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TEH-TUBE Report Summary

Project ID: 604049
Funded under: FP7-NMP
Country: France

Periodic Report Summary 2 - TEH-TUBE (Tissue engineering of the right heart outflow tract by a biofunctionalized bioresorbable polymeric valved tube)

Project Context and Objectives:
Approximately 42% of infants’ mortality in the world is related to congenital heart defects (prevalence: 8-12/1000 births). Over 1/3 require the reconstruction of the right ventricular outflow tract (RVOT) by surgical procedures which currently use inert materials without any growth potential. Consequently, multiple reoperations are often required, with their attendant high risk of mortality and morbidity. The TEH-TUBE project coordinated by Pr. David Kalfa will address these limitations by creating an innovative completely bioabsorbable polymeric valved tube device either seeded with autologous adipose tissue derived stem cells (ADSC) or functionalized by a peptidic sequence or a hydrogel triggering homing of the host cells onto the scaffold to make it a living self-populated structure. The main objectives of the project are to:
• Compare different polymers processed by electrospinning (ES) to generate a competent valved tube.
• Identify the optimal ES parameters and the optimal design of the valved scaffold to meet the mechanical specifications.
• Compare, in the selected polymer, ADSC seeding and peptide/hydrogel-based biofunctionalization using in vitro mechanical and biological tests as well as in vivo animal experiments (primarily rats).
• Validate the ultimate combination (polymer + biofunctionalization) in a clinically relevant large animal model (in this case, the growing lamb to specifically assess the regenerative and growth potential of the composite construct).

The expected final result is to develop an innovative biomaterial for the treatment of congenital heart abnormalities in children and young adults. By creating a material whose growth will keep pace with that of the patient, this product, geared to become an Advanced Therapy Medicinal Product (ATMP), should decrease the risk of reoperative surgeries, improve the quality of life and ultimately have a positive impact on healthcare costs.

Project Results:
The work performed since the beginning of the project and the main results obtained are:
- Optimised conditions for ES of valved and non-valved tubes have been achieved. Using a bespoke mandrel, high quality and reproducible tube thickness has been achieved. The ES of complex shapes, including tubes with sinuses, has been achieved.
- Following consideration of a range of polymers and a systematic review of the supplier base, partner HZG has produced a novel polymer meeting the requirements of the THE-TUBE project. A patent application for this polymer is currently being drafted.
- The final design of the device is referred to as T-shape tube-in-tube device, with the inner tube playing the role of the valve and the following features: external tube with sinuses, the diameter of the inner tube is equal or slightly above the diameter of the external tube, the inner tube is sutured circumferentially below the sinuses and vertically along 5 mm. An additional ring of polymer is required to provide additional mechanical support for the valve and this has been optimised.
- Bench tests of the various prototypes has confirmed that the final design prototype has appropriate functioning for implantation.
- Isolation and culture protocols of functional hADSC and oADSC were validated. All tested clinical media were validated for isolation and expansion of hADSC, StemMACS medium being considered as most suited to the project. 106 cells/cm2 was demonstrated as the optimal cell density for seeding ADSC on patches of polymers.
- Biofunctionalisation of the polymer has been investigated and functionalised polymer patches produced for implantation into rats.
- The implantation of implantation of biofunctionalised and non-biofunctionalised patches made of HZG polymer has been performed during a 90 days rat study and shown that biofunctionalisation does not result in any additional biological benefit. The full analysis of the 90 day rat study has been completed.
- Deliverables associated with design specifications, validation plan, functional analysis and risk analysis have been submitted. Other actions ensuring that the project has the expected level of quality include Raw material suppliers qualification, Raw material selection, Solvent residuals guidelines, Finite Element Analysis, Project Plan Establishment, QA recommendations, Standards for bench tests requirements, Organization for Validation Master Plan, and support for establishment of NDAs and MTAs have been completed. A pre-submission dossier has been prepared for an FDA meeting in 2017.
- The clinical-grade manufacturing for the production of the HZG polymer has been initiated.
- Statice has commenced the production of non-valved tubes for lamb implantations during 2017.
- Protection and dissemination of the technology are ongoing. Patentability reviews of the biodegradable T-shaped valved tube in tube showed that this concept was novel compared to the prior art and that there was a high chance to get a patent granted. Patent meetings have taken place and a patent application will be made in 2017. HZG are leading a patent application for their novel polymer and this is expected to be submitted in 2017. Dissemination has been performed in many international meetings. An economical model and a review of competitors in the field are ongoing as part of the business plan development for post-project activities.

Potential Impact:
In the future, successful treatment of congenital cardiac abnormalities is expected to rely on ATMPs and medical devices. Around 36,000 children are born each year with a CHD; these are the most frequent congenital abnormalities (8-12/1000 births). Existing treatment involves reconstruction of the RVOT, using materials that do not grow as the patient develops. This means that patients treated for a CHD in must undergo repeat surgery (1-4 revision surgeries in their lifetime) with a high risk of mortality and morbidity. Our aim is to combine and develop existing methodologies to produce a technology that will allow treatment of CHDs with a biomaterial that can reconstruct the heart with a single surgery without the need for re-intervention as the patient grows. This will address the currently unmet clinical need and poor clinical outcome in this patient population. For this reason, TEH-TUBE is supported by the French Association Nationals des Cardiaques Congenitaux. The TEH-TUBE project will improve the quality of life of patients due to improved biocompatibility and longer duration of these interventions. The improvement of quality of life is obvious, as the product would avoid revision surgeries during the growth of the child. However, the impact is not only related to the surgery but also to indirect issues such as related pathologies, permanent medication, controlled physical activity, loss of performance during studies and professional activities due to treatments, surgeries and other issues. The development of such a device that can efficiently and permanently replace the RVOT will significantly reduce all these drawbacks allowing children to lead a completely normal life. In addition to such healthcare costs directly related to surgery, there are other additional costs. Children with CHD often require numerous hospital visits, care by a multidisciplinary team of specialists, frequent imaging and other diagnostic testing, drug and device therapy, and life-long outpatient follow-up. In another study, costs were grouped as financial, emotional and family burden. Financial costs include job change or job loss (e.g., mothers unable to return to work after maternity leave due to the inability to place a child in day care) loss of earnings due to taking time off work to attend appointments. Emotional impact was most commonly reported to be substantial stress in immediate family but also extended family who assist in taking time off work for childcare. In addition, due to repeated surgeries with cardiopulmonary bypass and their potential morbidity, some children/adolescents/adults display lower cognitive function and a decreased quality of life, with an impact on social function. Secondary clinical impacts are numerous. The technology can be applied to all patients with an abnormality of the left ventricular outflow tract, heart valve disease, patients requiring a vascular surgical reconstruction, or cardiac reconstruction using a bioabsorbable patch. Secondary impacts and applications include polymeric meshes for abdominal wall reconstruction, polymeric films to decrease pericardial adhesions after cardiac surgery, biofunctionalized reconstruction scaffold in laryngofacial and plastic surgery, biofunctionalized bioabsorbable tubes for pediatric urologic surgery, hemodialysis access shunts. Finally, TEH-TUBE will support the EU2020 Strategy and health policies within the group of patients who experience CHD to:
• Improve health
• Promote sustainability in EU healthcare systems by decreasing the economic burden of healthcare costs
• Reduce numbers of deaths due to major/chronic disease
• Increase employment within the patient group
• Promote social cohesion.
This also aligns with aspirations of the EU2020 programme to support the Innovation Union in the development of knowledge and producing an innovative product concerning health and the aging population. Together, these will help to promote a sustainable, more competitive economy.

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