Bridging Biology and Technology

In order to achieve this, the researchers are looking at "all the building blocks of life" at the nano, micro, and macro levels, starting with genetic information, proteins, and individual cell types and ending with organs that communicate with one another. The potential fields of application for the innovations being developed there are just as wide-ranging as the research profile, because biomedical systems are needed in everything from diagnostics and therapy to rehab applications.

A glance at Prof. Roland Kontermann's "antibody workshop" and at the therapeutic antibody map 2022 shows this. “Not only are there more and more, but the applications are also becoming broader,” says the expert in biomedical engineering, who works at the Institute of Cell Biology and Immunology (IZI). As he explains, over 130 of these proteins, which are produced by the immune system and designed for use in humans, have now been approved as drugs to fight cancer, inflammatory diseases, metabolic disorders, infections and even neurodegenerative diseases, and many more are currently at the clinical trials stage – tailor-made drugs of the kind that are also being developed in the IZI laboratory. 

A current example is the “Atrosimab” molecule, which switches off proteins that trigger and repeatedly reignite the inflammatory process in diseases, such as rheumatism, in a targeted manner and without side effects. The so-called cytokine TNF, which is largely responsible for inflammation, has two receptors to which an antibody can bind in order to neutralize it. In addition to the pro-inflammatory one, there is another that prevents such things as the degeneration of cells or the re-germination of tuberculosis. The researchers have now succeeded in targeting and eliminating only the disease-causing docking station using "Atrosimab", which has just been successfully tested in the first clinical phase.

The IZI team is also following novel paths in the treatment of solid tumors such as breast or colon carcinomas. Whilst the use of antibodies has now become established in this area, sometimes in combination with other therapies, it is more challenging than, for example, the treatment of leukemias and lymphomas because solid tumor tissue is extremely complex, and the cells are difficult to access in addition to which, no two tumors are alike. So far, antibodies can attack them in three ways, either by inducing cell death in tumor cells, blocking the supply of blood vessels to the tumor, or activating the immune defense system. A so-called antibody-drug conjugate (ADC), which is an antibody chemically coupled with active substances, has been developed to target the so-called tumor stroma and thus a fourth predetermined breaking point. This connective tissue can account for up to 90 percent of a tumor.

Dr. Tian Qiu, a biomedical engineer at the University of Stuttgart's Institute of Physical Chemistry (IPC), and his "Biomedical Microsystems" research group are advancing cancer treatment from a different angle. In his VIBEBOT project, which is funded by the European Research Council (ERC), he is working on a micro robot that can penetrate human tissue in order, for example, to deliver chemotherapeutic agents precisely to the right spot on a tumor. “Usually when such drugs are administered orally or intravenously,” he explains, “only about one percent of the dose reaches its target.“The restdisperses throughout the body, causing side effects.” 

Qiu likes to compare these drug delivery vehicles to fish in a net: they either have to be small enough slip through the meshes or able to destroy the net. To achieve this, the bioengineer takes inspiration from nature and his team has already achieved a first breakthrough. They have created a 500-nanometer robot inspired by Escherichia coli, which can "swim" through the tissue network of an eyeball. This "nano propeller" is controlled by a magnetic field. Its target is the retina, where it deposits the active ingredient. This method, which has been successfully tested in a pig's eye, represents a real advance in the treatment of eye diseases, which is usually done with drops that are difficult to dose and are slow-acting. 

Other soft tissues are made up of a denser polymer network than that of the eyeball and are more difficult to penetrate. Thus, what is needed is a stronger robot with a different design. The researchers are now planning to build the 100-micrometer VIBEBOT (Vibrational Micro-robot), which will be modeled on another microorganism, namely the schistosoma (blood fluke), a parasite that can penetrate human skin within a few minutes by vibrating its body. “To penetrate biological tissues,” says Qiu, “we need a similar system.” But how could one navigate such a mini-machine through the body in a controlled, wireless manner? How should the drive system be designed? How could the micro-robot sense its surroundings? And how could it be reliably located? These are the questions Qiu and his team will be addressing over the next five years. However, he is already clear about one thing: “Our research has huge potential for the minimally invasive treatment of hard-to-reach regions in the body, such as the brain.”

Minimally invasive methods are already state of the art in surgery and orthopedics for the treatment of many diseases and injuries. But the projects being carried out in the Emerging Field of Biomedical Systems are revealing how much room there is for improvement and how much research remains to be done, for example, by the "EndoPrint3D" consortium. The physicists, bio-technologists, and engineers involved in the project have set themselves an ambitious goal: “We are currently collaborating on the development of the world's smallest 3-D printer,” says collaboration coordinator Andrea Toulouse. The goal is for it to fit on the point of a needle and "reprint" destroyed tissue within the body from biogenic materials, i.e., materials known to the body, such as collagen or hyaluronic acid in order, for example, to restore parts of a spinal disk or an ear bone, or to close tiny holes in the cardiac septum of embryos. The intended aim of the procedure is to heal injuries quickly and with such precision that the surrounding tissue suffers as little damage as possible.

The printer is located at the end of a fiber optic endoscope, with a diameter of one millimeter, which is connected to a modified ultrashort pulse laser, used by a research group headed up by Prof. Harald Giessen at the 4th Physics Institute. This laser hardens the "bio-ink", which is delivered in a microfluidic process. A fine mesh of tissues, the extracellular matrix, which Michael Heymann, Junior Professor at the Institute of Biomaterials and Biomolecular Systems, describes as a "climbing frame", is reconstructed at the injured site, which can accommodate the cells needed for the regeneration process.

Atrosimab, OMTX705, VIBEBOT and EndoPrint3D are just a few examples from the large portfolio of excellent research being conducted in this emerging field. Above all, coordinator Monilola Olayioye relies on one thing to orchestrate them: a lot of communication. “To achieve scientific success and for a diverse set of teams to develop products together, you need a common language.” And a lot of stamina: It took the IZI team 15 years to get its new antibodies into human trials. On the other hand, according to Tian Qiu's estimates, it will take at least a decade before the nano- and microrobots being built in the IPC's labs will be ready to be deployed in patients – and that's being optimistic. “Many things are possible and are already being implemented in clinical practice,” says Prof. Olayioye. “But we also need to think big and ultimately develop intelligent systems that are not only customizable, but also easily constructed, adaptable, and affordable.”

Author: Jutta Witte