Early Stage Researchers (ESR)

Early Stage Researchers (ESRs) is a typical EU project terminology. This expression is basically a synonym for PhD students: young researchers at an early stage of their career who hold a masters degree and are aiming for a doctoral one.

MgSafe trains 15 ESRs in imaging and implant technologies, because biomedical imaging has gained a significant technological push and is the mainstay for diagnosis and therapy monitoring.
Still, imaging is yet not optimized for the new class of biodegradable Mg-based implants.

All ESRs will develop their individual Personal Learning Environment (PLE) and be trained based on the “T-skills concept” in technologies and transferable skills relevant for their career development and prepared to take over leadership positions in an area of tremendous research promises and clinical relevance where the lack for experts is severe and very well recognized.

The ESRs will quantify the physical impact and suitability of a variety of modalities on Mg implants.
Highly sophisticated imaging techniques (nano and μCT, MRT, PET, USPA, IR) will be developed beyond the forefront of medical device production in vivo and with in situ labelling options to deliver non-invasively data on different time and length scales of the body reaction and material behavior during Mg degradation with a precision and plethora of details which is currently not available.

 

In vivo characterisation of designated Mg materials (pins and wires) by µCT and fluorescence imaging in rats. | Related to WPs 2-4. (WP1, Task 1.1)

Fellow: ESR1 | Host Institution: MUG


Objectives:

  1. Quantification of implant degradation and bone response in vivo together with molecular activities of osteoblast, osteoclast and inflammatory cells

  2. Histological correlation with fluorescence signal of osteoblast, osteoclast and inflammatory response

  3. Ex vivo NMR-based metabolic phenotyping of bone and surrounding tissue

  4. Delivery of data, explants and tissue to network partners


Enrolment in Doctoral Degree: MUG 

Large animal in vivo characterisation of designated full size Mg implants (K-Wires, screws) by clinical CT in a juvenile sheep model. | (WP1, Task 1.1, also related to WPs 2-4)

Fellow: ESR2 | Host Institution: MUG


Objectives:

  1. Quantitative and qualitative analysis of implantation site with attention to clinically relevant aspects

  2. Determination of the suitability of clinically relevant implant shape and magnesium amount with respect to local side effects (osteolysis, necrosis, pseudoarthrosis)

  3. Analysis of degradation beha-viour (volume and surface changes) and gas evolution in large animals


Enrolment in Doctoral Degree: MUG 

Histological validation of advanced bone-implant imaging techniques. | Related to WPs 2-4. (WP1, Task 1.2)

Fellow: ESR3 | Host Institution: UiO


Objectives:

  1. Verify performance of Mg alloys in animal experiments by means of histomorphometry and immunohistochemistry (IHC).

  2. Verify correlation between imaging techniques (µCT, PET, MRI) with histological evidence from in vivo experiments.
    After fixation and prior to histological sections, the femur will undergo state-of-the-art non-invasive µCT leading to 3D models of the defects. For histological and immunohistochemical analyses the specimens will be stained with haematoxylin and eosin (H&E), hematoxylin-eosin-methylene blue (HEA) and Masson’s trichrome for the assessment of general morphology and osteogenesis. They will be examined qualitatively by light and confocal microscopy. Immunohistochemical analysis will be performed to evaluate the extent of macrophage (pro-inflammatory, immunomodulatory and tissue remodelling) infiltration and for assessment of inflammatory cell phenotypes at the implantation site. The comparisons of histological evidence and imaging techniques will be fed into Task 3.3 (ESR 12).


Enrolment in Doctoral Degree: UiO

Molecular and structural analyses during bone healing and soft-tissue inflammation. | Related to WPs 2-4. (WP1, Task 1.3)

Fellow: ESR4 | Host Institution: UGOT


Objectives:

  1. Ultrastructural and compositional analysis of the bone implant interface, including evalu-ation of the osteocyte network in association with the implant surface.

  2. Determine the molecular activities of major cellular events during bone healing and regeneration, including inflammation, bone formation and bone remodelling as well as osteocyte specific markers. To correlate the gene expression and structural aspects of the bone formation.

  3. Study the early and late inflammatory response in an in vivo soft-tissue model, and to relate that to the degree of tissue healing and/or encapsulation around the implanted materials.

  4. Deliver data and tissue to network partners.


Enrolment in Doctoral Degree: UGOT

MRI development for Mg implants to study inflammation. | Related to WPs 2-4. (WP2, Task 2.1)

Fellow: ESR5 | Host Institution: MHH


Objectives:

  1. Determine the influence of static (B0) and RF (B1) heterogeneity on MRI and MRS mea-surements in the presence of Mg implants.

