Emerging Technologies for Fighting Orthopedic-Implant Infections

Hundreds of thousands of hip and knee replacement surgeries are performed each year, enabling patients with severe joint ailments to be mobile and active again. However, approximately one in 100 patients develops an infection following orthopedic procedures, resulting in the need for revision surgery. In the following Q&A, Noreen J. Hickok, associate professor in the departments of orthopaedic surgery and biochemistry and molecular biology at Thomas Jefferson University (Philadelphia), discusses a range of technologies for combating implant-induced infections, such as silver-based antimicrobial systems, implant-surface modifications, and hydrogels. These and other themes will be the subject of her presentation at the MD&M East MedTech Innovate Seminar on June 18 titled "Anti-Infective Technologies in Orthopedic Implants: Strategies for Constitutive and Bacterially Triggered Release of Antimicrobials."

MPMN: You specialize in orthopedic-implant-related infections. Could you please share your thoughts on them from a broad perspective?

Hickok: The first thing to say is that orthopedic implant-associated infections are rare, especially in high-throughput surgical practices in which a sterile environment has been optimized. Such infections can arise either through the introduction of bacteria during the surgical procedure, which can result in infection during the first six months after surgery--or through the spread of bacteria from a distant site, such as a bacteremia from a urinary tract infection that then contaminates an implant. In the first case, the more that I learn about bacterial modes of survival in harsh conditions, the more amazed I am that infection rates can be kept as low as they are. At any rate, once bacteria have been introduced to the implant site, the same remedies apply for both scenarios.

Studies have been performed indicating that infections are much more likely to be established in the presence of any implant, whether it is made from metal or devitalized allograft bone. Whereas a minimum of about 10,000 bacteria are required to cause an infection in nonimplant situations, as few as 10 can cause in infection in the presence of an implant. In such situations, bacteria can easily grow as a result of airflow in the surgical theater or because of the hematogenous spread of bacteria from an infection site. When bacteria are in the presence of an implant, they adhere to the surface, which has been made even more attractive to bacteria because it is coated with serum proteins. Even in healthy individuals, this process occurs and is exacerbated by the attenuated immune response in the vicinity of the implant. As a foreign object, the implant is treated differently by the immune system than the occasional ingress of immune triggers in the bloodstream.

Once bacteria adhere to the implant, they become relatively resistant to antibiotics. This translates into a need for use of higher doses of antibiotics for longer periods of time to try to cure the infection at the implant site. However, high systemic levels of antibiotics come with significant side effects, including life-threatening allergies and organ failure. Spinal infections are usually treated using systemic antibiotics because of the relatively good blood flow near the site and the requirement for some sort of implant for spinal stability. These antibiotic treatments tend to be more efficacious than similar treatments in other parts of the body.

In the case of infections affecting joint prostheses, the probability of a cure without removal of the implant is low, so that the usual treatment is removal of the infected component. At least two treatments exist for the joint. The first is a one-stage procedure in which the implant is removed, the site is debrided, and the implant is reinserted along with some sort of antibiotic-releasing system. However, the gold standard is a two-stage procedure in which only the controlled-release system is inserted after debridement and removal of the infected implant. After at least six weeks of antibiotic treatment and release, the controlled release system (usually an antibiotic-laden spacer block) is removed, a new implant is inserted, and the infection watch begins.

Reinfection rates can be as high as 20 to 30%. For patients, such infections mean pain, an extended course of antibiotics at the least, and additional surgeries. Recalcitrant infections can result in the need for joint fusion, amputation when possible, or death. Clearly, if this cycle could be stopped before it starts or reliably interrupted, it would be of great benefit to patients, helping them to preserve mobility, lessen pain and suffering, and lower healthcare costs.

The risk of infection depends on the surgery site--spine or foot and ankle surgeries are associated with greater numbers of infections than hips, for example. The infection rate for spine or foot and ankle surgeries hovers between 1 and 7%, depending on the population, while hip surgeries involve infection rates of much less than 1% in high-throughput orthopedic surgery centers. Thus, the surgery site is point one.

Point two is the health of the individual. Older people and people with compromised immune systems are at greater risk for implant-associated infection than younger people and those with strong immune systems. This phenomenon can probably be viewed from two perspectives. First, the former subset of patients is less able to fight off infection should it establish itself, so that any bacterial insult is more likely to result in an infection than among other population subsets. Second, this group is less able to fight off infection at a distal site, increasing the probability that bacteria will spread hematogenously to the implant site. 

