One of the cornerstones of the 'Bioeconomy' will rest on our ability to exploit renewable carbon resources to produce environmental eco-friendly fuels and chemicals that will profitably replace those derived at present from fossil resources. The POLYDHB project is in frame with this endeavour. This project originality stands on previous works carried out by two partners of this proposal which have exploited synthetic biology toolbox combined to metabolic and enzymes engineering to construct a synthetic pathway that leads to the microbial production of a non-naturally metabolite 2,4-dihydroxybutyric acid (DHB) from renewable carbon sources (i.e. sugars). Initially conceived as a precursor for the synthesis of the methionine to target the field of animal nutrition, this molecule actually turns out to be a unique ‘green’ platform chemical for the production of other bio-based products with application in chemical and pharmaceutical industries. The purpose of the POLYDHB project is here to demonstrate that DHB can be used as an original non-natural monomer for the production of new bio-sourced and biodegradable polymers. The scientific and technical challenges of this project will be realized through three workpackages: (I) production of pure enantiomers and lactide /lactone derived from DHB, (II) development of a chemocatalytic process of (co)polymerisation of DHB and/or its lactone and lactide derivatives alone or with other monomers, and (III) conception of a microbial process for the synthesis of DHB-based polymers. In each of these workpackages, scientific risks have been identified and contingency solutions clearly proposed. To succeed in this objective, a multidisciplinary and complementary core of expert in the field of Systems and Synthetic Biology (LISBP, Toulouse), Polymer Chemistry (LCPO, Bordeaux) with the participation of a Japanese team expert in molecular biology of bio-sourced polymers has been set-up. Moreover, the strong commitment of the industrial partner Adisseo in this project is not solely justified by its indispensable position in mastering the chemical and microbial process for DHB production, but it is also an asset for the industrial exploitation of this molecule on markets other than nutrition animal that can be opened from the results obtained in this project. The ambition of POLYDHB project is to reach the technology readiness level of 4 within the 3 years period.

Polyethylene is by far the most significant polymer worldwide in terms of volume of production, and demand for this product continues to rise. The size of the market and increasing demand means that producers need to increase capacity either by improving existing processes, or building newer, more efficient processes. For gas phase processes which represent nearly 50% of all production processes, fluidized bed reactors are the equipment of choice at the industrial scale, where the polymer is grown in the form of particles suspended in a flowing gas stream. One of the major operational issues associated with increasing capacity in gas phase reactors is the ability to remove the significant amount of heat produced during the reaction. On the one hand, one needs to avoid dangerous overheating of the reactor, and on the other hand it is necessary to have precise temperature control in order to maintain the quality of the polymer in terms of molecular weight and particle size, minimizing particle aggregation and sintering. A popular approach to control overheating is the so-called “condensed operating mode” where liquid species are injected together with the monomer feed. The temperature and composition of the feed are chosen so the feed is below its dew point, which in turn is below the reactor temperature. Upon entering the reactor the liquefied components vaporize and the latent heat of evaporation helps to cool the system. However, it has recently been demonstrated that the inert species most typically used for this purpose can strongly influence the solubility of all species in the growing polymer particles, and since they also act as plasticizers they can also impact the physical properties of the particles. Despite the wide-spread use of condensed mode cooling, very little is understood about the impact of the inerts on the reaction rate, molecular weight distribution, particle morphology and particle agglomeration. The aim of this project is therefore to develop a fundamental understanding of the different phenomena observed during condensed mode cooling in ethylene polymerization, and translate this new knowledge into a sophisticated model able to predict the reactor performance. Accordingly, the project is organized into three subsequent tasks covering the different scales typical of the system, from the single particle to the reactor. Namely, the equilibrium partitioning of different species (monomer, comonomers, solvents, inerts) into polyethylene films and particles will be studied experimentally using different techniques. Then, such thermodynamic knowledge will be incorporated into a single-particle model accounting for the reaction and diffusion phenomena as well as the thermal behavior. Such model will be validated by comparison with experimental data obtained using specially designed spherical stirred bed reactors that are well adapted for gas phase polymerization. Finally, taking advantage of computational efficient methods, a comprehensive model of stirred-bed reactor will be developed, accounting for all phenomena affecting the particle size distribution, such as aggregation due to polymer softening related to the plasticization induced by additional species. The model will be validated by experimental data collected in the same type of stirred bed reactor mentioned above. Such detailed model is expected to become a key tool for the design of intrinsically safer, more efficient reaction modes while ensuring precise polymer quality control.

