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Larva therapy makes a comeback

David Armstrong faced a predicament. He had a patient with an open wound that he needed to clean to remove dead tissue that could prevent proper healing, or worse. Infection could lead to severe pain and require limb amputation. But he didn’t have access to an operating room. Left with few other choices, he turned to an unexpected surgical assistant: maggots.

David Armstrong is a podiatric surgeon at the University of Southern California, who uses maggots to treat persistent wounds.
CREDIT: DAVID ARMSTRONG

While this scene might seem like one that unfolded on the front lines of the US Civil War or in a remote field hospital, Armstrong is actually a present-day surgeon at the University of Southern California. He is one of many clinicians turning to medical maggots as a tool for treating challenging wounds. The critters he uses, an early larval stage of a fly called Lucilia sericata, have an insatiable appetite for dead tissue and can claw their way through a wound, cleaning it with precision that even the most dexterous surgeon might envy.

The therapeutic use of maggots can be traced back for centuries, but it fell out of fashion with the rise of antibiotics in the 1940s, which tamped down many common infections that used to threaten wounds. Now, maggot-based treatments are undergoing a sort of “renaissance” in the face of new kinds of wounds like diabetic ulcers, said Andreas Vilcinskas, an insect biotechnology researcher at Justus Liebig University. These difficult-to-treat wounds have spurred some scientists into investigating what we might learn from these creepy crawly critters.

“Sometimes the most modern, evidence-based, cutting-edge approach is something that is ancient,” Armstrong said.

An ancient discovery, rediscovered

Armstrong first encountered maggots well before he ever considered them as a therapeutic option. Patients who were unhoused or otherwise unable to keep wounds clean often came into the emergency room teeming with larvae.

Records show that Mayans and other populations around the world began using maggots medicinally centuries ago (1). Mayan healers wrapped wounds with dressings soaked in cow blood and left out to attract flies. Hundreds of years later, military doctors during the Civil War noticed that soldiers whose uncleaned wounds attracted maggots recovered better than those without an infestation and began to either leave maggots in wounds or intentionally add them.

Maggots used therapeutically are the larvae of Lucilia sericata, or the common blowfly. They are only a few millimeters long.
CREDIT: RON SHERMAN, BTER FOUNDATION

In the 1920s, William Baer, a former World War I surgeon, did the first clinical studies of maggot therapy (2). During his time at war, he noticed that soldiers who had been left on the battlefield with large wounds colonized by maggots didn’t become infected. When he returned to his lab at Johns Hopkins University, he thought that he could recreate battlefield conditions to treat young patients with bone infections. At the time, he grew maggots from flies that he caught around Baltimore, which limited his trials to the warmer months when the flies were more plentiful.

He soon realized that he risked giving patients additional infections, so he began growing sterile maggots to use in therapy instead. The maggots broke down dead or unhealthy tissue in a process called “debridement,” which happens naturally when the body breaks down foreign substances. This process can be expedited through surgical or chemical intervention. Baer’s repeated success motivated a brief heyday for maggot therapy among surgeons in the 1930s — until antibiotics reduced the risk of infectious wound complications.

At the time, physicians thought that the larva’s greatest assets were its voracious appetite and discerning palate. The larvae ate unhealthy tissue, while sparing adjacent healthy portions, and appeared to destroy bacteria during digestion. Now, research indicates that maggots may be more multitalented. Their secretions are a Swiss army knife of sorts; they contain enzymes to digest tissue before slurping it up and molecules that kill microbesspur cell growth, and trigger immune responses to promote faster healing (3-5).

Vilcinskas has been inspired by these insects’ diverse skills, which he believes we can use for human benefit. “Learning from insects means learning how to win,” he said.

Vilcinskas thinks that Lucilia sericata might provide a source of insect-derived microbe-fighting compounds. He measured all the genes expressed in the bugs’ salivary glands and found more than 40 potential antimicrobials; some were even effective in the lab against multidrug-resistant gram-negative bacteria, which have been elusive targets for conventional antibiotics (6). His team is working on showing that these molecules also kill bacteria in patients and finding ways to embed the molecules in wound dressings.

