Strategies for Developing Shape-Shifting Behaviours and Potential Applications of Poly (N-vinyl Caprolactam) Hydrogels.

Stimuli-responsive hydrogels are one type of smart hydrogel, which can expand/contract in water according to changes in the surrounding environment. However, it is difficult to develop flexible shapeshifting behaviours by using a single hydrogel material. This study exploited a new method to utilise single and bilayer structures to allow hydrogel-based materials to exhibit controllable shape-shifting behaviours. Although other studies have demonstrated similar transformation behaviours, this is the first report of such smart materials developed using photopolymerised N-vinyl caprolactam (NVCL)-based polymers. Our contribution provides a straightforward method in the fabrication of deformable structures. In the presence of water, the bending behaviours (vertex-to-vertex and edge-to-edge) were achieved in monolayer squares. By controlling the content and combination of the NVCL solutions with elastic resin, the bilayer strips were prepared. The expected reversible self-bending and self-helixing behaviours were achieved in specific types of samples. In addition, by limiting the expansion time of the bilayer, the layered flower samples exhibited predictable self-curving shape transformation behaviour in at least three cycles of testing. These structures displayed the capacity of self-transformation, and the value and functionality of the produced components are reflected in this paper.

Synthesis and Characterisation of Hydrogels Based on Poly (N-Vinylcaprolactam) with Diethylene Glycol Diacrylate.

Poly (N-vinylcaprolactam) is a polymer that is biocompatible, water-soluble, thermally sensitive, non-toxic, and nonionic. In this study, the preparation of hydrogels based on Poly (N-vinylcaprolactam) with diethylene glycol diacrylate is presented. The N-Vinylcaprolactam-based hydrogels are synthesised by using a photopolymerisation technique using diethylene glycol diacrylate as a crosslinking agent, and Diphenyl (2, 4, 6-trimethylbenzoyl) phosphine oxide as a photoinitiator. The structure of the polymers is investigated via Attenuated Total Reflectance-Fourier Transform Infrared Spectroscopy. The polymers are further characterised using differential scanning calorimetry and swelling analysis. This study is conducted to determine the characteristics of P (N-vinylcaprolactam) with diethylene glycol diacrylate, including the addition of Vinylacetate or N-Vinylpyrrolidone, and to examine the effects on the phase transition. Although various methods of free-radical polymerisation have synthesised the homopolymer, this is the first study to report the synthesis of Poly (N-vinylcaprolactam) with diethylene glycol diacrylate by using free-radical photopolymerisation, using Diphenyl (2, 4, 6-trimethylbenzoyl) phosphine oxide to initiate the reaction. FTIR analysis shows that the NVCL-based copolymers are successfully polymerised through UV photopolymerisation. DSC analysis indicates that increasing the concentration of crosslinker results in a decrease in the glass transition temperature. Swelling analysis displays that the lower the concentration of crosslinker present in the hydrogel, the quicker the hydrogels reach their maximum swelling ratio.

Modulation of the Lower Critical Solution Temperature of Thermoresponsive Poly(N-vinylcaprolactam) Utilizing Hydrophilic and Hydrophobic Monomers.

Four-dimensional printing is primarily based on the concept of 3D printing technology. However, it requires additional stimulus and stimulus-responsive materials. Poly-N-vinylcaprolactam is a temperature-sensitive polymer. Unique characteristics of poly-N-vinylcaprolactam -based hydrogels offer the possibility of employing them in 4D printing. The main aim of this study is to alter the phase transition temperature of poly-N-vinylcaprolactam hydrogels. This research focuses primarily on incorporating two additional monomers with poly-N-vinylcaprolactam: Vinylacetate and N-vinylpyrrolidone. This work contributes to this growing area of research by altering (increasing and decreasing) the lower critical solution temperature of N-vinylcaprolactam through photopolymerisation. Poly-N-vinylcaprolactam exhibits a lower critical solution temperature close to the physiological temperature range of 34-37 °C. The copolymers were analysed using various characterisation techniques, such as FTIR, DSC, and UV-spectrometry. The main findings show that the inclusion of N-vinylpyrrolidone into poly-N-vinylcaprolactam increased the lower critical solution temperature above the physiological temperature. By incorporating vinylacetate, the lower critical solution temperature dropped to 21 °C, allowing for potential self-assembly of 4D-printed objects at room temperature. In this case, altering the lower critical solution temperature of the material can potentially permit the transformation of the 4D-printed object at a particular temperature.

