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Biofunctionality and functionalization VIANNA

Institute of AudioNeuroTechnology (VIANNA): www.vianna.de

In the various application fields, biofunctionality and functionalization are important research challenges of medical implant development. The optimization of the cell-specific implant surface and the implant‘s function are inseparable and of fundamental importance to all organ systems joined in NIFE.

An optimized electrode-nerve-interface e.g. of audio- and neuroprostheses will be created by micro- and nanostructuring of biocompatible electrode material with a cell-specific link (artificial synapsis) to the neuron. The material will be (bio-)chemically functionalized and biologicalized including local drug delivery. The signal coding e.g. of the acoustic signal has to be optimally aligned to the interface to offer the brain information that is as natural as possible and neuronally implementable. In audio- and neuroprosthetics, the implant functionalization is clinically especially important: Over 15 % of the population needs to be treated for hearing loss. The percentage increases with age from 0.1 % in infants to about 50 % in over 65-year olds. Due to the demographic change, this is expected to increase even more. 20 % suffer from so called sound conduction hearing loss that is usually the result of a middle ear infection. 80 % have so called sensorineural hearing loss due especially to damage of the hair cells in the inner ear. There is currently no possible regeneration of damaged hair cells.

In the past twenty years, a broad range of hearing aids (apparative hearing aids) were developed allowing the prosthetic treatment of different types of hearing loss and hearing severities. Important progress has been made in the so called signal processing, the acoustic-mechanical converter, as well as the impulse electrodes of these prostheses. For patients with intermediate to high-grade hearing loss passive implants or mechanical converters are used that directly stimulate the middle or inner ear. For high-grade hearing loss and deafness direct electrical stimulation of the auditory nerve is achieved with cochlear implants. These implants make it possible for the majority of deaf people to comprehend speech without additional help and for deaf children to develop normal speech. However, modern prostheses do not completely restore normal hearing. Speech comprehension in the presence of background noise, directional hearing and thus the ability to communicate in everyday life, as well as hearing music are strongly impaired. An important reason for the impaired performance of hearing aids is e.g. the low specificity of the electrical auditory nerve stimulation and the highly limited numbers of information transmission channels, which are only about 1 % of normal hearing.

Both the implant-tissue-interface and the biofunctionality will be centrally studied. The cooperating scientists in NIFE have created work groups in the SFB 599 and SFB TR 37 as well as in the EU-project NanoEar and the Excellence Cluster Hearing4all. They are working on fundamental scientific issues and have created exceptional methodological expertise.

The research planned in NIFE is aimed at functionally restoring hearing as well as other neuronal functions. This includes the restoration of natural stimulation patterns in the CNS and optimizing the electrode-nerve-interface. Biohybrid electrodes with artificial synapses and alternative stimulation modi with optoacoustic, biophotonic, and mechanical actuators will be developed. In particular it will be studied e.g. whether coatings with colloidal laser-generated platinum-, platinum-iridium-, or tungsten-nanoparticles can improve the long term stimulation or derivation characteristics of microelectrodes. There are already collaborations in the development of electrodes between the ENT-clinic (research group of Prof. Lenarz), Neurosurgery (research groups of Prof. Schwabe and Prof. Krauss), and the Laserzentrum Hannover (research group of Prof. Chichkov).

On the one hand, future hearing implants will additionally contain local drug delivery systems (fluid-based, degradable polymer coating, nanoparticle) for protection of the residual hearing capacity, for regeneration, and for gene therapy. On the other hand, they will contain cellularized electrodes. This will make the development of real neuronal interfaces and stem cell-based regeneration of the damaged organ possible. This can e.g. be achieved by using mesenchymal stem cells. Functionalization of the auditory implant surfaces to improve their function include physical micro- and nanostructuring, chemical/biochemical functionalization using polymer coatings or covalent binding of biologically active groups and drugs. In addition, the biological functionalization will be improved by adhesion of genetically modified cells that overexpress growth factors and release these to the surrounding cochlear tissue. Optimization and characterization of the electrode-nerve-interactions will be done exemplarily on Cochlear-implant- and central auditory electrodes (auditory-midbrain-implant [AMI]). Jointly with the work groups Nanomaterials, Laserzentrum Hannover (Prof. Chichkov) multifunctional nanoparticles will be developed that allow different molecules such as chemicals, proteins, genes, or gene products to latch on to the cochlear implant, to be transported to the inner ear, to be specifically released, and then to enfold a specific effect with low toxicity. The functionalization and microstructuring of the surfaces will be done using laser optical methods (Prof. Chichkov, Prof. Lubatschowski) in collaboration with work groups from the ENT-Clinic (Prof. Lenarz, Prof. Kral). Also involved is the inorganic chemistry at Leibniz University Hanover (Prof. Behrens). The work with transfected cells and stem cells will be done jointly by the ENT-Clinic,MHH (Prof. Warnecke), the Small Animals Clinic, TiHo (Prof. Nolte), and the Trauma Surgery Clinic, MHH (Prof. Hoffmann). The cell integration and optimization of the electrode-nerve-interaction will be followed in vivo using imaging procedures (Prof. Heisterkamp). Studies relevant for approval will be performed jointly by the Ototoxicology Laboratory, ENT-Clinic (Dr. Voigt), BioMedimplant (Dr. Sowa-Söhle), and HCTC (Hannover Clinical Trial Center). Functionality testing of the auditory and neuronal prostheses will be studied in suitable animal models.

