Enzymatic reactions occur in an abundance of enzymes in an ecological setting. As a result, this approach has received a great deal of interest for cellular technologies. Enzymatic reactions necessitate appropriate cross-linking circumstances, which include physiological pH, biological surroundings, and temperature (Badali et al., 2021). A key benefit of this technology for hydrogel creation is the unique enzyme substrate, which possesses the capacity to inhibit the penetration of harmful chemicals induced by adverse responses. Horseradish peroxidase (HPR), modified glutamines, and tyrosinases are some of the enzymatic accelerators utilized to create hydrogel systems for tissue engineering. HPR is one of the enzymes utilized to generate hydrogels in this process because of its great mechanical stability and simplicity of filtration (Bae et al., 2015). As a result, it is employed in a variety of health-related purposes including the release of medications, rehabilitation and regeneration, and tissue engineering. The HPR-H₂O₂ enzyme water system is commonly used to produce natural hydrogels from chitosan, hyaluronic acid, dextran, and gelatin. In a study by Kurosawa et al. It was produced by enzymatic processes and utilized for releasing therapeutic proteins. In this investigation, hyaluronic acid has been modified with tyramine and labelled with the fluorescent marker amino fluorescein. The subcutaneous gelling time was shortened, indicating that the utilization of enzymatic processes to generate cross-linking is an appropriate approach for hydrogel creation owing to its versatility and cell friendliness (Kurisawa et al., 2005).

Sharples et al. describe click chemistry as “specific forms of processes with the inclusion of an initiator that exhibit superior rapidity and efficacy, outstanding physiological characteristics, and favorable reactions parameters” (Nguyen et al., 2015; Guaresti et al., 2018). It performs a substantial part in polymer production and triggering, and it is an efficient and versatile approach for functionalizing compounds. Because of the advantages of click chemistry, it is utilized to produce hydrogels, nanogels, and microgels. It has been served as a foundation for tissue engineering and medication delivery. Click chemistry is seen as a promising platform for dynamic chemically cross-linked polysaccharide-based. Click reactions typically encompass an extensive number of processes, such as: copper (I) interactions (catalyzed by alkyne azide sequestered), catalytic reactions of free pairs of alkyne azides, silicosterone reaction with disaccharide (DA), among which the intergroup reactions Alkynes, and azides are the most prominent instances of click chemistry because of their benefits, including outstanding effectiveness in physiological settings and good specificity (Nguyen et al., 2015). In the lack of thermally reversible byproducts which enable the level of interaction to be regulated, the reaction occurs without a catalyst or primer, preserving the material’s biocompatibility (Guaresti, García–Astrain, Aguirresarobe, Eceiza and Gabilondo, 2018). Starch-based hydrogels were created via a click reactions between the thiol and allyl groups of starch for biomedical and tissue engineering purposes. The resultant hydrogel demonstrated remarkable swelling and biological degradation (Samadian et al., 2020).

Among them, natural polymers such as chitosan have been extensively used to construct several types of mucoadhesive drug delivery systems with successful treatments. Chitosan is a naturally existing biopolysaccharide that has been utilized in mucoadhesive devices owing to its strong adhesion properties. Chitosan’s mucoadhesivity could be described by the electrostatic contact between its positively charged cationic molecules and the negatively charged mucin (Hasnain and Nayak, 2022). However, chitosan’s insufficient aqueous solubility at both basic and neutral pHs is one of the most significant limitations to its application as a biopolymer in mucoadhesive networks. To address this issue, various chemical alterations to chitosan have been researched and effectively implemented (Atia et al., 2022a). CS’s inherent characteristics (molecular mass, extent of deacetylation) determine how it will be used. Peng et al. employed N-acetylation to create an acetylated carboxymethyl CS for inclusion into an intelligent hydrogel for periodontal therapy. His research revealed that by varying the level of acetylation of the carboxymethyl CS hydrogels, the gelation temperature could be adjusted (Peng et al., 2023). The gel formation temperature was 36.9°C when the extent of acetylation was 63.9%, and 33.2°C when the percentage of acetylation was 85.3%.

