Novel biomaterials as well as combination products made of scaffold material and cellular components (tissue engineering) must be comprehensively tested before they are applied to humans. This is necessary to rule out complications such as material-related adverse reactions and implant failure before use in and on humans. Often established procedures can only be partially applied to new products. Therefore, test development is always done in parallel to product development. Biomaterials have to be tested for their functionality (e.g. mechanical resilience, abrasion resistance) as well as their biointeraction (e.g. biocompatibility).
During all development phases, the aforementioned planned areas of biological, biohybrid, and biofunctionalized implant creation require constant monitoring/follow-up and active influencing of tissue, cell, and immune responses as well as biofilm development. The methods of choice for the characterization, evaluation, or influencing in this area are the optical technologies. Aside from chemistry, microtechnology, and nanotechnology, particularly the optical methods can give significant impulses for the development and testing of novel implant functionality in vivo and in vitro. In contrast to costly sample preparations for histologic analyses, the purely optical-based methods offer the possibility of non-invasively following vital-reactions of cells and tissues. For in vivo questions this method offers the opportunity to directly observe and visualize processes in vivo over a long period. This can be done without having to sacrifice an animal at every time point. Thus, less animals are needed and also their individual reaction variations are reduced. The methodological and clinical competencies will be bundled at the NIFE location so that the existing methods spectrum at Hannover’s universities can be directly implemented. In addition, the demands that arise from working on medical issues will be directly transferred to new technological solutions. Tissue Engineering thus represents a cross section that accompanies and supports different research areas throughout the implant development process. Aside from the characterization and evaluation of novel implants in vivo and in vitro, the development and study of various optical imaging procedures such as non-linear laser microscopy, optical coherence tomography, and optical project tomography will be studied. Large proportions of these imaging methods exist so far mainly in basic research. They have not been used in clinical applications. Especially by combining these and other established imaging techniques, novel aspects will be created. This for example will allow high-definition imaging methods over several scales, which will make the use of cellular resolution on living animal models for implant-related issues possible. Additionally, the key issues will be expanded by follow-up/tracking of marked or modified cells in vivo. This will be based on specific markings that are achieved with fluorescence-based methods or CT/MRI-contrast medium. Furthermore, methods to specifically manipulate or monitor tissue cells such as laser printing of tissue in the research group of Prof. Chichkov, Laserzentrum Hannover, optogenetics in the research group of Prof. Heisterkamp, or piezo mechanical modification in the research group of Prof. Glasmacher will be investigated.
Research projects between the Leibniz University Hanover, the Laserzentrum Hanover, and the Hanover Medical School have already existed for several years and there is close cooperation in this area.
The Laserzentrum Hanover is currently already working intensively on various issues in the area of biomedical optics with the partners in NIFE and the MHH clinics. A central question is the abovementioned linking of different optical imaging scales in one device. By linking different optical modalities, vital tissue can be captured in an overview and if desired, individual areas can be enlarged to a cellular resolution (multiscale imaging). A possible application in the area of implantology will be directly following the cellular tissue reactions at the interface implant-tissue and thereupon allocate them according to the different image scales. This work on cellular laser-microscopy will be done in cooperation with the MHH (Prof. Haverich, Wilhelmi, Lenarz, Voigt, Krauss, Schwabe). Here, the focus will be on high-resolution multiscale imaging of cardiovascular implants and nerve tissue.
In combination with multiphoton-microscopy, approaches on laser-supported cellular manipulations will be studied. Recently, this has been done in connection with nanoparticles, by plasmon resonance and field enhancement on their surfaces, and in the area of optogenetics.
Another novel application for optical procedures in NIFE’s focus is the direct laser manipulation. Examples are the high-precision laser drilling and cutting for precise work and manipulation on bone, hard and soft tissue, laser printing of cells and tissue, up to selective handling of individual cells as well as isolation of cell clusters supported by volumetric imaging methods. Additionally, the high-resolution imaging will be combined with laser-processing making a “seeing scalpel” for robot-assisted surgery (Prof. Ortmaier, Ptok) possible. Further applications in NIFE are the characterization of tissue engineering constructs. Currently in collaboration with Witte, optical methods for tissue characterization at implant interfaces are being used in an in vivo mouse model. The Institute for Information Processing (Prof. Rosenhahn) will handle the analysis of the optically collected data.
A summary of the central issues:
Tissue function regeneration by implants is strongly dependent on the implant’s mechanical and physical properties and the material used. They have to be adapted to the particular application, and have to be studied under application conditions (e.g. body temperature, environment properties). In addition to standardized material testing such as pull or pressure tests, application related functionality and constant strength tests have to be performed. The research group Glasmacher has comprehensive competencies and the necessary equipment to test these properties. Aside from tempered mechanical test stations, functionality test stations for cardiovascular implants (heart valve and vessel prostheses), peripheral nerve implants, as well as bone implants are available.
Degradable implants have to be tested for their degradation kinetics. For cardiovascular applications the effect of hemodynamics (blood flow) has to be additionally investigated. For both issues, test stations as well as measuring systems such as particle image velocimetry (PIV) are available in the research group Glasmacher.
Aside from mechanical properties, the implant’s surface properties dictate the product’s clinical success. These can be specifically modified for each application. Typical tests that are used to investigate these properties in the research group Glasmacher are the determination of surface tension and surface topography (atomic force microscope). To test the effect of surface topography on biointeraction (e.g. blood tolerance) special circulatory systems are generally used that comprehensively simulate the conditions at the application site (flow condition, temperature).
Toxicity and biocompatibility tests (according to ISO 10993) that are relevant for approval of the material will be done by BioMedimplant and the Laboratory for Ototoxicology as part of the in vivo and in vitro testing. The latter can perform preclincal evaluations of auditory implants under GLP-conditions. The cooperation with the accredited Test Laboratory for Medical Devices of the MHH, BioMedimplant, and the Laboratory for Ototoxicology completes the value chain for clinical applications.