Hydrogen Bonding Principle-Based Molecular Design of a Polymer Excipient and Impacts on Hydrophobic Drug Properties: Molecular Simulation and Experiment.

Although some commercial excipients for improving the solubility of highly crystalline drugs are widely used, they still cannot cover all types of hydrophobic drugs. In this regard, with phenytoin as the target drug, related molecular structures of polymer excipients were designed. The optimal repeating units of NiPAm and HEAm were screened out through quantum mechanical simulation and Monte Carlo simulation methods, and the copolymerization ratio was also determined. Using molecular dynamics simulation technology, it was confirmed that the dispersibility and intermolecular hydrogen bonds of phenytoin in the designed copolymer were better than those in the commercial PVP materials. At the same time, the designed copolymers and solid dispersions were also prepared during the experiment, and the improvement of their solubility was confirmed, which is in accordance with the simulation predictions. The new ideas and simulation technology may be used for drug modification and development.

3D-printed electrospun fibres for wound healing.

Wound management for acute and chronic wounds has become a serious clinical problem worldwide, placing considerable pressure on public health systems. Owing to the high-precision, adjustable pore structure, and repeatable manufacturing process, 3D-printed electrospun fibre (3DP-ESF) has attracted widespread attention for fabricating wound dressing. In addition, in comparison with 2D electrospun fibre membranes fabricated by traditional electrospinning, the 3D structures provide additional guidance on cell behaviour. In this perspective article, we first summarise the basic manufacturing principles and methods to fabricate 3DP-ESF. Then, we discuss the function of 3DP-ESF in manipulating the different stages of wound healing, including anti-bacteria, anti-inflammation, and promotion of cell migration and proliferation, as well as the construction of tissue-engineered scaffolds. In the end, we provide the current challenge faced by 3DP-ESF in the application of skin wound regeneration and its promising future directions.

Endothelial cell-derived exosomes boost and maintain repair-related phenotypes of Schwann cells via miR199-5p to promote nerve regeneration.

BACKGROUND: Schwann cells (SCs) respond to nerve injury by transforming into the repair-related cell phenotype, which can provide the essential signals and spatial cues to promote axonal regeneration and induce target reinnervation. Endothelial cells (ECs) contribute to intraneural angiogenesis contributing to creating a permissive microenvironment. The coordination between ECs and SCs within injury sites is crucial in the regeneration process, however, it still unclear. As the intercellular vital information mediators in the nervous system, exosomes have been proposed to take a significant role in regulating regeneration. Thus, the main purpose of this study is to determine the facilitative effect of ECs-derived exosomes on SCs and to seek the underlying mechanism. RESULTS: In the present study, we collected exosomes from media of ECs. We demonstrated that exosomes derived from ECs possessed the favorable neuronal affinity both in vitro and in vivo. Further research indicated that EC-exosomes (EC-EXO) could boost and maintain repair-related phenotypes of SCs, thereby enhancing axonal regeneration, myelination of regenerated axons and neurologically functional recovery of the injured nerve. MiRNA sequencing in EXO-treated SCs and control SCs indicated that EC-EXO significantly up-regulated expression of miR199-5p. Furthermore, this study demonstrated that EC-EXO drove the conversion of SC phenotypes in a PI3K/AKT/PTEN-dependent manner. CONCLUSION: In conclusion, our research indicates that the internalization of EC-EXO in SCs can promote nerve regeneration by boosting and maintaining the repair-related phenotypes of SCs. And the mechanism may be relevant to the up-regulated expression of miR199-5p and activation of PI3K/AKT/PTEN signaling pathway.

Non-Invasive Thermal Therapy for Tissue Engineering and Regenerative Medicine.

Owing to the development of nanotechnology and noninvasive treatment, thermal therapy in combination with external stimuli has been applied for tissue engineering and regenerative medicine (TERM), which has attracted more and more attention in recent years. In this review, the recent progress of applying a variety of non-invasive thermal therapeutic modalities for TERM, including photothermal therapy, magnetic thermotherapy, and ultrasound thermotherapy, as well as other thermal therapeutics are discussed. The parameters and conditions that need to be considered and regulated to realize a well-controlled thermal therapy for tissue regeneration are also discussed. Afterwards, the current concerns and challenges of putting thermal therapy into clinical applications are pointed out. At last, perspectives are provided for the future development directions, aiming to providing opportunities and a novel pathway for TERM.

Polyurethanes Based on Polylactic Acid for 3D Printing and Shape-Memory Applications.