Lower Critical Solution Temperature Tuning and Swelling Behaviours of NVCL-Based Hydrogels for Potential 4D Printing Applications.

The phase transitions of poly (N-vinyl caprolactam) (PNVCL) hydrogels are currently under investigation as possible materials for biomedical applications thanks to their thermosensitive properties. This study aims to use the photopolymerisation process to simulate the 4D printing process. NVCL-based polymers with different thermal properties and swellability were prepared to explore the possibility of synthetic hydrogels being used for 4D printing. In this contribution, the thermal behaviours of novel photopolymerised NVCL-based hydrogels were analysed. The lower critical solution temperature (LCST) of the physically crosslinked gels was detected using differential scanning calorimetry (DSC), ultraviolet (UV) spectroscopy, and cloud point measurement. The chemical structure of the xerogels was characterised by means of Fourier transform infrared spectroscopy (FTIR). Pulsatile swelling studies indicated that the hydrogels had thermo-reversible properties. As a result, the effect of varying the macromolecular monomer concentration was apparent. The phase transition temperature is increased when different concentrations of hydrophilic monomers are incorporated. The transition temperature of the hydrogels may allow for excellent flexibility in tailoring transition for specific applications, while the swelling and deswelling behaviour of the gels is strongly temperature- and monomer feed ratio-dependent.

A Development of New Material for 4D Printing and the Material Properties Comparison between the Conventional and Stereolithography Polymerised NVCL Hydrogels.

The term 4D printing refers to the idea that the shape or properties of a printed object can be changed when an external stimulus is applied. In this contribution, a temperature-responsive polymer Poly (N-vinyl caprolactam) (PNVCL), which is normally prepared via radical free polymerization, was used to justify the 4D printing concept. As a result, by using a Stereolithography (SLA) 3D printer, 4D prints were successfully prepared. These prints were able to demonstrate intelligent and reversible expansion/shrinkage behaviour as the temperature increases and decreases. Additionally, in order to examine the differences in chemical structure, thermal properties, mechanical properties, and swelling behaviours of the photopolymerised and printed parts, a series of characterisation tests, including Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), goniometry, tensile test, gel fraction measurement and pulsatile swelling study were performed on this study. In conclusion, the differences between polymerisation methods are significant; despite their chemical structures and thermal properties being similar, there were significant differences with regard to tensile properties, swellability and wettability of samples. The implications of conducting this study are remarkable, not only in providing a new way of preparing NVCL, but also in demonstrating the possibility of using 4D printed NVCL for practical applications.

Additive Manufacturing of Personalized Pharmaceutical Dosage Forms via Stereolithography.

The introduction of three-dimensional printing (3DP) has created exciting possibilities for the fabrication of dosage forms, paving the way for personalized medicine. In this study, oral dosage forms of two drug concentrations, namely 2.50% and 5.00%, were fabricated via stereolithography (SLA) using a novel photopolymerizable resin formulation based on a monomer mixture that, to date, has not been reported in the literature, with paracetamol and aspirin selected as model drugs. In order to produce the dosage forms, the ratio of poly(ethylene glycol) diacrylate (PEGDA) to poly(caprolactone) triol was varied with diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (Irgacure TPO) utilized as the photoinitiator. The fabrication of 28 dosages in one print process was possible and the printed dosage forms were characterized for their drug release properties. It was established that both drugs displayed a sustained release over a 24-h period. The physical properties were also investigated, illustrating that SLA affords accurate printing of dosages with some statistically significant differences observed from the targeted dimensional range, indicating an area for future process improvement. The work presented in this paper demonstrates that SLA has the ability to produce small, individualized batches which may be tailored to meet patients' specific needs or provide for the localized production of pharmaceutical dosage forms.

