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FP7

IMMODGEL Report Summary

Project ID: 602694
Funded under: FP7-HEALTH
Country: Germany

Periodic Report Summary 2 - IMMODGEL (Local Immunomodulation around implants by innovative auxiliary hydrogel-based systems encapsulating autologous and phenotype controlled macrophages)

Project Context and Objectives:
IMMODGEL aims to identify adverse immune reactions to dental and larynx titanium implants and to develop a novel therapeutic strategy to significantly decrease the implant and medical device failure caused by these reactions via the design of an innovative immunomodulatory system.
Immune reactions to implants, biomedical devices, engineered tissues and transplants are a big obstacle in the biomedical field. Many implants and biomedical devices such as electrodes can lose their functionality after implantation due to immune responses, while the need to evade rejection of transplants narrows down the sources for the transplantable tissues and contributes to the persistent donor tissue shortage. The IMMODGEL project aims at understanding the nature and the underlying mechanisms of such adverse reactions with systems biology approaches. Such an understanding enables the development of immunomodulatory therapeutic systems with biomaterials using tissue engineering and regenerative medicine methodologies. Our aim is to design an immunomodulatory system applicable to different situations (transplants, implants, biomedical devices, etc.). The design will consist of an immunomodulatory hydrogel (first component) which contains encapsulated macrophages and is anchored to the titanium implant surface via a cytokine releasing adhesive layer (second component). The system will additionally present antimicrobial properties via release of antimicrobial agents from the adhesive component.
The third axis of research in IMMODGEL (aside from Systems biological understanding of immune responses to titanium and therapeutic immunomodulation) is the development of enabling technologies that would provide the tools for future research on immunomodulation, diagnostics of immune reactions to implants and overall immunology research. For this end, founded on the data generated, IMMODGEL will develop a patient immunoprofiler in the form of an on-chip system that is currently at the stage of validation. Additionally, a "Foreign Body Response on-a-chip" will be designed to predict patients´ specific responses to implant materials. The project will also develop immunocompetent engineered tissues to have in vitro models of immune reactions to biomaterials.
The key innovation will be the development of IMMODGEL as an auxiliary system to improve the outcomes of implantation and reduce the cost of implant complication and related medical costs in Europe. We aim to provide commercialisable marketable therapeutic, diagnostic systems and easily-transferable research tools at the end of the project together with a significant improvement in the understanding of the underlying causes of adverse reactions to biomaterials with methods to control them.

Project Results:
WP1: Parts of artificial larynx implants were put into contact with 1ary human macrophages. We detected markers that provide insight to the reaction to Ti in different patients, established the optimal biomaterial/cytokine cocktail delivery system for the hydrogel design and defined the components of the cocktail. To develop a diagnostic tool that predicts the immunological profile of the patient with respect to cytokine levels, target cytokines were selected. In Period 2, the validation of the immunoprofiling system was done, the cytokine cocktail system was elaborated further to attenuate the potential side effects and the specific effects of Ti on genes determined in period 1 were further demonstrated.
WP2: We produced and screened microwells, -pillars and -grooves with model monocytes and macrophages and determined the synergistic effects of cytokine induction and 2 selected surface patterns in terms of macrophage polarisation. The patterns can be introduced reproducibly to cell-laden hydrogels and used in the final therapeutic system. In Period 2, RT-monitoring of the shape induction by the patterns was carried out; together with image analyses to deconvolute the effects of pattern presence. Unbiased transcriptomic studies were done to better understand the effects.
WP3: 4 separate formulations have been successfully used for encapsulation of THP-1 cells and two were tested with 1ary macrophages. 4 optimal formulations were selected for further use in WP 4. Four working adhesive systems have been tested with 1ary macrophages for their ability to release cytokines. In Period 2, the assembly of the optimal gel formulations together with the optimal adhesive has been established and tested with different biomaterials. An additional wet adhesive was developed to ensure strong adhesion to the surfaces and the mechanical properties of the adhesive were characterised.
WP4: Several parameters such as stiffness, degradability, presence of cell adhesion sequences, hydrogel composition and crosslinking parameters have been varied and their effect on macrophage phenotype was tested in the presence and the absence of cytokine induction. This process fed into the selection process in WP3. In Period 2, we quantified the effect of adhesive and hydrogel composite on encapsulated macrophages in the presence of cytokine release. A strong correlation between macrophage phenotype with hydrogel degradability and hyaluronic acid presence was established.
WP5: We designed a prototype for a Foreign Body Response on-a-chip system which was first used to assess the macrophage reaction to Ti microbeads. For the immunocompetent epithelial tissue development, we developed artificial basement membrane mimics and tested them with respiratory epithelial cells. We also developed 3D sandwich-like structures for the connective part of the epithelial tissue and the methods of incorporating macrophages and macrophage-laden hydrogels in the model tissues. In period 2, an endothelial layer was added to Foreign Body Response on-a-chip system to mimic the monocyte movement from blood. Initial tests of hydrogel 3D printing were carried out. Co-cultures of macrophages with connective tissue cells were established.
WP6: In Period 2, the implantation protocol for testing of hydrogels was developed and implemented in a mouse model for the subcutaneous immunomodulation around implants. First proof-of-concept of IMMODGEL system in vivo was established. The second part of the WP will focus on immunomodulation in orthogonal positions (tracheal replacement).
WP7: In period 2, 20 scientific articles, 3 newsletter issues and 3 press releases (incl. an interview on YouTube with over 1660 views) were published. The project was further disseminated via social media, esp. Twitter. The consortium showed project results at 22 events worldwide in which IMMODGEL was highlighted. Partners UDS and Protip filed the first of four planned project-related patents.

