Development of Amorphous Solid Dispersion Sustained-Release Formulations with Polymer Composite Matrix-Regulated Stable Release Plateaus.

PURPOSE: This study was designed to develop ibuprofen (IBU) sustained-release amorphous solid dispersion (ASD) using polymer composites matrix with drug release plateaus for stable release and to further reveal intrinsic links between polymer' matrix ratios and drug release behaviors. METHODS: Hydrophilic polymers and hydrophobic polymers were combined to form different composite matrices in developing IBU ASD formulations by hot melt extrusion technique. The intrinsic links between the mixed polymer matrix ratio and drug dissolution behaviors was deeply clarified from the dissolution curves of hydrophilic polymers and swelling curves of composite matrices, and intermolecular forces among the components in ASDs. RESULTS: IBU + ammonio methacrylate copolymer type B (RSPO) + poly(1-vinylpyrrolidone-co-vinyl acetate) (PVP VA64) physical mixtures presented unstable release behaviors with large error bars due to inhomogeneities at the micrometer level. However, IBU-RSPO-PVP VA64 ASDs showed a "dissolution plateau phenomenon", i.e., release behaviors of IBU in ASDs were unaffected by polymer ratios when PVP VA64 content was 35% ~ 50%, which could reduce risks of variations in release behaviors due to fluctuations in prescriptions/processes. The release of IBU in ASDs was simultaneously regulated by the PVP VA64-mediated "dissolution" and RSPO-PVP VA64 assembly-mediated "swelling". Radial distribution function suggested that similar intermolecular forces between RSPO and PVP VA64 were key mechanisms for the "dissolution plateau phenomenon" in ASDs at 35% ~ 50% of PVP VA64. CONCLUSIONS: This study provided ideas for developing ASD sustained-release formulations with stable release plateau modulated by polymer combinations, taking full advantages of simple process/prescription, ease of scale-up and favorable release behavior of ASD formulations.

Ion presence during thermal processing modulates the performance of rice albumin/anthocyanin binary system.

Thermal processing with salt ions is widely used for the production of food products (such as whole grain food) containing protein and anthocyanin. To date, it is largely unexplored how salt ion presence during thermal processing regulates the practical performance of protein/anthocyanin binary system. Here, rice albumin (RA) and black rice anthocyanins (BRA) were used to prepare RA/BRA composite systems as a function of temperature (60-100 °C) and NaCl concentration (10-40 mM) or CaCl2 concentration (20 mM). It was revealed that the spontaneous complexing reaction between RA and BRA was driven by hydrophobic interactions and hydrogen bonds and becomes easier and more favorable at a higher temperature (≤90 °C), excessive temperature (100 °C), however, may result in the degradation of BRA. Moreover, the salt ion presence during thermal processing may bind with RA and BRA, respectively, which could restrict the interaction between BRA and RA. Additionally, the inclusion of Na+ or Ca2+ at 20 mM endowed the binary system with strengthened DPPH radical scavenging capacity (0.95 for Na+ and 0.99 for Ca2+). Notably, Ca2+ performed a greater impact on the stability of the system than Na+.

Cytotoxic Properties of Polyurethane Foams for Biomedical Applications as a Function of Isocyanate Index.

Polyurethane foams are widely used in biomedical applications due to their desirable mechanical properties and biocompatibility. However, the cytotoxicity of its raw materials can limit their use in certain applications. In this study, a group of open-cell polyurethane foams were investigated for their cytotoxic properties as a function of the isocyanate index, a critical parameter in the synthesis of polyurethanes. The foams were synthesized using a variety of isocyanate indices and characterized for their chemical structure and cytotoxicity. This study indicates that the isocyanate index highly influences the chemical structure of polyurethane foams, also causing changes in cytotoxicity. These findings have important implications for designing and using polyurethane foams as composite matrices in biomedical applications, as careful consideration of the isocyanate index is necessary to ensure biocompatibility.

Design strategies for composite matrix and multifunctional polymeric scaffolds with enhanced bioactivity for bone tissue engineering.

