Viscosity Of Hydrogel Research Articles

Multi-physics numerical simulation study on thermo-sensitive gel delivery for a local post-tumor surgery treatment

Numerous studies in the literature have proposed the use of thermo-responsive hydrogels for filling cavities after tumor resection. However, optimizing the injection process is challenging due to the complex interplay of various multi-physics phenomena, such as the coupling of flow and heat transfer, multi-phase interactions, and phase-change dynamics. Therefore, gaining a fundamental understanding of these processes is crucial. In this study, we introduce a thermo-sensitive hydrogel formulated with poloxamer 407 and Gellan gum as a promising filling agent, offering an ideal phase-transition temperature along with suitable elastic and viscous modulus properties.We performed multi-physics simulations to predict the flow and temperature distributions during hydrogel injection. The results suggested that the hydrogel should be kept at 4 °C and injected within 90 s to avoid reaching the transition temperature. Cavity filling simulations indicated a symmetric distribution of the hydrogel, with minimal influence from the syringe's position.The temperature gradient at the cavity edge delays gelation during injection, which is essential to guarantee its administration as a liquid. The hydrogel's viscosity follows a sigmoidal function relative to temperature, taking five minutes to reach its maximum value. In summary, the multi-physics simulations carried out in this study confirm the potential of thermo-responsive hydrogels for use in post-tumor surgery treatment and define the conditions for a proper administration. Furthermore, the proposed model can be widely applied to other thermo-responsive hydrogels or under different conditions.

Quantitative Characterization of RCA-Based DNA Hydrogels - Towards Rational Materials Design.

DNA hydrogels hold significant promise for biomedical applications and can be synthesized through enzymatic Rolling Circle Amplification (RCA). Due to the exploratory nature of this emerging field, standardized RCA protocols specifying the impact of reaction parameters are currently lacking. This study varied template sequences and reagent concentrations, evaluating RCA synthesis efficiency and hydrogel mechanical properties through quantitative PCR (qPCR) and indentation measurements, respectively. Primer concentration and stabilizing additives showed minimal impact on RCA efficiency, while changes in polymerase and nucleotide concentrations had a stronger effect. Concentration of the circular template exerted the greatest influence on RCA productivity. An exponential correlation between hydrogel viscosity and DNA amplicon concentration was observed, with nucleobase sequence significantly affecting both amplification efficiency and material properties, particularly through secondary structures. This study suggests that combining high-throughput experimental methods with structural folding prediction offers a viable approach for systematically establishing structure-property relationships, aiding the rational design of DNA hydrogel material systems.

Dynamic Covalent Boronic-Acid-Functionalized Alginate/PVA Hydrogels for pH and Shear-Responsive Drug Delivery.

Herein, we investigated hydrogels composed of boronic-acid-functionalized alginate and blended with polyvinyl alcohol (PVA) of different molecular weights to control the release of metoclopramide hydrochloride as a function of pH and shear stress. The functionalization of alginate introduced dynamic covalent bonding and pH-responsive properties that can modulate network connectivity. The study investigated the viscoelastic properties of the hydrogels, their drug release profiles, and their responsiveness to changes in pH and shear forces. The results showed that a higher PVA molecular weight and alkaline pH conditions increased hydrogel viscosity and stiffness due to a more stable and interconnected network structure than acidic pH. Metoclopramide release revealed that the hydrogels exhibited pH-responsive drug release behavior. The drug was more readily released under acidic conditions due to the instability of sp2-hybridized boronate ester bonds. The influence of shear forces on the release of metoclopramide was also investigated at shear rates of 1, 10, and 100 s-1, revealing their effect on matrix stiffening. Research shows that AlgBA/PVA hydrogels have unique properties, such as dynamic covalent bonding, that make them sensitive to external mechanical forces. This sensitivity makes them ideal for applications where physiological conditions trigger drug release.