Characterisation and controlled drug release from novel drug-loaded hydrogels.

Hydrogel based devices belong to the group of swelling controlled drug delivery systems. Temperature responsive poly(N-isopropylacrylamide)-poly(vinylpyrrolidinone) random copolymers were produced by free radical polymerisation, using 1-hydroxycyclohexylphenyketone as an ultraviolet-light sensitive initiator, and poly(ethylene glycol) dimethacrylate as the crosslinking agent (where appropriate). The hydrogels were synthesised to have lower critical solution temperatures (LCST) near body temperature, which is favourable particularly for 'smart' drug delivery applications. Two model drugs (diclofenac sodium and procaine HCl) were entrapped within these xerogels, by incorporating the active agents prior to photopolymerisation. The properties of the placebo samples were contrasted with the drug-loaded copolymers at low levels of drug integration. Modulated differential scanning calorimetry (MDSC), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and atomic force microscopy (AFM) were used to investigate the influence of the drugs incorporated on the solid-state properties of the xerogels. MDSC and swelling studies were carried out to ascertain their effects on the LCST and swelling behaviour of the hydrated samples. In all cases, drug dissolution analysis showed that the active agent was released at a slower rate at temperatures above the phase transition temperature. Finally, preliminary in vitro cytotoxicity evaluations were performed to establish the toxicological pattern of the gels.

Preparation of monolithic matrices for oral drug delivery using a supercritical fluid assisted hot melt extrusion process.

The use of supercritical fluids as plasticisers in polymer processing has been well documented. The body of work described in this research paper outlines the use of a supercritical CO(2) assisted extrusion process in the preparation of a hot melt extruded monolithic polymer matrix for oral drug delivery. Several batches of matrix material were prepared with Carvedilol used as the active pharmaceutical ingredient (API). These batches were subsequently extruded both with and without supercritical CO(2) incorporation. The resultant matrices were characterised using steady-state parallel plate rheometry, differential scanning calorimetry (DSC), atomic force microscopy (AFM), micro-thermal analysis (microTA) and dissolution testing. Dissolution analysis showed that the use of supercritical CO(2) during the extrusion process resulted in a faster dissolution of API when compared with unassisted extrusion. The supercritical CO(2) incorporation also resulted in reduced viscosity during processing, therefore allowing for quicker throughput and productivity. The results detailed within this paper indicate that supercritical fluid assisted hot melt extrusion is a viable enhancement to conventional hot melt extrusion for the production of monolithic dosage forms.

Synthesis, characterisation and phase transition behaviour of temperature-responsive physically crosslinked poly (N-vinylcaprolactam) based polymers for biomedical applications.

Poly (N-vinylcaprolactam) (PNVCL) is a polymer which offers superior characteristics for various potential medical device applications. In particular it offers unique thermoresponsive capabilities, which fulfils the material technology constraints required in targeted drug delivery applications. PNVCL phase transitions can be tailored in order to suit the requirements of current and next generation devices, by modifying the contents with regard to the material composition and aqueous polymer concentration. In this study, physically crosslinked Poly (N-vinylcaprolactam)-Vinyl acetate (PNVCL-VAc) copolymers were prepared by photopolymerisation. The structure of the polymers was established by Fourier transform infrared spectroscopy, nuclear magnetic resonance and gel permeation chromatography. The polymers were further characterised using differential scanning calorimetry and swelling studies. Determination of the LCST of the polymers in aqueous solution was achieved by employing four techniques; cloud point, UV-spectrometry, differential scanning calorimetry and rheometry. Sol-gel transition was established using tube inversion method and rheological analysis. This study was conducted to determine the characteristics of PNVCL with the addition of VAc, and to establish the effects on the phase transition. The PNVCL based polymers exhibited a decrease in the LCST as the composition of VAc increased. Sol-gel transition could be controlled by altering the monomeric feed ratio and polymer concentration in aqueous milieu. Importantly all copolymers (10wt% in solution) underwent gelation between 33.6 and 35.9°C, and based on this and the other materials properties recorded in this study, these novel copolymers have potential for use as injectable in situ forming drug delivery systems for targeted drug delivery.