Over the past few decades, various bioactive material-based scaffolds were investigated and researchers across the globe are actively involved in establishing a potential state-of-the-art for bone tissue engineering applications, wherein several disciplines like clinical medicine, materials science, and biotechnology are involved. The present review article's main aim is to focus on repairing and restoring bone tissue defects by enhancing the bioactivity of fabricated bone tissue scaffolds and providing a suitable microenvironment for the bone cells to fasten the healing process. It deals with the various surface modification strategies and smart composite materials development that are involved in the treatment of bone tissue defects. Orthopaedic researchers and clinicians constantly focus on developing strategies that can naturally imitate not only the bone tissue architecture but also its functional properties to modulate cellular behaviour to facilitate bridging, callus formation and osteogenesis at critical bone defects. This review summarizes the currently available polymeric composite matrices and the methods to improve their bioactivity for bone tissue regeneration effectively.

Design and Characterization of a Bioinspired Polyvinyl Alcohol Matrix with Structural Foam-Wall Microarchitectures for Potential Tissue Engineering Applications.

Traditional medical soft matrix used in a surgical treatment or in wound management was not good enough in both the structural support and interconnectivity to be applied in tissue engineering as a scaffold. Avian skeleton and feather rachises might be good reference objects to mimic in designing a scaffold material with good structural support and high interconnectivity because of its structural foam-wall microarchitectures and structural pneumaticity. In this study, a biomimetic airstream pore-foaming process was built up and the corresponding new medical soft matrix derived from polyvinyl alcohol matrix (PVAM) with air cavities inspired by avian skeleton and feather rachises was prepared. Furthermore, the resulting medical soft matrix and bovine Achilles tendon type I collagen could be employed to prepare a new collagen-containing composite matrix. Characterization, thermal stability and cell morphology of the bioinspired PVA matrix and the corresponding collagen-modified PVA composite matrix with open-cell foam-wall microarchitectures were studied for evaluation of potential tissue engineering applications. TGA, DTG, DSC, SEM and FTIR results of new bioinspired PVA matrix were employed to build up the effective system identification approach for biomimetic structure, stability, purity, and safety of target soft matrix. The bioinspired PVA matrix and the corresponding collagen-modified PVA composite matrix would be conductive to human hepatoblastoma HepG2 cell proliferation, migration, and expression which might serve as a promising liver cell culture carrier to be used in the biological artificial liver reactor.

Simple and facile carbon dots based electrochemical biosensor for TNF-α targeting in cancer patient's sample.

Tumour Necrosis Factor (TNF-α) is a pro-inflammatory cytokine having key roles in cell death, differentiation, survival, proliferation, migration and is a modulator of immune system. Therefore, TNF-α is an ideal biomarker for several disease diagnosis including cancer. However, out of all the biomarkers of cancer, TNF-α) is less explored for cancer detection. Only a few reports are available of developing biosensors for TNF-α targeting in human serum samples. Also, Carbon Dots (CDs) remains less explored in biosensor application. In this regard, for the first time, a sensitive and low-cost electrochemical biosensor based on CDs has developed. CDs were synthesized by simple yet facile microwave pyrolysis. Poly methyl methacrylate (PMMA) was selected as the matrix to hold CDs to fabricate the biosensing platform. This novel CD-PMMA nanocomposite featuring excellent biocompatibility, exceptional electrocatalytic conductivity, and large surface area. CD-PMMA was applied as transducing material to efficiently conjugate antibodies specific towards TNF-α and fabricate electrochemical immunosensor for specific detection of TNF-α. The fabricated immunosensor was used for the detection of TNF-α within a wide dynamic range of 0.05-160 pg mL-1 with a lower detection limit of 0.05 pg mL-1 and sensitivity of 5.56 pg mL-1 cm-2. Furthermore, this CDs based immunosensor retains high sensitivity, selectivity, and stability. This immunosensor demonstrated a high correlation with the conventional technique, Enzyme-Linked Immunosorbent Assay for early screening of cancer patient serum samples.

A Polymer for Application as a Matrix Phase in a Concept of In Situ Curable Bioresorbable Bioactive Load-Bearing Continuous Fiber Reinforced Composite Fracture Fixation Plates.

