Recent advances of injectable in situ-forming hydrogels for preventing postoperative tumor recurrence

Abstract

The unavoidable residual tumor tissue from surgery and the strong aggressiveness of tumor cells pose challenges to the postoperative treatment of tumor patients, accompanied by in situ tumor recurrence and decreased quality of life. Therefore, there is an urgent need to explore appropriate postoperative therapeutic strategies to remove residual tumor cells after surgery to inhibit tumor recurrence and metastasis after surgery. In recent years, with the rapid development of biomedical materials, the study of local delivery systems as postoperative delivery of therapeutic agents has gradually attracted the attention of researchers. Injectable in situ-forming hydrogel is a locally administered agent injected in situ as a solution that can be loaded with various therapeutic agents and rapidly gels to form a semi-solid gel at the treatment site. This type of hydrogel tightly fills the surgical site and covers irregular excision surfaces. In this paper, we review the recent advances in the application of injectable in situ-forming hydrogels in postoperative therapy, focusing on the matrix materials of this type of hydrogel and its application in the postoperative treatment of different types of tumors, as well as discussing the challenges and prospects of its clinical application.

1. Introduction

Now, cancer remains one of the diseases with high morbidity and mortality all over the world, seriously threatening human life and health (Bray et al., 2021; Xia et al., 2022). Global cancer data released by the World Health Organization’s International Agency for Research on Cancer (IARC) in 2024 shows that nearly 20.0 million new cases of tumors and almost 10 million deaths from cancer occurred worldwide in 2022 (Jokhadze et al., 2024). Other data shows that cancer is the first or second leading cause of death in 112 of the 183 countries included in the statistics (Deo et al., 2022). In addition, over 90% of cancer patients die from tumor recurrence and metastasis, and local tumor recurrence and metastasis are the leading cause of postoperative death (Zhang et al., 2022).

The main reasons for tumor recurrence and metastasis after surgery are as follows: (1) Surgical resection is currently the method of treatment for clinical malignant solid tumors (breast cancer, skin cancer) (Quazi et al., 2020). However, despite the advancement of surgical techniques, surgical resection cannot completely eradicate the tumor tissue, and the residual cancer cells can rapidly proliferate at the surgical site or even enter the body circulation through blood vessels due to their strong infiltration and invasiveness, which greatly increases the risk of in situ recurrence and distant metastasis after surgery (Yin et al., 2021; Hou et al., 2022; Okusaka, 2022); (2) The removal of tumor tissues inevitably removes the normal tissues at the margins, causing certain tissue defects, which may cause some adverse postoperative complications (such as wound inflammation and bacterial infection) and hinder wound healing and tissue regeneration. Meanwhile, the postoperative immunosuppressive tumor microenvironment will inhibit the autoimmune killing function, significantly increasing the tumor recurrence rate after surgery (Lorente-Herce et al., 2021; Pretzsch et al., 2021; Cheng et al., 2022a; Moloudi et al., 2024). (3) It takes two weeks or more for a cancer patient’s body to recover before following up with adjuvant therapy after surgery. However, the residual highly infiltrative tumor cells will take the opportunity to proliferate during this period, resulting in missing the best time for postoperative adjuvant therapy to kill the residual tumor cells and eventually leading to tumor recurrence (Schiapparelli et al., 2020). Therefore, there is an urgent need to develop a novel therapeutic approach to meet the requirements of comprehensive postoperative oncology treatment.

To remove residual tumor cells after surgery to reduce tumor recurrence rate, postoperative adjuvant systemic chemotherapy or radiotherapy has achieved good results in the postoperative treatment of patients with different types of tumors (Adams et al., 2024). Systemic chemotherapy can not only treat in the primary area of the tumor but also affect cancer cells outside the primary area, inhibiting cancer cell metastasis while suppressing tumor recurrence in situ (Poláková et al., 2019). Traditional systemic chemotherapy requires the administration of chemotherapeutic agents either orally or intravenously, which are prone to rapid degradation during systemic circulation, resulting in lower therapeutic concentration at the target site and poorer efficacy (Wu et al., 2024). However, high-dose administration is prone to many adverse effects on normal tissues due to its lack of targeting and susceptibility to drug resistance, jeopardizing human health (Askari et al., 2020). Compared with systemic drug delivery, local drug delivery shows unique application advantages. By delivering the therapeutic agent directly to the tumor resection site for release and deposition, the systemic drug circulation is minimized, which can effectively increase the local drug concentration and eliminate the latency period of postoperative chemotherapy, as well as reduce the toxicity and side effects on normal tissues (Cheng et al., 2024). In recent years, more and more and more researchers at home and abroad have been devoted to the development of local drug delivery systems for application after tumor surgery (Fan et al., 2024). In the absence of distant metastases, local therapy is ideal for postoperative treatment of tumors (Bu et al., 2019; Abdelkader et al., 2021). With the development of synthetic chemistry, several locally implantable polymers including wafers (Jones et al., 2020; Ricciardi et al., 2022), scaffolds (Shang et al., 2022), foams (Marques et al., 2018), thin films (Malathi et al., 2020; Puiu et al., 2021), and micron/nanoparticles (Zeng et al., 2023) have been developed for localized drug delivery (Mozafari et al., 2024). Significantly, although these implants have good tissue regenerative and degradable properties, they may still cause adverse reactions such as inflammation and bacterial infections, resulting in reduced tissue regeneration rates. Among local drug ­delivery systems, the tumor treatment platforms based on hydrogel have attracted much attention. Hydrogel is a three-dimensional mesh porous structure formed by polymer cross-linking, with excellent swelling properties, biocompatibility and permeability, and easily adjustable physicochemical and mechanical properties (Peng et al., 2024). In addition, the hydrogel forms a protective layer on the surface of the tissue, isolating the tissue from the outside environment while providing a long-lasting moist environment for the wound, which effectively prevents bacterial infection and reduces water loss, providing a strong condition for postoperative tissue reconstruction (Cai et al., 2021). Although traditional hydrogel is easy to fabricate and ­biocompatible, their poor self-healing properties and non-injectable nature prevent them from completely covering irregular surgical cavities, greatly limiting their use in postoperative tumor treatment (Zhou et al., 2019). Therefore, injectable in situ-forming hydrogels are ideal topical drug delivery systems because they not only allow for sustained and controlled release of drugs, but also can be converted from a solution to a semisolid gel triggered by physiological stimuli (e.g. temperature, pH, and light). They can adapt to any shape of the tumor resection cavity and overcome the problem of poor coverage of traditional hydrogels, which has a broader application prospect.

This review summarizes the recent advances of injectable in situ-forming hydrogels for preventing postoperative tumor recurrence (Figure 1). Finally, we discuss and look ahead to the problems and challenges of injectable in situ-forming hydrogels and the potential for clinical translation. We expect to clarify the prominence and broad prospects of injectable in situ-forming hydrogels in postoperative tumor treatment.

Figure 1.

Schematic illustration demonstrates the application process and function of an injectable in situ-forming hydrogel for prevention of postoperative tumor recurrence.

2. Advantages

2.1. Encapsulation of various therapeutic substances for multimodal antitumor therapy

Injectable in situ-forming hydrogels are usually in a flowable solution state at room temperature, which facilitates the mixing of therapeutic agents (e.g. conventional chemotherapeutic drugs, phototherapeutic, photosensitizing, and immunotherapeutic agents, and even cells) with a hydrogel precursor solution, which is then further transformed by a phase change to form hydrogel loaded with various therapeutic agents. Various therapeutic substances encapsulated in hydrogels can be targeted to the resected area of the tumor for multimodal antitumor therapy at appropriate therapeutic concentrations with low systemic toxicity (Wang et al., 2020b). Meanwhile, the application of hydrogel as a drug carriers can solve the problems of low solubility and rapid metabolism of certain drugs (Mu et al., 2024). The injectable hydrogel can effectively avoid immune rejection and systemic toxicity, which is the key to successful local drug delivery (Naahidi et al., 2017). For example, hydrogel was used to deliver Polyoxometalate and R848 for combined phototherapy and immunotherapy (Liu et al., 2022a), for the delivery of platinum monatomic platinum and gemcitabine for combined chemotherapy and phototherapy (Wang et al., 2024a).

2.2. Filling irregular surgical surfaces with a gentle gelation process and minimal tissue invasion

Injectable in situ-forming hydrogels are formed by rapid polymerization or sol-gel phase change in response to external stimulation (e.g. light, heat, enzymes, etc.) and without the use of chemical cross-linking agents (Dimatteo et al., 2018). This unique morphology transformation property enables it to tightly fill and cover the irregular resection surface after surgery, make direct contact with the residual tumor cells, and release the therapeutic agents in situ for more efficient anti-tumor effects (Park et al., 2020). For example, PLGA-PEG-PLGA is in a solution state at room temperature and a semi-solid gel state at temperatures up to 37 °C and is used to release therapeutic agents within irregular surgical cavities (Zhao et al., 2021). Gel solutions were prepared by mixing poly (ethylene glycol) methacrylate and sericin methacryloyl, which can form hydrogels under 405 blue light irradiation (Mi et al., 2023). Rapid hydrogel formation by co-injecting fibrin solution and thrombin solution into the tumor resection cavity (Huang et al., 2024). The excellent performance of irregular surgical cavity coverage makes its clinical application prospect very wide, and it has become a hotspot of research in the field of postoperative tumor treatment in recent years.

