TY - GEN A1 - Küenburg, Bernhard A1 - Teuschl, Andreas T1 - Regenerative silk ligament: scale up and regulatory strategy of a textile engineered silk implant for tissue regeneration of injured human ACL (anterior cruciate ligament) N2 - 61 a93591 27-SY-1 Regenerative silk ligament: scale up and regulatory strategy of a textile engineered silk implant for tissue regeneration of injured human ACL (anterior cruciate ligament) Bernhard Küenburg，Andreas Teuschl MorphoMed, Austria In the USA around 370.000 annual ACL ruptures in the predominately young population (age 18-30) following sport injuries cause a lot of pain and long term troubles for the affected patients. The well established standard procedure of autologous tissue transplantation stabilizes the knee and allows sport activities after 9-12 months. However, harvest of autologous tissue such as patellar tendon or semitendinosus (the most frequently used autograft) weakens other body areas and long term data show an increased rate of arthroses (up to 50% after 10 years) associated with ACL reconstructions. Based on numerous preclinical data and data from a 12-month sheep study the scale-up as well as regulatory approval process of a novel textile engineered silk implant as ACL graft have been initiated. It is planned to enter a clinical trial and strive for regulatory approval as a medical class 3 implant. The sheep data (1) have revealed an approximately 50% degradation of the purified medical silk, which acts as scaffold for the regrowth of a new endogenous ligament. The formation of oriented collagenous tissue fibers including vascularization proves a ligament tissue regeneration for the first time. Scale-up and implementation of a commercial process require a defined set of specifications of commercial silkworm (Bombyx mori) silk, a biological raw material sourced from the textile industry as well as adequate analytical methods to characterize the depletion of sericin in the course of the production process. Based on first full scale samples, the defined biocompatibility program has to be executed, in the EU following the ISO requirements of the notified bodies, in the USA determined by the FDA. Upon submission of the full technical documentation as well as the biocompati-bility data, approval of a clinical trial can be achieved in order to demonstrate the clinical efficacy of the silk based ACL graft compared to the gold standard method in two different randomized groups. As primary endpoint the knee stability will be tested by an apparatus supported Lachmann test. In this study, besides the clinical benefit the patient safety is an important goal. The results of this study will be used for achievement of regulatory approval. References: 1) Teuschl A, Heimel P, Nürnberger S, van Griensven M, Redl H, Nau T. Am. J. Sports Med. 2016;44:1547–57. 2) Teuschl AH, van Griensven M, Redl H. Tissue Eng. Part C Methods. 2014;20:431–9. KW - Biomaterial KW - Ligament Y1 - ER - TY - JOUR A1 - Tallian, Claudia A1 - Herrero-Rollett, Alexandra A1 - Stadler, Karina A1 - Vielnascher, Robert A1 - Wieland, Karin A1 - Weihs, Anna A1 - Pellis, Alessandro A1 - Teuschl, Andreas A1 - Lendl, Bernhard A1 - Amenitsch, Heinz A1 - Guebitz, Georg M. T1 - Structural insights into pH-responsive drug release of self-assembling human serum albumin-silk fibroin nanocapsules. JF - European Journal of Pharmaceutics and Biopharmaceutics N2 - Inflammation processes are associated with significant decreases in tissue or lysosomal pH from 7.4 to 4, a fact that argues for the application of pH-responsive drug delivery systems. However, for their design and optimization a full understanding of the release mechanism is crucial. In this study we investigated the pH-depending drug release mechanism and the influence of silk fibroin (SF) concentration and SF degradation degree of human serum albumin (HSA)-SF nanocapsules. Sonochemically produced nanocapsules were investigated regarding particle size, colloidal stability, protein encapsulation, thermal stability and drug loading properties. Particles of the monodisperse phase showed average hydrodynamic radii between 438 and 888 nm as measured by DLS and AFM and a zeta potential of -11.12 ± 3.27 mV. Together with DSC results this indicated the successful production of stable nanocapsules. ATR-FTIR analysis demonstrated