MPMN: What are some examples of the cutting-edge technologies in either the R&D or manufacturing stage for preventing bacterial adhesion and biofilm formation in orthopedic implants?

Hickok: Silver applications seem to be the newest growth areas. Such applications include sol-gel-like ceramics with silver and systems in which silver is sputter-coated onto the implant surface or otherwise embedded in the implant. Silver is definitely the hottest antimicrobial technology at present.

There's always a huge gap between development and use. Of course, some of the most versatile systems are made with hydrogels, but they still have too many problems to be viewed as serious contenders for bone replacements. If you talk about hydrogels for cartilage and disc replacements, however, that is another story. Many researchers in this field are probably aware of the trial data stemming from the laboratory of Jennifer Elisseeff, a professor in the Wilmer Eye Institute and the department of biomedical engineering at Johns Hopkins University who has performed work around an injectable hydrogel for use in cartilage repair.

MPMN: What do you imagine is the future role of hydrogels in orthopedic applications?

Hickok: There are many very powerful hydrogel systems out there, both for fostering new cell proliferation and for combating infection. Many labs are actively studying systems for releasing combinations of antibiotics, antimicrobial peptides, and growth inducers. Drug release can be initiated by a trigger such as ultrasound or merely by their final form. One could envision that given the right combination of a hydrogel and a stronger weight-bearing system, composites could be created that will foster new bone growth in an infection-free environment. The reports that I have seen, however, indicate that hydrogels suffer from the same problems as many other controlled-release systems in that their ability to control infection is limited to the first several days to weeks after surgery. In the case of their prophylactic use during a primary surgery, this elution time would probably be sufficient, but I have grave doubts as to whether this timeframe would be sufficient in a revision surgery.

While it is fair to say that the use of hydrogels for bone applications is still exploratory, their use in the very hydrated cartilage and disc environments is ideal. Several hydrogel products on the market for use in disc-replacement applications have achieved pretty good outcomes. However, the use of hydrogels to repair cartilage is stuck where all other cartilage technologies have been stuck: It is not superior to the ability of cartilage to heal small defects on its own. While a study on an injectable hydrogel that gels in situ and could serve as a vehicle for cell ingrowth is very promising, larger trials are necessary to truly assess its potential.

MPMN: What about other controlled-release and implant-modification systems?

Hickok: We would like to think that the antibiotic-bonded implants that we have developed at Thomas Jefferson University have real potential. A few other labs have designed more-potent variations on this theme, optimizing the original synthesis and showing that in combination therapies, antibiotic-bonded implants may help prevent bacterial resistance to antibiotics. Essentially seeking to prevent bacterial colonization on implants, our antibiotic-bonded-implant technology is based on the understanding that nonadherent bacteria can be efficiently eradicated either by the immune system or systemic antibiotics. In contrast, adherent bacteria are both highly resistant to antibiotics and are essentially inaccessible to the immune system. This implant technology has worked well in rodent and sheep trials in which control limbs show clear signs of infection whereas limbs with the modified implant show signs of healing and lack of infection. It is important to note that this system does not result in the release of antimicrobials, yet it seems to be able to create an environment in which the host can clear the infection.

Our work relies on direct coupling of antibiotics to the metal surface. For nonorthopedic applications, other researchers have used polymer surfaces in which a linker-like molecule is immobilized and--similar to an enzyme-linked immunosorbent assay--is used to capture the therapeutic molecule of choice to display it on the surface. While losing some control over the process, this design offers great flexibility.

Another area of great interest is drug release from nanostructured implant surfaces. Whether these surfaces can be used in the harsh mechanical bone environment remains to be seen, but they do offer a means for packing drugs in the device and allow for the use of various technologies to release them.

Many controlled-release systems are predicated on the use of biodegradable or nonbiodegradable polymers. Sometimes, these systems can be annealed to the implant itself or used as a sleeve to enable drug release. The major problems with such systems are the amounts of drugs that they release initially and the duration of the release. Nonbiodegradable spacer blocks used to treat orthopedic infections elute antibiotics for six weeks. Biodegradable coatings, on the other hand, generally exhibit a very fast elution rate within the first week, with a waning elution rate thereafter. However, this waning elution rate always raises the specter of bacterial resistance.

In short, while silver technology is available for use, as are various techniques for patterning implant surfaces that are thought to discourage bacterial adhesion, the other technologies that I have discussed are great ideas, but most of them are still either in the development stage at the bench or at the animal-testing stage.