# N‑Terminal Octylated Peptoid Hydrogels as 3D-Printable Cell Scaffolds and Proteolytically Robust Cargo Depots

## TL;DR

This paper introduces a new type of hydrogel made from peptoids that can be 3D printed and is stable in protease-rich environments, making it useful for tissue engineering and drug delivery.

## Contribution

A new class of supramolecular peptoid hydrogels with tunable properties, 3D printability, and proteolytic stability is developed.

## Key findings

- The hydrogels support fibroblast adhesion, spreading, and proliferation with over 95% cell viability.
- They maintain structural integrity in protease-rich conditions and enable sustained cargo release.
- The hydrogels can be used as inks for extrusion-based 3D printing due to their shear-thinning and self-healing properties.

## Abstract

Supramolecular hydrogels that mimic the extracellular
matrix (ECM)
represent promising materials for tissue engineering and drug delivery.
However, conventional hydrogels formed via the self-assembly of natural
or synthetic building blocks often face a trade-off between biological
functionality and biochemical stability, limiting their utility in
long-term or protease-rich environments. Peptoids, a class of peptide-inspired,
sequence-defined polymers, offer a compelling alternative due to their
exceptional proteolytic resistance and bioactivity. Despite this potential,
the development of supramolecular peptoid hydrogels has been hindered
by the absence of backbone hydrogen bond donors, which limits long-range
ordering necessary for efficient hydrogel formation. This work describes
a short peptoid functionalized at the N-terminus
with an octyl chain that readily self-assembles into hydrogels. Hydrophobic
interactions among pendant octyl groups promote directional peptoid
packing into highly ordered nanosheets, which interconnect to form
a porous hydrogel network. These hydrogels exhibit tunable viscoelasticity,
shear-thinning, and self-healing properties, enabling their use as
inks for extrusion-based 3D printing. They support NIH-3T3 fibroblast
adhesion, spreading, and proliferation, maintaining greater than 95%
cell viability over 4 days. Moreover, the hydrogels retain their macroscopic
integrity under protease-rich conditions, enabling sustained cargo
release and uniform cellular uptake. Together, this study demonstrates
a class of supramolecular peptoid hydrogelators that integrate biocompatibility,
3D printability, and proteolytic stability, providing a versatile
platform for ECM-mimetic scaffolds in regenerative medicine and long-term
therapeutic delivery.