After the material interacts with the organism, biocompatibility is primarily reflected in two aspects. The material must withstand organismic systems without rejection or damage, and the reactions generated during this process should be non-inflammatory and non-carcinogenic (Crawford et al., 2021). Biocompatibility is crucial for the successful use of hydrogel scaffolds in tissue engineering and regenerative medicine in clinical practice (Zor et al., 2019). Researchers often utilize methods such as synthetic conjugated polymers and the addition of ions to enhance tissue reconstruction and repair and address the poor biocompatibility of hydrogels (Zhang et al., 2022a).

The biodegradability of hydrogel materials is a significant advantage. The biodegradability of hydrogel involves the gradual decomposition of the material in the body through processes such as dissolution, enzymatic digestion, and cell engulfment. Upon tissue repair, the implanted material is completely replaced by the repaired tissue, without leaving any residual material during the tissue healing process (Xia et al., 2021). Ideally, hydrogel materials should exhibit controllable biodegradability, matching the growth of cells and tissue repair rate. Excessive degradation can result in a loss of mechanical integrity before complete tissue regeneration, whereas slow degradation can lead to delayed tissue healing (Fatahian et al., 2022). Therefore, determining the appropriate degradation rate is a crucial consideration in hydrogel design. Fortunately, there has been significant recent progress by researchers, including the utilization of surface modification, polymer blending, and incorporation of alkaline particles to enhance biodegradability (Gupta et al., 2024).

The hydrogel exhibits mechanical properties at both macroscopic and microscopic levels. On the macroscopic scale, the hydrogel scaffold offers stability and volume maintenance (Belgodere et al., 2023). On the microscopic level, cells adhered to the hydrogel matrix can sense mechanical stimuli, converting them into biochemical signals to regulate crucial physiological processes (Li et al., 2022c). Hydrogels offer extensive application potential in bone tissue engineering. Enhancing the mechanical performance of hydrogels is crucial for improving the effectiveness of bone defect repair (Zhao et al., 2022). Inadequate mechanical properties of the hydrogel material can cause the repaired defect to deform easily and fail to offer early-stage support. In order to improve the mechanical performance of hydrogels, researchers have employed diverse methods to enhance the mechanical performance of hydrogels, such as constructing double network structures (Guo et al., 2021), utilizing composite nano-technology (Cui et al., 2019), introducing conductive materials (Arambula-Maldonado et al., 2023), and reinforcing fiber networks (Brusentsev et al., 2023). Studies have demonstrated that biomaterials with mechanical properties matching those of bone can stimulate bone cell proliferation and mineralization, and effectively facilitate bone growth.

Chitin is usually extracted from natural shells of shrimp, crabs and insects, and part of the acetyl group is removed to obtain chitosan. Chitosan is the sole naturally occurring alkaline polysaccharide that contains free amino groups (Atia et al., 2022). Chitosan-based materials have the capacity to form chemical and physical cross-linked hydrogels through processes like exposure to ultraviolet light, pH alteration, and temperature adjustment (Yu et al., 2016). Its primary characteristic is the capacity to introduce specific functional groups with reactive properties, yielding a range of chitosan derivatives via chemical modification. Chitosan-based hydrogel systems exhibit outstanding biocompatibility, degradability, anti-inflammatory effects, broad-spectrum antibacterial properties, as well as the ability to facilitate cell adhesion, proliferation, and differentiation (Ma et al., 2022). Gu et al. (2024) used forty-eight male Wistar rats to establish a periodontitis model to detect the effects of chitosan/β-sodium glyceropylate (β-GP)/glycolic acid (GA) hydrogel carrying erythropoietin and FK506 (EPO-FK506-CS/β-GP/GA). The results showed that the hydrogel had drug stability and slow release, could significantly enhance new bone formation in the bone defect area, and had obvious bone induction properties. EPO-FK506-CS/β-GP/GA hydrogel could promote periodontal tissue regeneration. Eshwar et al. (2023) investigated an alginate-chitosan hydrogel, and clinical randomized trials indicated that the hydrogel enhanced the clinical attachment levels and fostered human bone regeneration, thus augmenting its potential in the field of tissue engineering.

