Promoting patient safety by a novel combination of imaging technologies for biodegradable magnesium implants

Project Information

MgSafe

Grant agreement ID: 811226

DOI

10.3030/811226

Project closed

EC signature date 20 August 2018

Start date 1 October 2018

End date 30 September 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 3 956 398,56

EU contribution

€ 3 956 398,56

Coordinated by

HELMHOLTZ-ZENTRUM HEREON GMBH
Germany

Periodic Reporting for period 2 - MgSafe (Promoting patient safety by a novel combination of imaging technologies for biodegradable magnesium implants)

Reporting period: 2020-10-01 to 2022-09-30

Summary of the context and overall objectives of the project

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. This class of implant materials serves a demand which rises from ageing populations, an ever-increasing incidence of obesity and a rapid rise in osteoporosis-related fractures, along with increasing high-risk sports activities. So far, these indications are typically treated with non-degradable metal implants, which commonly require surgical removal after complete bone healing. From the health care and patients’ point of view, degradable implants provide a viable, cost-effective, and patient-friendly alternative. From 2013 on, the first degradable metal implant made from a Mg-alloy (compression screw of partner SYN) was CE certified and has been implanted into tens of thousands of patients so far.
During the follow-up of Mg-based implants, it became evident that monitoring implant performance and degradation with the existing imaging techniques can be challenging: the contrast is low for X-ray imaging. MR artefacts are induced by the use of conducting metal. PET, IR or ultra-sound imaging are so far not used to study this new class of materials, and the proof of principle has to be given that the modalities can be used at all for these implants. Solving these scientific and technical issues may support a broad clinical acceptance of implantable products made of Mg.
The key research objective of MgSafe was and still is to develop and optimise imaging technologies for recently established Mg implants by quantifying their physical impact and suitability for this class of materials in future human applications. Highly sophisticated imaging techniques (nano and micro-computed tomography (nano, µCT), Magnetic Resonance Tomography (MRT), Positron Emission Tomography (PET), Ultrasound and Photoacoustic (USPA), Near Infra-red (NIR) imaging) were developed beyond the forefront of medical device production in vivo and with in situ labelling options to obtain as much information as possible over time. MgSafe delivered non-invasively data on different time and length scales of the body reaction and material behaviour during Mg degradation with a precision and plethora of details, which wasn’t available before.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Mg alloys and pure Mg as control (as test specimen and orthopedic implants) were manufactured, characterized and partially implanted. These implants were studied in parallel in rats and sheep, and the consortium took care that comparable animal models were chosen. Multimodal imaging techniques (nano and µCT, MRT, PET, USPA, IR) were used, further developed, and combined. Data obtained from non-invasive in vivo and in situ labelling studies is currently analysed to understand the correlation between Mg degradation and the body reaction on different time and length scales. An additional dimension was added by the analysis of explants to obtain the highest resolution chemical and material science data. In addition, for the larger implants, dummy studies - as required for biomedical approval - were performed (following ASTM rules). First concepts were developed to merge all relevant biological and chemical in vivo and ex vivo data by computational 3D methods, simulations and machine learning approaches. The combination of these results will not only allow for an upscaling of the processes towards humans but will also deliver valuable data in terms of patient safety.
Applications are essential driver for innovations. As mentioned above, the presence of Mg biodegradable implants inside an MRI scanner may reduce image quality and cause radio frequency heating induced safety hazards for patients. To study and address these constraints RF transmitter arrays were simulated and designed with the goal to provide a strong and uniform transmission field for MRI and to reduce local RF power deposition. For optimization a multi objective genetic algorithm (GA) was used. This approach provided substantial enhancements in transmission field efficiency and uniformity while reducing RF power deposition in the target region around the implant by about 46%. By using optimized multi-channel RF transmitter array configurations in conjunction with GA optimization facilitates mitigation of the undesired effects of Mg implants en route to the clinics. In parallel, the impact of Mg materials on artefact production in MRI has been quantified and reduced by novel MRI protocols which also minimize imaging artefacts for Mg implants (Fig 1).
The combination of USPA and NIR was further developed to study implants deep in the tissues, especially around the bone-implant interface. By a newly developed AI algorithm it was possible to extract functional, anatomical, and molecular information from tissues surrounding Mg implant by USPA imaging technology. The approach is based on Non-negative Matrix Factorization (NNMF) to detect and quantify the molecular tissue components from a spectral Photoacoustic data set. The algorithm has been optimized to extract the tissue chromophores in the wavelength range of 680–900 nm. As a result, the proposed approach can automatically detect Oxy/Deoxy Haemoglobin and exogenous dyes with higher sensitivity without any user interactions. Figure 2 summarizes the proposed unsupervised approach. The Photoacoustic spectral images were used to input the algorithm and source spectra (absorption curves of the prominent absorbers) and abundance maps (spatial distribution of the source components) were obtained as output.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The ESRs of MgSafe pushed the imaging modalities towards their limits to monitor the degradation processes of emerging Mg implants optimally and non‐invasively with high spatial and temporal resolution. Obtained multimodal in vivo data could be verified by highest resolution ex vivo data. The results of MgSafe will substantially increase the level of safety for patients currently treated with Mg‐based implants and will boost the further development of imaging modalities also on a clinical level. From an innovation point of view, MgSafe conveyed a unique methodical fine-tuning and intelligent combination of mostly independent imaging methods, which is also needed in other areas.
At the same time, MgSafe educated a new generation of young researchers. These experts will have both: the understanding of the material and its interaction with the tissue AND the knowledge how to monitor these parameters by multimodal imaging. This broad knowledge can possibly be transferred to any kind of biomaterial, plus the training in MgSafe enables the ESRs to think and work ‘from bench to bedside’.
The ESRs had access to outstanding facilities and training in the academia sector complemented by offers of the private sector participants. This will facilitate mobility between academia and industry and enhance the employability of the ESRs.
MgSafe can serve as a best practice example for future doctoral programs on a European level in the area of biomedical device development because currently mainly national activities for structural doctoral programmes exist. The inclusion of the non-academic section in the training program was essential and is not available at this level in any European country. All non-academic beneficiaries were directly involved in the supervision of individual ESRs.

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