Qiaojie Luo

The construction of hierarchical structure on Ti substrate with superior osteogenic activity and intrinsic antibacterial capability

The deficient osseointegration and implant-associated infections are pivotal issues for the long-term clinical success of endosteal Ti implants, while development of functional surfaces that can simultaneously overcome these problems remains highly challenging. This study aimed to fabricate sophisticated Ti implant surface with both osteogenic inducing activity and inherent antibacterial ability simply via tailoring surface topographical features. Micro/submciro/nano-scale structure was constructed on Ti by three cumulative subtractive methods, including sequentially conducted sandblasting as well as primary and secondary acid etching treatment. Topographical features of this hierarchical structure can be well tuned by the time of the secondary acid treatment. Ti substrate with mere micro/submicro-scale structure (MS0-Ti) served as a control to examine the influence of hierarchical structures on surface properties and biological activities. Surface analysis indicated that all hierarchically structured surfaces possessed exactly the same surface chemistry as that of MS0-Ti, and all of them showed super-amphiphilicity, high surface free energy, and high protein adsorption capability. Biological evaluations revealed surprisingly antibacterial ability and excellent osteogenic activity for samples with optimized hierarchical structure (MS30-Ti) when compared with MS0-Ti. Consequently, for the first time, a hierarchically structured Ti surface with topography-induced inherent antibacterial capability and excellent osteogenic activity was constructed.

Fabrication and in vitro evaluation of the collagen/hyaluronic acid PEM coating crosslinked with functionalized RGD peptide on titanium

Surface modification of titanium (Ti) using biomolecules has attracted much attention recently. In this study, a new strategy has been employed to construct a stable and bioactive coating on Ti. To this end, a derivative of hyaluronic acid (HA), i.e. HA-GRGDSPC-(SH), was synthesized. The disulfide-crosslinked Arg-Gly-Asp (RGD)-containing collagen/hyaluronic acid polyelectrolyte membrane (PEM) coating was then fabricated on Ti through the alternate deposition of collagen and HA-GRGDSPC-(SH) with five assembly cycles and subsequent crosslinking via converting free sulphydryl groups into disulfide linkages (RGD-CHC-Ti group). The assembly processes for PEM coating and the physicochemical properties of the coating were carefully characterized. The stability of PEM coating in phosphate-buffered saline solution could be adjusted by the crosslinking degree, while its degradation behaviors in the presence of glutathione were glutathione concentration dependent. The adhesion and proliferation of MC3T3-E1 cells were significantly enhanced in the RGD-CHC-Ti group. Up-regulated bone specific genes, enhanced alkaline phosphatase activity and osteocalcin production, the increased areas of mineralization were also observed in the RGD-CHC-Ti group. These results indicate that the strategy employed herein may function as an effective way to construct stable, RGD-containing bioactive coatings on Ti.

Acid-triggered drug release from micelles based on amphiphilic oligo(ethylene glycol)–doxorubicin alternative copolymers

We report a facile strategy to synthesize pH-sensitive amphiphilic oligo(ethylene glycol) (OEG)-doxorubicin (DOX) alternative conjugates. Poly[oligo(ethylene glycol) malicate] (POEGM) with numerous pendent hydroxyl groups was first synthesized by the direct polycondensation of oligo(ethylene glycol) (OEG) with malic acid under mild conditions. Then, benzaldehyde groups were introduced into the POEGM backbone via esterification between the pendant hydroxyl groups and 4-formylbenzoic acid. DOX moieties were finally attached to the polymeric backbone via benzoic imine linkages to obtain the OEG-DOX conjugates. Because of the high molecular weight and alternate architecture, this type of amphiphilic OEG-DOX alternative conjugates can form stable micelles in aqueous solution with a high DOX loading content (38.2 wt%) and low critical micelle concentrations (0.021 mg mL-1). Due to the pH-sensitive benzoic imine linkages between the DOX moieties and polymeric backbone, DOX could be rapidly released from the micelles at pH 5.8, whereas only a minimal amount of DOX was released at pH 7.4 under the same conditions. The cytotoxicity assay indicates that the OEG-DOX conjugates show cytotoxic effects to MCF-7 tumor cells, while the corresponding polymer material POEGM-CHO exhibits a great biocompatibility for MCF-7 tumor cells. These pH-sensitive and high drug loading nano-carriers based on the OEG-DOX alternative conjugates provide a promising platform for targeted cancer therapy.

Facile preparation of shell crosslinked micelles for redox-responsive anticancer drug release

We report a “one-pot” method to synthesize an amphiphilic triblock copolymer with multiple pendant mercapto groups in the hydrophilic block. Shell crosslinked micelles were prepared in a facile manner via the self-assembly of this copolymer in aqueous solution and crosslinking of the micellar shell by H2O2. These shell crosslinked micelles show rapid bioreductive responsiveness for anticancer drug release.

Metal and light free “click” hydrogels for prevention of post-operative peritoneal adhesions

This study presented a facile method to prepare two PEG derivatives with multi-thiols or multi-enes by polycondensation on a large scale using scandium trifluoromethanesulfonate (Sc(OTf)3) as highly efficient and chemoselective catalyst. A novel type of biodegradable and biocompatible PEG hydrogel was easily obtained through the thiol–ene “click” reaction under physiological conditions. 1H NMR spectra and GPC were used to characterize the chemical compositions and molecular weights of the two PEG derivatives. FT-IR and rheological experiments were used to investigate the gelation behavior of the PEG hydrogel. Degradation studies revealed a precursor concentration-dependent degradation behavior of the resultant PEG hydrogel. In vitro cell viability assay showed the excellent biocompatibility of the two precursors and also the resultant hydrogel. Furthermore, the rat model of abdominal sidewall defect-cecum abrasion suggested that the PEG hydrogel developed in the present study is a promising physical barrier for the prevention of post-operative peritoneal adhesion.

