Nature has inspired many scientific breakthroughs — and for Phillip Messersmith, it’s a blueprint for healing. From marine mussels to mice, Messersmith draws on biology to develop cutting-edge materials for medicine. The professor of bioengineering and of materials science and engineering makes adhesives and therapies designed to work with the human body, offering new ways to repair tissues, heal wounds and treat disease.
His journey began with an unlikely source of inspiration: the sea. More specifically, with the natural glue of marine mussels. By studying how mussels stick to rocks and piers in wet, turbulent environments, Messersmith is creating synthetic versions of natural adhesives for surgical applications.
“I have been fascinated by marine mussels and their protein glues for 25 years,” says Messersmith. “Mussels tether themselves to surfaces with protein fibers called byssal threads, which resemble a series of taut strings extending from their shells. Byssal threads are sometimes called a mussel’s ‘beard’ and are not living tissue. Their only purpose is mechanical adhesion — to glue a mussel to a rock or other marine surface — which they accomplish with a little dollop of glue. This allows them to cling to rocks as the tide rushes in and out, twice per day.”
“The glue proteins contain an unusual amino acid called L-DOPA,” says Messersmith. “It is used in medications for Parkinson’s Disease, but in nature, it is almost never found in proteins, except in marine mussels. L-DOPA is a key element in the adhesive performance of these proteins, and we make synthetic polymers that have the same chemical constituents found in L-DOPA.”
Polymers are large molecules composed of many repeating subunits. And Messersmith’s lab makes synthetic polymers that mimic byssal glue proteins by including the adhesive chemical group found in L-DOPA. The adhesives he makes in his lab at Berkeley can glue together skin and bone, close up the spinal canal after trauma surgery — or even seal the womb after surgery on a fetus.
“Early in my career, I realized there is a lot that medicine can learn from nature, when it comes to wet tissue adhesives,” says Messersmith. “In my lab, we study the proteins in nature and learn how they work. Then, we try to distill out the key elements of their proteins. We synthesize polymers with similar characteristics and test whether they could work as an adhesive or sealant for humans.”
Insights straight from surgery
If you’ve ever had a flesh wound, you might have had it resealed with a kind of dissolving glue applied directly to the cut. Informally known as liquid stitches, these glues are among the most used medical adhesives. But adhesives are also used for all kinds of other medical applications — including in spinal, heart and intestinal surgeries — which each have a unique set of demands.
“The required mechanical performance varies a lot,” Messersmith says. “Dental adhesives need to be very, very strong, and those demands are difficult to meet. Whereas a dural sealant — a kind of adhesive that seals the spinal canal after surgery — doesn’t need to be as strong. Any adhesive’s mechanical performance needs to be appropriate to the tissue it seals and the circumstances of its use.”
To determine these needs, Messersmith talks to surgeons about the problems they encounter in the operating room. Surgeons are the ones on the front lines, after all. And they help Messersmith understand the nature of the challenges they face.
“No matter how creative and experienced I think I am, I can’t predict how a material we’ve developed in the lab might be used in the clinic,” Messersmith says. “Sometimes, I talk to a clinician, and they tell me it would never work to use a material in the way I thought they could. But they may also tell me that if we had a material with slightly different properties, we might have something.”
Working with researchers at UCSF’s Department of Orthopaedic Surgery, Messersmith brings formulations of adhesives he’s developing, and they experiment with ways to use them.
“Until surgeons can feel a material, and play around with it and modify it, we don’t really know what the material’s best applications will be,” says Chelsea Bahney, an associate professor at UCSF.
For Messersmith, an adhesive that could instantly glue broken bones back together is the dream. While it’s unlikely an adhesive will ever be strong enough to glue major bone breaks back together, one might work for something like a collar bone fracture. And adhesives could also speed the healing process for other orthopedic procedures.
“Adhesives might be able to supplement orthopedic hardware like screws and plates, and help patients bear weight faster,” says Bahney. “That could help people heal faster and be more mobile, more quickly.”
Obtaining this type of feedback plays an essential role in shaping the research that Messersmith pursues, and it helps pave the path from the laboratory to the clinic.
“Sometimes a new material comes to fruition before a conversation with a clinician, and sometimes it comes after,” says Messersmith. “But these conversations are always useful in understanding the challenges surgeons face.”
Operating in utero
Fetal surgery can save a life, but it can also put one at risk. The procedure can correct twin-to-twin transfusion syndrome, a potentially fatal condition in which blood flow from the placenta goes disproportionately to one twin. In a fetus with spina bifida, it can close an opening in the spinal canal that causes damage to the spine and nerves, yielding better results than post-birth surgery. But fetal surgery is among the most delicate tasks in medicine, and no such operation is considered routine. At least not yet.