It has just been discovered that introducing hydroxyl-containing polymers including β-GP may end up in thermo-sensitive CS-based hydrogels. The hydrogel formed by mixing CS and -GP is frequently employed in the medical area, and this approach has been extensively utilized after Chenite originally described it. (Chenite et al., 2000). Since the hydrophobic and hydrogen linking forces surpass the electrostatic repulsive power, certain portions between the CS chains develop physical bonding when the hydrogel reaches gelation temperature (Molinaro et al., 2002).

Shen et al. encapsulated dental pulp stem cell-derived exosomes in a CS and -GP crosslinked hydrogel to treat periodontitis (DPSC-Exos/CS) (Shen et al., 2020). This hydrogel solidified at 37°C, and the bulk of the packed exosomes were ejected from DPSC-Exos/CS within 7 days in PBS at 37°C, with an exosome loading efficiency of around 80%. RNA sequencing investigation of periodontitis model mice subjected to DPSC-Exos/CS and CS indicated that genes linked with chemotactic processes, inflammatory reactions, and immunological reactions were decreased in periodontitis mice treated with DPSC-Exo/CS.

In comparison to the traditional gelation approach, the introduction of gelatin (Gel) enables the cross-linking of CS and β-GP via cation-anion electrostatic forces, reducing gelation time (Tóth et al., 2021). Xu et al. developed an injectable thermo-sensitive hydrogel containing CS, β-GP, and Gel loaded with aspirin, and erythropoietin for periodontal regeneration by regulating the inflammation-producing milieu and stimulating tissue regeneration. This hydrogel demonstrated prolonged aspirin and erythropoietin releasing (Xu et al., 2019). In vitro release tests verified these features, with aspirin and erythropoietin release rates of 86.6% and 69.4%, respectively, during the first 3 days. It maintained aspirin discharge at its initial stage, creating a regional milieu free of inflammation and boosting erythropoietin’s pharmacological action.

Zhang et al. incorporated HA into a CS/β-glycerophosphate sodium system (Zhang et al., 2018). The addition of HA alters the structural characteristics of the hydrogel and could minimize pore dimensions, which could be used to modulate the pharmaceutical distribution speed. Because HA molecules possess a substantial amount of hydroxyl, carboxyl, and amino groups, they may engage more strongly with CS, increasing its durability.

The architectural impact of β-GP during warming enhances hydrophobic contacts and connection between the CS and HA chains, and the solution transforms into a hydrogel because of the synergistic impact of these ionic reactions. Furthermore, the inclusion of HA has been shown to enhance the hydrogel formed in situ’s adhesion (Deng et al., 2017).

Curdlan is a polysaccharide derived from microbes that comprises 300–500 glucose units connected by −1,3-glycosidic bonds (Zhang and Edgar, 2014). Without the addition of crosslinking substances, curdlan may undergo physical gelation by warming to generate a high-set thermally irreversible gel (80°C) and low-set thermally bidirectional gel (55°C). Curdlan, as a result, holds enormous potential for application in periodontal regeneration. Tong et al. employed photothermal treatment to obtain regulated and proper discharge of antimicrobial medicines following near-infrared (NIR) light stimulation (Tong et al., 2020). They mixed the antibacterial agent chlorhexidine acetate and the photothermal agent polydopamine (PDA) with curdlan. After 50 s of radiation, the hydrogel’s temperature increased to about 58°C, allowing it to eradicate 74.4% of the total bacteria (Staphylococcus aureus) in three light cycles with just minor tissue damage.

Compound hydrogels have been shown to have stronger retaining capabilities, a smaller swelling volume, and improved stability. Human periodontal ligament cells are also biocompatible with compound hydrogel. Furthermore, the photothermal agent’s cumulative and locally induced release improves the bactericidal action. This combinatorial antibacterial technique expands curdlan’s capabilities, enabling it to effectively combat periodontitis with more complicated treatments that concentrate and react to outside factors or its regional environment.

Cellulose is the most common carbohydrate found in nature (Seddiqi et al., 2021). It garnered substantial interest as a desirable replacement material, because of its beneficial features, including being harmless, biodegradable and biocompatible, chemical durability, low prices, and significant hydrophilic nature, which makes it an ideal solution for the production of biologically compatible hydrogels (Ciolacu and Suflet, 2018). Venkatesh et al. used Pluronic F-127 and hydroxyethyl cellulose as the hydrogel matrix to create a thermo-responsive hydrogel preloaded with azithromycin to facilitate the cure of periodontitis (Venkatesh et al., 2013). The polyoxyvinyl chains of Pluronic F-127 interact with hydroxyethyl cellulose to promote dehydration, improve tangling with surrounding molecules, and significantly increase hydrogen bonds between molecules. As a result, it may be possible to lower the gelation temperature and use a hydrogel to treat periodontitis more effectively. Rheological investigations indicate that this hydrogel’s density increases with temperature, reaching a notable peak at 37°C.

