Interdisciplinary-Inspired Smart Antibacterial Materials and Their Biomedical Applications.

The discovery of antibiotics has saved millions of lives, but the emergence of antibiotic-resistant bacteria has become another problem in modern medicine. To avoid or reduce the overuse of antibiotics in antibacterial treatments, stimuli-responsive materials, pathogen-targeting nanoparticles, immunogenic nano-toxoids, and biomimetic materials are being developed to make sterilization better and smarter than conventional therapies. The common goal of smart antibacterial materials (SAMs) is to increase the antibiotic efficacy or function via an antibacterial mechanism different from that of antibiotics in order to increase the antibacterial and biological properties while reducing the risk of drug resistance. The research and development of SAMs are increasingly interdisciplinary because new designs require the knowledge of different fields and input/collaboration from scientists in different fields. A good understanding of energy conversion in materials, physiological characteristics in cells and bacteria, and bactericidal structures and components in nature are expected to promote the development of SAMs. In this review, the importance of multidisciplinary insights for SAMs is emphasized, and the latest advances in SAMs are categorized and discussed according to the pertinent disciplines including materials science, physiology, and biomimicry.

Recent Advances in "Functional Engineering of Articular Cartilage Zones by Polymeric Biomaterials Mediated with Physical, Mechanical, and Biological/Chemical Cues".

Articular cartilage (AC) plays an unquestionable role in joint movements but unfortunately the healing capacity is restricted due to its avascular and acellular nature. While cartilage tissue engineering has been lifesaving, it is very challenging to remodel the complex cartilage composition and architecture with gradient physio-mechanical properties vital to proper tissue functions. To address these issues, a better understanding of the intrinsic AC properties and how cells respond to stimuli from the external microenvironment must be better understood. This is essential in order to take one step closer to producing functional cartilaginous constructs for clinical use. Recently, biopolymers have aroused much attention due to their versatility, processability, and flexibility because the properties can be tailored to match the requirements of AC. This review highlights polymeric scaffolds developed in the past decade for reconstruction of zonal AC layers including the superficial zone, middle zone, and deep zone by means of exogenous stimuli such as physical, mechanical, and biological/chemical signals. The mimicked properties are reviewed in terms of the biochemical composition and organization, cell fate (morphology, orientation, and differentiation), as well as mechanical properties and finally, the challenges and potential ways to tackle them are discussed.

Design and Properties of Antimicrobial Biomaterials Surfaces.

Emergence of antibiotic-resistance pathogens has caused serious health issues and if the current trend is to continue, treatment of the infection will become complicated and even unsuccessful due to new antimicrobial resistance (AMR). Therefore, there is a global drive to identify new methods to treat infection and develop better antibacterial materials and therapy. Although new and more potent antibiotics have aided the fight against microbes, they only offer a temporary solution because future bacteria strains may become resistant to these antibiotics and drugs. Recently, application of non-biological methods such as, electrical currents and photothermal/dynamic therapies to kill bacteria, reveal new approaches to design antimicrobial biomaterials, as complications stemming from drug-resistant bacteria can be obviated. Furthermore, recent research has focused on mimicking the surface patterns on plants and insects such as lotus leaves and dragonfly wings. Bio-inspired micro/nano patterns have been replicated on a variety of biomaterials to improve the bacterial resistance and other properties with good success. This is an exciting research area with immense practical and clinical potentials. In this review, recent advances in the application of chemical/biological approaches to combat bacterial infection and AMR are summarized and the related mechanisms are discussed.

A dual functional chondro-inductive chitosan thermogel with high shear modulus and sustained drug release for cartilage tissue engineering.

We report a chitosan-based nanocomposite thermogel with superior shear modulus resembling that of cartilage and dual pro-chondrogenic and anti-inflammatory functions. Two therapeutic agents, kartogenin (KGN) and diclofenac sodium (DS), are employed to promote chondrogenesis of stem cells and suppress inflammation, respectively. To extend the release time in a controlled manner, KGN is encapsulated in the uniform-sized starch microspheres and DS is loaded into the halloysite nanotubes. Both drug carriers are doped into the maleimide-modified chitosan hydrogel to produce a shear modulus of 167 ± 5 kPa that is comparable to that of articular cartilage (50-250 kPa). Owing to the hydrogel injectability and relatively suitable gelation time (5 ± 0.5 min) at 37 °C, this system potentially constitutes a manageable platform for clinical practice. Moreover, sustained linear drug release for over a month boosts chondro-differentiation of stem cells to eliminate the necessity for multiple administrations. Considering virtues such as thermogel strength and ability to co-deliver anti-inflammatory and chondro-inductive biomolecules continuously, the materials and strategy have promising potential in functional cartilage tissue engineering.

