The SBR outcomes

Biomaterial engineering - OZB

Role within SBR

Within the SBR project, OZB has been responsible for two different tasks:

• First, OZB provided biofunctionalization to the conductive silver nanoparticles and films that would be used in the sensors within the SBR device. The SBR project focused on monitoring in real time the healing process after device implantation by using sensors that would record key chemical and biological data such as pH or temperature. To be efficient, these sensors required biocompatible inks that needed to be electrically conductive enough to allow the sensors to work efficiently. They also needed to be totally biocompatible to not alter the regenerative process. OZB’s 20 years of expertise in crafting iron-based nanoparticles for biological purposes and biofunctionalising cytotoxic silver-based material gave way to innovative silver-based inks that combine efficient electrical properties and a biocompatible character.
• OZB was also responsible for providing nanoparticles or nanocapsules that would support the regenerative activity of viral vectors developed by TUM-MED. There were several objectives in this respect:
• enhancing the activity of the chosen vector without increasing its cytotoxicity,
• protecting the vector within the biological medium to extend its activity over time,
• limit the diffusion of the vector after implantation on the SBR device to increase its efficiency and long-term activity.

OZB has been developing over the years a wide library of proprietary molecules that can be used as transduction enhancers in biological environments. Such reagents have been sold to customers for years. This experience combined with the expertise available within the consortium represented a key opportunity to develop a new class of enhancers that would prove efficient in different contexts, from in-vitro testing to pre-clinical setups.

State of the art before SBR

Examples of silver nanoparticles or film biofunctionalization existed before the SBR project. However, to our knowledge, none of these previous works combined efficiently the different aspects required by the consortium:

• efficient, reproducible and scalable chemical functionalization process that leads to biocompatible particles;
• functionalization strategies compatible with the formulation of conductive inks;
• choice of biocompatible materials that are consistent with the thermal curing of the obtained nanoparticles required for the formulation of the conductive biocompatible inks.

Thanks to the feedback of our SBR partners (CSEM, LEITAT, GNK, UPAT), we have screened dozens of polymer candidates to encapsulate silver nanoparticles and confer them biocompatible properties. Upon finding the best candidate, we demonstrated that our polymeric coating did not alter electrical properties of the related inks, and that this coating is resistant to the experimental settings of the ink formulation by thermal curing. OZB and UPAT’s results confirmed the non-cytotoxic nature of films printed with this ink (in opposition of ink formulated from non-coated silver nanoparticles) while LEITAT demonstrated that functional sensors could be printed successfully using this new-era ink.

There are only rare examples of polymers able to efficiently enhance AAV-infection in-vitro or in-vivo. Therefore, very few technologies devoted to AAVs are available and none of them offers an all-around solution for enhancing AAV-transduction from different serotypes in different context.

We decided to leverage our proprietary compound’s library (from our patent filled in July 2019) in order to develop dozens of original formulations that could face the challenge brought by the project. The idea was to use a technology we developed and patented in the past, and to adapt it further to the requirements presented in the proposal.

In addition, we modulated the formulation parameters to confer our candidates hydro-gelling properties that are useful to protect the viral vectors from degradation and inactivation and to limit their diffusion within the medium. Thanks to regular feedback rounds with TUM-MED, we were able to isolate one hit-formulation that consistently enhances the viral activity on a broad range of cell lines, while preventing the AAV to degrade under harsh experimental workups. These results were confirmed by TUM-MED, who also demonstrated that AAVs activity of different serotypes could be prolonged over time when associated with our hit candidate, and that this association could be used within an in-vivo setup by modulating the method of deposition onto the SBR scaffold.