This hydrogel also features a quick gelation time and an excellent gelation temperature. This hydrogel’s gelation temperature is lower than body temperature (29.8°C–33.1°C), and the time necessary for the hydrogel to attain the gelation temperature is between 33 and 42 s.

Xyloglucan is a carbohydrate present in higher plant cell walls along with numerous seeds. It is of the highest quality biocompatible material that is readily available and biodegradable. When contrasted to other hydrogels, it has been extensively explored because of its higher capability for taking in and keeping water, as well as its superior biocompatibility. It has piqued research curiosity in the creation of hydrogels for biological purposes (Kulkarni et al., 2017). It was also lately tested as a potential cell transport vehicle via the addition of poly-D-lysine, which under physiological conditions caused a sol-gel transformation (Simi and Abraham, 2010). Cell confinement in regenerative medicine purposes requires the existence of microporous, three-dimensional structures that have connections (Silva et al., 2013; Ajovalasit et al., 2018).

Agarose is a seaweed-derived carbohydrate (Chudasama et al., 2021). This polysaccharide’s molecular arrangement is left-handed triple-double helices, which allows it to produce highly durable gels even at small amounts (Utech and Boccaccini, 2016). Agarose has a fascinating thermosensitivity: depending on the type of agarose, its polymer chains can display a random coil structure at high temperatures (N65C-95C), and they can also form double helical aggregates at around 35°C (Zeng et al., 2015). It is water soluble at different temperatures and is extensively used as a cell immobilization matrix, pharmaceutical carrier, and cellular incorporation. These hydrogels’ interconnecting porosity morphologies, excellent mechanical strength with moderate biodegradation, extraordinary tissue adhesiveness, and self-healing potential render them attractive options for long-lasting wound dressings (Zeng et al., 2015).

Hyaluronic acid (HA) is an organic polymer. The physiological effects of HA can be divided into two categories: signaling molecules and passive architectural molecules. As an extracellular substance, HA stabilizes the space by forming a hydrated and organized system while also changing tissue hydration and osmotic equilibrium. It can, on the other hand, function as a signaling molecule, interacting with binding proteins. By being highly biocompatible, biodegradable, and mechanically viscoelastic, HA-based hydrogel not only retains the biological capabilities of HA but also endows the hydrogel with skeletal functioning. In order to boost the efficacy of BMP-2 in bone therapy, injectable substances that are safe and break down in a controlled way, including HA, with increased vehicle qualities were created (Patterson et al., 2010). HA was chosen as a sample of mucoadhesive compounds. This choice is significant because, in some ways, HA represents the worst-case scenario for mucoadhesive polymers. In fact, HA has been regarded a borderline material that may have particular reactions with cellular elements when delivered through routes other than mucosal regions (Vasvani et al., 2020).

Starch is a plant-derived material that is frequently engaged in bone tissue engineering and medicine delivery. Swelling capabilities, rheological features, enzymatic digestion, shape, and solubility are some of its major characteristics that increase its application in drug delivery studies. As a result of differing manufacturing processes, starch may associate into an array of semi-crystalline forms and construct numerous hydrogel formulations. Native starch granules absorb water and expand when heated in excess water. Following the permanent loss of granule structural and crystalline order, amylose leaches into the surrounding media, a method known as starch gelatinization (Nikolenko et al., 2023).

Starch has considerable potential for the creation of “green” hydrogel-based products since it is an accessible, sustainable, and ecologically friendly substance with a diverse spectrum of rheological, chemical, physical, and biochemical characteristics (Bertoft, 2017). For hemostatic usage, a new Kappa carrageenan (CA)-coated Starch/cellulose nanofiber (CNF) with customizable biomechanical characteristics. The durability of CA-coated Starch/CNF hydrogels was greatly increased (up to 2 times) when compared to Starch/CNF hydrogels, depending on the CA concentration.

