions for long-term glycemic control in diabetic mice.

Transplantation technologies of pancreatic islets as well as stem cell-derived pancreatic beta cells encapsulated in hydrogel for the induction of immunoprotection could advance to treat type 1 diabetes mellitus, if the hydrogel transplants acquire retrievability through mitigating foreign body reactions after transplantation. Here, we demonstrate that the diameter of the fiber-shaped hydrogel transplants determines both in vivo cellular deposition onto themselves and their retrievability. Specifically, we found that the in vivo cellular deposition is significantly mitigated when the diameter is 1.0 mm and larger, and that 1.0 mm-thick xenoislet-laden fiber-shaped hydrogel transplants can be retrieved after being placed in the intraperitoneal cavities of immunocompetent diabetic mice for more than 100 days, during which period the hydrogel transplants can normalize the blood glucose concentrations of the mice. These findings could provide an innovative concept of a transplant that would promote the clinical application of stem cell-derived functional cells through improving their in vivo efficacy and safety.

Preparation of tough, thermally stable, and water-resistant double-network ion gels consisting of silica nanoparticles/poly(ionic liquid)s through photopolymerisation of an ionic monomer and subsequent solvent removal.

We report the preparation of tough, thermally stable, and water-resistant double-network (DN) ion gels, which consist of a partially-clustered silica nanoparticle network and poly(ionic liquid) (PIL) network holding an ionic liquid. Silica nanoparticles/poly([Evim][Tf2N]) DN ion gels are prepared by photo-induced radical polymerisation of [Evim][Tf2N] in a mixture containing silica nanoparticles, [Bmim][Tf2N], ionic liquid based cross-linker [(VIM)2C4][Tf2N]2, and ethyl acetate, followed by subsequent solvent evaporation. Tensile strength measurements show that the mechanical properties of the PIL DN ion gels were higher than those of the PIL single-network (SN) ion gel. A rheological study indicates that an enhancement in mechanical strength of the PIL DN ion gels can be achieved when silica nanoparticles form partial clusters in [Bmim][Tf2N]. The cyclic stress-strain measurement of the PIL DN ion gels shows hysteresis loops, suggesting that the silica nanoparticle clusters rupture and dissipate the loading energy when the PIL DN ion gels undergo a large deformation. The fracture strength and Young's modulus of the PIL DN ion gels increase as the diameter of the silica nanoparticles is decreased. Thermogravimetric analysis measurement shows that the PIL DN ion gel has a high decomposition temperature of approximately 400 °C. Moreover, the swelling test shows that the PIL DN ion gel possesses an excellent water-resistant property because of the hydrophobic nature of the PIL backbone. We believe that such tough, thermally stable, and water-resistant PIL DN ion gels can be used as carbon dioxide separation membranes, sensors, and actuators for soft robotics.

One-pot synthesis of poly(ionic liquid)s with 1,2,3-triazolium-based backbones via clickable ionic liquid monomers.

Clickable α-azide-ω-alkyne ionic liquid monomers were developed and subsequently applied to the one-pot synthesis of ionically conducting poly(ionic liquid)s with 1,2,3-triazolium-based backbones through a click chemistry strategy. This approach does not require the use of solvents, polymerisation mediators, or catalysts. The obtained poly(ionic liquid)s were characterized by NMR, differential scanning calorimetry, thermogravimetric analysis, and impedance spectroscopy analysis. Moreover, these poly(ionic liquid)s were cross-linked via N-alkylation with a dianion quarternizing agent to achieve enhanced ionic conductivity and mechanical strength. The resulting free-standing films showed a Young's modulus up to 4.8 MPa and ionic conductivities up to 4.60 × 10-8 S cm-1 at 30 °C. This facile synthetic strategy has the potential to expand the availability of poly(ionic liquid)s and promote the development of functional materials.

Metal Microcapsules Prepared via Electroless Plating at Liquid-Liquid Interface.

We report the facile preparation of metal microcapsules via the formation of a Pickering emulsion, stabilized by catalytic palladium nanoparticles (PdNPs), and subsequent electroless plating at an oil-water interface induced by the adsorbed PdNPs. Metal microcapsules with smooth metal shells are formed by simply agitating the mixture of the plating solution and 1,2-dichloroethane containing poly(vinylpyrrolidone)-coated PdNPs, without external heating or electrical sources as energy inputs. We found that the metal microcapsules had thin copper metal shells with a relatively smooth surface and metallic luster. The metal shells were composed of more than 99 atom % copper in the form of Cu and Cu2O. We believe that this simple metal microcapsule preparation method may be beneficial to produce novel functional microcapsules with metal shells.

