Advanced surface engineering of titanium materials for biomedical applications: From static modification to dynamic responsive regulation.

Titanium (Ti) and its alloys have been widely used as orthopedic implants, because of their favorable mechanical properties, corrosion resistance and biocompatibility. Despite their significant success in various clinical applications, the probability of failure, degradation and revision is undesirably high, especially for the patients with low bone density, insufficient quantity of bone or osteoporosis, which renders the studies on surface modification of Ti still active to further improve clinical results. It is discerned that surface physicochemical properties directly influence and even control the dynamic interaction that subsequently determines the success or rejection of orthopedic implants. Therefore, it is crucial to endow bulk materials with specific surface properties of high bioactivity that can be performed by surface modification to realize the osseointegration. This article first reviews surface characteristics of Ti materials and various conventional surface modification techniques involving mechanical, physical and chemical treatments based on the formation mechanism of the modified coatings. Such conventional methods are able to improve bioactivity of Ti implants, but the surfaces with static state cannot respond to the dynamic biological cascades from the living cells and tissues. Hence, beyond traditional static design, dynamic responsive avenues are then emerging. The dynamic stimuli sources for surface functionalization can originate from environmental triggers or physiological triggers. In short, this review surveys recent developments in the surface engineering of Ti materials, with a specific emphasis on advances in static to dynamic functionality, which provides perspectives for improving bioactivity and biocompatibility of Ti implants.

Cell osteogenic bioactivity mediated precisely by varying scaled micro-pits on ordered micro/nano hierarchical structures of titanium.

Hierarchical surface structures with micro-nano scale play a crucial role in regulation of cell proliferation and osteogenic differentiation. It has been proven that cells are extremely sensitive to the nanoscaled structure and show multifarious phenotypes. Though a vital function of microstructure on osseointegration has been confirmed, the cell performances response to different microscaled structure is needed to be further dissected and in depth understood. In this work, the ordered micro-nano hierarchical structures with varying micro-scaled pits were precisely fabricated on titanium successfully by the combination of electrochemical, chemical etching and anodization as well. In vitro systematical assessments indicated that the micro-nano multilevel structures on titanium exhibited excellent cells adhesion and spreading ability, as well as steerable proliferation and osteogenic differentiation behaviors. It is shown that smaller micro-pits and lower roughness of the hierarchical structures enabled faster cell propagation. Despite cell growth was delayed on micro-nano titanium with relatively larger cell-match-size micro-pits and roughness, osteogenic-specific genes were significantly elevated. Furthermore, the alkaline phosphatase activity, collagen secretion and extracellular matrix mineralization of MC3T3-E1 on multi-scaled titanium were suppressed by a large margin after adding IWP-2 (an inhibitor of Wnt/ß-catenin signal pathway), indicating this pathway played a crucial part in cell osteogenic differentiation modulated by micro-nano structures.

Hydroxyapatite-modified micro/nanostructured titania surfaces with different crystalline phases for osteoblast regulation.

Surface structures and physicochemical properties critically influence osseointegration of titanium (Ti) implants. Previous studies have shown that the surface with both micro- and nanoscale roughness may provide multiple features comparable to cell dimensions and thus efficiently regulate cell-material interaction. However, less attention has been made to further optimize the physicochemical properties (e.g., crystalline phase) and to further improve the bioactivity of micro/nanostructured surfaces. Herein, micro/nanostructured titania surfaces with different crystalline phases (amorphous, anatase and anatase/rutile) were prepared and hydroxyapatite (HA) nanorods were deposited onto the as-prepared surfaces by a spin-assisted layer-by-layer assembly method without greatly altering the initial multi-scale morphology and wettability. The effects of crystalline phase, chemical composition and wettability on osteoblast response were investigated. It is noted that all the micro/nanostructured surfaces with/without HA modification presented superamphiphilic. The activities of MC3T3-E1 cells suggested that the proliferation trend on the micro/nanostructured surfaces was greatly influenced by different crystalline phases, and the highest proliferation rate was obtained on the anatase/rutile surface, followed by the anatase; but the cell differentiation and extracellular matrix mineralization were almost the same among them. After ultrathin HA modification on the micro/nanostructured surfaces with different crystalline phases, it exhibited similar proliferation trend as the original surfaces; however, the cell differentiation and extracellular matrix mineralization were significantly improved. The results indicate that the introduction of ultrathin HA to the micro/nanostructured surfaces with optimized crystalline phase benefits cell proliferation, differentiation and maturation, which suggests a favorable biomimetic microenvironment and provides the potential for enhanced implant osseointegration in vivo.

Aptamer-functionalized hydrogel for self-programmed protein release via sequential photoreaction and hybridization.