SBR’s impact on OZB

The pluri-disciplinarity of the SBR consortium represented a unique opportunity for OZB to extend its technical knowledge out of its core market, gene delivery. We had for the first time the chance to work with silver particles produced by valuable industrial partners who provided us with qualitative batches of raw materials, making our screening of polymeric coating smoother and faster. The product obtained thanks to this close collaboration has been tested in different experimental setups, thanks to the available expertise. We planned to use the knowledge we collected all along the grant for the development of future biocompatible nanoparticles to help our customers and the scientific community to fulfil their research efforts. SBR has also been an opportunity to work extensively on AAVs transduction, which has been an objective of our company for long. The quality of the viral particle batches presented by our partners made our screening of the best possible formulation quicker and smoother. Furthermore, the expertise of TUM-MED in AAV-mediated transduction helped us to generate consistent and trustable scientific data that would accelerate the development of an efficient and flexible polymeric AAV enhancer, available to the scientific community. Finally, the core of the SBR project included the testing of the device in in vivo setup for large bone defect treatment. It is a unique opportunity to see our technological innovation tested in an ambitious pre-clinical program and generate strong and consistent data that likely validates our R&D strategy within an exciting and challenging therapeutic program.

Genetic engineering - TUM-MED

Role within SBR

Within the SBR project, TUM-MED has been responsible for the genetic modification of the implant as a possible way of improving large bone defect healing. Growth factors expression plays a crucial role in the defect healing process. We aimed for a local production at the site where they are needed to optimise the healing process. This local growth factor production enabled an extended production and a correct post-translational format of protein. The dose can therefore be reduced, unlike with the application of recombinant protein. We chose adeno-associated viral vectors (AAV) as they are non-pathogenic, effective, have a satisfactory safety profile and are the least immunogenic among the viral vectors available to the field. Several AAV-based gene medicines tackling a wide scope of diseases not related to bone defects have recently obtained FDA approval. Therefore, we chose AAV for the delivery of growth factor genes and local expression and secretion of these growth factors.

State of the art before SBR

AAV therapy had so far only been used for treating osteochondral defect among others, and had not yet been used in pre-clinical trials of large bone defects. Different AAV formats and serotypes (defined by the capsid) are available to the field. In our project, TUM-MED analysed which AAV would prove best in the local secretion of growth factors for transduced cells (e.g. mesenchymal stromal cells, which indicate cell invasion from the bone marrow). TUM-MED furthermore determined if and how the AAV could be attached to the biomaterials used in the SBR-device to maintain the vector locally and possibly enhance the gene transfer to invading cells. Together with our partners OZB, UNILEEDS and RESC we were able to demonstrate that AAV can be attached to such a scaffold material. We characterized the particle release and additionally demonstrated that adding a polymer enhances and extends gene transfer and gene expression by stabilizing the viral vector.

SBR's impact on TUM-MED

Within the Institute of Molecular Immunology at TUM-MED, AAV had so far mainly been used in infectious disease and other model systems. Regenerative approaches of the skeleto-muscular system gain visibility and that the optional use of AAV-mediated viral gene transfer might be a vital option in regenerative approaches. Only the cooperations within the SBR project allowed for pre-clinical testing of the AAV in a model of large bone defects.

Before testing in any animal model, extended in vitro testing of gene transfer vectors is mandatory but not always feasible with all AAV serotypes. Thus, the combination of AAV of different serotypes with the enhancer developed by OZB will allow for more efficient in vitro testing in the absence of toxicity and now allows for transduction and gene expression analysis even of hard to transduce primary cells.

Sensor design - CSEM

Role within SBR

Within the SBR project, CSEM was responsible for developing a biocompatible, flexible, and wireless system of sensors embedded within a 3D-printed implant. This system is designed to monitor bone regeneration and implant acceptance in real-time. The decision to propose this technology was driven by the need to overcome the limitations of current treatments for large bone defects. Traditional methods often involve multiple surgical interventions and lack real-time monitoring capabilities. The sensor-embedded implant aims to provide timely data on the healing process, enabling more effective and personalized medical interventions.