Because of the collaborative impacts. of starch/CNF hydrogel and CA coating, remarkable features like improved mechanical capabilities, tunable rates of decomposition, and blood coagulation capacity were obtained, making CA-coated starch/CNF hydrogel a suitable choice for hemostasis (Tavakoli et al., 2021). Starch/Chitosan Gelation duration and compressive modulus studies revealed that the particles had a substantial impact on the mix network density and hydrogel mechanical characteristics (Baniani et al., 2017). The freeze-thaw process was used to create antibacterial starch-citrate hydrogels. This hydrogel showed remarkable antibacterial action against Gram-negative bacteria strains such as E. coli, Staphylococcus pyogenes, Salmonella thypimurium, and S. aureus. As a result, the potential utilization as both an antibacterial agent and a drug delivery carrier is predicted (Chin et al., 2019). Cardoso et al. (de Oliveira Cardoso et al., 2017) created hydrogels from gellan gum and starch retrograded combinations for pharmaceutical delivery purposes by adjusting polymer and cross-linker proportions. Structural changes to the retrograded starch mix hydrogels were achieved through isothermal cycles at 4°C or alternate thermal cycles. Under chilling temperatures (4°C/8 days), hydrogels developed a more organized and resilient architectural system, resulting in a tougher and more cohesive substance. Under cycled temperatures (4°C and 30°C/16 days), hydrogels formed a looser network with more mobility and increased adhesiveness. Furthermore, Cardoso et al. (de Oliveira Cardoso, Cury, Evangelista and Gremião, 2017) showed that these hydrogels may be tailored to have appropriate adhesiveness, durability, and flexibility, making them suitable compounds for mucoadhesive devices for drug delivery. Dong et al. (Dong et al., 2019) also created a starch-based thermosensitive hydrogel that exhibits reversible swelling and deswelling as the temperature varies. They found that combining hydroxybutyl starch and PEG resulted in more porous architectures and enhanced the swelling ratio. Furthermore, these hydrogels displayed recurrent swelling at 25°C and deswelling at 45°C.

Alginate (AG) is an organically existing anionic polymer composed of 1,4-linked-D-mannuronic acid and -L-guluronic acid that generally comes from brown seaweed. It has been deeply studied and utilized in numerous fields of medicine due to its biocompatibility, low toxicological profile, affordable price, and straightforward gelation ability via the introduction of divalent cations like calcium (Ca²⁺) (Chan and Neufeld, 2010; Alkhursani et al., 2023). ALG is classed as an anionic mucoadhesive polymer because it has carboxyl groups that may interact with the hydroxyl groups of mucin glycoproteins. Furthermore, ALG has gelling characteristics. Despite the numerous benefits of ALG, ALG-based drug delivery devices have disadvantages such as poor flexibility, inadequate mechanical characteristics, and brittleness. As a result, novel strategies to improve the properties of ALG preparations are required (Szekalska et al., 2016; Kruk and Winnicka, 2022). COL and AG can operate together to bring together their beneficial attributes and overcome the limitations associated with every substance.

The key barriers limiting their wide range of applicability are the poor mechanical characteristics of COL and the intrinsic absence of cell-binding motifs within AG, which may be solved by combining them with increased cell-binding motifs and boosted durability. Furthermore, the simplicity with which these composite gels under moderate circumstances allows for the preservation of bioactive substances and improves cell encapsulation (Hu and Lo, 2021). Nerve growth factors (NGF) are significant in bone healing (Yada et al., 1994). Human NGF’s quick removal from the body via enzymatic breakdown is one of its limitations. To address this issue, NGF was added into a COL/nHAp/AG hydrogel and tested for bone formation potential in a rabbit mandibular distraction osteogenesis model (0.75 mm/12 h for 6 days). The results demonstrated the hydrogel system’s osteoconductive ability and that human NGF might maintain its biological functions for an extended amount of time after being released from the NPs/hydrogel combination (Cao et al., 2012).