Enhanced corrosion resistance and reduced cytotoxicity of the AZ91 Mg alloy by plasma nitriding and a hierarchical structure composed of ciprofloxacin-loaded polymeric multilayers and calcium phosphate coating.

Much effort has made to lessen the cytotoxicity and enhance the corrosion resistance of biodegradable magnesium alloys, for example, by depositing multilayered polymeric coatings containing hydroxyapatite. In this work, a hierarchical structure composed of ciprofloxacin (Cip)-loaded on polyacrylic acid (PAA) and poly (ethyleneimine) (PEI) as biocompatible polymeric multilayers and calcium phosphate coating as the top layer is formed by the sol-gel method on the AZ91 Mg alloy with an intermediate layer formed by nitrogen plasma immersion ion implantation. The thicknesses of the multilayered coating and nitrided layer (Mg3 N2 ) are 10 µm and 140 nm, respectively. The corrosion current density decreases by 95.6% and the corrosion potential in the polarization curve shifts to the positive direction by 23%. The passivation process which occurs at defects by deposition of corrosion products mitigates both galvanic and localized corrosion. Slight increase in the contact angle and surface free energy, enhanced corrosion resistance, and reduced cytotoxicity are observed from the multilayered structure. The better corrosion resistance enables better control of release of Cip. Biological assessment indicates that the antibacterial activity against Escherichia coli is improved by 100% after culturing for 24 hr and the cell viability and noncytotoxic behavior of the coated AZ91 are enhanced as well. The corrosion behavior and biological results suggest that the strategy of using a hierarchical structure composed of Cip-loaded polymeric multilayers in conjunction with an intermediate plasma nitrided layer has large potential in the development of biodegradable orthopedic implants made of Mg alloys.

Corrosion resistance, nano-mechanical properties, and biocompatibility of Mg-plasma-implanted and plasma-etched Ta/TaN hierarchical multilayered coatings on the nitrided AZ91 Mg alloy.

A tantalum/tantalum nitride (Ta/TaN) multilayered coating is deposited on plasma-nitridedAZ91 Mg alloy. The top TaN layer undergoes O2+ Ar plasma etching to improve the antibacterial properties and Mg plasma immersion ion implantation (MgPIII) is performed to enhance the biocompatibility and wound healing capability. A uniform, compact, homogeneous, and columnar nanostructured MgPIII and plasma-etched TaN layer with a cluster size of about 17 nm, surface roughness of 0.28 nm, and needle morphology is observed. Although, plasma etching increases the corrosion current density (icorr) from 0.02 to 0.19 µA cm-2due to larger surface roughness and different potentials between sharp points and smooth points, MgPIII decreasesicorrfrom 0.19 to 0.02 µA cm-2besides a more positive corrosion potential. The amounts of Mg+2released to the simulated body fluid (SBF) diminishes from 89.63 ± 0.54 to 60.30 ± 0.47 mg l-1cm-2indicating improved corrosion resistance. Under fever conditions (40 °C),icorrdecreases by 63%, but the open circuit potential does not change due to the constant chemical composition of the surface as well as thicker double layer and less defects, as confirmed by the larger amount of Mg+2of 71.49 ± 0.22 mg l-1cm-2leached to the SBF. In the self-healing process which occurs via the reactions between the tantalum intermediate layer and electrolytes and penetrating ions through the defects as well as formation of oxide compounds, creation and propagation of defects are deterred as shown the 24 h destructive polarization test in SBF. The combination of plasma etching and MgPIII enhance not only the bacterial resistance and biocompatibility of the super-hard TaN layer by providing the rougher surface on TaN-P-Mg, but also the nano-mechanical properties and anticorrosion properties. As a result, the hardness increases by 7%, elastic modulus decreases by 19%, and the stiffness increases by 21%.

Lectin Staining of Microvascular Glycocalyx in Microfluidic Cancer Cell Extravasation Assays.

