Comparison of the performance of two grades of metformin hydrochloride elaboration by means of the SeDeM system, compressibility, compactability, and process capability indices.

Quality by design, applied to the development of a pharmaceutical drug, demands scientific methodologies, representing a source of information that will allow for a complete understanding the production process and the materials used for its manufacturing. Although the SeDeM system is a tool that enables a rational development of a product, result does not assure that an assessed material or mixture will be successful in terms of compression, hence, further research will be necessary on these features. The objective of this study was to assess and compare two grades of metformin hydrochloride elaboration: crystalline and direct compression using PXRD, the SeDeM expert system, the Heckel and Ryshkewitch-Duckworth models, as well as process control tools such as control charts and process capability indices to characterize and predict the performance of the materials in a direct compression process. The assessment identified that in spite of dealing with two different technical grades of a material with specific critical quality attributes for each one, PXRD analysis showed we dealt with the same crystalline structure, while the SeDeM system profiles obtained have very close values, and the main differences in materials were observed when subjecting them to conditions that simulate a compaction process with the Ryshkewitch-Duckworth model, in which a 46-times higher mechanical resistance was observed in the direct compression material compared with the crystalline one. The statistical control analysis revealed that only the direct compression material could be used to elaborate tablets whose weight variation was always maintained within the specification and control limits.

Bioadhesive hydrogel comprising bilirubin/ß-cyclodextrin inclusion complexes promote diabetic wound healing.

CONTEXT: Chronic non-healing diabetic wound therapy is an important clinical challenge. Manipulating the release of bioactive factors from an adhesive hydrogel is an effective approach to repair chronic wounds. As an endogenous antioxidant, bilirubin (BR) has been shown to promote wound healing. Nonetheless, its application is limited by its low water solubility and oxidative degradation. OBJECTIVE: This study developed a bilirubin-based formulation for diabetic wound healing. MATERIALS AND METHODS: Bilirubin was incorporated into ß-CD-based inclusion complex (BR/ß-CD) which was then loaded into a bioadhesive hydrogel matrix (BR/ß-CD/SGP). Scratch wound assays were performed to examine the in vitro pro-healing activity of BR/ß-CD/SGP (25 µg/mL of BR). Wounds of diabetic or non-diabetic rats were covered with BR or BR/ß-CD/SGP hydrogels (1 mg/mL of BR) and changed every day for a period of 7 or 21 days. Histological assays were conducted to evaluate the in vivo effect of BR/ß-CD/SGP. RESULTS: Compared to untreated (18.7%) and BR (55.2%) groups, wound closure was more pronounced (65.0%) in BR/ß-CD/SGP group. In diabetic rats, the wound length in BR/ß-CD/SGP group was smaller throughout the experimental period than untreated groups. Moreover, BR/ß-CD/SGP decreased TNF-α levels to 7.7% on day 3, and elevated collagen deposition and VEGF expression to 11.9- and 8.2-fold on day 14. The therapeutic effects of BR/ß-CD/SGP were much better than those of the BR group. Similar observations were made in the non-diabetic model. DISCUSSION AND CONCLUSION: BR/ß-CD/SGP promotes wound healing and tissue remodelling in both diabetic and non-diabetic rats, indicating an ideal wound-dressing agent.

Effects and Characterization of Some Topical Ointments Based on Vegetal Extracts on Incision, Excision, and Thermal Wound Models.

The present paper aims to formulate and characterize four phytotherapeutic ointments based on Hippophae fructus, Calendulae flos, Bardanae folium, and Millefolii herba, which are included in a novel ointment base. In order to investigate the healing properties of the ointments, in vivo experimental wound models of linear incision, circular excision, and thermal burn were performed on Wistar rats. Topical treatment was performed daily for 21 days. Determination of the wound contraction rate (WCR), the period of reepithelization, and histopathological examination were achieved. Additionally, for the tested ointments, oscillatory and rotational rheological tests were carried out, and for the extracts, HPLC analysis was performed. The results demonstrate that the tested novel ointments are safe for use and the most effective ointment proved to be the one based on Arctium lappa, followed by that of Calendulae flos.

