Surface Patterning of Hydrogel Biomaterials to Probe and Direct Cell–Matrix Interactions

Abstract

Due to their mechanical and structural similarity to native tissues, hydrogel biomaterials have gained tremendous popularity for applications in 3D tissue culture, therapeutic screening, disease modeling, and regenerative medicine. Recent advances in pre‐ and post‐synthetic processing have afforded anisotropic manipulation of the biochemical, mechanical, and topographical properties of biocompatible gels, increasingly in a dynamic and heterogeneous fashion that mimics natural processes in vivo. Herein, the current state of hydrogel surface patterning to investigate cellular interactions with the surrounding matrix is reviewed, both in techniques utilized and biological findings explored, and the perspective on proposed future directions for the field is offered.

Chemically Crosslinked Methylcellulose Substrates for Cell Sheet Engineering

“…On this topic, it is widely accepted that mechanical (e.g., stiffness, viscosity) cues are essential parameters in surface design to modulate biological processes and even control cell fate (e.g., attachment, spreading, differentiation), similar to biochemical signals [ 31 , 32 ]. In particular, Young’s modulus of biological tissues ranges from 100 Pa (e.g., neural tissue) to 10 GPa (e.g., bone tissue) [ 33 ]. CA-crosslinked MC hydrogels would represent self-standing substrates capable to provide adequate mechanical cues to the seeded cells.…”

An In Vitro Mat‐on‐Gel Construct for Engineering Cardiac Tissue

“…[ 25,38,39 ] However, these substrates lack the nano fibrillary structure of the native ECM, though some can be surface‐patterned by different techniques. [ 40 ] On the contrary, electrospun mats well‐mimic the fibrillary features of ECM, but the mechanical properties usually range in MPa, which is out of the desired range for CM. [ 19 ] Although existing approaches like introducing water‐absorbable materials to the base material could reduce the mat's mechanical property in hydrated condition, [ 20–22 ] it might not be adaptable to inert biomaterials and could compensate for increased fiber diameter and cytotoxicity due to swelling and the remaining organic solvent from the spinning solution.…”

Multiphoton Laser Fabrication of Hybrid Photo-Activable Biomaterials

“…Hydrogel microstructures can be post-processed chemically or physically [ 6 ] to gain chemical sensing features or to be shaped in suitable forms and become effective platforms for tissue engineering. For these applications, MPL and laser ablation (LA) offer, in addition, the unique possibility to spatially and selectively functionalize preformed 3D hydrogels and to dynamically tune their biophysical or biochemical properties.…”

“…More recently, De Forest and coworkers [ 96 ] extended this approach to other click chemistry reactions and showed the interesting possibility to covalently decorate cell-laden natural hydrogels with bioactive proteins, including growth factors. These methods were then used to anisotropically govern cell fates in ways not easily obtainable otherwise with high resolution [ 6 ]. In 2019, the same group overcame some limitations of the use of azide-based click reactions by developing genetically encoded photocleavable linkers for patterned protein release from biomaterials.…”

“…In particular, we will explore the recent developments in the photolithographic microfabri-cation of biocompatible hydrogel-based structures capable of guiding the cell cycle and fate and monitoring the cell state. Recent comprehensive reviews have appeared on the microfabrication of resins (organics, hybrids, renewables, functionalized) by photolithography and light confinement [4], on the laser ablation of hydrogels [5], on the surface patterning of hydrogels [6] and on the use of different fabrication methods for tissue engineering [7]. However, these three aspects, fabrication, ablation and functionalization, can be combined in a more effective R&D strategy for cell manipulation and stimulation, and our aim here is to review the efforts in this direction.…”