The use of agar as a novel filler for monolithic matrices produced using hot melt extrusion.

The use of filler materials in an extended release monolithic polymer matrix can lead to a vastly altered release profile for the active pharmaceutical ingredient. A range of excipients for use in monolithic matrices have been discussed in the literature. The body of work described in this research paper outlines the use of agar as a novel filler material in a hot melt extruded polymer matrix. Several batches of matrix material were prepared with Diclofenac sodium used as the active pharmaceutical ingredient (API). Agar and microcrystalline cellulose were used as the filler materials in varying ratios, to examine the effect of % filler content as well as filler type on the properties of the hot melt extruded matrix. The resultant extrudates were characterised using steady state parallel plate rheometry, differential scanning calorimetry (DSC) and dissolution testing. The rheometry analysis concluded that the fillers used resulted in an increase in the matrix viscosity. The DSC scans obtained showed negligible effects on the melting behavior of the matrix as a result of the filler inclusion. Dissolution analysis showed that the presence of the fillers resulted in a slower release rate of API than for the matrix alone. The results detailed within this paper indicate that agar is a viable filler for extended release hot melt produced dosage forms.

Multifunctional polyvinylpyrrolidinone-polyacrylic acid copolymer hydrogels for biomedical applications.

Copolymers of N-vinylpyrrolidinone and acrylic acid, crosslinked with ethylene glycol dimethacrylate and polyethylene glycol 600 dimethacrylate were prepared by UV-polymerisation. These polymers were analysed for their extractable content by Soxhlet extraction of the samples at 100 degrees C for 72 h. Aspirin and paracetamol were incorporated into the polymer structure at 25 wt.% during the curing process and their presence confirmed by Fourier transform infrared spectroscopy. It was found that the release rate of the drug from the polymer matrix was dependent on intermolecular bonding between the polymer and active agent with aspirin being released slower than paracetamol in all cases. Results showed that paracetamol was completely released after 24h whereas complete release of aspirin took up to 70 h. Finally preliminary in vitro biocompatibility testing was performed for crosslinked polyvinylpyrrolidinone, by determining human hepatoma HepG2 cell viability in the MTT assay and DNA damage in the comet assay following direct contact with various concentrations of polyvinylpyrrolidinone-containing media. Cytotoxicity data suggests a dose-dependent effect for both crosslinkers, with concentrations in the range 0.025-2.5 mg ml(-1) showing a marginal decrease in viability to, at most, 70% that of untreated cells. Again DNA migration in the comet assay following short-term exposure to EGDMA crosslinked hydrogels correlates with MTT data.

Fabrication and in vitro biological evaluation of photopolymerisable hydroxyapatite hydrogel composites for bone regeneration.

The aim of this study was to improve the bioactive and compressive properties of photopolymerisable polyethylene glycol hydrogels with the incorporation of hydroxyapatite at different loadings. The synthesis of pure hydroxyapatite was verified through Fourier transform infrared spectroscopy (FTIR) analysis by the complete reaction of all constituents. The formation of a bioactive layer of the hydrogel based composites was confirmed through the formation of carbonate hydroxyapatite after soaking the samples in simulated body fluid. The incorporation of hydroxyapatite into the system resulted in an increase in Young's modulus from 4.36 to 12.73 MPa and an increase in the stress at limit value from 1.20 to 4.42 MPa. This was due to the hydroxyapatite absorbing the compressive load, the polymer matrix distributing the load, a reduction in swelling and the presence of physical crosslinking between both components. Drug dissolution testing showed that the release rate of a drug from the hydrogels was dependent on the molecular weight of the polymer and the type of drug used.

Hydrogel/bioactive glass composites for bone regeneration applications: synthesis and characterisation.