State of the art before SBR

Before the project, the state of the art in treating large bone defects involved techniques such as bone transport and the induced membrane technique. These methods, while effective, were invasive and did not offer real-time monitoring of the bone healing process. CSEM's main achievements include the successful integration of advanced sensor technology into a 3D-printed, resorbable bone implant. The sensors, which monitor pH, temperature, strain, and transforming growth factor (TGF-β1), have shown promising results in tracking the healing process. The Bluetooth communication framework coupled with an ultra-low power design ensures real-time data transmission, providing continuous insights into the bone regeneration process. The operating lifetime of the communications is expected to last approximately a year inside the body. The pH and TGF-β1 sensors were manufactured with printed technologies. The double coating of the system ensured biocompatibility and water-tightness.

SBR's impact on CSEM

Participation in the SBR project has significantly advanced CSEM's capabilities in integrating sensor technology with 3D printing and biocompatible materials. It has allowed CSEM to develop a comprehensive solution for real-time monitoring of bone regeneration, therefore demonstrating expertise in creating innovative medical devices. This project has positioned CSEM as a leader in the field of implantable sensors and bone regeneration, opening new avenues for research and collaboration. The successful preliminary findings and readiness for in vivo testing highlight progress and potential for future advancements.

SBR's impact on the future

The development of the implantable sensor system represents a significant leap forward in medical technology. Its impact extends beyond bone regeneration, potentially revolutionizing the approach to real-time monitoring in various medical applications. By providing continuous, real-time data on the healing process, this technology can lead to more personalized and effective treatments, reducing the need for multiple surgeries and improving patient outcomes. Furthermore, this innovation contributes to the broader scientific community by demonstrating the practical application of advanced sensors and 3D printing in medical devices, inspiring further research and development in this area. The societal benefits include improved healthcare quality, reduced healthcare costs, and enhanced patient experiences.

Scaffold and callus assessment - UPAT Orthopaedic Department

Role within SBR

Within the SBR project, UPAT was responsible for determining the scaffold degradation and the callus formation at 12 and 24 weeks after implantation, in the pilot animal study. After dissecting the soft tissues, the scaffold, and the callus were investigated with:

the use of pQCT imaging to scan and evaluate the callus formation around the scaffold, the possible demineralization of the scaffold and the mineralization of the newly created bone. Moreover, the pqCT imaging could provide insights on the mechanical properties of the newly formed bone regarding the quantity and the quality of the callus.
the RAMAN spectroscopy was used to compare the mineralization between the newly formed bone and the already existed cortex; and the demineralization of the scaffold at 12 weeks, in order to have a perception on the quantity of calcium phosphate that is required to the maturation process.

State of the art before SBR

During the SBR project, pQCT imaging studies or RAMAN spectroscopy was not improved. However, we used that knowledge to observe the mineralization of the newly formed bone and the demineralization of the scaffold; and to determine the time frame that the experiment could last until mature callus would be formed. We found that 24 weeks after the implantation was enough time to investigate the callus maturation and the scaffolds’ stability in in vivo experiments. The results on the quality of the newly formed bone obtained by the pQCT imaging studies were correlated with those of the biomechanical axial loaded tests, providing an overall understanding of the bone maturation process and mechanical performance.

SBR's impact on UPAT

By participating in the SBR project, our investigators gained experience in using the pQCT studies for studying several bone tissues at different maturation periods. They were able to compare their mechanical properties, the quality of the bone and the quantity of callus. In addition, they could correlate the different periods of the callus formation with the resulting stability of the scaffold. The results of the quality of the newly formed bone obtained via pQCT imaging studies were correlated with those of the biomechanical axial loaded tests, giving an overall understanding of the bone maturation process.

Fiber engineering - Applus+ Rescoll

Role within SBR

The Applus+ Rescoll team is responsible for the development of appropriate formulation, compounding and extrusion of medical grade filaments for additive manufacturing.

The overall concept of BGR-D consists of a semirigid external scaffold, which will provide the structural bridge to connect the edges of the bone defect, with an electrospun fibre membrane, for guided bone regeneration as well as a guide for the central part of the bone. Both components will be manufactured with additive manufacturing, using resorbable materials (medical-grade thermoplastics).

These technologies were proposed because it allows for tremendous development in the manufacturing of complex shapes while enabling particular properties, such as a high porosity and the capacity to mimic the extracellular matrix in order to promote fluid and nutrient migration through the implant. In parallel, the implant acts as a structural bridge in between the bone defect and allows for a better stabilisation of the system.

