Checking in on Exciting Advancements in Antimicrobial Implants
by Dan Cook on Nov 26, 2024
There’s no doubt that infections related to contaminated orthopedic implants are serious complications that need to be addressed. However, industry stakeholders might not fully grasp the troubling extent of the issue.
Patrick Treacy, Founder and CEO of Onkos Surgical, said that the five-year mortality rate for a periprosthetic joint infection (PJI) is higher than that of skin cancer, testicular cancer, breast cancer, melanoma, Hodgkin’s lymphoma and, in some studies, colon cancer. The economic burden of PJIs is equally alarming. By 2030, Treacy noted, the cost of treating implant-related infections in the U.S. alone is expected to reach nearly $2 billion.
Those troubling statistics add urgency to a significant clinical problem. Preventative efforts are made at the frontlines of surgical care, but surgical site infections are a complex, multifactorial issue that is incredibly challenging to address.
“The complexity stems from a combination of factors, including the patient’s immune system, surgical environment and other variables,” Treacy said. “What is reasonably well understood, however, is that about two-thirds of joint infections originate at the time of surgery.”
That stark reality has sparked interest within orthopedics to develop solutions that prevent harmful bacteria from forming on implant surfaces. It’s a largely untapped area of innovation that has the potential to significantly improve patient care and reduce healthcare costs.
Starting With Spine
In April, Orthobond received a De Novo request for the use of Ostaguard, a proprietary antibacterial implant surface treatment. It was reportedly the first ever granting by FDA of a De Novo submission for a non-eluting coating designed to actively kill bacteria on the surface of permanent medical devices.
“As complications in spine surgery are examined, it’s becoming clear that contaminated screws and implants may play a significant role in adverse outcomes,” said David Nichols, CEO of Orthobond. “Addressing this issue is crucial for improving the outcomes of spinal procedures.”
Ostaguard bonds a 60- to 80-nanometer-thick antibacterial coating to implant surfaces “The coating kills bacteria during the critical window from when sterile packaging is opened in the operating room until implants are inserted into patients,” Nichols said.
Ostaguard features positively charged nitrogen that is covalently bound to the implant’s surface and ruptures bacteria upon contact. The treatment is permanent, an important element for obtaining FDA clearance.
“FDA wanted to know if our antibacterial treatment would have adverse effects on mammalian cells,” Nichols said. “To address this concern, we conducted extensive large animal studies for up to one year and the results showed no toxicity.”
Ostaguard has received FDA De NoVo approval for treating pedicle screws. Orthobond is exploring applications in hips and knees and trauma screws. The company holds a patent for the technology’s adhesion layer, which is covalently bonded to the implant, and a patent related to the antibacterial component that’s attached to that layer. The chemistry of the product is patented, and the entire application process is protected until 2037.
Calcium Phosphates and Biocompatibility
Due to increasing bacterial resistance to antibiotics, infections are becoming progressively harder to treat in clinical settings. “One promising approach is the development of antimicrobial coatings that reduce the risk of infection at the source,” said Giuseppe Cama, Ph.D., Head of R&D at CAM Bioceramics.
Dr. Cama emphasized the important distinction between treating an implant infection and preventing one. Once an infection is established, antibiotics often prove ineffective because bacteria are protected through the formation of biofilms. “Once formed, biofilms are highly resistant and challenging to eradicate,” Dr. Cama said. “Consequently, we focus our work on the development of antimicrobial coatings made from calcium phosphate that can prevent implant infections.”
Calcium phosphate coatings are commonly used with uncemented implants, which is especially beneficial for younger patients who have the bone growth necessary for optimal implant integration, according to Dr. Cama, who added. “The unique advantage of calcium phosphates lies in their bioactivity and osteoconductivity, and ability to promote seamless integration with surrounding bone tissue.”
Dr. Cama noted that calcium phosphates, beyond their biocompatibility, can incorporate various elements within their crystal structure to impart a range of beneficial properties, including antimicrobial characteristics.
Antimicrobial materials, like ion-doped calcium phosphate coatings, could play a vital role in preventing bacterial colonization and settlement on implants when antibiotics prove to be ineffective. While substantial ex vivo and in vitro research supports this approach, several challenges remain for successful clinical implementation.
