Research On 3D Printing Of High-Strength Hydrogels And Their Application As Meniscus Substitutes

Extrusion 3D printing of high strength hydrogels provides a novel route for constructing the meniscus replacements.However,most of the reported exstrusion 3D printed high strength hydrogels exhibit poor swelling resistance and fail to maintain their shapes and mechanical properties in physiological environment,which limit their applications in fabricating meniscus substitutes.Although multiple hydrogen-bonding crosslinked poly(N-acryloyl glycinamide)(PNAGA)hydrogels exhibit excellent nonswelling behavior and mechanical properties,extrusion 3D printing PNAGA hydrogelbased replacement still remains a great challenge owing to insurmountable trade-off between strength and printability.To address this issue,a self-thickening and selfstrengthening strategy,that is,loading the concentrated NAGA monomer into the thermoreversible PNAGA soft gel is proposed to extrusion 3D printing H-bondingreinforced hydrogels.On the one hand,PNAGA soft gel serves to thicken the concentrated NAGA monomer,affording an appropriate viscosity for extrusion printing of the 3D construct;on the other hand,concentrated NAGA monomer loaded in the printed PNAGA soft gel-based construct can be further polymerized to eventually generate high-strength and non-swelling hydrogels due to the reconstruction of strong H-bonding interactions from post-compensatory PNAGA.In view of the excellent mechanical properties of extrusion 3D printed PNAGA hydrogel(tensile strength: 0.96± 0.09 MPa;Young’s modulus: 0.86 ± 0.05 MPa;compressive strength under 80%strain: 7.10 ± 0.29 MPa;compression modulus: 0.90 ± 0.01 MPa),a high strength hydrogel-based meniscus scaffold is further printed and implanted in rabbit’s knee as a substitute with in vivo outcome showing an appealing ability to efficiently alleviate the cartilage surface wear.Considering that Young’s modulus of extrusion 3D-printed PNAGA hydrogel is much lower than the circumferential tensile modulus(100-300 MPa)of natural meniscus,an “aggregation crosslinking” strategy is proposed,that is,soaking the extrusion 3D-printed poly(N-acryloyl glycinamide-co-N-acryloyl glycine)gel structure in ammonium sulfate solution firstly to induce the aggregation of molecular chain(based on Hofmeister effect),and then introduction of the additional ionic crosslinking to ‘freeze’ the conformation of clustered molecular chains in the gel network,thus fabricating 3D hydrogel-based constructs with high Young’s modulus.Finally,an upgraded self-thickening and self-strengthening strategy,that is,employing PNASC gel microparticle systems to thicken the NASC monomer is proposed to extrusion 3D print PNASC high modulus hydrogel with excellent swelling stability in physiological environment.The extrusion 3D printed PNASC hydrogel is shown to exhibit ultra-high Young’s modulus(～ 128 MPa),which is comparable to the circumferential tensile modulus of the natural meniscus.Based on this,a high/low modulus hydrogel composite strategy is further proposed to construct a replacement that is more similar to natural meniscus.On the one hand,the skeleton of meniscus replacement is constructed by extrusion 3D printing PNASC high-modulus hydrogel to mimic the circumferential orientation of collagen fiber structure in the natural meniscus and provide the higher tensile modulus;on the other hand,the PNAGA hydrogel(with lower modulus)is cast in the above scaffold to mimic the proteoglycan composition in the natural meniscus and provide the lower compressive modulus.As a consequence,a meniscus substitute with “high circumferential tensile modulus” and “low compressive modulus” is constructed,which is expected to go to the animal experiments,to verify its applicability.