“The fundamental problem is a surgical one,” says Michael Harrison, a professor of surgery at UCSF. Sometimes called the “father of fetal surgery,” Harrison pioneered fetal surgery with a procedure to repair diaphragmatic hernia, a relatively common birth defect that hinders lung development and hurts the chances of survival after birth.
“You need to make an incision in the uterus, and amniotic fluid can leak out through that incision, which can lead to pre-term labor. To seal the uterus, we only have our crude surgical ways — stitches and staples. What we really need is some kind of biological sealant that can seal the membrane back up.”
Messersmith is working on it. He is seeking to create a sealant that can patch up incisions of the uterus. No such product currently exists, and the mechanical demands are high, with elasticity being a major challenge. As a pregnancy progresses, a fetus continues to grow. The membrane around the uterus gets stretched, and the fetus kicks against it. Any sealant would need to be elastic enough to stretch with the uterus and be durable enough to maintain adhesion for at least a few weeks.
“You also need to pay attention to the biological effects,” says Messersmith. “Any material used to seal up the uterus can’t affect the development of the fetus. It is a very challenging problem.”
To solve it, Messersmith is collaborating with researchers at the University Hospital Zurich in Switzerland. The hospital’s head of research, Martin Ehrbar, developed a device to deliver a sealant from inside the uterus. The device is shaped like a tiny umbrella, and it collapses through a tube inserted in the incision to pass surgical equipment in and out of the uterus. Inside the uterus, the device opens, and upon withdrawal, applies the sealant from within. Early results are promising.
Ehrbar conducted research that demonstrated the effectiveness of Messersmith’s sealant in sheep. The study reported survival rates of 100% for mothers and 91% for their offspring.
“We are very excited about the results,” says Messersmith. “And we are already planning another study with our newest adhesive, called Asparaglue. I like to think of the mussel glue as generation one, and Asparaglue as generation two. Its chemistry is based on sulfur-containing compounds like asparagusic acid, a compound found in asparagus.”
According to Harrison, a glue that could seal a membrane would find all kinds of applications in the operating room.
“There are many situations in which a surgeon needs to seal a membrane,” he says. “For example, a neurosurgeon needs to seal the membrane around the brain after they perform surgery. If there were a sealant that could prevent fluid leakage, it could be applied to many different types of surgery.”
Of mice and men
Messersmith’s approach to regenerative medicine is also biologically inspired. About 15 years ago, he began collaborating with researchers at the Wistar Institute, a cancer lab in Philadelphia. In 1999, researchers there bred the Murphy Roths Large (MRL) mouse, originally as part of a program to study genetic autoimmune disease. But they found the mouse had a quite unexpected trait: superhealing. Unlike typical mice, an MRL mouse wouldn’t form scar tissue in response to wounds; instead, it would regrow the damaged tissue.
“It is very unusual for a mammal to orchestrate true regeneration, but that’s what this appeared to be,” says Messersmith. “All of the tissues were reformed.”
The MRL mouse has an abundance of a protein called HIF-1a that allows it to regenerate tissue. This protein is present in other animals and in humans, but its levels are curtailed by an enzyme called prolyl hydroxylase. Messersmith keyed in on these two molecules.
In 2024, his lab developed a technique for treating colitis using DPCA, a small molecule prolyl hydroxylase inhibitor shown to trigger regeneration in mammals. In mouse models, DPCA protected against and repaired colon damage by stabilizing HIF-1a.
“Our strategy was to try and get regeneration in otherwise nonhealing animals by elevating levels of HIF-1a,” he says. “But the drug we created doesn’t target HIF-1a directly. Instead, it inhibits the activity of prolyl hydroxylase, which normally destroys HIF-1a.”
Results showed that DPCA prevented intestinal lesions and weight loss when administered before disease onset. Remarkably, even after colitis developed, a single injection of the DPCA gel accelerated colon healing and promoted weight gain.
With this drug delivery system, Messersmith and his colleagues have been able to regenerate tissue in other, non-healing strains of mouse. They have regenerated gum tissue damaged by periodontal disease, and intestinal tissue damaged by inflammatory bowel disease.
“Periodontal disease is very common. In the United States, almost two-thirds of adults over the age of 60 have some form of it,” says Messersmith. “In mice, we were able to reverse periodontal disease. When we tested this drug as a treatment for inflammatory bowel disease, the mice regenerated damaged intestinal tissue after a few weeks of treatment. And it’s all happening because the drug increased the levels of the HIF-1a protein.”
A drug that regenerates gum and intestinal tissues and an adhesive that seals a womb after fetal surgery might seem like two very different lines of research. But these projects are all part of Messersmith’s vision for the future. “I hope to bring these two things together” Messersmith says. “These projects appear very different, but they’re converging. We want to make an adhesive that can mechanically seal the amniotic sac and incorporate a regenerative drug. Then, hopefully, we can regenerate the amniotic sac after surgery is performed.”
Read this story on the UC Berkeley College of Engineering website.