Formulation and dermal delivery of a new active pharmaceutical ingredient in an in vitro wound model for the treatment of chronic ulcers

The aim of this study was to investigate dermal delivery of the new active pharmaceutical ingredient (API) TOP-N53 into diabetic foot ulcer using an in vitro wound model consisting of pig ear dermis and elucidate the impact of drug formulation and wound dressing taking into consideration clinical relevance in the home care setting and possible bacterial infection. Different formulation approaches for the poorly water-soluble API including colloidal solubilization, drug micro-suspension and cosolvent addition were investigated; moreover, the effect of (micro-)viscosity of hydrogels used as primary wound dressing on delivery was assessed. Addition of Transcutol® P as cosolvent to water improved solubility and was significantly superior to all other approaches providing a sustained three-day delivery that reached therapeutic drug levels in the tissue. Solubilization in micelles or liposomes, on the contrary, did not boost delivery while micro-suspensions exhibited sedimentation on the tissue surface. Microbial contamination was responsible for considerable metabolism of the drug leading to tissue penetration of metabolites which may be relevant for therapeutic effect. Use of hydrogels under semi-occlusive conditions significantly reduced drug delivery in a viscosity-dependent fashion. Micro-rheologic analysis of the gels using diffusive wave spectroscopy confirmed the restricted diffusion of drug particles in the gel lattice which correlated with the obtained tissue delivery results. Hence, the advantages of hydrogel dressings from the applicatory characteristic point of view must be weighed against their adverse effect on drug delivery. The employed in vitro wound model was useful for the assessment of drug delivery and the development of a drug therapy concept for chronic diabetic foot ulcer. Mechanistic insights about formulation and dressing performance may be applied to drug delivery in other skin conditions such as digital ulcer.

The influence of viscosity of hydrogels on the spreading and migration of cells in 3D bioprinted skin cancer models.

Various in vitro three-dimensional (3D) tissue culture models of human and diseased skin exist. Nevertheless, there is still room for the development and improvement of 3D bioprinted skin cancer models. The need for reproducible bioprinting methods, cell samples, biomaterial inks, and bioinks is becoming increasingly important. The influence of the viscosity of hydrogels on the spreading and migration of most types of cancer cells is well studied. There are however limited studies on the influence of viscosity on the spreading and migration of cells in 3D bioprinted skin cancer models. In this review, we will outline the importance of studying the various types of skin cancers by using 3D cell culture models. We will provide an overview of the advantages and disadvantages of the various 3D bioprinting technologies. We will emphasize how the viscosity of hydrogels relates to the spreading and migration of cancer cells. Lastly, we will give an overview of the specific studies on cell migration and spreading in 3D bioprinted skin cancer models.

An Approach for Fabricating Hierarchically Porous Cell‐Laden Constructs Utilizing a Highly Porous Collagen‐Bioink

AbstractIn bioprinting procedures, bioinks typically comprise hydrogels, necessitating a balance between printability and bioactivity. Achieving good printability requires a relatively high hydrogel viscosity, but this can reduce bioactivity due to poor cell‐to‐cell interactions of the encapsulated cells. Therefore, developing hydrogels with excellent printability and bioactivity is a significant challenge in bioprinting. Here, a collagen‐based bioink with excellent printability and bioactivity is developed. The bioink is prepared through a two‐step process: first, by subjecting the bioink to whipping to create a non‐homogeneous porous structure, and subsequently, by employing centrifugation to refine this porous structure into a uniform and relatively smaller microscale porous structure (with a specific diameter of 15.7 ± 9.2 µm). Using the designed bioink, a hierarchical porous structure is fabricated without any special equipment or supporting/sacrificing materials. To demonstrate the feasibility of the collagen bioink laden with human adipose stem cells, a hierarchical cell construct is fabricated using a bioprinter. The construct exhibits significantly enhanced cellular activities and superior osteogenic differentiation compared to the bioprinted cell constructs using normal collagen bioink. These findings suggest that collagen‐based bioinks, which are both printable and bioactive, hold significant promise for extensive utilization in a variety of tissue regeneration applications.

