Design and Development of Injectable, Tough and Intrinsically-Adhesive Hydrogels for Biomedical Applications

Despite the development of hydrogels with a wide range of mechanical properties, insufficient adhesion between these materials and biological surfaces limits their use in the biomedical applications. Most recent advancements in highly adhesive hydrogel systems are focused on the preformed hydrogel patches and dry tapes. In the past proposed strategies for highly adhesive hydrogels, the developed materials are not intrinsically adhesive, but adhere to the targeted tissues thanks to specific developments such as chemically modifying the contacting surface. Therefore, hydrogels that exhibit both sufficient intrinsic adhesion to various biological surfaces and proper injectability, has yet to be demonstrated. The need for design, fabrication and characterization of adhesive hydrogel systems with broad physicochemical properties has remained a central challenge in the biomedical field. In the first part, by controlling toughening processes, we design a composite double-network hydrogel with high water content, which creates a dissipative interface and robustly adheres to soft tissues. No tissue surface modification was needed to obtain high adhesion properties of the developed hydrogel. Instead, mechanistic principles were used to control interfacial cracks propagation. The integration of the dissipative polymeric network on the soft tissue surfaces allowed increasing significantly the adhesion strength. Our findings highlight the significant role of controlling hydrogel structure and dissipation processes for toughening the interface. In the second part, we propose a universal framework for the design of injectable hydrogels that are intrinsically adhesive to various tissues. We fabricate a family of original polymeric backbones using a two-step functionalization process in order to make new hydrogels with available adhesive sites and the capability to form hybrid networks, as well as further enhancements through the fiber reinforcement for stronger synergetic effects. To achieve that, our approach (i) provides strong chemical bonds with nucleophiles at interface, immediately upon contact with tissues thanks to the designed available adhesive bonding sites, and (ii) forms a hybrid network by covalent and physical interactions between our engineered chains, so that the interfacial bonds and the hydrogel capability of dissipating energy produce a synergic effect for achieving high adhesion. In addition to high level of adhesion performance, the injectable hydrogel system presents a broad and tunable range of physicochemical properties. This is particularly important for biomedical applications which require superior material properties, such as for cartilage tissue engineering. Fast adhesion formation and one-pot polymerization are achieved while the biosafety concerns, which are crucial for many clinical applications, are satisfied. Finally, with various in vitro, ex vivo, and preliminary in vivo studies, the biocompatibility and potential biomedical applications of our injectable adhesive hydrogels are demonstrated for cells scaffolding, soft tissues repair and tissue sealing. This is a design strategy which has potent implication in the way hydrogels are designed to reach high tissue adhesion, as it is not only a way towards synthesis of new biomaterials, but a general design approach based on an understanding of adhesion mechanism. Our approach can even further be used to fabricate more advanced adhesive systems with novel performances.

Composite Double-Network Hydrogels To Improve Adhesion on Biological Surfaces

Pierre-Etienne Bourban, Martin Broome, Peyman Karami, Azadeh Khoushabi, Christophe Moser, Dominique Pioletti, Andreas Schmocker, Céline Samira Wyss

Despite the development of hydrogels with high mechanical properties, insufficient adhesion between these materials and biological surfaces significantly limits their use in the biomedical field. By controlling toughening processes, we designed a composite double-network hydrogel with ∼90% water content, which creates a dissipative interface and robustly adheres to soft tissues such as cartilage and meniscus. A double-network matrix composed of covalently cross-linked poly(ethylene glycol) dimethacrylate and ionically cross-linked alginate was reinforced with nanofibrillated cellulose. No tissue surface modification was needed to obtain high adhesion properties of the developed hydrogel. Instead, mechanistic principles were used to control interfacial crack propagation. Comparing to commercial tissue adhesives, the integration of the dissipative polymeric network on the soft tissue surfaces allowed a significant increase in the adhesion strength, such as ∼130 kPa for articular cartilage. Our findings highlight the significant role of controlling hydrogel structure and dissipation processes for toughening the interface. This research provides a promising path to the development of highly adhesive hydrogels for tissues repair.