Due to the deficiencies of current commercially available biological bone grafts, alternative bone graft substitutes have come to the forefront of tissue engineering in recent times. The main challenge for scientists in manufacturing bone graft substitutes is to obtain a scaffold that has sufficient mechanical strength and bioactive properties to promote formation of new tissue. The ability to synthesise hydrogel based composite scaffolds using photopolymerisation has been demonstrated in this study. The prepared hydrogel based composites were characterised using techniques including Fourier Transform Infrared Spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), Energy-dispersive X-ray spectrometry (EDX), rheological studies and compression testing. In addition, gel fraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), porosity and swelling studies of the composites were carried out. It was found that these novel hydrogel bioglass composite formulations did not display the inherent brittleness that is typically associated with bioactive glass based bone graft materials and exhibited enhanced biomechanical properties compared to the polyethylene glycol hydrogel scaffolds along. Together, the combination of enhanced mechanical properties and the deposition of apatite on the surface of these hydrogel based composites make them an ideal candidate as bone graft substitutes in cancellous bone defects or low load bearing applications.

Cell encapsulation and cryostorage in PVA-gelatin cryogels: incorporation of carboxylated ε-poly-L-lysine as cryoprotectant.

It is desirable to produce cryopreservable cell-laden tissue-engineering scaffolds whose final properties can be adjusted during the thawing process immediately prior to use. Polyvinyl alcohol (PVA)-based solutions provide platforms in which cryoprotected cell suspensions can be turned into a ready-to-use, cell-laden scaffold by a process of cryogelation. In this study, such a PVA system, with DMSO as the cryoprotectant, was successfully developed. Vascular smooth muscle cell (vSMC)-encapsulated cryogels were investigated under conditions of cyclic strain and in co-culture with vascular endothelial cells to mimic the environment these cells experience in vivo in a vascular tissue-engineering setting. In view of the cytotoxicity DMSO imposes with respect to the production procedure, carboxylated poly-L-lysine (COOH-PLL) was substituted as a non-cytotoxic cryoprotectant to allow longer, slower thawing periods to generate more stable cryogels. Encapsulated vSMC with DMSO as a cryoprotectant responded to 10% cyclic strain with increased alignment and proliferation. Cells were stored frozen for 1 month without loss of viability compared to immediate thawing. SMC-encapsulated cryogels also successfully supported functional endothelial cell co-culture. Substitution of COOH-PLL in place of DMSO resulted in a significant increase in cell viability in encapsulated cryogels for a range of thawing periods. We conclude that incorporation of COOH-PLL during cryogelation preserved cell functionality while retaining fundamental cryogel physical properties, thereby making it a promising platform for tissue-engineering scaffolds, particularly for vascular tissue engineering, or cell preservation within microgels.

Mechanical properties and thermal behaviour of PEGDMA hydrogels for potential bone regeneration application.

Poly(ethylene glycol) hydrogels are currently under investigation as possible scaffold materials for bone regeneration. The main purpose of this research was to analyse the mechanical properties and thermal behaviour of novel photopolymerised poly(ethylene glycol) dimethacrylate (PEGDMA) based hydrogels. The effect of varying macromolecular monomer concentration, molecular weight and water content on the properties of the resultant hydrogel was apparent. For example, rheological findings showed that storage modulus (G') of the hydrogels could be tailored to a range between approximately 14,000 and 70,000 Pa by manipulating both of the aforementioned criteria. Equally striking variations in mechanical performance were observed using uniaxial tensile testing where reduction in PEGDMA content in the hydrogels resulted in decrease in both tensile strength and Young's modulus values. Conversely, increases in the elongation at break values were observed as would be expected. Differential scanning calorimetry and dynamic mechanical thermal analysis showed that there was an increase in Tg with an increase in the molecular weight of PEGDMA. The relationship between the initial feed ratio, molecular weight of the macromolecular monomer and the subsequent mechanical properties of the hydrogels are further elucidated throughout this study.

Thermal behavior and mechanical properties of physically crosslinked PVA/Gelatin hydrogels.

