Project acronym 3D-JOINT
Project 3D Bioprinting of JOINT Replacements
Researcher (PI) Johannes Jos Malda
Host Institution (HI) UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Call Details Consolidator Grant (CoG), LS7, ERC-2014-CoG
Summary The world has a significant medical challenge in repairing injured or diseased joints. Joint degeneration and its related pain is a major socio-economic burden that will increase over the next decade and is currently addressed by implanting a metal prosthesis. For the long term, the ideal solution to joint injury is to successfully regenerate rather than replace the damaged cartilage with synthetic implants. Recent advances in key technologies are now bringing this “holy grail” within reach; regenerative approaches, based on cell therapy, are already clinically available albeit only for smaller focal cartilage defects.
One of these key technologies is three-dimensional (3D) bio-printing, which provides a greatly controlled placement and organization of living constructs through the layer-by-layer deposition of materials and cells. These tissue constructs can be applied as tissue models for research and screening. However, the lack of biomechanical properties of these tissue constructs has hampered their application to the regeneration of damaged, degenerated or diseased tissue.
Having established a cartilage-focussed research laboratory in the University Medical Center Utrecht, I have addressed this biomechanical limitation of hydrogels through the use of hydrogel composites. Specifically, I have pioneered a 3D bio-printing technology that combines accurately printed small diameter thermoplast filaments with cell invasive hydrogels to form strong fibre-reinforced constructs. This, in combination with bioreactor technology, is the key to the generation of larger, complex tissue constructs with cartilage-like biomechanical resilience. With 3D-JOINT I will use my in-depth bio-printing and bioreactor knowledge and experience to develop a multi-phasic 3D-printed biological replacement of the joint.
Summary
The world has a significant medical challenge in repairing injured or diseased joints. Joint degeneration and its related pain is a major socio-economic burden that will increase over the next decade and is currently addressed by implanting a metal prosthesis. For the long term, the ideal solution to joint injury is to successfully regenerate rather than replace the damaged cartilage with synthetic implants. Recent advances in key technologies are now bringing this “holy grail” within reach; regenerative approaches, based on cell therapy, are already clinically available albeit only for smaller focal cartilage defects.
One of these key technologies is three-dimensional (3D) bio-printing, which provides a greatly controlled placement and organization of living constructs through the layer-by-layer deposition of materials and cells. These tissue constructs can be applied as tissue models for research and screening. However, the lack of biomechanical properties of these tissue constructs has hampered their application to the regeneration of damaged, degenerated or diseased tissue.
Having established a cartilage-focussed research laboratory in the University Medical Center Utrecht, I have addressed this biomechanical limitation of hydrogels through the use of hydrogel composites. Specifically, I have pioneered a 3D bio-printing technology that combines accurately printed small diameter thermoplast filaments with cell invasive hydrogels to form strong fibre-reinforced constructs. This, in combination with bioreactor technology, is the key to the generation of larger, complex tissue constructs with cartilage-like biomechanical resilience. With 3D-JOINT I will use my in-depth bio-printing and bioreactor knowledge and experience to develop a multi-phasic 3D-printed biological replacement of the joint.
Max ERC Funding
1 998 871 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym AGGLONANOCOAT
Project The interplay between agglomeration and coating of nanoparticles in the gas phase
Researcher (PI) Jan Rudolf Van Ommen
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
Call Details Starting Grant (StG), PE8, ERC-2011-StG_20101014
Summary This proposal aims to develop a generic synthesis approach for core-shell nanoparticles by unravelling the relevant mechanisms. Core-shell nanoparticles have high potential in heterogeneous catalysis, energy storage, and medical applications. However, on a fundamental level there is currently a poor understanding of how to produce such nanostructured particles in a controllable and scalable manner.
The main barriers to achieving this goal are understanding how nanoparticles agglomerate to loose dynamic clusters and controlling the agglomeration process in gas flows during coating, such that uniform coatings can be made. This is very challenging because of the two-way coupling between agglomeration and coating. During the coating we change the particle surfaces and thus the way the particles stick together. Correspondingly, the stickiness of particles determines how easy reactants can reach the surface.