Development of semisolid pharmaceutical forms with mometasone furoate

Abstract Objective This study aims to develop semisolid pharmaceutical forms for the topical administration of mometasone furoate. Methods Two creams (O1 and O2) and four hydroxypropyl methylcellulose-based hydrogels were prepared (H3-H6). Two different sorts of hydroxypropyl methylcellulose were used in concentrations of 15 and 20%. Consistency, spreadability, viscosity, and pH were measured. In vitro drug release was determined by a vertical, Franz diffusion cell. Mathematical models were applied for a better understanding of release phenomena. Results O1 and O2 presented lower values for penetration depth and spreadability. Hydrogel viscosity is influenced by the type and concentration of the gel-forming agent. Viscosity decreases in the order H6, H5, H4, and H3. pH varies between 4.6 to 5.92, fulfilling the requirements of European Pharmacopiea. Creams showed 5.49 and 6.59% of mometasone released after 6 hours. The lowest viscosity hydrogel presented the best dissolution of 40.11% mometasone after 6 hours. Conclusions H3 hydrogel releases the highest amount of mometasone furoate after 6 hours. The release is best described by the Korsmeyer-Peppas model explained by water diffusion and polymeric chain relaxation happen during the swelling of the polymer.

Photomodulated Extrusion as a Localized Endovascular Hydrogel Deposition Method.

Minimally invasive endovascular embolization is used to treat a wide range of diseases in neurology, oncology, and trauma where the vascular morphologies and corresponding hemodynamics vary greatly. Current techniques based on metallic coils, flow diverters, liquid embolics, and suspended microspheres are limited in their ability to address a wide variety of vasculature and can be plagued by complications including distal migration, compaction, and inappropriate vascular remodeling. Further, these endovascular devices currently offer limited therapeutic functions beyond flow control such as drug delivery. Herein, a novel in situ microcatheter-based photomodulated extrusion approach capable of dynamically tuning the physical and morphological properties of injectable hydrogels, optimizing for local hemodynamic environment and vascular morphology, is proposed and demonstrated. A shear thinning and photoactivated poly(ethylene glycol diacrylate)-nanosilicate (PEGDA-nSi) hydrogel is used to demonstrate multiple extrusion modes which are controlled by photokinetics and device configurations. Real-time photomodulation of injected hydrogel viscosity and modulus is successfully used for embolization in various vasculatures, including high-flow large vessels and arterial-to-arterial capillary shunts. Furthermore, a generalizable therapeutic delivery platform is proposed by demonstrating a core-shell structured extrusion encapsulating doxorubicin to achieve a more sustained release compared to unencapsulated payload.

Lyophilized Progenitor Tenocyte Extracts: Sterilizable Cytotherapeutic Derivatives with Antioxidant Properties and Hyaluronan Hydrogel Functionalization Effects.

Cultured primary progenitor tenocytes in lyophilized form were previously shown to possess intrinsic antioxidant properties and hyaluronan-based hydrogel viscosity-modulating effects in vitro. The aim of this study was to prepare and functionally characterize several stabilized (lyophilized) cell-free progenitor tenocyte extracts for inclusion in cytotherapy-inspired complex injectable preparations. Fractionation and sterilization methods were included in specific biotechnological manufacturing workflows of such extracts. Comparative and functional-oriented characterizations of the various extracts were performed using several orthogonal descriptive, colorimetric, rheological, mechanical, and proteomic readouts. Specifically, an optimal sugar-based (saccharose/dextran) excipient formula was retained to produce sterilizable cytotherapeutic derivatives with appropriate functions. It was shown that extracts containing soluble cell-derived fractions possessed conserved and significant antioxidant properties (TEAC) compared to the freshly harvested cellular starting materials. Progenitor tenocyte extracts submitted to sub-micron filtration (0.22 µm) and 60Co gamma irradiation terminal sterilization (5-50 kGy) were shown to retain significant antioxidant properties and hyaluronan-based hydrogel viscosity modulating effects. Hydrogel combination products displayed important efficacy-related characteristics (friction modulation, tendon bioadhesivity) with significant (p < 0.05) protective effects of the cellular extracts in oxidative environments. Overall, the present study sets forth robust control methodologies (antioxidant assays, H2O2-challenged rheological setups) for stabilized cell-free progenitor tenocyte extracts. Importantly, it was shown that highly sensitive phases of cytotherapeutic derivative manufacturing process development (purification, terminal sterilization) allowed for the conservation of critical biological extract attributes.