2.3. Sustained and controlled release of therapeutic substances

Injectable in situ-forming hydrogels have a long retention time in the tumor resection area after injection and have slow-release properties, which ensures proper local drug concentration while reducing the possible toxic side effects caused by high drug concentration (Dong et al., 2021). The addition of sensitive agents or specific structural modifications to the hydrogel system allows the hydrogel structure to contract and expand reversibly under certain external stimuli (e.g. pH (Suhail et al., 2022), light (Raman et al., 2020), near-infrared (NIR) (Liang et al., 2019; Liu et al., 2019), alternating magnetic field (AMF) (Fisher et al., 2020), ultrasound (Yildirim et al., 2019), temperature (Koga et al., 2020), enzymes (Zhao et al., 2020), electric field and ionic strength, etc.), thus achieving responsive drug release (Zong et al., 2022). For example, injectable thermosensitive hydrogel encapsulating drug-loading nanoparticle is warmed by near-infrared light, which in turn induces the release of therapeutic agents from the hydrogels (Jia et al., 2020). Hydrogel is prepared by combining phase change nanoparticles and alginate solution for ultrasound-responsive local delivery of tranilast and long-term retention (Cao et al., 2024). OE peptide hydrogels exhibit good drug pH-responsive release behavior (Liu et al., 2022b). Therefore, the hydrogel can be personalized according to different anti-tumor needs.

2.4. Promotes postoperative tissue reconstruction

In addition to improving therapeutic efficacy, hydrogel has shown great potential for tissue reconstruction and has been widely applied in tissue engineering. Tissue cell proliferation and remodeling are key to wound healing, mainly involving fibroblast proliferation, angiogenesis and collagen deposition (Guan et al., 2022). Co-delivery of chemotherapeutic drugs mixing with hemostatic, anti-inflammatory and antibacterial materials and growth factors in hydrogel can promote fibroblast proliferation and angiogenesis at the tumor resection sites. The excellent moisture retention and permeability of hydrogel can also provide a biomechanically supported three-dimensional microenvironment for cell proliferation and migration, which can further accelerate wound healing after surgery (Zhang et al., 2021c). For example, Injectable thiolated chitosan hydrogel can be used as a wound filler for tissue reconstruction (Li et al., 2021). Quaternized polyglutamic acid hydrogel has broad-spectrum antibacterial ability and can be used to repair tissue defects after Melanoma (Xu et al., 2020a). In addition, the hydrogel is similar in structure to the extracellular matrix (ECM) and can absorb wound tissue exudate to relieve pain, forming a protective layer to isolate the wound tissue from the external environment for preventing inflammatory reactions and bacterial infections.

3. Matrix materials

Injectable in situ-forming hydrogels are usually composed of different monomers such as natural polymers, synthetic polymers and low-molecular-weight gelators, and the typical structures of the monomers are shown in Figure 2. The different matrix materials endow hydrogels with unique biocompatibility, biodegradability, mechanical strength, porosity, and therapeutic agent release properties. Hydrogel precursor solutions loaded with multiple therapeutic agents form hydrogels by physical or chemical crosslinking after injection at the site of tumor removal (Figure 3). The following section focuses on the different matrix materials for the preparation of injectable in situ-forming hydrogels and their properties (Table 1).

Figure 2.

The typical classification of hydrogel matrix materials and structures of representative polymers.

Figure 3.

Gelation principle for injectable in situ hydrogel formation.

Table 1.

List of some matrix materials for the preparation of injectable in situ-forming hydrogels.

Type	Matrix materials	Gelling mechanism	Advantages	Disadvantages	Ref.
Natural polymer	Chitosan, β-GP	Crosslinking by anionic electrostatic attraction and response to temperature	Injectable; thermosensitive; good biocompatibility;	Batch variance; uncontrollable release rate; poor mechanical property	(Chen et al., 2022b) (Saeednia et al., 2019)
	Alginate	Crosslinking by electrostatic attraction of opposite charges	Injectable; good biocompatibility; in situ cross-linking with Ca2+	Limited mechanical strength and stability	(Shen et al., 2022) (Hwang et al., 2022)
	Fibrin	Crosslinked by thrombin	Injectable; hemostatic; high tissue adhesion	Poor mechanical properties; degradation is not controllable	(Zhang et al., 2019) (Zhou et al., 2024) (Zhu et al., 2024)
	Hyaluronic acid	Cross-linking by complexation action and response to light	Injectable; non-immunogenic; well biocompatible	Limited mechanical strength and stability; non-controllable release	(Byun et al., 2023) (Wang et al., 2022a) (Zhuang et al., 2020)
	Cellulose and its derivatives	Crosslinking by hydrogen bonding and hydrophobic interaction	Injectable; thermosensitive; anti-adhesion; biodegradable	Limited mechanical strength; non-controllable release	(Zhang et al., 2014) (Chang et al., 2022) (Chen et al., 2019)
Synthetic polymer	PNIPAm	Crosslinking by hydrogen bonding and response to temperature	Thermosensitive; Strong mechanical strength	Slow gelation rate; non-degradable; poor biocompatibility;	(Li et al., 2018) (Fan et al., 2022a)
	P407	Crosslinking by hydrogen bonding and hydrophobic interaction	High porosity; strong mechanical strength; excellent viscoelasticity and self-healing ability	Poor biocompatibility; poor adhesion, long in-situ gelation times; excessive release rates	(Zhao et al., 2023) (Turabee et al., 2019) (Fan et al., 2022) (Su et al., 2023)
	PLGA-PEG-PLGA	Crosslinking by hydrophobicity and response to temperature	Injectable; thermosensitive	Poor adhesion; poor biocompatibility	(Gu et al., 2022)
	PEG-PCL	Crosslinking by hydrophobicity and response to temperature	Thermosensitive; biodegradable	Poor adhesion; poor biocompatibility	(Deng et al., 2019)
	PDLLA-PEG-PDLLA	Crosslinking by hydrophobicity and response to temperature	Thermosensitive; biodegradable	Poor adhesion; poor biocompatibility	(Chen et al., 2023)
Proteins and peptides	Oligopeptide	Crosslinking by reversible chemical bonding and electrostatic interactions	Injectable; self-synthesized	Expensive; poor amino acid stability; difficult peptide purification	(Zhang et al., 2021b)
	Collagen	Crosslinking by reversible chemical bonding and electrostatic interactions	Injectable; self-assembled; strong mechanical property	Expensive; poor amino acid stability; difficult peptide purification	(Xing et al., 2016)
	melittin-(RADA)6	Crosslinking by reversible chemical bonding and electrostatic interactions	Injectable; self-assembled	Expensive; difficult peptide purification	(Dai et al., 2020)
	Human serum protein	Crosslinking by reversible chemical bonding and electrostatic interactions	Injectable; rapid gelation	Expensive; poor amino acid stability; difficult peptide purification	(Gačanin et al., 2017)

3.1. Natural polymers

Natural polymers exhibit outstanding biocompatibility and biodegradability (Reddy et al., 2021). In addition, natural polymers have an abundance of bindable functional groups in their polymer chains. Natural polymers commonly used for the preparation of injectable in situ-forming hydrogels include Chitosan (CS), Alginate (ALG), Fibrin (FI), Hyaluronic acid (HA), Cellulose and its derivatives. However, the poor stability and mechanical properties limit the wide application of these biomaterials. It seems to be an inevitable trend for researchers to work on optimizing the properties of the hydrogel by making appropriate adjustments.

3.1.1. CS

CS is a linear polysaccharide formed by the deacetylation of chitin and is one of the most commonly used materials for the preparation of natural hydrogel (Petroni et al., 2023). CS itself is not temperature-sensitive and can show good temperature sensitivity after modification or combination with excipients (Zeng et al., 2019; He et al., 2020). By blending CS with β-glycerophosphate (β-GP), the amino group on CS is combines with the phosphate of β-glycerophosphate through electrostatic interaction to form a gel (Fathi et al., 2019; Zheng et al., 2019); or by grafting hydrophobic polymers, the hydrophobic interaction on the polymer chain is enhanced with increasing temperature, resulting in gel formation. Chen et al. (2022b) prepared a temperature-sensitive hybrid hydrogel composed of CS, gelatin and β-GP, which was injected into the excisional cavity and gelated at physiological temperature to form a hydrogel with a stable structure. Saeednia et al. (2019) doped methotrexate-loaded carbon nanotubes into thermosensitive and injectable hydrogels made from CS and β-GP, showing that the incorporation of the carbon nanotubes resulted in a strong viscosity and mechanical strength of the hydrogels.

