Vascular intervention therapies (VITs) are minimally invasive strategies that have been developed over the last few decades to replace complex surgery for the treatment of vascular malformation, cancer, and hemorrhage control ^[1][2]. These strategies drew attention recently due to their minimally invasive and image-guided interventions which often result in better outcomes with fewer complications ^[3]. Blood vessels are considered common routes of entry into the body in any endovascular approach. Embolization is a VIT where blood flows are deliberately blocked around the blood vessels of a target lesion via intravascular deposition of embolic agents from catheters for therapeutic purposes ^[4]. Previous reports demonstrated that therapeutic endovascular embolization has the potential to treat acute gastrointestinal bleeding, arteriovenous malformations, fistulas, and targeted cancer treatments ^[5][6][7][8].

In the past, autologous blood clots, muscle fragments, or stainless-steel pellets were used in embolization ^[9]. In the 1970s, due to the failure of natural analogues for embolization, researchers advanced to drive the development of modern materials as embolic agents, i.e., gelatin sponges ^[10]. Gelatin sponges were first used to occlude a carotid-cavernous fistula and showed successful occlusion without any vision loss or complications in the patient after surgery ^[10].

Embolic agents are broadly two types, i.e., mechanical embolic agents such as metal coils and plugs and flow-directed embolic agents such as polymers, particulates, or in situ gelling materials ^[9]. Flow-directed agents can be delivered via catheters positioned within a specific vascular supply to treat vascular malformations. From a clinical standpoint, depending on the therapeutic goal, flow-directed agents are subdivided into temporary and permanent embolic agents ^[11]. A temporary fast-acting embolic agent is required to obstruct a hemorrhaging vessel, while embolization for a vascular malformation often requires a more precise and permanent embolic material. A wide range of calibrated microspheres and bioglue made of both natural and synthetic polymers have been developed as flow-directed embolics ^[4].

The number of polymer-based embolic materials is growing regularly based on their potential for embolization. Currently available commercial embolics, including different polymer-based particulates and liquid glues, were developed for endovascular therapies. These embolic materials are the most commonly used agents due to their various functionalities.

2. Polymer-Based Embolic Agents

2.1. Particulate Embolic Agents

2.1.1. Gelatin Sponge

Gelatin-based embolic agents are biodegradable and commercially available for temporary embolization. Gelatin foams are manufactured by Pfizer Inc., New York, NY, USA (i.e., Gelfoam^®) and have been used widely in endovascular therapies since 1964 ^[12][13]. Gelatin foams can be used as hemostatic embolic agents to reduce subsequent blood loss during surgery. Their hemostatic ability is closely similar to that of fibrin when directly bound to the bleeding region ^[14]. It is reported that the coagulation time is decreased from 9.5 min to 6.2 min when gelatin powder is mixed with a whole blood sample ^[15]. Gelfoam sheets can be cut into small cubes or pledgets, and the particle size is typically 1 mm or more. A smaller slurry can be created from the sheets by mixing pledgets and a contrast medium such as an iodinated contrast agent for injection ^[16]. Another available form of gelatin sponge is powder (particle size: 40–60 μm), though it may increase the risk of ischemic tissue or neural injury through distal migration of the tiny particles ^[17]. Moreover, porous gelatin foam serves as a scaffold to induce cell adhesion and tissue regeneration. In general, gelatin foams have shown promising results in treating uterine fibroids, massive arterial bleeding, liver tumors, and bone malignancies ^[18][19]. Gelatin embolization is considered a temporary solution because of its enzymatic degradation. The gelatin-based agent is more suitable for internal iliac arteries’ embolization and occluding hepatic arteries in chemoembolization due to its degradable nature ^[15]. Due to its unpredictable degradability nature, gelatin-based embolization may lead to early recovery of blood flow; thus, it is not suitable for permanent occlusion.