State of the art and innovation

According to the classical concept of bone regeneration, four essential factors are needed: the mechanical stability, an osteoconductive scaffold, osteoinductive growth factors and osteogenic cells (Giannoudis, 2007). Most often, the scaffold used is rigid thus fulfilling the first two functions at once.

The main innovation comes from the development of a specific design that fits optimally the bone defect and the development of a new formulation that promotes bone regeneration. In addition, the scaffold is composed of two compartments and integrates a fully adaptable system depending on clinical needs and ready to use for the surgeon. Throughout the project, the capability of the scaffold to withstand mechanical forces while degrading over time has been demonstrated.

Growth factors could further be incorporated in an industrial way and their release could be fully monitored. An in vivo proof of concept is currently ongoing to demonstrate the suitability of the scaffold for such innovation.

SBR's impact on Applus+ Rescoll

Applus+ Rescoll’s participation to the SBR project presents a unique opportunity to manufacture porous electrospun membranes that integrate active ingredients. The behaviour of these active ingredients and their release capacity were evaluated throughout the process and better understood. Ultimately, these findings might contribute to the development of the next generation of membranes.

The advancements in the design of the implant also enabled to overcome technical limitations, such as the need to use a flexible material without compromising on the rigidity of the final implant’s structure.

SBR's impact on the future

The project addresses the current need for better integration of implants in the human body, offering a less invasive approach while maintaining high functionality. At this stage, combining the two technologies allows us to leverage the benefits of both processes.

Regulatory strategy - Asphalion

Role within SBR

Asphalion's involvement in the SBR project has focused on providing essential regulatory guidance. By mapping out a regulatory pathway that is both comprehensive in its application and considerate of the project's innovation, Asphalion ensured that the project’s technological progress is achieved within the bounds of regulatory compliance.

State of the art before SBR

Prior to SBR, the regulatory environment for novel medical devices presented challenges that could potentially hinder innovation. Recognising this, Asphalion offered their expertise to help navigate complex regulatory roadblocks and support the project's aim to pioneer advancements for the treatment of large bone defects.

Approach

Through the project’s collaborative efforts, the resulting regulatory strategy now serves as a testament to how innovation and compliance can coexist. Our conclusions from this process underscore the importance of a forward-thinking regulatory approach in the field of medical device development.

SBR's impact on Asphalion

Our participation in the SBR project has been a journey of shared learning and mutual growth. This experience has honed our expertise and may, in turn, contribute to shaping future regulatory frameworks. This endeavour has been a privilege, and we hope our small part will ultimately aid in delivering new and innovative medical solutions to society.

Nanoink development - GenesInk

Role within SBR

During the SBR project, GenesInk was involved in the innovation process. Using its strong know-how, GenesInk has contributed to the development of biocompatible silver and platinum inks for the design of biosensors and antennas. Our main goal was to reach the highest level of performance of materials and to be competitive when introducing new technologies into already robust and well-installed production lines. The main advances of our processes reside in several parameters:

• Eco-friendly: our inks support an eco-friendly manufacturing footprint with additive manufacturing, 10x less ink consumption and reduced waste
• User-friendly: our inks are ready to use without any need for thinner- or thicker-to-adjust rheology, and they are easy to process with standard additive manufacturing processes. Equipment can be cleaned easily with our cleaning material solution provided with the ink.
• Sustainable: our inks contain no Cancerogenic Mutagen Reprotoxic substances and do not release nanoparticles during the printing processes.

State of the art before SBR

At least two types of conductive inks are employed for printed electronic applications when it comes to biocompatible printed sensors for in-body implants. These are conductive pastes based on Ag microparticles or conductive nanoinks based on highly conductive metals. However, they lack biocompatibility properties and usually contain hazardous solvents and stabilizing agents that partially shield the particles while reducing their conductivity. Furthermore, the connected implants are made using sophisticated methods such as selective laser micromachining. Within the SBR project, these issues were overcome and efforts were focused on developing biocompatible inks while using nontoxic solvents that are polar and water-based. More significantly, the developed biocompatible inks can be applied using straightforward additive printing methods that are considered cost-effective and environmentally friendly. These methods include the widely used screen-printing, inkjet printing and 3D dispenser process.

