This project is regarding the FY2021 PROP ARA Focus Area of “Osseointegration.” There have been 2,216 deployment-related, major limb amputations sustained by 1,705 U.S. Service Members during 2001-2017, including 453 Service Members with multiple major limb amputations. Mainstream socket prosthetic limbs have limitations, including discomfort, skin breakdown, and infections, that result in an impaired quality of life for the amputee. A new type of prosthetic limb involving a titanium (Ti) implant directly anchored to the bone (osseointegrated) offers promising advantages and improvement over the currently used socket prosthetic limbs. These advantages include direct load transfer to the skeleton, better control of prosthetic movement, and, potentially, the return of some sensory function known as osseoperception. However, the widespread utilization of this prosthesis has been limited due to concerns of infection originating at the site where the Ti implant protrudes through the skin. Additionally, poor quality osseointegration of the implant can raise concerns about mechanical instability of the implant. Therefore, it is important to address issues related to enhancement of bone ingrowth while also minimizing infections of the implant.

Previous work supported by funding through the CDMRP has allowed our research team to develop a new technology involving the application of electrical stimulation directly to orthopaedic implants to kill bacteria and prevent infection. Our approach utilizes the implant itself as an electrode through which cathodic voltage-controlled electrical stimulation (CVCES) is delivered to disrupt and kill the infecting bacteria. We have generated proof-of-principle data that CVCES of a Ti implant is an effective stand-alone antimicrobial therapy against a variety of problematic bacteria and, furthermore, it enhances the effectiveness of traditional antibiotic therapy. We also have pilot data showing that CVCES can promote new bone formation and enhanced osseointegration of Ti implants.

We have patented this electrical stimulation technology and are working with Garwood Medical DevicesTM (GMD) to commercialize this technology. GMD has already developed a first-generation device called BioPraxTM that is intended to deliver CVCES therapy for clinical use in humans. The BioPraxTM system has received Breakthrough Device Designation from the U.S. Food and Drug Administration (FDA) in 2019. GMD is working with the FDA to determine the requirements for allowing clinical use of BioPraxTM in treating infections associated with knee implants. Clinical trials are being planned to begin soon and GMD anticipates filing for De Novo classification/approval in 2024 or 2025. In parallel, GMD is working with this proposal’s research team to develop a BioPraxTM system that could be adapted for use with osseointegrated prosthetic limbs (BioPraxTM OI). The outcomes of the proposed project will help guide the development of the BioPraxTM OI system.

The main goal of this project is to assess how effective our electrical stimulation technology is at eradication of implant infections and also enhancement of osseointegration in the presence and absence of infection. The project would utilize a rodent model of Ti implant osseointegration to address three main research aims. Aim 1 focuses on the use of CVCES to eradicate infections of a problematic bacteria (MRSA) from an osseointegrated Ti implant. This will be assessed through three outcomes: bacterial burden, histology, and mechanical testing. The enumeration of bacterial burden will allow for analysis of bacterial presence both on the bone and implant following CVCES treatment. The histology will assess the quantity and quality of bone formed at the implant-bone interface following CVCES treatment. The mechanical tests will determine how strongly the fixation is between the implant and surrounding bone following CVCES treatment. Aims 2 and 3 focus on the enhancement of osseointegration of the implant in the absence of infection either in late-stage (Aim 2) or early-stage (Aim 3) osseointegration. These two aims will focus primarily on osseointegration viability using histological and mechanical analysis. Our overarching hypothesis is that the application of CVCES to Ti implants will eliminate bacterial infections and increase quality and quantity of bone adjacent to and integrated with the implant.

We believe that, when infection risk is mitigated and osseointegration is promoted by CVCES, osseointegrated prosthetic limbs can lead to functional independence and improved quality of life for injured Service Members with limb loss. The use of CVCES may also allow for expanding the inclusion criteria used to identify patients that are suitable for osseointegrated prosthetics. Infection and implant loosening due to poor osseointegration are problematic in many other areas of orthopaedics, including joint replacement, fracture fixation, and dental implants. In the long term, we believe that optimized CVCES delivered by the BioPraxTM can provide solutions to all of these clinical areas because CVCES is (1) broadly applicable to all implant metals (Ti, stainless steel, and cobalt-chromium alloys) used in orthopaedics, (2) has potent stand-alone antimicrobial properties, (3) synergistically enhances existing antibiotics, and (4) promotes new bone formation and enhanced osseointegration. Our commercialization partner, Garwood Medical DevicesTM, has a proven commercialization record, a robust business model, and a strategic product development/regulatory plan that will incorporate results of the proposed work to ensure a successful venture.