Maggots for the masses

Ron Sherman, a physician and director of the BioTherapeutics, Education and Research Foundation (BTER), was interested in bugs long before he began to think about them as medical tools. He studied entomology in college before proceeding to medical school at the University of California, Los Angeles. In the 1980s, he attended a lecture where his insect-adorned tie caught the attention of Edward Pechter, chief resident in plastic and reconstructive surgery at the time. As they wrote a review of maggot therapy together, Sherman’s interest was piqued. He even started collecting maggots that he found in patients.

Antibiotics have made infection-related wound complications rare, but Sherman thinks that maggot therapy is most applicable in another arena: chronic, non-healing wounds. These injuries tend to occur in patients with nutritional deficiencies, immunodeficiency, or autoimmunity, who aren’t able to rebuild damaged tissue and fight off infection.

The larvae are often contained in a dressing that is applied to the wound or in a tea-bag-like “biobag.”
CREDIT: WIKIMEDIA COMMONS

Armstrong also sees a great need for new wound treatment solutions for diabetes in particular, which is a major cause of the chronic foot wounds that he encounters as a podiatric surgeon. Diabetes can cause a combination of nerve damage in the feet and poor circulation, which slows delivery of key building blocks for reconstructing the tissue at the wound site. With growing rates of diabetes and improved strategies for long-term diabetes management, more people live longer with diabetes and develop ulcers that lead to a high risk for infection and eventual amputation.

Sherman started designing a modern-day approach to maggot therapy by looking to his historic predecessors. Carefully combing through papers from the 1930s, he learned how doctors disinfected the larvae and built dressings to contain them.

“I learned as much as I could from them, but ultimately needed to modify their designs, efforts, and methods to meet the environment and situation of modern age,” Sherman said.

The kinds of techniques described in the early papers weren’t always feasible or safe, so Sherman used them as inspiration rather than instructions; he substituted modern disinfectants for dangerous mercuric chloride used in the 1930s, and built a hydrocolloid dressing to contain the maggots instead of plaster and metal mesh.

To see if maggots could pass muster, Sherman conducted a prospective clinical study including more than 100 patients with pressure ulcers (bed sores) at the VA Medical Center in Long Beach. His results, published in 2002, showed that maggots thoroughly cleaned 80% of the wounds, while conventional treatments only cleaned around half of the wounds (7). Armstrong also studied the benefit of maggot therapy for patients with diabetic foot wounds, and found that more than half of the wounds subjected to maggot debridement healed significantly quicker — by around four weeks — than people who healed without maggots (8).

Of course, larvae aren’t a cure-all. Data collected over the past two decades show that maggots aren’t up to the task for some wounds, such as those with significant scabbing. Although maggots are less expensive than surgery, they need to be ordered in advance, and they clear the wound relatively slowly, usually taking around 48 hours. Some patients with particularly painful wounds might feel extreme discomfort as the maggots crawl near exposed nerves. And it is possible (but uncommon) for maggots to escape their dressing. After all, they can only find a meal in the wound. When it does happen, the rogue larvae need to be vacuumed up.

Making sterile larvae available to anyone who wants them has been a priority for Sherman. “I certainly believe that there is great utility, great need, and use for maggot therapy in the present day,” Sherman said.

Sherman originally raised maggots in his lab at the University of California, Irvine, but then they became subject to FDA medical device regulations. He started a company called Monarch Labs that supplies medical maggots in the United States. He estimates that 50,000-60,000 maggot treatments are administered each year across 32 countries.

“It is as easy to access as it is to write a prescription,” Sherman said.

Maggots cleaning dead and unhealthy tissue from a leg wound before further surgery.
CREDIT: DAVID ARMSTRONG

Armstrong is one of these maggot-wielding doctors. He first tried them during his limb salvage fellowship at the University of Texas, San Antonio in the 1990s. At the time, Sherman was still doling out larvae from his own lab, so Armstrong called him up and soon a jar of worms was headed to him in the mail.

Now, maggots are still a key element of Armstrong’s arsenal when tackling hard-to-treat wounds. He has treated more than 1,000 patients’ wounds with these larvae, including one particularly challenging case at the height of the coronavirus pandemic: a home-bound patient  with a wound that needed cleaning, who was too sick to come into a hospital that was already at ICU capacity (9). Armstrong shipped larvae to the patient’s home, and gave nurses instructions via WhatsApp to put the dressing in place, a process that took around 20 minutes. Family members replaced the dressing regularly, and in just two days, the larva eroded the dead tissue to one third of its original extent. After five days, there was almost none left. The patient came a few weeks later for surgery and further wound clean-up and is now recovered, Armstrong said.

