Design of Self-antibacterial and Biocompatible Titanium Surfaces for Biomedical Applications

Metals and alloys are the first generation bio-inert biomaterials. These materials possess excellent mechanical strength, low elastic modulus and good corrosion resistance. Titanium (Ti) and its alloys are one of the commonly used metallic biomaterials for orthopedic applications e.g. bone plates, screws, dental implants and prostheses. Both bulk and surface properties of a biomaterial decide its fate. The initial contact between the surface and biological fluids regulates biointerfacial interactions like wetting, protein adsorption and cell adhesion. Once an implant (biomaterial) comes into contact with body fluids, biointerfacial interactions follow as surface-water, surface-protein and surface-cells according to the relative diffusivity of biomacromolecules. These interactions are governed by intermolecular interactions, namely van der Waals, ionic, ion-dipole, hydrophobic and hydrogen bonds. As we do not have control over biological macromolecules (body fluids), surfaces are engineered to tune biointerfacial interactions. Typically, surface wettability/ hydrophobicity, surface chemistry, surface charge, and surface roughness regulate the biointerfacial interactions. It is worth mentioning that many of these factors are correlated with each other. For example, surface chemistry affects surface hydrophobicity and surface charge. The surface roughness is related to surface wettability using the Wenzel equation.

Various physical, chemical and biological routes of surface modification have been explored to obtain engineered Ti surfaces. The deposition of bioactive materials like bioceramics e.g. bioglass and hydroxyapatite over the surface of Ti alloys using different coating techniques such as spinning and sputtering is considered as the physical route. Here coating thickness is a major deposition parameter.  Interactions (bonding) between surface and functional groups of modifiers take place during chemical modification. Chemical modifiers include polydopamine, polyphenols, thiols and silanes. Typically, thin layers are formed with covalent linkage during chemical routes. Self-assembled monolayers (SAMs) of different functional groups form a nono-scale thick layer. In the case of biological modification, chemical modifiers are replaced with biomacromolecules like peptides and proteins e.g. RGD peptide, collagen and fibronectin. However, the selected surface engineering routes should not compromise the bulk properties. Recent multidisciplinary research has enabled to upgrade these metallic alloys to smart biomaterials encompassing bioactivity, osteoconductivity and no inflammation.

The recent challenge of implant-associated infections (IAIs) or hospital-acquired infections (HAIs) and the development of antibiotic resistance is driving towards designing self-antibacterials biomaterials. The prolonged usage of antibiotics to manage IAIs generate antibiotic (antibacterial) resistance.  IAIs lead to the formation of biofilms comprising polysaccharides, lipids, proteins and extracellular DNA (eDNA). Hereafter, the traditional antibiotics become ineffective. Common pathogens forming biofilm include Staphylococcus aureus, Pseudomonas aeruginosa, and Staphylococcus epidermidis. The biofilms are responsible for antibiotic resistance and, eventually the failure of metallic implants. For this purpose, novel antimicrobial agents like peptides, biosurfactants, nanomaterials and multi-functional coatings are being utilised for designing self-antibacterial surfaces.

Selected nanomaterials e.g. ZnO, Al or Fe-doped ZnO, CuO, Zn or Ag doped-TiO2 display broad-spectrum antibacterial activities and thus have the potential to be used as nano-antibiotics in the place of conventional antibiotics. The minimum inhibitory concentration (MIC) values of these nanomaterials are found to be comparable or even lesser compared to chemical antibiotics. These nanomaterials can be coated using physical methods like laser cladding or radio frequency sputtering or immobilised after chemical modifications e.g. nanoparticles attached on SAMs. The release of ions from nanomaterials results in antibacterial activities through damage to cell wall, internalisation or generation of reactive oxygen species (ROS). In addition, the presence of some ions like Zn and Fe also improves cell proliferation. The presence of more than one metal ions offers multi-functionality. Examples of multi-functional Ti include the coating with strontium-doped fluorapatite (Sr-FAP) nanopowders or zinc-doped strontium-calcium-phosphate (SrCaP). Apart from bactericidal activity, the multi-functionality also imparts osseointegration and corrosion protection. It is to note that cytotoxicity of nanomaterials is concententration dependent and thus, the cytotoxicity of the selected nanomaterials should be cautiously considered.

Antioxidant chemicals like caffeic acid, tannic acid and α-tocopherol also result in bacteriostatic properties. Amphiphilic antimicrobial peptides like GL13K are immobilised on the surfaces of Ti implants to improvise bactericidal activity. Peptides rich is certain amino acids like lysine, proline, cysteine, arginine, tyrosine and tryptophan also exhibit antibacterial properties. Biosurfactants are another class of amphiphilic molecules derived from biological origin. Thus, these molecules are biocompatible (exhibit no cytotoxicity) but at the same kill bacteria by damaging the cell wall. These chemicals are attached to Ti surfaces mostly through chemical routes. Linker molecules like glutaraldehyde, 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)/ N-hydroxysuccinimide (NHS) and different SAMs are first applied on surfaces before immobilising desired chemicals.

The targeting of eDNA is also explored to inhibit biofilm formation. For example, immobilisation of DNase I on surfaces of Ti discs was reported to significantly diminish the biofilm formation of Pseudomonas aeruginosa, and Staphylococcus aureus. This is an example of biological modification. For such cases, surfaces are first functionalised with amine groups using polydopamine or amine SAMs followed by immobilising biomacromolecules.

Further, many of the above strategies have been integrated to achieve synergistic results. A few examples list (i) deposition of antioxidant caffeic acid and antibacterial chitosan on Ti alloys, (ii) micro/nano-texturing to tune cell adhesion and surface modification for the bactericidal properties, (iii) coatings of bioceramics doped with antibacterial metals on Ti alloys and (iv) immobilisation of antimicrobial peptide coupled with silver nanoparticles on Ti surfaces. The hybrid coatings enhanced the antibacterial performances. In addition, the multi-functionality induces osseointegration and stability (corrosion resistance).

Summarily, new frontiers of Ti-based implants should comprehend adequate bulk and surface properties, including similar mechanical strength, enhanced osseointegration, and improved bioactivity, killing of pathogens, inhibition of biofilm formation and no inflammation. The design of Ti alloy surfaces with multifunctional hybrid coatings is expected to serve these purposes of the required biocompatibility along with antimicrobial characteristics. The self-antibacterial properties are likely to significantly minimise the IAIs (HAIs) and combat antibiotic resistance.

Reference:
Pandey, L. M. (2022). Design of Biocompatible and Self-antibacterial Titanium Surfaces for Biomedical Applications. Current Opinion in Biomedical Engineering, 100423.