Oral viscous budesonide solution for enhanced localized treatment of eosinophilic esophagitis through improved mucoadhesion and permeation.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus that is immune/antigen-mediated and often requires targeted treatment. In clinical practice, an oral viscous budesonide suspension prepared by adding sucralose to a budesonide suspension for inhalation (Pulmicort®) is used to treat adult EoE and enhance retention in the esophageal mucosa. Inspired by this off-label drug use, oral viscous budesonide solutions (OVBSs) were developed in this study, and their capacities for adhesion, permeation, and stability were explored. Given the insolubility of budesonide as a BCS II drug, we first evaluated its equilibrium solubility and found that Transcutol® HP was an excellent choice for creating an OVBS at a concentration of 0.2 mg/g. The rheological properties of the OVBSs were evaluated with a rheometer, and shear-thinning, which aids in swallowing, was observed. The addition of hydroxyethyl cellulose (HEC) increased the adhesion strength of the preparation, which was associated with the hydration and thickening mechanism. This result was confirmed in a dynamic gelation study and in vitro elution experiment conducted with porcine esophagus tissue. Furthermore, the permeabilities of the OVBSs in the porcine esophagus were evaluated with a Franz diffusion cell device. >80 % of the budesonide was released after 24 h, and the release profile was similar to that of the solution. To explore the storage conditions of OVBSs, critical factors such as pH, content, and impurities were determined. It was found that OVBSs exhibited different behaviors at different pH values and temperatures. Notably, the OVBSs containing 1.7 % HEC could be stored for >6 months at a temperature of 5 °C ± 3 °C and a pH of 4.5 without significant degradation. Overall, this study demonstrated that OVBSs have the potential to adhere to the esophageal mucosa, permeate the tissue, and remain stable during storage. Moreover, OVBSs exhibit a distinct advantage over traditional converted inhalation-to-oral budesonide therapies by enabling flexible dose adjustment in clinical applications, thereby potentially minimizing systemic side effects commonly associated with oral glucocorticoid administration.

Novel strategy for optimizing of corn starch-based ink food 3D printing process: Printability prediction based on BP-ANN model.

Although starch has been intensively studied as a raw material for 3D printing, the relationship between several important process parameters in the preparation of starch gels and the printing results is unclear. In this study, the relationship between different processing conditions and the gel printing performance of corn starch was evaluated by printing tests, rheological tests and low-field nuclear magnetic resonance (LF-NMR) tests, and a back-propagation artificial neural network (BP-ANN) model for predicting gel printing performance was developed. The results revealed that starch gels exhibited favorable printing performance when the gelatinization temperature ranged from 75 °C to 85 °C, and the starch content was maintained between 15 % and 20 %. The R2adj of the BP-ANN models were all reached 0.894, which indicated good predictive ability. The results of the study not only provide theoretical support for the application of corn starch gels in 3D food printing, but also present a novel approach for predicting the printing performance of related materials. This method contributes to the optimization of printing parameters, thereby enhancing printing efficiency and quality.

Versatile xanthan gum-based support bath material compatible with multiple crosslinking mechanisms: rheological properties, printability, and cytocompatibility study.

Extrusion-based bioprinting is a promising technology for the fabrication of complex three-dimensional (3D) tissue-engineered constructs. To further improve the printing accuracy and provide mechanical support during the printing process, hydrogel-based support bath materials have been developed. However, the gel structure of some support bath materials can be compromised when exposed to certain bioink crosslinking cues, hence their compatibility with bioinks can be limited. In this study, a xanthan gum-based composite support material compatible with multiple crosslinking mechanisms is developed. Different support bath materials can have different underlying polymeric structures, for example, particulate suspensions and polymer solution with varying supramolecular structure) and these properties are governed by a variety of different intermolecular interactions. However, common rheological behavior can be expected because they have similar demonstrated performance and functionality. To provide a detailed exploration/identification of the common rheological properties expressed by different support bath materials from a unified perspective, benchmark support bath materials from previous studies were prepared. A comparative rheological study revealed both the structural and shear behavior characteristics shared by support bath materials, including yield stress, gel complex moduli, shear-thinning behavior, and self-healing properties. Gel structural stability and functionality of support materials were tested in the presence of various crosslinking stimuli, confirming the versatility of the xanthan-based support material. We further investigated the effect of support materials and the diameter of extrusion needles on the printability of bioinks to demonstrate the improvement in bioink printability and structural integrity. Cytotoxicity and cell encapsulation viability tests were carried out to confirm the cell compatibility of the xanthan gum-based support bath material. We propose and demonstrate the versatility and compatibility of the novel support bath material and provide detailed new insight into the essential properties and behavior of these materials that serve as a guide for further development of support bath-based 3D bioprinting.

