Purpose: Total Joint Replacement (TJR) is predicted to become the number one elective surgery in the USA by 2030, with about 5 million people opting for TJR each year to relieve pain. Although the infection rate after TJR (1-4%) is low, infection remains a major causative factor prompting up to 25% of revision TJR surgeries. Moreover, the infection rate can be as high as 20-30% after revision surgery. Treating these infections is particularly challenging due to the complex nature of TJR and the local bone environment that fosters unfettered bacterial growth. Currently, standard treatment options include high dose systemic antibiotic, non-biodegradable antibiotic-releasing bone cements and pellets, and surgical debridement etc. Unfortunately, these treatments do not provide adequate local antibiotic concentration, and the fluctuating drug release kinetics play a role in the emergence of antibiotic resistance due to persistent bacterial presence at the surgical site. Furthermore, many polymer-based scaffolds, including the gold standard bone cement, do not support osseointegration due to their prolonged presence at the surgical site and limited bone ingrowth, exacerbating and inadvertently promoting chronic osteomyelitis. An easy to use, moldable and biodegradable Antibiotic-Eluting Bone Void Filling (ABVF) putty, which releases antibiotic above the minimal inhibitory concentration up to six weeks, generally considered the most infection prone period after TJR, and supports osseointegration and bone growth, can be a better treatment option. Moreover, doctors prefer to use putty like material as bone void fillers due to their ease of use and press fitting ability into bony defects. Here, we report a biodegradable vancomycin-releasing ABVF putty that shows putty like moldable characteristics and achieves therapeutic drug release over six weeks.
Methods: ABVF putty was formulated using polymers (PLGA, PEG, PCL), a tri-calcium phosphate and hyaluronic acid substrate (Pro-osteon), and vancomycin. To get the desired size and shape, the composition was homogeneously mixed and cast in to a 3D printed mold. ABVF putty was characterized by micro computed tomography (µ-CT) for homogeneity. Scanning electron microscopy (SEM) was used for outer and inner surface structure determination. In vitro polymer degradation study was done by submerging the putty in phosphate buffered saline (PBS) for 1 week and 4 weeks, followed by SEM evaluation of the inner and outer surface of the ABVF putty for signs of degradation. Putty like material characteristics was determined by rheometry. The moldability of the putty material was assessed by casting the material into a variety of 3D printed shapes. To determine the vancomycin pharmacokinetics of release, ABVF putty was released in 2 mL of PBS. At specific time points the samples were collected; the release study was carried out for six weeks. A Zone of Inhibition (ZOI) study was done using Staphylococcus aureus (107 CFU/mL) to assess in vitro antibacterial efficacy of the released milieu.
Results: Initially, µ-CT images showed homogenous distribution of substrate (pro-osteon) in the polymer matrix, while SEM images showed rough outer surface and macro and microporous inner surface, both traits conducive to osseointegration. Additionally, SEM images showed degradation of the putty over 1 to 4 weeks incubation in PBS. Rheology data confirmed the putty like material characteristics of the ABVF. Furthermore, ABVF could be molded into different shapes by press fitting. In vitro drug release, determined that vancomycin was not only released up to six weeks within the therapeutic range but it was also bioactive, killing S. aureus for up to six weeks (13.14±1.88 mm).
Conclusion: ABVF putty showed desired putty like material property, biodegradability and a structure conducive to osseointegration. In vitro drug release and antibacterial activity indicated that the ABVF putty can be a promising alternative and effective treatment after revision TJR surgery to treat osteomyelitis.
Abbey Wohlers– PharmD Candidate, College of Pharmacy, North Dakota State University
Bradley Hoffmann– Graduate Research Assistant, North Dakota State University
Amanda Brooks– Assistant Professor, Department of Pharmaceutical Sciences, North Dakota State University