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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - FACTA (An innovative process to extend commercial bioprosthetic heart valves lifespan.)

Teaser

Summary

Heart valve disease is one of the main causes of morbidity and mortality worldwide.
In 2017, around 400.000 patients underwent heart valve replacement; this incidence is expected to exceed 850.000 units in 2050. When a heart valve is no longer able to perform its function (due to congenital factors, various diseases or due to of ageing) it must be replaced surgically. Prosthetic heart valves substitutes are classified into two main categories: Mechanical (MHVs) and Bioprosthetic Heart Valves (BHVs, including tissue and transcatheter heart valves) . Although MHVs last longer, they are composed of thrombogenic material and therefore patients with MHV require lifetime anticoagulation therapy, which increases the risk of bleeding, haemorrhage, anaemia and renal disease. About 50% of the implanted prosthetic heart valves in the world are biological since they have better biocompatibility, do not require lifelong anticoagulant therapy and show a more physiological hemodynamics . In order to guarantee immunological tolerance, the adequate mechanical resistance and conservation over time, current BHVs are subjected by manufacturing companies to chemical treatment with cross-linking agents such as glutaraldehyde (GLU), but unfortunately their durability is limited due to onset of calcific degenerations that prevent their correct functionality. GLU shows limited efficacy: about half of the alpha-Gal epitopes remain available and reactive towards circulating antibodies, allowing the creation of inflammatory states which can evolve in immune-mediated reactions related to tissue calcification . These degenerative phenomena begin to affect the BHV tissue after 5 years from implantation. 50% of implanted BHVs need to be replaced 10/12 years after surgery. In the case of young patients, this duration is dramatically reduced (100% of BHVs do not exceed the tenth year of activity) . Technological evolution and new treatments/products have greatly reduced the mortality rate for people suffering from valvulopathies, but none of the current BHVs can definitively restore the native function.
Why is it important for society?
The FACTA technology developed by BCI presents several competitive advantages about both for the treatments currently applied by the BHVs manufacturers and for the possible future approaches that are still under study and development. Currently chemical treatments of BHVs manufacturers have: limited biocompatibility; immune response activation; high propensity to calcification and limited duration. Moreover, they are not recommended in young patients and entail high costs for hospitals and health facilities due to frequently new operations. The FACTA technology allows: high biocompatibility degree; low thrombogenicity; resistance to degradation phenomena; resistance to calcification and increase in duration. It is also potentially suitable for young patients and reduces costs for hospitals and health facilities avoiding new operations.
Overall Objectives:
The current project has the objective to carry out a feasibility study for FACTA, both on business and technical level:
- The business feasibility study has been focused on the validation of the BCI business model, that provides for the direct purchase of the starting animal tissue, its treatment with the FACTA method and its sale as a semi-processed product to BHV manufacturing companies.
- The technical feasibility study has been focused on the assessment of the need for a second pre-clinical trial to confirm the in-vivo inactivation of the alpha-Gal molecule. Since the recognition of the alpha-Gal by circulating anti alpha-Gal antibodies is considered a primary event that can initiate the deposition of calcium salts on the tissue, the immunological reactivity towards the treated tissue will be especially considered. If the feasibility study reveals this need as common to all the contacted BHV manufacturers, it will be necessary to evaluate times and costs of this new exper

Work performed

BCI has developed and patented a technology called FACTA able to define a new concept of biocompatibility through the stable and safe inactivation of more than 90% of the alpha-Gal epitopes present in the animal tissues constituting the current BHVs. The reliability and efficacy of FACTA have been validated by extensive in-vitro investigations that confirm a significant decrease in calcification propensity (over 85% of calcium deposits less than untreated samples) and a better resistance of the treated tissue to degenerative/degradation phenomena mediated by enzymes and oxidative stress.
The results of these tests were published in the scientific journal Tissue Engineering . In-vitro studies have shown how the developed treatment does not alter the hydrodynamic and biomechanical features of the BHVs ensuring the maintenance of the correct compliance and valve competence. The treatment is a single and simple step added to the normal manufacturing line of BHVs and can be considered as a minimal manipulation according to the FDA guidelines 2014 . FACTA can be applied to tissues before the delicate phases of BHVs sterilization and packaging, thus not involving a critical treatment on the finished product rather a simple intermediate processing phase, with significant cost and time savings.

Final results

It is widely recognized that the alpha-Gal epitope is related to the onset of calcific processes that limit the duration of BHVs. Recently, an alarming correlation between the presence of the alpha-Gal epitope and premature BHVs degenerations within 2 years of implantation has been reported . The need to increase the durability of the HVBs is a key objective shared by all manufacturing companies and is considered fundamental to guarantee the acquisition of new market shares with the introduction of a new technology able to solve the current critical issues. The development of a treatment able to efficiently inactivate the alpha-Gal epitope present in the animal tissues used for the production of BHVs, avoiding recognition by the host immune system, is potentially able to reduce the onset of calcium dystrophic phenomena responsible for the degeneration of these biomedical devices. Avoiding calcium deposition, can significantly prolong the duration of BHVs to the benefit of the patient\'s quality of life by lowering the percentage of re-interventions in elderly and ensuring greater autonomy in younger ones. This would also affect the costs of intervention and subsequent health care. Furthermore, allowing the use of BHVs also in young adults (a cohort of patients now excluded due to the high rate of calcification speed of the device) would allow a disruptive expansion of the market potential.