The use of bioresorbable fracture fixation plates made of aliphatic polyesters have good potential due to good biocompatibility, reduced risk of stress-shielding, and eliminated need for plate removal. However, polyesters are ductile, and their handling properties are limited. We suggested an alternative, PLAMA (PolyLActide functionalized with diMethAcrylate), for the use as the matrix phase for the novel concept of the in situ curable bioresorbable load-bearing composite plate to reduce the limitations of conventional polyesters. The purpose was to obtain a preliminary understanding of the chemical and physical properties and the biological safety of PLAMA from the prospective of the novel concept. Modifications with different molecular masses (PLAMA-500 and PLAMA-1000) were synthesized. The efficiency of curing was assessed by the degree of convergence (DC). The mechanical properties were obtained by tensile test and thermomechanical analysis. The bioresorbability was investigated by immersion in simulated body fluid. The biocompatibility was studied in cell morphology and viability tests. PLAMA-500 showed better DC and mechanical properties, and slower bioresorbability than PLAMA-1000. Both did not prevent proliferation and normal morphological development of cells. We concluded that PLAMA-500 has potential for the use as the matrix material for bioresorbable load-bearing composite fracture fixation plates.

Cross-Linkable Microgel Composite Matrix Bath for Embedded Bioprinting of Perfusable Tissue Constructs and Sculpting of Solid Objects.

Tissue engineering is a rapidly growing field, which requires advanced fabrication technologies to generate cell-laden tissue analogues with a wide range of internal and external physical features including perfusable channels, cavities, custom shapes, and spatially varying material and/or cell compositions. A versatile embedded printing methodology is proposed in this work for creating custom biomedical acellular and cell-laden hydrogel constructs by utilizing a biocompatible microgel composite matrix bath. A sacrificial material is patterned within a biocompatible hydrogel precursor matrix bath using extrusion printing to create three-dimensional features; after printing, the matrix bath is cross-linked, and the sacrificial material is flushed away to create perfusable channels within the bulk composite hydrogel matrix. The composite matrix bath material consists of jammed cross-linked hydrogel microparticles (microgels) to control rheology during fabrication along with a fluid hydrogel precursor, which is cross-linked after fabrication to form the continuous phase of the composite hydrogel. For demonstration, gellan or enzymatically cross-linked gelatin microgels are utilized with a continuous gelatin hydrogel precursor solution to make the composite matrix bath herein; the composite hydrogel matrix is formed by cross-linking the continuous gelatin phase enzymatically after printing. A variety of features including discrete channels, junctions, networks, and external contours are fabricated in the proposed composite matrix bath using embedded printing. Cell-laden constructs with printed features are also evaluated; the microgel composite hydrogel matrices support cell activity, and printed channels enhance proliferation compared to solid constructs even in static culture. The proposed method can be expanded as a solid object sculpting method to sculpt external contours by printing a shell of sacrificial ink and further discarding excess composite hydrogel matrix after printing and cross-linking. While aqueous alginate solution is used as a sacrificial ink, more advanced sacrificial materials can be utilized for better printing resolution.

The improved performance of MALDI-TOF MS on the analysis of herbal saponins by using DHB-GO composite matrix.

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is an excellent analytical technique for rapid analysis of a variety of molecules with straightforward sample pretreatment. The performance of MALDI-TOF MS is largely dependent on matrix type, and the development of novel MALDI matrices has aroused wide interest. Herein, we devoted to seek more robust MALDI matrix for herbal saponins than previous reported, and ginsenoside Rb1, Re, and notoginsenoside R1 were used as model saponins. At the beginning of the present study, 2,5-dihydroxybenzoic acid (DHB) was found to provide the highest intensity for saponins in four conventional MALDI matrices, yet the heterogeneous cocrystallization of DHB with analytes made signal acquisition somewhat "hit and miss." Then, graphene oxide (GO) was proposed as an auxiliary matrix to improve the uniformity of DHB crystallization due to its monolayer structure and good dispersion, which could result in much better shot-to-shot and spot-to-spot reproducibility of saponin analysis. The satisfactory precision further demonstrated that minute quantities of GO (0.1 µg/spot) could greatly reduce the risk of instrument contamination caused by GO detachment from the MALDI target plate under vacuum. More importantly, the sensitivity and linearity of the standard curve for saponins were improved markedly by DHB-GO composite matrix. Finally, the application of detecting the Rb1 in complex biological sample was exploited in rat plasma and proved it applicable for pharmacokinetic study quickly. This work not only opens a new field for applications of DHB-GO in herbal saponin analysis but also offers new ideas for the development of composite matrices to improve MALDI MS performance.

