Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Medical Biophysics

Collaborative Specialization

Musculoskeletal Health Research

Supervisor

David W. Holdsworth

Affiliation

Robarts Research Institute

Abstract

The delivery of antibiotics is an important component of therapy for orthopedic device-related infections (ODRI). In this study, we have investigated new techniques to characterize and enhance antibiotic delivery for ODRI. Characterization of small-molecule diffusion is essential to the development of drug-delivery systems. We have developed a quantitative, non-invasive, longitudinal, micro-CT technique to quantify the diffusion of small-molecules in an intact phantom. We employed a radio-opaque molecule (i.e., Iohexol) as a surrogate for commonly used antibiotics (e.g., Vancomycin). We characterized diffusion from a finite-core carrier into an agar, tissue-equivalent phantom. The estimate of the diffusion coefficient was derived from the analysis of radial diffusion distance of Iohexol and the cumulative release amount of this drug surrogate. This micro-CT method enabled us to describe the elution of small-molecules from enhanced carriers within a porous metal scaffold. To enhance antibiotic delivery, we designed and fabricated gyroid-based scaffolds with appropriate mechanical properties and filled with Iohexol-loaded carriers. Diffusion characteristics within the porous structures were evaluated using the micro-CT technique.

Summary for Lay Audience

Orthopedic device-related infection is a devastating problem that is associated with metal implants. Infection can occur any time after primary orthopedic surgery, and can result in severe residual disability and in-hospital mortality; thus, is a burden for the health care system and for patients. In this work, we focused on infection near orthopedic joint implants, since more than 130,000 knee and hip joint replacement surgeries are performed each year in Canada and thousands become infected.

The current treatment for implant-associated infection is two-stage revision surgery. The first challenge is to eliminate the infection; thus, patients would undergo invasive surgery to remove the infected components. During this stage, the patient would also receive systemic antibiotics in addition to local antibiotics to the target joint.

Local treatment would be performed by placing a temporary component that can be loaded with antibiotics. This temporary component maintains the structure of the joint and releases drugs to the target tissue. However, current antibiotic carriers are not highly effective for local infection treatment and release an insufficient amount of the drugs to the target tissue. After 6-8 weeks, if the infection is eradicated, temporary carriers should be removed due to the low mechanical properties of these carriers; hence, a second surgery would be performed to remove the carrier and place the final revision implants.

In this work, our goal was to understand how antibiotics are being released through carriers to the surrounding tissue. We used a micro-CT imaging technique to monitor the release of a drug mimic from a commonly used orthopedic carrier to a tissue-equivalent phantom and characterized the release. We were able to optimize the imaging technique for evaluating the diffusion of the drug from various carriers, qualitatively, and quantitatively.

Upon understanding of drug release, we proposed the application of highly-porous 3D-printed metal structures in combination with current antibiotic carriers. The pores of the structure can be filled with the antibiotic-loaded carrier to satisfy the needs for local infection treatment, while the material properties (i.e., titanium alloy) would maintain the mechanical strength that is required for a joint implant; thus can be retained in the joint and eliminate the need for multiple surgeries.

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