  2. Elaborate existing MRI and MRS methods for in vivo non-invasive monitoring of physiological parameters and develop specialised methods that can compensate such influences. The focus will be on spatial encoding, short echo time projection reconstruction and advanced shimming strategies to significantly reduce susceptibility artefacts and to enable quantifiable spectroscopy by use of localised constant time spin echo correlation spectroscopy.


Enrolment in Doctoral Degree: MHH

Multimodal imaging of bone regeneration and remodelling after implantation of degradable Mg-based devices in experimental animal models. | Related to WPs 1, 3-4. (WP2, Task 2.2)

Fellow: ESR6 | Host Institution: CNR-IFC


Objectives:

  1. Study of the dynamic regulation of bone regeneration and remodelling.

  2. Validation of the probes/target combination, both in vitro and in vivo, following a multimodal approach (µPET/CT, µECO, USPA).

  3. Integration of bone metabolism and homeostasis together with morphometric measurements.

  4. Development of new preclinical imaging strategies to be translated in a clinical setting.
    The rat models will be the primary choice for evaluation of osteo-integration. If required, selected studies on sheep-model can be performed with PET/CT. MRI will be used to evidence muscle and bone oedema considered as bio-marker of the damage and implant associated effects. The studies will be performed at 3T. The set up and validation of the tracers for µPET/CT in vivo will be performed by [18F]-FDG to evidence the glycolytic pathway enhanced by inflammation process, while suitable [68Ga]-cRGD-peptide ligands binding αvβ3 integrin will be used to follow the angiogenetic process non-invasively.


Enrolment in Doctoral Degree: CNR-IFC

Biochemical and biohumoral studies of bone regeneration and remodelling after implantation. | Related to WPs 1, 3-4. (WP2, Task 2.2)

Fellow: ESR7 | Host Institution: CNR-IFC


Objectives:

  1. in vitro validation studies with specific probes labelling integrin αvβ3 to detect angiogenesis in vivo

  2. Validation of the probes/target combination, both in vitro and in vivo, following a multimodal approach (µPET/CT, µECO, photoacoustic imaging)

  3. Integration of biohumoral and biochemical information with image-derived parameters of bone metabolism.
    Studies will be performed primarily on rats; single studies might be performed in sheep. Circulating biomarkers for inflammation (IL-1, IL-6, IL-8, IL-10, TNF-α, MCP-1), recruitment of osteoprogenitor cells (TGF-β, PDGF, BMP-2, IGF-1), angiogenesis (VEGF and angiopoietin) and bone metabolism (15 markers) will be studied. Biomarker and biohumoral assays will be performed before and after implantation (1, 3, 7 and 30 days of follow-up);
    circulating biomarkers will be evaluated by a multi-marker approach.


Enrolment in Doctoral Degree: CNR-IFC

In vivo monitoring of the body reaction to the implant by using a novel optical probe and near IR spectroscopy. | Related to WPs 1, 3-4. (WP2, Task 2.3)

Fellow: ESR8 | Host Institution: OsloMet


Objectives:

  1. Measurement and analysis of the near infrared absorption spectra & local perfusion at the implant-tissue interface by using either a single or multiple probes to achieve a spot measurement or a two-dimensional image. it is possible to reconstruct The probe will be specifically designed to measure the perfusion close to the implant with less influence from the superficial tissue layer.

  2. Calibration & validation of the spectroscopic data by multivariate and SPM (Statistical Parameter Mapping) methods.

  3. Analysis & combination of spectroscopic data with fluorescence, µCT, PET, MRI and USPA in animal models.

  4. Validation of the technique for human application.


Enrolment in Doctoral Degree: HiOA

Characterisation of corrosion layer structure and composition in explants. | Related to WPs 1, 2 & 4. (WP3, Task 3.1)

Fellow: ESR9 | Host Institution: WUT


Objectives:

  1. Characterise surface and interface properties as well as topography of Mg-explants after in vivo degradation.

  2. Obtain high-resolution surface nano- and micro-structural information about Mg-based explants.

  3. Determine corrosion layer composition by using high-resolution surface spectroscopy of Mg-based explants.

  4. Derive information about the degradation progress of Mg material in vivo based on the obtained results.


Enrolment in Doctoral Degree: WUT

Structural characterisation of explants by synchrotron radiation: differential phase contrast (DPC) µ and nano tomography for investigation of Mg implant tissue interface | Related to WP1, 2 and 4. (WP3 Task 3.2)

Fellow: ESR10 | Host Institution: HZG


Objectives:

  1. Imaging of Mg implants in native tissue environment.

  2. High-energy DPC imaging for cre-ation of multimodal image data sets integrating phase, attenuation and dark field CT-data.

