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Periodic Report Summary 1 - BIOTRACHEA (Biomaterials for Tracheal Replacement in Age-related Cancer via a Humanly Engineered Airway)

Project Context and Objectives:

Primary tracheal cancers are neoplastic lesions of the airways with a high mortality rate, significantly impacting upon the lives and careers of thousands of patients each year throughout Europe. In almost all cases, surgical resection with primary reconstruction is regarded as the gold standard for treatment. However, as definitive diagnosis is often reached when more than 50% of the total tracheal length is affected by primary malignant disease, it is only possible to treat patients palliatively. For these patients prognosis is poor with a 5-year survival rate of about 5%. Even for patients with operable tumours, the proportion of complete tumour resection is less than 60%, due to limitations in performing the reconstruction of the trachea. The outcome for patients with primary tracheal cancers would be radically transformed if a trachea replacement with similar anatomical, physiological and biomechanical properties to those of the native trachea, could be available. This clinical need has given rise to the concept of manufacturing a tissue engineered trachea.

Constructing a tissue engineered trachea involves utilising a donor trachea which undergoes a de-cellularisation process to remove all donor cells and antigens. This process should ideally provide a non-immunogenic, pro-angiogenic tracheal scaffold which also maintains its biomechanical properties. Subsequently, airway epithelium cells are seeded intra-luminally and mesenchymal stem cell-derived chondrocytes extraluminally to allow re-cellularization of the tracheal scaffold prior to its implantation in the patient in need of trachea replacement. An alternative approach to obtaining a trachea scaffold is to construct it using biosynthetic materials, which can mimic the properties of the native trachea. While this option can possibly provide a made-to-measure scaffold for each patient and does not rely on the availability of donor organs, meeting the physiochemical, structural and mechanical properties of the native trachea is a challenge.

The BIOtrachea EU consortium, consisting of 13 EU-based, clinical, academic and commercial participants brings together their expertise in Tissue Engineering, Airway Epithelium and Stem Cell Biology, Pharmacology, Stem Cell Mobilisation, Cell Therapy, Cellular and Molecular Immunology, Pre-clinical and Translational study Design, Radiobiology, Proteomics, Membrane bioreactors and Membrane technology, GMP manufacturing and development, Bioethics and commercialisation of bioreactors, in order to optimise the production and implantation of Tissue Engineered Tracheas. Once this is achieved, it will become possible to offer a curative treatment to trachea cancer patients who are currently only offered palliative therapy. Furthermore, it will be possible to apply the knowledge gained to Tissue Engineering protocols for other organs.

The overall objective of this programme is to both improve and optimise the approach using de-cellularized biological scaffold and to develop synthetic biomaterial scaffolds by using innovative next generation polymeric nanocomposite materials. At the same time, new pharmacological strategies will be developed to improve tracheal regeneration. The BIOtrachea consortium will ensure that the synergistic outputs of the project will far exceed the sum of each individual component.

The main objectives of the BIOtrachea programme are:

1. Iterative improvement of the procedure and widening of our clinical experience with tracheal implantation.
2. Tissue engineering and clinical methods development for airway regeneration using synthetic scaffolds.
3. To scale-up airway engineering methods and develop Good Manufacturing Practice (GMP) procedures for commercial production.
4. To develop airway tissue engineering as a model.

Project Results:

The first year of the consortium has focussed on developing a number of platform technologies, developing the synthetic scaffold for in vitro and in vivo testing, performing in vitro assays to examine the efficacy of regenerative factors on the growth of human tracheal epithelial cells (HTEpC) epithelial and human mesenchyaml stem cells (HMSC) in the context of inflammatory cytokines and establishing a bioethics committee in line with the deliverables and milestones as per annexe 1. Thus WP3, WP6, WP16 had deliverables for the first year of the BIOtrachea consortium and the work performed in this period is summarised here.

In vitro testing of the synthetic POSS-PCU scaffold is complete and it has been shown to possess suitable mechanical properties as a trachea scaffold and to be biocompatible with human MSC cultures and human HTEpC. An in vitro trauma model has been established in a multiwell bioreactor. Using this system it has been shown that specific regenerative pharmacological factors (HuEPO, G-CSF and TGF,) can increase the proliferation of HTEpC in the presence of trauma cytokines under both normoxic and hypoxic conditions. Experiments performed with HMSCs showed that G-CSF and TGF were similarly effective in stimulating proliferation of MSCs in the context of trauma and ischemia. Work has started using shot-gun proteomics to investigate the effect of HuEpo on HTEpCs.

