Extended Release Combination Antibiotic Therapy from a Bone Void Filling Putty for Treatment of Osteomyelitis

Abstract

In spite of advances in Total Joint Replacements (TJR), infection remains a major concern and a primary causative factor for revision surgery. Current clinical standards treat these osteomyelitis infections with antibiotic-laden poly(methyl methacrylate) (PMMA)-based cement, which has several disadvantages, including inadequate local drug release kinetics, antibiotic leaching for a prolonged period and additional surgical interventions to remove it, etc. Moreover, not all antibiotics (e.g., rifampicin, a potent antibiofilm antibiotic) are compatible with PMMA. For this reason, treatment of TJR-associated infections and related complications remains a significant concern. The objective of this study was to develop a polymer-controlled dual antibiotic-releasing bone void filler (ABVF) with an underlying osseointegrating substrate to treat TJR implant-associated biofilm infections. An ABVF putty was designed to provide sustained vancomycin and rifampicin antibiotic release for 6 weeks while concurrently providing an osseointegrating support for regrowth of lost bone. The reported ABVF showed efficient antibacterial and antibiofilm activity both in vitro and in a rat infection model where the ABVF both showed complete bacterial elimination and supported bone growth. Furthermore, in an in vivo k-wire-based biofilm infection model, the ABVF putty was also able to eliminate the biofilm infection while supporting osseointegration. The retrieved k-wire implants were also free from biofilm and bacterial burden. The ABVF putty delivering combination antibiotics demonstrated that it can be a viable treatment option for implant-related osteomyelitis and may lead to retention of the hardware while enabling single-stage surgery.

Recent Advances in the Evaluation of Antimicrobial Materials for Resolution of Orthopedic Implant-Associated Infections In Vivo

“…, silicone nanotopography that can repel bacteria, , chitosan, hyaluronic acid, ,, etc. ), it is often necessary to incorporate antibiotics into polymeric materials to impart antimicrobial activity. ,,,− The rate of enzymatic/hydrolytic degradation of biodegradable polymers such as chitosan, ,, hyaluronic acid, , alginate, , poly­(lactic acid) derivatives ( e.g. , poly­[ l -lactic] acid, poly­[ d , l -lactide- co -lactide], poly­[ d - l -lactide]), − ,− polycaprolactone, ,, and poly­(lactic- co -glycolic acid) (PLGA) ,,,,, dictates the rate of antibiotic release from the implanted material and subsequent duration of antimicrobial activity.…”

“…), it is often necessary to incorporate antibiotics into polymeric materials to impart antimicrobial activity. ,,,− The rate of enzymatic/hydrolytic degradation of biodegradable polymers such as chitosan, ,, hyaluronic acid, , alginate, , poly­(lactic acid) derivatives ( e.g. , poly­[ l -lactic] acid, poly­[ d , l -lactide- co -lactide], poly­[ d - l -lactide]), − ,− polycaprolactone, ,, and poly­(lactic- co -glycolic acid) (PLGA) ,,,,, dictates the rate of antibiotic release from the implanted material and subsequent duration of antimicrobial activity. An advantage of biodegradable polymeric materials is that their rate of degradation can be tailored through several means including their molecular weight and degree of crystallinity .…”

“…Nondegradable polymeric materials such as poly­(ether ether ketone), ,− poly­(ethylene glycol) (PEG), − ,,, poly­(ethyleneimine), , cyclodextrin, ,− poly­(methyl methacrylate) (PMMA), ,,,,,− polyethylene terephthalate, , silicone, , and polyesters , have the potential to serve as long-term antimicrobial materials. Since the release of antibiotics from nondegradable materials is not associated with the rate of degradation of the material, these materials primarily rely on diffusion and affinity-based interactions to dictate the release kinetics of antibiotics.…”

“…In vivo models have been established to enable evaluation of the ability of antimicrobial biomaterials to prevent orthopedic implant-associated infections in a variety of species including mice, ,− ,− ,− rats, − ,− ,,,,− rabbits, ,,− ,,,,− sheep, ,,− and goats , (Table ). In these models, a metallic component is placed in either the tibia or femur and the prophylactic antimicrobial material is placed at the time of bacterial inoculation to enable evaluation of the ability of the material to prevent the development of implant-associated infection.…”

Additive Manufacturing Techniques for Fabrication of Bone Scaffolds for Tissue Engineering Applications

“…In addition to the cellular components of tissue engineering, the formation of an artificial tissue requires the presence of a scaffold, which behaves as a template for tissue growth in both the cellular and acellular approaches to tissue engineering. In addition to fulfilling its primary role as a cell carrier and new tissue foundation, scaffolds can also be equipped as pharmaceutical or bio molecule delivery vehicles (e.g., antibacterial [40][41][42][43] or growth factors [44]). As schematically shown in Figure 2, tissue engineering is a multidisciplinary research field founded on three major components: the scaffold, the cells, and growth factors.…”