  3. Optimisation of SR tomography methods and data analysis protocols for metallic implants.

  4. Implementation of Deep / Machine Learning approaches for multimodal data analysis.


Enrolment in Doctoral Degree: CAU Kiel (R. Willumeit-Römer is full professor at the CAU Kiel)

Structural characterisation of explants by synchrotron radiation: Bone remodelling at the implant-bone interface, SAXS investigations. | Related to WPs 1 and 2. (WP3, Task 3.2)

Fellow: ESR11 | Host Institution: HZG


Objectives:

High-resolution studies of the structure of the bone-implant interface. ESR 11 will scan explants by small angle x-ray scattering with a synchrotron beam of only 250 nm to elucidate:

  1. differences in bone structure close to the implant interface and in distant bone, and

  2. if the corrosion products (e.g. hydroxyapatite) is ordered in a bone like fashion. This is complemented by

  3. histological (ESR 3) and surface cha-racterisation techniques (ESR 9) to correlate structure and function of degradable implants.

  4. Implementation of Deep / Machine Learning approaches for multimodal data analysis.


Enrolment in Doctoral Degree: CAU Kiel (R. Willumeit-Römer is full professor at the CAU Kiel)

Software development for management and visualisation of multimodal data. | Related to WPs 1 & 2. (WP3, Task 3.3)

Fellow: ESR12 | Host Institution: SCANCO


Objectives:

The project is expected to generate a vast amount of 2D, 3D and 4D data from different modalities. ESR 12 will provide a system to join these data and to describe their relative relation in space and time. For this, the development of a new registration concept and new software is required. The software shall be developed to visualise the combined data of any two modalities or time points. Thus, the objectives are:

  1. Repository for data from 2D and 3D imaging systems produced from partners in WPs 1, 2 and 4.

  2. Develop a concept to link and relate datasets originating from different modalities and different time points.

  3. Develop software for combined visualisation of multimodal and multidimensional datasets.


Enrolment in Doctoral Degree: CAU Kiel (R. Willumeit-Römer is full professor at the CAU Kiel)

En route to the clinic: MR safety - MR antenna design tailored for Mg alloy implants. | Related to WPs 2 and 3. (WP4, Task 4.1)

Fellow: ESR13 | Host Institution: MRI.TOOLS


Objectives:

An Mg-based conductive implant in the patient’s body interacts with the radiofrequency (RF) field of an MR scanner. This may result in local RF induced heating in the tissue, which might constitute a patient safety hazard. En route to clinical applications of Mg implants it is essential to understand and control the interaction of passive, conductive Mg-based implants with RF fields. ESR 13 will focus on

  1. electromagnetic field (EMF) simulations to detail electric fields and local RF power deposition in humans for frequencies accommodating today’s clinical and research MR scanners,

  2. E-EMF measurements to benchmark the outcome of the computational modelling with experiments,

  3. thermal numerical simulations and their verification in RF heating experiments,

  4. development of an implant friendly RF antenna using multi-channel transmission MR,

  5. development of RF shimming algorithms that use the degrees of freedom of multi-channel transmission to generate reduced RF field zones or “null mode” excitations that induce minimal RF current in Mg implants, thereby decreasing the RF heating hazard, while still allowing imaging of the surrounding volume.


Enrolment in Doctoral Degree: Medical University Berlin (T. Niendorf is full professor at the Charité Medical University Berlin)

En route to the clinic: MR safety - Influence of Mg implants on MR signal. | Related to WPs 2 and 3. (WP4, Task 4.2)

Fellow: ESR14 | Host Institution: SYN


Objectives:

Mg implants cause image artefacts in MR imaging (MRI) and might increase the temperature in the adjacent tissues. Their impact on MRI quality is, however, marginal compared to artefacts and temperature rises caused by current permanent metallic implants. Yet, no information is available how the degradation of Mg influences the image quality of MR investigations and local tissue heating. Therefore, CE approved magnesium screws (MAGNEZIX® by SYN) shall undergo

  1. in vitro and in vivo corrosion subsequently analysed with regard to heating effects after MRI with different parameters at partner MHH. At SYN,

  2. 3D MRI data will be collected, processed, visualised and interpreted, and

  3. a tool will be developed, which allows to predict heating based on a given implant geometry and

  4. the state of the implant’s degradation.


Enrolment in Doctoral Degree: MHH

High-resolution ultrasound and photoacoustic (USPA) imaging for human application. | Related to WPs 1-3. (WP4, Task 4.3)

Fellow: ESR15 | Host Institution: VSI


Objectives:

In collaboration with WP2 (CNR-IFC, HiOA), ESR 15 will

  1. explore additional possibilities of the technology in detecting anatomical functional and molecular information of implant degradation and tissue remodelling,

  2. validate the obtained results with other imaging approaches,

  3. modify the current transducer design and the working interface to allow patient measurements in a clinical setup,

  4. design a semi-portable system, and

  5. perform validation studies on larger animals like sheep, the result of which can be translated to the clinic.


Enrolment in Doctoral Degree: MHH