Ultrasound-Controlled Drug Delivery for Application in Spinal Surgical Infections
Abstract
Implant-associated biofilm formation and subsequent surgical site infection is a feared complication in orthopaedic surgery. For knee and hip replacements alone, more than 45,000 people are affected every year and 5-year survival rates are ~70%, making these infections the second most common cause of death among Americans 65 and older. Infections after spinal surgeries are even more devastating, given the risk of replacing an infected implant at a very delicate site. In order to prevent this complication, systemic antibiotics are administered. However, biofilm studies reveal sessile bacteria to be up to 1000x less sensitive to antibiotics than their planktonic counterparts. Local antibiotic prophylaxis would achieve higher concentrations with attenuated systemic effects; most surgeons also place vancomycin (VAN) powder at the spinal site during implantation. However, the efficacy of VAN placement is uncertain and there is a need for a robust local prophylactic approach. Within this thesis, two lines of investigation are explored, in vitro bacterial adhesion and antibiotic susceptibility studies and ultrasound (US)-controlled drug delivery systems. The use of physiological fluids, synovial fluid and serum, formed a crucial part of our investigations. We showed that local antibiotic levels obtained in an animal model fell short of concentrations required to eradicate biofilms formed in synovial fluid or serum. In further in vitro analyses, we added more variations on physiological fluids as surrogate of wound fluid to elucidate adhesion and antibiotic susceptibility trends over ranges of media, antibiotic concentration, and duration of treatment. We discovered that biofilm formation may be attenuated in the wound fluid compared to standard culture medium, while antibiotic susceptibility revealed heterogeneous findings. For the drug delivery design, the goal was to achieve US-controlled delayed delivery. Studies suggest pulse-dosing antibiotics may resuscitate persister phenotype in biofilm bacteria, rendering them more vulnerable, which makes delayed drug delivery after initial VAN prophylaxis an intriguing idea. First iteration of the design used alginate hydrogels, which demonstrated initial burst release followed by diffusion. Next, polylactic acid (PLA) films were used to create a pocket containing drugs and microbubbles. These pockets were engineered with regards to their shape, film properties, types of microbubbles and modes of US. Pockets with VAN-embedded PLA films achieved the most favorable profile in terms of stability and US-controlled release. All together, the work in this thesis shows that the requirements of successful prophylaxis cannot be met using clinically-tolerated levels of systemic antibiotics alone. The PLA film pocket that we have engineered can achieve controlled local drug delivery with US. In vivo experiments will further explore the viability and applicability of the film pocket to achieve delayed, effective local drug delivery.
Subject Area
Biomedical engineering|Medicine|Medical imaging|Surgery
Recommended Citation
Isguven, Selin, "Ultrasound-Controlled Drug Delivery for Application in Spinal Surgical Infections" (2023). ProQuest ETD Collection - Thomas Jefferson University. AAI30688936.
https://jdc.jefferson.edu/dissertations/AAI30688936
