Cell‐Free Bilayered Porous Scaffolds for Osteochondral Regeneration Fabricated by Continuous 3D‐Printing Using Nascent Physical Hydrogel as Ink

Abstract

Cartilage is difficult to self‐repair and it is more challenging to repair an osteochondral defects concerning both cartilage and subchondral bone. Herein, it is hypothesized that a bilayered porous scaffold composed of a biomimetic gelatin hydrogel may, despite no external seeding cells, induce osteochondral regeneration in vivo after being implanted into mammal joints. This idea is confirmed based on the successful continuous 3D‐printing of the bilayered scaffolds combined with the sol‐gel transition of the aqueous solution of a gelatin derivative (physical gelation) and photocrosslinking of the gelatin methacryloyl (gelMA) macromonomers (chemical gelation). At the direct printing step, a nascent physical hydrogel is extruded, taking advantage of non‐Newtonian and thermoresponsive rheological properties of this 3D‐printing ink. In particular, a series of crosslinked gelMA (GelMA) and GelMA‐hydroxyapatite bilayered hydrogel scaffolds are fabricated to evaluate the influence of the spacing of 3D‐printed filaments on osteochondral regeneration in a rabbit model. The moderately spaced scaffolds output excellent regeneration of cartilage with cartilaginous lacunae and formation of subchondral bone. Thus, tricky rheological behaviors of soft matter can be employed to improve 3D‐printing, and the bilayered hybrid scaffold resulting from the continuous 3D‐printing is promising as a biomaterial to regenerate articular cartilage.

Viscoelastic Cell Microenvironment: Hydrogel‐Based Strategy for Recapitulating Dynamic ECM Mechanics

“…[ 60,61,129,130 ] There are several molecular sources or mechanisms that lead to viscoelasticity in hydrogels. For example, physical or non‐covalent crosslinking based on ionic interaction, [ 24–27 ] hydrogen bonding, [ 28–33 ] hydrophobic interaction, [ 34–37 ] metal‐ligand coordination, [ 38–40 ] self‐assembly, [ 41,42 ] and supramolecular interaction [ 43–46 ] is one important source of hydrogel viscoelasticity. In these hydrogels, physical crosslinks can unbind and allow subsequent polymer flow under stress or strain, and they can rebind or reform following flow, contributing to the viscoelasticity.…”

“…Recently, many viscoelastic hydrogels have been developed based on various crosslinking strategies. Generally, there are two primary crosslinking approaches, including: i) physical crosslinking such as ionic bonding, [ 24–27 ] hydrogen bonding, [ 28–33 ] hydrophobic interaction, [ 34–37 ] metal‐ligand coordination, [ 38–40 ] self‐assembly [ 41,42 ] and supramolecular interactions including supramolecular stacks of small molecules, [ 43 ] and guest−host supramolecular recognition [ 44–46 ] and ii) dynamic covalent crosslinking. [ 47–50 ] Hydrogel viscoelasticity can be efficiently tuned through various methods, for instance changing molecular weight or length of polymer chain, varying polymer concentration or crosslinking density, regulating the kinetics of reversible covalent bonds, and providing hindrance to polymer reorganization or reducing breaking/re‐forming crosslinks through adding static covalent crosslinks in the network.…”

“…With recent boom in advanced hydrogel‐based biomaterials, great effects have been put forth to develop viscoelastic hydrogels for constructing dynamic mechanical microenvironment that more closely recapitulates the native ECM mechanics, including hydrogels crosslinked via physical interactions [ 23 ] (e.g., ionic bonding, [ 24–27 ] hydrogen bonding, [ 28–33 ] hydrophobic interaction, [ 34–37 ] metal‐ligand coordination interaction, [ 38–40 ] self‐assembly, [ 41,42 ] and supramolecular interaction [ 43–46 ] ) and dynamic covalent interactions. [ 47–50 ] These hydrogels serving as powerful platforms have been utilized to reveal whether viscoelastic mechanical cues influence cell behaviors.…”

Emerging Biofabrication Techniques: A Review on Natural Polymers for Biomedical Applications

“…3D printing is capable of producing scaffolds that simulate the structure of this tissue. For example, Gao et al designed a multilayer system using GelMA with or without hydroxyapatite to obtain a scaffold that simulates the ECM in the osteochondral tissue [165]. The design of a proper bioink is a crucial point for the correct regeneration of the tissue.…”

Coordination Insertion Mechanism of Ring‐Opening Polymerization of Lactide Catalyzed by Stannous Octoate†

“…Biodegradable polymers are promising in many fields. [ 1‐6 ] In particular, aliphatic polyesters are very useful both as eco‐friendly thermoplastics for daily use and biomaterials for medical applications, [ 7‐19 ] since they are biocompatible and biodegradable, and exhibit excellent mechanical and processing properties. The polyester family includes mainly polylactide (PLA), polyglycolide (PGA), poly(ε‐caprolactone) (PCL), other small‐ring cyclic esters, and their copolymers.…”