Innovatively the project will be the first systematic study into this multi-scale phenomenon with investigations at all relevant length scales. Current synthesis approaches – mostly carried out in the liquid phase – are typically developed case by case. I will coat nanoparticles in the gas phase with atomic layer deposition (ALD): a technique from the semi-conductor industry that can deposit a wide range of materials. ALD applied to flat substrates offers excellent control over layer thickness. I will investigate the modification of single particle surfaces, particle-particle interaction, the structure of agglomerates, and the flow behaviour of large number of agglomerates. To this end, I will apply a multidisciplinary approach, combining disciplines as physical chemistry, fluid dynamics, and reaction engineering.
Summary
This proposal aims to develop a generic synthesis approach for core-shell nanoparticles by unravelling the relevant mechanisms. Core-shell nanoparticles have high potential in heterogeneous catalysis, energy storage, and medical applications. However, on a fundamental level there is currently a poor understanding of how to produce such nanostructured particles in a controllable and scalable manner.
The main barriers to achieving this goal are understanding how nanoparticles agglomerate to loose dynamic clusters and controlling the agglomeration process in gas flows during coating, such that uniform coatings can be made. This is very challenging because of the two-way coupling between agglomeration and coating. During the coating we change the particle surfaces and thus the way the particles stick together. Correspondingly, the stickiness of particles determines how easy reactants can reach the surface.
Innovatively the project will be the first systematic study into this multi-scale phenomenon with investigations at all relevant length scales. Current synthesis approaches – mostly carried out in the liquid phase – are typically developed case by case. I will coat nanoparticles in the gas phase with atomic layer deposition (ALD): a technique from the semi-conductor industry that can deposit a wide range of materials. ALD applied to flat substrates offers excellent control over layer thickness. I will investigate the modification of single particle surfaces, particle-particle interaction, the structure of agglomerates, and the flow behaviour of large number of agglomerates. To this end, I will apply a multidisciplinary approach, combining disciplines as physical chemistry, fluid dynamics, and reaction engineering.
Max ERC Funding
1 409 952 €
Duration
Start date: 2011-12-01, End date: 2016-11-30
Project acronym AUTOCOMPLEMENT
Project The role of complement in the induction of autoimmunity against post-translationally modified proteins
Researcher (PI) Leendert TROUW
Host Institution (HI) ACADEMISCH ZIEKENHUIS LEIDEN
Call Details Consolidator Grant (CoG), LS7, ERC-2016-COG
Summary In many prevalent autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) autoantibodies are used as diagnostic and prognostic tools. Several of these autoantibodies target proteins that have been post-translationally modified (PTM). Examples of such modifications are citrullination and carbamylation. The success of B cell-targeted therapies in many auto-antibody positive diseases suggests that B cell mediated auto-immunity is playing a direct pathogenic role. Despite the wealth of information on the clinical associations of these anti-PTM protein antibodies as biomarkers we have currently no insight into why these antibodies are formed.
Immunization studies reveal that PTM proteins can induce antibody responses even in the absence of exogenous adjuvant. The reason why these PTM proteins have ‘autoadjuvant’ properties that lead to a breach of tolerance is currently unknown. In this proposal, I hypothesise that the breach of tolerance towards PTM proteins is mediated by complement factors that bind directly to these PTM. Our preliminary data indeed reveal that several complement factors bind specifically to PTM proteins. Complement could be involved in the autoadjuvant property of PTM proteins as next to killing pathogens complement can also boost adaptive immune responses. I plan to unravel the importance of the complement–PTM protein interaction by answering these questions:
1) What is the physiological function of complement binding to PTM proteins?
2) Is the breach of tolerance towards PTM proteins influenced by complement?
3) Can the adjuvant function of PTM be used to increase vaccine efficacy and/or decrease autoreactivity?
With AUTOCOMPLEMENT I will elucidate how PTM-reactive B cells receive ‘autoadjuvant’ signals. This insight will impact on patient care as we can now design strategies to either block unwanted ‘autoadjuvant’ signals to inhibit autoimmunity or to utilize ‘autoadjuvant’ signals to potentiate vaccination.
Summary
In many prevalent autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) autoantibodies are used as diagnostic and prognostic tools. Several of these autoantibodies target proteins that have been post-translationally modified (PTM). Examples of such modifications are citrullination and carbamylation. The success of B cell-targeted therapies in many auto-antibody positive diseases suggests that B cell mediated auto-immunity is playing a direct pathogenic role. Despite the wealth of information on the clinical associations of these anti-PTM protein antibodies as biomarkers we have currently no insight into why these antibodies are formed.
