Periodic Reporting for period 1 - ELR-SCAR (A novel multi-functional elastin-like recombinant hydrogel for the prevention of scar tissue formation following a myocardial infarction: "ELR-SCAR")
Período documentado: 2022-12-01 hasta 2024-05-31
CONTEXT AND OVERALL OBJECTIVES:
The ELR-SCAR project aims to complete preclinical validation of a novel biomaterial, an elastin-like recombinant (ELR) hydrogel, to prevent scar tissue formation in the heart following myocardial infarction (MI), commonly known as heart attack. MI, the endpoint of ischaemic heart disease (IHD), affects approximately 26.5 million patients in Europe and has the highest rates of IHD worldwide. Current post-MI interventions have serious limitations in treatment efficacy and patient safety, leading to a clear medical need for new solutions that prevent scar tissue formation and irreversible cardiac remodelling.
Our preclinical data indicate that the ELR-hydrogel has promising functionality owing to its multiple unique characteristics. ELR hydrogels provide mechanical support to damaged cardiac tissues post-myocardial infarction (MI). This mechanical reinforcement helps to maintain the structural integrity of the heart during the healing process, preventing adverse remodelling, which can lead to heart failure. It also provides selective cell adhesion to the endocardium, offers a barrier to scar tissue formation, exhibits high biospecificity to the ischaemic microenvironment, and has enhanced biodegradability, allowing for safe disintegration in the body.
To facilitate endocardial delivery, we are developing a minimally invasive endocardial catheter (Partner BSC) alongside the hydrogel. Both components will be advanced to the readiness level for a first-in-human (FIH) validation study post-MI. Regulatory and intellectual property rights (IPR) strategies are being developed for clinical validation. Considering the high societal impact of IHD and MI, a comprehensive health economic evaluation will also be developed to assess potential savings and patient benefits. ELR-SCAR aims to transform clinical practice and reduce the burden of MI and IHD on society and patients.
The ELR-SCAR project aims to complete preclinical validation of a novel biomaterial, an elastin-like recombinant (ELR) hydrogel, to prevent scar tissue formation in the heart following myocardial infarction (MI), commonly known as heart attack. MI, the endpoint of ischaemic heart disease (IHD), affects approximately 26.5 million patients in Europe and has the highest rates of IHD worldwide. Current post-MI interventions have serious limitations in treatment efficacy and patient safety, leading to a clear medical need for new solutions that prevent scar tissue formation and irreversible cardiac remodelling.
Our preclinical data indicate that the ELR-hydrogel has promising functionality owing to its multiple unique characteristics. ELR hydrogels provide mechanical support to damaged cardiac tissues post-myocardial infarction (MI). This mechanical reinforcement helps to maintain the structural integrity of the heart during the healing process, preventing adverse remodelling, which can lead to heart failure. It also provides selective cell adhesion to the endocardium, offers a barrier to scar tissue formation, exhibits high biospecificity to the ischaemic microenvironment, and has enhanced biodegradability, allowing for safe disintegration in the body.
To facilitate endocardial delivery, we are developing a minimally invasive endocardial catheter (Partner BSC) alongside the hydrogel. Both components will be advanced to the readiness level for a first-in-human (FIH) validation study post-MI. Regulatory and intellectual property rights (IPR) strategies are being developed for clinical validation. Considering the high societal impact of IHD and MI, a comprehensive health economic evaluation will also be developed to assess potential savings and patient benefits. ELR-SCAR aims to transform clinical practice and reduce the burden of MI and IHD on society and patients.
WORK PERFORMED AND MAIN ACHIEVEMENTS:
To date, significant progress has been made in hydrogel optimisation and production, led by the partner TPNBT, as reflected in Deliverable 4.1. Standard operating procedures (SOPs) for GMP manufacturing have been documented, capturing refined methodologies and optimisation achieved during the lab-scale phase, providing a guide for successful integration into GMP manufacturing (Deliverable 4.2). TPNBT is refining ELR-hydrogel production with a fed-batch hydrogel synthesis method and scaling laboratory processes for manufacturing. Discussions with GMP companies are ongoing to ensure seamless scaling up of the hydrogel with high-quality standards.
The optimisation of the hydrogel formulation and detailed physicochemical characterisation, such as swelling ratio, swelling capacity, and transition temperature, were conducted by the University of Galway (NUIG) (Deliverable 1.1). The cytocompatibility of the hydrogel was established by subjecting the ELR-hydrogel to cardiac fibroblast cells, which resulted in a significant enhancement in both metabolic activity and DNA content over a six-day period. This demonstrated the stimulatory effect of hydrogel treatment on cellular metabolism and proliferation dynamics.