Poly (vinyl alcohol)/Gelatin hydrogels are under active investigation as potential vascular cell culture biomaterials, tissue models and vascular implants. The PVA/Gelatin hydrogels are physically crosslinked by the freeze-thaw technique, which is followed by a coagulation bath treatment. In this study, the thermal behavior of the gels was examined by differential scanning calorimetry (DSC) and dynamic mechanical thermal analysis (DMTA). Rheological measurement and uniaxial tensile tests revealed key mechanical properties. The role of polymer fraction in relation to these mechanical properties is explored. Gelatin has no significant effect on the thermal behavior of PVA, which indicates that no substantial change occurs in the PVA crystallite due to the presence of gelatin. The glass transition temperature, melting temperature, degree of crystallinity, polymer fraction, storage modulus (G') and ultimate strength of one freeze-thaw cycle (1FT) hydrogels are inferior to those of 3FT hydrogels. With coagulation, both 1FT and 3FT hydrogels shifted to a lower value of T(g), melting temperature and polymer fraction are further increased and the degree of crystallinity is depressed. The mechanical properties of 1FT, but not 3FT, were strengthened with coagulation treatment. This study gives a detailed investigation of the microstructure formation of PVA/Gelatin hydrogel in each stage of physical treatments which helps us to explain the role of physical treatments in tuning their physical properties for biomechanical applications.

The synthesis of novel pH-sensitive poly(vinyl alcohol) composite hydrogels using a freeze/thaw process for biomedical applications.

Physically cross-linked hydrogels composed of 75% poly(vinyl alcohol) PVA and 25% poly(acrylic acid) were prepared by a freeze/thaw treatment of aqueous solutions. Between 0.5 and 1wt% of aspirin was incorporated into the systems. The purpose of the research was the development of a novel pH-sensitive hydrogel composite for the delivery of aspirin to wounds. Extensive research has being conducted on freeze/thaw poly(vinyl alcohol) hydrogels for use in active pharmaceutical ingredient (API) delivery. However very little research has been reported on the effects of an API on the overall properties of a freeze/thaw hydrogel. From the rheological analysis undertaken it was apparent that aspirin has a limiting effect on the formation of hydrogen bonding leading to hydrogels with reduced mechanical strength. To counteract this, a novel hydrogel system was developed encompassing a reinforcing film in the centre of the hydrogels. Freezing profiles were obtained to gain a better knowledge of the freezing behaviour of the hydrogels during the formation stage. Thermograms obtained from modulated differential scanning calorimetry (MDSC) indicated that the aspirin lowered the glass transition temperatures (T(g)) of the constituent polymers. The pH-sensitive nature of the hydrogels was apparent from solvent uptake studies carried out. Increasing alkaline media led to a greater degree of swelling due to increased ionisation of PAA. The hydrogels exhibited non-Fickian release kinetics. The release rates were relatively slow with total release achieved at between 30 and 40 h. The quantity of drug incorporated was found to influence the release rates considerably.

Development and characterisation of an agar--polyvinyl alcohol blend hydrogel.

Numerous authors have reported on hydrogel technologies providing products suitable for applications in biomedical, personal care as well as in nano-sensor applications. Hydrogels fabricated from single polymers have been extensively investigated. However, in many cases a single polymer alone cannot meet divergent demands in terms of both properties and performance. In this work, hydrogels were prepared by physically blending the natural polymer agar with polyvinyl alcohol in varying ratios to produce a new biosynthetic polymer applicable for a variety of purposes. Hydrogen bonding was observed to take place between the polyvinyl alcohol and the agar molecules in the composite materials leading to changes in the thermal, mechanical and swelling characteristics of the composite hydrogels. The composite hydrogels exhibited a slightly higher melting temperature than pure agar (116.81 degrees C). Irreversible compressive damage was found to occur at lower strain levels during compression testing of the dehydrated samples consisting of higher PVOH concentrations. Rheological analysis of hydrated sample revealed G' values of between 5000 and 10,000 Pa for the composite blends, with gels containing higher PVOH percentages exhibiting poorer mechanical strength.