Formulation and Pharmacokinetics of HSA-core and PLGA-shell Nanoparticles for Delivering Gemcitabine.

Gemcitabine-loaded core-shell nanoparticles (CSNPs), comprised of a cross-linked HSA-core and PLGA-shell, were prepared through a modified double emulsification method, and the processing parameters were systematically investigated. The optimized CSNPs had a particle size of 241 ± 36.2 nm and an encapsulation efficiency of 41.52%. The core-shell structure was characterized by optical microscope (OM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The amorphous nature of the encapsulated drug was confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). An in vitro release study demonstrated that the CSNPs had an improved sustained release profile controlled by erosion of materials in combination with drug diffusion. In vivo pharmacokinetics of CSNPs obtained a bigger area under concentration-time curve (AUC), t 1/2, and C max compared to free drug solution. The results suggest that HSA-PLGA-based CSNPs can be a promising carrier for the sustained release of gemcitabine.

Revelation of adhesive proteins affecting cellular contractility through reference-free traction force microscopy.

Over the past few decades, the critical role played by cellular contractility associated mechanotransduction in the regulation of cell functions has been revealed. In this case, numerous biomaterials have been chemically or structurally designed to manipulate cell behaviors through the regulation of cellular contractility. In particular, adhesive proteins including fibronectin, poly-L-lysine and collagen type I have been widely applied in various biomaterials to improve cell adhesion. Therefore, clarifying the effects of adhesive proteins on cellular contractility has been valuable for the development of biomaterial design. In this study, reference-free traction force microscopy with a well-organized microdot array was designed and prepared to investigate the relationship between adhesive proteins, cellular contractility, and mechanotransduction. The results showed that fibronectin and collagen type I were able to promote the assembly of focal adhesions and further enhance cellular contraction and YAP activity. In contrast, although poly-L-lysine supported cell spreading and elongation, it was inefficient at inducing cell contractility and activating YAP. Additionally, compared with cellular morphogenesis, cellular contraction was essential for YAP activation.

Incorporating charged Ag@MOFs to boost the antibacterial and filtration properties of porous electrospinning polylactide films.

Faced with the pollution caused by particulate matter (PM) in the air, the prevalence of infectious diseases, and the environmental burden by use of nondegradable polymers, the existing filter materials such as meltblown cloth of polypropylene cannot satisfactorily meet people's requirements. In this study, Ag nanoparticles were loaded onto ZIF-8 particles by impregnation reduction to prepare the positively charged Ag@ZIF-8. The porous fibrous membranes of Ag@ZIF-8 with polylactide (PLA) were manufactured by electrostatic spinning technology. Due to the inherently charged feature of Ag@ZIF-8 particles and the presence of pores on fibers, the prepared membranes showed a stable good filtration efficiency of over 97 % at different humidity (30-90%RH, relative humidity). Meanwhile, the presence of charge on Ag@ZIF-8 and the synergistic effects of Ag and ZIF-8 particles made the membranes exhibit good antibacterial effects. The width of the inhibition zone of 3 wt%Ag@ZIF-8/PLA membrane reached 1.33 mm for E. coli and 1.35 mm for S. aureus, respectively.

MOFs-alginate/polyacrylic acid/poly (ethylene imine) heparin-mimicking beads as a novel hemoadsorbent for bilirubin removal in vitro and vivo models.

Metal-organic frameworks (MOFs) have a potential application in blood purification, but their microcrystalline nature has hampered their industrial application. Here, novel MOFs-polymer beads based on UiO, sodium alginate, polyacrylic acid, and poly (ethylene imine) were prepared and applied as a whole blood hemoadsorbent for the first time. The amidation among polymers immobilized UiO66-NH2 into the network of the optimal product (SAP-3), and the NH2 of UiO66-NH2 significantly increased the removal rate (70 % within 5 min) of SAP-3 on bilirubin. The adsorption of SAP-3 on bilirubin mainly obeyed the pseudo-second-order kinetic, Langmuir isotherm and Thomas models with a maximum adsorption capacity (qm) of 63.97 mg·g-1. Experimental and density functional theory simulation results show that bilirubin was mainly adsorbed by UiO66-NH2via electrostatic force, hydrogen bonding, and π-π interactions. Notably, the adsorption in vivo show that the total bilirubin removal rate in the whole blood of the rabbit model was up to 42 % after 1 h of adsorption. Given its excellent stability, cytotoxicity, and hemocompatibility, SAP-3 has a great potential in hemoperfusion therapy. This study proposes an effective strategy for settling the powder property of MOFs and could provide experimental and theoretical references for application of MOFs in blood purification.

