Medical care of tomorrow

An implant that heals

As in the MIRACLE II project, bone injuries are the focus of the “Smart implants” project at Saarland University, Saarland University Medical Center, the Center for Mechatronics and Automation Technology and the German Research Center for Artificial Intelligence. The team led by Professor Bergita Ganse and Professor Tim Pohlemann are aiming to develop an implant that not only monitors the healing process of complex fractures but that also promotes healing through its autonomous, activating movements.

To realise their multi-tasking implant, the researchers are integrating a wire made of nickel and titanium—so-called shape-memory alloys, which are materials that can assume two different states, depending on the temperature. The alloys can be moved back and forth, like an artificial muscle, and they’re able to transfer large amounts of energy in a small space.

In a recently published study, the Saarland researchers used simulations to show for the first time how powerful one of the implant’s “micro-massages” should be to support healing. The results showed that, depending on the type of fracture and healing phase, the implant’s range of motion would have to be restricted to between 0.1 and 0.5 millimetres. “In this micro-movement, very large forces are transferred, up to several hundred kilogrammes,” as Tim Pohlemann explains. Indeed, one of the project’s major challenges lies in managing this area of tension between micro-movements and macro-forces.

Data in the soles of their shoes

Another difficulty the team face is determining which patients need a micro-massage—and when. For this, the implant must have access to precise data on stress and strain in the fracture gap. These data are gathered through the sensors in the smart implants themselves, but also from insoles fitted with sensors that patients wear in their shoes. “The conventional approach would be to collect relevant data, analyse the information and then send it all back to the implant,” Bergita Ganse says. “But our vision is to create automated, AI-controlled data interpretation—that way, the implant can function autonomously.”

The researchers have already compiled data in profusion in their specialised gait lab, where the insole-sensors record patient data on strain, acceleration and weight-bearing. “We’ve learned a lot about how these parameters change in patients who are healing well—and also how they change when healing is suboptimal,” Bergita Ganse says. “And we’re now able to use the gait and movement data to assess early on whether or not a fracture will heal well.”

The team have also made progress in another crucial part of the project. “We asked ourselves how we’ll be able to prove that it’s actually the implant that impacts healing,” Ganse says. Their solution is to measure blood flow in the fracture tissue. By doing so, the researchers were able to demonstrate that circulation and oxygen saturation change during a favourable healing process. In future, this knowledge will enable them to measure whether massaging the site of a fracture will—as they believe—improve these parameters.

Immense potential

At present, the smart implant has a long way to go before it’s ready for market entry, as Tim Pohlemann says. Currently, they have a demonstrator, but before they can use it to build a prototype, they must first make several advances. In short, it will take years before a highly complex, auto-regulating implant that’s safe for use in the human body will be approved for medical care. “We have to plan many steps in advance—but also streamline the project wherever possible,” Pohlemann explains.

One potential simplification involves controlling how the implant should move in the body. “At first, we were thinking the implant would need complete freedom to move in all directions,” Tim Pohlemann explains. “But, when dealing with the kinds of forces that are involved in the motions, it’s almost impossible to control mechanically.” To solve the problem, the researchers are exploring variations with a somewhat limited range of movement that are much easier to manufacture. “We probably don’t need to have the device moving in every single direction.”

Tim Pohlemann and Bergita Ganse are convinced that the Saarland smart implant model can do far more than treat bone fractures. “After all,” Pohlemann says, “we virtually look through skin and can influence body processes from the outside. The approach has immense potential.” One possible application would be treating osteoporosis or bone tumours that cause bones to disintegrate over time. In such cases, a minimally invasive implant could increase bone stability while simultaneously serving as a sensor: should the implant detect a decrease in stability, a surgeon can operate to prevent more serious damage.

Regenerating damaged cartilage

The TriggerINK project at DWI – Leibniz Institute for Interactive Materials in Aachen is also focusing on influencing healing processes from outside the body. Researchers in the teams of Laura De Laporte, Stefan Hecht, Andreas Herrmann and Matthias Wessling are developing a novel strategy for regenerating damaged cartilage—in cases of osteoarthritis, for example. Put simply, their vision is to form a supportive hydrogel scaffold made of a gelatinous substance—starting from a bio-ink—into a damaged joint. Once the structure is in place, innovative techniques and materials designed by the researchers will trigger a process of cartilage regeneration along the scaffold.