Derived from marine algae cell walls and intercellular spaces, sodium alginate is a linear natural anionic polysaccharide (Liu et al., 2023). It is a natural high molecular weight polymer created by linking β-1, 4-D-mannuronic acid (M segment) and α-1, 4-L-guluronic acid (G segment) via (α-1, 4) glycosidic bonds. Due to its non-toxicity, low cost, good biocompatibility, low immunogenicity, and its capability to form gels through crosslinking with divalent or multivalent cations, it has extensive potential applications in oral tissue engineering (Sanchez-Ballester et al., 2021). The three-dimensional network structure of sodium alginate hydrogel offers a novel environment for cell adhesion and proliferation, mimicking the microenvironment of human bone tissue. Furthermore, sodium alginate hydrogel holds significant promise as a scaffold material for bone tissue engineering. It not only offers suitable physical support and biocompatibility but also guides cell proliferation to form specific tissues (Suo et al., 2023). Presently, researchers have started blending sodium alginate with other high molecular weight materials to facilitate cell growth (Ouyang et al., 2024). This blending technique offers a novel approach to develop biomedical materials with outstanding performance and is anticipated to be pivotal in the realm of tissue engineering.

One of the main components of the extracellular matrix is hyaluronic acid (HA), which is synthesized into HA hydrogels through physical or chemical crosslinking methods. It has good biocompatibility, does not easily cause immune reactions, and the HA hydrogel has good degradability, gradually degrading into metabolites that exist in the body without burdening the human body (Marinho et al., 2021). HA hydrogels exhibit good biocompatibility and biological activity, which have made them widely used in various fields. In bone tissue repair, HA hydrogels can provide a scaffold structure similar to the bone microenvironment to promote the differentiation of stem cells into bone cells, and promote bone regeneration through the release of growth factors and other bioactive substances (Wang et al., 2021). In tissue engineering, HA hydrogels can serve as cell carriers, providing a suitable environment to support cell adhesion, proliferation, and differentiation, thus achieving tissue regeneration and repair (Fujioka-Kobayashi et al., 2016). Despite the advantages of hyaluronic acid hydrogels including non-toxicity, biodegradability, and biocompatibility, their extremely high water absorption and enzyme degradation make them prone to corrosion and degradation in the body. Thus, combining hyaluronic acid with other smart hydrogels can yield new, environmentally friendly materials with enhanced performance (Liu et al., 2022a). The classification of natural polymer-based hydrogels is summarized in Table 1.

Polyethylene glycol (PEG) is a linear, neutral polyether polymer that possesses excellent biocompatibility, biodegradability, low immunogenicity, and affordability, making it an important biomaterial in the field of biomedicine. Merrill et al. (1982) first investigated PEG and polyethylene oxide (PEO) as hydrophilic biomaterials, and the results showed that the adsorption of proteins on glass surfaces could be effectively inhibited by the presence of PEO. Since then, various types of PEG have been utilized for different purposes, such as protein surface modification to confer resistance and enhance surface biocompatibility. Fraser and Benoit (2022) found that the presentation of RGD and GFOGER peptides in PEG hydrogels enhanced the functionality of periodontal ligament cells (PDLCs), and this hydrogel system effectively controlled the function and activity of PDLCs, promoting periodontal tissue regeneration. Liu et al. (2021a) studied an intelligent gingival protease-responsive hydrogel loaded with SDF-1 (PEGPD@SDF-1) and observed that the PEGPD@SDF-1 hydrogel exhibited good biocompatibility, promoting the proliferation, migration, and differentiation of periodontal ligament stem cells. Moreover, this hydrogel inhibited the proliferation of porphyromonas gingivalis, creating a low-inflammatory environment and inducing osteogenesis, thus possessing the ability to promote in situ regeneration of periodontal tissues.

Polyvinyl alcohol-based hydrogels, after crosslinking and swelling, form three-dimensional network-like colloidal dispersion. They possess high water absorption, degradability, good biocompatibility, and mechanical properties, making them widely applied in various medical fields (Rivera-Hernández et al., 2021). Due to the relatively simple structure and limited functionality of PVA, reinforcing components and functional materials are often incorporated into PVA hydrogel networks to improve and modify the overall performance of the hydrogel. Xiang et al. (2022) prepared a polyvinyl alcohol/hydroxyapatite/tannic acid (PVA/HA/TA) composite hydrogel, which exhibited high water content, porous structure, and good mechanical properties. In vitro cell experiments demonstrated excellent cell compatibility of the PVA/HA/TA composite hydrogel, promoting cell growth and adhesion, making it a promising material for bone tissue engineering. Zhou et al. (2020) developed a novel guided tissue regeneration (GTR) membrane using a composite hydrogel of polyvinyl alcohol (PVA) and fish collagen (Col). By adjusting the ratio of PVA/Col, they achieved control over the adhesion and proliferation of human periodontal ligament fibroblasts (HPDLFs) and human gingival fibroblasts (HGFs). The PVA/Col composite hydrogel exhibited unlimited potential as a GTR membrane for guiding periodontal tissue regeneration.