3.1.2. ALG

ALG is a natural polysaccharide compound derived from brown algae with good biocompatibility and degradability, as well as the unique property of cross-linking with divalent cations to form gels (Zhang et al., 2021a). In the presence or addition of Ca²⁺, the negatively charged ALG and Ca²⁺ crosslink under the electrostatic complexation of opposite charges to form a hydrogel, which is a convenient and rapid gelation process and does not produce any toxic substances (Zhang & Zhao, 2020). Shen et al. (2022) prepared ALG-based injectable hydrogel loaded with SPIIN (NIR-II absorbent) and CpG (immune adjuvant), and the precursor mixture solution formed by simple mixing of ALG with SPIIN and CpG was injected into the tumor resection site, where the hydrogel was formed in situ by interacting with Ca²⁺ in the tumor microenvironment. The hydrogel can serve as an excellent carrier for CpG, overcoming the problems of low CpG cell uptake, easy degradation and damage, insufficient content in the tumor area, and short residence time, and enhancing the depth of NIR laser penetration, thus effectively inhibiting breast cancer tumor recurrence and metastasis after surgery. However, ALG also has the limitation that the hydrogel formed by cross-linking ALG with divalent cations has poor mechanical properties and soft texture, which is not suitable for tumor treatment in weight-bearing areas of the body (Ahmad Raus et al., 2021). To overcome this problem, researchers have successfully formed stronger ALG composites by incorporating various materials into the ALG gel system. Hwang et al. (2022) prepared an injectable in situ hydrogel crosslinked with ALG and collagen and loaded with ICG (photosensitizer) and polyI:C (immune agonist). Collagen is an abundant protein in animals, and the cross-linking of ALG and collagen effectively improves the mechanical strength of the hydrogel system, allowing rapid gelation and gel formation after in situ tumor injection. Meanwhile, the hydrogel effectively overcomes the problems of rapid degradation and poor stability of ICG in vivo (Figure 4).

Figure 4.

Characterization of the thermally responsive hydrogel (TRG). Reproduced with permission from reference (Hwang et al., 2022). Copyright 2022, Journal of Nanobiotechnology.

3.1.3. FI

Fibrin is composed of fibrinogen, a soluble protein from the liver that has excellent biocompatibility and biodegradability and is widely used in regenerative medicine (Al Enezy‐Ulbrich et al., 2020). Fibrin is cleaved by thrombin to form fibrinogen, which subsequently crosslinks to form hydrogel, an in situ gelling property that allows it to be used as a carrier for antitumor drugs and as a wound healing system (Ogunnaike et al., 2021). Fibrin hydrogel has great potential in the treatment of tumor recurrence after surgery, especially in the treatment of hepatocellular carcinoma after surgery. Zhang et al. (2019) developed a fibrin hydrogel loaded with the therapeutic agents CTX and aPDL1. The prepared hydrogel allows the sequential release of the therapeutic agents to maximize the synergistic anti-tumor effect at the tumor resection site. However, the poor mechanical properties of fibrin hydrogels limit their wide application (Gila-Vilchez et al., 2023). To avoid this, researchers have combined fibrin hydrogels with different natural or synthetic polymers to obtain composite hydrogels with stronger mechanical properties (Sanz-Horta et al., 2023). Zhou et al. (2024) constructed an injectable hydrogel with high tissue adhesion by mixing fibrin and alginate. Fibrin and alginate could be triggered to self-assemble by thrombin and calcium ions, respectively, to form a high-strength and stable interacting gel network, and their loaded therapeutic agents were released with the degradation of the hydrogel. Zhu et al. (2024) developed a crosslinked nanoparticle composite fibrin hydrogel for the prevention of surgical bleeding and recurrence of hepatocellular carcinoma. The incorporation of magnesium carbonate nanoparticles endowed the fibrin hydrogel with excellent mechanical properties and stability.

3.1.4. HA

HA is a naturally occurring acidic mucopolysaccharide composed of D-glucuronic acid and N-acetylglucosamine, a component of ECM, with superior hydrophilic and degradable properties (Bayer, 2020). The HA chain contains hydroxyl, carboxyl and acetylamino sites that can be easily chemically modified, and hydrogels can be formed by physical or chemical crosslinking when HA is modified or mixed with other substances (Trombino et al., 2019). Leng et al. (2021) prepared an injectable in situ-forming hydrogel loaded with PTX nanoparticles and Epirubicin from HA, which has non-immunogenic and good biocompatibility and can significantly enhance the aqueous solubility of chemotherapeutic drugs. Byun et al. (2023) injected a solution of hyaluronic acid-tyramine conjugate in situ to form a hydrogel under irradiation with cold atmospheric plasma. The hydrogel has a network structure that supports sustained release of the therapeutic agent. Wang et al. (2022a) developed a photo-crosslinked hydrogel network consisting of thiolated HA and methacrylated F127. The hydrogels showed good mechanical properties, and crosslinked hydrogels with complete coverage of the tumor resection site could be obtained in a short time by photocatalytic methods. HA is present in the body for a short period due to its high water-absorbent properties and easy degradation by enzymes (Li et al., 2022c). Zhuang et al. (2020) prepared an in situ forming hydrogel based on a Schiff base reaction using aldehyde hyaluronic acid and carboxymethyl chitosan. The gel not only completely filled the breast cancer surgical excision cavity but also had strong mechanical strength to support the breast.

3.1.5. Cellulose

Cellulose is a class of polysaccharides consisting of D-glucose units, and cellulose derivatives are biomolecules linked by β-1,4-glycosidic bonds on cellulose, which have good temperature sensitivity (Vinatier et al., 2009). The gelation mechanism lies in cellulose and its derivatives contain a large number of hydrogen bonds, so that its hydrophobic groups at low temperatures can only be simple entanglement without aggregation, after the temperature rises, the hydrogen bonds are destroyed and caused by dehydration, cellulose and its derivatives to enhance the intermolecular hydrophobicity and the formation of hydrogel, which is representative of the polymers are carboxymethyl cellulose (CMC) and hydroxypropyl methylcellulose. Zhang et al. (2014) prepared thermosensitive hydrogels with anti-adhesion properties based on MC as the gel matrix with the addition of polyethylene glycol (PEG), CMC and chitosan sulfate (CS-SO₃). The gel obtained a gelation temperature below body temperature by adjusting the concentration of each component, while the addition of PEG, CMC, and CS-SO₃ conferred anti-adhesion properties and enhanced the mechanical strength of the hydrogel. Chang et al. (2022) used oxidized carboxymethyl cellulose (CMC-CHO) as matrix material and added the thermosensitive copolymer P (NIPAm-co-AH) to prepare thermo-responsive biodegradable hydrogels, which were more regulated by the specific gravity of P (NIPAm-co-AH)/CMC-CHO, with a lower critical solution temperature (LCST), and the resulting hydrogels had good bio-adhesion and bio-degradation properties. Chen et al. (2019) used hydrazide-modified CMC and aldehyde-modified CMC as precursors for cellulose-based injectable hydrogels, which were formed by co-extruding the two hydrogel precursor solutions through a syringe, mixing them, and then cross-linking them by Schiff base reaction.

3.2. Synthetic polymers

Compared to natural polymers, synthetic polymers can be modified to endow them more functionality and stimulus responsiveness, and have a wide range of applications. However, synthetic hydrogels tend to have poor bioactivity compared to natural hydrogels due to the chemical cross-linking agents required to synthesize the polymers and the nature of the materials used to synthesize the polymers themselves. In previous studies, common synthetic polymers used to prepare injectable in situ-forming hydrogels include poly(N-isopropylacrylamide) (PNIPAm), poly(ethylene glycol diacrylate) (PEGDA), poloxamer (F127), and poly(ethylene glycol) polyester copolymers, etc., which are often combined with each other or with other substances to form composite hydrogels with desired properties.

3.2.1. Poly(N-isopropylacrylamide)

PNIPAm has a unique heat-sensitive property, which makes PNIPAm widely used for the production of injectable in situ-forming hydrogels. The gelling mechanism of PNIPAm is that it contains both hydrophilic amide group (–CONH–) and hydrophobic isopropyl group (–CH(CH₃)₂–). When the temperature is lower than LCST, the internal hydrogen bonding of PNIPAm is strong and it is in solution; when it is higher than the LCST, the internal hydrogen bonding of PNIPAm is destroyed, and hydrophobicity is strengthened and it is in gel state (Ansari et al., 2022). However, hydrogels prepared based on PNIPAm suffer from slow and non-degradable gelation rates, as well as poor mechanical properties, which greatly limit their application. It is often modified by block copolymerization, grafting, blending and interpenetrating network structure to improve its properties (Handa et al., 2022). Li et al. (2018) developed thermosensitive hybridized hydrogels based on PNIPAm and acrylolsobutyl polyhedral oligomeric silsesquioxane (MAPOSS), and the mechanical strength of the hydrogels was enhanced by the incorporation of rigid MAPOSS in the PNIPAm network (Figure 5). Fan et al. (2022a) blended poly(N-isopropylacrylamide) with soluble starch to form a polymer and a composite thermosensitive hydrogel with Lugol’s iodine solution, which was injected and then transformed to form a hydrogel by a sol-gel phase transition at 35 °C.

Figure 5.

Schematic of preparation of PNIPAM-MAPOSS hybrid hydrogels. Reproduced with permission from reference (Li et al., 2018). Copyright 2018, Polymers.