that SF had a positive effect on particle formation and stability due to induced beta-sheet formation and enhanced crosslinking. The pH-responsive release was found to depend on the SF concentration. In in-vitro release studies, HSA-SF nanocapsules composed of 50% SF showed an increased pH-responsive release for all tested model substances (Rhodamine B, Crystal Violet and Evans Blue) and methotrexate at the lowered pH of 4.5 to pH 5.4, while HSA capsules without SF did not show any pH-responsive drug release. Mechanistic studies using confocal laser scanning microscopy (CLSM) and small angle X-ray scattering (SAXS) analyses showed that increases in particle porosity and decreases in particle densities are directly linked to pH-responsive release properties. Therefore, the pH-responsive release mechanism was identified as diffusion controlled in a novel and unique approach by linking scattering results with in vitro studies. Finally, cytotoxicity studies using the human monocytic THP-1 cell line indicated non-toxic behavior of the drug loaded nanocapsules when applied in a concentration of 62.5 µg mL-1. KW - Biomaterial KW - Tissue Engineering Y1 - ER - TY - GEN A1 - Teuschl, Andreas A1 - Schuh, Christina A1 - Weihs, Anna A1 - Guillaume, Olivier A1 - Monforte Vila, Xavier A1 - Redl, Heinz A1 - Kaplan, David A1 - Rünzler, Dominik T1 - Tailoring bioactivity of silk-based biomaterials via delivering and functionalization strategies with fibrinogen/thrombin, plant lectins or laminin KW - Biomaterials KW - Tissue Engineering KW - Silk Y1 - ER - TY - JOUR A1 - Slezak, Paul A1 - Slezak, Cyrill A1 - Hartinger, Joachim A1 - Teuschl, Andreas A1 - Nürnberger, Sylvia A1 - Redl, Heinz A1 - Mittermayr, Rainer T1 - A Low Cost Implantation Model in the Rat That Allows a Spatial Assessment of Angiogenesis. JF - Frontiers in Bioengineering and Biotechnology N2 - There is continual demand for animal models that allow a quantitative assessment of angiogenic properties of biomaterials, therapies, and pharmaceuticals. In its simplest form, this is done by subcutaneous material implantation and subsequent vessel counting which usually omits spatial data. We have refined an implantation model and paired it with a computational analytic routine which outputs not only vessel count but also vessel density, distribution, and vessel penetration depth, that relies on a centric vessel as a reference point. We have successfully validated our model by characterizing the angiogenic potential of a fibrin matrix in conjunction with recombinant human vascular endothelial growth factor (rhVEGF165). The inferior epigastric vascular pedicles of rats were sheathed with silicone tubes, which were subsequently filled with 0.2 ml of fibrin and different doses of rhVEGF165, centrically embedding the vessels. Over 4 weeks, tissue samples were harvested and subsequently immunohistologically stained and computationally analyzed. The model was able to detect variations over the angiogenic potentials of growth factor spiked fibrin matrices. Adding 20 ng of rhVEGF165 resulted in a significant increase in vasculature while 200 ng of rhVEGF165 did not improve vascular growth. Vascularized tissue volume increased during the first week and vascular density increased during the second week. Total vessel count increased significantly and exhibited a peak after 2 weeks which was followed by a resorption of vasculature by week 4. In summary, a simple implantation model to study in vivo vascularization with only a minimal workload attached was enhanced to include morphologic data of the emerging vascular tree. KW - Tissue Engineering KW - Bioreactor KW - Biomaterial Y1 - ER - TY - JOUR A1 - Berkovitch, Yulia A1 - Cohen, Talia A1 - Peled, Eli A1 - Schmidhammer, Robert A1 - Hildner, Florian A1 - Teuschl, Andreas A1 - Wolbank, Susanne A1 - Yelin, Dvir A1 - Redl, Heinz A1 - Seliktar, Dror T1 - Hydrogel composition and laser micropatterning to regulate sciatic nerve regeneration. JF - Journal of Tissue Engineering and Regenerative Medicine N2 - Treatment of peripheral nerve injuries has evolved over the past several decades to include the use of sophisticated new materials endowed with trophic and topographical cues that are essential for in vivo nerve fibre regeneration. In this research, we explored the use of an advanced design strategy