Thermally Induced Phase Separation Research Articles

Preparation and evaluation of ion-exchange porous polyvinyl alcohol microspheres as a potential drug delivery embolization system

The present study aimed to develop a new drug delivery system with efficient drug loading and sustained drug release for potential application in transarterial chemoembolization (TACE). The porous polyvinyl alcohol microspheres (PPVA MS) were prepared by a combination of inverse emulsification and thermal-induced phase separation (TIPS) method, this was followed by the grafting polymerization of sodium 4-styrene sulfonate (SSS) onto the PPVA MS to obtain the grafted PPVA-g-PSSS MS. The prepared PPVA MS showed a well-defined spherical shape with ‘honeycomb-like’ porous structure, which could be readily tailored by adjusting the quenching temperature. In vitro biocompatibility analysis indicated the non-cytotoxic and hemocompatible nature of PPVA MS. The porous structure and presence of ionically charged groups in the PPVA-g-PSSS MS favoured the loading of cationic doxorubicin (DOX) onto the MS through ionic-interactions and demonstrated a sustained drug release pattern. Moreover, the cytotoxicity of DOX-loaded PPVA-g-PSSS (DOX@PPVA-g-PSSS) MS against HepG2 cells and the intracellular uptake of DOX demonstrated the potent in vitro antitumor activity. Furthermore, the central auricular artery embolization in rabbits showed that both the PPVA-g-PSSS and DOX@PPVA-g-PSSS MS could occlude the auricular arteries and induced superior embolization effects, such as progressive ear appearance changes, irreversible parenchymal damage and fibrosis, and ultrastructural alternations in endothelial cells. Besides, the DOX fluorescence was distributed around the embolized arteries, without decreasing its intensity when prolonged embolization up to 15 days. These findings suggest that the newly developed DOX@PPVA-g-PSSS MS could be employed as a promising drug-loaded embolic agent for the treatment of hepatocellular carcinoma.

Effect of the molecular weight of polymer and diluent on the performance of hydrophilic poly(vinyl butyral) porous heddle via thermally induced phase separation

Hydrophilic Poly (vinyl butyral) (PVB) porous heddles were prepared via blending hydrophilic PVB and green diluent Polyethylene glycol (PEG) through liquid-liquid thermally induced phase separation (TIPS) process. To further investigate the effect of the molecular weight (MW) of polymer and diluent on phase diagram of PVB-PEG blending system and performance of hydrophilic PVB porous heddle, the cloud point (Tcloud), microstructure, overall porosity and mechanical property, i.e were mainly analyzed. The results highlighted that the Tcloud of the PVB-PEG blending shifted to lower temperature with increasing PEG MW and PVB MW. Overall porosity reached up to 82.3% and tensile strength was 9.88 MPa when polymer and diluent with lowest MW. To extend the application air, the fabrication conditions of prepared porous heddle were studied. Overall porosity increased and the tensile strength decreased with extrusion temperature increasing. In addition, the PVB-PEG porous heddles proved effective hydrophilic performance and demonstrate the potential application in water treatment.

3D-printed monolithic biofilters based on a polylactic acid (PLA) – hydroxyapatite (HAp) composite for heavy metal removal from an aqueous medium

High flux, monolithic water purification filters based on polylactic acid (PLA) functionalised with fish scale extracted hydroxyapatite (HAp) were prepared by solvent-assisted blending and thermally induced phase separation (TIPS), followed by twin-screw extrusion into filaments and processed via three-dimensional (3D) printing. The printed filters with consistent pore geometry and channel interconnectivity as well as homogenous distribution of HAp in the PLA matrix showed adsorption capabilities towards heavy metals i.e. cadmium (Cd) and lead (Pb) with maximum adsorption capacity of 112.1 mg gHAp−1 and 360.5 mg gHAp−1 for the metal salt of Pb and Cd, respectively. The adsorption was found to be driven by a combination of ion exchange, dissolution and precipitation on HAp and surface complexation.