3.2.2. Poloxamer

Poloxamer is a heat-sensitive polymer that is a triblock copolymer (PEO-PPO-PEO) consisting of two hydrophilic poly(ethylene oxide) (PEO) blocks and a hydrophobic poly(propylene oxide) (PPO) (Xu et al., 2020b). Based on hydrogen bonding and hydrophobic interaction, the PPO blocks are dehydrated when the temperature of the poloxamer solution is increased, and the hydrophobic interactions are enhanced, resulting in aggregation of the solution into micelles, followed by further gelation to form a hydrogel (Russo & Villa, 2019). Poloxamer 407 (P407) and Poloxamer 188 (P188) are widely used hydrogel matrix materials. Zhao et al. (2023) prepared a P407 hydrogel (PFRM) co-dopped with ropivacaine (PFR) and the TLR7 agonist imiquimod, which had excellent thermosensitive properties. The hydrogel is a free-flowing liquid at 4 °C and forms a hydrogel at 37 °C. However, hydrogels prepared with poloxamer suffer from poor adhesion, long in situ gelation time, and fast release rate, so they are usually used in combination with bio-adhesive agent, strength-enhancing excipients, or compounds from the same family as poloxamer (Chen et al., 2022a). Turabee et al. (2019) used N,N,N-trimethyl chitosan in combination with the thermosensitive polymer P407, and TMC increased the porosity and mechanical strength of the gel network and improved the release behavior of the drug loaded in the hydrogel. Fan et al. (2022b) prepared paclitaxel nanocrystalline thermosensitive hydrogel by applying both P407 and P188 and introducing a bio-adhesive agent, carbomer 974 P. The hydrogel has a clear and regular network structure with good viscoelasticity and self-healing ability, and it can be gelatinized in several minutes at 33.1 °C. Su et al. (2023) prepared PTCPP thermosensitive hydrogels with P407 and P188 as temperature-sensitive matrices and CS as antimicrobial hydrogel matrix and bio-adhesive with excellent adhesion and mechanical properties.

3.2.3. PEG-based block copolymers

PEG can form block copolymers with polyesters (e.g. polycaprolactone (PCL), poly(D,l-lactide) (PDLLA), poly(lactide-co-glycolic acid) (PLGA), etc.), which form spherical micelles in aqueous solution with a core-shell structure and have good temperature-sensitivity (Turabee et al., 2018; Yu et al., 2019b). The gelling mechanism lies in the presence of hydrophilic and hydrophobic groups in the polymer chain. When the temperature is lower than the phase transition temperature, the polymer self-assembles to form micelles in the form of a hydrophobic polyester core and a hydrophilic PEG outer core and is in a solution state. After the temperature is increased, the hydrophilic shell is dehydrated the interaction force between the hydrophobic groups is increased, and the micelles aggregate to make the solution form a gel (Zhou et al., 2021). Gu et al. (2022) produced a thermosensitive injectable hydrogel using PLGA-PEG-PLGA triblock copolymer as a matrix material, which was a highly fluid liquid at room temperature, turned into a gel at about 32 °C and stayed in a gel state at a body temperature of 37 °C. Deng et al. (2019) prepared a thermosensitive biodegradable hydrogel using an amphiphilic polymer assembled with PEG and biodegradable PCL, which can form a gel at physiological temperature (at 37 °C) and has good mechanical properties. Chen et al. (2023) prepared a biodegradable temperature-sensitive hydrogel based on PDLLA-PEG-PDLLA triblock copolymer, and the PLEL hydrogel could be simply mixed at room temperature and gelatinized to form an in situ gel at body temperature.

3.3. Proteins and peptides

Proteins and peptides have good biocompatibility, biodegradability, self-assembly properties, and tunable mechanical properties (Xing et al., 2019). Hydrogels based on proteins and peptides are more similar to ECM and they are more biocompatible than synthetic polymers (Mathew et al., 2018). Protein hydrogels can be made from proteins or mixtures of proteins combined with other polymers. Protein hydrogels themselves have good self-assembling properties and form in situ hydrogels through reversible chemical bonding and electrostatic interactions after injection (Giang Phan et al., 2019). At the same time, specific peptide sequences or peptide ligands can be linked by physical or chemical crosslinking to further improve protein hydrogel responsive gelation ability (Li et al., 2020). However, peptide and protein hydrogels are relatively more expensive compared to polymers, while two major challenges need to be overcome during hydrogel synthesis, poor amino acid stability and difficulty in peptide purification. Zhang et al. (2021b) designed a self-synthesized oligopeptide hydrogel as a drug reservoir for CXCL10 and THINR. After injection via syringe, it was transformed from a solution to a hydrogel, and the drug was continuously released from the hydrogel. Xing et al. (2016) combined AuCl₄⁻ ions with collagen to produce self-assembled collagen-gold ion hybrid hydrogels that could be rapidly gelatinized after injection. The negatively charged ions can act as cross-linking agents of the hydrogels, which can enhance the mechanical strength of the hydrogels. Dai et al. (2020) designed a series of hybrid peptide hydrogels with different RADA self-assembling sequences based on melittin-(RADA)₆. Melittin is the main peptide component of bee venom with anti-tumor effects, and RADA is an amphiphilic self-assembling short peptide, and the prepared heterogeneous peptide hydrogels have the best gel-forming ability and in vitro anti-tumor effects. Gačanin et al. (2017) made an injectable hybridized hydrogel by combining human serum proteins and DNA residues, which induced rapid gelation of the hydrogel by DNA self-hybridization and thus by DNA self-hybridization without the use of any cross-linking agent.

4. Application in postoperative treatment of tumors

Clinically, tumors are divided into non-solid and solid tumors. Solid tumors mainly form a mass locally, which can be examined by X-ray, CT scan, ultrasound, and mass response. In recent decades, with the rapid development of biomedical technology, new tumor therapies such as photothermal therapy (PTT), magnetothermal therapy (MHT), photodynamic therapy (PDT), and chemodynamic therapy (CDT) have attracted much attention due to their unique advantages such as high specificity, low invasiveness, and precise spatial selectivity, etc. The combination of two or even more therapies tends to show better anti-tumor recurrence inhibitory effect and reduce side effect (i.e. ‘1 + 1 > 2’). We collected solid tumors with high incidence in different cells, tissues or organs throughout the body, and derived the application of injectable in situ forming hydrogels based on them in the postoperative treatment of different types of tumors, and listed some representative examples of their application in the postoperative treatment of tumors (Table 2).

Table 2.

Recent studies of hydrogels directedly applied in localized postoperative tumors treatment.

Cancer model	Host material	Therapeutic agents	Fuction	Ref.
Brain cancer	PPS60, T lipids	TMZ	Avoiding the blood-brain barrier; drug dual response (MMPs and ROS) release	(Zhu et al., 2021)
	PLGA-NPs, CS, gelatin, β-GP	TMZ, BCNU	Drug ROS response release; dual chemotherapeutic agents synergize against tumors	(Chen et al., 2022b)
	diCPT-iRGD	CPT, STING agonist	Combined chemotherapy and immunotherapy; prolonged drug release	(Wang et al., 2020a)
Skin cancer	LPFEG	PDA-NPs, DOX	Photothermal therapy; achieving thermally triggered drug release; reducing inflammatory response; promoting wound healing	(Wang et al., 2022b)
	GelMA	PCD-Fe3+	Photothermal therapy; reduces inflammatory response; promotes wound healing	(Luo et al., 2022)
Bone cancer	GelMA, Odex	MMT-Sr, DOX,PVP-NPs	Combined chemotherapy and photothermal therapy; promotes bone regeneration	(Liu et al., 2023)
	Gel, OCS	MTX-SS-MBGN	Drug dual response (PH and GSH) release; promotes bone regeneration	(Cai et al., 2022)
	HF, GelMA	Mel	Sequential release of different concentrations of Mel from the core-shell structure; anti-tumor and bone regeneration promotion	(Huang et al., 2023b)
Breast cancer	MC	PLGA MPs, IR 820	Photothermal therapy; breast cavity fillers; promoting breast reconstruction	(Yang et al., 2021)
	PEGDA, SA	125I-GNR-RGDY	Combined photothermal and radiotherapy; improving tumor hypoxic microenvironment; preventing bacterial infection	(Wu et al., 2022)
	Collagen, silk fibroin	thrombin	Heat-triggered release of thrombin; Inhibiting neovascularization	(Wang et al., 2021b)
Liver cancer	OS, gel	MBGNs, NK cells	Neutralization of acidic tumor microenvironment; drug pH response release; hemostasis	(Cheng et al., 2022b)
	NDP	FG	Magnetothermal therapy; hemostasis; transarterial embolization	(Yan et al., 2022)
Colorectal cancer	P407, P188, ALG	5-FU	Rapid gelation; sustained drug release	(Al Sabbagh et al., 2020)
	Alginate	Bi2S3 NPs, TPZ	Combined phototherapy and chemotherapy; low oxygen concentration triggered drug release; radiation sensitization	(Luo et al., 2021b)

4.1. Brain cancer

Glioblastoma (GBM) is the most common malignant primary tumor of the brain, with a higher incidence in middle-aged adults (McKinnon et al., 2021). Adjuvant chemotherapy after surgical resection is a common clinical tool to inhibit the recurrence of GBM after surgery, but the special location of GBM growth. Deep GBM and the blood-brain barrier (BBB) always affect the delivery of chemotherapeutic drugs, resulting in a poor effect of chemotherapy (Saito, 2021). Meanwhile, the immunosuppressive tumor microenvironment (TME) in the postoperative period makes the autoimmune role of GBM patients poor, accompanied by the strong invasiveness of the residual tumor cells, resulting in GBM recurrence often occurring surely, which makes the average survival of GBM patients only 12–15 months (Wang et al., 2021a; Mitre et al., 2022). Gliadel®Water is an FDA-approved local delivery agent for postoperative GBM, which can effectively improve chemotherapeutic efficacy and prolong the survival of GEM patients by avoiding the BBB for direct chemotherapeutic drug delivery at the tumor resection site (Fisher & Adamson, 2021; Iuchi et al., 2022). However, such formulations often release chemotherapeutic agents in uncontrolled bursts, and the high concentration of chemotherapeutic agents is prone to damage normal tissues and drug resistance, and may cause infections and wound-healing-related complications, which make the therapeutic efficacy unsatisfactory (Nishikawa et al., 2021). In recent years, hydrogels have been developed as carriers for chemotherapeutic agents, and injectable in situ-forming hydrogels are particularly suitable for postoperative treatment of GBM. Injecting the precursor solution of the hydrogel into the deep GBM resection cavity can rapidly form the hydrogel, which can then be used to slowly release the drug in the resected area of the tumor (Bastiancich et al., 2016; Zhang et al., 2024a). Zhu et al. (2021) designed a drug-loaded hydrogel (T/PPs) with dual response properties to reactive oxygen species (ROS) and matrix metalloproteinases (MMPs) for local delivery of the chemotherapeutic drug temozolomide (TMZ). Injecting T/PPs into the surgical cavity, which avoids the BBB and responds to high concentrations of ROS and MMPs for precise drug delivery (up to 89.3% release), effectively inhibits the proliferation of residual GBM cells after surgery and prolongs the survival of mice (up to 50.5 days) (Figure 6).