Facile fabrication of reduction-responsive nanocarriers for controlled drug release

An amphiphilic multiblock poly(ether–ester) containing multiple thiols was facilely synthesized by “one-pot” polycondensation of dihydroxyl poly(ethylene glycol), 1,4-butanediol and mercaptosuccinic acid, which could be used to fabricate reduction-responsive core-crosslinked micelles for controlled drug release.

Reduction/pH dual-responsive nano-prodrug micelles for controlled drug delivery

In this work, an amphiphilic alternating multiblock copolymer poly[oligo(ethylene glycol)fumarate-co-dithiodiethanol fumarate] (POEGSSFM) with multiple enes and disulfides in hydrophobic blocks was synthesized facilely by the “one-pot” method, which can self-assemble into nano-scaled micelles and encapsulate mercapto-modified doxorubicin (DOX-SH) with 1,6-hexanedithiol into the core for in situ drug conjugation and core-crosslinking (CCL) via a thiol–ene “click” reaction, resulting in a reduction and pH dual-responsive nano-prodrug micelle (CCL-POEGSSFM-DOX). The obtained nano-prodrug micelles presented stable nano-scaled spherical particles under physiological conditions, while quickly dissociating in response to 10 mM DL-dithiothreitol (DTT). As doxorubicin (DOX) was conjugated via a pH-sensitive hydrazone linkage, the in vitro release results showed a minimized release of DOX at pH 7.4, while a rapid release at pH 5.8. Particularly, the release of DOX in an acidic environment could also be significantly accelerated by treating with DTT, owing to the cleavage of the disulfide bonds, which leads to the disassociation of the micelles. Confocal laser scanning microscopy further demonstrated that the nano-prodrug can be easily taken into cells, presenting a rapid DOX release in the cytoplasm. Cytotoxicity assay indicated that the nano-prodrug micelles exhibited excellent cytotoxic effects on HeLa cells, while blank CCL-POEGSSFM micelles were biocompatible. This facilely prepared pH and reduction dual-responsive CCL nano-prodrug would be a promising candidate for cancer chemotherapy.

Topography-dependent antibacterial, osteogenic and anti-aging properties of pure titanium

After nearly half a century of development under the guidance of the osseointegration theory, the major dilemmas for current implant dentistry are the implant associated infection and insufficient osseointegration. Moreover, biological aging of titanium (Ti) implants also brings great uncertainty to clinical results. In the present study, a novel nano-micro-hierarchical topography pattern is created by sandblasting and dual acid-etching on a Ti surface. The physico-chemical properties of the surfaces were characterized by scanning electron microscopy, contact angle measurement, X-ray photoelectron spectroscopy and X-ray diffraction. The effects of the hierarchical surfaces on osteoprogenitor cell growth and bacterial activities were separately evaluated. The optimized nano-micro-hierarchical Ti surface exhibits surprisingly topography-dependent antibacterial capacity via inhibiting bacterial adhesion of several species in the early stage and better osteogenesis ability than the microscaled surface. Aging studies demonstrate that, compared with the surface with a microscale structure, the nano-micro-hierarchical Ti surface has greater anti-aging ability manifested as being more capable to retain hydrophilicity and bioactivity during aging. Furthermore, the present study reveals that the biological aging of the Ti implant is attributed to two decisive factors during the aging period: the progressively thickened amorphous TiO2 layer by autoxidation and the unavoidable accumulation of hydrocarbons on the Ti implant surface.

Biomimetic ECM coatings for controlled release of rhBMP-2: construction and biological evaluation

As we all know biochemical surface modification is promising for implantable biomedical device applications due to its ability to directly provide therapeutic molecular cues for tissue repair. However, presenting multiple molecular cues on implant surfaces in the proper way is challenging. In this study, a multi-component polyelectrolyte multilayer (PEM) coating composed of collagen type I, RGD peptide functionalized hyaluronic acid, and recombined human BMP-2 (rhBMP-2) was constructed on Ti via a layer by layer technique. Subsequently, this coating was crosslinked via disulfide bonds to form a surface gel coating with a semi-interpenetrating network. A disulfide-crosslinked RGD-containing biomimetic extracellular matrix coating that could serve as a reservoir for rhBMP-2 was thus obtained. The embedded rhBMP-2 displayed a sustained release profile and a strong resistance to the physiological environment. In vitro biological evaluation revealed that the resultant disulfide crosslinking bioactive coating could effectively modulate cellular behaviors of pre-osteoblasts such as adhesion, proliferation and differentiation. In vivo study further revealed that this coating could enhance the bone-to-implant integration characterized by the increased removal torque values.

Injectable cationic hydrogels with high antibacterial activity and low toxicity

Antibacterial materials have always suffered from high toxicity. In this study, we fabricated injectable and biodegradable hydrogels utilizing poly(hexamethylene guanidine) hydrochloride and poly(ethylene glycol) as the backbone through a thiol–ene “click” reaction under physiological conditions, and they showed remarkably low toxicity and high and broad-spectrum antibacterial activity.