The endothelial glycocalyx forms the inner-most lining of human microvasculature. It ensures the physiological function of blood vessels and plays a crucial role in the occurrence and progression of microvascular diseases. The present communication aims to highlight the usefulness of high-resolution imaging of lectin (Bandeiraea Simplicifolia) stained endothelial glycocalyx in 3-dimensional microfluidic cell cultures. The microfluidic system allowed visualizing cancer cell extravasation, which is a key event in metastasis formation in cancer pathologies. In brief, microvascular networks were created through spontaneous vasculogenesis. This occurred from 3 dimensional (3D) suspensions of human umbilical vein endothelial cells (HUVECs) in hydrogels confined within microfluidic devices. Extravasation of MDA-MB-231 breast cancer cells from perfusable endothelial lumens was observed with confocal imaging of lectin-stained microvascular networks. The present work provides guidance towards optimizing the methodology used to elucidate the role of the endothelial glycocalyx during cancer cell extravasation. In particular, a high-resolution view of the endothelial glycocalyx at the site of extravasation is presented. The occurrence of glycocalyx defects is well aligned with the contemporary notion in the field that glycocalyx shedding precedes cancer cell extravasation.

Enhanced corrosion resistance, antibacterial properties, and biocompatibility by hierarchical hydroxyapatite/ciprofloxacin-calcium phosphate coating on nitrided NiTi alloy.

Multi-functional hierarchical coatings are deposited on the nitrided NiTi alloy. The nitrided layer is first deposited by nitrogen plasma immersion ion implantation and a middle layer containing porous hydroxyapatite and ciprofloxacin (Cip) is produced before the top calcium phosphate coating is deposited by the sol-gel method. The thicknesses of the coating and nitrided intermediate layer are about 1.54 µm and 160 nm, respectively and Cip penetrates to a depth of about 530 nm. Calcium phosphate reduces surface defects resulting in a surface roughness of 17 ± 2 nm compared to 34 ± 5 nm of the porous hydroxyapatite coating. The corrosion resistance is improved due to reduced defects and localized corrosion as manifested by the decrease in the Ni2+ release rate by 11.6% from 0.0198 to 0.0175 mg L-1 cm-2. The bacterial resistance against E. coli is also improved by about 88 times on account of Cip release and good biocompatibility is confirmed by proliferation of MC3T3 cells. This multi-functional hierarchical coating has large potential in orthopedic and dental applications.

A Biomimetic Nano-Engineered Platform for Functional Tissue Engineering of Cartilage Superficial Zone.

Articular cartilage has limited regeneration capacity because of its acellular and avascular nature. Although tissue engineering has been shown to be life-saving, reforming cartilage zones required by the appropriate tissue functions are challenging. Herein, the need is addressed by designing and producing a nano-engineered structure mimicking the superficial zone (SZ) of articular cartilage. The substrate is based on silk with good mechanical properties in conjunction with nano-topographical and biochemical cues. Nanopillar arrays are produced on the silk surface to regulate the stem cell morphology rendering them with a flattened ellipsoidal shape that is similar to that of chondrocytes in the SZ of natural cartilage. The cell interactions are enhanced by nitrogen ion implantation and the biomolecule, kartogenin (KGN), is loaded to promote chondrogenesis of the stem cells and furthermore, a thermosensitive chitosan hydrogel is formed on the nanopatterned silk to produce rheological properties similar to those of a synovial fluid. Based on the in vitro results and mechanical properties, it is a desirable implantable smart structure mimicking the cartilage SZ with the ability of continuous drug release for cartilage regeneration.

Nanopatterned silk-coated AZ31 magnesium alloy with enhanced antibacterial and corrosion properties.