Microfluidic Formation of Hydrogel Microcapsules with a Single Aqueous Core by Spontaneous Cross-Linking in Aqueous Two-Phase System Droplets.

We report a simple process to fabricate monodisperse tetra-arm poly(ethylene glycol) (tetra-PEG) hydrogel microcapsules with an aqueous core and a semipermeable hydrogel shell through the formation of aqueous two-phase system (ATPS) droplets consisting of a dextran-rich core and a tetra-PEG macromonomer-rich shell, followed by a spontaneous cross-end coupling reaction of tetra-PEG macromonomers in the shell. Different from conventional techniques, this process enables for the continuous production of hydrogel microcapsules from water-in-oil emulsion droplets under mild conditions in the absence of radical initiators and external stimuli such as heating and ultraviolet light irradiation. We find that rapid cross-end coupling reaction of tetra-PEG macromonomers in ATPS droplets in the range of pH from 7.4 to 7.8 gives hydrogel microcapsules with a kinetically arrested core-shell structure. The diameter and core-shell ratio of the microcapsules can be easily controlled by adjusting flow rates and ATPS compositions. On the other hand, the slow cross-end coupling reaction of tetra-PEG macromonomers in ATPS droplets at pH 7.0 and lower induces structural change from core-shell to Janus during the reaction, which eventually forms hydrogel microparticles with a thermodynamically stable crescent structure. We believe that these hydrogel microparticles with controlled structures can be used in biomedical fields such as cell encapsulation, biosensors, and drug delivery carriers for sensitive biomolecules.

Free-Standing Metal Films Prepared via Electroless Plating at Liquid-Liquid Interfaces.

We report a simple preparation of free-standing metal films via electroless plating (ELP) at the liquid-liquid (L-L) interface between an aqueous electroless plating solution and an organic solvent. The use of ELP does not require any external energy in the form of heating and stirring. We find that the affinity of the organic solvent for the palladium nanoparticles (PdNPs) as catalysts and the vertical position of the organic and aqueous phases in the biphasic system are important considerations for synthesizing a robust copper film. Specifically, 1,2-dichloroethane which has an appropriate affinity for PdNPs and a higher density than water was found to be a good candidate for use as the organic phase in this system. However, a poor-quality copper film was obtained in the system with 1-hexanol as the organic phase. We also controlled the microscale surface structure of the copper films by using different concentrations of the injected PdNP dispersion. A high density of PdNPs caused smaller regions of metal growth, which contributed to the formation of smoother metal films. Moreover, under the optimal synthesis condition, we confirmed the electrical conductivity of the obtained copper film to be 1.16 × 10-7 Ωm. We believe that this metal film preparation represents a promising way to produce a range of metal film structures through the use of flexible L-L interfaces as templates.

Microfluidic devices for small-angle neutron scattering.

A comparative examination is presented of materials and approaches for the fabrication of microfluidic devices for small-angle neutron scattering (SANS). Representative inorganic glasses, metals, and polymer materials and devices are evaluated under typical SANS configurations. Performance criteria include neutron absorption, scattering background and activation, as well as spatial resolution, chemical compatibility and pressure resistance, and also cost, durability and manufacturability. Closed-face polymer photolithography between boron-free glass (or quartz) plates emerges as an attractive approach for rapidly prototyped microfluidic SANS devices, with transmissions up to ∼98% and background similar to a standard liquid cell (I ≃ 10-3 cm-1). For applications requiring higher durability and/or chemical, thermal and pressure resistance, sintered or etched boron-free glass and silicon devices offer superior performance, at the expense of various fabrication requirements, and are increasingly available commercially.

Polydopamine-Based 3D Colloidal Photonic Materials: Structural Color Balls and Fibers from Melanin-Like Particles with Polydopamine Shell Layers.

Nature creates beautiful structural colors, and some of these colors are produced by nanostructural arrays of melanin. Polydopamine (PDA), an artificial black polymer produced by self-oxidative polymerization of dopamine, has attracted extensive attention because of its unique properties. PDA is a melanin-like material, and recent studies have reported that photonic materials based on PDA particles showed structural colors by enhancing color saturation through the absorption of scattered light. Herein, we describe the preparation of three-dimensional (3D) colloidal photonic materials, such as structural color balls and fibers, from biomimetic core-shell particles with melanin-like PDA shell layers. Structural color balls were prepared through the combined use of membrane emulsion and heating. We also demonstrated the use of microfluidic emulsification and solvent diffusion for the fabrication of structural color fibers. The obtained 3D colloidal materials, i.e., balls and fibers, exhibited angle-independent structural colors due to the amorphous assembly of PDA-containing particles. These findings provide new insight for the development of dye-free technology for the coloration of various 3D colloidal architectures.