Preparation and Mechano-Functional Characterization of PEGylated Fibrin Hydrogels: Impact of Thrombin Concentration.

Three-dimensional (3D) neuronal cultures grown in hydrogels are promising platforms to design brain-like neuronal networks in vitro. However, the optimal properties of such cultures must be tuned to ensure a hydrogel matrix sufficiently porous to promote healthy development but also sufficiently rigid for structural support. Such an optimization is difficult since it implies the exploration of different hydrogel compositions and, at the same time, a functional analysis to validate neuronal culture viability. To advance in this quest, here we present a combination of a rheological protocol and a network-based functional analysis to investigate PEGylated fibrin hydrogel networks with gradually higher stiffness, achieved by increasing the concentration of thrombin. We observed that moderate thrombin concentrations of 10% and 25% in volume shaped healthy networks, although the functional traits depended on the hydrogel stiffness, which was much higher for the latter concentration. Thrombin concentrations of 65% or higher led to networks that did not survive. Our results illustrate the difficulties and limitations in preparing 3D neuronal networks, and stress the importance of combining a mechano-structural characterization of a biomaterial with a functional one.

Rheological Characterization of Three-Dimensional Neuronal Cultures Embedded in PEGylated Fibrin Hydrogels.

Three-dimensional (3D) neuronal cultures are valuable models for studying brain complexity in vitro, and the choice of the bulk material in which the neurons grow is a crucial factor in establishing successful cultures. Indeed, neuronal development and network functionality are influenced by the mechanical properties of the selected material; in turn, these properties may change due to neuron-matrix interactions that alter the microstructure of the material. To advance our understanding of the interplay between neurons and their environment, here we utilized a PEGylated fibrin hydrogel as a scaffold for mouse primary neuronal cultures and carried out a rheological characterization of the scaffold over a three-week period, both with and without cells. We observed that the hydrogels exhibited an elastic response that could be described in terms of the Young's modulus E. The hydrogels without neurons procured a stable E≃420 Pa, while the neuron-laden hydrogels showed a higher E≃590 Pa during the early stages of development that decreased to E≃340 Pa at maturer stages. Our results suggest that neurons and their processes dynamically modify the hydrogel structure during development, potentially compromising both the stability of the material and the functional traits of the developing neuronal network.

Physicochemical and rheological characterizations of a novel exopolysaccharide EPSKar1 and its iron complex EPSKar1-Fe: Towards potential iron-fortification applications.

Iron is a micronutrient essential for human health and physiology. Iron-deficiency anemia, the most common form of anemia, may occur from an iron homeostasis imbalance. Iron fortification is a promising and most sustainable and affordable solution to tackle the global prevalence of this anemia. Herein, we investigate physicochemical, rheological and stability characteristics of a novel exopolysaccharide 'EPSKar1' (derived from Lacticaseibacillus rhamnosus strain Kar1) and its iron complex 'EPSKar1-Fe (II)'. Our findings demonstrate that EPSKar1 is a high molecular-weight (7.8 × 105 Da) branched-chain heteropolysaccharide composed of galactose, N-acetylglucosamine, and mannose in a molar ratio of 8:4:1, respectively, and exhibits strong emulsifying and water-holding capacities. We find that EPSKar1 forms strong complexes with Fe, wherein the interactions between EPSKar1-Fe (II) complexes are mediated by sulfate, carboxyl, and hydroxyl groups. The rheological analyses reveal that the EPSKar1 and EPSKar1-Fe (II) complexes exhibited shear thickening and thinning properties in skim milk and water, respectively; however, the suspension of EPSKar1 in skim milk is viscoelastic with predominantly elastic response (G'>G" and tan Î´ < 1). In comparison, EPSKar1-Fe (II) complex exhibits remarkable stability under various processing conditions, highlighting its usefulness for the development of fortified dairy products. Together, these findings underpin considerable prospects of EPSKar1-Fe (II) complex as a novel iron-fortifier possessing multifarious rheological benefits for food applications.

