Treating breast cancer requires a barrage of medications, radiation, and surgery that tax patients. Often, one of the most difficult steps is a mastectomy: an aggressive surgery to completely remove one or both breasts to stem the spread of the malignant cells. Breast removal can leave people with not only physical pain, but also lower self-esteem (1). 

That’s why more than 100,000 people undergo breast reconstruction surgery every year in the United States alone (2). Most receive breast implants, gel-filled silicone capsules that mimic soft breast tissue. Others undergo a surgery known as autologous breast reconstruction, where surgeons move a small piece of fatty tissue called a flap from the patient’s own stomach or back to their chest to rebuild a breast. 

Pierre Guerreschi, a plastic surgeon at the Lille University Hospital, knows firsthand that these methods don’t work for everyone. Silicone implants place a foreign substance in the body, which can trigger defense mechanisms in some patients. They also need to be replaced periodically, which requires additional surgeries. On the other hand, autologous breast reconstruction surgery can take as long as 10 hours to extract the flap, insert it into the breast area, and microscopically reattach all of its blood vessels.

“I knew that there was something in between the two: something very technically simple, but without any long-term foreign body,” said Guerreschi.

After years of mechanical experimentation and preclinical testing in animal models, Guerreschi and his team have formulated a new 3D-printed device that combines the simplicity of an implant with the body’s power to grow its own tissue. The device, which is being commercially developed and manufactured by the biotechnology company Lattice Medical, entered clinical trials last year with the hope of soon making breast reconstruction an accessible option for more people.

Harnessing the body for tissue engineering

Based on conversations with patients and physicians, the task was fairly clearcut. “They are looking for a natural, minimally invasive, and long-lasting breast reconstruction,” said Jaime Destouesse, a research and development manager at Lattice Medical.

That meant that researchers needed a way for the body to regrow the fat tissue that makes up breasts on its own, while minimizing the number of surgeries and scars and maintaining blood flow to keep the new tissue healthy. Guerreschi’s team chose an approach called a tissue engineering chamber (3). These hollow devices are typically made from plastic or easily degradable polymers and can be customized to the size of whatever tissue needs to be grown. When implanted into the body, they create empty space where the new tissue should grow. “The body doesn't like empty space inside,” Destouesse said. “We want to recreate this space with the patient’s own tissue.”

The principle here is something that I agree with, which is using the body as the bioreactor. Of course, the body is the best tissue engineer. 
- Jason Spector, Weill Cornell Medicine

To get the new breast started, they drew inspiration from an earlier study led by Wayne Morrison, a plastic surgeon then at the University of Melbourne, showing that tissue engineering chambers could be used to grow fat tissue in humans (4). The surgeon seeded the chamber with a fat flap, but unlike traditional flaps in autologous breast reconstruction, the surgeon cut the fat tissue from the side of the patient’s torso so that it can be moved to the chest while remaining connected to the blood supply. The act of cutting the tissue and moving it also helps spur the initial wound healing required to start building the breast.

Next, the researchers needed to create a chamber that was up to this task. The implant should protect the flap from pressure and other physical stress. Molecules that stimulate healing and tissue growth should be able to enter the chamber, and the implant itself shouldn’t linger in the body after the breast forms. Importantly, to make it accessible in the clinic, it should be easy to make a new chamber for any patient who needs it.

Guerreschi’s team showed in 2020 that they could 3D print a tissue engineering chamber using material that would degrade over time in the body (5). In pigs, when surgeons created a fat flap and encased it in the chamber, the chamber disappeared over time while the fat flap grew more fat tissue that remained connected to blood vessels — a process that could hopefully create a breast in humans.

Jason Spector, a plastic surgeon at Weill Cornell Medicine, is not involved in this work, but knows firsthand the challenges of rebuilding soft tissues like breasts. “The principle here is something that I agree with, which is using the body as the bioreactor,” Spector said. “Of course, the body is the best tissue engineer.” 

A simple solution

The device is dubbed “Matisse,” an homage to the early 20th-century painter who hailed from a town just 80 kilometers from the hospital where the device was conceived. Outside the body, Matisse looks inconspicuous. It is made of two pieces: a small, hollow dome with a perforated white surface and a flat base. It’s hard to imagine that once surgeons place it in the body, this unassuming shell will become an incubator for a whole new piece of living, growing tissue.

To churn out the scaffolds, Lattice Medical has built a 3D printing facility in their research labs. Their “printing farm” consists of 16 3D printers in a clean room to ensure the sterility of the implants. “We are proud of this,” Destouesse said. “There are not a lot of printing farms in clean rooms in the world.”