Effect of Chitin Nanofibrils on Biocompatibility and Bioactivity of the Chitosan-Based Composite Film Matrix Intended for Tissue Engineering.

This paper discusses the mechanical and physicochemical properties of film matrices based on chitosan, as well as the possibility of optimizing these properties by adding chitin nanofibrils. It is shown that with the introduction of chitin nanofibrils as a filler, the mechanical stability of the composite materials increases. By varying the concentration of chitin nanofibrils, it is possible to obtain a spectrum of samples with different bioactive properties for the growth of human dermal fibroblasts. Film matrices based on the nanocomposite of chitosan and 5 wt % chitin nanofibrils have an optimal balance of mechanical and physicochemical properties and bioactivity in relation to the culture of human dermal fibroblasts.

An auxiliary matrix for routine analysis of small molecules and biological macromolecules using matrix-assisted laser desorption ionization mass spectrometry.

The great hurdles related with matrix-assisted laser desorption/ionization (MALDI) analysis are inhomogeneous crystallization, poor reproducibility, and low sensitivity. To effectively improve the performance of MALDI mass spectrometry (MS), graphene oxide (GO) was first utilized as an auxiliary matrix of the conventional matrices, including 2,5-dihydroxybenzoic acid (DHB), α-cyano-4-hydoxycyanocinnamic acid (CHCA), 2,4,6-trihydroxyacetophenone (THAP), and 3,5-dimethoxy-4-hydroxycinnamic acid (SA), for the analysis of small molecules and biological macromolecules on different MALDI MS systems. The results revealed that the DHB-GO composite matrix could provide much superior crystal homogenization, better reproducibility, higher sensitivity, and more excellent linearity for the statins' tissue imaging on iMScope than the single-use DHB matrix. Moreover, the DHB-GO dramatically improved the spot-to-spot and shot-to-shot reproducibility, crystal homogenization, sensitivity, and linearity of MALDI-TOF MS for statins' analysis in dried droplet. The capability of THAP on the analysis of lipids, similarly, could be greatly enhanced by the combined use of GO. THAP-GO composite matrix was expected to be widely used in the MALDI MS-based liposome studies. It was also found that CHCA-GO could provide superior analytical performance for peptides. The sensitivity and reproducibility of intact proteins could be greatly improved by SA-GO composite matrix. More importantly, the better reproducibility produced by the composite matrices sufficiently indicated that low concentration (0.1 mg mL-1) of GO almost did not cause contamination to MALDI MS system. Thus, GO was proved to be a versatile auxiliary matrix for the MALDI MS-based routine analysis of small molecules and biological macromolecules. Graphical abstract ᅟ.

Unusual Mesoporous Carbonaceous Matrix Loading with Sulfur as the Cathode of Lithium Sulfur Battery with Exceptionally Stable High Rate Performance.

Unusual three-dimensional mesoporous carbon/reduced graphene oxide (MP-C/rGO) matrix possessing graphene nanolayer pore walls built up by three to five graphene monosheets and some carbon particles with the sizes of about 5 nm located between the graphene nanolayers was prepared by facile freeze-drying and then carbonization of the poly(vinyl alcohol) and graphene oxide mixture. The mesoporous carbonaceous MP-C/rGO sample has a high specific surface area of 661.6 m2 g-1, large specific pore volume of 1.54 m3 g-1, and focused pore size distribution of 2-10 nm. About 64 wt % sulfur could be held in the pores of the MP-C/rGO matrix. As the cathode of a Li-S battery, the MP-C/rGO/S composite showed excellent electrochemical property including a high initial specific capacity of 919 mA h g-1 at 1 C with the capacity retention ratio of 63.3% and the Coulombic efficiency above 90% after 500 cycles. Meanwhile, the initial specific capacity of 602 mA h g-1 at 5 C and remaining capacity of 391 mA h g-1 after 500 cycles with an outstanding Coulombic efficiency of 97% indicate its exceptionally stable rate performance.

Composite glycerol/graphite/aromatic acid matrices for thin-layer chromatography/matrix-assisted laser desorption/ionization mass spectrometry of heterocyclic compounds.