Because of unique properties such as the lightweight, natural biodegradability, and biocompatibility, magnesium alloys are promising in biomedical implants. However, inadequate corrosion resistance in the physiological environment remains a technical hurdle and application of coatings is a viable means to overcome the deficiency. Also, the antibacterial properties are very important in order to mitigate post-implantation complications arising from bacterial infection. In this study, a biocompatible silk film is deposited on AZ31 Mg alloy to enhance the corrosion resistance and by means of oxygen plasma etching, nature-inspired nanopatterns are fabricated on the surface of the silk film to improve the inherent antibacterial properties. The biocompatibility and antibacterial properties are determined with MC3T3-E1 osteoblast cells and E. coli and S. aureus, respectively. The antimicrobial properties of the silk coated AZ31 are better than those of the bare alloy probably due to the combined effects of the nanopatterns and alkalinity associated with leaching of Mg ions. The ß-sheets formed on the silk film is found to result in 104 times reduction in the corrosion current density and 50% reduction in Mg leaching after 1 day. Although degradation of the ß-sheets is observed to begin after 1 day, the amount of Mg ions leached to the medium from silk-coated AZ31 is still 17% lower than that from the bare one. The biomimicking nanopatterns on the natural silk film improve the corrosion resistance, biocompatibility, and antibacterial properties simultaneously and have large clinical potential.

A Quantitative Bacteria Monitoring and Killing Platform Based on Electron Transfer from Bacteria to a Semiconductor.

A platform with both bacteria killing and sensing capabilities is crucial for monitoring the entire bacteria-related process on biomaterials and biomedical devices. Electron transfer (ET) between the bacteria and a Au-loaded semiconductor (ZnO) is observed to be the primary factor for effective bacteria sensing and fast bacteria killing. The electrons produce a saturation current that varies linearly with the bacteria number, semi-logarithmically, with R2 of 0.98825, thus providing an excellent tool to count bacteria quantitatively in real-time. Furthermore, ET leads to continuous electron loss killing of about 80% of Escherichia coli in only 1 h without light. The modularity and extendability of this ET-based platform are also demonstrated by the excellent results obtained from other semiconductor/substrate systems and the stability is confirmed by recycling tests. The underlying mechanism for the dual functions is not due to conventional attributed Zn2+ leaching or photocatalysis but instead electrical interactions upon direct contact. The results reveal the capability of real-time detection of bacteria based on ET while providing information about the antibacterial behavior of ZnO-based materials especially in the early stage. The concept can be readily incorporated into the design of smart and miniaturized devices that can sense and kill bacteria simultaneously.

Nonleaching Antibacterial Concept Demonstrated by In Situ Construction of 2D Nanoflakes on Magnesium.

In bone implants, antibacterial biomaterials with nonleaching surfaces are superior to ones based on abrupt release because systemic side effects arising from the latter can be avoided. In this work, a nonleaching antibacterial concept is demonstrated by fabricating 2D nanoflakes in situ on magnesium (Mg). Different from the conventional antibacterial mechanisms that depend on Mg2+ release and pH increase, the nanoflakes exert mechanical tension onto the bacteria membranes to destroy microorganisms on contact and produce intracellular stress via physical interactions, which is also revealed by computational simulations. Moreover, the nanoflake layer decelerates the corrosion process resulting in mitigated Mg2+ release, weaker alkalinity in the vicinity, and less hydrogen evolution, in turn inducing less inflammatory reactions and ensuring the biocompatibility as confirmed by the in vivo study. In this way, bacteria are killed by a mechanical process causing very little side effects. This work provides information and insights pertaining to the design of multifunctional biomaterials.

Antibacterial and Cytocompatible Nanoengineered Silk-Based Materials for Orthopedic Implants and Tissue Engineering.

Many postsurgical complications stem from bacteria colony formation on the surface of implants, but the usage of antibiotic agents may cause antimicrobial resistance. Therefore, there is a strong demand for biocompatible materials with an intrinsic antibacterial resistance not requiring extraneous chemical agents. In this study, homogeneous nanocones were fabricated by oxygen plasma etching on the surface of natural, biocompatible Bombyx mori silk films. The new hydroxyl bonds formed on the surface of the nanopatterned film by plasma etching increased the surface energy by around 176%. This hydrophilic nanostructure reduced the bacterial attachment by more than 90% for both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria and at the same time improved the proliferation of osteoblast cells by 30%. The nanoengineered substrate and pristine silk were cultured for 6 h with three different bacteria concentrations of 107, 105, and 103 CFU mL-1 and the cell proliferation on the nanopatterned samples was significantly higher due to limited bacteria attachment and prevention of biofilm formation. The concept and materials described here reveal a promising alternative to produce biomaterials with an inherent biocompatibility and bacterial resistance simultaneously to mitigate postsurgical infections and minimize the use of antibiotics.