Efficient anti-tumor effect of photodynamic treatment with polymeric nanoparticles composed of polyethylene glycol and polylactic acid block copolymer encapsulating hydrophobic porphyrin derivative.

To develop potent and safer formulation of photosensitizer for cancer photodynamic therapy (PDT), we tried to formulate hydrophobic porphyrin derivative, photoprotoporphyrin IX dimethyl ester (PppIX-DME), into polymeric nanoparticles composed of polyethylene glycol and polylactic acid block copolymer (PN-Por). The mean particle size of PN-Por prepared was around 80nm and the zeta potential was determined to be weakly negative. In vitro phototoxicity study for PN-Por clearly indicated the significant phototoxicity of PN-Por for three types of tumor cells tested (Colon-26 carcinoma (C26), B16BL6 melanoma and Lewis lung cancer cells) in the PppIX-DME concentration-dependent fashion. Furthermore, it was suggested that the release of PppIX-DME from PN-Por would gradually occur to provide the sustained release of PppIX-DME. In vivo pharmacokinetics of PN-Por after intravenous administration was evaluated in C26 tumor-bearing mice, and PN-Por exhibited low affinity to the liver and spleen and was therefore retained in the blood circulation for a long time, leading to the efficient tumor disposition of PN-Por. Furthermore, significant and highly effective anti-tumor effect was confirmed in C26 tumor-bearing mice with the local light irradiation onto C26 tumor tissues after PN-Por injection. These findings indicate the potency of PN-Por for the development of more efficient PDT-based cancer treatments.

Augmented EPR effect by photo-triggered tumor vascular treatment improved therapeutic efficacy of liposomal paclitaxel in mice bearing tumors with low permeable vasculature.

The effects of photo-triggered tumor vascular treatment (PVT) on the structural and functional properties of tumor vasculature were assessed in Colon-26 (C26) and B16/BL6 (B16) tumor-bearing mice. Furthermore, anti-tumor efficacy of subsequently injected PEG liposomal paclitaxel (PL-PTX) was also evaluated. As a photosensitizer, a hydrophobic porphyrin derivative was used and formulated in polymeric nanoparticle composed of polyethylene glycol-block-polylactic acid to avoid its non-specific in vivo disposition. In the mice bearing C26 with high permeable vasculature, the prominent anti-tumor activity was confirmed by PVT alone, but the subsequently injected PL-PTX did not show any additive effect. PVT itself initially induced apoptotic cell death of tumor vascular endothelial cells and platelet aggregation, which would have subsequently induced apoptosis of C26 tumor cells surrounding the vasculature. On the other hand, in the mice bearing B16 with low permeable vasculature, PVT enhanced the anti-tumor activity of subsequently injected PL-PTX, which would be attributed to the tumor disposition amount and area of PEG liposomes enhanced by PVT. These results clearly indicated that the treatment would have made it possible to provide more efficient extravasation of PL-PTX, leading to its more potent anti-tumor effect.

Microfluidic-SANS: flow processing of complex fluids.

Understanding and engineering the flow-response of complex and non-Newtonian fluids at a molecular level is a key challenge for their practical utilisation. Here we demonstrate the coupling of microfluidics with small angle neutron scattering (SANS). Microdevices with high neutron transmission (up to 98%), low scattering background (≲10⁻² cm⁻¹), broad solvent compatibility and high pressure tolerance (≈3-15 bar) are rapidly prototyped via frontal photo polymerisation. Scattering from single microchannels of widths down to 60 µm, with beam footprint of 500 µm diameter, was successfully obtained in the scattering vector range 0.01-0.3 Å(-1), corresponding to real space dimensions of ≃10-600 Å. We demonstrate our approach by investigating the molecular re-orientation and alignment underpinning the flow response of two model complex fluids, namely cetyl trimethylammonium chloride/pentanol/D2O and sodium lauryl sulfate/octanol/brine lamellar systems. Finally, we assess the applicability and outlook of microfluidic-SANS for high-throughput and flow processing studies, with emphasis of soft matter.