Sucrose Esters and Beeswax Synergize to Improve the Stability and Viscoelasticity of Water-in-Oil Emulsions.

W/O emulsions are commonly used to prepare stable low-fat products, but their poor stability limits widespread applications. In this study, sucrose ester (SE) and beeswax were utilized to prepare an oil dispersion system in rapeseed oil, which was used as the external oil phase to further synergistically construct the W/O emulsion systems. The results show that spherical and fine crystals are formed under the synergistic effect of SE and BW (1.5 SE:0.5 BW). In this state, a dense interfacial crystal layer was easily formed, preventing droplet aggregation, leading to droplet size reduction (1-2 µm) and tight packing, improving viscoelasticity and resistance to deformation, and increasing the recovery rate (52.26%). The long-term stability of W/O emulsions containing up to 60 wt% water was found to be more than 30 days. The increase in the aqueous phase led to droplet aggregation, which increased the viscosity (from 400 Pa·s to 2500 Pa·s), improved the structural strength of the emulsion, and increased the width of the linear viscoelastic region (from 1% strain to 5% strain). These findings provide some technical support for the further development of stable low-fat products.

MacGyvered Multiproperty Materials Using Nanocarbon and Jam: A Spectroscopic, Electromagnetic, and Rheological Investigation.

As part of a biopolymer matrix, pectin was investigated to obtain an engineered jam, due to its biodegradability. Only a few examples of pectin-based nanocomposites are present in the literature, and even fewer such bionanocomposites utilize nanocarbon as a filler-mostly for use in food packaging. In the present paper, ecofriendly nanocomposites made from household reagents and displaying multiple properties are presented. In particular, the electrical behavior and viscoelastic properties of a commercial jam were modulated by loading the jam with carbon nanotubes and graphene nanoplates. A new nanocomposite class based on commercial jam was studied, estimating the percolation threshold for each filler. The electrical characterization and the rheological measurements suggest that the behavior above the percolation threshold is influenced by the different morphology-i.e., one-dimensional or two-dimensional-of the fillers. These outcomes encourage further studies on the use of household materials in producing advanced and innovative materials, in order to reduce the environmental impact of new technologies, without giving up advanced devices endowed with different physical properties.

Fabrication and characterization of oleogels and temperature-responsive water-in-oil emulsions based on candelilla (Euphorbia cerifera) wax.

Developing novel fats with zero trans and low saturated fatty acids represents a research hotspot in the colloid field today. Herein, natural candelilla (Euphorbia cerifera) wax was used as an oleogelator to construct oleogel systems, and can make strong oleogels at low concentrations (3 wt%). These oleogels were further employed as continuous phases to fabricate surfactant-free W/O emulsions with excellent stability (at least 30 days). Microstructural observation confirmed that the stability of emulsions was attributed to the interface and bulk phase crystallization of wax. All oleogels and emulsions were pseudoplastic fluids whose gel properties could be tuned via regulating oleogelator concentration. Water content also influenced the emulsion rigidity, denoting the droplets acted as "active fillers". Additionally, the emulsions displayed a temperature-responsive property, beneficial in mimicking the "fat-like" melt-in-the-mouth effect. These findings greatly enrich the formulation of surfactant-free W/O emulsions, providing technical support for the development of novel fats.

3D Bioprinting of Prevascularized Full-Thickness Gelatin-Alginate Structures with Embedded Co-Cultures.