2.1.2. Spherical and Nonspherical PVA

Poly(vinyl alcohol) or PVA has been used in different morphologies for embolization treatment. Noncalibrated or nonspherical particles are prepared by mechanical fragmentation of PVA block polymer and sieve to separate particles with different size ranges from 50 to 1200 μm in the dry state ^[16]. PVA particles are usually mixed with diluted contrast agents to prepare a trackable suspension. PVA-based embolics were first reported in 1974 as an embolic agent in patients with vascular tumors such as liver, head and neck, and uterine cancer ^[20]. Since then, this embolic agent has been widely used to treat different tumors and hemorrhagic conditions such as gastrointestinal bleeding and hemoptysis. Due to the surface charges and surface hydrophobicity of PVA particles, they tend to aggregate and lead to the unintended occlusion of proximal larger vessels. Such an event is often disadvantageous when more distal embolization is required. Moreover, irregular shape and lack of size precision are other main challenges of PVA particles, which results in unpredictable embolization and catheter blockage ^[16]. In addition, PVA particles often adhere to the vessel wall and develop an intravascular lattice while leaving space between particles. As a result, though vessel occlusion is completed with thrombus formation among particles, recanalization can occur by capillary proliferation inside the organized thrombus. To overcome some of the shortfalls associated with PVA particles, calibrated or spherical PVA microspheres were developed in 2003–2004 ^[16]. For example, Bead Block (Biocompatibles UK Ltd., Farnham, United Kingdom) is a commercially available embolic microsphere (PVA cross-linked with acrylic polymer) with size ranges of 100–300, 300–500, 500–700, 700–900, and 900–1200 μm for embolization ^[16]. Additionally, two other FDA-approved PVA microspheres for the embolization of hypervascular tumors and AVMs are DC Bead^® and LC Bead^® (Biocompatibles UK Ltd., Farnham, United Kingdom) and LC Bead LUMI^® (with intrinsic radiopacity) (Biocompatible UK Ltd.) ^[21]. LC Bead^® are PVA microspheres containing sulfonic acid groups with a negative charge. Hence, these microspheres can load positively charged antitumor therapeutics such as doxorubicin and irinotecan via an ion-exchange mechanism. Histologically, due to their lower resistance to compression, these PVA microspheres can travel more distally, and therefore are more successful in distal embolization. Commercially available polymeric embolic agents are summarized in Table 1.

2.1.3. HepaSphere^TM/QuadraSphere^TM

HepaSpheres^TM or QuadraSpheres^TM are microspheres composed of vinyl alcohol and sodium acrylate copolymers. In the late 1990s, these microspheres were developed and clinically used for bland embolization of HCC and peripheral AVMs ^[33][34]. Histologically, compared with spherical TGMS, these microspheres were able to swell and deform and conform to the vessel lumen ^[24]. These microspheres could swell up to 4 times in diameter within 10 min when added to a saline solution or nonionic contrast media. HepaSphere^TM/QuadraSphere^TM are commercially available in dry states with the size ranges of 50–100, 100–150, and 150–200 μm, or reconstituted size ranges of 200–400, 400–600, and 600–800 μm, respectively ^[16]. These microspheres were approved in Europe in 2004 and in the USA in 2006. Since the microspheres are negatively charged, they can load positively charged therapeutics such as doxorubicin. The drug loading in this microsphere occurs similarly to DC Bead^® by an ion-exchange mechanism. These microspheres also have the potential to load noncharged drugs such as cisplatin via a reservoir effect, although the release rate of cisplatin is relatively faster within 24 h ^[35]. Comparative studies have been conducted recently to address the differences between HepaSpheres^TM and DC Bead^®. In an in vitro study, the drug loading ability, physical properties, and release profile of doxorubicin and irinotecan from HepaSphere^TM and DC Bead^® were evaluated ^[36]. During loading, DC Bead^® uses its ionized sulfonate groups and exchanges a water molecule for the charged drug molecule when submerged in the drug solution. In contrast, HepaSphere^TM utilizes mechanical loading where drug molecules are transported into the microsphere matrix via rapid water absorption. Charge interaction between the drug and the carboxylic groups holds it inside the microspheres. From the loading profile analysis, DC Bead^® requires 2 h for drug loading while HepaSphere^TM takes only 1 h to load drugs. Both drugs showed a similar loading profile for each microsphere. However, release kinetics for both drugs exhibited different results in 0.9% saline media under 5 mL/min flow. The total percent of doxorubicin released from HepaSphere^TM was 18 ± 2%, while 27 ± 7% was the total for the DC Bead^® microspheres. Moreover, the time required for both microspheres to reach 75% of the plateau value was 2.2 h. In contrast, the total percent of irinotecan released from HepaSphere^TM was 95 ± 9% and 102 ± 11% for the DC Bead^®, while t_75% for each of the beads was 0.12 h and 1.1 h, respectively. This result indicates that the interaction between drugs and the microspheres matrices during loading occurred differently. The highly positive charge of the primary amine of doxorubicin provides stronger binding kinetics with the carboxylic groups in the HepaSphere^TM and the sulfonate groups in the DC Bead^® microspheres. Contrarily, tertiary amine in the irinotecan provides less strong binding kinetics with the respective functional groups of these two microspheres. Furthermore, differences in release kinetics also affect the distribution of drugs into the tissue of the patients.