Polylactic acid (PLA) has received increased attention in the development of shape-memory polymers and biomedical materials owing to its excellent physical properties and good biocompatibility and biodegradability. However, the inherent brittleness and high shape-recovery temperature of this material limit its application in the human body. Herein, we fabricated a PLA-based thermoplastic polyurethane (PLA-TPU) prepared from modified PLA-diol, dicyclohexylmethane-4,4'-diisocyanate, and 1,4-butanediol to solve the limitations of pure PLA. The glass transition temperature (Tg) of the designed TPU can be tailored from 6 to 40.5 °C by adjusting the content of hard segments or molecular weight of soft segments. The shape of the designed TPU can be fixed at room temperature and recovered at temperatures above 37 °C. Moreover, the prepared PLA-TPUs exhibited recyclability, three-dimensional printing capability, non-cytotoxicity, blood compatibility, and biodegradability. The shape of PLA-TPU/nano-Fe3O4 composites can be recovered by exposure to near-infrared light. These results collectively indicate that PLA-TPUs and their composites may have potential applications as intelligent flexible medical scaffolds for surgical and medical implantation equipment.

Identification of proline-rich protein 11 as a major regulator in mouse spermatogonia maintenance via an increase in BMI1 protein stability.

BACKGROUND: Spermatogenesis accompanied by self-renewal and differentiation of spermatogonia under complicated regulation is crucial for male fertility. Our previous study demonstrated that the loss of the B-lymphoma Mo-MLV insertion region 1 (BMI1) could cause male infertility and found a potential interaction between BMI1 and proline-rich protein 11 (PRR11); however, the specific co-regulatory effects of BMI1/PRR11 on spermatogonia maintenance remain unclear. METHODS AND RESULTS: The expression of PRR11 was downregulated in a mouse spermatogonia cell line (GC-1) via transfection with PRR11-siRNAs, and PRR11 knockdown was verified by real-time reverse transcriptase polymerase chain reaction (RT-qPCR). The proliferative activity of GC-1 cells was determined using the cell counting kit (CCK-8), colony formation, and 5-ethynyl-2-deoxyuridine (EdU) incorporation assay. A Transwell assay was performed to evaluate the effects of PRR11 on GC-1 cell migration. A terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to measure GC-1 cell apoptosis. Furthermore, co-immunoprecipitation, RT-qPCR, and western blot analyses were used for investigating the regulatory mechanisms involved in this regulation. It was found that downregulation of PRR11 could cause a marked inhibition of proliferation and migration and induced apoptosis in GC-1 cells. Moreover, silencing of PRR11 obviously led to a reduction in the BMI1 protein level. PRR11 was found to interact with BMII at the endogenous protein level. PRR11 knockdown produced a decrease in BMI1 protein stability via an increase in BMI1 ubiquitination after which derepression in the transcription of protein tyrosine phosphatase receptor type M (Ptprm) occurred. Importantly, knockdown of Ptprm in PRR11-deficient GC-1 cells led to a reversal of proliferation and migration of GC-1 cells. CONCLUSIONS: This study uncovered a novel mechanism by which PRR11 cooperated with BMI1 to facilitate GC-1 maintenance through targeting Ptprm. Our findings may provide a better understanding of the regulatory network in spermatogonia maintenance.

Theoretical and experimental study of the microstructure of a metallic melt in an In50Bi50 alloy based on the Wulff cluster model.

In this paper, the Wulff cluster model which has been proved to successfully describe the melt structure of pure metals, homogenous alloys and eutectic alloys has been extended to an alloy with intermetallic compounds (In50Bi50). According to the cohesive energy and the solid-state XRD patterns, the most possible types of clusters in the melt are Bi and InBi. At relatively high temperatures, the superimposed XRD (simulated) patterns of Bi and InBi clusters are in good agreement with the experimental HTXRD patterns in terms of the position and intensity of the peaks. With the decrease of temperature, there is an obvious deviation in the simulated XRD value at the second peak caused by the nucleation process of Bi clusters, which would be modified by adding simulated XRD patterns of the Bi bulk. The proportion of the superimposed Bi bulk XRD pattern increases with the decrease of temperature suggesting that the nucleation process of the Bi cluster begins at 160 °C.

Electrospinning and Electrospun Nanofibers: Methods, Materials, and Applications.

