Philadelphia University + Thomas Jefferson University


Looking for Gunk in All the Dead Spaces

John Eisenbrey, PhD and Flemming Forsberg, PhD
(L) John Eisenbrey, PhD and (R) Flemming Forsberg, PhD

Jefferson Radiology ultrasound PhD researchers, Flemming Forsberg and John Eisenbrey, in collaboration with Rothman surgeon, Chris Kepler, MD, and Noreen Hickok, PhD, an expert on orthopedic infection, give new meaning to “translational research."

“John and I get to work with patients,” says Flemming Forsberg, PhD, “which is unique for someone with an engineering background.” Engineering previously unthought-of ways of using ultrasound can make all the difference for patients in the clinic.

Forsberg and Eisenbrey are part of a multidisciplinary effort to rethink what the modality can do, moving from imaging to intervention. The team is pioneering the use of ultrasound as a therapeutic tool. They are fine-tuning ways to release antibiotics in bulk, using ultrasound waves. The ultrasound treatment would be combined with antibiotic release as a post-operative prophylaxis that would break up early-stage bacterial colonies in order to make them more susceptible to treatment.

Unhappy Medium

Spine surgeries are more susceptible to infection than most other orthopedic procedures—they are long, so the patient is left exposed for an extended period and are difficult to treat once an infection sets in. “In joint replacement,” says Chris Kepler, MD, the project’s clinical collaborator, “we can take out the implant, treat the infection with IV and local antibiotics, and then put in a temporary antibiotic-eluding spacer.” “While infection in the extremities has multiple options including amputation, but there aren’t any alternative like that for spine,” says Noreen Hickok, PhD.

The issue of infection stems from the fact that implants—coated in blood serum proteins to disguise them from a possible immune response—are super-surfaces for bacterial growth. The proteins that tell the body the implant is “supposed” to be there also attract bacteria, which see it as a delicious blood clot. Typically, the attraction to blood clots concentrates bacteria before immune cells destroy the invaders. But around a metal implant, the immune response is attenuated, allowing bacterial growth.

Visible with the naked eye, these colonies can spell disaster for the joint environment, often making bacteria as much as a thousand times less responsive to antibiotics. In biofilm, microorganisms slow down their metabolism and block the antibiotic from penetrating the colony, which means things like “minimum inhibitory concentration”—the smallest amount of antibiotic needed to fight an infection—go out the window. So resilient are these biofilms, says Hickok, treatment via “systemic antibiotics are likely to result in side effects like renal toxicity before they reach levels that can kill the bacteria.”

Prevention becomes the name of the game, with spine surgeons commonly preempting infection by sprinkling in a few grams of vancomycin before closing up an incision. Vancomycin targets bacteria like staph—so-called Gram-positive organisms, recognizable by their cell walls. But, that leaves Gram-negative bacteria largely untouched, since they lack the cell walls vancomycin binds to.

In the current clinical algorithm, the left-behind antibiotics drain over two or three days while the patient recovers in the hospital. The suction drains are removed and the patient is sent home. The protocol helps offset the risk of perioperative infection, but does little to combat an infection that has already set in. According to Kepler, this leaves physicians with the “potentially devastating clinical situation where we have to retain metal in an infected wound.”

Sound Ideas

Noreen Hickok, PhD and Chris Kepler, MD
(L) Noreen Hickok, PhD and (R) Chris Kepler, MD

“One day John, Flemming and I were sitting in my office talking about how we have the technology to do a bulk release of antibiotics, but no application,” recalls Hickok, “then Chris walked in and told us he had our application.” Hickok had worked with chemical applications of ultrasound in the past, while Eisenbrey is highly facile with implant materials after working with them as part of his dissertation research.

Their solution is surprisingly straightforward—create an implant that can clip-on to spinal stabilization rods. To increase efficiency, make the hollowed-out, hole-filled device out of Polyether ether ketone (PEEK)—a durable polymer that is widely used for spinal hardware. Fill it with antibiotics that target both Gram-positive and Gram-negative organisms, and then sealing it all in a biodegradable coating already used for surgical screws.

Here’s how it would work. After the standard observation period, the patient would take a trip to the ultrasound suite for a ten minute procedure. There, a doctor could use noninvasive, high-intensity ultrasound to trigger the PEEK clip by exciting gas pockets in the biodegradable cover, bursting the shell and spilling antibiotics onto the implant and into the wound.

A controlled release often means antibiotic concentrations are only high enough to temporarily sterilize the area without killing off more resistant bacteria, says Hickok, “So the idea is get it all out at once in order to avoid fostering that antibiotic resistance.” With an ultrasound-triggered device, physicians could deliver an additional prophylaxis with high concentrations of antibiotics where they are needed.

“There’s nothing about this idea that is much of a departure philosophically from what we’re doing right now,” remarks Kepler, “It’d be a way to deliver the same thing we’re already doing, just more effectively.”

In a related application, the team is looking into ways of moving past prophylaxis to attack early stage bacterial colonies using microbubbles. Something of a Jefferson Radiology specialty, the bubbles—the size of red blood cells—are injected into a patient’s vasculature before an ultrasound exam. “While normal tissue is interconnected and relatively rigid,” says Eisenbrey, “microbubbles, composed of only a shell and gas, are flexible enough to make irregular motions and double-beats, which stand out under ultrasound and make them an effective form of contrast.”

Usually physicians work assiduously to avoid bubbles in the bloodstream because, as Forsberg puts it, “you don’t want a bunch of bubbles to go ‘Kumbaya’ and clump together,” spelling disaster in the form of an embolism. But researchers have devised a way to coat the bubbles with an electrically charged shell, which makes them repel each other. For now, they are only FDA-approved for the heart and, recently, the liver, but that hasn’t stopped Jefferson ultrasound researchers from developing their off-label expertise even further.

With trials underway in infected cadaver knees and simulated joint environments—variations of immunity “privileged spaces”—the research program is showing results right out of the gate. The idea is to make biofilm susceptible to antibiotics by breaking it up with microbubbles, thereby returning the bacteria to their more active, non-biofilm state. This is done by injecting commercially-available microbubbles into the synovial fluid of the joint and then bursting them with another high-intensity ultrasound beam.

The force from popping microbubbles is relatively small, but it’s enough to scour the surface of the biofilm and dislodge much of the colonizing bacteria. The sound waves also increase the permeability of the remaining biofilm and further increase penetration. In trials the techniques to activate bacterial metabolism, increasing the efficacy of antibiotics by several orders of magnitude, and bringing a previously intractable problem into the realm of the treatable.

Human trials are still years away, but still very much in sight, as grant funding comes through and early tests yield promising proofs of concept. Stay tuned, as Jefferson’s ultrasound experts find new ways of improving lives at the speed of sound.

fileImages of the microbubbles before and after the are burst under ultrasound.