“That would not have happened were it not for our little friends, our little critters,” Armstrong said.

Teaching old maggots new tricks

Armstrong has already seen how larva therapy can interface with telehealth and modern surgical tools. He thinks that the larva therapy of the future can be improved by designing better delivery mechanisms and finding markers that might suggest that a wound is particularly conducive to maggot debridement. Sherman also thinks that it could be useful to augment the wound healing or disinfecting capacity of the maggots.

Max Scott is a researcher at North Carolina State University, who genetically engineered Lucilia sericata to make a human growth factor.
CREDIT: MAX SCOTT

Max Scott, an entomologist at North Carolina State University, published a proof-of-concept study in 2016 showing that it is possible to genetically engineer Lucilia sericata to produce additional molecules (10). His team created transgenic larvae that secreted human platelet-derived growth factor, which normally prompts cells to grow so that wounds heal.

But research on maggots requires laying a lot of groundwork first. “Drosophila is a model organism, and there’s a huge community of people developing resources, so you can take advantage of what other people have developed,” Scott said. “But for this species, we have to figure it out ourselves.”

Scott’s team had to start with the basics to figure out how to even inject genetic material into the delicate eggs. They recently published Lucilia sericata’s full genome sequence and measured which genes are expressed in different tissues, providing the kind of foundational resource that can help other scientists design their own research questions.

An important next step is to show that these engineered larvae can actually stimulate tissue growth or wound healing in a patient, which wasn’t possible with the original strain designed in the study. But Scott’s recent genomic studies could help inform a better way to turn on genes of interest specifically in the maggots’ salivary glands so that the molecules can be released in maggot spit.

Stimulating growth isn’t the only power that these maggots might be engineered to employ. Genetic engineering might also boost their ability to make an assortment of helpful proteins, including growth factors, antimicrobial peptides, and molecules to stimulate the immune system — ”a whole cocktail,” Scott said.

Perception matters 

One big obstacle has been funding. Scott hasn’t been able to secure stable funding for his maggot research, which he thinks is because they are seen as an “old technology.” Sherman has also shifted his focus to less expensive endeavors, such as designing better dressings and training clinicians through BTER.

Scott hopes that having genomes and gene expression data readily available will lower the barrier for further studies. He has noticed a paradox in conversations around genetically engineered maggot therapy. “[Maggot therapy] is promoted as a natural treatment,” Scott said. “But there’s a large segment of the community that does not consider GMOs as natural.”

There’s a similar hesitance in Germany, where Vilcinskas works.

“Perception matters a lot,” he said, and a technology that the public doesn’t want to use is hard to fund. That motivated Vilcinskas to turn his focus away from engineering larvae to make more antimicrobial proteins to instead finding ways to synthesize and deliver standalone proteins. This could still offer exciting insights, Sherman said, not just for wound care but for other infectious diseases.

According to Armstrong, the broader medical community has always been intrigued by maggots. Whenever he does a maggot procedure, hospital staff crowd around him, craning their heads to get a look. “It never ceases to draw a crowd,” Armstrong said.

In recent work that Sherman co-authored, researchers surveyed doctors who use maggot therapy (11). They found that the main barriers to widespread adoption are the stigma that maggots are an obsolete treatment, lack of insurance coverage, and of course, “the ‘yuck’ factor.”

“It would be logical to think that our patients would somehow look at this kind of thing as horrible or disgusting or something like that,” Armstrong said.

But that’s not what he has seen. The reception from his patients has been overwhelmingly positive, and interestingly, many of Armstrong’s patients who are in denial or ignoring their condition become more attentive and engaged when Armstrong offers them maggot therapy.

Seeing maggot therapy’s utility during the coronavirus pandemic also suggests that it may have potential in other settings where hospital resources are scarce or temporarily unavailable.

“It would be the height of hubris to think somehow we should discard something that has been around for a long time that is quite helpful,” Armstrong said.

[ Tratto da: www.drugdiscoverynews.com ]

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