2.1.4. Embosphere^®

Trisacryl gelatin microspheres (TGMS) are commercially available as Embosphere^® (Merit Medical, South Jordan, UT, USA). This material was the first commercial product made of crosslinked acrylic polymer embedded with gelatin. Commercially, these microspheres are available in different size ranges, i.e., 40–120, 100–300, 300–500, 500–700, 700–900, and 900–1200 μm. In the early 1990s, this microsphere was developed and clinically used to treat head and neck tumors and AVMs ^[25]. Since FDA approval in 2000, TGMS or Embosphere has been the most popular microsphere for hypervascular tumors, AVMs, and uterine fibroid embolization. Embosphere^® microspheres are soft and suitable for delivery via microcatheters without clogging or aggregate formation ^[4]. Histologically, it forms chains instead of a cluster in smaller vessels. Moreover, a single particle can completely occupy a vessel lumen. Therefore, a strong correlation was found between the sizes of the Embosphere^® microspheres and the diameter of occluded vessels ^[37]. EmboGold^® microspheres are commercially available TGMS particles doped with 2% gold to enhance visualization during injection ^[4]. It has been reported that injection with smaller microspheres (100–300 μm) resulted in marked inflammatory responses due to their deeper penetration and allogeneic overcoat ^[26]. In another clinical study, similar deeper penetration of smaller microspheres in meningioma embolization was also reported.

2.1.5. Embozene^®

Polyphosphazene-coated polymethylmethacrylate microspheres (Embozene^®, Celonova Biosciences, San Antonio, TX, USA) were developed and received approval from the FDA in 2007 ^[38]. These microspheres are commercially available in more precise calibrated sizes with a narrower range compared with other microspheres, i.e., 40, 75, 100, 250, 400, 500, 700, 900, 1100, and 1300 μm, respectively ^[16]. Microspheres with different particle sizes are also incorporated with various contrast agents for particle visibility and easy size recognition. Furthermore, the unique coating of polyphosphazene (commercial name: Polyzene-F^®) act as an antithrombogenic and anti-inflammatory material ^[38]. The properties of Polyzene-F^® help it persist for a long time in patients with benign conditions such as uterine fibroid or meningioma. This microsphere does not have biodegradability, which hinders its application in temporary embolization, e.g., to treat hemorrhage.