Self-Assembling Injectable Hydrogel for Controlled Drug Delivery of Antimuscular Atrophy Drug Tilorone.

A two-component injectable hydrogel was suitably prepared for the encapsulation and prolonged release of tilorone which is an antimuscular atrophy drug. The rapid (7-45 s, depending on the polymer concentration) in situ solidifications of the hydrogel were evoked by the evolving Schiff-base bonds between the aldehyde groups of modified PVA (4-formyl benzoate PVA, PVA-CHO, 5.9 mol% functionalization degree) and the amino groups of 3-mercaptopropionate chitosan (CHIT-SH). The successful modification of the initial polymers was confirmed by both FTIR and NMR measurements; moreover, a new peak appeared in the FTIR spectrum of the 10% w/v PVA-CHO/CHIT-SH hydrogel at 1647 cm-1, indicating the formation of a Schiff base (-CH=N-) and confirming the interaction between the NH2 groups of CHIT-SH and the CHO groups of PVA-CHO for the formation of the dynamic hydrogel. The reaction between the NH2 and CHO groups of the modified biopolymers resulted in a significant increase in the hydrogel's viscosity which was more than one thousand times greater (9800 mPa·s) than that of the used polymer solutions, which have a viscosity of only 4.6 and 5.8 mPa·s, respectively. Furthermore, the initial chitosan was modified with mercaptopropionic acid (thiol content = 201.85 ± 12 µmol/g) to increase the mucoadhesive properties of the hydrogel. The thiolated chitosan showed a significant increase (~600 mN/mm) in adhesion to the pig intestinal membrane compared to the initial one (~300 mN/mm). The in vitro release of tilorone from the hydrogel was controlled with the crosslinking density/concentration of the hydrogel; the 10% w/v PVA-CHO/CHIT-SH hydrogel had the slowest releasing (21.7 h-1/2) rate, while the 2% w/v PVA-CHO/CHIT-SH hydrogel had the fastest releasing rate (34.6 h-1/2). Due to the characteristics of these hydrogels, their future uses include tissue regeneration scaffolds, wound dressings for skin injuries, and injectable or in situ forming drug delivery systems. Eventually, we hope that the developed hydrogel will be useful in the local treatment of muscle atrophy, such as laryngotracheal atrophy.

Eco-friendly whey/polysaccharide-based hydrogel with poly(lactic acid) for improvement of agricultural soil quality and plant growth

A set of renewable and biodegradable hydrogels based on acid whey and cellulose derivatives blended with poly(lactic acid) (PLA) were designed as eco-friendly biopolymeric material for sustainable agricultural applications. The physico-chemical properties of the hydrogel were evaluated using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and rheological measurements. The effect of the whey/polysaccharide/PLA hydrogel on soil quality improvement (water retention study, biodegradability, loading capacity and release of the fertilizers) and the growth pattern of Raphanus sativus and Phaseolus vulgaris has been also studied. The addition of PLA has been found to improve mechanical properties of the hydrogel. The introduction of 20% wt PLA extended decomposition time of hydrogels by 25% which makes the material more stable in the environment and maintaining the soil humidity for longer. The increasing the amount of PLA led to a rise in hydrogel viscosity brought about better entrapment efficiency of the fertilizers (86–92% for KNO3 and 87–96% for urea, resp.) compared to control (82% for KNO3 and 85% for urea, resp.). The novel hydrogels with swelling ratio of up to 500% showed potential as a sustainable water reservoir for plants improving water retention capacity of the soil by 30%.

Characterization and In Vitro Cytotoxicity Safety Screening of Fractionated Organosolv Lignin on Diverse Primary Human Cell Types Commonly Used in Tissue Engineering.