An important drawback of electrical stimulation is the spreading of the electrical field, which expands spherically with homogenous resistance. Laser light is inherently much more focused. The basics of spatial selective nerve system activation by optoactors have been preliminarily studied in the SFB TR 37. This will be continued in the Excellence Cluster H4a. “Biophotonic“ stimulation allows a very precisely defined tissue stimulation. This is especially beneficial in the inner ear. The mechanical properties of the optoactors that were developed for this purpose will be optimized by suitable nanomechanical actors for an atraumatic positioning. Efficacy and the evaluation of possible damage potentials will be investigated using isolated Cochlear samples as well as in acute animal models. Biocompatibility and long term stability will be tested in suitable experimental animal models.

The research group Optoacoustics (Prof. Lenarz, Kral, Baumhoff, Balster) collaborates closely with the work groups Biomedical Optics, Biophotonics (Dr. Ripken) and Institute for Quantum Optics, LUH (Prof. Ertmer). The electrophysiology, central processing, effects of hearing loss, interactions of electrical and acoustic stimulation of residual hearing, questions on central laser stimulation, as well as functional testing of surface conditioning will be handled by the research group of Prof. Kral in cooperation with Prof. Büchner and Prof. Kopp.

Aside from electrical and optical stimulation of the interface implant-nerve-tissue, it is of great interest for an objective efficacy evaluation of these novel strategies to test the signal processing during auditory implant use. So far, there are no suitable approaches. By developing new energy optimized signal processing strategies, natural neuronal stimulation patterns will be created. This will lead to better auditory discrimination performance. These new procedures will lead to a clear advancement of successively reaching neuronal stimulation patterns between electrical and natural stimulation of the cochlear. The research group Signal Processing (Prof. Büchner) has been successfully working on this issue for years with the Institute for Information Technology, LUH (Prof. Edler, Ostermann) and the Neurologic Clinic, MHH (Prof. Dengler).

Concurrent with the development of the auditory implant, special operation techniques for the minimal invasive insertion will be developed. In a three stage concept, using the integration of cochlear implants (CI) as an example, equipment adjustments and new functional patterns will be developed and preclinically and clinically tested. Possibilities of minimal invasive access for CI-operations , robot-assisted drilling, navigation-supported positioning of the drill, and mini-stereotactical drilling, as well as positioning of the electrodes using automated insertion tools will be developed and tested. Studies on the electrode kinematics of passive CI-electrodes, the optimization of insertion by considering the specific bending properties, the development of active CI-electrodes for steerable insertion e.g. by integration of shape memory elements in the form of individual wires, multiactor-arrays, or hydraulic actors will be done. The implementation of these high-grade surgical techniques will allow patient-specific implantation by minimally invasive, robot-assisted interventions. These newly developed surgery techniques can also be used in other areas such as orthopedics. The research group CAS (computer- and robot-assisted surgery, Prof. Majdani) is collaborating closely with the Institute for Mechatronic Systems, LUH (Prof. Ortmaier).

Results achieved in the areas of biofunctionality and functionalization will also be beneficial for other organ-specific work groups in NIFE. Existing collaborations of SFBs and the Excellence Cluster will be developed further and will be optimized by the bundling of different groups in NIFE at one location. Due to the close proximity of the Deutsche HörZentrum Hannover (DHZ) and the industrial partners located there, a direct transfer of the achieved basic research results to the corresponding clinical research is excellently accomplished.

"Hören für alle – Hearing4all Forschung im Exzellenzcluster"