Titanium Implants and Local Drug Delivery Systems Become Mutual Promoters in Orthopedic Clinics

Abstract

Titanium implants have always been regarded as one of the gold standard treatments for orthopedic applications, but they still face challenges such as pain, bacterial infections, insufficient osseointegration, immune rejection, and difficulty in personalizing treatment in the clinic. These challenges may lead to the patients having to undergo a painful second operation, along with increased economic burden, but the use of drugs is actively solving these problems. The use of systemic drug delivery systems through oral, intravenous, and intramuscular injection of various drugs with different pharmacological properties has effectively reduced the levels of inflammation, lowered the risk of endophytic bacterial infection, and regulated the progress of bone tumor cells, processing and regulating the balance of bone metabolism around the titanium implants. However, due to the limitations of systemic drug delivery systems-such as pharmacokinetics, and the characteristics of bone tissue in the event of different forms of trauma or disease-sometimes the expected effect cannot be achieved. Meanwhile, titanium implants loaded with drugs for local administration have gradually attracted the attention of many researchers. This article reviews the latest developments in local drug delivery systems in recent years, detailing how various types of drugs cooperate with titanium implants to enhance antibacterial, antitumor, and osseointegration effects. Additionally, we summarize the improved technology of titanium implants for drug loading and the control of drug release, along with molecular mechanisms of bone regeneration and vascularization. Finally, we lay out some future prospects in this field.

Keywords: bone regeneration; drug effect; local drug delivery system; titanium implants; titanium processing technology.

Figure 2

(A), P. aeruginosa biofilm on platinum; scale bar = 2 μm; reprinted with permission from [36]; copyright 2020 Kirchhoff et al. (B) Experimental scheme of Fathi et al. (a) Bare TiO₂-NTs layer created on Ti substrate by electrochemically anodizing; (b) loading of Vancomycin within TiO₂-NTs structures; (c) SF Nanofibers coated on TiO₂-NTs to control Vancomycin release, antibacterial properties and enhance bone integration. The scheme presents a diffusion of Vancomycin molecules via SF Nanofibers; reprinted with permission from [42]; copyright 2019 Elsevier B.V. (C) A cross-sectional image of the SF nanofiber coating on TiO₂-NTs (along with loaded vancomycin); reprinted with permission from [42]; copyright 2019 Elsevier B.V. (D) Experimental scheme of Xiang et al.; reprinted with permission from [44]; copyright 2018 Elsevier B.V. (E) Different antibacterial activity between the experimental group and the control group at different pH values; reprinted with permission from [44]; copyright 2018 Elsevier B.V. (F) The osteomyelitis scores of the experimental group and the control group (** denotes p ≤ 0.05); reprinted with permission from [29]; copyright 2020 The Royal Society of Chemistry. (G) Images showing X-ray examination 3 weeks post-surgery; the rats in group I (antibiotic) and group II (Ag-NTs) exhibited classic symptoms of implant infection, including bone absorption (black arrow) and fibrosis (red arrow); the group III (Ag-NTs + antibiotic) rats showed no signs of infection; reprinted with permission from [45]; copyright 2017 Dove Press Ltd.

Figure 1

Schematical presentation of local drug delivery system on a titanium implant modified by metal processing technology, and the excellent advantages after implantation.

Figure 3

(A) Experimental scheme of Zhang et al.; reprinted with permission from [29]; copyright 2020 The Royal Society of Chemistry. (B) Intuitive structure of the designed material; reprinted with permission from [50]; copyright 2015 Martin B. Bezuidenhout et al. (C) Top-view and cross-sectional SEM images of the material; reprinted with permission from [30]; copyright 2014 Elsevier B.V. (D) Representative topographical AFM images of chitosan and a drug-eluting composite coating; reprinted with permission from [30]; copyright 2014 Elsevier B.V. (E) Drug release curve of experimental and control groups; reprinted with permission from [30]; copyright 2014 Elsevier B.V. (F) Experimental scheme of Nancy et al.; reprinted with permission from [58]; copyright 2018 Elsevier B.V.

Figure 4

(A) Adhesion and aggregation of fibroblasts under an electron microscope; reprinted with permission from [31]; copyright 2017 American Chemical Society. (B) In vitro drug release of different drugs loaded onto TNT-3D-Ti implants (Apo2L/TRAIL); reprinted with permission from [31]; copyright 2017 American Chemical Society. (C) The experimental scheme of Zhang et al; reprinted with permission from [74]; copyright 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (D) The experimental scheme of Jing et al; reprinted with permission from [76]; copyright 2021 Zehao Jing et al. (E) Images of tumors collected from tumor-bearing mice after various treatments; reprinted with permission from [74]; copyright 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (F) The experimental scheme of Sarkar et al.; reprinted with permission from [77]; copyright 2020 American Chemical Society.

Figure 5

(A) MTT assay showing the effects of curcumin, vitamin K2, and curcumin + vitamin K2 on osteosarcoma cell viability (* denotes p ≤ 0.001, ** denotes p ≤ 0.05); reprinted with permission from [77]; copyright 2020 American Chemical Society. (B) Scanning electron microscopy image of the experimental implant at 10× magnification, and surgical placement of control; reprinted with permission from [81]; copyright 2017 John Wiley & Sons A/S. (C) The experimental scheme of He et al.; reprinted with permission from [82]; copyright 2019 Elsevier B.V. (D) The release curves of VD3 on samples; reprinted with permission from [82]; copyright 2019 Elsevier B.V. (E) Scanning electron micrograph (SEM) images of anodized 3D-printed Ti; reprinted with permission from [83]; copyright 2016 John Wiley & Sons, Ltd. (F) The cumulative release profile of SV from SV-LbL-coated Ti substrate in PBS; reprinted with permission from [84]; copyright 2018 Taylor & Francis. (G) Fractions of lamellar bone in contact with the implant surface and in a 0–1 mm zone around the implant; paired data are connected by a line; reprinted with permission from [85]; copyright 2017 Orthopaedic Research Society.