Electrospinning is a versatile and viable technique for generating ultrathin fibers. Remarkable progress has been made with regard to the development of electrospinning methods and engineering of electrospun nanofibers to suit or enable various applications. We aim to provide a comprehensive overview of electrospinning, including the principle, methods, materials, and applications. We begin with a brief introduction to the early history of electrospinning, followed by discussion of its principle and typical apparatus. We then discuss its renaissance over the past two decades as a powerful technology for the production of nanofibers with diversified compositions, structures, and properties. Afterward, we discuss the applications of electrospun nanofibers, including their use as "smart" mats, filtration membranes, catalytic supports, energy harvesting/conversion/storage components, and photonic and electronic devices, as well as biomedical scaffolds. We highlight the most relevant and recent advances related to the applications of electrospun nanofibers by focusing on the most representative examples. We also offer perspectives on the challenges, opportunities, and new directions for future development. At the end, we discuss approaches to the scale-up production of electrospun nanofibers and briefly discuss various types of commercial products based on electrospun nanofibers that have found widespread use in our everyday life.

Promoting Cell Migration and Neurite Extension along Uniaxially Aligned Nanofibers with Biomacromolecular Particles in a Density Gradient.

A simple method based upon masked electrospray is reported for directly generating both unidirectional and bidirectional density gradients of biomacromolecular particles on uniaxially aligned nanofibers. The method has been successfully applied to different types of biomacromolecules, including collagen and a mixture of collagen and fibronectin or laminin, to suit different types of applications. Collagen particles in a unidirectional or bidirectional gradient are able to promote the linear migration of bone marrow stem cells or NIH-3T3 fibroblasts along the direction of increasing particle density. In the case of particles made of a mixture of collagen and fibronectin, their deposition in a bidirectional gradient promotes the migration of Schwann cells from two opposite sides toward the center, matching the scenario in peripheral nerve repair. As for a mixture of collagen and laminin, the particles in a unidirectional gradient promote the extension of neurites from embryonic chick dorsal root ganglion in the direction of increasing particle density. Taken together, the scaffolds featuring a combination of uniaxially aligned nanofibers and biomacromolecular particles in density gradient can be applied to a range of biological studies and biomedical applications.

Transforming Nanofiber Mats into Hierarchical Scaffolds with Graded Changes in Porosity and/or Nanofiber Alignment.

A method for generating hierarchical scaffolds with graded changes in porosity and/or fiber alignment through solution-masked, vapor-induced welding of electrospun poly(lactic-co-glycolic acid) (PLGA) nanofibers is reported. The success of this method relies on the fact that the PLGA nanofibers are swollen and welded more slowly by ethanol when immersed in its aqueous solution relative to direct exposure to its vapor. For a mat composed of random nanofibers, the treatment generates a gradation in porosity (both surface and bulk), with the over-welded region evolving from a highly porous mat into a dense film. If uniaxially aligned nanofibers are involved, however, graded changes are observed in both surface porosity and fiber alignment. When bone marrow stem cells are cultured on such a scaffold, they exhibit highly organized and random morphologies on the regions of uniaxially aligned nanofibers and dense film, respectively, with gradual changes in between. Such a scaffold shows promise in mimicking the connective tissue, such as the tendon-to-bone insertion, that relies on a graded transition in cell morphology from uniaxially aligned to random.

Engraving the Surface of Electrospun Microfibers with Nanoscale Grooves Promotes the Outgrowth of Neurites and the Migration of Schwann Cells.

We report a simple method based upon coaxial electrospinning for the fabrication of aligned microfibers engraved with nanoscale grooves to promote neurite outgrowth and cell migration. The success of this method relies on the immiscibility between poly(ϵ-caprolactone) (PCL) and poly(vinyl pyrrolidone) (PVP) in 2,2,2-trifluoroethanol (TFE) for the generation of PVP/TFE pockets on the surface of a PCL jet. The pockets are stretched and elongated along with the jet, eventually resulting in the formation of nanoscale grooves upon the removal of PVP. The presence of nanoscale grooves greatly enhances the outgrowth of neurites from both PC12 cells and chick embryonic dorsal root ganglia (DRG) bodies, as well as the migration of Schwann cells. The enhancements can be maximized by optimizing the dimensions of the grooves for potential use in applications involving neurite extension and wound closure.

Cobalt(II)-Based Metal-Organic Framework as Bifunctional Materials for Ag(I) Detection and Proton Reduction Catalysis for Hydrogen Production.

A novel cobalt(II)-based metal-organic framework, Co-MB, was prepared by hydrothermal reaction of Co(NO3)2·6H2O, 3,3'-methylenediphthalic acid (H4mda), and 1,4-bis(imidazol-1-ylmethyl)-benzene in sodium hydroxide aqueous solution and structurally characterized. It shows a high stability in water within the pH range from 2.2 to 11.6, which could be used as a highly selective and sensitive luminescent sensor for Ag(I) detection in a luminescent enhancement manner, with LOD about 23 nM. Importantly, such stable Co-MB could also work as proton reduction catalyst for photodriven hydrogen production coupled with visible-light organic dyes as photosensitizer. The influence factors of hydrogen production including pH, TEA (triethylamine) contents, and kinds of organic dyes are studied in detail. Under optimal condition, the TON value was up to 5133 per cycle, and this Co-MB could also be reused at least 3 times.

