The thesis, entitled “Synthesis of photosensitive cellulose derivates and development of hydrogels by additive manufacturing for the design of medical devices” , was directed by Bruno JEAN (CNRS Research Director at CERMAV, SPG team) and co-supervised by Sébastien ROLERE, Guillaume NONGLATON and Isabelle TEXIER-NOGUES, Research Engineers at CEA LETI.
Abstract:
“Innovative medical devices are increasingly based on the use of biomaterials, particularly polysaccharides, which display high biocompatibility, controlled biodegradability, and show specific advantageous biological properties, such as muco-adhesion, antimicrobial characteristics or bioaffinity. These natural macromolecules can be shaped into hydrogels with controllable properties to mimick the mechanical characteristics and dimensions of human tissues or for drug encapsulation purposes, for example. In some cases, sophisticated 3D structures based on these materials are required. In this regard, additive manufacturing technologies are well suited to meeting the technical specifications of biomedical devices. Specifically, 3D printing by “vat photopolymerization” enables complex forms to be fabricated from liquid resins using UV-induced photopolymerization. In this work, we explored digital light processing (DLP) and two-photon polymerization (2PP) to develop hydrogels made from carboxymethylcellulose (CMC), a hydrophilic derivative of cellulose. This work required a multidisciplinary approach, from the chemistry of polysaccharides to the understanding of 3D printing processes, via the study of the physico-chemical and even biological properties of the designed materials.”Innovative medical devices are increasingly based on the use of biomaterials, particularly polysaccharides, which display high biocompatibility, controlled biodegradability, and show specific advantageous biological properties, such as muco-adhesion, antimicrobial characteristics or bioaffinity. These natural macromolecules can be shaped into hydrogels with controllable properties to mimick the mechanical characteristics and dimensions of human tissues or for drug encapsulation purposes, for example. In some cases, sophisticated 3D structures based on these materials are required. In this regard, additive manufacturing technologies are well suited to meeting the technical specifications of biomedical devices. Specifically, 3D printing by “vat photopolymerization” enables complex forms to be fabricated from liquid resins using UV-induced photopolymerization. In this work, we explored digital light processing (DLP) and two-photon polymerization (2PP) to develop hydrogels made from carboxymethylcellulose (CMC), a hydrophilic derivative of cellulose. This work required a multidisciplinary approach, from the chemistry of polysaccharides to the understanding of 3D printing processes, via the study of the physico-chemical and even biological properties of the designed materials.
CMC was first chemically modified with methacrylic anhydride (MA) in aqueous medium to obtain carboxymethylcellulose methacrylate (mCMC), a photocrosslinkable polymer. Different aqueous formulations containing varying concentrations of mCMC with degrees of methacrylation (DM) controlled over a wide range [0; 76%] were used to form hydrogels, then cryogels after freeze-drying. The adjustment in these two materials of the density of cross-linked methacrylates, ranging from 4.3 to 13 µmol/cm³, results in a wide variety of properties, including swelling (from 20 to 86), viscoelasticity (with a range of elastic modulus G’ from 1.4 to 16.7 kPa) and structure. Cellulose nanocrystals (CNC), biosourced nanorods, either pre-functionalized with methacrylate groups with a DM = 0.83 % or non-functionalized CNCs were added to the formulations to further tailor the properties of photo-crosslinked hydrogels and cryogels. Thanks to their participation in the reticulated network, the introduction of mNCCs resulted in faster cross-linking kinetics, better spatial resolution, and more stable and robust hydrogels after swelling in water than pure mCMC or NCC-containing formulations. The designed materials proved to be non-cytotoxic and showed properties compatible with an application such as the repair of soft tissues like kidneys or lungs. However, the pore size of the three-dimensional structures was in the range of 10-20 µm, which was not conducive to cell growth in these tissues. The manufacture of hydrogels by DLP did not provide matrices with sufficient porosity (100 to 200 µm), but this characteristic was achieved by 2PP, enabling a wall-thickness resolution of 10 µm. In addition, it was shown that DLP-printed hydrogels do not swell in physiological media (PBS, 37°C) and degrade in the presence of cellulases.”
