Table 1 Key points and related notices of endogenous and exogenous stimulus

Endogenous stimulus

 pH

① pH changes in disease: 4–6 for normal skin, decreased pH for acute wounds and increased pH for chronic wounds.

② Owing to ionizable groups’ protonation or the destruction of acid-cleavable bonds, pH-responsive materials experience physiochemical changes (including dissociation, swelling, degradation, shrinking, etc.).

Ionizable protonating copolymer or acid cleavable linkers.

① Little opportunity for chemical reaction. because of physiological pH fluctuations.

② Hard to enable ON/OFF switch resulted from continuous property,

[49, 50]

 Redox

The redox potential of normal cells, normal tissues, and malignant tissues differs significantly, and concentration gradients of redox couples (such as glutathione/glutathione disulfide couple or diselenide linkage) can be applied to scavenge ROS generated in chronic wounds.

Diverse polymers such as iselenide-containing block copolymer.

Redox-responsive material may generate ROS on its own or be influenced by other unknown intracellular factors.

[51]

 Enzyme

① High selectivity for substrate.

② Function under mild conditions.

③ Regulated in certain diseases.

④ The degradation of ECM (collagen, fibrin, elastin) is triggered by specific enzymes.

MMPs, protease, trypsin, furin, phospholipase, and galactosidase/glycosidase, etc.

The carriers’ resistance to enzyme assaults, as well as their stability in a diverse biological milieu, limit enzymatic triggers.

[52]

 Hypoxia

Hypoxia is related to numerous diseases, including cancer, cardiomyopathy, ischaemia and chronic wounds.

Nitro aromatic derivatives, 2-nitroimidazole-grafted conjugated polymer, etc.

Hypoxia as a responsive trigger is still in its early stages of development, with limited reports on wound healing.

[53]

 Glucose

① To achieve blood sugar monitoring and insulin injection (‘open-loop’ treatment).

② To design wounds dressings with glucose-responsive drug release or that consume the local glucose in situ.

Glucose oxidase (catalyzing the oxidation of glucose), yeast extract (converting glucose to ethanol)

Potential toxicity of ethanol produced by glucose consumption.

[54]

 ATP

① The fluctuation of ATP concentrations between organelles, between external and intracellular environments, and between normal and diseased cells.

② The chemical energy of ATP is supplied to initiate self-assembling systems or it is utilized as a co-assembling component.

ATP-binding aptamers.

The selectivity of co-assembling systems is still an important issue.

[55]

Exogenous stimulus

 Thermo

① Temperature gradients and sensitivity that are abnormal in the tumor microenvironment or inflamed tissues are key physiochemical differences from healthy tissues.

② A phase transition occurs in thermosensitive polymers near their LCST values.

PNIPAM, synthetic polypeptides (including elastin-like polypeptides)

Challenges in clinical translation limited by non-degradability and toxicity.

[56]

 Light

① Strong spatiotemporal resolution, full bioorthogonality, and precise wavelength and intensity tunability

② Light functions in the fabrication (such as initiating hydrogel gelation) and applications of biomaterials.

③ PDT (generating ROS) and PTT (generating heat) are two common applications of light therapy.

o-nitrobenzyl moiety, photosensitizers (PSs, for PDT), noble metal nanomaterials (for PTT), etc.

① Classical PSs are restricted by poor water solubility, photobleaching, short absorption wavelengths and undesirable bacterial selectivity.

② Overcoming lower energy conversion, poor photothermal stability, and complicated synthesis processes, NIR-responsive inorganic nanomaterials are more appropriate in PTT.

[57, 58]

 Magnetic field

① Functioning in controlled release or redosing of drugs, mechanical stimulus of cells, and scaffold assembly into required structures.

② MHT (generating heat) demonstrates the thermogenic effect of magnetic fields as a trigger.

Iron oxide particles.

Currently, wound repair and tissue regeneration are not as common.

[59, 60]

 Ultrasound

① Ultrasound affects the degradability and drug release kinetics of various small molecules and proteins.

② Easily accessible, painless, non-invasive, safe and able to penetrate tissues.

Degradable scaffolds (polyanhydrides, PEGs esters, and polylactide) and microstructures responsive to ultrasound (like liposomes, microbubbles and micelles)

Rarely used in wound healing.

[50]

 Mechano-stimuli

① Mechanical cues prevalently participate in several biomechanical processes.

② The design of mechano-triggered biomaterials is advanced based on interactions between network components and non-covalent interactions.

① Mechano-sensitive protein transducers (such as Piezo1/Piezo2).

② Wearable, tensile strain-triggered drug delivery devices.

Trigger threshold is needed to be balanced.

[61, 62]

 Electric fields

Possibility to trigger both cellular responses and biomaterial simultaneously.

Electroactive polymers, such as polyaniline, polypyrrole, polythiophene, ethylene vinyl acetate, and polyethylene.

Potentially invasive insertion of electrodes as triggers.

[63]