Robert Kamphof, a Ph.D. candidate in functional biomaterials at Leiden University Medical Center, is working with CAM Bioceramics to create novel calcium phosphate biomaterials. He conducted research to determine which ions can be considered antimicrobial.
“While there is extensive fundamental research on a variety of ions, a critical follow-up question pertains to the level of antimicrobial effectiveness that each can reliably and safely deliver,” Kamphof said.
CAM Bioceramics has achieved promising in vitro results from lab-scale materials. “We’re working to overcome the scaling challenges that emerge when moving from small-scale production to full-scale production,” Kamphof said.
Several other antimicrobial technologies exist, such as antimicrobial peptides and quaternary ammonium salts. “However, many of these alternative solutions are overly complex,” Kamphof said. “Though they may show promising results in controlled lab settings, this complexity often makes real-world application difficult, posing challenges for effective implementation.”
According to Kamphof, CAM Bioceramics’ technology stands out for its elegance and simplicity. “Calcium phosphates already have a well-established track record of biocompatibility and efficacy,” he said. “By offering a straightforward solution, we’re confident our approach can succeed in clinical settings.”
Treating devices that are placed in patients with antimicrobial coatings is another way to address the issue of periprosthetic joint infection.
Reducing Bacterial Load
Onkos Surgical secured De Novo approval for its proprietary antibacterial-coated implants in April. The company worked closely with FDA for over six years to earn the classification and completed 63 individual tests, studies and assays for the submission.
Onkos Surgical’s technology features a 70-nanometers-thick-surface and kills bacteria without affecting the implant’s overall performance or harming surrounding healthy mammalian cells. The technology contains quaternary ammonium molecules that disrupt bacterial cell walls.
FDA initially considered classifying the coating technology as a drug, but Onkos Medical demonstrated why it should be categorized as a device based on its mechanical mechanism of action, especially in the complex field of infection prevention technologies. The mechanism is broad-spectrum, meaning it’s effective against gram-negative and gram-positive bacteria.
“The depth and rigor of our De Novo submission were comparable to a Class III premarket approval or IDE study, though a human clinical trial wasn’t required,” Treacy said. “Since we demonstrated the mechanical mechanism of action and established that it functioned as a device, FDA agreed to classify the technology as a Class II De Novo. The evidence we provided showed both safety and efficacy, allowing us to move forward.”
Antimicrobial surface technology is a relatively new approach to infection prevention, so FDA posed challenging requirements for Onkos Surgical to address. One was to conduct a large animal study to simulate the effects of a fully treated implant in an average-sized human. Onkos Surgical used a sheep model, running cohorts at two weeks, six months and one year for male and female sheep.
FDA and the Onkos Surgical team also focused on ensuring that the technology wouldn’t contribute to antimicrobial resistance. “To address this concern, we developed specific assays to demonstrate that our implant does not promote resistance, and the results were excellent,” Treacy said. “That was a significant milestone in the De Novo process.”
Onkos Surgical’s solution is designed to protect implants during surgery by targeting bacteria present in the operating room that may settle on the devices before they’re placed in patients.
“There isn’t likely to be a single solution to PJIs,” Treacy said. “However, given that approximately two-thirds of joint infections are thought to originate during surgery, our focus is on protecting the implant from bacteria that land on it in that critical moment. It’s one more piece of comprehensive infection prevention efforts.”
Onkos Surgical’s technology involves sophisticated organic chemistry. “The precise control of this chemical reaction is critical because it sets the density of the molecules on the surface, allowing it to stay within safe limits for mammalian cells while effectively targeting bacteria,” Treacy said. “Although complex, the process is highly scalable. Now that we have FDA clearance, our goal is to scale up manufacturing, achieve first-in-human use and expand this technology across our portfolio.”
Treacy said rates of PJIs haven’t improved in 30 years but believes the orthopedic industry is making significant strides to address the ongoing issue.
“Alongside our work, there are exciting developments in therapeutic options for treating existing infections,” he said. “We’re entering an era where advancements in surgical techniques, therapeutics and implant protection will complement each other, offering a more comprehensive strategy for preventing and treating this surgical complication.”