Immunization studies reveal that PTM proteins can induce antibody responses even in the absence of exogenous adjuvant. The reason why these PTM proteins have ‘autoadjuvant’ properties that lead to a breach of tolerance is currently unknown. In this proposal, I hypothesise that the breach of tolerance towards PTM proteins is mediated by complement factors that bind directly to these PTM. Our preliminary data indeed reveal that several complement factors bind specifically to PTM proteins. Complement could be involved in the autoadjuvant property of PTM proteins as next to killing pathogens complement can also boost adaptive immune responses. I plan to unravel the importance of the complement–PTM protein interaction by answering these questions:
1) What is the physiological function of complement binding to PTM proteins?
2) Is the breach of tolerance towards PTM proteins influenced by complement?
3) Can the adjuvant function of PTM be used to increase vaccine efficacy and/or decrease autoreactivity?
With AUTOCOMPLEMENT I will elucidate how PTM-reactive B cells receive ‘autoadjuvant’ signals. This insight will impact on patient care as we can now design strategies to either block unwanted ‘autoadjuvant’ signals to inhibit autoimmunity or to utilize ‘autoadjuvant’ signals to potentiate vaccination.
Max ERC Funding
1 999 803 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym Bio-ICD
Project Biological auto-detection and termination of heart rhythm disturbances
Researcher (PI) Daniël Antonie PIJNAPPELS
Host Institution (HI) ACADEMISCH ZIEKENHUIS LEIDEN
Call Details Starting Grant (StG), LS7, ERC-2016-STG
Summary Imagine a heart that could no longer suffer from life-threatening rhythm disturbances, and not because of pills or traumatizing electroshocks from an Implantable Cardioverter Defibrillator (ICD) device. Instead, this heart has become able to rapidly detect & terminate these malignant arrhythmias fully on its own, after gene transfer. In order to explore this novel concept of biological auto-detection & termination of arrhythmias, I will investigate how forced expression of particular engineered proteins could i) allow cardiac tissue to become a detector of arrhythmias through rapid sensing of acute physiological changes upon their initiation. And how after detection, ii) this cardiac tissue (now as effector), could terminate the arrhythmia by generating a painless electroshock through these proteins.
To this purpose, I will first explore the requirements for such detection & termination by studying arrhythmia initiation and termination in rat models of atrial & ventricular arrhythmias using optical probes and light-gated ion channels. These insights will guide computer-based screening of proteins to identify those properties allowing effective arrhythmia detection & termination. These data will be used for rational engineering of the proteins with the desired properties, followed by their forced expression in cardiac cells and slices to assess anti-arrhythmic potential & safety. Promising proteins will be expressed in whole hearts to study their anti-arrhythmic effects and mechanisms, after which the most effective ones will be studied in awake rats.
This unexplored concept of self-resetting an acutely disturbed physiological state by establishing a biological detector-effector system may yield unique insight into arrhythmia management. Hence, this could provide distinctively innovative therapeutic rationales in which a diseased organ begets its own remedy, e.g. a Biologically-Integrated Cardiac Defibrillator (Bio-ICD).
Summary
Imagine a heart that could no longer suffer from life-threatening rhythm disturbances, and not because of pills or traumatizing electroshocks from an Implantable Cardioverter Defibrillator (ICD) device. Instead, this heart has become able to rapidly detect & terminate these malignant arrhythmias fully on its own, after gene transfer. In order to explore this novel concept of biological auto-detection & termination of arrhythmias, I will investigate how forced expression of particular engineered proteins could i) allow cardiac tissue to become a detector of arrhythmias through rapid sensing of acute physiological changes upon their initiation. And how after detection, ii) this cardiac tissue (now as effector), could terminate the arrhythmia by generating a painless electroshock through these proteins.
To this purpose, I will first explore the requirements for such detection & termination by studying arrhythmia initiation and termination in rat models of atrial & ventricular arrhythmias using optical probes and light-gated ion channels. These insights will guide computer-based screening of proteins to identify those properties allowing effective arrhythmia detection & termination. These data will be used for rational engineering of the proteins with the desired properties, followed by their forced expression in cardiac cells and slices to assess anti-arrhythmic potential & safety. Promising proteins will be expressed in whole hearts to study their anti-arrhythmic effects and mechanisms, after which the most effective ones will be studied in awake rats.
