A Bioglass-Based Antibiotic (Vancomycin) Releasing Bone Void Filling Putty to Treat Osteomyelitis and Aid Bone Healing.

While the infection rate after primary total joint replacements (TJR) sits at 1-2%, for trauma-related surgery, it can be as high as 3.6 to 21.2% based on the type of trauma; the risk of reinfection after revision surgery is even higher. Current treatments with antibiotic-releasing PMMA-based bone cement/ beads and/or systemic antibiotic after surgical debridement do not provide effective treatment due to fluctuating antibiotic levels at the site of infection, leading to insufficient local antibiotic concentration. In addition, non-biodegradable PMMA does not support bone regrowth in the debrided void spaces and often must be removed in an additional surgery. Here, we report a bioactive glass or bioglass (BG) substrate-based biodegradable, easy to fabricate "press fitting" antibiotic-releasing bone void filling (ABVF-BG) putty to provide effective local antibiotic release at the site of infection along with support for bone regeneration. The ABVF-BG putty formulation had homogenously distributed BG particles, a porous structure, and showed putty-like ease of handling. Furthermore, the ABVF-BG putty demonstrated in vitro antibacterial activity for up to 6 weeks. Finally, the ABVF-BG putty was biodegradable in vivo and showed 100% bacterial eradication (as shown by bacterial cell counts) in the treatment group, which received ABVF-BG putty, compared to the infection control group, where all the rats had a high bacterial load (4.63 × 106 ± 7.9 × 105 CFU/gram bone) and sustained osteomyelitis. The ABVF-BG putty also supported bone growth in the void space as indicated by a combination of histology, µCT, and X-ray imaging. The potential for simultaneous infection treatment and bone healing using the developed BG-based ABVF-BG putty is promising as an alternative treatment option for osteomyelitis.

The next frontier of oncotherapy: accomplishing clinical translation of oncolytic bacteria through genetic engineering.

The development of a 'smart' drug capable of distinguishing tumor from host cells has been sought for centuries, but the microenvironment of solid tumors continues to confound therapeutics. Solid tumors present several challenges for current oncotherapeutics, including aberrant vascularization, hypoxia, necrosis, abnormally high pH and local immune suppression. While traditional chemotherapeutics are limited by such an environment, oncolytic microbes are drawn to it - having an innate ability to selectively infect, colonize and eradicate solid tumors. Development of an oncolytic species would represent a shift in the cancer therapeutic paradigm, with ramifications reaching from the medical into the socio-economic. Modern genetic engineering techniques could be implemented to customize 'Frankenstein' bacteria with advantageous characteristics from several species.

Lay abstract Side effects of chemotherapeutics are thought to often be a reflection of our inability to target these toxic substances to only cancer cells; hence, scientists have spent centuries searching for alternative treatments that would confine their actions to tumor cells, sparing healthy tissue. Unfortunately, the dense nature of tumor tissue along with altered blood vessels, that lead to diminished tumor tissue oxygenation, altered tissue pH and cellular metabolic inactivity or even cell death have proven challenging. Importantly, these barriers have contributed to local and even sometimes systemic suppression of the patient's immune system that can allow the tumor to grow and progress unchecked. While most non-cancer cells are inhibited by the local tumor environment, certain microbes, including some bacteria and viruses, are drawn to it, possessing a natural ability to selectively infect, colonize and eradicate solid tumors. These microbes may also restore the patient's immune balance. However, use of these microbes is not without its own problems; nevertheless, modern genetic engineering techniques could be implemented to develop customized, safe, effective bacteria with advantageous characteristics. The development and clinical translation of cancer-fighting bacteria would represent a shift in cancer therapeutics and would have ramifications that reach beyond medical efficacy into the realm of socioeconomics. This review seeks to marry the current field of oncolytic bacteria with the expanding field of modern bacterial genetic engineering techniques in prospect of such a therapeutic.

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

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.