New composite matrices have been suggested for the analysis of mixtures of different synthetic organic compounds (N-containing heterocycles and erectile dysfunction drugs) by thin layer chromatography/matrix-assisted laser desorption ionization time-of-flight mass spectrometry (TLC/MALDI-TOF). Different mixtures of classical MALDI matrices and graphite particles dispersed in glycerol were used for the registration of MALDI mass spectra directly from TLC plates after analytes separation. In most of cases, the mass spectra possessed [M+H]+ ions; however, for some analytes only [M+Na]+ and [M+K]+ ions were observed. These ions have been used to generate visualized TLC chromatograms. The described approach increases the desorption/ionization efficiencies of analytes separated by TLC, prevent spot blurring, simplifies and decrease time for sample preparation.

Gastroretentive extended release of metformin from methacrylamide-g-gellan and tamarind seed gum composite matrix.

Formulation of a gastroretentive extended release tablet of metformin based on polymethacrylamide-g-gellan (Pmaa-g-GG)-tamarind seed gum (TSG) composite matrix is the main purpose of this study. Tablets were prepared employing wet granulation method taking amount of Pmaa-g-GG, TSG and NaHCO3 (SBC, buoyancy contributor) as independent formulation variables. The tablets were then evaluated for in vitro drug release, buoyancy, ex vivo mucoadhesion, swelling and surface morphology. Compatibility between drug and excipients was checked by DSC, FTIR and XRD analysis. Buoyancy-lag-time, mucoadhesive strength, % drug release and release-rate constant were statistically analyzed using Design-Expert software (version 9.0.4.1) and the formulation was then numerically optimized to obtain USP-reference release profile. The optimized formulation showed excellent buoyancy over a 10h period with buoyancy lag time of 2.76min, significant mucoadhesion and drug release over a period of 10h with f2=71.58. Kinetic modeling unveiled anomalous non-Fickian transport based drug release mechanism.

A Novel High Mechanical Property PLGA Composite Matrix Loaded with Nanodiamond-Phospholipid Compound for Bone Tissue Engineering.

A potential bone tissue engineering material was produced from a biodegradable polymer, poly(lactic-co-glycolic acid) (PLGA), loaded with nanodiamond phospholipid compound (NDPC) via physical mixing. On the basis of hydrophobic effects and physical absorption, we modified the original hydrophilic surface of the nanodiamond (NDs) with phospholipids to be amphipathic, forming a typical core-shell structure. The ND-phospholipid weight ratio was optimized to generate sample NDPC50 (i.e., ND-phospholipid weight ratio of 100:50), and NDPC50 was able to be dispersed in a PLGA matrix at up to 20 wt %. Compared to a pure PLGA matrix, the introduction of 10 wt % of NDPC (i.e., sample NDPC50-PF10) resulted in a significant improvement in the material's mechanical and surface properties, including a decrease in the water contact angle from 80 to 55°, an approximately 100% increase in the Young's modulus, and an approximate 550% increase in hardness, thus closely resembling that of human cortical bone. As a novel matrix supporting human osteoblast (hFOB1.19) growth, NDPC50-PFs with different amounts of NDPC50 demonstrated no negative effects on cell proliferation and osteogenic differentiation. Furthermore, we focused on the behaviors of NDPC-PFs implanted into mice for 8 weeks and found that NDPC-PFs induced acceptable immune response and can reduce the rapid biodegradation of PLGA matrix. Our results represent the first in vivo research on ND (or NDPC) as nanofillers in a polymer matrix for bone tissue engineering. The high mechanical properties, good in vitro and in vivo biocompatibility, and increased mineralization capability suggest that biodegradable PLGA composite matrices loaded with NDPC may potentially be useful for a variety of biomedical applications, especially bone tissue engineering.

Cost-effective nanoporous Agar-Agar polymer/Nickel powder composite particle for effective bio-products adsorption by expanded bed chromatography.