Figure 6.

The T/PPS + TMZ hydrogel reduced recurrence in orthotopic U87 and C6-GFP-Luci tumor resection model mice. Reproduced with permission from reference (Zhu et al., 2021). Copyright 2021, Journal of Nanobiotechnology.

Single administration of anti-tumor relapse treatment period is long and prone to drug resistance and cytotoxicity. This will not only reduce the sensitivity of tumor cells to chemotherapeutic drugs or even destroy normal cells, ultimately leading to poor chemotherapy results. Therefore, the combination and efficient release of multiple drugs in the hydrogel is essential to achieve synergistic effects in local therapy for faster and more efficient multiple antitumor effects. Chen et al. (2022b) used PLGA nanoparticles (PLGA NPs) to encapsulate the chemotherapeutic drugs TMZ and carmustine (BCNU), and then loaded the drug-loaded PLGA NPs into a thermosensitive CS-based gel. The cross-linked gel network can firmly immobilize the drug-carrying PLGA NPs and stably release chemotherapeutic drugs, realizing dual chemotherapeutic synergistic anti-tumor effects. Wang et al. (2020a) designed supramolecular hydrogels spontaneously assembled from hydrophilic peptides for the co-delivery of camptothecin as a chemotherapeutic agent and STING agonist as an immunotherapeutic agent for combined chemotherapy and immunotherapy. The results of in vivo experiments showed that the designed hydrogel could exist for a long time and release drugs into the brain parenchyma, inhibiting tumor recurrence and prolonging the survival of mice.

4.2. Skin cancer

Melanoma, a malignant tumor formed by the malignant transformation of melanocytes, is one of the most common skin cancers, and its incidence and lethality have been increasing over the past decade (Ahmed et al., 2020; Leiter et al., 2020). Postoperative adjuvant radiotherapy and chemotherapy in melanoma patients still have a high recurrence rate, and the short half-life of the drugs and inflamed and infected wounds often lead to a poor prognosis for patients. Since melanoma is located at the skin site, near-infrared (NIR)-based PTT offers tremendous advantages in postoperative melanoma treatment. Injectable in situ forming hydrogels can easily encapsulate photothermal agents (PTA) and multiple therapeutic agents for excellent PTT multimodal combination therapy (Liu et al., 2024a). Wang et al. (2022b) developed a biomimetic supramolecular hydrogel for delivery of polydopamine nanoparticles (PDA-NPs) and doxorubicin (DOX) for combined chemotherapy (CT) and PTT treatment using chiral L-phenylalanine (LPFEG). LPFEG hydrogel triggers local warming and release of therapeutic agents under NIR irradiation to rapidly remove residual tumor cells and free radicals. The results of in vivo experiments showed that CT-PTT combination therapy could effectively inhibit postoperative tumor growth. In vivo experimental results showed that LPFEG hydrogel could effectively inhibit the growth of postoperative tumors by CT-PTT combination therapy. Luo et al. (2022) prepared a citrate-iron hydrogel scaffold (GPDF) with double-network using gelatin methacrylic anhydride (GelMA) as the host material in the presence of polycitrate-dopamine (PCD) and Fe³⁺ ions. GPDF hydrogel exhibits good photothermal and antioxidant properties. Highly similar to ECM, GPDF hydrogel fills tumor irregular postoperative wounds and provides a moist environment that promotes wound tissue regeneration and healing by attenuating the inflammatory response and promoting angiogenesis. The results of in vivo experiments showed that the wounds of mice in the GPDF + NIR group were completely healed by day 14 with no tumor recurrence.

4.3. Bone cancer

Osteosarcoma (OSA) is the most common primary bone tumor with high morbidity and mortality, occurring mostly in children and young adults between the ages of 10 and 30 years old (Meltzer & Helman, 2021). Surgical resection (e.g. limb-sparing surgery) combined with adjuvant chemotherapy is the standard of care for the treatment of OSA, but strongly aggressive residual tumor cells and unavoidable extensive bone damage lead to a poor prognosis for patients (Li et al., 2022a). Therefore, it is important to develop novel therapeutic approaches that provide both anti-tumor therapy and an osteogenic microenvironment to promote bone repair (Hayashi & Tsuchiya, 2022). Liu et al. (2023) designed a dual gel network hydrogel for the co-delivery of DOX and polyvinylpyrrolidone nanoparticles (PVP-NPs). The results of in vivo antitumor experiments showed that hydrogel could exert excellent CT-PTT synergistic effects to promote tumor cell apoptosis and inhibit tumor recurrence. This multifunctional hydrogel has the functions of chemotherapy, photothermal therapy and promoting bone regeneration, and has shown great application prospects in the treatment of OSA. Cai et al. (2022) designed injectable pH-responsive GO hydrogels for precise delivery of mesoporous bioactive glass nanoparticles (MTX-SS-MBGN) loaded with chemotherapeutic drugs. During the pre-implantation treatment period, GO hydrogel releases MTX-SS-MBGN in response to acidic pH, and MTX-SS-MBGN further responds to acidic pH and glutathione (GSH) for precise delivery of MTX at the target site. GO hydrogel regulates the TME by depleting H⁺ and GSH, which in turn induces tumor metabolism disruption and reverses drug resistance to achieve the efficient antitumor effect.

The multiple roles of melatonin (Mel) in antitumor and promoting bone reconstruction have attracted much attention and have shown great potential for application in the postoperative treatment of OSA. Studies have shown that high concentrations of Mel can significantly inhibit tumor growth, while low concentrations of Mel can promote bone formation (Lu et al., 2018; Liu et al., 2021). Inspired by the hierarchical differential release of Janus, Huang et al. (2023b) used HAMA and F127 (HF) loaded with low concentrations of Mel as the core layer of hydrogel (Mel@HF), and GelMA loaded with high concentrations of Mel as the shell layer of hydrogel (Mel@Gel), to design a hydrogel with a core-shell structure (Mel@Gel/Mel@HF). Differences in degradation based on the core-shell structural matrix can achieve differential release of melatonin during different treatment stages after OSA, effectively removing residual tumor cells and promoting bone repair (Figure 7).

Figure 7.

Mel@Gel/Mel@HF accelerates the healing of bone defects in vivo. Reproduced with permission from reference (Huang et al., 2023b). Copyright 2023, ACS Applied Materials & Interfaces.

4.4. Breast cancer

Breast cancer is the most common malignant tumor among women all over the world, and about 7% of breast cancer patients experience in situ recurrence after surgical resection (Corso et al., 2018). Surgical resection inevitably causes normal tissue loss, inflammation and bacterial infection leading to poor recovery and prolonged recovery period, increasing the chance of tumor recurrence (Wu et al., 2018). Therefore, there is a need to achieve both anti-tumor recurrence and repair of breast defects in postoperative breast cancer treatment (Jin et al., 2021). Drug-loaded hydrogels are not only effective against breast cancer recurrence to improve patient survival, but also can be used as postoperative breast fillers and to facilitate breast reconstruction to improve patient acceptance of surgery due to their strong mechanical properties (Abdul-Al et al., 2020). In response to the needs of postoperative patients, researchers have extensively studied the use of hydrogels as postoperative breast fillers in breast reconstruction (O’Halloran et al., 2018; Donnely et al., 2020). Yang et al. (2021) prepared a thermoresponsive hydrogel for delivery of the photothermal agent indocyanine green (IR820) from the natural polymer methylcellulose (MC). The hydrogel could firmly fix IR820, allowing it to accumulate in large quantities at the tumor resection site and exert a stable PTT antitumor effect (Figure 8).

Figure 8.

The scheme of hydrogel platform (IR820/Mgel) preparation and its applications for preventing post-surgical tumor recurrence and improving breast reconstruction. Reproduced with permission from reference (Yang et al., 2021). Copyright 2021, Journal of Nanobiotechnology.

The combined treatment modality of PTT and RT can compensate for the penetration depth of NIR and synergistically improve the therapeutic efficacy of tumor therapy, offering a great potential treatment strategy for preventing breast cancer recurrence and wound infection. Wu et al. (2022b) designed dual-network composite hydrogel, which can trigger gelation in response to the tumor microenvironment and heat, for the delivery of ¹²⁵I-labeled gold nanorods (¹²⁵I-GNR-RGDY) that act as both PTA and RT therapeutic agents. The hydrogel precursor solution was injected into the breast tumor resection cavity, which induced the formation of a dual polymer network under the effect of high temperature and endogenous Ca²⁺ around the tumor after NIR light irradiation. This dual polymer network not only has strong mechanical strength, but also firmly fixes ¹²⁵I-GNR-RGDY, which helps to precisely achieve the combined antitumor therapy of PTT and brachytherapy, and effectively prevent the local recurrence of breast cancer (Figure 9).