The effect of Allium cepa extract on the chitosan/PLGA scaffolds bioactivity

Allium cepa extracts (AC) allow the fabrication of a biomaterial that, together with chitosan and PLGA, could be osteoconductive and promote a better and faster regeneration of bone tissue, with biocompatibility and biomineralization properties. In this work, scaffolds were developed by the thermally induced phase separation (TIPS) technique. An in vitro bioactivity analysis was performed using simulated body fluid (SBF). Scanning electron microscopy (SEM), energy dispersion spectroscopy, and infrared spectroscopy were used for the scaffolds characterization. The results showed a structure with a pore size distribution between 50 and 100 μm, which allowed the uniform formation of biological apatite crystals on the surface of the scaffolds. The chitosan/policaprolactone/Allium cepa scaffold (ChPAC) showed the most promising results with a ratio of P/Ca between 1.6 and 1.7, a value very close to that of hydroxyapatite.

Construction of a nanofiber network within 3D printed scaffolds for vascularized bone regeneration.

Three-dimensional (3D) printed scaffolds provide a promising prospective for application in bone tissue engineering. 3D printed scaffolds with micro- and nano-fibrous structures that facilitate cell adhesion and migration, and combined vascularization and osteoinduction bioactivity will be ideal implants for bone defect repair. Here, we fabricated a 3D printed biodegradable poly (glycerol-co-sebacic acid-co-l-lactic acid-co-polyethylene glycol) (PGSLP)-based scaffold that was internally filled with gelatin nanofibers and allowed the local release of deferoxamine (DFO), which is essential for angiogenesis and osteogenesis in bone regeneration. The nanofibrous structured gelatin/PGSLP (NGP) scaffold was fabricated using a thermally induced phase separation (TIPS) technique, and the macroporous structured gelatin/PGSLP (MGP) scaffold was prepared by directly freeze-drying. The in vitro experiments demonstrated that both DFO-loaded NGP and DFO-loaded MGP scaffolds can promote the migration and tubular formation of human umbilical vein endothelial cells (HUVECs), and enhance the mineralized nodule formation and osteogenic-related gene expression during osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). In a rat critical-sized calvarial defect model, the results suggested that the scaffolds with DFO loading significantly promote the vascular formation and accelerate bone regeneration, while the enhancement of vascularization and osteogenesis in vivo in DFO-loaded NGP scaffold was better than that in DFO-loaded MGP scaffold. Therefore, the constructed PGLSP-based scaffolds with micro- and nano-fibrous structures would be promising candidates to match the structural and functional requirements for vascularized bone regeneration.

Hydrophobic and hydrophilic modification of hierarchically porous monolithic polyimide derivatives as functional liquid absorbers

Thermally induced phase separation (TIPS) and thermal imidization were used to prepare PI-based monoliths in sequence. The hybridized PI (PI-co-POSS) monoliths exhibit potential in liquid diode application to achieve oil–water separation.

Nitric oxide and reactive oxygen species-releasing polylactic acid monolith for enhanced photothermal therapy of osteosarcoma

Photothermal therapy (PTT) has been extensively explored as a promising alternative therapeutic approach for many malignant tumors. However, PTT agents never repair bone defects because of their lack of osteogenic activity. Therefore, the integration of multi-modal therapies into one platform could show great promise in overcoming the drawbacks of conventional single-modal therapy and achieving improved therapeutic efficacy in cancer. In this study, an indocyanine green (ICG) and diethylenetriamine/nitric oxide adduct (DETA/NO)-loaded polylactic acid (PLA) (PLIN) monolith was created via simple thermally induced phase separation (TIPS) and used to enhance PTT efficacy by killing residual cancer cells and regenerating bone defects after surgical resection of tumor tissues. The resulting PLIN monolith exhibited interconnected microporous structures and uniform morphology composed of leaf-like small units. The results of in vitro PTT efficacy tests demonstrated that the PLIN monolith exhibited enhanced photothermal activity on osteosarcomas but did not caused phototoxicity in normal osteoblasts. The synergistic cancer therapy efficacy of PLIN was mainly caused by high local temperature and elevated intracellular generation of ONOO− in MG63 cells. In addition, PLIN induced significant apoptotic cell death following laser irradiation. Therefore, the PLIN monolith has potential for application in osteosarcoma therapy and bone regeneration.

