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Engineering responsive and biomimetic hydrogels for biomedical therapeutic and diagnostic applications

Periodic Reporting for period 1 - BIOGEL (Engineering responsive and biomimetic hydrogels for biomedical therapeutic and diagnostic applications)

Reporting period: 2015-01-01 to 2016-12-31

BIOGEL is set up to educate young scientists to develop innovative hydrogel chemistries and systems for biomedical applications.
The objective is to provide a platform for 14 young researchers to undergo a PhD education, focused on translational skills for a career in biomedical research and medical technology development. Biomedical research is an interdisciplinary topic, based on chemistry, biology, engineering, medicine, and physics. Thus, the students need an all-embracing education and learn how to communicate and find solutions across disciplines.
The second objective in ESR education is to engineer functional and responsive hydrogels, which resemble specific properties of the extracellular matrix (ECM).
The third objective is application directed
- to enhance the efficacy of medical devices by 2D biointegrative coatings that direct and orchestrate the interface to living cells and tissue and enable improved integration in the body,
- to advance therapeutic measures by 3D templates for tissue repair,
- to enable new diagnostic tools by responsive diagnostic hydrogels.
BIOGEL follows an international, interdisciplinary, and intersectoral approach organized in 9 and 8 interwoven work & training packages respectively, focused on synthetic and biohybrid macromolecules to build clinically translatable hydrogels with specific, application directed bioactivities. To enable efficient biohybridisation and minimal invasive application, emphasis is set on in situ gelation of precursors not affecting the viability of cells and living tissue that interlink bioactive subunits to stimulate tissue regeneration and serve as functional component in biomedical devices. Structural incorporation of such units must be flexible, dynamic, and responsive to stimuli. This is directed to enhance cell behavior and receptor interaction, tailor the mechanical properties, and enable spatial, temporal, and topographical control of functional components. Translational aspects focus on coatings of medical devices, diagnostic hydrogels, cartilage and bone repair, tissue engineering for cardiovascular implants, and nerve regeneration.
Hydrogels were prepared based on synthetic polymers, e.g. star polyethylene glycol, poly (N-isopropylacrylamide), and polyisocyanides, and natural materials, like hyaluronic acid, Elastin-like recombinamers (ELRs), and fibrinogen. Hybrid hydrogels and grafting of hybrid polymer brushes have been developed to obtain tailored properties. Novel bicyclic fibronectin peptides and optimized laminin derived peptides were designed to bio-modify the hydrogels. Hydrogels were prepared with a wide range of mechanical properties. By using thermoresponsive polymers and ELRs, hydrogels responsive to temperature were produced.
(i) Biointegrative coatings for implantable sensors via routes to synthesize stable, crosslinked biomacromolecule nanoparticles with controlled diameters between 70–200nm, applicable to coat medical devices for enhanced biointegration were developed. Coatings were obtained via “grafting from” of defined layer thickness, stable for more than 2 M in solution and leading to an order of magnitude better anti-fouling properties compared to reference.
(ii) BIOGEL progressed towards developing 3D templates for tissue repair. The 3D patterning to spatially control biological domains inside the gel to guide cell growth was developed. Biocompatible microgels were fabricated using microfluidics and will further be investigated for cell encapsulation. Work started towards the production of HA/PEG hydrogels and biocompatible, synthetic PIC-based gels were developed that are currently studied as artificial matrix material for different cell types to study differentiation as function of material properties. Studies to induce in vitro vascularization and stem cell differentiation inside the 3D matrices are ongoing. Different cross-linking motifs and adhesion sites have been integrated into ELRs for the formation of in situ gelling 3D cell culture gels. The latter were applied inside ex vivo models to test the behavior and function of the hydrogel materials. A bioreactor was established to test cell cultures in hydrogels for long-term periods, including changes in mechanical properties and production of degradation products. A dynamic hydrogel system to analyze the mechanosensitivity of different cell types and bacteria was designed.
(iii) Novel plasmonic structures comprising stimuli-responsive hydrogels were developed by techniques that combine UV-laser interference and UV nano-imprint lithography, and template stripping. Plasmonic nanostructures including arrays of plasmonic nanoholes and nanoparticles supporting collective localized surface plasmons were characterized in terms of morphology and tunable optical properties. Current work focuses on employment of the nanostructures for sensing by using local modification of plasmonic hotspot with ligand molecules for specific capture of target analyte.
BIOGEL focuses on the development of hydrogel biomaterials to coat medical devices, as tissue engineering constructs, to develop ex vivo tissue models, and to design diagnostic systems. This requires an interdisciplinary approach and convergence between different research institutes and companies addressing the pressing issues in biomedical research.
One of the challenges with implants and medical devices is the rejection from the body or inflammation, which leads to dysfunctional products requiring replacement and increased medical costs. Better bio-integration leads to less failure and long term function in the body.
Tissue engineering products are developed to address the need to regenerate tissues after damage or disease. These therapies open the path to offer solutions to the growing list of patients (>119,000 US, organdonor.gov11/16) waiting for an organ donor.Though the global market of tissue engineering products increased significantly over the last decade up to approx. $25 billion (MedMarket Diligence) we are still facing multiple challenges.
Moreover, the mechanism of many diseases is still unknown or effective drugs have to be found. To investigate these pathologies and find therapeutic solutions, ex vivo tissue models can contribute to provide a research platform. Commercial ex vivo tissue models are currently limited to skin models, e.g. Phenion® Full-Thickness Skin Model, Henkel and Epsikin, l’Oreal, mainly applied to test cosmetics. To mimic relevant disease models, we need to vascularize and innervate these constructs, and expand them to other tissues besides skin. The availability of these models would create a large market to elucidate how certain diseases occur, and develop and test drugs and therapies, reducing the need for animal research.
For diagnostic purposes, tailored hydrogel materials are deployed at the interface between the biological sample and technical transducer that probes the specific capture of target species. To efficiently probe complex samples or enable continuous monitoring with implanted sensors, the hydrogel coating assures biocompatibility and avoids blocking of the sensor surface. The novel hydrogel-based biointerfaces are expected to enable the sensitive analysis of trace amounts of biomarkers in new settings that are closer to the patient and do not require centralized laboratories.
Hollow poly (ethylene glycol) microgels loaded with fluorescently labeled dextran (10 kDa) for the
Enzymatic patterning of biofunctional RGD peptides inside a 3D poly (ethylene glycol) hydrogel