Materials and Design Approaches for a Fully Bioresorbable, Electrically Conductive and Mechanically Compliant Cardiac Patch Technology.

Myocardial infarction (MI) is one of the leading causes of death and disability. Recently developed cardiac patches provide mechanical support and additional conductive paths to promote electrical signal propagation in the MI area to synchronize cardiac excitation and contraction. Cardiac patches based on conductive polymers offer attractive features; however, the modest levels of elasticity and high impedance interfaces limit their mechanical and electrical performance. These structures also operate as permanent implants, even in cases where their utility is limited to the healing period of tissue damaged by the MI. The work presented here introduces a highly conductive cardiac patch that combines bioresorbable metals and polymers together in a hybrid material structure configured in a thin serpentine geometry that yields elastic mechanical properties. Finite element analysis guides optimized choices of layouts in these systems. Regular and synchronous contraction of human induced pluripotent stem cell-derived cardiomyocytes on the cardiac patch and ex vivo studies offer insights into the essential properties and the bio-interface. These results provide additional options in the design of cardiac patches to treat MI and other cardiac disorders.

Degradable, antibacterial and ultrathin filtrating electrospinning membranes of Ag-MOFs/poly(l-lactide) for air pollution control and medical protection.

The widely used melt-blown polypropylene (PP) non-woven fabrics had no antibacterial functions and its large-scale use also increased the burden on the environment owing to its non-degradable property. Herein, silver (I) metal organic frameworks (Ag-2MI) were prepared with AgNO3 and 2-methylimidazole and embedded into degradable poly(l-lactide) (PLLA) to make an ultrathin filtration and antibacterial membrane by electrospinning technology with low loading of Ag-2MI. The morphology, mechanical properties, adsorption performance and antibacterial activities of the prepared films were tested and the results indicated that the addition of Ag-2MI could reduce the diameter of PLLA fibers from 910 nm to 520 nm (1.8 wt% of Ag-2MI), while the tensile strength, elongation at break of the membrane and the contact angle of the films were enhanced. Although the thickness of the prepared membranes was only about one-third of that of commercially available melt-blown cloth, they exhibited better filtering performances than the melt-blown cloth. The fiber membrane with low loading of 1.8 wt% Ag-2MI showed 99.99% inhibition rate against Escherichia coli and Staphylococcus aureus.

Hierarchical core-shell nanoplatforms constructed from Fe3O4@C and metal-organic frameworks with excellent bilirubin removal performance.

Hemoperfusion has become the third-generation treatment strategy for patients suffering from hyperbilirubinemia, but adsorbents used for bilirubin removal mostly face intractable problems, such as unsatisfactory adsorption performance and poor hemocompatibility. Metal-organic frameworks (MOFs) are promising adsorbents for hemoperfusion due to their high specific surface areas and easily modified organic ligands. However, their microporous properties and separation have hampered their application. Here, a novel hierarchical core-shell nanoplatform (named Double-PEG) with tailored binding sites and pore sizes based on Fe3O4@C and Uio66-NH2 was constructed. Notably, Double-PEG showed excellent bilirubin uptake of up to 1738.30 mg g-1 and maintained excellent bilirubin removal efficiency in simulated biological solutions. A study on the adsorption mechanism showed that the adsorption of Double-PEG towards bilirubin tended to be chemical adsorption and in accordance with the Langmuir model. Besides, the good separability, recyclability, cytotoxicity and hemocompatibility of Double-PEG show great potential in hemoperfusion therapy. The finding of this study may provide a novel insight into the application of MOF materials in the field of hemoperfusion.

Preparation and characterization of n-hydroxyapatite/PCL-pluronic-PCL nanocomposites for tissue engineering.