The use of bioprinting allows the creation of complex three-dimensional cell laden grafts with spatial placements of different cell lines. However, a major challenge is insufficient nutrient transfer, especially with the increased size of the graft causing necrosis and reduced proliferation. A possibility to improve nutrient support is the integration of tubular structures for reducing diffusion paths. In this study the influence of prevascularization in full-thickness grafts on cell growth with a variation of cultivation style and cellular composition was investigated. To perform this, the rheological properties of the used gelatin-alginate hydrogel as well as possibilities to improve growth conditions in the hydrogel were assessed. Prevascularized grafts were manufactured using a pneumatic extrusion-based bioprinter with a coaxial extrusion tool. The prevascularized grafts were statically and dynamically cultured with a monoculture of HepG2 cells. Additionally, a co-culture of HepG2 cells, fibroblasts and HUVEC-TERT2 was created while HUVEC-TERT2s were concentrically placed around the hollow channels. A static culture of prevascularized grafts showed short-term improvements in cell proliferation compared to avascular grafts, while a perfusion-based culture showed improvements in mid-term cultivation times. The cultivation of the co-culture indicated the formation of vascular structures from the hollow channels toward avascular areas. According to these results, the integration of prevascular structures show beneficial effects for the in vitro cultivation of bioprinted grafts for which its impact can be increased in larger grafts.

Lyotropic Liquid Crystals: A Biocompatible and Safe Material for Local Cardiac Application.

The regeneration of cardiac tissue is a multidisciplinary research field aiming to improve the health condition of the post-heart attack patient. Indeed, myocardial tissue has a poor ability to self-regenerate after severe damage. The scientific efforts focused on the research of a biomaterial able to adapt to heart tissue, thus guaranteeing the in situ release of active substances or growth promoters. Many types of hydrogels were proposed for this purpose, showing several limitations. The aim of this study was to suggest a new usage for glyceryl monooleate-based lyotropic liquid crystals (LLCs) as a biocompatible and inert material for a myocardial application. The main advantages of LLCs are mainly related to their easy in situ injection as lamellar phase and their instant in situ transition in the cubic phase. In vivo studies proved the biocompatibility and the inertia of LLCs after their application on the myocardial tissue of mice. In detail, the cardiac activity was monitored through 28 days, and no significant alterations were recorded in the heart anatomy and functionality. Moreover, gross anatomy showed the ability of LLCs to be bio-degraded in a suitable time frame. Overall, these results permitted us to suppose a potential use of LLCs as materials for cardiac drug delivery.

Rheological Characterization and Modeling of Thermally Unstable Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV).

Presently, almost every industry uses conventional plastics. Its production from petroleum and extensive plastic pollution cause environmental problems. More sustainable alternatives to plastics include bioplastics such as poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), which is produced by bacteria and is biodegradable even in seawater. High temperature sensitivity as well as massive thermal degradation cause difficulties during the processing of PHBV. The aim of this work is to create a detailed rheological characterization and master curves to gain deeper knowledge about the material and its processing parameters. The rheological characterization was performed with frequency sweeps in the range of 0.1 rad/s to 628 rad/s and time sweeps over 300 s. Creating master curves at the reference temperature of 180 °C with the software IRIS delivers Carreau and Arrhenius parameters. These parameters allow for a calculation of the master curves for all other temperatures by means of the temperature shift factor. Moreover, the rheological measurements reveal a minimum rheological measurement temperature of 178 °C and a surprisingly high activation energy of 241.8 kJ/mol.

Coffee Cherry Pulp by-Product as a Potential Fiber Source for Bread Production: A Fundamental and Empirical Rheological Approach.

Effects of substituting of wheat flour with coffee cherry pulp powder (CCPP) (coffee by-product as fiber source) at 0, 1.2, 2.3, and 4.7% dry basis (0, 1.25, 2.5, and 5% wet basis) on dough and gluten rheological properties and baking quality were investigated. Rheological properties were analyzed during mixing, compression recovery, and creep-recovery. A rheological approach was adopted to study the viscoelasticity of dough enriched with fiber. The data obtained were analyzed with the Kelvin-Voigt model and the parameters were correlated to bread volume and crumb firmness to assess the effect of incorporating CCPP. A decrease in gluten's elastic properties was attributed to the water-binding and gelling properties of CCPP. Stiffness of dough and crumb firmness increased as the level of CCPP increased and bread volume decreased. Stiffer dough corresponded with lower compliance values and higher steady state viscosity compared to the control. A follow-up study with 5% CCPP and additives is recommended to overcome the reduction in elastic recovery and bread volume.

Evaluation of the Healing Effect of Ointments Based on Bee Products on Cutaneous Lesions in Wistar Rats.