SBR's impact on GenesInk

The SBR project was relevant for its impact in the business development and strategic activities of GenesInk. GenesInk has the opportunity to introduce new products to the market by developinginks for the SBR project. A standardized strategy will be employed for this, starting with alpha and beta testing, qualification and pre-industrialization before moving on to industrialization. GenesInk has participated in numerous international and European events (exhibition, conferences) to communicate and promote the new products developed in the framework of the SBR project. Additionally, GenesInk ambitions to file a patent on the biocompatible inks’ manufacturing process in order to capitalize on its cutting-edge technology. Thanks to this project and GenesInk's business model, we were able to present and market SBR’s innovative technology to customers. Licensing will further meet specific market challenges, such as when the market segment is seeking large volumes that GenesInk might not be able to supply.

Device design - UNIVLEEDS (UoL)

Achievements made withing the project

The UoL team (Orthopaedic & Trauma surgery and Materials Engineering) proposed a novel two-compartment concentric cylindrical geometrical implant with resorbable materials. The outer layer is a PCL-based material, whereas the inner hollow cylinder is derived from chitosan and calcium phosphate mineral in spongy form for PRP and any anti-infective ion loading, which prevents any risk of infection. The chitosan/mineral based materials were derived by freeze-drying and were integrated with the PCL-based outer layer. The two-layer implantable scaffold was also found to be sufficiently rigid for load bearing, yet resorbable for promoting osteogenesis.

State of the art before SBR

The existing technology before the project involved a cage designed to contain the bone graft of PLLA base with no distinct biomechanical properties and no capacity to be loaded with indicative and cellular therapies. Our main achievements are the design and connection of two compartments which can contain bone graft and be loaded with autologous (patient derived) indicative molecules (PRP) and progenitor cells (concentrated bone marrow aspirate). The designed scaffold model has been successfully tried in ovine model (n=6). The CT-scan holds significant promise for future first-in-human trials. Since the scaffold is classed as a medical device with PRP and/or Bone Marrow Aspirate, the regulatory approval is likely to be simpler than if the scaffold was also loaded with biologically active molecules (classed as drug).

The collaborative dimension

The UoL team cooperated with a large panel of partners and helped Applus+ Rescoll in developing a 3D-printing method for scaffolds. In addition , the UoL team also offered their support in the area of materials selection, 3D-printing properties control and cell/stem cell characterisation.

Technological impact

The research output has positioned the technology above TRL5-6, with details on Regulatory complaint outcomes that involve the next level of Regulatory Approval. This positions the medical device technology above TRL7.

Sensor design - Leitat

Role within SBR

The main achievement for LEITAT during the SBR project was the complete development of the biosensor used to monitor the in vivo regeneration of the SBR implant from the manufacturing to its use with real samples. The biosensor electrodes were formulated and printed following good biocompatibility and high efficiency:

• Formulation of biocompatible conductive Platinum inks.
• Printing of the platinum electrodes over flexible substrates using 3D Dispensing printing. These printed electrodes were biofunctionalized and used to monitor the inflammatory biomarker (TGFbeta 1) for point-of-care detection and in vivo screening of bone healing.
• TGFbeta 1 biosensor biofuncionalisation of printed electrodes
• Biosensor electrochemical characterization and electronics development for point-of-care testing of the samples SPOTLIGHT
• Biosensor validation for point-of-care detection of the biomarker
• Biosensor biocompatibility studies

State of the art before SBR

The typical commercial biosensors are produced by techniques such as screen printing over rigid ceramic substrates. Within the SBR project, it was proposed to formulate a water-based platinum ink devised to be printed with a versatile and cost-effective technique, such as the 3D dispensing printing, where only small volumes of these expensive inks are necessary.