Flexible Solid-State Supercapacitors Derived from Biomass Konjac/Polyacrylonitrile-Based Nitrogen-Doped Porous Carbon.

Energy shortage and wasting of resources are two main challenges for human society. To solve these problems, nitrogen-doped porous carbon was synthesized through a simple thermally induced phase separation (TIPS) method with subsequent carbonization and activation with biomass konjac/polyacrylonitrile composites as the raw materials and nitrogen source for the first time. The obtained composite carbon with hierarchical porosity, large specific surface areas, and high content of nitrogen doping shows promise due to its desirable electrochemical performance. Nitrogen-doped porous carbon exhibits a high specific capacitance of 390 F g-1 in a three-electrode system and a good rate characteristic with 70% capacitance retention at 20 A g-1. Excellent stabilization was observed with only a 4.5% capacitance decay under 10 000 cycles at 5 A g-1. The practical application of the composite porous carbon on flexible symmetrical supercapacitors was evaluated, showing a maximum energy density of 9.0 W h kg-1 when the power density was 250.2 W kg-1. More importantly, the fabricated flexible supercapacitor could still keep an excellent supercapacitor performance under bending and shows only a slight capacitance loss of 9% even after 1000 cycles (180°) of repetitive bending. The current study promotes the development of nitrogen-doped carbon materials on flexible energy storage devices.

Preparation of hollow fiber membrane via grafting tannic acid and its influence on microstructure, permeability and anti-fouling

Polyvinylidene fluoride/polyamide6-grafting-tannic acid (PVDF/PA6-g-TA) hollow fiber membrane was prepared via the reaction between TA and PA6 on the membrane surface by thermally induced phase separation (TIPS) technique. The reaction mechanism and the distribution for TA on outer surface were explored. The change of surface morphology, hydrophilicity, chargeability, anti-fouling capacity and permeability was investigated after grafting. It was found that Schiff base reaction occurred between amino group and phenolic hydroxyl group, and thus avoided the falling of TA. The uniform distribution of TA on outer surface enhanced the hydrophilicity, rejection and anti-fouling capacity. Finally, the improvement of anti-fouling capacity and permeability was analyzed from chargeability for TA and bond water layer on repulsing the stackage of the pollutants. This work provides an efficient way to enhance the anti-fouling performance of membrane via TIPS.

One step surfactant entrapment onto PVDF hollow fiber membrane surface by the TIPS process using a triple-layer orifice spinneret

One step entrapment of the several kinds of surfactants on the outer surface of the PVDF hollow fiber membrane during the air gap distance was studied by extruding the surfactant solution as the outermost layer of the triple layer nozzle via thermally induced phase separation (TIPS) process. Effect of the membrane preparation conditions, including the air gap distance, surfactant concentration and types of surfactant with different hydrophilic-lipophilic balance (HLB) number and molecular weight on the membrane surface hydrophilicity and protein fouling resistance were evaluated. Using a long air gap distance with optimal surfactant concentration was resulted in a membrane with a considerable improvement in hydrophobicity. Surfactants with the lowest HLB number and molecular weight improved membrane hydrophilicity and resistance against pure water permeability decrease after drying membrane in air. Based on water contact angle results, entrapment of the surfactant with a more hydrophobic segment to hydrophilic segment ratio (smaller HLB) plays a crucial role to increase the membrane surface hydrophilicity regardless the intrinsic hydrophilicity of the surfactant molecule. The stability of the surfactant entrapped by this method was higher than that of the simple coating method. Static adsorption of the lysozyme on the surface of the surfactant entrapped membrane was in line with water contact angle results. Thus, entrapping surfactants with low HLB number and molecular weight was recommended to obtain a membrane with the considerable anti-fouling property.