PAA is a type of synthetic polymer with high hydrophilicity and a large number of carboxyl groups. It can form hydrogels through physical or chemical crosslinking. Wen et al. (2023) prepared a novel composite mineral matrix PAA-CMC-TDM hydrogel using amorphous calcium phosphate (ACPs), PAA, carboxymethyl chitosan (CMC), and dentin matrix (TDM) as the matrix. The hydrogel exhibited good biocompatibility and degradability, and its mechanical properties could be adjusted without affecting the functional activity of TDM. The experimental results showed that the hydrogel significantly improved the differentiation ability of mesenchymal stem cells into tooth or bone, and could repair irregular hard tissue defects in situ. Fan et al. (2023) combined PAA and sodium alginate (SA) to obtain a double polymer network hydrogel, in which ion crosslinking and SiO2 nanoparticles were introduced as dual reinforcement materials. Compared with standard PAA hydrogel, the hydrogel exhibited enhanced adhesion and shape memory properties, and further improved biocompatibility and osteogenic potential. SA-PAA-SiO2 has great potential in bone tissue engineering. The classification of synthetic polymer-based hydrogels is summarized in Table 2.

Temperature-responsive hydrogels, also known as thermoresponsive hydrogels or temperature-sensitive hydrogels, are hydrogel materials with both hydrophilic and hydrophobic groups on their polymer chains. They exhibit temperature-responsive phase transition properties. When the temperature reaches a certain critical point, the affinity of the thermoresponsive hydrogel towards the solvent changes, leading to a swelling-shrinking transition. This temperature transition point is referred to as the lowest critical solution temperature (LCST) or utmost critical solution temperature (UCST). Injecting thermoresponsive hydrogels into periodontal pockets, they undergo an in situ sol-gel transition response under the stimulation of oral temperature. Xu et al. (2019) developed a thermosensitive hydrogel composed of chitosan (CS), sodium glycerophosphate (β-GP), and gelatin, which can sustainably release aspirin and erythropoietin (EPO) when injected. The study demonstrated that CS/β-GP/gelatin hydrogel is a novel drug carrier with easy preparation and excellent biocompatibility. The loaded aspirin/EPO in CS/β-GP/gelatin hydrogel exhibited significant anti-inflammatory and periodontal tissue regeneration-promoting effects. This hydrogel holds promise as a potential candidate for the clinical treatment of periodontitis.

pH-responsive hydrogels are a type of hydrogel material that undergoes swelling or shrinking in response to changes in pH. These hydrogels contain specific acidic groups (such as carboxyl groups) or basic groups (such as amino groups). The physicochemical properties of pH-responsive hydrogels largely depend on the charge changes within the material at different pH values and the interactions between charges. Yu et al. (2022) developed a dual-crosslinked gel system with a polyhedral oligomeric silsesquioxane (POSS) matrix, surrounded by a shell of six dithiol-linked PEG and two 2-ureido-4[1H]-pyrimidinone (UPy) groups. The thiol-disulfide exchange reaction exhibited pH-responsive “on/off” functionality, allowing for controlled structure of the hydrogel. The results showed that the hydrogel improved mechanical strength and had a positive effect on the proliferation, adhesion, and osteogenic ability of periodontal ligament stem cells (PDLSCs). In summary, pH-responsive hydrogels hold great potential for various applications, including drug delivery, tissue engineering, and biomedical devices, due to their ability to respond to changes in pH and provide controlled release and targeted therapy.

Light-responsive hydrogels are a type of hydrogel that undergo changes in their morphology, crosslinking density, and other properties under different light conditions, such as ultraviolet light, near-infrared light, or visible light. There are two different response mechanisms for light-responsive hydrogels: firstly, due to the presence of photosensitive functional groups (such as spiropyran, azobenzene, and other groups) within the hydrogel itself, the properties of the hydrogel change when it absorbs a certain amount of photon energy; secondly, by introducing nanomaterials with photothermal effects (such as gold nanoparticles, graphene oxide, etc.) into thermosensitive hydrogels, the light energy of the nanomaterials is converted into heat energy under light conditions using the photothermal effect, raising the temperature of the hydrogel and thus regulating its properties (Liu et al., 2021b). Zhai et al. (2021) studied a clay-based nanocomposite hydrogel using 4-acryloylmorpholine as a monomer. After exposure to ultraviolet light, the hydrogel exhibited good biocompatibility and mechanical properties. Additionally, animal experimental results demonstrated that the hydrogel had the ability to promote osteoblast differentiation, providing a new clinical approach for bone defect repair. Magalhães et al. (2022) prepared a nanocomposite hydrogel using laponite and polyethylene glycol diacrylate (PEGDA) and utilized ultraviolet radiation to enhance its bone regeneration ability, showcasing its potential application value in the field of bone regeneration. The classification of smart hydrogels is summarized in Table 3.