Implantable biosensors are making significant progress, but several challenges still need to be addressed before they are widely used in medical practice. As noted during the project, further research needs to explore biocompatibility, long-term performance and power sources. The development of implantable sensors is a complex aim that calls for collaborative efforts between engineers/research and clinicians.

Therefore, the reason to propose the development of implantable sensors was to continue the direction of this research and make some progress in implanting sensor for real-time monitoring of implants.

Technological advancements

• Custom-made 3D dispenser for 3D printed electrodes for the biosensor
• 3D dispensing
• Biosensor for Transforming Growth Factor (TGFbeta1) development
• Biofunctionalization of electrodes
• Biocompatibility testing
• Point-of-care testing of real blood samples.

State of the art before now

Biosensors made from platinum electrodes were successfully printed. Unfortunately, they were not conductive enough to guarantee a good sensibility on the final biosensor. Some alternatives with biocompatible coated silver inks were tested and positively printed to produce a functional biosensor. However, these inks did not show enough biocompatibility to be implanted inside the body. Therefore, there is still a need to investigate biocompatible inks that can be used for implantable electrodes.

The TGbeta1 biosensor is now in TRL5, it was developed and characterized, and it was used during the project with real blood samples withdraw from the animal testing. However, the biosensor was not implanted as the biocompatibility and implantability of electrodes inside the body is still under research.

SBR's impact on LEITAT

This project allowed LEITAT to work on electrode production and inject-printing technologies for biosensing applications. LEITAT was able to develop a point-of-care biosensor for the inflammatory biomarker (TGFbeta1), which successfully reached the state of a diagnostic device. However, biocompatibility and implantability of the biosensor inside the body need further investigation. The SBR project is a novel and ambitious concept and represents the first study with animal models of both bone scaffold - for regenerating large bone defects - and implanted sensors monitoring the bone healing process inside the body.

Preclinical studies - ARI

Role within SBR

ARI conducted the preclinical study to assess the developed SBR construct. We were responsible for two key processes:

1. Establishing a novel model for testing the SBR construct: The plate fixation needed to be very stable to counteract the weight-bearing forces of a 75kg adult sheep. This is especially relevant during the early healing period, when load sharing cannot be expected yet. Therefore, the created large defect in the femur was successfully stabilised by two locking plates.
2. During the healing period, biological measurements around the bone defect were taken using the developed biological sensor by CSEM. Several versions of the sensor were investigated to advance their performance.

State of the art before SBR

1. In the current literature, there is no published large animal model for stabilisation of a large bone defect in the femur. Stabilising a long bone with a large defect is very challenging as the bone cannot participate in weight bearing, so that the stability is completely up to the plate fixation construct. Previous studies have used a combination of locking plates and decompression plates which have resulted in implant failure like screw pull out and screw breakage. However, in this study the used plating method resulted in stable bone fixation for the duration of the 20-week study period without any implant failure.
2. Biological sensors were implanted, to measure not only strain of one of the plates, but also pH and temperature in the area of the surgical site. Several versions of the developed sensors were tested. The main achievements in this respect were (1) stable fixation of the sensor to the plate without loosening and (2) increased protection and subsequent longevity of the flex part securing in-vivo measurements during a time period of at least 4 weeks after surgery.

SBR's impact on ARI

Participation in the SBR project has given us the opportunity to establish a novel model for a large bone defect in the femur. Such models are prerequisite for translational research to improve patient care and outcome.

Impact on the future

The established model can be used for many future research projects investigating novel treatment modalities for large bone defects. This plating model can also be adopted by other research institutions working with translational models.
Further, in this model sensors for biological measurements were tested under realistic conditions to investigate their in vivo performance.

Bioactive integration - UPAT Pharmacy group

Role within SBR

The UPAT Pharmacy group was responsible for the development of liposomal bioactive molecules (BA) as BA delivery systems (for protection of BA’s and sustained release from the implant) and for identification of an appropriate method to integrate the BA’s on the implant without harming their biological activity.

