Yunbing Wang

Vascular restoration therapy and bioresorbable vascular scaffold

This article describes the evolution of minimally invasive intervention technologies for vascular restoration therapy from early-stage balloon angioplasty in 1970s, metallic bare metal stent and metallic drug-eluting stent technologies in 1990s and 2000s, to bioresorbable vascular scaffold (BVS) technology in large-scale development in recent years. The history, the current stage, the challenges and the future of BVS development are discussed in detail as the best available approach for vascular restoration therapy. The criteria of materials selection, design and processing principles of BVS, and the corresponding clinical trial results are also summarized in this article.

Dopamine-assisted deposition of poly (ethylene imine) for efficient heparinization.

Mussel-inspired self-polymerization of dopamine in the presence of catechols and amines can be used to form coatings on various substrates. In this work dopamine was co-polymerized with poly (ethylene imine) (PEI) to form coatings on 316L stainless steel (SS). The coating formation was confirmed by Fourier transform infrared spectra (FTIR) and X-ray photoelectron spectroscopy (XPS). Compared with a pure polydopamine coating, such hybrid coating presented a higher ratio of nitrogen and increased zeta potential due to the introduction of PEI components. QCM measurement showed good affinity for heparin immobilization on the amine-rich surfaces. Moreover, the heparin-binding surface significantly suppressed platelet adhesion and activation. Further, the interaction with vascular cells, like endothelial cells (ECs) and smooth muscle cells (SMCs) was also investigated. The heparin coating not only decreased the cytotoxicity of amines on ECs, but also significantly inhibited SMCs proliferation. These results showed that the hybrid coating allowed effective heparin immobilization, providing a promising platform for vascular devices modification.

Identification and characterization of the free fatty acid receptor 2 (FFA2) and a novel functional FFA2-like receptor (FFA2L) for short-chain fatty acids in pigs: Evidence for the existence of a duplicated FFA2 gene (FFA2L) in some mammalian species

Free fatty acid receptor 2 (FFA2, also called GPR43) is reported to play a critical role in mediating the actions of short-chain fatty acids (SCFAs) in humans and mice. However, little is known about the structure, functionality, and tissue expression of FFA2 in other mammalian species, including pigs. In the present study, the full-length cDNAs of FFA2 (pFFA2) and a novel FFA2-like gene (named pFFA2L) were cloned from pig intestines by reverse transcription PCR. Both cloned pFFA2 and pFFA2L are predicted to encode 2 receptors of remarkable structural similarity and share high amino acid sequence identities with FFA2 from other mammalian species. Interestingly, the novel FFA2L could also be identified in 9 other mammalian species, suggesting that FFA2L was likely duplicated from FFA2 in the last common ancestor of these species. With the use of a pGL4-SRE-luciferase reporter assay, we demonstrated that pFFA2 expressed in human embryonic kidney 293 cells could be activated by acetate, propionate, and butyrate equipotently, whereas pFFA2L could be activated only by acetate and propionate, indicating that both pFFA2 and pFFA2L are functional receptors for SCFAs with nonidentical pharmacologic properties. Reverse transcription PCR found that pFFA2 mRNA was widely expressed in nearly all tissues examined, including adipose tissue and gastrointestinal (GI) tract, whereas pFFA2L expression was mainly restricted to the GI tract. Taken together, our findings raise a novel concept that the actions of SCFAs are likely mediated by 2 FFA2s (FFA2 and FFA2L) in target tissues of some mammalian species, such as the GI tract of pigs.

Electrospun silk fibroin/poly (L-lactide-ε-caplacton) graft with platelet-rich growth factor for inducing smooth muscle cell growth and infiltration.

The construction of a smooth muscle layer for blood vessel through electrospinning method plays a key role in vascular tissue engineering. However, smooth muscle cells (SMCs) penetration into the electrospun graft to form a smooth muscle layer is limited due to the dense packing of fibers and lack of inducing factors. In this paper, silk fibroin/poly (L-lactide-ε-caplacton) (SF/PLLA-CL) vascular graft loaded with platelet-rich growth factor (PRGF) was fabricated by electrospinning. The in vitro results showed that SMCs cultured in the graft grew fast, and the incorporation of PRGF could induce deeper SMCs infiltrating compared to the SF/PLLA-CL graft alone. Mechanical properties measurement showed that PRGF-incorporated graft had proper tensile stress, suture retention strength, burst pressure and compliance which could match the demand of native blood vessel. The success in the fabrication of PRGF-incorporated SF/PLLA-CL graft to induce fast SMCs growth and their strong penetration into graft has important application for tissue-engineered blood vessels.

pH-sensitive doxorubicin-conjugated prodrug micelles with charge-conversion for cancer therapy

Intelligent drug delivery systems with prolonged circulation time, reduced drug leakage in blood, target site-triggered drug release and endosomal escape are attractive and ideal for malignant tumor therapy. Herein, doxorubicin (DOX)-conjugated smart polymeric micelles based on 4-carboxy benzaldehyde-grafted poly (L-lysine)-block-poly (methacryloyloxyethyl phosphorylcholine) (PLL(CB/DOX)-b-PMPC) copolymer are prepared. DOX and electronegative 4-carboxy benzaldehyde are conjugated to the PLL block via an imine linkage and as a result, the drug loaded micelles exhibited the pH-triggered charge-conversion property and accelerated drug release at tumor pH. In vitro cytotoxicity studies of these DOX-loaded micelles exhibited great tumor inhibition against HeLa and 4T1 cells. Moreover, in mice models of breast cancer, these DOX-loaded micelles showed better anti-tumor efficacy and less organ toxicity than free drug. In summary, these polymeric micelles could be applied as potential nanocarriers for cancer therapy. STATEMENT OF SIGNIFICANCE As a typical anti-cancer drug, Doxorubicin (DOX) exhibited remarkable tumor inhibition but was limited by its low drug utilization and strong toxicity to organs. To overcome these challenges, we developed a DOX-conjugated polymeric micelle as a nano drug carrier which was endowed with pH-sensitivity and charge-conversion function. The structure of micelles would quickly disintegrate with surface charge-conversion in acidic environment, which would contribute to the endosomal escape and accelerated drug release. These DOX-conjugated micelles would provide a promising platform for the efficient DOX delivery and better anti-cancer efficiency.

