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Periodic Report Summary 2 - IMAVALVE (Intelligent materials for in-situ heart Valve tissue engineering)

Project Context and Objectives:
Valve replacement with mechanical or bioprosthetic prostheses is the most common intervention for valvular disease, with almost 300.000 annual replacements worldwide. There are more and more patients with grown-up congenital heart disease (GUCH) who have survived into adulthood thanks to surgical innovations and will require one or more heart valve replacements later in life. Although existing valve prostheses generally have resulted in enhanced survival and quality of life, prosthesis associated problems affect 30-35% of the patients within 10 years post operatively. In particular young recipients of current heart valve replacements have significantly reduced life expectancy (up to 50%) compared to age matched healthy individuals, and experience a high probability of serious valve-related morbidity throughout life. In patients younger than 18 years freedom from reoperation is only 58-68% at 15 years.
Heart valve prosthesis associated complications include thrombo-embolic events requiring lifelong anticoagulation in case of mechanical valves, and limited durability due to calcification and structural failure in case of biological valve substitutes. Prosthetic valves are non-viable structures and, therefore, do not have the ability to grow, repair or adjust to functional demand changes. Living, tissue engineered heart valves are expected to overcome these limitations.
In situ tissue engineering using a biodegradable synthetic scaffold that recruits endogenous cells from the bloodstream is emerging as a promising technology to create living heart valves inside the human body having the potential to last a lifetime. Compared to classical tissue engineered heart valves this new technology demonstrates off-the-shelf availability at substantially reduced cost, logistics and regulatory complexity.
The ImaValve project aims to develop intelligent materials needed for the in-situ engineering of heart valves, to process these materials into a functional heart valve scaffold that can be implanted via a minimally-invasive (transcatheter) implantation technique at the aortic position, and to take all necessary (pre-clinical) steps to enable a first-in-man clinical trial after completion of the project.
A novel approach to the biodegradable scaffold is pursued, that combines a relatively slow degrading elastomeric material with a fast degrading bioactive hydrogel material. These materials are processed into a fibrous heart valve scaffold by means of electrospinning. The elastomeric material ensures long term functionality of the valve while supporting in-vivo mature tissue formation, whereas the fast eroding hydrogel material modulates the early inflammatory host response to the scaffold and creates the necessary void space for cells and neo-tissue formation between the elastomeric fibers.