2.1.6. Other Degradable Microspheres

Degradable starch microspheres are composed of crosslinked hydrolyzed starch and amilomeres and were developed in the mid-1970s by Pharmacia AB to provide a highly transient embolic effect ^[9]. This microsphere is available under two commercial names, i.e., EmboCept^® S by PharmaCept and Spherex^® by Magle Life Sciences ^[39]. Although the material half-life is around 40 min per manufacturer, in practice, this range is between 25 and 60 min ^[9][27]. Both commercially available DSMs are 50 μm in size, hence, intended for the temporary embolization of small vessels. DSMs have been clinically practiced for cTACE to treat HCC by providing transient occlusion to decrease blood flow in the tumor bed. This material also helps to enhance the time to keep chemotherapeutic emulsion in the cancerous tissue. DSMs have been recommended for use in patients who need multiple chemotherapeutic treatments by cTACE ^[40]. This material also has been used in patients with a reduced hepatic function who cannot endure more damage to the surrounding hepatic tissue induced by ischemic necrosis ^[41]. Some other degradable polymeric particulates such as hyaluronic acid and poly(lactic-co-glycolic acid) (PLGA) have been designed for embolization application. For instance, a PLGA microsphere has been developed by entrapping the doxorubicin (DOX) and hyaluronic acid–ceramide (HACE) in PLGA ^[42]. The DOX/HACE nanoassembly is released from the microspheres after being administered into the hepatic artery. A better drug release profile was observed for DOX/HACE microsphere group over the DOX microsphere in the acidic environment (i.e., tumor-specific region). The cellular internalization efficiency of the therapeutic was higher for the DOX/HACE microsphere in liver tumor cells (HepG2 and McA-RH7777 cells) over the control group (DOX microsphere only). Interestingly, the elevation in the cellular accumulation of DOX and its better anticancer performance was observed in DOX/HACE-based nanoassembly released from the DOX/HACE microspheres. Such microspheres can be used as a therapeutic agent-loaded hyaluronic acid nanoassembly-releasing microsphere system for HCC embolization application.

2.2. Liquid Embolic Agents

Liquid embolic materials can flow through the vessels, which allows them to deeply penetrate the smaller vessels. Once they reach the target vessel, they become solidified to occlude vasculature. Unlike particulate embolics, liquid embolic agents can be used to occlude vasculature of a wide range of diameters.

2.2.1. N-Butyl Cyanoacrylate (NBCA)

Embolic glue, N-butyl cyanoacrylate was approved by the FDA in 2000 to treat cerebral arteriovenous malformations ^[43]. NBCA is a clear liquid in its monomer state, but once it encounters ionic substances such as blood, saline, or ionic contrast media, it polymerizes to form a stiff matrix. Primarily, NBCA is recommended for AVM embolization, acute bleeding in the gastrointestinal tract, or preoperative embolization for hepatectomy (partial) ^[44]. The adhesive nature of NBCA allows this material to be used in coagulopathic patients, while other embolic materials such as coils or Gelfoam^® are not recommended due to their high chance of occlusive thrombus formation within the vessels ^[45][46]. NBCA embolic material mechanically occupies the intravascular lumen via adhesion and halts the blood flow in patients. The adhesive nature of NBCA is also a limitation in some cases where multiple injections are required ^[47]. NBCA may adhere to the catheter and occlude the lumen in a case where the subsequent injection is crucial. Trufill^® is a commercial ‘ready-to-use’ glue that contains NBCA, ethiodized oil, and tantalum powder. Depending on the flow properties and the anatomy of target vessels, NBCA concentration ranges between 25 and 67% in the glue ^[43]. When NBCA combines with ethiodized oil in blood, polymerization slows down from fewer than 1 s at 67% NBCA to 6 s at 25% NBCA. One of the main limitations of NBCA is that it releases formaldehyde upon polymerization, resulting in the inflammation of the vessel wall and surrounding tissue and sometimes causes chronic granulomatous inflammation.

2.2.2. Precipitating Hydrophobic Injectable Liquid (PHIL^TM)

A recently developed injectable liquid embolic is PHIL^TM (manufactured by MicroVention Inc., Aliso Viejo, CA, USA), which has been approved in Europe for clinical use in the embolization of lesions in arteriovenous malformations, hypervascular tumours, and other peripherals and neurovasculature ^[30]. PHIL^TM is a nonadhesive embolic agent consisting of poly(lactide-co-glycolide) and poly(hydroxyl ethyl methacrylate) copolymers. A contrast agent (i.e., triiodophenol) is also incorporated into the monomers by covalent bonding to provide radiopacity for visualization ^[48]. Initially, PHIL^TM is suspended in dimethyl sulfoxide (DMSO) until it encounters body fluids such as blood or water. Once it reaches there, polymers precipitate into a solid and block the vasculature instead of forming layers. Commercially, three concentrations of PHIL^TM are available, i.e., 25%, 30%, and 35% (concentration of polymer by weight) ^[9]. One of the major distinguishable features of PHIL^TM is that no microcatheter occlusion occurs during the injection. In addition, this embolic offers less resistance to injection, hence, allowing for deeper penetration. This lower resistance often increases the risk of overpenetration into the venous drainage. Clinical data for PHIL^TM to treat dural arteriovenous fistulas (DAVFs) showed that the enhanced venous penetration of PHIL^TM was advantageous to filling fistula feeders and provided better outcomes ^[49]. Another clinical study reported the successful use of PHIL^TM to treat ruptured plexiform AVMs ^[50].

