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Abstract In situ hydrogelation of injectable precursors upon biological stimulus is relevant to generate hydrogels under mild conditions and, potentially, at a biological side of interest. Here, it is shown that hydrolytic enzymes can be used to initiate the formation of covalent hydrogel networks, realizing a cleavage‐leading‐to‐gelation strategy. For this purpose, a two‐component system is used, consisting of a 4‐arm polyethylene glycol‐thiodepsipeptide conjugate, PEG4TDPo containing the matrix metalloproteinases MMP‐2‐ and MMP‐9‐cleavable Ac‐Pro‐Leu‐Gly#SLeu‐Leu‐Gly‐ thiodepsipeptide sequence releasing a thiol upon hydrolysis, and a maleimide functionalized 4‐armed PEG (PEG4MAL). PEG4TDPo is synthesized in a PEG‐functionalization protocol involving convergent and divergent synthetic steps without the need for rigorous purification procedures. In a fluorometric assay, it is shown that the construct is in fact cleaved by both investigated MMPs. PEG4TDPo in the presence of 10 wt.% PEG4MAL formed hydrogels upon addition of MMP‐2 or ‐9 with average gelation times of 28 and 40 min, respectively, as is investigated by rheology. The much faster gelation times compared to the enzyme‐free system showed the specific input of the enzymatic reactions. The MMP‐assisted activation and crosslinking strategy can potentially become useful by targeting tissues showing an increased expression of MMPs, such as cancers, or to detect MMPs.

Abstract The basement membrane (BM) is a biointeractive ultrathin network with distinct composition and organization of its epithelial and stromal sides, which render BMs with asymmetric biofunctions and mechanical properties. There are difficulties in the recapitulation of the highly hierarchical structure and function of BM. Here, the interfacial assembly method for the generation of BM mimics is applied. Dopamine is the starting material for the polymerization and assembly of polydopamine (PDA) into asymmetric materials. Compared to the PDA coating formed at the solid/liquid interface (≈20 nm), the PDA film formed at the air/liquid interface displays a thickness of ≈100 nm. Moreover, it possesses an asymmetric surface topography and an apparent Young's modulus of ≈1.0 MPa, which is structurally and mechanically similar to natural BMs. Of interest, the airside and the waterside of the PDA film exhibit differences in their adhesion affinity to the human skin keratinocytes. With stronger active mechanical processes between living cells and the waterside of PDA film, epithelial folding could be mimicked. Together, the PDA film is able to recapitulate the structural and mechanical complexity of natural BMs, indicating the prospective future of using PDA films for in vitro modeling cell‐BM interaction and tissue formation.

In vitro transcribed (IVT)-mRNA has been accepted as a promising therapeutic modality. Advances in facile and rapid production technologies make IVT-mRNA an appealing alternative to protein- or virus-based medicines. Robust expression levels, lack of genotoxicity, and their manageable immunogenicity benefit its clinical applicability. We postulated that innate immune responses of therapeutically relevant human cells can be tailored or abrogated by combinations of 5′-end and internal IVT-mRNA modifications. Using primary human macrophages as targets, our data show the particular importance of uridine modifications for IVT-mRNA performance. Among five nucleotide modification schemes tested, 5-methoxy-uridine outperformed other modifications up to 4-fold increased transgene expression, triggering moderate proinflammatory and non-detectable antiviral responses. Macrophage responses against IVT-mRNAs exhibiting high immunogenicity (e.g., pseudouridine) could be minimized upon HPLC purification. Conversely, 5′-end modifications had only modest effects on mRNA expression and immune responses. Our results revealed how the uptake of chemically modified IVT-mRNA impacts human macrophages, responding with distinct patterns of innate immune responses concomitant with increased transient transgene expression. We anticipate our findings are instrumental to predictively address specific cell responses required for a wide range of therapeutic applications from eliciting controlled immunogenicity in mRNA vaccines to, e.g., completely abrogating cell activation in protein replacement therapies.

Adaptivity is an essential capability of creatures to develop skills for surviving and reproducing. Mimicking such behavior would enable the design of biologically inspired functions. Hydrogel actuators are promising candidate materials capable of stimuli-responsive movements via water uptake and release. Here, for the first time, the adaptive-like movement of reprogrammable hydrogel actuators is demonstrated by integrating two independent functions: a temperature-triggered actuation and a medium- and pH-based modulated swelling, into one multiphase network. Reversible crystallization of poly(ε-caprolactone) (PCL) provided bending movements up to 71° (realized by temperature changes between 5 °C and 40 °C). Changing solvent from water to ethanol increased swellability up to 240 vol%. Bending angles decreased by 32° as some PCL fractions are dissolved in ethanol and cannot participate in the crystallization-induced elongation guiding the movement. When the actuators were modified with acrylic acid moieties, a modulated swelling between 270 vol% at pH = 13 and 130 vol% at pH = 1 was achieved. The resulting swelling/deswelling response induced reversible bending movements up to 54°. In consequence, the coupled functionalities (actuation and modulated swelling) resulted in conditioned actuation behavior as an intermediate feature between stimuli-sensitivity and adaptivity.

Movements in plants, such as the coiling of tendrils in climbing plants, have been studied as inspiration for coiling actuators in robotics. A promising approach to mimic this behavior is the use of multimaterial systems that show different elastic moduli. Here, we report on the development of magnetically controllable/triggerable multimaterial fibers (MMFs) as artificial tendrils, which can reversibly coil and uncoil on stimulation from an alternating magnetic field. These MMFs are based on deformed shape-memory fibers with poly[ethylene-co-(vinyl acetate)] (PEVA) as their core and a silicone-based soft elastomeric magnetic nanocomposite shell. The core fiber provides a temperature-dependent expansion/contraction that propagates the coiling of the MMF, while the shell enables inductive heating to actuate the movements in these MMFs. Composites with mNP weight content ≥ 15 wt% were required to achieve heating suitable to initiate movement. The MMFs coil upon application of the magnetic field, in which a degree of coiling N = 0.8 ± 0.2 was achieved. Cooling upon switching OFF the magnetic field reversed some of the coiling, giving a reversible change in coiling ∆n = 2 ± 0.5. These MMFs allow magnetically controlled remote and reversible actuation in artificial (soft) plant-like tendrils, and are envisioned as fiber actuators in future robotics applications.