Implanting a medical device inside the body is tricky. For a start, there’s the fact that the body is actively hostile to foreign objects. Anything that the immune system considers to be ‘non-self’ will trigger an immune and/or inflammation response. Prof. Carmelo De Maria, a bioengineer at the University of Pisa in Italy, notes that there are already plenty of wearable medical devices, such as implantable or stick-on sensors for monitoring blood glucose. But the problem, he says1, is that most of these sensors are based on silicon. “So they are pretty rigid, pretty stiff.” And when you try to implant them, he adds, “the human body will create a sort of capsule, a sort of a scar around the tissue to isolate something that it does not recognise as ‘self’.” What’s more, he continues, most of the implantable devices currently available tend to focus on the cardiovascular system; by contrast, the human gut has received much less attention. “If you want to monitor how you digest something, if you want to monitor the health of your microbiome, […] there are very few technologies.” With this mind, De Maria and a group of scientists, doctors and engineers at the universities of Pisa, Perugia and Florence have developed a biocompatible monitoring patch2 that can be placed in the intestine to monitor motility, or the contraction of muscles in the gastrointestinal tract. It could have a wide variety of potential applications, from providing information on gut function in people with short bowel syndrome, to monitoring patient recovery after bowel cancer surgery. The patch is piezoelectric, meaning it can generate an electrical charge from the pressure exerted on it by the gut wall, and it’s constructed from carefully selected materials that are much less likely to provoke an immune or foreign-body response.

Gut friendly

The core components of the piezoelectric patch are regenerated silk, graphene and tannins. Silk has innate piezoelectric properties, generating charge in response to tensile stress, and regenerated silk has been purified to retain only the fibroin fibres, which are dissolved in a solvent. Most importantly, it won’t cause an adverse response. “It's a protein, a biological molecule,” says De Maria. “So something natural, something that is composed of the same elements we have in our body.” Graphene nanoplatelets are the second key ingredient. Again, graphene is an inherently biocompatible material, since it’s composed of carbon, and as well as being a conductor, it can form incredibly strong and incredibly thin layers where its molecules are arranged in a lattice. The idea is that it can conduct electricity generated by the silk in response to gut contraction, and these electrical signals can be used to monitor motility. Finally, there are tannins. These naturally produced molecules are most often associated with tea and wine, but they occur in a large variety of plants: the tannins used by De Maria et al. were derived from chestnut. Tannins are most widely known for their antioxidant properties, but they can also act as a kind of glue3. Aside from the problem of biocompatibility, one of the biggest issues with implanting a medical device is ensuring it stays put. The body is a naturally slimy, undulating and constantly moving environment, so attaching anything anywhere can be difficult. But tannins interact with the body’s proteins, establishing a stable complex through non-covalent bonds, thus providing a natural means to firmly adhere the patch to the gut wall. And because the patch is flexible, it can conform exactly to the shape of the surface it’s planted on.

3D printing

De Maria’s research is focused on 3D printing, which has evolved enormously since the first commercial 3D printers became available in the 1980s. Now it’s possible to print objects using several different materials at once, with each material being deposited via a different nozzle, much like the different inks in an inkjet printer. For De Maria, the fact that the piezoelectric patch can be printed on demand is what makes it truly exciting. “If you are able to 3D print something, you can produce devices in remote areas,” he says, meaning that access to the patch could be opened up to any hospital anywhere in the world. 

The technology is advancing all the time. Irene Chiesa, a PhD student in De Maria’s group, is focusing her research on what’s called 4D printing, where the printed object is designed to change shape in response to stimuli such as pH levels or temperature. She says this concept could have great importance in biomedical applications. “Think about the difference between room temperature, 26 °C, and the inner temperature of the body, 37 °C,” she says. “We can use this difference to create the movement and the shape shifting of our structure.” When it came to developing the piezoelectric patch, De Maria says the greatest difficulty was finding ways to print materials such as silk that are not naturally suited to printing. Ultimately, he says, “We need to identify, or even to build from scratch, new printers, new extruders, new protocols, just to preserve the special properties of these materials [and] give them the shape that we need.”

Next steps

The patch has already been tested as a proof of concept in the intestines of rats2, and De Maria’s group, together with the University of Perugia and the University of Florence, has submitted funding proposals to develop the technology further, initially with larger animal studies. “The first serious discussion about going into the clinic with such devices will start in six to eight years from now,” he reckons, and the next step will be to find a way to ensure the patches can migrate to the correct part of the gut automatically, without the need for surgical insertion. 

But De Maria couldn’t imagine even getting to this stage without the benefits of multidisciplinary collaboration. “This is the most, most, most important point,” he says. “There are a lot of clinical problems that we as bioengineers are not aware of at all. There are a lot of technologies that clinicians are not aware of at all. And then there are a lot of interesting materials that […] chemists know, but they don't know how to exploit them.” He adds that the several of the works his group has published over the past few years have directly resulted from gathering chemists, clinicians, engineers and material scientists in the same room to discuss advances and problems in their respective fields. “Many problems were solved by multidisciplinarity,” he says. “That is fundamental: sometimes for identifying the application, sometimes for solving the challenge.”

Next steps

1. Interview with Prof. Carmelo De Maria and Irene Chiesa, February 2023.
2. Chiesa I, De Maria C, Ceccarini MR, Mussolin L, Coletta R, Morabito A, Tonin R, Calamai M, Morrone A, Beccari T, Valentini L. 3D Printing Silk-Based Bioresorbable Piezoelectric Self-Adhesive Holey Structures for In Vivo Monitoring on Soft Tissues. ACS Appl Mater Interfaces. 2022;14(17):19253−19264.
3. Chiesa I, De Maria C, Tonin R, Ripanti F, Ceccarini MR, Salvatori C, Mussolin L, Paciaroni A, Petrillo C, Cesprini E, Feo F, Calamai M, Morrone A, Morabito A, Beccari T, Valentini L. Biocompatible and printable ionotronic sensing materials based on silk fibroin and soluble plant-derived polyphenols. ACS Omega. 2022;7(48): 43729-43737.