Simple SummaryAs global efforts to use eco-friendly and reusable materials increase, the use of lignin from waste biomass will continue to intensify. Lignin is an underutilized biowaste macromolecule that is gaining considerable interest in biomedical research. However, the source of lignin and the extraction process heavily influence its chemistry, which can influence a cell’s reaction to lignin. Organosolv lignin is extracted via an eco-friendly process from leftover waste material. Few studies have tested the biocompatibility of organosolv lignins with human cells. We extensively characterized fractionated organosolv lignin and performed in vitro cytotoxicity safety screening on diverse primary human cell types commonly used in tissue engineering. This is the first study to show that, at a balanced concentration, fractionated low MW beechwood-derived organosolv lignin is non-cytotoxic to highly relevant human cell types used in tissue engineering including human bone marrow-derived mesenchymal stromal cells (MSCs), chondrocytes, osteoblasts, periodontal ligament fibroblasts, gingival fibroblasts and keratinocytes. Additionally, we show that organosolv lignin can be used to fabricate cell scaffolds and that addition of lignin increased the stiffness and viscosity of the scaffolds as well as cell attachment. This suggests that organosolv lignin may be used in the generation of tissue-like biomaterial-based constructs for tissue repair.There is limited data assessing the cytotoxic effects of organosolv lignin with cells commonly used in tissue engineering. Structural and physico-chemical characterization of fractionated organosolv lignin showed that a decrease of the molecular weight (MW) is accompanied by a less branched conformation of the phenolic biopolymer (higher S/G ratio) and an increased number of aliphatic hydroxyl functionalities. Enabling stronger polymer−solvent interactions, as proven by the Hansen solubility parameter analysis, low MW organosolv lignin (2543 g/mol) is considered to be compatible with common biomaterials. Using low MW lignin, high cell viability (70–100%) was achieved after 2 h, 24 h and 7 days using the following lignin concentrations: MSCs and osteoblasts (0.02 mg/mL), gingival fibroblasts and keratinocytes (0.02 to 0.04 mg/mL), periodontal ligament fibroblasts and chondrocytes (0.02 to 0.08 mg/mL). Cell viability was reduced at higher concentrations, indicating that high concentrations are cytotoxic. Higher cell viability was attained using 30/70 (w/v) NaOH vs. 40/60 (w/v) EtOH as the initial lignin solvent. Hydrogels containing low MW lignin (0.02 to 0.3 mg/mL) in agarose dose-dependently increased chondrocyte attachment (cell viability 84–100%) and hydrogel viscosity and stiffness to 3–11 kPa, similar to the pericellular matrix of chondrocytes. This suggests that low MW organosolv lignin may be used in many tissue engineering fields.

Marrying the incompatible for better: Incorporation of hydrophobic payloads in superhydrophilic hydrogels

HypothesisThe entrapment of lyophobic in superhydrophilic hydrogels is challenging because of the intrinsic incompatibility between hydrophobic and hydrophilic molecules. To achieve such entrapment without affecting the hydrogel’s formation, the electrospinning of nanodroplets or nanoparticles with a water-soluble polymer could reduce the incompatibility through the reduction of interfacial tension and the formation of a barrier film preventing coalescence or aggregation. ExperimentsNanodroplets or nanoparticles dispersion are electrospun in the presence of a hydrophilic polymer in hydrogel precursors. The dissolution of the hydrophilic nanofibers during electrospinning allows a redispersion of emulsion droplets and nanoparticles in the hydrogel’s matrix. FindingsSuperhydrophilic hydrogels with well-distributed hydrophobic nanodroplets or nanoparticles are obtained without detrimentally imparting the viscosity of hydrogel’s precursors and the mechanical properties of the hydrogels. Compared with the incorporation of droplets without electrospinning, higher loadings of hydrophobic payload are achieved without premature leakage. This concept can be used to entrap hydrophobic agrochemicals, drugs, or antibacterial agents in simple hydrogels formulation.