This unexplored concept of self-resetting an acutely disturbed physiological state by establishing a biological detector-effector system may yield unique insight into arrhythmia management. Hence, this could provide distinctively innovative therapeutic rationales in which a diseased organ begets its own remedy, e.g. a Biologically-Integrated Cardiac Defibrillator (Bio-ICD).
Max ERC Funding
1 485 028 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
Project acronym BIO-ORIGAMI
Project Meta-biomaterials: 3D printing meets Origami
Researcher (PI) Amir Abbas Zadpoor
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
Call Details Starting Grant (StG), PE8, ERC-2015-STG
Summary Meta-materials, best known for their extraordinary properties (e.g. negative stiffness), are halfway from both materials and structures: their unusual properties are direct results of their complex 3D structures. This project introduces a new class of meta-materials called meta-biomaterials. Meta-biomaterials go beyond meta-materials by adding an extra dimension to the complex 3D structure, i.e. complex and precisely controlled surface nano-patterns. The 3D structure gives rise to unprecedented or rare combination of mechanical (e.g. stiffness), mass transport (e.g. permeability, diffusivity), and biological (e.g. tissue regeneration rate) properties. Those properties optimize the distribution of mechanical loads and the transport of nutrients and oxygen while providing geometrical shapes preferable for tissue regeneration (e.g. higher curvatures). Surface nano-patterns communicate with (stem) cells, control their differentiation behavior, and enhance tissue regeneration.
There is one important problem: meta-biomaterials cannot be manufactured with current technology. 3D printing can create complex shapes while nanolithography creates complex surface nano-patterns down to a few nanometers but only on flat surfaces. There is, however, no way of combining complex shapes with complex surface nano-patterns. The groundbreaking nature of this project is in solving that deadlock using the Origami concept (the ancient Japanese art of paper folding). In this approach, I first decorate flat 3D-printed sheets with nano-patterns. Then, I apply Origami techniques to fold the decorated flat sheet and create complex 3D shapes. The sheet knows how to self-fold to the desired structure when subjected to compression, owing to pre-designed joints, crease patterns, and thickness/material distributions that control its mechanical instability. I will demonstrate the added value of meta-biomaterials in improving bone tissue regeneration using in vitro cell culture assays and animal models
Summary
Meta-materials, best known for their extraordinary properties (e.g. negative stiffness), are halfway from both materials and structures: their unusual properties are direct results of their complex 3D structures. This project introduces a new class of meta-materials called meta-biomaterials. Meta-biomaterials go beyond meta-materials by adding an extra dimension to the complex 3D structure, i.e. complex and precisely controlled surface nano-patterns. The 3D structure gives rise to unprecedented or rare combination of mechanical (e.g. stiffness), mass transport (e.g. permeability, diffusivity), and biological (e.g. tissue regeneration rate) properties. Those properties optimize the distribution of mechanical loads and the transport of nutrients and oxygen while providing geometrical shapes preferable for tissue regeneration (e.g. higher curvatures). Surface nano-patterns communicate with (stem) cells, control their differentiation behavior, and enhance tissue regeneration.
