A nonsurgical path to treating pelvic organ prolapse

(Press-News.org) Pelvic organ prolapse (POP) is a disorder that primarily affects older women who have experienced multiple vaginal childbirths. 

Repeated vaginal deliveries can cause the muscles and connective tissue that hold the pelvic organs—the vagina, bladder, uterus, urethra, and rectum—to weaken, causing one or more of the organs to drop out of position and bulge or extrude outside the body. 

“There’s a breakdown and loss of the elastic matrix which contributes to tissue elasticity, similar to how a rubber band can stretch and recoil,” says Lehigh University Professor Anand Ramamurthi, who is chair of the Department of Bioengineering in the P.C. Rossin College of Engineering and Applied Science. “In adults, those elastic fibers aren’t regenerated or repaired because most of what exists in the body is produced just before or just after a woman is born.”

The disorder affects approximately three to 11 percent of all women, according to the Cleveland Clinic. Although a history of multiple vaginal deliveries is the primary risk factor, others include being overweight, having connective tissue disease, and having a family history of the disease.  

In addition to causing emotional stress and a degradation in quality of life, POP creates significant discomfort and pain, says Ramamurthi. “For some women in the early stages, specific exercises, called Kegel exercises, that strengthen pelvic floor muscles can help. But for those in more advanced stages, surgery is the only option.”

The problem with surgery, he says, is that the mesh traditionally used to hold the organs in place is made of polypropylene materials that stimulate fibrotic thickening, or scarring, that causes pain. The FDA has since banned meshes consisting of such polymeric materials, and surgeons must now rely on tissue grafts taken from the patient, which can generate complications that include infection, urinary retention, or incontinence due to graft placement, pain, and recurrence of prolapse.

“So there are very few options for them,” says Ramamurthi. “We want to develop a nonsurgical solution that could be applied in the early stages of POP to delay the disorder’s onset and/or its progression. If we’re successful in doing that, we believe that in the future, our treatment could be applied to reduce the severity of POP in patients at a more advanced stage.”

To that end, Ramamurthi and his team, which includes Margot Damaser, a biomedical engineering researcher at the Cleveland Clinic, recently received an approximately $3.2 million, five-year grant from the National Institutes of Child Health and Development (NICHD) with approximately $1.6 million of the total funding going to Lehigh.

The team will explore a three-phase research methodology. In the first, they’ll use cell cultures to investigate therapies that could inhibit the breakdown of the elastic matrix.

“We’ve developed nanoparticles that can be used to deliver a drug called doxycycline, which inhibits the enzymes that cause the breakdown of tissue structures,” he says. “We’ve previously shown that when we deliver this drug at very small doses, it not only has anti-degradative effects, but it also regenerates the elastic matrix, which is a novel finding.”

The nanoparticles themselves, he says, are also modified to inhibit degradative enzymes and stimulate elastic matrix production, and so act synergistically with the drug. The team will test the nanoparticles in cell cultures of non-epithelial vaginal cells from patients who underwent POP surgery.

“The purpose of the first phase is to discover novel molecular targets for therapy,” he says. “We want to identify what target proteins the drugs are acting on, and if there are other targets we’re not yet aware of.” 

In the second stage of the research, the team will test the nanoparticles on surgically extracted tissues in a long-term culture to determine if the nanoparticles improve tissue health. In the third phase, they’ll evaluate the treatment in vivo.

“We’ll be using a cutting-edge mouse model,” he says. “The mice are missing a specific gene, called Loxl1, which means they lack the protein required for crosslinking elastin precursor molecules into a structural matrix in adult tissues. The mouse model is unique in that mice lacking Loxl1 spontaneously develop POP after multiple vaginal births in a manner that closely evokes the clinical condition. We will deliver the nanoparticles into the vaginal wall, and we want to know: Do the nanoparticles stay in place? Do they release the drug? Where does the drug go? Does the condition improve? We will essentially be looking at how the tissue structure improves across time.”

If successful, such a nonsurgical intervention could prevent or even reverse the matrix degradation that leads to POP, reduce the severity of later stages of the disorder, and potentially help younger women with POP who want to have more children.

“Despite the prevalence of POP, it’s a disease without mainstream visibility,” says Ramamurthi. “There are only a few research groups focusing on it, and even fewer looking into regenerative therapies. Our lab’s expertise lies in regenerative therapies for elastic matrix assembly and we’ve been collaborating with the Damaser lab for the past 10 years. What we’re proposing here is an extremely high level of innovation—a nonsurgical therapeutic that could reverse the pathophysiology of disease. There are very, very few groups in the world capable of doing this.”

Related Links: 

Rossin College Faculty Profile: Anand Ramamurthi Cleveland Clinic: Pelvic Organ Prolapse Cleveland Clinic: Margot Damaser Laboratory National Institutes of Child Health and Development (NICHD) END