Nanoparticles are becoming an increasingly popular tool for biomedical imaging and drug delivery. While the prevalence of nanoparticle drug-delivery systems reported in the literature increases yearly, relatively little translation from the bench to the bedside has occurred. It is crucial for the scientific community to recognize this shortcoming and re-evaluate standard practices in the field, to increase clinical translatability. Currently, nanoparticle drug-delivery systems are designed to increase circulation, target disease states, enhance retention in diseased tissues, and provide targeted payload release. To manage these demands, the surface of the particle is often modified with a variety of chemical and biological moieties, including PEG, tumor targeting peptides, and environmentally responsive linkers. Regardless of the surface modifications, the nano–bio interface, which is mediated by opsonization and the protein corona, often remains problematic. While fabrication and assessment techniques for nanoparticles have seen continued advances, a thorough evaluation of the particle’s interaction with the immune system has lagged behind, seemingly taking a backseat to particle characterization. This review explores current limitations in the evaluation of surface-modified nanoparticle biocompatibility and in vivo model selection, suggesting a promising standardized pathway to clinical translation.

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.

Frequent and inappropriate usage of antibiotics has changed the natural evolution of bacteria by reducing susceptibility and increasing resistance towards antibacterial agents. New resistance mechanisms evolved in the response to host defenses and pharmaceutical interventions are threatening our ability to treat common infections, resulting in increased mortality. In the face of this rising epidemic, antibiotic drug discovery, which has long been overlooked by big pharma, is reaching a critical low. Thus, the development of an infection-responsive drug delivery system, which may mitigate multidrug resistance and preserve the lifetime of our current antibiotic arsenal, has garnered the attention of both popular science and funding agencies. The present work describes the development of a thrombin-sensitive linker embedded into a recombinant spider silk copolymer to create a nanosphere drug delivery vehicle. Recent studies have suggested that there is an increase in thrombin-like activity during Staphylococcus aureus infection; thus, drug release from this new “smart” nanosphere can be triggered in the presence of infection. A thrombin sensitive peptide (TSP) was synthesized, and the thrombin cleavage sensitivity was determined by HPLC. The results showed no cleavage of the peptide when exposed to human serum whereas the peptide was cleaved when incubated with S. aureus exudate. Subsequently, the peptide was coupled with a silk copolymer via EDC-NHS chemistry and formulated into nanospheres encapsulating antibiotic vancomycin. These nanospheres were evaluated for in vitro infection-responsive drug release and antimicrobial activity. Finally, the drug responsive nanospheres were assessed for efficacy in an in vivo septic arthritis model. Our study provides evidence that the protein conjugate was enzyme responsive and can be used to formulate targeted drug release to combat infections against multidrug-resistant bacterial strains.

The number of total joint replacements (TJR) is on the rise with a corresponding increase in the number of infected TJR, which necessitates revision surgeries. Current treatments with either non-biodegradable, antibiotic-releasing polymethylmethacrylate (PMMA) based bone cement, or systemic antibiotic after surgical debridement do not provide effective treatment due to fluctuating antibiotic levels at the site of infection. Here, we report a biodegradable, easy-to-use “press-fitting” antibiotic-releasing bone void filling (ABVF) putty that not only provides efficient antibiotic release kinetics at the site of infection but also allows efficient osseointegration. The ABVF formulation was prepared using poly (D,L-lactide-co-glycolide) (PLGA), polyethylene glycol (PEG), and polycaprolactone (PCL) as the polymer matrix, antibiotic vancomycin, and osseointegrating synthetic bone PRO OSTEON for bone-growth support. ABVF was homogenous, had a porous structure, was moldable, and showed putty-like mechanical properties. The ABVF putty released vancomycin for 6 weeks at therapeutic level. Furthermore, the released vancomycin showed in vitro antibacterial activity against Staphylococcus aureus for 6 weeks. Vancomycin was not toxic to osteoblasts. Finally, ABVF was biodegradable in vivo and showed an effective infection control with the treatment group showing significantly higher bone growth (p < 0.001) compared to the control group. The potential of infection treatment and osseointegration makes the ABVF putty a promising treatment option for osteomyelitis after TJR.

Exosomes, naturally secreted extracellular bilayer vesicles (diameter 40–130 nm), have been rendered echogenic (responsive to ultrasound) allowing their potential use as a dual agent for drug delivery and ultrasound imaging.