In the present work a novel kind of dense nanoporous composite matrix for expanded bed application has been successfully first prepared with Nickel powder as a densifier and was covered with Agar-Agar layer as a skeleton, through the method of water-in-oil emulsification. Agar-Agar is a porous and inexpensive polymer. In order to fabricate cost-effective adsorbent with favorable qualities Agar-Agar polymer was used. Thereafter, the customized composite particle was modified by pseudo-affinity dye-ligand, Reactive Blue 4 (RB4), aimed at preparing a pseudo-affinity adsorbent (RB4-Agar-Ni) for bioprodut adsorption from aqueous solution. Bovine Serum Albumin (BSA) was selected as a model protein to investigate the adsorption behavior in batchwise and expanded bed chromatography, and the obtained results were evaluated with that of Streamline™ (Amersham-Pharmacia Biotech, Sweden). Spherical appearance and porous structure of composite particles were observed by the optical microscope (OM) and scanning electronic microscope (SEM). The results suggested that the matrices followed the logarithmic normal size distribution with the range of 65-300 µm and average diameter of 126.81-151.47 µm, proper wet density of 1.64-2.78 g/ml, water content of 62.74-34%, porosity of 98-90% and pore size of about 38-130 nm. For better comprehension of the impact of solid phase properties on the performance of the expanded bed, the expansion and hydrodynamic properties of a composite matrix with a series of densities was evaluated and estimated by the retention time distribution method (RTD) in an expanded bed and was compared with that of other matrices. According to obtained results the expansion factors under the same fluid velocity decreased by increasing the matrix density. Moreover, the axial dispersion coefficient (Dax) is the most appropriate parameter for evaluating the stability of expanded bed, on various operating conditions, such as different flow velocity, bed expansion degree, viscosity of the liquid phase and the density of adsorbent. It was observed that the application of matrix with high density was proper for high operation, fluid velocity, since the addition of densifier improves the rigidity of the matrix. Three momentous factors, pH, ionic strength and initial concentration of BSA were analyzed. The best results showed that the adsorption equilibrium isotherms seems to follow a typical Langmuir isotherm and also the maximum adsorption capacity (qm) of BSA on RB4-Agar-Ni (64.01 mg/ml adsorbent) was higher than that on RB4-Streamline commercial adsorbent (about 54 mg.ml adsorbent). Additionally kinetic adsorption processes were characterized by the pseudo-first-order and pseudo-second-order kinetics equations. The experimental data followed the pseudo-first-order kinetic equation. Also the breakthrough curves were investigated. It was found that dynamic binding capacity (DBC) decreased with increasing the flow rate and the values of DBC decreased from 21.08 to 11.15 mg/ml adsorbent when the density of composite beads increased from 1.64 to 2.78 g/ml. All results indicate that the prepared composite is promising for efficient bioproduct adsorption with good hydrodynamic characteristics, high stability and it is suitable for expanded bed usage as a cost-effective adsorbent.

Characterization and evaluation of the novel agarose-nickel composite matrix for possible use in expanded bed adsorption of bio-products.

Agarose-nickel (Ag-Ni) composite matrix was evaluated for its use in expanded bed adsorption (EBA). Bovine serum albumin (BSA) and lysozyme were used as model proteins in batch and column adsorption studies. Accordingly, Reactive Green 19 (RG19) dye-ligand was covalently immobilized onto the support matrix to prepare affinity adsorbent for protein adsorption. Results were then compared with data obtained from Streamline commercial matrix. In batch experiments RG19 derivatives of Ag-Ni (RG19-Ag-Ni) exhibited high adsorption rate; and also a higher binding capacity of BSA (31.4mg/ml adsorbent) was observed for Ag-Ni compared to the commercial adsorbent. More than 70% of the adsorption capacity was achieved within 30min which is a reasonable contact time for EBA operations. The equilibrium adsorption data well agreed with Langmuir isotherm model. The expanded bed adsorption studies showed a reasonable breakthrough behavior at high flow rates and a higher dynamic binding capacity (DBC) was obtained for novel matrix in compare to streamline at the same fluid velocity. DBC at 10% breakthrough reached 66% of the saturated adsorption capacity at the high flow velocity of 450cm/h which indicates the favorable column efficiency. Additionally, two different Ag-Ni size fractions (75-150 and 150-300µm) were examined to investigate the expanded bed performance dependency on the adsorbent particle size with respect to the hydrodynamic stability and adsorption properties using lysozyme as model protein. Interestingly, the small ones showed less axial dispersion coefficient (<1.0×10(-5)m(2)/s) which resulted in higher bed stability in high fluid viscosities. Overall, the adsorption experiments results demonstrated that small size fraction of Ag-Ni matrices acts more effectively for expanded bed adsorption of bio-molecules.