Given its biological compatibility and breakdown, gellan gum (GG), a polysaccharide substance, is utilized to make injectable hydrogels (Ahmed, 2015). GG is a thermally responsive biomaterial with a UCST (ultimate critical solution temperature). The GG solution turns into the gel at temperatures lower than this. Additionally, the elevated carboxyl groups in GG particles have the potential to react with ambient calcium ions and trap local Ca ion levels, which is advantageous for bone regeneration. Injectable thermosensitive hydrogel based on gellan gum and cross-linked with 2-methacrylamidoethyl dihydrogen phosphate (MDP) enhanced the survival of the preosteoblast MC3T3-E1 cell line and elevated the amount and rate of hydroxyapatite production (Li A et al., 2020).

Albumin is a well-known macro-molecule carrier that may be found in numerous foods. It facilitates in the delivery of nutrients to cells, in addition to the regulation of osmotic pressure (Loureiro et al., 2016). Nontoxicity, biodegradability, ease of manufacturing, no immunogenicity, with clearly established dimensions make albumin carriers widely implemented in tissue engineering Nontoxicity, biodegradability, ease of manufacturing, non-immunogenicity, with clearly established dimensions make albumin carriers are widely implemented in tissue engineering (Belinskaia et al., 2021).

Gliadin is a Gluten protein obtained from wheat. Gliadin’s capacity to adhere to the mucus barrier makes it a popular ingredient in mucoadhesive treatments. Its exceptional features, which include being biodegradable material, its organic prevalence, safety, and reliability, render it an ideal choice for drug delivery systems. They can safeguard the loaded medicine for controlled and prolonged release due to their hydrophobic nature and solubility (Voci et al., 2021).

Zein is a prolamine-rich protein that includes hydrophobic amino acids, proline, and glutamine. Zein has been authorized by the FDA for human consumption. Several medications and bioactive compounds have been encased in zein protein nanoparticles (Corradini et al., 2014).

Fibrin, a biodegradable and biocompatible protein, is generated by the polymerization of the enzyme fibrinogen. Fibrin is an excellent bone-healing agent (Riedelová-Reicheltová et al., 2016). Fibrinogen is a glycoprotein present in the blood that is composed of three pairs of non-identical polypeptide chains. After arterial damage, thrombin cleaves fibrinogen to create fibrin, the most prevalent constituent of blood clots. When blood coagulates because of an injury, fibrin gel can develop in a matter of seconds. Fibrinogen may react with cells via integrin receptors, which include two RGD sequences as well as non-RGD sequence integrin binding sites and non-integrin receptors (Joo et al., 2015), and this provides the fibrinogen hydrogel with great bio compatibility.

At biological conditions, fibrin gel forms easily and is suited for local administration via direct injection to the target location (Lei et al., 2009). Because fibrin may be derived from a patient’s plasma, immunological rejection is avoided. The fibrinogen cleavage byproducts and fibrin degradation substances are non-toxic and have diverse regulating impacts on cell division and development. They specifically increase angiogenetic and vasoactive activity, as well as the accumulation of collagen, during tissue healing (Herrick et al., 1999). Because of these benefits, fibrin is often utilized as a platform in tissue engineering.

Fibrinogen can operate as a repository for growth mediators, proteases, and protease suppressors by attachment to other ECM components. This interaction not only improves enzymatic attachment to the framework and cellular-mediated fibrinogen cleavage, but it also allows for the release of bioactive compounds in the immediate microenvironment (Karamanos et al., 2018). As a result, fibrinogen hydrogel may be employed as a bioactive carrier.

Fibrinogen hydrogel has limitations as a biological biomaterial, including weak mechanical properties and less predictable degradation. Copolymerization with artificial biomaterials allows for a certain degree of control over the fibrinogen hydrogel’s architectural features and biodegradation while preserving its intrinsic biocompatibility (Almany and Seliktar, 2005).

Sericin, a water-soluble and hydrophilic protein acts as a glue and accounts for 20%–30% of the cocoon’s mass. With the inclusion of sulphate, it has intrinsic capabilities such as anti-cancer, antioxidant, and coagulation inhibition as a sericin nanoparticle (Nayak and Kundu, 2016). Sericin is also non-toxic to fibroblast cells. The existence of cysteine and methionine amino acids promotes cell development (Cao and Zhang, 2016). Water-soluble silk sericin has little immunogenicity. Sericin demonstrates easy wound healing without the inflammatory process (Cao and Zhang, 2016).

