Biomaterial development may be seen as an elementary example for the interdisciplinary cooperation in NIFE. Clinical routine defines the requirements for synthetic and biological implant materials. The implants are created either conventionally artificially, as a biohybrid with resorbing structures, or completely biologically. The scientific groups of chemistry and biochemistry are developing intelligent materials and methods for specific modification and/or functionalization. The engineering sciences use these approaches to provide an industrial scale for tissue engineering and implant technology. The materials have to be tested beforehand to determine whether they fulfill the desired mechanical and biological properties. The development of implant production follows in cooperation with the work groups at the Leibniz University Hanover and the functional testing on lab samples in cooperation with the Hanover Medical School.
The material development focus is on nanoporous, nanoparticular, as well as polymer or composite materials. The materials must demonstrate the mechanical, physical, biological, and (bio-)chemical characteristics in bulk and on the surface as defined by their clinical application. Thus, they must demonstrate suitable mechanical stability, biocompatibility and possibly be resorbable as well as sterilizable. They will be functionally equipped on the surface or with nanoporous depots (release of bioactive substances) to achieve the desired cell and tissue integration, the prevention of biofilm development, and the resistance against infections. The trend is towards a temporal and site controlled supply with various substances (small-molecule drugs, specific growth factors, adhesion proteins), away from simple drug-delivery-systems. Aside from dense materials, surface-structures or nanoporous materials will specifically regulate growth of individual cell systems and will make specific material-cell contacts (e.g. signal transduction, adhesion, permission) possible. Matrices for tissue engineering will be e.g. made chemically using template methods. They will be appropriately equipped. Nanoparticles will be supplied with magnetic and fluorescing properties for the tempo-spatial control and for imaging, respectively. The materials have to be custom-made for each medical issue.
To achieve this goal, it is necessary to create material modules. This includes not only the composition of the basic materials and their structure, but also the specific chemical preparation of their surfaces to equip them with the desired chemical, physicochemical, and biological surface traits. Especially, the custom adjustment of the carrier material‘s biological properties needs close cooperation between the material- and substance-oriented work groups (research groups of Prof. Behrens and Kirschning). Furthermore, the implementation of biotechnological expertise (research group Scheper/Blume) is needed to decorate the surfaces for example with adhesion factors, toxins, and cytokines as well as antibiotics.
The Institute for Multiphase Processes/Biomedical Engineering (research group of Prof. Glasmacher) is developing methods to produce synthetic substances created at a laboratory scale to the desired scale according to GMP, to produce lab samples of the implants, and to characterize their properties and functions. The materials may also be created by cryostructuring e.g. biomimetic pearl or collagen or by electrospinning/electrosprays and can simultaneously be functionalized. A close, direct cooperation of the work groups for each application field is necessary to effectively transfer knowledge.
Audio-neurological, cardiovascular, dental, orthopedic, and skeletal medical groups will be involved in material development. On patients, they will define and communicate the future clinical demands. This will enable the chemical and technical groups to seek a clear goal that will be achieved accordingly.
The newly developed materials’ biocompatibility as well as its specific clinical requirements will be tested and trained in the research group Biotesting (Prof. Blume, Institute f. Technical Chemistry, director Prof. Scheper). For this purpose, a graded assay system is available that works with human cells from cell lines as well as primary cells. The development of a need-based bioreactor is also possible to test the culture of possible scaffold materials. Adjusted bioreactors will be equipped for dynamic cultivation with sensors and corresponding electronics to collect important cultivation and cell metabolism parameters (e.g. oxygen, glucose, pH-value, temperature) (in cooperation with research group of Prof. H. Blume, eNIFE). The development of the bioreactor also includes the functional strain on the cell-based implants (mechanotransduction) with defined applied shear forces for the cardiovascular area, tensile loading in the musculoskeletal area, or pressure burden in the osseous area.
Furthermore, need-based modified and functionalized biomacromolecules and organic-inorganic composite materials will be synthesized for the implants that are being developed. The Technical Chemistry in close cooperation with the MHH-work groups will produce and supply the necessary cytokines and growth factors, but also the essential biomolecules for scaffolds such as fibrinogen or human collagen etc. These biologically active substances will be produced in bacterial and mammalian cell cultures. The substances will be purified and tested for their biological activity before they are made available to the Organic and Inorganic Chemistry for biomaterial functionalization. In cooperation with different groups, biohybrid implants will be developed using optogenetic methods that allow an optical control of cell functions or high-definition stimulation of nerve and muscle cells (research groups of Prof. Heisterkamp, H. Blume (eNIFE), Behrens, LUH).
Structuring will be done in cooperation with the research groups Nanomaterials and Nanotechnology, LZH; methods based on optical processes for surface functionalization, construction using two photon polymerization, or specific nanoparticles are available. In the next step biological cells will be applied. For this purpose, cell-based testing of scaffolds for tissue engineering as well as for implant coating and the optimization of its colonization and cultivation will be performed under dynamic conditions in appropriate bioreactors. The materials will be colonized with suitable cell lines and primary cells under controlled, static as well as dynamic culture conditions. The so called LIFT-procedure (laser-induced forward transfer) allows the direct colonization with cells in 3D. Using different laser-based methods, the developed constructs can be tested and characterized under high-definition conditions using various scales.
In cooperation with the clinical groups, functional testing equipment for endoprostheses (knee, hip) or dental implants are already available. Bioreactor-developments are being initiated as in vivo-test systems e.g. for growing heart valves (tissue engineering). Here, a direct cooperation with the cross sectional area of in vivo-imaging with innovative video-based image analysis for the online cell growth monitoring is essential (research group Rosenhahn, eNIFE).
n material development, the scientific and engineering groups are working closely together with the medical work groups audio-neurology as well as the cardiovascular, dental, orthopedic, and skeletal areas. A core work group Cytokine Production and Biotesting between LUH and MHH exists (Blume/Scheper). Functionalization and structuring of biomaterials and nanoparticle systems are being handled by Chemistry (research groups of Prof. Behrens, Kirschning), Mechanical Engineering (Prof. Glasmacher), and LZH (Prof. Chichkov, Dr. Ripken). Various innovative processing methods for implants and hybrids are offered in close cooperation with the partners by the engineering-technical groups (Prof. Heisterkamp, Chichkov, Glasmacher). The bioreactor and mechanotransduction system development will be jointly advanced by the work groups of the MHH and the LUH (Prof. Glasmacher, Haverich, Vogt, Blume/Scheper, Dr. Gryshkov). Diverse analysis, sensors, and imaging systems to monitor the production and test the functionality (incl. steering technology and integrated electronics) will be made available and will be adapted to various issues by the work groups of the LUH (Prof. Blume, Heisterkamp, Glasmacher, Rosenhahn, Scheper, Ostermann, Zimmermann). Testing procedures for the different hybrids, implants, and functionalized tissues will mainly be supervised by the engineering side (Prof. Glasmacher) in cooperation with the different work groups.