Interconnected porous nanofibrous gelatin scaffolds prepared via a combined thermally induced phase separation/particulate leaching method

To mimic the fibrous architecture of collagen, the nanofibrous gelatin scaffolds are fabricated employing a thermally induced phase separation (TIPS) technique. The influences of processing parameters, including polymer concentration and solvent mixture composition on the scaffold microstructure are investigated. However, using the TIPS technique, a limited pore size range is generally obtained. To yield the well-interconnected macroporous structures with equiaxed pores and nanofibrous architectures, the TIPS technique is combined with particulate leaching. The macroporous structure of produced scaffolds duplicates the predefined three-dimensional template structure. The homogenous macrostructure with well-interconnected equiaxed pores and no particular orientation is created. Modulating the size and shape of microspheres has precise control over porosity, pore size, and interconnection of the matrix. Because of the well-interconnected macroporous nanofibrous structure, the useful applications of these scaffolds in the tissue engineering field are expected.

In vitro characterization of hierarchical 3D scaffolds produced by combining additive manufacturing and thermally induced phase separation

This paper reports on the hybrid process we have used for producing hierarchical scaffolds made of poly(lactic-co-glycolic) acid (PLGA) and nanohydroxyapatite (nHA), analyzes their internal structures via scanning electron microscopy, and presents the results of our in vitro proliferation of MC3T3-E1 cells and alkaline phosphatase activity (ALP) for 0 and 21 days. These scaffolds were produced by combining additive manufacturing (AM) and thermally induced phase separation (TIPS) techniques. Slow cooling at a rate of 1.5 °C/min during the TIPS process was used to enable a uniform temperature throughout the scaffolds, and therefore, a relatively uniform pore size range. We produced ten different scaffold compositions and topologies in this study. These scaffolds had macrochannels with diameters of ∼300 µm, ∼380 µm, and ∼460 µm, generated by the extraction of embedded porous 3D-plotted polyethylene glycol (PEG) matrices. The other experimental factors included different TIPS temperatures (−20 °C, −10 °C, and 0 °C), as well as varying PLGA concentrations (8%, 10%, and 12% w/v) and nHA content (0%, 10%, and 20% w/w). Our results indicated that almost all these macro/microporous scaffolds supported cell growth over the period of 21 days. Nevertheless, significant differences were observed among some scaffolds in terms of their support of cell proliferation and differentiation. This paper presents the results of our in vitro cell culture for 0 and 21 days. Our optimal scaffold with a porosity of ∼90%, a modulus of ∼5.2 MPa, and a nHA content of 20% showed a cell adhesion of ∼29% on day 0 and maintained cell proliferation and ALP activity over the 21-day in vitro culture. Hence, the use of additive manufacturing and designed experiments to optimize the scaffold fabrication parameters resulted in superior mechanical properties that most other studies using TIPS.

Investigation of Formation for Poly(vinylidene fluoride) Membrane Using Thermally Induced Phase Separation.

In this study, thermally induced phase separation (TIPS) was used to fabricate a water treatment membrane composed of poly(vinylidene fluoride) (PVDF) and silica. Dioctyl phthalate (DOP) and dibutyl phthalate (DBP) were used as diluents. Crystallization temperature, cloud point, and morphology were observed to investigate the conditions of PVDF/silica/diluent membrane preparation. SEM revealed that the porosity of the membranes was increased with an increase in silica content. Phase diagram and morphology results revealed that 50 wt% PVDF+silica with a PVDF:silica weight ratio of 4.5:1 is the best composition for manufacturing a porous membrane.

Effect of polymer molecular weight on structure and performance of PVDF hollow fiber membranes prepared via TIPS process with co-extrusion of solvent using triple orifice spinneret

The co-extrusion of solvent at the outer layer of a dope solution in a thermally induced phase separation (TIPS) process has led to significant improvements in membrane characteristics, especially pure water permeability stability. This work investigates the effects of the poly (vinylidene fluoride) (PVDF) molecular weight and concentration on the characteristics of hollow fiber membranes prepared using this method. The PVDF molecular weight had little effect on the phase diagram of the PVDF/diphenyl carbonate (DPC) system, and effectively controlled the penetration depth and quantity of the extruded solvent (propylene carbonate (PC)) inside the polymer dope solution as well as the overall performance of the hollow fiber membranes. When the PVDF concentration was low, the PVDF molecular weight was crucial in controlling the penetration of the extruded solvent. For a PVDF/DPC system that led to the mainly bicontinuous structure which resulted from L-L phase separation, the penetration of the PC inside the membrane considerably changed the surface and sublayer structure from a bicontinuous structure with spherulite to a composite spherulite embedded in the bicontinuous structure and isolated spherulite structure. To obtain an appropriate membrane with considerable water permeability stability, it is necessary to choose an appropriate polymer molecular weight and concentration.