Keratin, a structural protein that’s high in the amino acid cysteine, proclaims the greatest mechanical capacity. Keratin nanosuspension is employed as a coating to examine cellular multiplication, and it is a less expensive alternative to fibronectin or collagen. Furthermore, keratin hydrogels are employed in tissue engineering (Chen et al., 2022).

The most plentiful plant-based protein resource is soybean (glycine max). Its isolates are an enhanced type of soy protein that has been shown to have excellent nutritional values and ingredient functions. Glycinin and conglycinin are significant components of soy protein isolate (Qin et al., 2022). Soy protein isolate aggregates when crosslinking chemicals are added, and at specific temperatures, microspheres, hydrogels, and polymer mixes develop.

Casein is plentiful in milk and dairy products and is considered. Its nature enhances particle development, and crosslinking may be used to boost the resilience of their frameworks and their practical usefulness (Liu S et al., 2018).

Silk Fibroin (SF) is an easy material to deal with, and its outstanding mechanical properties and controlled biodegradation render it an outstanding option for bone regeneration scaffolds (Saleem et al., 2020). The SF is composed of two components known as sericin and fibroin, and fibroin was employed to reduce inflammatory and allergic reactions following surgical procedures (Sun et al., 2021). SF scaffolds were previously adjusted with a range of osteogenic bioactive sources such as natural-derived materials, bone growth agents, and chemicals (Celikkin et al., 2017).

Elastin is a protein present in connective tissues that offers elasticity and toughness to tissues that need to be extensible and rebound. It is formed of hydrophobic domains containing residuals of glycine, valine, and proline, in addition to crosslinking domains including lysine and alanine (Wang et al., 2021). Natural elastin received fewer considerations for biomaterial applications than collagen due to the challenges in isolating it and the high chance of calcification upon transplantation (MacEwan and Chilkoti, 2010).

A temperature rise, for example, leads soluble protein to separate from the solvent and form an aggregated phase, whereas a fall in temperature increases the possibility of the protein self-aggregating (Costa et al., 2009). Elastin-like proteins (ELPs), which may be useful in tissue engineering and cancer therapeutics, have been recombinantly generated as oligomeric repeats of the pentapeptide sequence VPGXG, where X indicates an amino acid other than proline (Despanie et al., 2016). They are soluble below 35°C and form a gel-like matrix above body temperature (37°C) after injection. Consequently, ELP enables the integration of cells and other therapeutic agents into its solution state at room temperature, as well as the formation of a gel-like matrix at normal temperatures that can contain them for tissue engineering, cell therapy, and therapeutic purposes (Varanko et al., 2020).

In the ECM and mammals, collagen is the most abundant protein. Collagen may be derived from a wide range of mammals and tissues, therefore being extensively accessible for research and treatment. To minimize batch-to-batch variances and possible sensitization of animal-originated collagen, recombinant collagen has been examined as a replacement to resemble human collagen (Rezvani Ghomi et al., 2021). Collagen gels were initially employed as a means of skin regeneration before being extensively utilized for other regenerative purposes (Zhang et al., 2023). Furthermore, injectable collagen gels have been demonstrated to stimulate stem cell adipogenesis and osteogenesis (Hao et al., 2008). Collagen-based hydrogels have been created by either letting collagen fibrils self-assemble or employing chemical crosslinking reagents.

Rebuilding of the periodontal attachment apparatus was shown to be facilitated by implanting a three-dimensional scaffold composed of collagen hydrogel and shaped like a sponge, as shown by studies by Kosen et al. (Kosen et al., 2012), and Kato et al. (Kato et al., 2015). Adverse periodontal reactions, including as ankylosis and root resorption, were consistently absent when collagen hydrogel was used. Conversely, the amount of periodontal tissue that was growing was about half that of the experimental deficit. To induce periodontal rebuilding, an integrated strategy for tissue engineering is required.

Gelatin is a possible naturally formed polymer for the development of hydrogels due to its non-antigenicity, nontoxicity, biodegradability, biocompatibility, and low cost (Amadori et al., 2015). Despite this, gelatin loses physical durability and flexibility in vivo due to continual water imbibition (Wisotzki et al., 2014). Consequently, unexpected waves of hydrogels occur. Additionally, gelatin’s heat stability is restricted, with the sol-gel transition happening at body temperature (37°C), constraining its practical application (Biswal et al., 2016). These problems can be solved by using strengthening agents and cross-linking procedures (Skopinska-Wisniewska et al., 2021). Attempts in the past to cross-link gelatin with glutaraldehyde have led to toxicological challenges. Genipin, a natural crosslinking agent, can be used as an ecologically benign alternative to glutaraldehyde; however, due to its high cost, its applicability is (Serpico et al., 2023).