To meet our goals we have planned to:
i. Develop supramolecular slow degrading (months), durable elastomeric materials and fast eroding (week) hydrogel materials that can be rendered bioactive. Combine these materials into an electrospun heart valve scaffold.
ii. Develop a stent-scaffold combination that is suitable for transcatheter delivery of the heart valve scaffold, and that has sufficient strength and durability to sustain the pulsatile hemodynamic loads.
iii. Develop a mechanistic understanding of the human host response to the scaffold, and the effect of selected bioactives (i.e. TGF-β, MCP-1, SDF-1α) on this host response and subsequent early tissue formation
iv. Achieve sufficient alignment and associated matrix anisotropy of the in-situ deposited collagen to prevent valve leaflet retraction and to attain long-term cell and tissue homeostasis.
v. Demonstrate that the implanted heart valve scaffold in vivo will transform into a functional, living stable heart valve.
Project Results:
UPy-polymers were designed and synthesized compatible with GMP. Biocompatibility was shown using a standard suite of tests. The material was made into an improved design heart valve scaffold showing excellent hydrodynamic performance.
Significant progress has been made with UPy-modified bioactive compounds to enhance cell-ingrowth to accelerate tissue formation. This included design, synthesis, characterization and protocols for their incorporation.
Stent, scaffold and delivery device:
Stent Imaging markers were added. The scaffold is sutured in the stent using soft suture wires and is pre-shaped to achieve a geometry optimized by computational modelling for functioning under load. The valve is tested in simulated in-vivo and clinical conditions. A cross project design team oversees this procedure documenting all tests, failures and successes.
Changes to the delivery prototype include a size increase to 28 Fr and a change from a metal capsule to polymer to improve release, and a progressive two step deployment solving a temporary blocking of the aorta flow during delivery. Ergonomics were improved and tested by the surgeon.
Recruitment, tissue forming and stability:
Peptides that can recruit the patient’s macrophages and stimulate them towards the tissue-forming fate, were successfully incorporated into the supra-molecular scaffold. This can help reduce inherent inter patient variation and improve outcomes of treatment.
After their recruitment and differentiation, cells need to produce a matrix that upon degradation of the scaffold will achieve cell and tissue homeostasis to maintain valve stability. Mechanistic insights are needed; a novel bioreactor allows the measurement of cell traction and temporal changes in tissue mechanics. This will inform models that help understand and possibly control the interplay of hemodynamics, tissue formation and homeostasis, and assess long-term valve functionality.
Preclinical experiments:
Crimping procedure, loading and functionality were assessed during the acute survival phase in pulmonary (n=2) and aortic (n=5) positions assisted by various imaging modalities. Pulmonary delivery confirmed implantation feasibility but showed that optimization of the delivery device was needed. Preserved valve functionality was confirmed, allowing for a transition to the aortic side.
First TAVIs confirmed the valves’ ability to withstand crimping and delivery under aortic pressure, but showed insufficiency due to inadequate cooptation. Valve geometry, leaflets thickness and length were changed, positively influencing delivery, flow preservation, closing-opening patterns as well as reduction of regurgitation. Histological evaluation of the early cellular infiltration has started. Some stent strut malposition was observed, with in vitro testing suggesting stent fatigue factored into this issue. Additional testing will verify functionality before start of chronic experiments.
Regulatory plan:
A two-pronged approach was taken towards a valvular scaffold: a) initial development of a scaffold without biological factors as a first generation, and b) investigation in parallel of the effects of biological factors. The heart valve of the first generation will then be a classical medical device with a regulatory pathway without involvement of medicinal Competent Authorities. Regulatory monitoring was continued and further formalized throughout the period.
The first-in-man study design was initiated. Since long-term pre-clinical data may not become available in time, a clinical study concept will be developed as basis for a study protocol.
Dissemination and exploitation:
At several (bio)medical conferences, scientific fairs and public lectures ImaValve was presented. Articles were published in several journals. A movie was produced to show the goals and potential impact.
The exploitation plan was further refined, and concrete steps were taken towards a meaningful route to market for heart valve scaffolds.
Potential Impact:
When successful the ImaValve project will result in a novel off-the-shelf available synthetic heart valve scaffold – suitable for transcatheter delivery via a purposely-designed stent and delivery system – which in-vivo gradually transforms into a living, durable aortic heart valve that lasts a lifetime. In addition, the project aims to provide preclinical proof of concept and a regulatory strategy including preclinical safety evaluation, to receive approval of a clinical trial by the responsible medical ethical committee and competent authorities after the project. Next to this, the project will:
• Enhance our knowledge of biodegradable scaffolds and their safety and behavior in-vivo; and will deliver a novel library of degradable elastomeric supramolecular materials of interest to the biomedical field,
• Substantially increase our understanding of the (inflammatory) foreign body response to degrading, bioactive materials, relevant to harnessing this response via material design.
• Provide novel insights into the relationship between early tissue formation and later stage tissue maturation and organization, in order to guide neo tissue formation and maintain valve mechanical function.
• Provide important information about the compliance of novel in-situ tissue engineering solutions with current clinical regulations, guidelines and standards.

We are working towards potential impacts and implications of ImaValve (end) results that include:
Novel biomaterials: The materials and material processing technologies developed in ImaValve have wide applicability in the field of regenerative medicine. The biodegradable elastomers are exceptionally versatile; their biomechanical and degradation properties can be tuned, which makes these materials particularly attractive for many tissue regeneration applications. Moreover, these biodegradable elastomeric materials provide independent control of the biomechanical and bioactive properties of the scaffold. Applications include, but are not limited to: (small) diameter vascular substitutes, venous valve replacements to treat peripheral artery disease, articular cartilage repair, myocardial regeneration, intervertebral disc regeneration, muscle regeneration, etc. Each of these applications address unmet clinical needs and represent huge market opportunities.
In-situ heart valve tissue engineering using synthetic biodegradable materials circumvents the key obstacles of traditional heart valve tissue engineering. The in-situ methodology bypasses the labor intensive, complex and costly cell and bioreactor culture phases (which require a total throughput time of about 8-10 weeks), and has off-the-shelf availability. The intrinsic manufacturing cost of the proposed technology is low. As such, the approach is attractive for commercialization.
Enhanced European collaboration: ImaValve combines the unique expertise, experience and infrastructures necessary to achieve the ambitions of the project. This combination of expertise and experience is not available in a single European member state.
Improved quality of life: The use of a living valves is expected to drastically alleviate current prosthesis associated problems that affect 30-35% of the patients within 10 years post operatively. In particular young recipients of current heart valve replacements have significantly reduced life expectancy (up to 50%) compared to age matched healthy individuals, and experience a high probability of serious valve-related morbidity (including stroke) throughout life. In patients younger than 18 years freedom from reoperation is only 58-68% at 15 years. The prevalence of aortic stenosis in Europe is 2.5% at the age of 75 years and almost 8% at 85 years. Today, it is estimated that 600,000 individuals in the EU have severe symptomatic aortic stenosis, while only a fraction of these patients is treated. Many of these patients would benefit from a transcatheter implantation of an ImaValve heart valve substitute.
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