Microfluidic approach to the formation of internally porous polymer particles by solvent extraction.

We report the controlled formation of internally porous polyelectrolyte particles with diameters ranging from tens to hundreds of micrometers through selective solvent extraction using microfluidics. Solvent-resistant microdevices, fabricated by frontal photopolymerization, encapsulate binary polymer (P)/solvent (S1) mixtures by a carrier solvent phase (C) to form plugs with well-defined radii and low polydispersity; the suspension is then brought into contact with a selective extraction solvent (S2) that is miscible with C and S1 but not P, leading to the extraction of S1 from the droplets. The ensuing phase inversion yields polymer capsules with a smooth surface but highly porous internal structure. Depending on the liquid extraction time scale, this stage can be carried out in situ, within the chip, or ex situ, in an external S2 bath. Bimodal polymer plugs are achieved using asymmetrically inverted T junctions. For this demonstration, we form sodium poly(styrenesulfonate) (P) particles using water (S1), hexadecane (C), and methyl ethyl ketone (S2). We measure droplet extraction rates as a function of drop size and polymer concentration and propose a simple scaling model to guide particle formation. We find that the extraction time required to form particles from liquid droplets does not depend on the initial polymer concentration but is rather proportional to the initial droplet size. The resulting particle size follows a linear relationship with the initial droplet size for all polymer concentrations, allowing for the precise control of particle size. The internal particle porous structure exhibits a polymer density gradient ranging from a dense surface skin toward an essentially hollow core. Average particle porosities between 10 and 50% are achieved by varying the initial droplet compositions up to 15 wt % polymer. Such particles have potential applications in functional, optical, and coating materials.

Microfluidic fabrication of monodisperse polylactide microcapsules with tunable structures through rapid precipitation.

We describe a versatile and facile route to the continuous production of monodisperse polylactide (PLA) microcapsules with controllable structures. With the combination of microfluidic emulsification, solvent diffusion, and internal phase separation, uniform PLA microcapsules with a perfluorooctyl bromide (PFOB) core were successfully obtained by simply diluting monodisperse ethyl acetate (EA)-in-water emulsion with pure water. Rapid extraction of EA from the droplets into the aqueous phase enabled the solidification of the polymer droplets in a nonequilibrium state during internal phase separation between a concentrated PLA/EA phase and a PFOB phase. Higher-molecular-weight PLA generated structural complexity of the microcapsules, yielding core-shell microcapsules with covered with small PFOB droplets. Removal of the PFOB via freeze drying gave hollow microcapsules with dimpled surfaces. The core-shell ratios and the diameter of these microcapsules could be finely tuned by just adjusting the concentration of PFOB and flow rates on emulsification, respectively. These biocompatible microcapsules with controllable size and structures are potentially applicable in biomedical fields such as drug delivery carriers of many functional molecules.

Formulation and evaluation of paclitaxel-loaded polymeric nanoparticles composed of polyethylene glycol and polylactic acid block copolymer.

To develop potent paclitaxel (PTX) formulations for cancer chemotherapy, we formulated PTX into polymeric nanoparticles composed of polyethylene glycol (PEG) and polylactic acid (PLA) block copolymer (PN-PTX). First, the physicochemical properties of PN-PTX prepared were assessed; the mean particle size was around 80 nm and the zeta potential was found to be almost neutral. Next, the in vitro PTX release property was assessed by a dialysis method. Although rapid release of PTX was observed just after dosing, around 70% of PTX was stably incorporated in polymeric nanoparticles for a long time in the presence of serum. Then, the in vivo pharmacokinetics of PN-PTX after intravenous administration was investigated in Colon-26 (C26) tumor-bearing mice. Both polymeric nanoparticles and PTX incorporated exhibited a long blood circulating property, leading to enhanced permeability and retention (EPR) effect-driven, time-dependent tumor disposition of PTX. Tumor distribution increased gradually for 24 h, and tissue uptake clearance of polymeric nanoparticles in the liver and spleen was lower than that of PEG liposomes. Since these results indicated that the in vivo disposition characteristics of PN-PTX were very favorable, we then evaluated the anti-tumor effect of PN-PTX in C26 tumor-bearing mice. However, PN-PTX did not exhibit any significant anti-tumor effect, presumably due to the poor PTX release from polymeric nanoparticles. From these results, it is considered that the favorable pharmacokinetic properties of nanoparticles and the drug incorporated do not always lead to its potent in vivo pharmacological activity, suggesting the importance of PTX release properties within tumor tissues.