There are relevant opportunities to develop innovative synthetic strategies at the frontier between biotechnology and traditional organic chemistry to produce polymers fulfilling requirements of sustainability and precision, towards the development of functional, high value-added, polymer materials such as those used in the biomedical field. The present research project proposes the use of protein-engineering techniques to access functional precision polymer scaffolds with exquisite control over monomer sequence and length, namely with an exact “primary structure”. Orthogonal bioconjugation strategies will then be applied to chemoselectively modify specific residues of the recombinant polypeptides so as to introduce biologically relevant motifs, as a means to access well-defined and high molecular weight multivalent bioconjugates. As a proof of concept, the project will be applied to the synthesis of chemical tools for glycobiology, where there is a critical need for the rational design of glycoprotein mimics for drug-targeting and vaccination strategies. Recombinant elastin-like polypeptide (ELP) scaffolds will therefore be glycosylated with specific carbohydrates and different grafting densities to address major questions in multivalent glyconjugates’ design.

This ANR MRSEI PEPTIMPULSE (Advanced functional polypeptide, pseudo-polypeptide and protein-based materials) aims at setting up an Innovative Training Network (ITN) programme, to be submitted to the H2020 Marie Sklodowska Curie Actions (MSCA) call (H2020-MSCA-ITN-2020 European Training Network). The ITN PEPTIMPULSE will train a new generation of multidisciplinary experts in materials science capable of managing the effective translation of macromolecular innovations into ready-to-use applicable biomaterial solutions. Within the proposed PEPTIMPULSE framework, a new generation of PhD students will develop a broad know-how about amino acid-based biomaterials development, from bench to industries, especially focusing on cosmetic and pharmaceutical ones, following a safety-by-design preparation and processing, as well as corresponding technological and regulatory aspects. These scientists will develop unique cross-disciplinary skills in polymer (bio)chemistry, soft matter engineering, pharmacology, cosmetology and biomaterial sciences under Good Manufacturing Practices (GMP) compliance allowing them to develop effective, safe and efficient biomaterials of the future. The timeliness and relevance of this project are in line with the priorities of the research and training policy of Europe, as attested by the coherence with the current sectorial policies, such as OECD policies (Chemical safety and Biosafety) and EU policies (Public health and Research and Innovation).

The main objective of this research project is to develop new environmentally friendly synthetic pathways for the synthesis of aromatic chemicals by selective heterogeneous catalysis from renewable biomass, here lignins, with a long term application to the synthesis of bio-active molecules and technical polymers. Following our interest in the discovery of environmentally friendly procedures for the synthesis of relatively complex organic molecules or in the valorisation of biomass (wood materials), we intend to propose alternative production processes to the current syntheses from petrochemicals whose resources are currently decreasing. This approach also answers the current chemical industry concerns linked to REACH. Indeed, innovative and clean catalytic technologies designed to reduce energy consumption and the amount of wastes produced during the synthesis of high added value building blocks and molecules of interest from a non-alimentary bio-resource will be developed throughout the project. Moreover, we intend to avoid the intermediate functionalisation of the aromatic compounds issued from lignin limiting thus strongly the wastes production but also the chemical risk for human and its environment. Additionally, we would like to point out that within this project, through the industrial partnership, we will consider the up-grading of lignin obtained from the paper and bioethanol industries giving thus a like second life to wood resources, instead of simply using it as energy source. The project is divided in two main areas: 1/ the selective catalytic depolymerisation of lignin to access an aromatic pool addressing the problems of selectivity and purifications, and, 2/ the transformation of obtained aromatics towards targeted building blocks for fine chemicals and technical polymers by innovative catalytic procedures. To achieve these goals new catalytic materials will be developed and evaluated in close relationship with process development in order to gain the highest possible selectivity required for a viable process. If both areas have been, and are currently, the centre of investigation, mainly by academic researchers in France and Europe, to the best of our knowledge none has complementarily investigated the overall approach that consists in producing aromatic stuff from lignin and to implement them in the synthesis of (a) target compound(s). This is the objective of this ambitious project. In more details, while lignin valorisation has been described by research group in Europe (mainly: France, Germany, Italy, Norway, Sweden and Switzerland), Canada and USA, to date no process to access to an aromatic pool, as expected from this project, runs except that linked to vanillin production (like in Borregaard AG). If several research groups around the world are currently developing so-called innovative cross-coupling methodologies, none of those has described the use of functional molecules like phenols or carboxylic acids as the aromatic stuff made available through lignin depolymerisation. These observations are acknowledged as well when considering technical polymers (like varnishes or paints) are still today produced from petrochemicals. These are the fields in which the team proposes to carry out researches. The team, whatever one considers the bio-polymers and particularly the lignin, or the catalytic reactions from the key building-blocks issued from lignin degradation to the target molecules, or the multifunctional catalysts, possesses all expertises to perform this project by putting together strongly implied researchers and technicians from very different subfields (i.e. organic synthesis, organometallic chemistry, biopolymers, material preparation and characterisation, catalysis, kinetic….). Noteworthy, this project was submitted to the 2010 call for proposal from the ANR in the CD2I program. We took all the recommendations from the ANR into consideration, and modified the proposal accordingly.