Figure 9.

Schematic illustration of the fabrication of 125I-GNR-RGDY and nanocomposite double-network GPA hydrogel and their theranostic application for inhibition of postoperative breast cancer recurrence and wound infection through synergistic brachytherapy and photothermal therapy. Reproduced with permission from reference (Wu et al., 2022). Copyright 2022, Advanced Science.

Another postoperative treatment strategy is to inhibit breast cancer recurrence and distant metastasis through nutritional deprivation. Blood vessels can provide abundant nutrients to the site of tumor resection, which allows tumor cells to proliferate rapidly and promotes neovascularization after tumor resection. Therefore, nutrient deprivation by rapidly blocking residual blood vessels and inhibiting neovascularization at the site of tumor resection is a promising strategy for postoperative treatment of breast cancer. Wang et al. (2021b) prepared a photo-responsive injectable hydrogel for local delivery of thrombin using collagen and silk fibroin as host materials. After NIR irradiation, the hydrogel could absorb light energy and convert it into heat for controlled delivery of thrombin at the tumor resection site. Thrombin induces thrombosis to promote vascular occlusion and inhibit neovascularization, inducing necrosis of residual tumor cells by permanently blocking nutrient supply.

4.5. Liver cancer

In 2022, hepatocellular carcinoma (HCC) has become the sixth most common cancer in the world and the fourth most common cause of cancer-related deaths, with a high recurrence rate of 50% to 70% at five years after surgery and a low patient survival rate (Yang et al., 2019; Hack et al., 2020; Zhang et al., 2021d). Currently, surgery (hepatectomy and liver transplantation) is the main treatment option for HCC patients, but it is still limited by factors such as postoperative recurrence, intraoperative blood loss, and tissue defects, which lead to a poor postoperative outcome (Sugawara & Hibi, 2021; Vogel et al., 2022). Surgically removed vascular defects cause ischemia, hypoxia, inadequate nutrient supply, and lactate accumulation, which leads to acidic lesion sites (Ding et al., 2021). The acidic immunosuppressive microenvironment is the main cause of immunocompromise and poor treatment with antitumor therapeutic agents in HCC patients. Therefore, hydrogels that can both stop bleeding and modulate the immunoacidic microenvironment have good potential for hepatocellular carcinoma treatment. Cheng et al. (2022b) prepared an injectable viscous hemostatic hydrogel that co-delivered MBGNs as tumor acidity neutralizers and NK cells as immunotherapeutic agents. Hydrogel precursor solution could be injected into the HCC tumor resection site and rapidly form a strongly adherent hemostatic gel. The hydrogel neutralized the tumor acidity and assisted the NK cells in reaching the tumor cells. This combination therapy would be a feasible option to significantly enhance NK cell therapy to inhibit HCC recurrence.

Local thermal therapy is considered a safe method to prevent postoperative cancer recurrence, and magnetic heat therapy (MHT) has been successfully applied in the treatment of clinical malignant tumors (Noh et al., 2017). MHT demonstrates excellent tissue penetration performance in the treatment of deep-seated tumors (e.g. hepatocellular carcinoma) and can achieve reliable tumor killing. Therefore, in situ injectable hydrogels with excellent MHT properties are reasonable and promising candidates for synergistic hemostasis and prevention of recurrence after HCC (Huang et al., 2021; Pan et al., 2021). Yan et al. (2022) prepared an in situ thermal-responsive magnetic hydrogel for the delivery of graphene oxide nanosheets modified with iron oxide nanoparticles using a triblock polymer (NDP) formed by cross-linking of PNIPAm-DA and PEG as the host material. The hydrogel has advantages in hemostasis and vascular embolization, and the nanosheets, when in contact with blood, can rapidly seal wounds to promote blood coagulation and exert highly effective anti-tumor effects after liver cancer surgery, effectively increasing the survival rate of patients (Figure 10).

Figure 10.

Hemostasis behaviors of NDP-FG hydrogel. Reproduced with permission from reference (Yan et al., 2022). Copyright 2022, Nano Letters.

4.6. Colorectal cancer

Colorectal cancer (CRC) is the third most common cancer in the world and the second leading cause of cancer-related deaths (Al-Saraireh et al., 2021). Postoperative adjuvant chemotherapy or radiotherapy is commonly used clinically to prevent CRC recurrence. Despite this, patients with CRC have a high recurrence rate and suffer from multiple postoperative complications that lead to poor quality of life (Luo et al., 2021a). The main problems of poor prognosis of CRC are as follows: (1) Most of the therapeutic agents lack targeting and poor water solubility, which usually leads to relatively low drug concentration at the tumor resection site and a variety of serious side effects, resulting in poor postoperative treatment of the tumor (Fokas et al., 2019); (2) tumor hypoxic microenvironment will make tumor cells more resistant to laser radiation, and radiotherapy will further aggravate the hypoxia level at the tumor resection site, which severely limits the therapeutic efficacy of radiotherapy and chemotherapy; (3) tissue adhesion is a very common and persistent complication after abdominal surgery, which can lead to intestinal obstruction, chronic pelvic pain, and female infertility, etc., which can severely affect patients’ quality of life after surgery. Therefore, localized and precise delivery of chemotherapeutic drugs through hydrogels is a more promising strategy to enhance the therapeutic effects of drugs (Yi et al., 2010). Al Sabbagh et al. (2020) designed a thermosensitive poloxamer-based hydrogel (P407/P188/ALG) for local delivery of the chemotherapeutic drug 5-fluorouracil (5-FU). 5-FU is released by free diffusion, and encapsulation in a hydrogel effectively prolongs its release time and exerts a good antitumor growth effect. Nkanga & Steinmetz (2022) designed a chitosan-based in situ hydrogel for local delivery of cowpea mosaic virus nanoparticles (CPMV NPs) as an immunotherapeutic agent. The results of in vivo experiments showed that the hydrogel could sustain the release of CPMV NPs for up to three weeks, effectively prolonging the immunostimulatory effect and significantly inhibiting after tumor resection (Figure 11). These results suggest that the hydrogel may provide a simple and effective means of local therapeutic agent delivery (Chung et al., 2021).

Figure 11.

CPMV-in-chitosan/GP hydrogel inhibits colon cancer growth in the intraperitoneal (IP) space (n = 5 mice per group). Reproduced with permission from reference (Nkanga & Steinmetz, 2022). Copyright 2022, ACS Biomaterials Science & Engineering G.

RT is often used for postoperative treatment of CRC, and researchers have attempted to improve the sensitivity of RT by sensitizing it with chemotherapy, and combining RT with hypoxia-activating drugs is a therapeutic strategy to safely and effectively inhibit CRC tumor recurrence. Luo et al. (2021b) prepared a novel alginate-based hydrogel loaded with Bi₂S₃ NPs and tirazamine (TPZ). After injection at the tumor surgical site, the released Bi₂S₃ NPs exhibited good radiation sensitization and CT imaging ability, which could be used for tumor detection to effectively eliminate residual tumor cells and inhibit tumor recurrence after CRC surgery.

5. Application in postoperative adjuvant treatment

Surgical removal of tumors is often accompanied by a series of postoperative complications such as tissue damage, bleeding, inflammation, bacterial infections and inter-tissue adhesions, which may be important causes of poor patient prognosis or even treatment failure. Regarding the suitability of injectable in situ-forming hydrogels for postoperative adjuvant treatment of tumors, it is necessary to consider how to alleviate and avoid the occurrence of the above complications. Therefore, researchers have successively developed hydrogel platforms with multifunctional features such as hemostasis, anti-inflammatory and antibacterial properties, tissue repair, anti-adhesion and wound healing, aiming to achieve better and faster postoperative treatment results.

5.1. Hemostasis

The injectable hydrogel can be used as a dressing for wound closure and is particularly effective as an adjuvant treatment for hepatocellular carcinoma (Gong & Li, 2022). Liver tumors are surrounded by abundant blood vessels, which need to be removed during hepatectomy, leading to prolonged operation time due to intraoperative bleeding, and contributing to an increased risk of bacterial infections and metastasis of the cancer cells, while the application of injectable hydrogel can quickly close the wound and stop the bleeding (Yu et al., 2019a). Liang et al. (2021) prepared a hemostatic antimicrobial hydrogel (QH/ZDH) with glycidyl methacrylate-functionalized quaternized chitosan (QCSG), dopamine-modified hyaluronic acid (HA-DA), and hematoporphyrin monomethyl ether-loaded dopamine-modified ZIF-8 (ZDH). QCSG endowed the hydrogel with good coagulation and antimicrobial properties, HA-DA improved the coagulation properties and endowed the hydrogel with good tissue adhesion, and ZDH further improved the antimicrobial properties of the hydrogel. In vivo studies demonstrated that QH/ZDH possessed the effective hemostatic ability and significantly inhibited tumor recurrence after surgery, and this hydrogel provided an effective therapeutic strategy integrating rapid hemostasis and cancer recurrence prevention. In addition, hydrogels provide a highly aqueous environment around the postoperative tumor removal site, keeping the wound moist and thus promoting regeneration of damaged blood vessels (Cai et al., 2024).