In this paper, a new kind of polymeric nanocomposite materials based on nano-hydroxyapatite (n-HA) and PCL-Pluronic-PCL (PCFC) copolymer were prepared by in situ combination method. Firstly, the PCFC copolymer was synthesized by ring-opening polymerization of epsilon-caprolactone initiated by Pluronic (PEG-PPG-PEG); Secondly, n-HA powder were combined with PCFC to form polymeric composites in the presence of hexamethylene diisocyanate (HDI). The obtained composites were characterized by 1H-NMR, FTIR, XRD, TEM, SEM, DTA/TGA, and tensile testing. The results revealed that n-HA could be dispersed into polymer matrix uniformly, and the n-HA/PCFC composite showed great mechanical properties when the content of n-HA was 10 wt%. The microstructure and thermal properties of the composites were discussed in the paper too. The experimental results suggested that this polymeric nanocomposite might have great potential application in the field of tissue engineering.

The preparation of nano-MIL-101(Fe)@chitosan hybrid sponge and its rapid and efficient adsorption to anionic dyes.

The polymer adsorbents in the sponge form have the porous structure and high elasticity that endow them with good adsorption capacity and recyclability. The immobilization of nano-materials in the sponges can improve their adsorption properties evidently. The nano-MIL-101(Fe)@chitosan(CS) hybrid sponge was prepared by freeze-drying method. Characterization results indicated that rhombic nano-MIL-101(Fe) particles were uniformly dispersed throughout the hybrid sponge. The hybrid sponge showed higher efficiency for the adsorption of anionic dyes compared with the pristine CS sponge. The maximum adsorption capacity of MIL-101(Fe)@CS sponge for Acid Red 94 reached 4518 mg/g and the rapid suction experiments on different dyes showed that the hybrid sponge could be used as a filter for the quick removal of anionic dyes in low concentration solution.

Influence of Cell Spreading Area on the Osteogenic Commitment and Phenotype Maintenance of Mesenchymal Stem Cells.

Osteogenic differentiation and commitment of mesenchymal stem cells (MSCs) is a complex process that is induced and regulated by various biological factors and biophysical cues. Although cell spreading area, as a biophysical cue, has been demonstrated to play a critical role in the regulation of osteogenic differentiation of MSCs, it is unclear how it affects the maintenance of the committed phenotype after osteogenic differentiation of MSCs. In this study, poly (vinyl alcohol) was micropatterned on a tissue culture polystyrene surface, and the micropatterns were used to culture MSCs to control their cell spreading area. The influence of cell spreading area on osteogenic differentiation and maintenance of the differentiated phenotype of MSCs was investigated. MSCs with a larger spreading area showed a higher degree of osteogenic differentiation, slower loss of differentiated phenotype and slower re-expression of stem cell markers compared with MSCs with a smaller spreading area. A large cell spreading area was beneficial for osteogenic differentiation of MSCs and maintenance of their differentiated phenotype.

An unusual polyoxometalate-encapsulating 3D polyrotaxane framework formed by molecular squares threading on a twofold interpenetrated diamondoid skeleton.

Threading molecular square "beads" on a twofold interpenetrated diamondoid skeleton gives a new type of 3D metal-organic polyrotaxane framework with large channels, in which nanosized Keggin anions as guests are encapsulated for the first time.

Expression of core binding factor 1 and osteoblastic markers in C2C12 cells induced by calcium phosphate ceramics in vitro.

The in vivo osteoinductive capacity of porous calcium phosphate ceramics (Ca/P ceramics) with special structure and phase composition had been found for almost decades. The mechanism of the osteoinductivity of porous calcium phosphate is studied by C2C12 cells culture in this paper. C2C12 cells were cocultured with four kinds of porous Ca/P ceramics for 2 and 5 days, without adding other growth factors. The four kinds of Ca/P ceramics were pure HA sintered at 1250 degrees C and HA/TCP with a ratio of 60/40 sintered at 1100, 1200, and 1250 degrees C respectively. RT-PCR analysis found that the Ca/P ceramics induced the expression of Cbfa1, collagen type I, bone sialoprotein, and osteocalcin in C2C12 cells, while they did not induce mRNA expression of Indian hedgehog (IHH) that regulate chondrocyte differentiation. Our results showed that Ca/P ceramics alone were sufficient to induce C2C12 cells differentiation. The induction of bone-related markers expression by Ca/P ceramics in osteoprogenitor cells suggested that the osteogenesis induced by the ceramics was intramembranous and the osteoinductivity was their intrinsic property.