Partner BSC has successfully developed the initial catheter prototype, which underwent thorough bench testing and involved key stakeholders such as cardiac surgeons (Partner CRCV) (Deliverable 2.1). They are now in the process of refining the catheter prototype for further testing in human cadavers and animals. Partner HMX is leading the way in determining the regulatory pathway and identifying the classification of the ELR-hydrogel, as outlined in the annual regulatory report (D5.3). Lastly, Partners LSMU and SUM have been actively planning cadaver and animal studies in collaboration with University of Galway (NUIG).
To date, significant progress has been made in hydrogel optimisation and production, led by the partner TPNBT, as reflected in Deliverable 4.1. Standard operating procedures (SOPs) for GMP manufacturing have been documented, capturing refined methodologies and optimisation achieved during the lab-scale phase, providing a guide for successful integration into GMP manufacturing (Deliverable 4.2). TPNBT is refining ELR-hydrogel production with a fed-batch hydrogel synthesis method and scaling laboratory processes for manufacturing. Discussions with GMP companies are ongoing to ensure seamless scaling up of the hydrogel with high-quality standards.
The optimisation of the hydrogel formulation and detailed physicochemical characterisation, such as swelling ratio, swelling capacity, and transition temperature, were conducted by the University of Galway (NUIG) (Deliverable 1.1). The cytocompatibility of the hydrogel was established by subjecting the ELR-hydrogel to cardiac fibroblast cells, which resulted in a significant enhancement in both metabolic activity and DNA content over a six-day period. This demonstrated the stimulatory effect of hydrogel treatment on cellular metabolism and proliferation dynamics.
Partner BSC has successfully developed the initial catheter prototype, which underwent thorough bench testing and involved key stakeholders such as cardiac surgeons (Partner CRCV) (Deliverable 2.1). They are now in the process of refining the catheter prototype for further testing in human cadavers and animals. Partner HMX is leading the way in determining the regulatory pathway and identifying the classification of the ELR-hydrogel, as outlined in the annual regulatory report (D5.3). Lastly, Partners LSMU and SUM have been actively planning cadaver and animal studies in collaboration with University of Galway (NUIG).
RESULTS BEYOND STATE OF THE ART:
Initial studies in sheep MI-disease models, conducted by partner LSMU and University of Galway (NUIG), demonstrated that the hydrogel supports the functional and structural recovery of cardiac muscle. The ELR-hydrogel does not elicit a toxic or immunogenic response, and does not interfere with ongoing function or structural integrity.
Thermo-responsiveness and sensitivity to hydrogel degradation were evaluated by the University of Galway (NUIG), and the results demonstrated the hydrogel's high thermal stability. These findings highlight the potential for further development and translational research, paving the way for the hydrogel's practical application.
Partner BSC's capabilities in extrusion and moulding are harnessed for catheter prototype development (D2.1). ELR-SCAR Hydrogel was successfully injected into porcine heart tissue, demonstrating that the syringe pump system and needle are suitable for this purpose. At the same time, Partner CRCV's state-of-the-art cardiac catheterisation and imaging laboratories will support post-procedural analyses when the working prototype is available.
This work will facilitate proof-of-concept (PoC) studies in an established sheep model representing non-transmural MI scheduled to begin in Q3, Year 2.
Initial studies in sheep MI-disease models, conducted by partner LSMU and University of Galway (NUIG), demonstrated that the hydrogel supports the functional and structural recovery of cardiac muscle. The ELR-hydrogel does not elicit a toxic or immunogenic response, and does not interfere with ongoing function or structural integrity.
Thermo-responsiveness and sensitivity to hydrogel degradation were evaluated by the University of Galway (NUIG), and the results demonstrated the hydrogel's high thermal stability. These findings highlight the potential for further development and translational research, paving the way for the hydrogel's practical application.
Partner BSC's capabilities in extrusion and moulding are harnessed for catheter prototype development (D2.1). ELR-SCAR Hydrogel was successfully injected into porcine heart tissue, demonstrating that the syringe pump system and needle are suitable for this purpose. At the same time, Partner CRCV's state-of-the-art cardiac catheterisation and imaging laboratories will support post-procedural analyses when the working prototype is available.
This work will facilitate proof-of-concept (PoC) studies in an established sheep model representing non-transmural MI scheduled to begin in Q3, Year 2.