5.2. Anti-bacterial infection

Bacterial infection is one of the causes of poor prognosis of tumors (especially skin cancer). When the skin barrier is compromised, bacterial microorganisms can invade the body and easily cause serious bacterial infections, which can hinder wound healing and affect the patient’s recovery (Zhang et al., 2024b). Hydrogel fills the tumor removal site directly and prevents secondary infection damage. In addition, hydrogel as a postoperative filler for bone tumors can cause septic complications if bacterial infection occurs, leading to increased postoperative mortality in patients. Therefore, injectable hydrogels are considered to be an ideal platform to promote wound healing (Liu et al., 2024b). Thanks to the antimicrobial properties of the matrix material itself, Huang et al. (2022) prepared an advanced hydrogel with good injectability and antimicrobial properties by using iron ion-doped polyaniline (PANI(Fe)) and guar gum (GG) as raw materials and using borax as a cross-linking agent. The results of in vivo and in vitro experiments showed that the hydrogel exhibited good B16 cell inhibitory activity (98%) and bacteriostatic activity (97.1%). Meanwhile, the network structure formed by cross-linking could be used as a platform for tissue repair, promoting fibroblast proliferation and angiogenesis, and accelerating wound repair in mice with bacterial-infected wounds. Hydrogels are excellent carriers of therapeutic agents, researchers have loaded antibiotics and antimicrobial agents into hydrogel to obtain superior antimicrobial effects. Wu et al. (2022a) loaded ceftazidime into a hydrogel based on an antimicrobial peptide (DP7 peptide) and oxidized dextran (Odex), which had good dual functions of antimicrobial and wound repair. However, overuse of antibiotics can lead to bacterial resistance, resulting in decreased efficacy (Xiong et al., 2024). Nanosilver is a broad-spectrum antimicrobial material that has been investigated for use against bacterial infection. Chen et al. (2022c) prepared gold nanoparticles and silver nanoparticles encapsulated in carrageenan and further combined with F127 to form a multifunctional hydrogel, which was used to effectively fight against bacterial infections and inhibit tumor recurrence in the absence of chemotherapeutic agents and antibiotics. Over the past few years, chemodynamic therapy (CDT), which produces hydroxyl radicals (OH-) with broad-spectrum antimicrobial activity, has attracted the interest of researchers. Zhang et al. (2020) prepared a CDT-mediated hydrogel that could rapidly remove residual tumor cells in the presence of CDT to avoid bacterial infection and inhibit local tumor recurrence. In summary, the application of antimicrobial hydrogel can effectively prevent bacterial infection, reduce patient pain, and is expected to be a promising solution to improve wound prognosis.

5.3. Anti-inflammatory

Once a bacterial infection occurs, it may cause an inflammatory response in the body, and a prolonged inflammatory response can seriously affect the wound healing process. Therefore, anti-inflammatory therapy is also required in the postoperative treatment of tumors, and the application of hydrogels for anti-inflammatory drug delivery is the most common option. Li et al. (2022b) encapsulated the anti-inflammatory agent Dexamethasone into a hydrogel, which acted as an anti-inflammatory in inflammatory wounds and further initiated an immune response for anti-tumor. Notably, excess ROS activates multiple inflammatory message cascades that impede wound healing. Therefore, therapeutic strategies to balance ROS levels have attracted the interest of researchers. As ROS scavengers, artificial enzymes are considered to be promising alternatives to conventional anti-inflammatory agents, providing longer-lasting anti-inflammatory effects. Tong et al. (2022) introduced Prussian blue as a ROS scavenger and further synthesized hollow nanoparticles loaded with doxorubicin. Injectable hydrogels based on the host-guest interaction between cyclodextrin and adamantane were obtained and mixed with HMPB-Dox. The results of in vivo and in vitro experiments demonstrated that the hydrogel was effective in preventing tumor recurrence and promoting wound healing as a postoperative multifunctional implant.

5.4. Anti-adhesion

Postoperative adhesions are a common complication after abdominal tumor surgery, which may further lead to chronic pelvic pain, infertility, postoperative pain and bowel obstruction (Yuan et al., 2024). Postoperative adhesions require re-treatment or surgery, which not only increases the complexity and risk of the postoperative period, but also slows down the wound healing process, thus affecting the patient’s health and quality of life (Huang et al., 2023a). Hydrogel’s good biocompatibility and biodegradability allow it to be used as a barrier material to physically isolate the tumor resection site from the surrounding tissues, which is currently an effective means of preventing postoperative adhesions (Lu et al., 2024). In recent years, researchers have successfully developed anti-adhesion hydrogel platforms. Chen et al. (2021) designed a supramolecular drug-carrying nanocomposite NCH hydrogel. The NCH hydrogel acts as a barrier material, and simultaneous prevention of postoperative tumor recurrence and abdominal adhesions can be achieved by local minimally invasive drug delivery. Zhou et al. (2023) prepared a hydrogel based on collagen and aldehydeylated polyethylene glycol, which can effectively prevent intraperitoneal adhesions and inhibit tumor growth with minimal side effects. Overall, the development of an injectable in situ hydrogel platform for application at the surgical site could ideally prevent adhesion of the tumor resection site to the surrounding tissues and remove residual tumor cells, which is essential in the postoperative management of intestinal cancer with the potential for further clinical translation.

5.5. Tissue repair and wound healing

The process of removing tumors undoubtedly leads to tissue loss, impairing the normal tissue function, appearance, and mental health of patients. For tissue repair after cancer surgery, hydrogels should remove tumor cells first and then repair damaged tissues (Wang et al., 2024b). The special three-dimensional pore structure and functional groups of hydrogels can provide binding sites for cells and contribute to tissue repair-related cell attachment (Jiang et al., 2024). Jaiswal et al. (2023) prepared an injectable hydrogel by mixing two filipin proteins that could support adipose tissue stem cells (ADSCs) after removal of cancerous cells, and breast reconstruction through regeneration of ADSCs. Wang et al. (2023) prepared a highly tissue-adhesive hydrogel that can be used as a platform for postoperative chemoimmunotherapy and wound repair for tumors.

Bone regenerative repair is another type of tissue repair that is unique among connective tissues. Bone damage repair is a complex regenerative process that includes angiogenesis, osteogenic differentiation and biomineralization. Hydrogel itself is not osteogenic, so bioactive components (hydroxyapatite, carbon nanotubes, graphene oxide, and bioceramics, etc.) are added to hydrogel to accelerate the repair of bone damage. Li et al. (2022a) prepared a dual-network hydrogel containing magnesium ions based on chitosan and polyacrylamide, and the released magnesium ions could promote osteogenic differentiation and mineralization of bone marrow mesenchymal stem cells (BMSCs) and accelerate bone regeneration. The hydrogel is a flexibly designable biomaterial that can accelerate the repair of different types of tissues.

6. Clinical applications of hydrogels in tumor therapy

Injectable in situ-forming hydrogels have attracted much attention because of their unique ‘sol-gel’ morphology and excellent drug encapsulation ability, and they are expected to be further prepared into localized sustained-controlled release formulations loaded with various therapeutic agents, providing more intelligent and personalized treatments for postoperative patients with different types of tumors in the clinic. Clinically approved injectable hydrogels are mainly used for tissue regeneration, wound healing, cosmetic correction, and ocular drug delivery.

As shown in Table 3, few hydrogels for cancer therapy are available for direct local delivery of therapeutic agents, and most cancer therapeutic hydrogel research has focused on attenuating and minimizing the possible adverse effects of postoperative radiation therapy as well as acting as a filler at the site of tumor resection to promote rapid tissue reconstruction and wound healing. Endo’s Vantas® is an FDA-approved subcutaneous hormone delivery formulation for prostate cancer treatment, a hydrogel that utilizes a cylindrical diffusion-controlled reservoir system to allow for sustained release of the loaded gonadotropin-releasing hormone (GnRH) for up to 12 months, allowing for prolonged release of the medication after a single injection and providing great patient acceptance and convenience (Mandal et al., 2020). Another recent hydrogel used in cancer treatment is SpaceOAR^® hydrogel, a Boston Scientific company, which is injected between the prostate cancer and the rectum in patients undergoing radiation therapy to minimize the rectal radiation dose sparing the rectum, as evaluated in a clinical study (NCT02212548) (Grewal et al., 2023). TraceI T is a hydrogel that labels the exact edges of tumors for tumor imaging and guides the delivery of precision radiation therapy, thereby minimizing unnecessary radiation to cancer-free areas (Greer et al., 2021). Although hydrogel-based cancer therapies have achieved surprising therapeutic results, most of them are still in the initial preclinical experimental stage, and the strict market regulation and quality control requirements are such that clinical translation remains difficult.

Table 3.

A summary of hydrogels and their clinical application in cancer treatment.

