Nano Fibrillated Cellulose Based Composite Hydrogels for an Injectable Intervertebral Disc Implant

Replacing the gel-like central part of the intervertebral disc (IVD), so-called nucleus pulposus (NP), via a minimally invasive surgery is one of the most recent approaches in the lower back pain treatments. An appropriate biomaterial for NP replacement (NPR) preferably possesses the mechanical and swelling properties similar to those of the native tissue. Furthermore, it should be injectable, biocompatible and stable in the IVD environment. From the surgical point of view, employing a photopolymerizable hydrogel for NPR is beneficial as it can be injected in the liquid form to the IVD and subsequently cured in situ. Such an approach provides a better control for the surgeon over the operation and minimizes the invasion of the surrounding tissue. The application of hydrogels as load-bearing biomedical components is, however, limited by their mechanical properties. Conventional approaches to address such an issue often favors one mechanical property while compromising the others. The present study aims to develop a novel injectable, photopolymerizable hydrogel for NPR with concurrently enhanced mechanical properties and optimal processability. Hydrogels based on photopolymerization of a monomer, i.e. N-vinyl-2-pyrrolidone (NVP), and cross-linking of a preformed functionalized polymer, i.e. poly(ethylene glycol)dimethacrylate (PEGDM), are synthesized. The hydrogels are thoroughly characterized as a function of cross-link density and initial water content in order to examine their applicability for NPR. While a wide range of properties is obtained by variation of the aforementioned parameters, an enhancement of stiffness is associated with brittleness or loss of water content. In addition, homogenous volumetric photopolymerization of such hydrogels is found to be limited especially in case of local illumination. To resolve such issues, a composite material design approach is adopted and the abovementioned polymer networks of hydrogels are combined with nano fibrillated cellulose (NFC). It is demonstrated that the NFC significantly increases the hydrogelsâ stiffness (up to 275%) without compromising the failure strength or reducing the water content. Moreover, the NFC fibers effectively prevent formation of the swelling induced cracks in the NVP based hydrogels. The results of rheology experiments indicate that the dispersed NFC fibers form a network-like structure in the hydrogels precursor solution. Such a structure, as confirmed through the photorheology tests, serves as a light-scattering source when the solution is illuminated by UV light. The latter accelerates the kinetics of photopolymerization and consequently allows reducing the required concentration of photoinitiator. The enhanced and tunable properties of the PEGDM-NFC composite hydrogel, developed in this work, make it a promising implant material for NPR. The applicability and reliability of such a material design approach for NPR is examined using a bovine organ model. In order to meet the properties of the native tissue, the mechanical properties of the composite hydrogel are tuned. The performance of the optimized composite hydrogel versus the native NP tissue is evaluated in several functional tests such as extrusion, confined compression and swelling pressure...

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.

EPFL2021

Composite Hydrogels for the Replacement of the Nucleus Pulposus

Ana Borges de Couraça

The intervertebral disc (IVD), which provides flexibility to the spine and facilitates damping and motion, is composed of two distinct structures: the annulus fibrosus (AF) and the nucleus pulposus (NP). The AF, which is fibrous and elastic, confines the NP, a gel-like material, containing 65 to 90% of water. The NP mediates load bearing in the spine by maintaining a suitable disc height and adequate loading of the AF. The effectiveness of this mechanism depends on the swelling capacity of the NP and the intra-discal pressure, and it becomes severely limited once the NP has degenerated. Up to now, the main strategy for relieving back pain has been vertebral fusion or total disc replacement. However, there is currently a shift in emphasis towards preservation techniques. NP replacement in particular has attracted considerable interest and various types of synthetic NP have been investigated as a means to restore IVD functions. The present study has focused on injectable, UV curing composite hydrogels for NP replacement. The objectives have been to: (a) synthesize methacrylated monomers based on Tween 20 surfactant precursors, and to use these as a crosslinker in combination with linear hydrophilic molecules in order to obtain hydrogels, (b) investigate the UV curing kinetics, swelling and mechanical properties of the hydrogels and their variation with crosslinker and photoinitiator concentration, (c) evaluate their biocompatibility and (d) study the influence of the filler on the performance of composite hydrogels based on these materials, and hence assess their potential as NP implants. The synthesis of new methacrylated monomers based on Tween 20, yielded reproducible conversions between 75 to 85 %. Tween 20 trimethacrylate (T3), a branched molecule, was then used as a crosslinker in hydrogel systems derived from either N-vinyl-2-pyrrolidone (NVP) or 2-hydroxyethyl methacrylate (HEMA). The study of the curing kinetics by photorheology and photo differential scanning calorimetry of both systems showed that the concentration of T3 controled the crosslinking density whereas the amount of initiator and of UV intensity controled the time of curing and the formation of dangling chains and cyclization. The build-up of the network prior to gelation of the two blends was analyzed using existing growth models and particularly complex patterns of growth were identified for T3/NVP. From the study of the curing kinetics, optimum conditions for processing could be determined. The mechanical behavior of T3/NVP hydrogels was strongly dependent on the concentration of T3 and on the water content of the network. Swelling ratios varied from 1.6 to 5.8 with decreasing T3 content, which is comparable with the behaviour of the human NP, which shows swelling ratios from 1.8 to 9. The elastic modulus varied from about 4400 to 3 kPa for dried and fully hydrated samples, respectively, which is close to the modulus of 3 to 6 kPa observed in the native NP at swelling equilibrium. Preliminary biocompatibility studies showed cell viability and the hydrogels exhibited a highly interconnected porous structure at swelling equilibrium. They could also be further reinforced with nano-fibrillated cellulose (NFC), a hydrophilic material, with a 3 to 8-fold increase in elastic modulus being observed with respect to the neat hydrogel depending on the NFC content, i.e. greater stiffness than the native NP, as required. However, the swelling ratio was decreased compared to that of the neat hydrogel. To overcome this without compromising the mechanical properties, the NFC fibres were chemically modified to increase their hydrophilicity. The swelling ratio of these new composite hydrogels was increased by 1 to 20 % depending on the NFC content. The possibility of tailoring both the swelling behaviour and mechanical performance suggests these materials to be ideal for NP replacement.

EPFL2010

Hybrid hydrogels for load-bearing implants

Céline Samira Wyss

EPFL2021

Composite Hydrogels for the Replacement of the Nucleus Pulposus

Ana Borges de Couraça

EPFL2010