Radiation-induced cross-linking, on the other hand, is a relatively simple and low-cost strategy that employs non-chemical substances and permits concurrent sterilization of the crosslinked polymer (Hafeez et al., 2018; Zainal et al., 2021). Gelatin’s chemical backbone produced a three-dimensional architecture by producing gamma rays via cross-linking (Wan Ishak et al., 2018). A multifunctional hydrogel constructed from homologous injectable platelet-rich fibrin (iPRF) and Gel NPs was established to boost its durability and delay decomposition while slowly discharging iPRF-entrapped growth factors (Mu et al., 2020). This organic copolymer has a DN framework, which increases mechanical properties including injectability, durability levels, and number of deformations. Sinus chambers injected with Gel NPs-iPRF hydrogels revealed considerably greater fresh bone development following four and 8 weeks of application in a sinus augmentation paradigm, histologically and radiologically than Gel NP gels and the untreated control, with a greater extent of angiogenesis. After 8 weeks, the newly produced bone developed and remodeled into lamellar bones (Mu, Chen, Yuan, Li, Huang, Wang, Zhang, Liu, Luo and Liang, 2020). As a result, it serves as a carrier for the prolonged liberation of bioactive ingredients from iPRF.

In order to preserve the surrounding tissue, preserve the shape of the defect, and reduce distortion of the adjacent tissue, the passive regeneration of periodontal tissues through the use of bone grafts and inserts is based on the architectural reinforcement of the affected area. Stem cells or progenitor cells with the potential to differentiate into osteoblasts are used in osteogenic bone grafts and implants. They could also be osteoinductive, meaning they supply substances that stimulate the differentiation of pluripotent stem cells, which in turn promotes the formation of new bone. In the most basic case, the implants might be osteoconductive, meaning that their chemical and biological properties promote the formation of new bone. Bone grafts and other bone replacements are categorized as autologous, allogeneic, xenogeneic, or alloplastic based on their biological makeup (Reynolds et al., 2010).

Bone grafts that are autogenous, or self-generated, are taken from the patient and are believed to possess ideal osteogenesis, osteoinduction, and osteoconduction qualities. The extraoral or intraoral donor sites are the sources from which they can be received. Schallhorn et al. were the first to use the iliac crest as an extraoral bone transplant in periodontal regeneration surgery in the late 1960s. However, iliac bone marrow transplantations are no longer used because of the invasive extraction procedure (Sakkas et al., 2017).

Because allogeneic transplants are extracted from different humans, they offer some risks owing to the potential of antigenic properties (Sohn and Oh, 2019).

They are natural materials derived from animals that have had their organic parts eliminated to retain the bone framework in its unaltered inorganic state. Antigenicity is a persistent concern in allogeneic transplants, as it is in allogeneic grafts.

Alloplastic transplants are biocompatible artificial bone replacements with osteoconductive characteristics. These materials are classified as resorptive or non-resorptive based on their resorption (Eppley et al., 2005).

Guided tissue regeneration is the second stage of treatment for mucogingival and periodontal disease. Restitution ad integration, or the complete structural, morphologic, and histologic regeneration of the injured periodontal tissues, is the aim of the treatment. In the early 1980s, the idea of selectively controlling the regeneration of periodontal tissues by the use of a membrane positioned between the gingiva and the tooth surfaced (Uskoković et al., 2022). The notion of directed tissue regeneration suggests that the apical growth of the epithelium is stopped or prevented, allowing room for regeneration. Periodontal ligament cells can develop into fibroblasts, cementoblasts, or osteoblasts, allowing them to establish new attachments.

For directed tissue regeneration, three kinds of membranes are employed: natural, which degrades naturally, resorptive artificial, and non-resorbable artificial. An ideal membrane should be safe, that is, biocompatible and solid, incapable of transferring illness or collapsing into a defect, yet able to distribute antimicrobials, bioactive molecules, and other additional agents (Naung et al., 2019).