Guangyu Zha

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.

Fully biodegradable antibacterial hydrogels via thiol–ene “click” chemistry

In this work, fully biodegradable antimicrobial hydrogels were prepared facilely via a thiol–ene “click” reaction under human physiological conditions using multifunctional poly(ethylene glycol) (PEG) derivatives as precursors. Water soluble and degradable PEG derivatives with multi-enes and multi-thiols, respectively, were synthesized by polycondensation of oligo(ethylene glycol) (OEG) with “clickable” monomers. Ammonium groups with long alkyl chains were incorporated into one of the precursors covalently, using dodecyl bis(2-hydroxyethyl) methylammonium chloride as a comonomer. Proton nuclear magnetic resonance (1H-NMR) spectroscopy, gel permeation chromatography (GPC) and Fourier transform infrared spectroscopy (FT-IR) were used to characterize the precursors and hydrogels. These types of cationic PEG-type hydrogels showed strong antibacterial abilities against both Gram-negative and Gram-positive bacteria due to the ammonium moieties. Moreover, the hydrogel with fewer ammonium moieties still possessed significant antibacterial abilities, but low toxicity, and has the potential to be used as a medical material.

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.

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 ultrathin antibacterial hydrogel films via layer-by-layer “click” chemistry

We report a facile strategy to fabricate ultrathin hydrogel films via a layer-by-layer (LbL) technique and “click” chemistry. Poly[oligo(ethylene glycol)fumarate]-co-poly[dodecyl bis(2-hydroxyethyl)methylammonium fumarate] (POEGDMAM) containing multi-enes and poly[oligo(ethylene glycol)mercaptosuccinate] (POEGMS) containing multi-thiols were synthesized by polycondensation, which were used as precursors for a LbL thiol–ene “click” reaction under ambient conditions without any metal catalyst or light irradiation. Due to the presence of ammonium groups with long alkyl chains in the POEGDMAM, the ultrathin hydrogel films exhibited excellent antibacterial activity against both Staphylococcus aureus and Escherichia coli, which was enhanced by increasing the number of layers. These kinds of biocompatible, antibacterial, ultrathin hydrogel films are promising candidates for biomedical applications.

Sustained drug release from an ultrathin hydrogel film

We reported a facile method to prepare camptothecin (CPT) loaded ultrathin hydrogel films based on a polymeric prodrug via layer by layer (LbL) thiol–ene “click” chemistry. Free camptothecin could be sustainedly released from the ultrathin hydrogel film within 24 hours through the hydrolysis of ester bonds between the hydrogel backbone and the camptothecin moieties.

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.

An injectable drug-loaded hydrogel using a “clickable” amphiphilic triblock copolymer as a precursor

We developed a facile strategy to prepare an injectable drug-loaded hydrogel with chemical crosslinkages. A PCL-POEGM-PCL amphiphilic triblock copolymer was synthesized in “one pot” by a combination of polycondensation and ring-opening polymerization, which can disperse hydrophobic drugs in aqueous solution and be crosslinked by POEGMS under physiological conditions.