Table 1 Comparison of different response strategy types

Photoresponsive strategy

Loading photothermal agents as follows:

(1) gold nanostructures

(2) transition metal sulfides and oxides (e.g., CuFeSe₂ nanocrystals, Fe₃O₄ NPs, and copper silicate microspheres)

(3) organic NPs

(4) carbon-based NPs and graphene

(5) MXenes and single-elemental nanosheets (e.g., black phosphorus nanosheets)

(1) noninvasive with high controllability

(2) remarkable photothermal therapy effects

(1) low tissue penetration

(2) intense photothermal effect may cause damage to the surrounding normal tissue

(3) potential toxicity with the use of photoactivated materials

^{29,47,48,49,50,51,52,53}

Magnetic field-responsive strategy

Loading magnetic materials or thermally sensitive agents such as Fe₃O₄ NPs, MnFe₃O₄ NPs, or Fe₃O₄ NPs, and so on

(1) high tissue-penetrating capabilities

(2) noninvasive with high controllability

(3) harmless to normal tissues

(1) the magnetic heat was not uniform

(2) the high local heat could cause thermal damage to surrounding tissue

^{24,61,160,161}

Ultrasound-responsive strategy

Employing the effect of ultrasound activating sonosensitizers for therapy

(1) remarkable tissue penetration depth

(2) noninvasive

(3) no drug resistance

(1) low in vivo stability of sonosensitizer drugs

(2) potential toxicity of sonosensitizers

^27,31,62

Electroresponsive strategy

Loading electroactive materials, such as carbon nanotubes, metal, graphene, inorganic electroactive materials, and conductive polymers

(1) improved conductive characteristics

(2) remarkable tissue regeneration effect

(1) cytotoxicity, biocompatibility, and biodegradability remain uncertain

(2) low control precision

^67,73,76

Piezoelectricity-responsive strategy

Loading piezoelectric biomaterials, including piezo-bioceramics and some piezo-biopolymers

(1) improved conductive characteristics

(2) remarkable regeneration effect without extraneous drugs or growth factors

(1) densification, volatilization of alkali, and high temperature in synthesis processes

(2) long-term biosafety and cytotoxicity remain uncertain

^83,84,162

Mechanical stimuli-responsive strategy

Applying proper mechanical stimulus in the regeneration platform

remarkable regeneration effect without extraneous drug or growth factors

(1) optimal mechanical parameters, such as amplitude and frequency of mechanics, are still unknown

(2) noninvasive application method to applied in the processes is still needed

^96,97,98,99

Oxidative species-responsive strategy

Using excess endogenous ROS, such as peroxides, hydroxyl radical, superoxide, singlet oxygen and alpha-oxygen, as a trigger to enhance bone regeneration

(1) smart and rapid response according to the environment

(2) remarkable regeneration result and therapeutical effect

(1) the small action range and short lifespan of ROS would greatly affect the stimuli effect

(2) the effect will damage normal cells at the same time

^100,101,102

Acidic environment-responsive strategy

Applying the strategy to respond to the mildly acidic environment in pathological conditions, such as chronic inflammation, infected environment, or tumor environment

(1) smart and rapid response to the environment

(2) change the local acid environment to facilitate bone regeneration

(1) the duration of action may not be long enough for effective therapy

(2) the persistent acidic environment may impede further bone regeneration

^{106,107,108,109}

Endogenous electric field-responsive strategy

Response to endogenous electric fields and repairing the physiological electric microenvironment to enhance the bone regeneration

(1) smart and rapid response according to the environment

(2) change the local environment to facilitate further bone regeneration

(1) the long-term toxicity of the novel biomaterial need to be lucubrated

(2) the long-term control of the stimulus intensity remains uncertain

^28,112

Specific ionic concentration-responsive strategy

Using the specific ionic concentration as a biological trigger to enhance bone regeneration

(1) rapid and smart response according to the ionic concentration

(2) change the ionic concentration to facilitate bone regeneration

(1) the action duration of action may not be long enough for effective therapy

(2) the stimulus intensity was not enough for effective therapy

^{29,113,114,115}

Specific enzyme-responsive strategy

Applying the strategy to smart response to the enzyme specifically secrete in different disease statues (MMPs in tumor statues, glutamyl endonuclease in infection statues, etc.)

(1) remarkable selectivity for their substrates

(2) specific and sophisticated process

(1) the overlapping substrates between similar enzyme families would affect the specificity

(2) the biocompatibility and long-term cytotoxicity still need to be evaluated

(3) enzyme dysregulation will affect the action time

^29,113,120

Specific immune environment-responsive strategy

Response to different pathological immune environments by various methods such as developing drug delivery systems, exploiting novel immunomodulatory biomaterials, and applying novel coatings

(1) smart and rapid response according to the specific immune environment

(2) remarkable tissue regeneration effect

(1) the unrestricted activation of macrophages may damage the host immune homeostasis

(2) improperly polarized macrophages may evoke the osteoclast formation and reduce osteolysis

(3) the lowest concentration of IL-4 released needs to be further confirmed

^{128,136,143,149,150,151,152,153,154,156}