A dynamic hydrogel that sequentially responds to two independent but interrelated physical and biomolecular signals was reported in this work. Once hit by an external light signal, an immobilized internal molecular signal is activated and freed via photoreaction; and subsequently the freed molecular signal works as a self-programming factor of the hydrogel to induce the dissociation of a biomolecular complex to release protein via hybridization reaction. Notably, pulsatile external light input can be converted to periodical protein output from the hydrogel to regulate cell migration. Thus, this hydrogel holds potential as a self-programming platform for biological and biomedical applications such as controlled release of bioactive substances.

Nanoparticle-Programmed Surface for Drug Release and Cell Regulation via Reversible Hybridization Reaction.

A surface directly connects the bulk of a material to its surroundings. The ability to dynamically regulate the surface without affecting the bulk of a material holds great potential for new applications. The purpose of this work was to demonstrate that the surface can be dynamically changed using nanoparticles and oligonucleotides (ODNs) in a reversible and reiterative manner. A dual-functional nanogel was synthesized as the model of nanoparticles using miniemulsion polymerization and click chemistry. The nanogel can not only adsorb drugs for sustained drug release but also bind a surface functionalized with complementary ODNs. Importantly, hybridization reaction and ODN degradation can drive reversible and reiterative nanogel binding to the surface for dynamic change, which in principle is unlimited. Moreover, nanogel-mediated dynamic change offers the surface with the drug-releasing function for inhibiting the growth of surrounding cells. Because nanogels can be replaced by any functional nanoparticles with a diverse array of properties, nanoparticle-programmed surface change constitutes a promising platform for various applications such as drug delivery and stent implantation.

Effect of construction of TiO2 nanotubes on platelet behaviors: Structure-property relationships.

Blood compatibility of TiO2 nanotubes (TNTs) has been assessed in rabbit platelet-rich plasma (PRP), which combines activation of both blood plasma coagulation and platelets. We find that (i) amorphous TiO2 nanotubes (TNTs) with relatively larger outer diameters led to reduced platelet adhesion/activation, (ii) TNTs with relatively smaller outer diameters in a predominately rutile phase also inhibited platelet adhesion and activation, and (iii) a pervasive fibrin network formed on larger outer diameter TNTs in a predominately anatase phase. Thus, this study suggests that combined effect of crystalline phase and surface chemistry controls blood-contact behavior of TNTs. A more comprehensive mechanism is proposed for understanding hemocompatibility of TiO2 which might prove helpful as a guide to prospective design of TiO2-based biomaterials. STATEMENT OF SIGNIFICANCE: To realize optimal design and construction of biomaterials with desired properties for blood contact materials, a comprehensive understanding of structure-property relationships is required. In the existing literature, TiO2 nanotube has been reported to be a good candidate for biomedical applications. However, it is noticeable that the blood compatibility of TiO2 nanotubes (TNTs) remains obscure or even inconsistent in the previously published works. The inconsistency could derive from different research protocols, material properties or blood sources. Thus, a thorough investigation of the effect of surface properties on blood compatibility is crucial to the development of titanium based materials. In this paper, we explored the effect of surface properties on the response of platelet-rich plasma, especially surface morphology, chemistry, wettability and crystalline phase. The results indicated that crystalline phase was a dominant factor in platelet behaviors. Reduced adhesion and activation of platelets were observed on amorphous and rutile dominated TNTs, whereas anatase dominated TNTs activated the formation of fibrin network. We further proposed a hypothetical mechanism for better understanding of how surface properties affect the response of platelet-rich plasma. Therefore, this study expands the fundamental understanding of the structure-property relationships of titanium based materials.

Effect of Octacalcium-Phosphate-Modified Micro/Nanostructured Titania Surfaces on Osteoblast Response.

Surface structures and properties of titanium implants play a vital role in successful bone replacement. To mimic the natural bone structure, some strategies have recently focused on the preparation of multiscaled morphology on medical titanium and shown some promising results; however, relatively few efforts have been made for further enhancing the biocompatibility of such a hierarchical hybrid structure without compromising the superior bioactivity of the starting micro/nano roughness. In this study, a thin ribbonlike octacalcium phosphate (OCP) coating was electrodeposited on a hierarchically structured titania surface, maintaining its micro/nanospongelike morphology. It is indicated that the micro/nanostructured surface with deposited OCP showed an improved biomineralization ability, in comparison to that without OCP modification, when immersed in simulated body fluid (SBF). Further evaluations of cellular activities demonstrated that the introduction of OCP to the micro/nano spongelike-structured surface remarkably enhanced MC3T3-E1 cell proliferation, alkaline phosphatase activity, and extracellular matrix mineralization compared to that of cells on the micro/nanospongelike titania surface during 14 days of culturing. Meanwhile, the OCP-deposited micro/nanostructured surface displayed much a smaller passive current density and lower current response to the applied potential, resulting in the improvement of corrosion resistance. All of the evaluations suggested that the modification of the OCP coating on the prepared micro/nanospongelike titania is of superior chemical stability, biomineralization, and osteoblast activities, which indicates a favorable implant microenvironment for osseointegration in vivo.