Pharmaceutical polymer-based hydrogel formulations as prospective bioinks for 3D bioprinting applications: A step towards clean bioprinting

BackgroundThree-dimensional (3D) bioprinting has emerged as a game-changer technology in tissue engineering. Bioink is a crucial component in the 3D bioprinting process and is consists of biomaterials, cells, and growth factors. Current research on bioink formulations primarily uses animal-derived biomaterials for 3D bioprinting operations and soft tissue engineering, which possess challenges of batch-to-batch variability, immunogenicity, and microbial growth with aging. ObjectiveIn this study we aimed to investigate pharmaceutical polymers as biomaterials for hydrogel formulations and examine them for prospective bioink qualities. MethodsHydrogel formulations containing partially pregelatinized starch, sodium alginate along with either of hydroxypropyl methylcellulose or polyvinyl alcohol-polyethylene glycol graft co-polymer or sodium carboxymethyl cellulose were assessed for tensile strength of thin films; the viscosity of hydrogels, the structural integrity of crosslinked scaffolds, and effects of moist heat sterilization on physical properties, chemical properties and microbial contaminations. ResultsWe found that thin films made out of hydrogels found to have tensile strength suitable for soft tissue engineering. Viscosity results meet workable ranges for extrusion-based bioprinting. Structural integrity revealed crosslinked scaffolds were able to withstand in culture medias for few days and then started to disintegrate demonstrated biodegradation patterns of diffrent formulations. The moist heat sterilization process eliminated microbial contaminations effectively without altering the physicochemical properties of the hydrogels. ConclusionWe proved pharmaceutical polymers as biomaterials in hydrogel formulations that could be used as bioinks in future. These hydrogels has appropriate qualities for 3D bioprinting and soft tissue engineering. This study paves the way for clean bioprinting, with the possibility of formulating bioinks free from animal derived biomaterials.

New method for reducing viscosity and shear stress in hydrogel 3D printing via multidimension vibration

Microextrusion 3D bioprinting is a comparatively easy method to fabricate structures in tissue engineering. But high viscosity and wall shear stress in the tube and nozzle often lead to low cell survival rate of printed tissue. To reduce the viscosity and shear stress of materials in biological 3D printing, a multidimension microvibration assisted hydrogel 3D printing method was proposed. The compliant mechanism driven by piezoceramic was applied to 3D printing of hydrogels. The shear stress and viscosity of hydrogels could be effectively reduced by multidimension microvibration. Simulation analysis of the extrusion device was carried out to study the influence of vibration parameters on viscosity and shear stress, and optimized multidimension vibration forms and vibration parameters were selected for experiments. The experiment results show that multidimension microvibration can effectively reduce the viscosity of hydrogels and improve printing resolution and print speed.

Rheological and atomization behavior of glycyrrhizic acid based supramolecular gel propellant simulant

Gel propellant has attracted much more attention due to its advantages in reducing the leakage risk, adjustable thrust, being capable of multi-time ignition and easy handling. Conventional polymeric gellant or inorganic gellant based gel propellant suffered from several problems, such as high viscosity, inadequate atomization and insufficient combustion. As several pioneer reports, low-molecular weight gelators (LMWGs) based supramolecular gel fuels could exhibit good shear-thinning properties. The corresponding atomization property, however, is still unclear and needs further study. Herein, glycyrrhizic acid (GA) based hydrogel was employed as supramolecular gel propellant simulant, and its rheological and atomization behavior were well investigated. The 1.0%− 2.0% GA hydrogel exhibited a certain mechanical strength with storage modulus between 30 and 90 Pa. The shear viscosity of hydrogel decreased sharply under low shear rate (below 2 s−1), and then further decreased to 10−2-10−3 Pa.s under higher shear rate (2–1000 s−1). The resulting shear viscosity of 1.0% GA hydrogel was close to the magnitude of pure water, and an order of magnitude higher than pure water for 1.5% and 2.0% GA hydrogel systems. The atomization performance of GA hydrogel was investigated under both self-impinging doublet injector and centrifugal injector, it was found that the spray pattern, breakup length of liquid film and spray cone angle of 1.0% GA hydrogel were all similar as the pure water under two kinds of injectors, while the atomization performance degradation for 1.5% and 2.0% GA hydrogel. It was concluded that the shear viscosity plays an important role in determining the atomization properties for GA based hydrogel.