Nanoencapsulation of individual mammalian cells with cytoprotective polymer shell.

Nanoencapsulation of individual mammalian cells has great potential in biomedical, biotechnological and bioelectronic applications. However, existing techniques for cell nanoencapsulation generally yield short sustaining period and loose structure of encapsulation shell, which fails to meet the long-term cytoprotection and immunosuppression requirements. Here, we report a mild method to realize the nanoencapsulation of individual mammalian cells by layer-by-layer (LbL) assembly of gelatin inner layer and cross-linking of poly(ethylene glycol) (PEG) outer layer through thiol-click chemistry. With the present method, the encapsulated individual HeLa cells showed a high viability, long persistence period and effective resistance against macro external entities and high physical stress. Moreover, on-demand cell release could also be achieved by selective cleavage of succinimide thioether linkage in the outer PEG layer. The approach presented here may provide a new and versatile method for the cleavable nanoencapsulation of individual mammalian cells.

Influence of cell size on cellular uptake of gold nanoparticles.

Nanoparticles (NPs) have shown great potential for biomedical applications because of their unique physical and structural properties. A critical aspect for their clinical applications is cellular uptake that depends on both particle properties and the cell mechanical state. Despite the numerous studies trying to disclose the influencing factors, the role of cell size on cellular uptake remains unclear. In this study, poly(vinyl alcohol) was micropatterned on tissue culture polystyrene surfaces using UV photolithography to control the cell size, and the influence of cell size on the cellular uptake of gold NPs was investigated. Cells with a large size had a high total cellular uptake, but showed a low average uptake per unit area of cells. Cells with a small size showed opposite behaviors. The results were related to both cell/NP contacting area and membrane tension. A large cell size was beneficial for a high total cellular uptake due to the large contact area with the NPs. On the other hand, the large cell size resulted in high membrane tension that required high wrapping energy for engulfing of NPs and thus reduced the uptake. The two oppositely working effects decided the cellular uptake of NPs. The results would shed light on the influence of the cellular microenvironment on cellular uptake behavior.

Discriminating the Independent Influence of Cell Adhesion and Spreading Area on Stem Cell Fate Determination Using Micropatterned Surfaces.

Adhesion and spreading are essential processes of anchorage dependent cells involved in regulation of cell functions. Cells interact with their extracellular matrix (ECM) resulting in different degree of adhesion and spreading. However, it is not clear whether cell adhesion or cell spreading is more important for cell functions. In this study, 10 types of isotropical micropatterns that were composed of 2 µm microdots were prepared to precisely control the adhesion area and spreading area of human mesenchymal stem cells (MSCs). The respective influence of adhesion and spreading areas on stem cell functions was investigated. Adhesion area showed more significant influences on the focal adhesion formation, binding of myosin to actin fibers, cytoskeletal organization, cellular Young's modulus, accumulation of YAP/TAZ in nuclei, osteogenic and adipogenic differentiation of MSCs than did the spreading area. The results indicated that adhesion area rather than spreading area played more important roles in regulating cell functions. This study should provide new insight of the influence of cell adhesion and spreading on cell functions and inspire the design of biomaterials to process in an effective manner for manipulation of cell functions.

The osteogenic differentiation of mesenchymal stem cells by controlled cell-cell interaction on micropatterned surfaces.

Cell-cell interaction plays an important role in the control of cell functions. The precise control of cell-cell interaction will provide a useful tool to elucidate its influence on stem cell differentiation. In this study, four types of micropatterned surfaces were prepared by ultraviolet photolithography to investigate the effect of cell-cell interaction on the osteogenic differentiation of human mesenchymal stem cells (MSCs). Single MSCs adhered on the micropatterned surfaces following the micropatterns. Single cells on the isolated, barbell, linear, and honeycomb dot micropatterns had zero, one, two, and three cell-cell interaction partners, respectively. The number of cell-cell interaction of single MSCs was controlled by the different micropatterns, which showed evident effects on actin filament structure assembly and osteogenic differentiation of MSCs. MSCs with two and three interaction partners showed a significantly higher rate of osteogenic differentiation than did isolated single cells and cells with only one interaction partner. Thus, the osteogenic differentiation of MSCs was enhanced with increased cell-cell interaction. These results highlight the importance of cell-cell interaction in stem cell differentiation.