A carrier for BAs is required since BAs would rapidly be cleared from the area after in vivo administration. This happens in the case of BA delivery as free molecules and since several types of BA are sensitive and quickly lose their bioactivity after in vivo administration. In addition, when high BA concentrations are applied in order to compensate for their rapid clearance from diseased site, toxicity may be demonstrated. Nanocarriers can help to sustain the retention of BAs at the site (achieving a gradual release), protect them (structure and consequently bioactivity) and also abolish high BA dose toxicities.

We proposed liposomes (which are vesicles that have a lipid membrane as a shell that encapsulates an aqueous core) for their well-known and documented highest biocompatibility, compared to other types of drug nanocarriers, and their high versatility to incorporate water soluble and lipid soluble molecules.

In partnership with Applus+ Rescoll, we were responsible to identify an optimal method to integrate liposomal BAs in the final SIM. The integration of liposomes in a nanofiber-composed membrane that was prepared by electrospinning method, was identified as the optimal solution. This method enabled us to tune the number of liposomal BAs integrated and sustain their release at the diseased site (according to relevant literature). This approach also proved compatible with sterilization of the full system.

State of the art before SBR

Liposomes are the most biocompatible nano-sized DDSs and have been used in therapeutics for many years (more than 30) in the context of drug delivery. Drug administration and delivery has faced several obstacles due to several reasons, such as low solubility, low permeability (through biological membranes and barriers) rapid degradation (at the site of administration or site of action, or in the blood), etc. However, today, many liposomal drugs are approved for human use, the most recent examples being mRNA vaccines against COVID -19.

Nevertheless, one of the weak points of liposome nanotechnologies, is their limited potential to prolong drug release, compared to other nanocarriers. Usually, liposomes release entrapped molecules and break down after a few days or weeks following in vivo administration. Hybrid systems, such as Drug-in-liposome-in hydrogels, or drug-in-liposomes-in-electrospun fibers and others have been proposed in the literature, for prolongation of drug release.

Approach

Our main achievements are:

• We identified the optimal preparative parameter for manufacturing nano-sized liposomes of bioactive peptides with high loading capacity and stability by microfluidic flow-focusing method.
• We identified (together with Applus+ Rescoll) optimal preparative parameters for the development of optimal BA-in-Liposome-in ESM hybrid delivery systems that have the advantages of: (i) protection of BA bioactivities; (ii) salvage of high-BA-dose cytotoxicity’s; (iii) sustained/prolonged gradual release of bioactives, that retain their bioactivity up to 6 months after their implantation. (iv) potential to tune the number of BAs integrated into the membranes by several methods.
• We have proved that L929 cells, that are easy and fast to grow and available in most laboratories, may be used not only for cytotoxicity screening, but also (when cultured in osteoinductive media) for comparative screening of different BAs and/or different BA formulations, regarding their capacity to increase the osteogenic differentiation (mineralization/calcium deposition) of cells.

SBR's impact on UPAT (pharmacy group)

• We had the opportunity to set up and use new in vitro techniques (that were not set up before in our laboratory), such as methods for evaluation of osteogenetic differentiation of cells, cell migration/chemoattraction, genotoxicity. These necessities, gave the chance to our young researchers to search for new techniques and to gain new skills.
• We had the opportunely to collaborate closely with the R & D department of a company (Applus+ Rescoll) on the integration of liposomes in electrospun fibers.
• We had the opportunity to develop new liposomal forms with microfluidic flow-focusing devices that were recently set up (in the context of a previous project) in our lab, extending our knowledge and experience with these methods.

SBR's impact on the future

Our laboratory has been carrying out research for more than 30 years with the aim to provide novel solutions for the delivery of drugs or other bioactive molecules to specific areas of the body, where drug or BA delivery proves challenging due to several reasons. These reasons are related to the properties of the specific molecule (large MW, low solubility, low membrane permeability, low stability/rapid degradation in blood, site of administration and/or action, etc.), and/or related to the difficulty to reach the diseased site or retain the drug at the site for the required period.