There is one important problem: meta-biomaterials cannot be manufactured with current technology. 3D printing can create complex shapes while nanolithography creates complex surface nano-patterns down to a few nanometers but only on flat surfaces. There is, however, no way of combining complex shapes with complex surface nano-patterns. The groundbreaking nature of this project is in solving that deadlock using the Origami concept (the ancient Japanese art of paper folding). In this approach, I first decorate flat 3D-printed sheets with nano-patterns. Then, I apply Origami techniques to fold the decorated flat sheet and create complex 3D shapes. The sheet knows how to self-fold to the desired structure when subjected to compression, owing to pre-designed joints, crease patterns, and thickness/material distributions that control its mechanical instability. I will demonstrate the added value of meta-biomaterials in improving bone tissue regeneration using in vitro cell culture assays and animal models
Max ERC Funding
1 499 600 €
Duration
Start date: 2016-02-01, End date: 2021-01-31
Project acronym BIOCCORA
Project Full biomechanical characterization of the coronary atherosclerotic plaque: biomechanics meets imaging
Researcher (PI) Jolanda Wentzel
Host Institution (HI) ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary Myocardial infarction is responsible for nearly 40% of the mortality in the western world and is mainly triggered by rupture of vulnerable atherosclerotic plaques in the coronary arteries. Biomechanical parameters play a major role in the generation and rupture of vulnerable plaques. I was the first to show the relationship between shear stress – one of the biomechanical parameters - and plaque formation in human coronary arteries in vivo. This accomplishment was achieved by the development of a new 3D reconstruction technique for (human) coronary arteries in vivo. This reconstruction technique allowed assessment of shear stress by computational fluid dynamics and thereby opened new avenues for serial studies on the role of biomechanical parameters in cardiovascular disease. However, these reconstructions lack information on the vessel wall composition, which is essential for stress computations in the vessel wall. Recent developments in intravascular image technologies allow visualization of one or more of the different plaque components. Therefore, advances in image fusion are required to merge the different plaque components into one single 3D vulnerable plaque reconstruction. I will go beyond the state-of-the art in image based modeling by developing novel technology to 3D reconstruct coronary lumen and vessel wall, including plaque composition and assess biomechanical tissue properties allowing for full biomechanical characterization (shear stress and wall stress) of the coronary plaque. The developed technology will be applied to study 1) vulnerable plaque progression, destabilization and rupture, to improve identification of risk on myocardial infarction and 2) predicting treatment outcome of stent implantation by simulating stent deployment, thereby opening a whole new direction in cardiovascular research.
Summary
Myocardial infarction is responsible for nearly 40% of the mortality in the western world and is mainly triggered by rupture of vulnerable atherosclerotic plaques in the coronary arteries. Biomechanical parameters play a major role in the generation and rupture of vulnerable plaques. I was the first to show the relationship between shear stress – one of the biomechanical parameters - and plaque formation in human coronary arteries in vivo. This accomplishment was achieved by the development of a new 3D reconstruction technique for (human) coronary arteries in vivo. This reconstruction technique allowed assessment of shear stress by computational fluid dynamics and thereby opened new avenues for serial studies on the role of biomechanical parameters in cardiovascular disease. However, these reconstructions lack information on the vessel wall composition, which is essential for stress computations in the vessel wall. Recent developments in intravascular image technologies allow visualization of one or more of the different plaque components. Therefore, advances in image fusion are required to merge the different plaque components into one single 3D vulnerable plaque reconstruction. I will go beyond the state-of-the art in image based modeling by developing novel technology to 3D reconstruct coronary lumen and vessel wall, including plaque composition and assess biomechanical tissue properties allowing for full biomechanical characterization (shear stress and wall stress) of the coronary plaque. The developed technology will be applied to study 1) vulnerable plaque progression, destabilization and rupture, to improve identification of risk on myocardial infarction and 2) predicting treatment outcome of stent implantation by simulating stent deployment, thereby opening a whole new direction in cardiovascular research.
Max ERC Funding
1 877 000 €
Duration
Start date: 2013-05-01, End date: 2019-04-30
Project acronym BIOMECHTOOLS
Project Biomechanical diagnostic, pre-planning and outcome tools to improve musculoskeletal surgery
Researcher (PI) Nicolaas Verdonschot
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Call Details Advanced Grant (AdG), LS7, ERC-2012-ADG_20120314
Summary The aetiology of many musculoskeletal (MS) diseases is related to biomechanical factors. However, the tools to assess the biomechanical condition of patients used by clinicians and researchers are often crude and subjective leading to non-optimal patient analyses and care. In this project innovations related to imaging, sensor technology and biomechanical modelling are utilized to generate versatile, accurate and objective methods to quantify the (pathological) MS condition of the lower extremity of patients in a unique manner. The project will produce advanced diagnostic, pre-planning and outcome tools which allow clinicians and researchers for detailed biomechanical analysis about abnormal tissue deformations, pathological loading of the joints, abnormal stresses in the hard and soft tissues, and aberrant joint kinematics.
The key objectives of this proposal are:
1) Develop and validate image-based 3-D volumetric elastographic diagnostic methods that can quantify normal and pathological conditions under dynamic loading and which can be linked to biomechanical modelling tools.
