Combined Infection Control and Enhanced Osteogenic Differentiation Capacity on Additive Manufactured Ti‐6Al‐4V are Mediated via Titania Nanotube Delivery of Novel Biofilm Inhibitors

Abstract

Additive manufacturing (AM) of titanium alloys offers the capacity to fabricate patient-specific implants with defined porous architecture to enhance bone-implant fixation. However, clinical challenges associated with orthopedic implants include inconsistent osseointegration and biofilm-associated peri-implant infection, leading to implant failure. Here, a strategy is developed to reduce infection and promote osteogenesis simultaneously on AM Ti-6Al-4V implants by delivering biofilm inhibitor molecules via titania nanotube surface modification. Electrochemical anodization is performed on polished and as-manufactured Ti-6Al-4V to generate nanotubes, which are utilized for delivery of a novel methylthioadenosine nucleosidase inhibitor (MTANi) that targets MTAN-a key enzyme in bacterial metabolism involved in biofilm formation-thereby offering biofilm inhibition capacity combined with surface nano-topography for promoting osteogenesis. Clinical isolates of staphylococcus cohnii formed firm biofilms on polished and AM Ti-6Al-4V controls whereas modified implants loaded with MTANi inhibit biofilm formation. Anodized AM Ti-6Al-4V nanotube substrates enhance alkaline phosphatase production, bone-specific protein expression (osteocalcin, collagen I) and mineral deposition of human mesenchymal stromal cells (hMSCs), compared to as-manufactured controls. Importantly, no detrimental effects on hMSC proliferation and osteogenic differentiation are observed for MTANi-loaded substrates. Application of novel MTANi and electrochemical anodization offers a promising strategy for titanium alloy implant surface modification.

Advanced Surface Modification for 3D-Printed Titanium Alloy Implant Interface Functionalization

“…Mg 2+ is the most abundant cation in cells and regulates a variety of cellular functions such as cellular signal, cell growth, metabolism, and proliferation. A high concentration of Mg 2+ can activate the calcium channels on the cell membrane ( Li J et al, 2020 ). Furthermore, Mg is necessary for bone growth because it can inhibit osteoclast differentiation and bone resorption.…”

Tuning the Biointerface: Low-Temperature Surface Modification Strategies for Orthopedic Implants to Enhance Osteogenic and Antimicrobial Activity

“…Electrochemical anodization employs an electrolytic passivation process to coat the underlying metallic substrate with a layer of oxide. 31 Three variables govern electrochemical anodization: substrate surface pretreatment, bath chemistry, and anodizing voltage, each of which can be tuned to modify final nanotube morphology. 31−33 Anodization is a simple, economical, and versatile technique for introducing nanoscale surface features and antimicrobial therapeutics to Ti substrates.…”

“…39,40 The use of TNTs as a drug reservoir and mechanism for prolonged drug release has also been explored. 31,34 In a recent work by Li et al, wrought Ti-6Al-4 V and additively manufactured (AM) Ti-6Al-4 V samples were subjected to electrochemical anodization at 20 V for 3.5 and 1 h, respectively. 31 Both wrought Ti-6Al-4 V and AM Ti-6Al-4 V (which had additional microscale surface features from the precursor powder used for additive manufacturing) yielded coherent TNTs on the entire surface (see Figure 2a).…”

“…31,34 In a recent work by Li et al, wrought Ti-6Al-4 V and additively manufactured (AM) Ti-6Al-4 V samples were subjected to electrochemical anodization at 20 V for 3.5 and 1 h, respectively. 31 Both wrought Ti-6Al-4 V and AM Ti-6Al-4 V (which had additional microscale surface features from the precursor powder used for additive manufacturing) yielded coherent TNTs on the entire surface (see Figure 2a). The TNTs formed on the AM Ti-6Al-4 V substrate were smaller in diameter and shorter in length, compared to those found on the wrought Ti-6Al-4 V substrate.…”

3D Printing Technology for Fighting COVID-19 Pandemic

“…In addition to being drug carriers, these nanotubes have shown to upregulate osteogenic genes such as osteocalcin & collagen 1 and enhanced ALP production in comparison to as built or unmodified Ti-6Al-4V substrate. Li et al were successful in loading an MTAN inhibitor (which targets bacteria metabolism responsible for the formation of biofilm) inside nanotubes grown on the surface of the additively manufactured substrate (Li et al 2020). Apart from nanotube, microcraters and wire structures are also experimented to be used for encapsulation of drugs.…”