We have worked to provide drug delivery solutions for various unmet medical needs, such as: a low-cost microbicide for vaginal delivery to decrease possibility for sexual transmission of HIV; multitargeted and/or multifunctional liposomal drugs for the diagnosis and treatment of Alzheimer’s disease; targeted delivery systems (ligand targeted liposomes) decreasing toxicity and increasing activity of highly toxic anticancer drugs, due to targeting of cancer cells, etc. We publish many research papers, book chapters, abstracts in conferences, etc. with novel findings that have influenced/helped other researchers in their work.

Finally, as an academic institution, we have trained a high number (>200) of young researchers (undergraduates, graduates and PhD’s) and provide them with opportunities to work on funded projects (funded my several National and European, etc. sources), with the aim to find drug delivery solutions for different drugs or active substances in general.

Project and innovation management & communication - Eurice

Role within SBR

Within the Communication scope of Work Package 9 “Communication, Dissemination and Exploitation “, Eurice is responsible for the development of tools, platforms and contents supporting the communication outreach of the project towards relevant stakeholders and external audiences. Supported by the Communication committee, we have set up a website, provided communication materials and a promotional video for the project, and guided the online communication strategy. Eurice also supported partners in assessing their research results regarding their impact potential in the health care field, and pursue a strategic approach to valorise these results. This includes the crucial efforts to protect the intellectual property they created in the form of a groundbreakingly new implant and medical procedure in the treatment of large bone defects.

As management partner, Eurice also made sure that the project was always running smoothly and, when needed, that risks were identified early and appropriate mitigation measures were identified and applied swiftly. We also established management support structures to facilitate the workflow in the project, as well as the internal communication between all project partners.

Main achievements within the project

Throughout the project, we managed to communicate the activities of SBR partners, grow a community of relevant stakeholders and professionals in the field and highlight the impact of our early-stage researchers. By sharing real patient testimonials telling their struggles and their bone regeneration journey, we showed the human perspective and the concrete impact of bone regeneration innovation. The diffusion of an audiovisual material contributed to promote the project and include a wide audience in the conversation.

With an experience of more than 20 years in managing EU-funded projects, Eurice could draw upon a plethora of tried-and-true processes and structures to also manage the SBR project effectively. But of course, we also used a combination of current project management and videoconferencing tools to make sure that the project ran smoothly and efficiently. Our main achievement was guiding the consortium through challenging times, such as the impact of the COVID-19 pandemic. We also helped partners to navigate the process of managing and protecting their intellectual property in light of all the challenges that the intrinsic nature of the collaborative research creates, where results are co-created and jointly owned by multiple partners.

SBR's impact on Eurice

To structure our communication activities consistently, we developed new planning and measuring frameworks. This enabled us to define the frequency of communication activities, the kind of content we wanted to provide, and gave us a base for collaborative work with project partners, as the communication of the project heavily relies on their input.

These new processes paved the way to new internal processes and enables us to better our communication and project management expertise around strategic dynamics. In addition, the special focus given to the measurement of project communication raised fundamental questions on notions of impact, audience relevancy and overall KPI effective depiction.

While our established methods regarding management tasks also proved to be helpful in SBR, we gained some new insights regarding risk management and the application of mitigation measures that we can translate to other projects and consortia as well. Another interesting and unique experience in this project has been to foster an understanding and collaboration between such a diverse group of project partners that were coming from different technical, scientific and industrial fields.

Impact on the future

Eurice believes in the value of communication to widen the scope of research projects to external audiences and provide accurate, understandable information to a wide range of stakeholders. By continuously updating our communication practices, we contribute in connecting the general public to projects shaping the future of European innovation and experts from different institutions, countries and fields.

By steering ambitious, collaborative and innovative research projects, our projects do not only advance science in their respective fields. But by making sure they are seen to a fruitful end, Eurice plays an important part in safeguarding that ultimately these advancements can and will benefit society as a whole. Both the project management and innovation management activities of Eurice have enabled the consortium to perform excellent research that produces lasting impact in the wellbeing of patients, treatment options of clinicians, and the health care system economy.