Peritumoral Delivery of Docetaxel-TIPS Microparticles for Prostate Cancer Adjuvant Therapy.

Recurrence of prostate cancer after radical prostatectomy is a consequence of incomplete tumor resection. Systemic chemotherapy after surgery is associated with significant toxicity. Improved delivery methods for toxic drugs capable of targeting positive resection margins can reduce tumor recurrence and avoid their known toxicity. This study evaluates the effectiveness and toxicity of docetaxel (DTX) release from highly porous biodegradable microparticles intended for delivery into the tissue cavity created during radical prostatectomy to target residual tumor cells. The microparticles, composed of poly(dl‐lactide‐co‐glycolide) (PLGA), are processed using thermally induced phase separation (TIPS) and loaded with DTX via antisolvent precipitation. Sustained drug release and effective toxicity in vitro are observed against PC3 human prostate cells. Peritumoral injection in a PC3 xenograft tumor model results in tumor growth inhibition equivalent to that achieved with intravenous delivery of DTX. Unlike intravenous delivery of DTX, implantation of DTX‐TIPS microparticles is not accompanied by toxicity or elevated systemic levels of DTX in organ tissues or plasma. DTX‐TIPS microparticles provide localized and sustained release of nontoxic therapeutic amounts of DTX. This may offer novel therapeutic strategies for improving management of patients with clinically localized high‐risk disease requiring radical prostatectomy and other solid cancers at high risk of positive resection margins.

Preparation of Hydrophilic UHMWPE Hollow Fiber Membranes by Chemically Bounding Silica Nanoparticles

In this work, ultra-high molecular weight polyethylene (UHMWPE) microfiltration hollow fiber membranes prepared via the thermally induced phase separation (TIPS) method were modified by chemically bounding hydrophilic silica (SiO2) nanoparticles onto the surface to improve anti-fouling performance. A range of testing techniques including attenuated total reflection Flourier transformed infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), field emission scanning electron microscopy (FE-SEM), water contact angle, mechanical test, filtration and anti-fouling performance were carried out to discuss the influence of different modification conditions on the properties of the membranes. The prepared hollow fiber membranes display the significantly excellent performance when the vinyl trimethoxy silane (VTMS) concentration was 13%, the pH value of the hydrolyzate was 4 and the hydrolysis reaction time was 6 h. In particular, the hydrophilicity of modified membranes was improved effectively, resulting in the enhancement of membrane anti-fouling properties. The results of this work can be consulted for improving the anti-fouling performance of the UHMWPE microfiltration hollow fiber membrane applied in the field of water purification.

Enhanced physical, mechanical and protein adsorption properties of PVDF composite films prepared via thermally-induced phase separation (TIPS): Effect of SiO2@PDA nanoparticles

In this work, SiO2@PDA nanoparticles obtained by in-situ coating polydopamine (PDA) on the surface of spherical SiO2 nanoparticles were adopted to prepare the polyvinylidene fluoride (PVDF) composite films via thermally-induced phase separation (TIPS) method with diphenyl carbonate (DPC) as the diluent. PDA was proved to cover evenly on the surface of SiO2 nanoparticles, which was favorable to the dispersion of hydrophilic nanoparticles in the matrix. Effect of the presence of SiO2@PDA nanoparticles on crystallization behavior, thermal stability, mechanical properties and hydrophilicity of the composite films was intensively investigated. Heterogeneous nucleating effect on the crystallization of PVDF coupled with elevated crystallinity was found upon the incorporation of SiO2@PDA without altering the crystal form of PVDF. The rigidity, tensile strength as well as thermal stability of the composite films containing SiO2@PDA were significantly improved in comparison to both neat film and those containing unmodified nanoparticles. In addition, the hydrophilicity of PVDF composite films’ surface was remarkably enhanced with an increasing SiO2@PDA content, which helped to reduce the protein adsorption of the composite films considerably. The present study would supply an insight into the fabrication of PVDF composite films with desirable performance and capabilities.