Potential Impact:
The immunomodulatory system targeted in this project will consist of 1) autologous macrophages with a controlled phenotype 2) a composite hydrogel for macrophage and cytokine encapsulation and 3) a polyelectrolyte coating which will allow adhesion of the encapsulated macrophages to any implant. The efficiency and ability of the innovative immunomodulatory gel will be proven in vivo to achieve the overall project target of 80% improved integration rate and reduced immune reactions by 50%.
We have optimized several encapsulation systems and polyelectrolyte coatings that fit the requirements of the final therapeutic system. We have also developed the protocols for their assembly of the structures and their in vivo testing.
We have devised specific cytokine cocktails for precise control of macrophage phenotype that have been tested in 3D conditions. Artificial tissue model development for the testing of immunomodulation has been done and it will continue to be used in the second half of the project.
Via systems immunology, we were able to determine specific markers that can define the tissue response to medical grade titanium implants. This can be of significant prognostic value of the fate of such implants and will facilitate the clinicians and immunologists to holistically understand the adverse immune responses to implants, how these are controlled by macrophages and how to make judicious choices regarding host-implant compatibility. We also developed immunoprofiling methods based on cytokine measurements and epitope characterisation which can also be used for pre-implantation diagnostics applications.
To assess novel biomaterials, a foreign body response (FBR) on-a-chip system is being developed that will significantly reduce the research cost and the need for animal tests by replacing the compulsory biocompatibility tests with a sophisticated in vitro test. The initial design of the FBR on-a-chip system is ready and the final system will be finished in the second half of the project.
The results obtained on model implants can provide a necessary framework for a wide range of biomedical materials. By developing a system that can be applied to any kind of implant, transplant or biomedical device, the project will expand the capabilities of immunomodulation. In this sense, IMMODGEL will have a widespread impact and can improve the chances and success of many other European healthcare products. Our results up to now are in line with this claim and we hope to deliver the proposed impact following the animal tests.
IMMODGEL will yield high socio-economic impacts by significantly improving the health and quality of life of patients in EU and world-wide, and by decreasing therapy costs due to adverse immunological reactions. This research will not only improve the outcomes of implants and biomedical devices, but will also provide meaningful improvement of non-communicable diseases (NCDs). In an ageing society, by improving the lifetime of implants and biomedical devices, immunomodulatory systems can provide a meaningful saving on healthcare costs. The project will also help the development of personalized medicine or stratified medicine approaches to implantology and development of necessary tools to achieve the personalization.
The proposed system can be used in conjunction with all types of implants, particularly with the implants such as dental, orthopaedic, spine or larynx implants. Applicability to different structures can provide a comprehensive solution to adverse immunological responses without the need to change the design of the original implants. This will also allow reducing the need of animal experimentation due to the elimination of immune system related failures which will not only have positive economic impacts but also ethical ones. Also, the development of a diagnostic tool to quantify immune response to implants will decrease health costs by predicting and preventing possible excessive immune reactions. Creation of new employment opportunities followed by the newly developed technologies and the know-how will also offer a positive economic impact on the society.

List of Websites:
www.immodgel.org

Contact

Mercedes Laura Dragovits, (Project manager)
Tel.: +4972193519114
E-mail

Subjects

Life Sciences
Record Number: 199837 / Last updated on: 2017-06-21
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