The Expression of BNP, ET-1, and TGF-ß1 in Myocardium of Rats with Ventricular Arrhythmias.

Ventricular arrhythmia (VA) is a major component of sudden cardiac death (SCD). To investigate the expression of brain natriuretic peptide (BNP), endothelin-1 (ET-1), and transforming growth factor-beta 1 (TGF-ß1) during VA, we established a rat model of VA induced by BaCl2 solution through a microinjector pump. PD142893 (ET-1 receptor blocker) and SB431542 (TGF-ß1 receptor type I blocker) were used to explore the effect of ET-1 and TGF-ß1 on BNP expression in the myocardium after VA. BNP, ET-1, and TGF-ß1 in rat myocardium were assayed by western blot and immunohistochemical staining for proteins, and real-time quantitative polymerase chain reaction for mRNAs. We found increased expression of BNP and ET-1 in rat myocardium that was associated with the duration of VA. However, TGF-ß1 protein expression remained unchanged. Such early increases in BNP and ET-1 may be attributed to fatal arrhythmias associated with SCD, suggesting these may be novel biomarkers of this disease. After intraperitoneal injection of PD142893 and SB431542, respectively, BNP was downregulated in the myocardium of the left ventricle; however, this was abrogated by co-application of the two inhibitors. These results suggested that both ET-1 and TGF-ß1, by specifically binding to their receptors, might be involved in the myocardial synthesis of BNP during VA in vivo.

Photothermal Welding, Melting, and Patterned Expansion of Nonwoven Mats of Polymer Nanofibers for Biomedical and Printing Applications.

We report a simple method for the photothermal welding of nonwoven mats of electrospun nanofibers by introducing a near-infrared (NIR) dye such as indocyanine green. By leveraging the strong photothermal effect of the dye, the nanofibers can be readily welded at their cross points or even over-welded (i.e., melted and/or fused together) to transform the porous mat into a solid film upon exposure to a NIR laser. While welding at the cross points greatly improves the mechanical strength of a nonwoven mat of nanofibers, melting and fusion of the nanofibers can be employed to fabricate a novel class of photothermal papers for laser writing or printing without chemicals or toner particles. By using a photomask, we can integrate photothermal welding with the gas foaming technique to pattern and then expand nonwoven mats into 3D scaffolds with well-defined structures. This method can be applied to different combinations of polymers and dyes, if they can be co-dissolved in a suitable solvent for electrospinning.

Promoting the Outgrowth of Neurites on Electrospun Microfibers by Functionalization with Electrosprayed Microparticles of Fatty Acids.

Controlling the outgrowth of neurites is important for enhancing the repair of injured nerves and understanding the development of nervous systems. Herein we report a simple strategy for enhancing the outgrowth of neurites through a unique integration of topographical guidance and a chemical cue. We use electrospray to easily functionalize the surface of a substrate with microparticles of natural fatty acids at a controllable density. Through a synergistic effect from the surface roughness arising from the microparticles and the chemical cue offered by the fatty acids, the outgrowth of neurites from PC12 cells is greatly enhanced. We also functionalize the surfaces of uniaxially aligned, electrospun microfibers with the microparticles and further demonstrate that the substrates can guide and enhance directional outgrowth of neurites from both PC12 multicellular spheroids and chick embryonic dorsal root ganglia bodies.

Encapsulation of a Phase-Change Material in Nanocapsules with a Well-Defined Hole in the Wall for the Controlled Release of Drugs.

As a class of biocompatible and biodegradable phase-change materials, natural fatty acids have received considerable interest in recent years for temperature-controlled release of drugs. However, the poor dispersibility and colloidal stability of their nanoparticles under physiological conditions place a major limitation on their applications in biomedicine. Herein, we report a facile method for encapsulating a mixture of two natural fatty acids (with a eutectic melting point at 39 °C) in a biocompatible, silica-based nanocapsule to achieve both stable dispersion and controllable release of drugs. The nanocapsules have a well-defined hole in the wall to ensure easy loading of fatty acids, together with multiple types of functional components such as therapeutics and near-infrared dyes. The payloads can be released through the hole when the fatty acids are melted upon photothermal heating. The release profile can be controlled by varying the size of the hole and/or the duration of laser irradiation.

Integration of Phase-Change Materials with Electrospun Fibers for Promoting Neurite Outgrowth under Controlled Release.