Blending modification to porous polyvinylidene fluoride (PVDF) membranes prepared via combined crystallisation and diffusion (CCD) technique

PVDF membranes prepared by the combined crystallisation and diffusion (CCD) technique, a variation of ice templating, have shown permeation rates far superior to those made via conventional methods such as nonsolvent induced phase separation (NIPS) or thermally induced phase separation (TIPS). However, so far the smallest pore size achieved for PVDF membranes prepared by CCD is about 30 nm. In this study, the pore size of CCD PVDF membranes is reduced to 15 nm by blending poly(methyl methacrylate) (PMMA) into PVDF-dimethyl sulfoxide (DMSO) dope solutions without altering the operational conditions. Systemic study shows the pore size reduces when increasing PMMA concentration in the membranes; but after an initial drop compared to the pure PVDF membrane, the pure water flux doesn't decline with PMMA concentration. The effect of different molecular weights of PMMA (120 kDa and 35 kDa) was also investigated, where the results showed a smaller pore size for membranes prepared using the higher molecular weight PMMA. Scanning electron microscopy (SEM), cloud-point temperature measurement and Fourier transform infrared spectroscopy (FTIR) was used to characterise the membranes and help understand how PMMA affects membrane formation. From the evidence gathered, we attribute the effects of PMMA to the change in the number of nucleation centres, diffusional rates, as well as the gelation point based on a previously proposed CCD mechanism.

Non-Isothermal Crystallization Behavior of Poly(vinylidene fluoride) in Dialkyl Phthalate Diluents during Thermally Induced Phase Separation Process

The non-isothermal crystallization behavior of poly(vinylidene fluoride) (PVDF) in dialkyl phthalate diluents during the thermally induced phase separation (TIPS) process was investigated by differential scanning calorimetry (DSC) at various cooling rates. Dialkyl phthalates with different alkyl chain-length, namely dimethyl phthalate (DMP), diethyl phthalate (DEP) and dibutyl phthalate (DBP), were used as the diluent. The effects of alkyl chain-length of dialkyl phthalate and cooling rate on the non-isothermal crystallization behavior as implied by the Avrami analysis modified by Jeziorny and Mo’s analysis were determined. The values of half-time, t1/2, and the parameters Zc and F(t), which characterized the kinetics of non-isothermal crystallization, showed that the crystallization rate increased with the increase of the alkyl chain-length of dialkyl phthalate due to the lower compatibility between PVDF and dialkyl phthalate. Moreover, the alkyl chain-length of dialkyl phthalate also has a great impact on the compact spherulitic structure of PVDF membranes prepared from different PVDF/dialkyl phthalate blends. With the decrease of the alkyl chain-length of dialkyl phthalate, the number of spherulites increased and the size of spherulites became smaller. This research thus not only proves the effects of alkyl chain-length of dialkyl phthalate on the non-isothermal crystallization behavior of PVDF, but also provides a systematic strategy to evaluate a single diluent during the TIPS process.

Biomimetic Nanofibrous 3D Materials for Craniofacial Bone Tissue Engineering.

Repair of large bone defects using biomaterials-based strategies has been a significant challenge due to the complex characteristics required for tissue regeneration, especially in the craniofacial region. Tissue engineering strategies aimed at restoration of function face challenges in material selection, synthesis technique, and choice of bioactive factor release in combination with all aforementioned facets. Biomimetic nanofibrous (NF) scaffolds are attractive vehicles for tissue engineering due to their ability to promote endogenous bone regeneration by mimicking the shape and chemistry of natural bone extracellular matrix (ECM). To date, several techniques for generation of biomimetic NF scaffolds have been discovered, each possessing several advantages and drawbacks. This spotlight highlights two of the more popular techniques for biomimetic NF scaffold synthesis: electrospinning and thermally-induced phase separation (TIPS), covering development from inception in each technique as well as discussing the most recent innovations in each fabrication method.