TriggerINK is emblematic of an important paradigm shift in the field of medicine. “For the past several decades now, there’s been a movement away from conventional surgical interventions towards minimally invasive or even regenerative strategies,” says Laura De Laporte, professor of Macromolecular Materials for Medicine at RWTH Aachen University and member of the DWI scientific board.

Initially, the regenerative approach consisted mainly of cultivating replacement tissue in the lab and then implanting it in the body. “Unfortunately, this procedure often failed because the cultivated tissue integrated poorly into the surrounding body tissue,” De Laporte explains. And when the attempt was made to grow tissue directly inside the body, a serious problem arose: the method utilises proteins and other signals that are instrumental for embryonic development and wound healing—but that also play a role in tumour growth.

“It’s absolutely essential to ensure that these techniques don’t trigger unwanted growth,” De Laporte stresses. That’s why researchers have turned to a new tactic which involves programming materials with functions that can be steered and set in motion. “This is our goal at TriggerINK,” De Laporte says. The researchers work with tools such as magnetic fields, photochemistry, ultrasound and the emerging field of mechanobiology.

Molecular switch with visible light

Photochemistry is the domain of Stefan Hecht, Einstein Professor at Humboldt-Universität zu Berlin and associated researcher at DWI Aachen. His team is developing an innovative method to enable the polymer molecules in the bio-ink to link with each other and form a lattice-like gelatinous hydrogel structure. Specifically, they want to form this hydrogel directly in the wound by irradiating the polymer solution. The light stimulates the molecules in the bio-ink so that they begin to crosslink at certain points. Over time, they form the structured scaffold that supports growth of the cartilage tissue.

The crosslinking already works when the bio-ink is exposed to UV rays. “But our aim is to use visible light that’s gentler on the cells,” Stefan Hecht explains. This is easier said than done, as using a different wavelength calls for intense, complex research. “We’ve designed a whole array of different molecules, but the first of these didn’t deliver the desired results.” Recently, however, his team scored a success and proved that the principle of a molecular photoswitch based on visible light is indeed feasible.

They’ve also already identified optimal parameters for the hydrogel—how stiff it should be, for example—to best enable fast tissue regeneration. The researchers are also taking steps to ensure that the tissue grows in the right direction. This is achieved by means of rod-shaped microparticles in the bio-ink that are aligned via a magnetic field. Initial findings have shown that stem cells inside scaffolds with this kind of orientation differentiate into cartilage cells more effectively.

Targeted release of molecules

Nevertheless, even if the hydrogel parameters and alignment are perfect, the stem cells still need some assistance to differentiate and regenerate the tissue. To ensure the cells get the help they need, the researchers are integrating biologically active, cell-growth promoting molecules into the bio-ink. Andreas Herrmann’s group is working on ways to release these molecules by means of external ultrasound signals—that are sent at the right time and right place, deep within the regenerated tissue.

Last year, the researchers used an immunostimulatory molecule in living animals to show for the first time that a local release triggered by ultrasound is possible. In their experiment, they injected the compound into the tail vein of mice and waited until the substance spread via the blood vessels through the entire body. The researchers then activated the molecule via ultrasound—targeting only the liver of the animals, and this with pinpoint precision.

Like their WSS colleagues in the Smart implants project, the TriggerINK team also seek ways to promote healing via external stimulation, although their project functions on an even smaller scale. Instead of using an autonomous implant, the Aachen researchers are working with microgels in combination with gold nano particles. The nanoparticles are activated externally with safe infrared light that penetrates into the printed construct. The pulsing light causes the microgels to contract at regular intervals—every second, for example—and then expand again.

“We’ve taken a big step here, too,” Laura De Laporte says. “Initial tests have shown that the microgels we synthesised and set in motion do indeed activate the cells.” With this achievement, the team have met the first requirement: they’ve demonstrated that stimulation can influence the growth and regeneration properties of cartilage tissue.

It’s fair to say that the three micro-medical projects supported by the Werner Siemens Foundation are well underway. And despite their differences, they all pursue a common goal: improving medical care by making it less invasive, less traumatic and more patient-friendly.