We report a temperature-regulated system for the controlled release of nerve growth factor (NGF) to promote neurite outgrowth. The system is based upon microparticles fabricated using coaxial electrospray, with the outer solution containing a phase-change material (PCM) and the inner solution encompassing payload(s). When the temperature is kept below the melting point of the PCM, there is no release due to the extremely slow diffusion through a solid matrix. Upon increasing the temperature to slightly pass the melting point, the encapsulated payload(s) can be readily released from the melted PCM. By leveraging the reversibility of the phase transition, the payload(s) can be released in a pulsatile mode through on/off heating cycles. The controlled release system is evaluated for potential use in neural tissue engineering by sandwiching the microparticles, co-loaded with NGF and a near-infrared dye, between two layers of electrospun fibers to form a tri-layer construct. Upon photothermal heating with a near-infrared laser, the NGF is released with well-preserved bioactivity to promote neurite outgrowth. By choosing different combinations of PCM, biological effector, and scaffolding material, this controlled release system can be applied to a wide variety of biomedical applications.

Electrospun Nanofibers: New Concepts, Materials, and Applications.

Electrospinning is a simple and versatile technique that relies on the electrostatic repulsion between surface charges to continuously draw nanofibers from a viscoelastic fluid. It has been applied to successfully produce nanofibers, with diameters down to tens of nanometers, from a rich variety of materials, including polymers, ceramics, small molecules, and their combinations. In addition to solid nanofibers with a smooth surface, electrospinning has also been adapted to generate nanofibers with a number of secondary structures, including those characterized by a porous, hollow, or core-sheath structure. The surface and/or interior of such nanofibers can be further functionalized with molecular species or nanoparticles during or after an electrospinning process. In addition, electrospun nanofibers can be assembled into ordered arrays or hierarchical structures by manipulation of their alignment, stacking, and/or folding. All of these attributes make electrospun nanofibers well-suited for a broad spectrum of applications, including those related to air filtration, water purification, heterogeneous catalysis, environmental protection, smart textiles, surface coating, energy harvesting/conversion/storage, encapsulation of bioactive species, drug delivery, tissue engineering, and regenerative medicine. Over the past 15 years, our group has extensively explored the use of electrospun nanofibers for a range of applications. Here we mainly focus on two examples: (i) use of ceramic nanofibers as catalytic supports for noble-metal nanoparticles and (ii) exploration of polymeric nanofibers as scaffolding materials for tissue regeneration. Because of their high porosity, high surface area to volume ratio, well-controlled composition, and good thermal stability, nonwoven membranes made of ceramic nanofibers are terrific supports for catalysts based on noble-metal nanoparticles. We have investigated the use of ceramic nanofibers made of various oxides, including SiO2, TiO2, SnO2, CeO2, and ZrO2, as supports for heterogeneous catalysts based on noble metals such as Au, Pt, Pd, and Rh. On the other hand, the diameter, composition, alignment, porosity, and surface properties of polymeric nanofibers can be engineered in a controllable fashion to mimic the hierarchical architecture of an extracellular matrix and help manipulate cell behaviors for tissue engineering and regenerative medicine. To this end, we can mimic the native structure and morphology of the extracellular matrix in tendon using uniaxially aligned nanofibers; we can use radially aligned nanofibers to direct the migration of cells from the periphery to the center in an effort to speed up wound healing; and we can also use uniaxially aligned nanofibers to guide and expedite the extension of neurites for peripheral nerve repair. Furthermore, we can replicate the anatomic structures at the tendon-to-bone insertion using nanofiber scaffolds with graded mineral coatings. In this Account, we aim to demonstrate the unique capabilities of electrospun nanofibers as porous supports for heterogeneous catalysis and as functional scaffolds for tissue regeneration by concentrating on some of the recent results.

Enhancing the Mechanical Properties of Electrospun Nanofiber Mats through Controllable Welding at the Cross Points.

This communication describes a simple and effective method for welding electrospun nanofibers at the cross points to enhance the mechanical properties of their nonwoven mats. The welding is achieved by placing a nonwoven mat of the nanofibers in a capped vial with the vapor of a proper solvent. For polycaprolactone (PCL) nanofibers, the solvent is dichloromethane (DCM). The welding can be managed in a controllable fashion by simply varying the partial pressure of DCM and/or the exposure time. Relative to the pristine nanofiber mat, the mechanical strength of the welded PCL nanofiber mat can be increased by as much as 200%. Meanwhile, such a treatment does not cause any major structural changes, including morphology, fiber diameter, and pore size. This study provides a generic method for improving the mechanical properties of nonwoven nanofiber mats, holding great potential in various applications.