A major focus in the first year was to source, design and supply new platform technologies to enable the other partners to perform tasks in the following years. To this end a commercially available multi-well/multi- channel assay system has been sourced that enables simultaneous monitoring of physiological, metabolic and biochemical properties of cells. A hollow organ bath system has been developed and delivered that enables ex-vivo testing of entire organ scaffolds using organ-specific perfusion systems, allowing assay of cell adhesion, growth and cell proliferation along the entire construct as a three dimensional structure. A bioreactor has been designed to perform both the de-cellularization and re-cellularization processes automatically and a novel seeding device has been designed to allow dual or single cell intra- or extra-luminal seeding of the trachea scaffolds. Finally two database systems have been selected one (NI DIAdem) will contain all the data collected during airway harvesting, tissue de-cellularization and re-cellularization processes and the other (mediscinet)will contain the clinical data. These will be adapted for the purposes of this project.

While other WPs did not have deliverables within the first year they are working towards future deliverables: It has been shown that de-cellularized rat and human tracheas stored for 1 year under a variety of conditions do not retain the necessary mechanical properties and are thus unsuitable for implant. Treatment with the cross-linking agent Genipin, did not enhance the mechanical properties of the trachea stored for 1 year. Computer modelling is being utilized to study oxygen tensions across the trachea and to determine optimal seeding densities to re-populate the trachea. Standard operating procedures have been developed for the collection, isolation and culture of bone marrow stem cells to seed the trachea. The use of SEPAX 2 device for the mobile isolation of mononuclear cells is being evaluated. Using commercially available HTEpCs work has started to establish the culture conditions, reagents and tests for optimal culture of airway epithelial cells and stem cells that are GMP and ATMP compliant. Initial immunogenicity studies in rats and man indicate that there is no adverse immunogenic response to the implanted de-cellularized or re-cellularized trachea implants. Due to an adverse effect of Intra-operative Radiotherapy (IORT) in a single patient this will not be continued clinically until it has been fully evaluated in pre-clinical models. A murine model has been established for this purpose.

A platform for data and knowledge exchange has been established and the official BIOtrachea website is on-line.

The end goal of the BIOtrachea consortium is to perform First-Time-In Man (FTIM) clinical trials to this end a bioethics committee has been established and work has started to develop an appropriate regulatory strategy to gain CTA approval.

Potential Impact:

The main driver behind the whole BIOtrachea programme is to combine basic, translational and clinical research in order to generate robust protocols for the construction and use of Bioengineered Tracheal Implants in patients with primary tracheal malignancies. Bioengineered Tracheal Implants can facilitate a major leap in treatment of these patients who at the moment face a very poor prognosis even in cases where the disease is not metastatic. The challenge of advanced tissue engineering is highly complex and therefore demands a highly integrated innovative and multidisciplinary approach, hence the essential requirement for a European-wide collaboration. No single laboratory or EU country has all the qualified scientists, engineers, clinicians or industrialists with the vision, expertise, techniques and drive required to address this multi-faceted challenge and deliver a successful outcome for patients, European healthcare providers and the EU in general.

The BIOtrachea project aims to facilitate the rapid transfer from research into products and in doing so will significantly boost tissue engineering and cell-based therapy industries. Thus while the proposal plans to tackle a significant pan-European healthcare problem it will also generate economic wealth through high-value manufacturing and skilled job creation within the EU. In this way it will contribute to building a sustainable and Internationally competitive regenerative medicine industry in Europe. We will also create the opportunity to develop European centres for medical travel for this advanced cell-based procedure. In short, BIOtrachea plans to help put Europe in the spotlight for regenerative cell-based therapies, thus contributing to giving the EU a competitive edge in the emerging global cell therapy industry.

The technical approach of BIOtrachea is defined to reach the objective of scaling-up the tracheal implantation technique from one that can be used for individual patients to one that can be rolled-out in to a larger population of patients in a socially acceptable way. Furthermore, the long-term goal is to use the experience with trachea as a ‟baseline‟ on which to establish a technology platform for the engineering of even more complex hollow organs and eventually more complex three-dimensional organs. The development plan has been designed to maximize the success of the BIOtrachea project. Monitoring of the achievement of these objectives will be scheduled prospectively. The research portfolio activities is also balanced between short term and more achievable research aims as well as long term and more promising research tasks. One of the factors that could have an influence on the realisation of the above impacts is that all results will require regulatory approval and long‐term clinical trials which could restrict their immediate application. The aim of this project is to take BIOtrachea to point that its development risk/commercial potential ratio will be appropriate for attracting a larger pharmaceutical concern to invest the remaining €1-2 million that will be required to bring BIOtrachea to the market for the benefit of patients and society as a whole.

The success of the Biotrachea project will have longer term impacts on scientific research and business within the EU. Scientific research can be further intensified after the successful proof of principle within the BIOtrachea project. BIOtrachea may also encourage the creation of new biotech companies by successful dissemination and profitable exploitation of the BIOtrachea project results. These new SMEs will be the driving forces towards swift translation of new research results into standard medical care, which to our understanding can be only successful when performed on EU-level. All these steps will profit from the experience made within the BIOtrachea consortium.

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