2018

3D Printing and Supercritical Foaming of Hierarchical Cellular Materials

Matteo Gregorio Modesto Marascio

Hierarchical porous structures have been gathering interest in different fields owing to their unique properties associated with their multi-scale features. The observation of natural materials brought new insights into the functionality of cellular materials and inspired new processes to produce synthetic hierarchical structures. Such hierarchical cellular materials have shown significant potential in many applications, as filtering, tissue engineering and drug delivery. Polymers in particular gathered a burgeoning interest thanks to their ease of processing, which allows to produce structures at high strength/density ratio and high surface area with defined porosity. In the present study, it is proposed to develop novel technologies to manufacture polymer cellular structures. From the application of Supercritical Carbon Dioxide Foaming (ScCO2) to Fused Deposition Modelling / Fused Filament Fabrication (FDM / FFF), an extrusion based additive manufacturing technology, hierarchical porous structures were created. The material transformation phenomena and the processing window of this homothetic foaming processed were studied. The fine tuning of the foaming parameters allowed creating a micro cellular porosity with-in a 3D printed structure, without modifying the 3D topology. This allowed producing a wide range of cellular struc-tures with controlled multi scale porosity and stiffness reduced up to hundred times the stiffness of the 3D printed cellular structures. Homothetic foaming was then applied to biopolymers in order to create gradient hierarchical porous structures. In particular, articular cartilage and bone (osteochondral) defects were targeted. Cartilage repair is a challenging clinical problem because large defects do not regenerate. Tissue engineering offers a solution by implanting a material, defined as scaffold, loaded with cells to induce a regeneration in the tissue that otherwise would not occur. Multi material Poly(lactide-co-caprolactone) â Poly(lactide-BTCP) cellular structures were successfully processed into a scaffold able to replicate the complex gradient mechanical properties of the osteochondral tissue. In particular, the processing windows to process multi material 3D printed and foamed structures was established. The mechanical properties under compression of these scaffolds were compared to the values measured by nanoindentation on human articular cartilage, showing a good correlation between scaffold and target application. Furthermore, from the developed knowledge, a novel additive manufacturing method is proposed from the inte-gration of FDM/FFF and ScCO2 into a single process, named 3D Foam Printing. 3D Foam Printing was applied to process structures with hollow filaments or filaments with radial porosity with live porosity control during the process. The influence of processing parameters on foam morphology was investigated. Different cellular structures achievable by tuning the printing temperature and speed were described for different biomaterials. The processes described in this work allowed to mimic the complex mechanical properties of the osteochondral tissue, a natural hierarchical material. However, they demonstrated to be relevant to a wide range of materials, as polymers, blends and composites. This is particularly true for 3D Foam Printing, which could positively influence many engineering applications, as aerospace, medicine and energy, where tuneable cellular polymers are highly demanded.

EPFL2018

Hybrid hydrogels for load-bearing implants

Céline Samira Wyss

Load-bearing tissues such as articular cartilage or meniscus are not infallible. They might fail due to trauma, over-solicitations, or diseases, which could subsequently alter the mobility of the patient. Repairing these damaged tissues in a minimally invasive way is nowadays widely studied. Hydrogels are promising for repairing soft tissues. However, trying to reproduce the highly hierarchical microstructures of load-bearing tissues is extremely complicated. In fact, conceiving hydrogels with optimal properties for specific applications is challenging as most of the hydrogel's properties are interrelated, such as toughness, stiffness, swelling, or deformability. The improvement of one property usually comes at the cost of another. This thesis aims to develop different hydrogel microstructures and evaluate their potential for load-bearing implants. In particular, the study focuses on (i) designing tough and fatigue resistant hydrogels, (ii) establishing a methodology to control the stiffness and the swelling of hydrogels independently, and (iii) considering processing ease by tailoring each hydrogel precursor viscosity. An extensive parametric study on hydrogels' structure and composition allowed establishing complete property charts for mechanical, swelling, and rheological properties. Seven different hydrogel structures based on poly(ethylene glycol) dimethacrylate were developed: neat, double network, composite, double network composite, granular, hybrid granular, and silk granular hydrogels. The precursors of neat hydrogels had the lowest viscosity. Microgels of similar composition were added to the precursor to adapt and increase its viscosity for unconfined applications. In parallel, adding nano-fibrillated cellulose fibers was effective for increasing toughness. This method was more efficient than creating a double network with alginate. Moreover, fatigue tests revealed that hydrogel composites successfully survive 10 million loading cycles at 20% applied strain. However, it became softer after the first loading cycles and behaved similarly to the Mullins effect. Subsequently, we assessed how cyclic loading affects fracture behavior, distribution of strain fields, and microstructure. The study demonstrated that cyclic loading on hydrogel composites re-arrange the fiber network without seriously deteriorating the mechanical properties. Additionally, we demonstrated that combining composite and microgel approaches, i.e. hybrid granular hydrogels, effectively tailored hydrogels' swelling and viscosity without significantly affecting stiffness, toughness, and deformability. Finally, the microgels were swollen in silk fibroin solution for forming self-reinforced silk granular hydrogels. Those hydrogels exhibited considerably higher stiffness and lower swelling but also reduced elongation performances. We demonstrated that hydrogels' mechanical and physical properties could be effectively controlled with the microstructures and compositions of well-known biomaterials. Subsequently, a hydrogel composite and a silk granular hydrogel, based this time on gelatin hydrogels, were synthesized, validating the potential of studied structures with other hydrogels and microgels. Finally, the analyzed material systems can be combined through a sequential layering, forming hybrid hydrogels, to obtain local or gradient properties addressing specific biomedical applications, soft robotics, sensing applications, or even food packaging.