Name	Treatment	Details	Reference
Hydrogel spacer	Cervical cancer	Injecting hydrogel between the rectum and cervix in women to increase the efficiency and reduce the rectal radiation dose.	NCT05902390
SpaceOAR hydrogel	Localized T1-T2 prostate cancer	Safety evaluation in subjects who have been injected with hydrogel and have received or will receive radiotherapy	NCT05735652
Mitomycin C (MMC) mixed with TC-3 gel	Non-muscle-invasive bladder cancer	Liquid TC-3 gel is mixed with MMC to rapidly form a hydrogel. Upon contact of the hydrogel with urine, the gel dissolves and slowly releases the drug, which is finally cleared from the bladder.	NCT01799499
Polyethylene glycol hydrogel(TracelT)	Bladder cancer	Localizing bladder tumors and significantly reducing radiation dose with TraceIT hydrogel	NCT03125226
PEG hydrogel (SpaceOAR)	Prostate cancer	Isolation of the rectum from the prostate to reduce radiation dose delivered to the rectum during radiotherapy and to improve CT scanning results	NCT02212548
RadiaAce hydrogel	Postoperative inflammation after breast cancer	Providing a moist wound environment and preventing inflammatory reactions after radiation therapy for breast cancer	NCT04481802
SpaceIT hydrogel	Prostate cancer	Safety and efficacy of TracelT hydrogel after radiation therapy for prostate cancer evaluated	NCT06451614
RespaceTM hydrogel	Cervical cancer	Hydrogel reduces rectal radiation dose in cervical cancer radiotherapy	NCT05690906

7. Conclusion and outlook

As personalized precision therapy has become a hot topic in oncology treatment, injectable in situ-forming hydrogels have attracted much attention due to their potential for local drug delivery through injection into the tumor resection cavity. The most superior application feature of injectable in situ forming hydrogels is that they are composed of materials such as injectable polymers, peptides, or proteins, which are in a solution state during the injection process, and then solidify and transform into a stable gel state upon external stimulation, which would allow the drug-carrying hydrogel to completely cover the irregular wound surface after resection and to be precisely placed at the desired site. The desirable properties of such postoperative oncology therapeutic formulations are uniform distribution at the target site and a retention time long enough for sustained release of the therapeutic agent, replacing multiple intravenous injections of the therapeutic agent to improve patient compliance. On the other hand, undesired burst release of the therapeutic agent is avoided as well as release of the therapeutic agent at the target site within a predetermined time frame. In addition, this type of hydrogel has shown surprising efficacy in the treatment of certain tumors that are difficult to administer due to barrier protection, such as brain tumors. Local therapeutic agent sustained-release platforms may be a potential post-operative oncology treatment, where the therapeutic agent is released in a controlled manner at the target site and degraded over time, which could revolutionize the treatment of various diseases.

However, despite the progress made so far, there is still a long way to go before this type of hydrogel can be clinically applied in postoperative cancer therapy, and there are still some challenges to be solved. First, it is difficult to prepare hydrogels with both ideal mechanical strength and good injectability. Hydrogels serve both as delivery vehicles for therapeutic agents and as supports for postoperative surgical cavities, which requires hydrogels to be mechanically strong enough while allowing them to be injected in a minimally invasive manner. Achieving this delicate balance between the two is critical for postoperative tumor treatment, as it allows the hydrogel to be easily injected into the tumor resection site and perform its therapeutic role. Second, the in vivo biocompatibility and biodegradability of injectable in situ-forming hydrogels are critical for their successful clinical translation Most hydrogels are composed of synthetic polymers, which inevitably require the incorporation of organic solvents or cross-linking agents during the synthesis process, which results in the possibility of inflammatory reactions during degradation of the polymer matrix in the organism. In addition, the immunogenic response that may be induced by the degradation of polymer matrices is also a matter of concern. Currently, even though the biocompatibility of hydrogels has been evaluated by animal model experiments, often the experimental period is short, which is insufficient to demonstrate the long-term biocompatibility of hydrogels. Meanwhile, the degradation of hydrogels in the human body may not be fully reflected using animal model experiments. Third, the controlled release of therapeutics from injectable in situ-forming hydrogels remains a challenge. This type of hydrogel has the potential to load and deliver various anticancer therapeutic agents due to its special ‘sol-gel’ transition properties, and achieving a sustained, stable, and controlled release of these therapeutic agents is essential for optimal therapeutic efficacy. However, the development of hydrogels capable of controlled and precise release of therapeutic agents is a complex task, which requires careful consideration of factors such as the loading capacity, release rate, sensitivity to external stimuli, and diffusion properties of the hydrogel. To date, most experiments have investigated in vitro pharmacokinetics, while in vivo release kinetics and mechanisms are still unclear, making it difficult to achieve precise controlled release of drugs per unit of time. Fourth, bioactive injectable hydrogels have attracted much attention in recent years, but the practical application of this type of hydrogel is limited by the self-stability of its loaded bioactive components. The bioactive components may be inactivated and degraded at certain ambient temperatures, which necessitates more stringent production, transportation and storage conditions. Unfortunately, few studies have been conducted in recent years on the storage conditions and shelf life of bioactive hydrogels. Bioactive hydrogels are particularly unsuitable for patients because it is difficult for patients to ensure the conditions of use and storage of the hydrogel, which can seriously affect the efficacy of the hydrogel and is not conducive to patient compliance. Fifth, in practical clinical applications, hydrogels that can exert an integrated therapeutic strategy need to be designed and identified according to the patient’s pathological type and postoperative-specific tumor microenvironment. However, the peristalsis of the gastrointestinal tract makes it possible for hydrogels applied to the abdominal cavity to undergo structural changes, leading to a significant reduction in efficacy. Although good structural similarity of the ECM is favorable for the in vivo safety of hydrogels, it is unfavorable for intraperitoneal use, with a high likelihood of abdominal adhesions and an increased risk of reoperation. As a foreign body, hydrogels are prone to produce gastrointestinal flatulence, abdominal pain and other adverse reactions while playing a therapeutic role, and even lead to serious postoperative complications such as intestinal obstruction. Sixth, the anti-tumor recurrence effect of hydrogels in most of the existing studies was assessed by establishing subcutaneous models, but this did not take into account the tissue-specific and tumor-specific nature of different tumor resection cavities. Nonetheless, it is very difficult to establish certain in situ tumor models, such as bladder cancer, prostate cancer, and cervical cancer, etc. Finally, the clinical translation of injectable in situ-forming hydrogels for postoperative tumor therapy is ultimately hindered by market regulation and quality control. To ensure the safety, efficacy and quality of hydrogels, it is necessary to establish a standardized clinical translation evaluation system and strict quality control standards, but this also greatly increases the difficulty of clinical translation. Most of the current hydrogels are composed of multiple components and are further combined with a variety of therapeutic strategies, which makes the preparation and synthesis of hydrogels more complex and magnifies the difficulty of quality control and research. The complex preparation process is not conducive to the large-scale production of hydrogels and it is difficult to ensure the consistency between the same batch and different batches, which can lead to a significant increase in production costs. In conclusion, existing studies cannot fully mimic the pathology of human tumors. In terms of clinical translation of tumor therapeutics, hydrogels are not sufficient to completely replace the existing postoperative adjuvant therapy.

Hydrogels have a natural advantage in carrying therapeutic agents, enzymes, DNA and RNA, and a variety of treatments have demonstrated encouraging efficacy. Much of the existing research has also focused on combining one or more therapeutic agents with hydrogel matrix materials to achieve more efficient anti-tumor effects. Therefore, solving the problem of matching matrix materials with therapeutic agents is the development trend and focus of precise drug delivery in hydrogels in the future. In addition, it is necessary to establish in situ tumor models for pharmacodynamic validation of the anti-tumor recurrence effect of hydrogels as well as to evaluate the long-term safety of hydrogels, which can help to achieve clinical translation of hydrogels. In the future, focusing on the development of precisely adjustable and highly controlled hydrogels based on pH-responsive and photothermal-responsive properties, as well as the further development of multiple therapeutic agent co-delivery and sequential-release hydrogel drug delivery systems, is expected to maximize the overall therapeutic efficacy of cancer therapies and accelerate clinical translation. In addition, hydrogels are combined with fluorescent substances to visualize and track hydrogel degradation as well as for precision cancer therapy. In terms of hydrogel composition, there is a need to develop high-performance and simple hydrogels, which will help establish a safety evaluation system for hydrogels. In the future, we can also focus on the postoperative treatment method, in addition to the direct use of hydrogels for postoperative treatment, reducing the inflammatory state of the surgical site, preventing bacterial infection at the wound site, and improving the tumor microenvironment is also a promising postoperative treatment method for tumors.

In summary, reducing local recurrence of tumors and ­minimizing systemic toxicities are top priorities for the future. Further clinical translation of hydrogels is imperative. Fortunately, current hydrogel research is progressing very rapidly, and the research power continues to increase. For example, continued advances in biomaterials technology and the integration of multidisciplinary fields continue to promote the development of hydrogels, in situ drug delivery technologies may greatly address the difficulties in the application of hydrogels in postoperative oncology therapy, and the success of these technologies will increase the likelihood of the introduction of injectable in situ-forming hydrogels into postoperative oncology treatments in the clinic. If the deficiencies identified in the existing studies can be optimized, the functions can be focused, and the advantages can be reasonably exploited, injectable in situ-forming hydrogels will play an important role in future postoperative oncology treatments.

Funding Statement

This work was supported by the National Natural Science Foundation of China #1 under Grant number 82204935; and the disciplinary innovation team construction project of Shaanxi University of Chinese Medicine #2 under Grant number 2019-YL11.

Author contributions

Zhanpeng Wang drafted the original manuscript, Bingtao Zhai obtained funding and supervised the revision of the manuscript, Jing Sun and Xiaofei Zhang conceptualized and designed the study, Junbo Zou and Yajun Shi retrieved and organized the literature, and Dongyan Guo obtained funding and gave final approval of the version to be published. All authors revised and read the paper and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).