Electrically Induced Wire‐Forming 3D Printing Technology of Gallium‐Based Low Melting Point Metals

AbstractLow‐melting point metals and alloys, as emerging 3D printing ink, have attracted more and more attention especially for flexible or intelligent conductors and electronics. However, achieving 3D continuity of liquid metal structures or patterns using a common method is still challenging and worth pursuing. In this study, a generalized method is proposed for 3D printing structures made of low melting gallium‐based alloys with diverse melting points, which should greatly expand their applications. The mechanism for shaping liquid metal inks relies on the combination actions between electrocapillarity and oxidation, which significantly reduces the high surface tension as well provides solid frame for the inner liquid metals. Taken galinstan as an example, the printing conditions, including the viscosity of hydrogel, positive voltage (0–15 V), calcium chloride concentration, and velocity (the movement speed of the printing head) are explored to optimize the process. The printed galinstan is characterized to observe the morphology and elemental analysis of the surface oxide layer. During the process, the chemical reagents are all safe and non‐toxic, which is in line with the green product requirements. This printing method shall have broad application prospect in flexible electronics, biosensors, biomedical engineering, contrast agent in vivo, and other fields.

A supramolecular host-guest interaction-mediated injectable hydrogel system with enhanced stability and sustained protein release

Injectable hydrogels have been studied as drug delivery systems because of their minimal invasiveness and sustained drug release properties. Pluronic F127, consisting of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymers, exhibits thermo-responsive properties and hence is injectable due to its rapid sol-gel transition. Unmodified Pluronic F127-based hydrogels, however, have limited long-term stability and controllable release of drugs entrapped within them. In this study, host-guest interactions between adamantane-conjugated Pluronic F127 (F127-Ad) and polymerized β-cyclodextrin (CDP) were employed to develop a hydrogel-based protein delivery system. Single or multiple adamantane units were successfully introduced at the termini of Pluronic F127 with a 100% conversion yield, and the synthesized F127-Ad polymer produced a physically crosslinked micelle-packing structure when mixed with CDP. As the number of adamantanes at the terminal ends of Pluronic F127 increased, the critical gelation concentration of F127-Ad/CDP hydrogel decreased from 15 to 6% (w/v). The F127/CDP hydrogel was able to maintain its structure even with lower polymer content, and its injectability improved with a reduction of the hydrogel viscosity. The long-term stability of F127/CDP hydrogels was evaluated in vitro and in vivo, and it was demonstrated that the subcutaneously injected hydrogel did not disintegrate for up to 30 d. Throughout the drug release test using gelatin and insulin as model drugs, it was demonstrated that their release rates could be regulated via complexation between the protein drugs and the β-cyclodextrin molecules inside the hydrogel. In conclusion, the F127-Ad/CDP hydrogel is expected to be a versatile protein delivery system with controllable durability and drug release characteristics. Statement of significancePluronic F127 is one of the widely studied polymeric materials for thermo-sensitive injectable hydrogels due to its high biocompatibility and rapid sol-gel transition. Since the Pluronic F127-based hydrogel has some limitations in its long-term stability and mechanical property, it is inevitable to modify its structure for the application to drug delivery. In this study, mono- or multi- adamantane-conjugated Pluronic F127s were synthesized and mixed with β-cyclodextrin polymers to form hydrogels with host-guest interaction-mediated micelle-packing structures. The host-guest interaction introduced into the hydrogel system endowed it a sustained protein drug release behavior as well as high durability in vitro and in vivo. By increasing the number of adamantane molecules at the end of the Pluronic F127, both the stability and injectability of the hydrogel could be also modulated.