2) Create an ultrasound (US)-based system to assess internal joint kinematics which can be used as a diagnostic tool for clinicians and researchers and is a validation tool for biomechanical modelling.
3) Generate and validate an ambulant functional (force and kinematic) diagnostic system which is easy to use and which can be used to provide input data for biomechanical models.
4) Create and validate a new modelling approach that integrates muscle-models with finite element models at a highly personalized level.
5) Generate biomechanical models which have personalized mechanical properties of the hard and soft tissues.
6) Demonstrate the applicability of the personalized diagnostic and pre-planning platform by application to healthy individuals and patient subjects.
Support from the ERC will open new research fields related to biomechanical patient assessment and modeling of MS pathologies.
Summary
The aetiology of many musculoskeletal (MS) diseases is related to biomechanical factors. However, the tools to assess the biomechanical condition of patients used by clinicians and researchers are often crude and subjective leading to non-optimal patient analyses and care. In this project innovations related to imaging, sensor technology and biomechanical modelling are utilized to generate versatile, accurate and objective methods to quantify the (pathological) MS condition of the lower extremity of patients in a unique manner. The project will produce advanced diagnostic, pre-planning and outcome tools which allow clinicians and researchers for detailed biomechanical analysis about abnormal tissue deformations, pathological loading of the joints, abnormal stresses in the hard and soft tissues, and aberrant joint kinematics.
The key objectives of this proposal are:
1) Develop and validate image-based 3-D volumetric elastographic diagnostic methods that can quantify normal and pathological conditions under dynamic loading and which can be linked to biomechanical modelling tools.
2) Create an ultrasound (US)-based system to assess internal joint kinematics which can be used as a diagnostic tool for clinicians and researchers and is a validation tool for biomechanical modelling.
3) Generate and validate an ambulant functional (force and kinematic) diagnostic system which is easy to use and which can be used to provide input data for biomechanical models.
4) Create and validate a new modelling approach that integrates muscle-models with finite element models at a highly personalized level.
5) Generate biomechanical models which have personalized mechanical properties of the hard and soft tissues.
6) Demonstrate the applicability of the personalized diagnostic and pre-planning platform by application to healthy individuals and patient subjects.
Support from the ERC will open new research fields related to biomechanical patient assessment and modeling of MS pathologies.
Max ERC Funding
2 456 400 €
Duration
Start date: 2013-05-01, End date: 2018-04-30
Project acronym CELL HYBRIDGE
Project 3D Scaffolds as a Stem Cell Delivery System for Musculoskeletal Regenerative Medicine
Researcher (PI) Lorenzo Moroni
Host Institution (HI) UNIVERSITEIT MAASTRICHT
Call Details Starting Grant (StG), PE8, ERC-2014-STG
Summary Aging worldwide population demands new solutions to permanently restore damaged tissues, thus reducing healthcare costs. Regenerative medicine offers alternative therapies for tissue repair. Although first clinical trials revealed excellent initial response after implantation of these engineered tissues, long-term follow-ups demonstrated that degeneration and lack of integration with the surrounding tissues occur. Causes are related to insufficient cell-material interactions and loss of cell potency when cultured in two-dimensional substrates, among others.
Stem cells are a promising alternative due to their differentiation potential into multiple lineages. Yet, better control over cell-material interactions is necessary to maintain tissue engineered constructs in time. It is crucial to control stem cell quiescence, proliferation and differentiation in three-dimensional scaffolds while maintaining cells viable in situ. Stem cell activity is controlled by a complex cascade of signals called “niche”, where the extra-cellular matrix (ECM) surrounding the cells play a major role. Designing scaffolds inspired by this cellular niche and its ECM may lead to engineered tissues with instructive properties characterized by enhanced homeostasis, stability and integration with the surrounding milieu.
This research proposal aims at engineering constructs where scaffolds work as stem cell delivery systems actively controlling cell quiescence, proliferation, and differentiation. This challenge will be approached through a biomimetic design inspired by the mesenchymal stem cell niche. Three different scaffolds will be combined to achieve this purpose: (i) a scaffold designed to maintain cell quiescence; (ii) a scaffold designed to promote cell proliferation; and (iii) a scaffold designed to control cell differentiation. To prove the design criteria the evaluation of stem cell quiescence, proliferation, and differentiation will be assessed for musculoskeletal regenerative therapies.
