Mechanochemical Patternable ECM‐Mimetic Hydrogels for Programmed Cell Orientation

Abstract

Native human tissues are supported by a viscoelastic extracellular matrix (ECM) that can adapt its intricate network to dynamic mechanical stimuli. To recapitulate the unique ECM biofunctionality, hydrogel design is shifting from typical covalent crosslinks toward covalently adaptable networks. To pursue such properties, herein hybrid polysaccharide-polypeptide networks are designed based on dynamic covalent assembly inspired by natural ECM crosslinking processes. This is achieved through the synthesis of an amine-reactive oxidized-laminarin biopolymer that can readily crosslink with gelatin (oxLAM-Gelatin) and simultaneously allow cell encapsulation. Interestingly, the rational design of oxLAM-Gelatin hydrogels with varying aldehyde-to-amine ratios enables a refined control over crosslinking kinetics, viscoelastic properties, and degradability profile. The mechanochemical features of these hydrogels post-crosslinking offer an alternative route for imprinting any intended nano-or microtopography in ECM-mimetic matrices bearing inherent cell-adhesive motifs. Different patterns are easily paved in oxLAM-Gelatin under physiological conditions and complex topographical configurations are retained along time. Human adipose-derived mesenchymal stem cells contacting mechanically sculpted oxLAM-Gelatin hydrogels sense the underlying surface nanotopography and align parallel to the anisotropic nanoridge/nanogroove intercalating array. These findings demonstrate that covalently adaptable features in ECM-mimetic networks can be leveraged to combine surface topography and cell-adhesive motifs as they appear in natural matrices.

Stimuli‐Responsive Nanocomposite Hydrogels for Biomedical Applications

“…[ 161 ] Besides dictating the position of macroscale constructs, nanoparticle directional movement can pull and orient hydrogel matrices to achieve cell anisotropic alignment as observed in many biological tissues. [ 162,163 ] In particular, such type of nanocomposite hydrogels have showcased on‐demand cell alignment for directing nerve growth following injection, [ 164 ] as well as manufacturing soft robots with anisotropic matrices. [ 163 ] Concerning this, several studies have successfully demonstrated that magnetic nanoparticles embedded in collagen‐based bioinks/hydrogels could unidirectionally align collagen fibers upon magnetic stimulation, resulting in overall improved mechanical compressive strength, as well as directing cell orientation which dramatically promotes a myriad of cell activities (i.e., enhanced extracellular matrix production, biochemical signal propagation, myo‐ and neurogenesis).…”

“…Similarly, hydrogel‐based platforms can be imparted with mechano‐responsive features, inheriting the adaptable behavior of tissues and opening the possibility to modulate their physicochemical properties under external mechanical cues. [ 162,178 ]…”

“…In fact, advances in the nascent field of mechanochemistry have been increasingly transposed to the design of hydrogel‐based platforms benefiting from on‐demand topographical‐adaptability, sensing of structural damage, touch‐activated drug delivery implants, strain‐stiffening behavior, and shear‐induced anisotropic alignment of hydrogel matrices. [ 162,178 ] For encoding mechano‐responsiveness in nanocomposite hydrogels, two different strategies can be pursued. First, interactions between network components (i.e., hydrogel/hydrogel or nanoparticle/hydrogel) can feature mobile crosslinks in the form of supramolecular and non‐covalent interactions (i.e., host‐guest, slide‐ring topologies, hydrogen and ionic bonds), as well as adaptable dynamic covalent linkages (i.e., disulfide metathesis, retro Dies‐Alder scission and imine bond rearrangement) and mechanophore crosslinking agents (i.e., spiropyran, diazo, or triazoles).…”

The effects of surface topography modification on hydrogel properties

“…Inspired by the findings of the role of topographies in cell reposes, various dimensions of topographies have been incorporated to hydrogels to mimic native 3D extracellular environment. Examples of topographies on hydrogels for different application including pHEMA hydrogel, 147 PVA hydrogel, 148 collagen/gelatin hydrogel, 149 PEG hydrogel 150 and polyacrylamide (PAM) hydrogel 151–153 have been summarized in Table II . In this section, we will discuss how topographies are used to guide cell behaviors, including adhesion and morphology, migration, proliferation and differentiation on hydrogel for different application purposes.…”

Engineering (Bio)Materials through Shrinkage and Expansion

“…A number of studies have demonstrated several types of pHresponsive hydrogels, such as poly(acrylic acid) (PAAc)-based, [39] poly(methacrylic acid) (PMAA)-based, [41][42][43][44][45] poly(vinyl alcohol) (PVA)-based, [46][47][48] and poly(acrylamide) (PAAm)-based [49][50][51][52] materials. Take PAAc as an example, the carboxylic groups on PAAc are dissociated via proton release at higher pH (>pKa), while they are protonated at lower pH (<pKa).…”