A fully absorbable biomimetic polymeric micelle loaded with cisplatin as drug carrier for cancer therapy

Abstract cis-dichlorodiammineplatinum(II) (CDDP)-loaded polymeric micelles for cancer therapy have been developed to reduce the serious side effects of cisplatin CDDP. Herein, polymeric micelles incorporated with cisplatin are prepared based on the complexation between CDDP and hydrophilic poly (L-glutamic acid)-b-poly (2-methacryloyloxyethyl phosphorylcholine) (PLG-b-PMPC) diblock copolymers. These CDDP-loaded micelles possess an average size of 91 nm with narrow distribution, providing remarkable stability in media containing proteins. The release of CDDP from the micelles is faster at pH 5.0 and pH 6.0 than that at pH 7.4 and in a sustained manner without initial burst release. In addition, there is almost no difference in cellular uptake between these CDDP-loaded micelles and free CDDP. Moreover, in vitro cytotoxicity test shows they possess high efficacy to kill 4T1 cells as compared with free drug. Thus, PLG-b-PMPC copolymer might be a promising carrier for CDDP incorporating in cancer therapy.

Coaxial electrospinning multicomponent functional controlled-release vascular graft: Optimization of graft properties

Small diameter vascular grafts possessing desirable biocompatibility and suitable mechanical properties have become an urgent clinic demand. Herein, heparin loaded fibrous grafts of collagen/chitosan/poly(l-lactic acid-co-ε-caprolactone) (PLCL) were successfully fabricated via coaxial electrospinning. By controlling the concentration of heparin and the ratio of collagen/chitosan/PLCL, most grafts had the heparin encapsulation efficiency higher than 70%, and the heparin presented sustained release for more than 45 days. Particularly, such multicomponent grafts had relative low initial burst release, and after heparin releasing for 3 weeks, the grafts still showed good anti-platelet adhesion ability. In addition, along with the excellent cell biocompatibility, the fabricated grafts possessed suitable mechanical properties including good tensile strength, suture retention strength, burst pressure and compliance which could well match the native blood vessels. Thus, the optimized graft properties could be properly addressed for vascular tissue application via coaxial electrospinning.

Multifunctional mussel-inspired copolymerized epigallocatechin gallate (EGCG)/arginine coating: the potential as an ad-layer for vascular materials

Surface properties are considered to be important factors in addressing proper functionalities. In this paper, a multifunctional mussel-inspired coating was prepared via the direct copolymerization of epigallocatechin gallate (EGCG) and arginine. The coating formation was confirmed by X-ray photoelectron spectroscopy and Fourier transform infrared spectra. The EGCG/arginine coating contained diverse functional groups like amines, phenols and carboxyls, whose densities were also tunable. Such mussel-inspired coating could also be applied as an ad-layer for its secondary reactivity, demonstrated by quartz crystal microbalance technique. Moreover, the tunable surface density of phenols showed potential ability in modulating endothelial cell and smooth muscle cell viability. The coatings rich in phenols presented excellent free radical scavenging property. Current results strongly indicated the potential of EGCG/arginine coatings to be applied as an ad-layer for vascular materials.

A biomimetic and pH-sensitive polymeric micelle as carrier for paclitaxel delivery

Abstract As nano-scale drug delivery systems, smart micelles that are sensitive to specific biological environment and allowed for target site-triggered drug release by reversible stabilization of micelle structure are attractive. In this work, a biocompatible and pH-sensitive copolymer is synthesized through bridging poly (2-methacryloyloxyethyl phosphorylcholine) (PMPC) block and poly (D, L-lactide) (PLA) block by a benzoyl imine linkage (Blink). Biomimetic micelles with excellent biocompatibility based on such PLA-Blink-PMPC copolymer are prepared as carriers for paclitaxel (PTX) delivery. Due to the rapid breakage of the benzoyl imine linkage under acidic condition, the micelle structure is disrupted with accelerated PTX release. Such pH-sensitive triggered drug release behavior in synchronization with acidic conditions at tumor site is helpful for improving the utilization of drug and facilitating antitumor efficacy. These micelles can be used as promising drug delivery systems due to their biocompatible and smart properties.

Cation–anion interaction-directed formation of functional vesicles and their biological application for nucleus-specific imaging

A strategy for construction of counterion-induced vesicles in aqueous media has been described using imidazolium salts with multiple imidazolium moieties and alkyl carboxylate counteranions. The spontaneous formation of vesicles can be achieved by the simple selection of the counteranion to satisfy the requirement of the packing parameter for vesicle formation. Functional fluorescent vesicles can also be formed by the introduction of an aggregation-induced emission (AIE) fluorophore, tetraphenylethene (TPE), as the core of the imidazolium salt TPEI-C8, which also exhibits highly specific nucleus imaging in living cells. Considering the distinct AIE characteristic of TPEI-C8, the aggregation-induced strong fluorescence emission of TPEI-C8 in the cell nucleus may be the main reason for the specific fluorescence images of the cell nucleus. The strategy for the construction of functional vesicles reported in this study has shown great potential for the construction of other functional vesicles.