Summary
Aging worldwide population demands new solutions to permanently restore damaged tissues, thus reducing healthcare costs. Regenerative medicine offers alternative therapies for tissue repair. Although first clinical trials revealed excellent initial response after implantation of these engineered tissues, long-term follow-ups demonstrated that degeneration and lack of integration with the surrounding tissues occur. Causes are related to insufficient cell-material interactions and loss of cell potency when cultured in two-dimensional substrates, among others.
Stem cells are a promising alternative due to their differentiation potential into multiple lineages. Yet, better control over cell-material interactions is necessary to maintain tissue engineered constructs in time. It is crucial to control stem cell quiescence, proliferation and differentiation in three-dimensional scaffolds while maintaining cells viable in situ. Stem cell activity is controlled by a complex cascade of signals called “niche”, where the extra-cellular matrix (ECM) surrounding the cells play a major role. Designing scaffolds inspired by this cellular niche and its ECM may lead to engineered tissues with instructive properties characterized by enhanced homeostasis, stability and integration with the surrounding milieu.
This research proposal aims at engineering constructs where scaffolds work as stem cell delivery systems actively controlling cell quiescence, proliferation, and differentiation. This challenge will be approached through a biomimetic design inspired by the mesenchymal stem cell niche. Three different scaffolds will be combined to achieve this purpose: (i) a scaffold designed to maintain cell quiescence; (ii) a scaffold designed to promote cell proliferation; and (iii) a scaffold designed to control cell differentiation. To prove the design criteria the evaluation of stem cell quiescence, proliferation, and differentiation will be assessed for musculoskeletal regenerative therapies.
Max ERC Funding
1 500 000 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym CHEMCHECK
Project CHECKPOINTS IN CHECK: Novel Chemical Toolbox for Local Cancer Immunotherapy
Researcher (PI) Martijn Verdoes
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary Cancer evades the immune system by generating an immunosuppressive tumour-microenvironment through various mechanisms to enable unhampered growth. Recent breakthroughs in blocking one of these mechanisms – the so called ‘immune checkpoints’ – put cancer immunotherapy back in the spotlights. Although promising, clinical benefits of these checkpoint inhibitors as single treatment has been limited to a subset of patients and goes along with unwanted systemic autoimmune toxicity. I hypostasize, that attacking the tumour microenvironment from multiple immunological angles simultaneously by local, conditional, and multimodal immunomodulation will greatly improve success of cancer immunotherapy and patient wellbeing. To achieve this, I will develop a highly defined synergistic chemistry-based molecular therapeutic toolbox to specifically attack cancer, acting on effector T cells, macrophages as well as tumour cells simultaneously. In this highly multidisciplinary endeavour I will (i) generate novel multifunctional dendritic cell targeted anti-cancer vaccines to ‘educate’ the patient’s immune system to recognise the tumour, (ii) I will develop conditional, targeted immune checkpoint inhibitors to release the immunosuppressive break specifically within the tumour microenvironment without the risk of autoimmunity and (iii) I will generate chemical tools to locally eliminate the tumour-associated macrophages to tear down a major immunosuppressive barrier. I will do so utilizing the novel ModimAb technology which I developed to obtain functionalized antibody fragments. These individual therapeutic tools will allow me and my research team to explore uncharted tumour immunological territories in vitro as well as in vivo, greatly advancing the field of cancer immunotherapy. But above all, together they will form a highly dedicated symbiotic immunotherapeutic regime which will be extremely effective without systemic side effects, dramatically improving patient care.