The wound-healing capacity of ointments based on bee products was investigated in vivo on three experimental models of incision, excision and heat burn. For this purpose, four ointments were prepared with propolis, honey, apilarnil (drone brood homogenate) and a mixture of these three apitherapy products. The ointments were applied topically for 21 days. Clinical and macroscopic evaluation was performed throughout the experiment, with the recording of the re-epithelialization period and determination of the wound contraction rate on days 6 and 9. The histopathological examination was performed on days 1, 3, 12 and 21 of the treatment. The topical formulations were also characterized from a rheological point of view in order to verify their stability. HPLC analysis of propolis revealed the presence of phenolic compounds, particularly ferulic acid and p-coumaric which were found in high amounts. All ointments had beneficial effects on wound contraction and the re-epithelialization period, but the most significant result, both macroscopically and especially in terms of histological architecture, was presented by the ointment that contains all three apitherapy products, due to their synergistic effect.

Evaluation of the Wound Healing Potential of Some Natural Polymers on Three Experimental Models.

The aim of this paper was the preparation and investigation of the wound healing properties of four topical formulations based on natural polymers such as collagen, chitosan, lyophilized egg white, and a mixture of them. The therapeutic assessment of these four ointments was carried out in vivo on the incision, excision, and thermal burn wounds induced on Wistar rats. The treatment was applied topically on wounds once a day, for 21 days. The experimental results were analyzed from a clinical and histopathological point of view. The rheological characterization of the topical formulations was also performed in order to verify their spreadability and structural stability. All ointments had a positive effect on wound contraction and re-epithelization processes, but the one based on total polymers had a significant healing potential on the designed cutaneous lesions due to its synergistic effects.

Experimental Investigation on the Use of Selenice Natural Bitumen as an Additive for Pavement Materials.

As a good asphalt modifier, natural asphalt has been the focus of more attention because of its low price and ability to improve the performance of modified asphalt. In this paper, the incorporation of a natural asphalt binder in the production of bituminous materials for pavement application in China was experimentally investigated to evaluate the feasibility of such a process and its potential benefits in terms of performance. For this purpose, an asphalt binder conventionally used in the south of China was blended with various percentages of a hard natural binder obtained from the region of Selenice in Albania. The content of Selenice natural bitumen (SNB) was 80.5%, having high molecular weight and the advantages of good stability and compatibility with virgin asphalt. The physical, rheological, and mechanical properties, as well as the modification mechanism of the binder and corresponding asphalt mixture, were evaluated in the laboratory. It was observed that the hard binder improved the response of the binder blend at high and intermediate temperature; this reflected a better stability, improved moisture susceptibility, and enhanced rutting resistance of the mixture. Fluorescence microscopy showed that after dissolving, the size of the SNB modifier became smaller and its distribution was uneven, presenting three forms, granular, agglomerated, and flocculent properties. Chemical test results showed that the modification mechanism of SNB was mainly related to the enhancement of hydrogen bonds and Van der Waals forces caused by sulfoxide and carbonyl along with the stress concentration caused by silica particles. Molecular composition revealed that the proportion of middle molecules has reduced while the proportion of large molecules has increased. It is considered that SNB is a promising low-priced natural modifier with excellent rutting resistance properties. Future research will be focused on the economic analysis, pavement life cycle assessment of SNB modified asphalt, and its application in perpetual pavements.

Evaluation of calcium alginate bead formation kinetics: An integrated analysis through light microscopy, rheology and microstructural SAXS.

Ca(II)-alginate beads are being produced for a broad spectrum of biotechnological uses. Despite the simplicity of their manufacturing process, in these highly complex arrangements, the final properties of the material strongly depend on the supramolecular scaffolding. Here we present a cost-effective automatized Optical Video Microscopy approach for in situ evaluation of the kinetics of alginate bead formation. With simple mathematic modeling of the acquired data, we obtained key parameters that reveal valuable information on the system: the time course of gel-front migration correlates with the plateau of the storage module, and total volume shrinkage is highly related to the stabilization of shear strain and shear stress at the yield point. Our results provide feasible and reproducible tools, which allow for a better interpretation of bead formation kinetics and a rapid screening technique to use while designing gelling materials with specific properties for technological applications.