for peripheral nerve repair, using biological and semi-synthetic hydrogels that enable controlled environmental stimuli to regenerate neurons and glial cells in a rat sciatic nerve resection model. The provisional nerve growth conduits were composed of either natural fibrin or adducts of synthetic polyethylene glycol and fibrinogen or gelatin. A photo-patterning technique was further applied to these 3D hydrogel biomaterials, in the form of laser-ablated microchannels, to provide contact guidance for unidirectional growth following sciatic nerve injury. We tested the regeneration capacity of subcritical nerve gap injuries in rats treated with photo-patterned materials and compared these with injuries treated with unpatterned hydrogels, either stiff or compliant. Among the factors tested were shear modulus, biological composition, and micropatterning of the materials. The microchannel guidance patterns, combined with appropriately matched degradation and stiffness properties of the material, proved most essential for the uniform tissue propagation during the nerve regeneration process. KW - Tissue Engineering KW - Biomaterials KW - Nerve Regeneration Y1 - SP - 1049 EP - 1061 ER - TY - JOUR A1 - Nau, Thomas A1 - Teuschl, Andreas A1 - Ebner, Anna A1 - Jung, Ilse A1 - Schenk, Christian T1 - Low revision rate and excellent outcome of primary ACL repair with a minimum follow-up of 5 years. JF - Muscle, ligaments and tendons Journal N2 - Introduction: Due to limitations of ACL reconstruction, primary ACL repair has recently regained research interest. Although abandoned in the past, primary repair with conservation of the original ligament demonstrates considerable advantages compared to reconstruction. We hypothesized that early repair, strictly limited to patients with a proximal ACL rupture and excellent tissue quality of the remaining ACL stump, would lead to equal revision rates and subjective outcomes as reported for ACL reconstruction after a minimum of 5 years. Methods: In this questionnaire study, patients who had a primary ACL repair between 2002 and 2009 were invited to participate. Besides any potential revision surgery, the Tegner activity scale and the Knee Injury and Osteoarthritis Outcome Score were included in the evaluation. Results: Out of 1912 patients who had ACL related surgery during the observation period, 221 (11.4%) had a primary ACL repair. 60 patients (61 knees) were available for follow-up. In 2/61 (3.3%) cases ACL revision surgery was performed and one patient had meniscus surgery of the affected side. The median Tegner activity scale was 6 (range, 3 to 10). The mean KOOS subscores were 88.8% (Function/Sports), 86.6% (Quality of life), 94.6 (Symptoms), 94.0 (Pain) and 97.0 (Activities of Daily Living). Conclusion: Primary ACL repair, strictly limited to proximal ruptures with good tissue quality leads to revision rates and subjective outcome comparable to ACL reconstruction. Level of evidence: IV. KW - Regeneration Y1 - SP - 185 EP - 190 ER - TY - GEN A1 - Teuschl, Andreas A1 - Heimel, Patrick A1 - Monforte Vila, Xavier A1 - Nürnberger, Sylvia A1 - Tangl, Stefan A1 - van Griensven, Martijn A1 - Redl, Heinz A1 - Nau, Thomas T1 - Anterior cruciate ligament regeneration using the silk-based RegACL scaffold KW - Tissue Engineering KW - Silk KW - Biomaterial KW - Anterior Cruciate Ligament Y1 - ER - TY - CHAP A1 - Hackethal, Johannes A1 - Schuh, Christina A1 - Hofer, Alexandra A1 - Meixner, Barbara A1 - Hennerbichler, Simone A1 - Redl, Heinz A1 - Teuschl, Andreas T1 - Human Placenta Laminin-111 as a Multifunctional Protein for Tissue Engineering and Regenerative Medicine T2 - Advances in Experimental Medicine and Biology KW - Biomaterial KW - Tissue Engineering KW - Regenerative medicine Y1 - PB - Springer ER - TY - GEN A1 - Salzer, Elias A1 - Rieder, Bernhard A1 - Monforte Vila, Xavier A1 - Weihs, Anna A1 - Rünzler, Dominik A1 - Teuschl, Andreas T1 - Evaluation of a novel hydrostatic pressure bioreactor on bovine cartilage chips KW - Bioreactor KW - Tissue Engineering KW - Cartilage Y1 - ER - TY - GEN A1 - Hromada, Carina A1 - Tomasch, Janine A1 - Weihs, Anna A1 - Rünzler, Dominik A1 - Teuschl, Andreas T1 - Engineering of 3D Tissue Constructs Using our Novel MagneTissue Bioreactor as Alternatives to Animal Models KW - Bioreactor KW - Biomaterials Y1 - ER -