Summary
Cancer evades the immune system by generating an immunosuppressive tumour-microenvironment through various mechanisms to enable unhampered growth. Recent breakthroughs in blocking one of these mechanisms – the so called ‘immune checkpoints’ – put cancer immunotherapy back in the spotlights. Although promising, clinical benefits of these checkpoint inhibitors as single treatment has been limited to a subset of patients and goes along with unwanted systemic autoimmune toxicity. I hypostasize, that attacking the tumour microenvironment from multiple immunological angles simultaneously by local, conditional, and multimodal immunomodulation will greatly improve success of cancer immunotherapy and patient wellbeing. To achieve this, I will develop a highly defined synergistic chemistry-based molecular therapeutic toolbox to specifically attack cancer, acting on effector T cells, macrophages as well as tumour cells simultaneously. In this highly multidisciplinary endeavour I will (i) generate novel multifunctional dendritic cell targeted anti-cancer vaccines to ‘educate’ the patient’s immune system to recognise the tumour, (ii) I will develop conditional, targeted immune checkpoint inhibitors to release the immunosuppressive break specifically within the tumour microenvironment without the risk of autoimmunity and (iii) I will generate chemical tools to locally eliminate the tumour-associated macrophages to tear down a major immunosuppressive barrier. I will do so utilizing the novel ModimAb technology which I developed to obtain functionalized antibody fragments. These individual therapeutic tools will allow me and my research team to explore uncharted tumour immunological territories in vitro as well as in vivo, greatly advancing the field of cancer immunotherapy. But above all, together they will form a highly dedicated symbiotic immunotherapeutic regime which will be extremely effective without systemic side effects, dramatically improving patient care.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym CONQUEST
Project Clinical ultrasound platform for the quantitative and longitudinal imaging of theranostics and cellular therapy
Researcher (PI) Mangala Srinivas
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Call Details Starting Grant (StG), LS7, ERC-2013-StG
Summary The success of modern medical treatments such as cellular therapy and targeted treatments requires appropriate tools for in vivo monitoring. Imaging modalities, such as magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) are key candidates due to their noninvasive nature. However, these imaging techniques are extremely expensive and can involve radiation, both of which hinder their longitudinal and repetitive use.
Ultrasound has so far been unsuitable due to the absence of a label to differentiate regions of interest from tissue background, the main problem being that current ultrasound contrast agents (CAs) have active lifetimes in the order of minutes. The CoNQUeST platform (Clinical Nanoparticles for Quantitative Ultrasound with high STability) proposed here is an entirely new type of ultrasound CA that is extremely stable (lifetime of a year) and is not affected by insonation. This mechanism of contrast generation appears completely novel: The polymeric particles are under 200nm in diameter and must contain a soluble metal (M.Srinivas et al., patent pending, filed 09/2012). Based on the current state of the art, these particles are too small and do not contain the requisite gaseous component for ultrasound contrast.
CoNQUeST particles are applicable to longitudinal and repeated imaging, as is necessary for cell tracking, due to their stability. Furthermore, these particles can be chemically bound to targeting agents, dyes and drugs, and are suitable for multimodal imaging, including MRI (both 1H and 19F), fluorescence and SPECT. Finally, the CoNQUeST agents are suitable for clinical use.
I propose the application of the CoNQUeST agents to a clinical trial for tracking dendritic cell therapy in melanoma patients, longitudinal theranostic imaging in preclinical models and thorough characterisation of this novel mechanism of ultrasound contrast generation.
Summary
The success of modern medical treatments such as cellular therapy and targeted treatments requires appropriate tools for in vivo monitoring. Imaging modalities, such as magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) are key candidates due to their noninvasive nature. However, these imaging techniques are extremely expensive and can involve radiation, both of which hinder their longitudinal and repetitive use.
Ultrasound has so far been unsuitable due to the absence of a label to differentiate regions of interest from tissue background, the main problem being that current ultrasound contrast agents (CAs) have active lifetimes in the order of minutes. The CoNQUeST platform (Clinical Nanoparticles for Quantitative Ultrasound with high STability) proposed here is an entirely new type of ultrasound CA that is extremely stable (lifetime of a year) and is not affected by insonation. This mechanism of contrast generation appears completely novel: The polymeric particles are under 200nm in diameter and must contain a soluble metal (M.Srinivas et al., patent pending, filed 09/2012). Based on the current state of the art, these particles are too small and do not contain the requisite gaseous component for ultrasound contrast.
CoNQUeST particles are applicable to longitudinal and repeated imaging, as is necessary for cell tracking, due to their stability. Furthermore, these particles can be chemically bound to targeting agents, dyes and drugs, and are suitable for multimodal imaging, including MRI (both 1H and 19F), fluorescence and SPECT. Finally, the CoNQUeST agents are suitable for clinical use.
I propose the application of the CoNQUeST agents to a clinical trial for tracking dendritic cell therapy in melanoma patients, longitudinal theranostic imaging in preclinical models and thorough characterisation of this novel mechanism of ultrasound contrast generation.
Max ERC Funding
1 199 882 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