Metal-organic frameworks as potential drug delivery systems.

INTRODUCTION: Metal-organic frameworks (MOFs) are a unique class of hybrid porous solids based on metals and organic linkers. Compared to traditional porous materials, they possess predominance of large surface areas, tunable pore size and shape, adjustable composition and functionalized pore surface, which enable them unique advantages and promises for applications in adsorption and release of therapeutic agents. AREAS COVERED: This review addresses MOFs as a new avenue for drug delivery and exhibits their ability to efficiently deliver various kinds of therapeutic agents. It also details the requirements that MOFs need to satisfy for biomedical application, such as toxicological compatibility, stability, particle size, and surface modification. In addition, several approaches used to enhance encapsulation efficiency are summarized and parameters influencing delivery efficiency are also discussed. EXPERT OPINION: Benefiting from the unique advantages of MOFs materials, efficient delivery of various kinds of drugs has been achieved in some MOF materials. However, it is only the outset of MOFs in drug delivery system, and numerous work need to be done before clinical applications, for example, studying their in vivo toxicity, exploring degradation mechanisms so as to establish real stability of MOFs in body's liquid, providing appropriated surface modification avenue for MOFs, and researching in vivo efficiency and pharmacokinetics of drug-loaded MOFs.

n-Hydroxyapatite/PCL-Pluronic-PCL Nanocomposites for Tissue Engineering. Part 2: Thermal and Tensile Study.

In this work a series of nano-hydroxyapatite/poly(ε-caprolactone)-Pluronic-poly(ε-caprolactone) (n-HA/PCFC) nanocomposites has been prepared. Thermal properties of the nanocomposites are studied by thermogravimetry analysis (TGA) and differential scanning calorimetry (DSC). The TGA/DTG results reveal that thermal stability of n-HA/PCFC nanocomposites is improved by incorporation of n-HA into polymer matrix, and the thermo-degradation temperature increased slightly with increasing HA loading. DSC results show that the glass transition temperature (T g) changed by the addition of n-HA. The mechanical properties of the nanocomposites are investigated by tensile testing. The morphology for tensile-fractured surfaces of nanocomposites is observed by scanning electron microscopy. The effect of n-HA contents of nanocomposites on tensile strength and morphology is also discussed.

Fabrication and cellular biocompatibility of porous carbonated biphasic calcium phosphate ceramics with a nanostructure.

Microwave heating was applied to fabricate interconnective porous structured bodies by foaming as-synthesized calcium-deficient hydroxyapatite (Ca-deficient HA) precipitate containing H(2)O(2). The porous bodies were sintered by a microwave process with activated carbon as the embedding material to prepare nano- and submicron-structured ceramics. By comparison, conventional sintering was used to produce microstructured ceramics. The precursor particles and bulk ceramics were characterized by transmission electron microscopy (TEM), dynamic light scattering, scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier-transformed infrared spectroscopy (FTIR) and mechanical testing. TEM micrographs and assessment of the size distribution showed that the needle-like precursor particles are on the nanoscale. SEM observation indicated that the ceramics formed by microwave sintering presented a structure of interconnective pores, with average grain sizes of approximately 86 and approximately 167nm. XRD patterns and FTIR spectra confirmed the presence of carbonated biphasic calcium phosphate (BCP), and the mechanical tests showed that the ceramics formed by microwave sintering had a compressive strength comparable to that obtained by conventional methods. Rat osteoblasts were cultured on the three kinds of BCP ceramics to evaluate their biocompatibility. Compared with the microscale group formed by conventional sintering, MTT assay and ALP assay showed that nanophase scaffolds promoted cell proliferation and differentiation respectively, and SEM observation showed that the nanoscale group clearly promoted cell adhesion. The results from this study suggest that porous carbonated biphasic calcium phosphate ceramics with a nanostructure promote osteoblast adhesion, proliferation and differentiation. In conclusion, porous carbonated BCP ceramics with a nanostructure are simple and quick to prepare using microwaves and compared with those produced by conventional sintering, may be better bone graft materials.