Hyaluronic Acid/Laponite Clay Nanocomposites‐Based Hydrogels for 3D Bioprinting Applications

Hyaluronic acid (HA) is a glycosaminoglycan with excellent physicochemical and biological properties and represents a potential component to constitute inks used in tissues and organs 3D bioprinting process. On the other hand, it does not have an adequate degree of rigidity necessary for the structural maintenance of printed components. Laponite (Lap) is a synthetic nanoclay capable of increasing the rheological properties of polymeric hydrogels. The present study aimed to develop and characterize HA/Lap clay nanocomposites-based hydrogels for the constitution of inks for 3D bioprinting, considering the Lap potential to improve the rheological characteristics of HA. For this, HA (12 mg/mL) and Laponite-XLG (50 mg/mL) hydrogels were initially produced. Three additional hydrogels, composed from the association of different percentages of HA and Lap samples (w/w), were manufactured (HA/Lap 75:25%, 50:50%, and 25:75%). After constitution, all hydrogels samples were characterized by rheological and spectrophotometric analysis (Fourier-Transform Infrared Spectroscopy-FTIR). Finally, they were submitted to an in vitro cytotoxicity test, with cell viability (human fibroblasts-GM07492) established by a spectrophotometric Resazurin/Resorufin method. The rheological analysis results demonstrate a directly proportional increase in hydrogel viscosity concerning the increase in Lap percentage. The values of HA, Lap, and experimental HA/Lap clay nanocomposites-based hydrogels samples (75:25%, 50:50%, and 25:75%) were 4.9, 12.7, 4.0, 9.4, and 12.0 Pa.s, respectively. In FTIR analysis, bands (wavenumber 1000.7 cm-1) were identified in the Lap and HA/Lap samples, corresponding to the stretching of the Si-O interaction of Lap's tetrahedral layer. The viability tests demonstrated the non-toxic profile of the HA, Lap, and the hydrogels resulting from their associations. Such results demonstrate the biological safety of HA/Lap samples and the rheological modifying role from Lap on developed hydrogels. The viscosity levels achieved, especially in the proportions of HA/Lap of 50:50% and 25:75%, demonstrate its potential in the constitution of inks for use in 3D bioprinting. Further research should contribute to establishing the ideal composition (percentage of HA and Lap) and the printability characteristics of the HA/Lap clay nanocomposites-based hydrogels.

Parametric Optimization of 3D Printed Hydrogel-Based Cardiovascular Stent.

This study aimed to develop personalized biodegradable stent (BDS) for the treatment of coronary heart disease. Three-dimensional (3D) printing technique has offered easy and fast fabrication of BDS with enhanced reproducibility and efficacy. A variety of BDS were printed with 3 types of hydrogel (~5ml) resources (10%w/v sodium alginate (SA), 10%w/v cysteine-sodium alginate (SA-CYS), and 10%w/v cysteine-sodium alginate with 0.4%w/v PLA-nanofibers (SA-CYS-NF)) dispersed from an 22G print head nozzle attached to the BD-syringe. The printability of hydrogels into 3D structures was examined based on such variables as hydrogel's viscosity, printing distance, printing speed and the nozzle size. It was demonstrated that alginate composition (10%w/v) offered BDS with sufficient viscosity that defined the thickness and swelling ratio of the stent struts. The thickness of the strut was found to be 338.7 ± 29.3μm, 262.5 ± 14.7μm and 237.1 ± 14.7μm for stents made of SA, SA-CYS and SA-CYS-NF, respectively. SA-CYS-NF stent displayed the highest swelling ratio of 38.8 ± 2.9% at the initial 30min, whereas stents made of SA and SA-CYS had 23.1 ± 2.4% and 22.0 ± 2.4%, respectively. The printed stents had sufficient mechanical strength and were stable against pseudo-physiological wall shear stress. An addition of nanofibers to alginate hydrogel significantly enhanced the biodegradation rates of the stents. In vitro cell culture studies revealed that stents had no cytotoxic effects on human umbilical vein endothelial cells (HUVECs) and Raw 264.7 cells (i.e., Monocyte/macrophage-like cells), supporting that stents are biocompatible and can be explored for future clinical applications.