Although the implants look like they’re made of everyday plastic, they are actually made with a naturally produced degradable polymer material. The exact formulation is kept confidential, but Destouesse said that it is also used in other medical devices, such as those that build blood vessels. After around 10 hours of meticulously putting down layers of this material, the team can create a Matisse implant. It comes in 21 different sizes depending on the desired size of the fully grown breast; they range from 175 to 500 cubic centimeters, the equivalent of 1 to 3 cup sizes.

Once the team prepares the implant, they can package it and transport it to a trained plastic surgeon who will create the fat flap and attach it to the implant. “Nothing about this is daunting in terms of the surgical technique,” said Spector. “We all place devices. We all know how to raise flaps.”

That was Guerreschi’s goal. “We knew we had to develop a simple technique in order to spread the solution for many patients,” said Guerreschi. Moreover, making the flap and inserting the device only requires one surgery, unlike existing autologous reconstruction methods that require separate surgeries for extracting and inserting the flap. In patients who also require a mastectomy, the two procedures can be combined into one surgery.

Once surgeons place the implant, it takes around 15 days for the wound to heal. This is the first phase of reconstruction, which Destouesse calls the inflammatory phase. At this point, healing and growth molecules flock to the surgical site, aided by the holes in the implant and the intact blood vessels. Once the wound has healed, these molecules also spur the second phase of reconstruction when the fat tissue grows. In pigs, the fat tissue grew to three times its original size in around nine months; and in the same amount of time, the implant disappeared.

“I was really impressed with the product the first time I saw it,” said Destouesse. Not only was the device easy to use, the resulting tissue had the mechanical properties expected of fat. “You can see and feel the elasticity.”

Proving itself in the clinic

“When I hear about something new, my reaction is always one of cautious optimism,” Spector said. “There're a lot of claims made, and in my experience as a plastic surgeon, very few of them actually live up to the hype.”

Compared to the earlier work led by Morrison, Spector noticed that improvements in the blood supply meant that Matisse could grow larger amounts of fat tissue. However, Spector still wonders if the technological advancements are enough to grow fat tissue the size of a human breast, which is orders of magnitude larger than what is seen in the animal models.

We knew we had to develop a simple technique in order to spread the solution for many patients. 
- Pierre Guerreschi, Lille University Hospital

Rebuilding a human breast is the most important test for Matisse. Lattice Medical began a European clinical trial of the implant in July 2022 with a 62-year-old breast cancer patient in Tbilisi, Georgia. In a single, 1.5-hour procedure, surgeons conducted a mastectomy to remove the patient’s own breast tissue and inserted the implant. As of September 2022, Lattice Medical reported that the patient had finished the wound-healing phase without complications.

Under Guerreschi’s leadership, the clinical trial will soon expand to eight medical centers across Georgia, France, and Spain. The researchers will evaluate the device’s safety and performance in two studies of 50 patients total, who will be followed for at least one year. With these two key pieces of data, Destouesse expects that they will achieve their CE mark — a European regulatory standard for safety — by 2026.

In addition to safety, Spector hopes that the team also measures patient satisfaction and quality of life. For example, he wonders how patients will react to having a scar on their upper body instead of the traditional scars from creating a flap for autologous breast reconstruction, which are closer to the waist and easier to hide.

Guerreschi knows that there’s an urgent need for technologies like Matisse among patients — after all, that’s why he decided to work with a company to develop the device. “If we have time and money, we could do everything in the university,” he said. “But for such a project, we chose this way to go faster because of the need.”

References

1. Dominici, L. et al. Association of Local Therapy With Quality-of-Life Outcomes in Young Women With Breast Cancer. JAMA Surg  156, e213758 (2021).
2. Liu, D. New plastic surgery statistics and breast reconstruction trends. Connect by American Society of Plastic Surgeons.
3. Dolderer, J. H. et al. Spontaneous large volume adipose tissue generation from a vascularized pedicled fat flap inside a chamber space. Tissue Eng  13, 673-81 (2007).
4. Morrison, W. A. et al. Creation of a Large Adipose Tissue Construct in Humans Using a Tissue-engineering Chamber: A Step Forward in the Clinical Application of Soft Tissue Engineering. EBioMedicine  6, 238-45 (2016).
5. Faglin, P. et al. Rationale for the design of 3D-printable bioresorbable tissue-engineering chambers to promote the growth of adipose tissue. Sci Rep  10, 11779 (2020).