2.2.3. Onyx^®

Onyx^® is another potential liquid embolic agent made by Medtronic plc. for the embolization of intracranial AVMs in the 1990s ^[51]. This embolic liquid is made of ethylene–vinyl alcohol (EVOH) copolymers dissolved in DMSO. Once the DMSO dissipates within the bloodstream, Onyx^® solidifies in an ‘outside-in’ fashion due to the formation of solid EVOH precipitates ^[32]. As a result, an instantaneous solid cast forms around the exterior while the interior of the flow remains fluid, enabling it to flow deep into the lesion. Onyx^® formulations with lower concentrations of EVOH have low viscosity, thus travelling more distally from the catheter tip ^[52]. Contrarily, highly viscous Onyx^® formulations provide better control in a high-flow environment. Despite their different formulation, they completely solidify within 5 min after injection ^[53]. In addition to treating AVMs, Onyx^® has also been applied successfully to treat gastrointestinal and cardiopulmonary hemorrhages, bleeding from aneurysms, preoperative vascular tumors embolization, and peripheral arteriovenous malformations ^[53]. Onyx^® is a permanent occlusive material that remains stable up to 5.25 years after occlusion. The use of Onyx^® requires special attention in using DMSO-compatible catheters and flushing the catheters with DMSO before administration. Although Onyx^® is nonadhesive, the catheter may still become clogged if the long plug (>2 cm) forms around the tip during injection ^[9]. The liquid nature of Orynx^®, PHIL^TM, and NBCA allows them to pass through smaller vessels, which is advantageous over particulate embolics. For example, Onyx^® can occlude vessels of 5 μm in diameter while NBCA can occlude up to 20 μm in diameter ^[54]. Despite this advantage, NBCA has a quick working time because of the rapid polymerization upon contact with blood and adhesive to vessel walls and the delivery system ^[55]. As a result, permanent catheter clogging occurs, which requires delivery system replacement, thus extending the working time. In contrast, Onyx^® is nonadhesive and has a longer working time. However, if Onyx^® is injected rapidly, it may cause vascular inflammation and angionecrosis due to the high concentrations of DMSO at the catheter tip ^[39][56]. In a study of 32 patients (22 patients with Onyx^® and 10 with NBCA), Natarajan et al. analyzed the histopathological data of resected AVMs after embolization ^[54]. They found perivascular inflammatory damage among 90.9% of the Onyx^® and 90% of the NBCA tissue samples. This inflammatory damage could be explained as a response to the foreign material in the vessel lumen. Moreover, 60% of Onyx^®-injected vessels showed angionecrosis, while 40% of the NBCA-injected vessels had angionecrosis. In another study, PHIL^TM was used alone and combinedly with Onyx^® to treat AVMs ^[57]. It was found that PHIL^TM exhibited better outcomes over Onyx^® in terms of ease of use, quick plug formation, and lower imaging artifact at follow-up after treatment. Besides, histopathological data indicated that PHIL^TM caused moderate vascular inflammatory damage while Onyx^® had lower inflammation. Therefore, all these studies reflected favorable outcomes for PHIL^TM as a new and superior liquid embolic agent to treat disease conditions. Finally, these results reflect the complications with these materials that need to be addressed to make outstanding next-generation liquid embolics in future embolization.

2.3. Emerging Embolic Agents

Currently, a few embolic agents have received regulatory approval, and some of them are commercially available. Most liquid embolics have the potential for use in endovascular embolization. However, these materials have some pitfalls such as lack of biocompatibility and degradability. Furthermore, the polymer-based liquid embolic materials exhibited lower cell viability over nontreated cell cultures (fibroblast cell lines). Higher pH conditions that require chemical crosslinking are supposed to be partially responsible for lowering cell viability in a liquid gelling system. To overcome all these issues, emerging polymer-based injectable embolics are explored in the following subsections.

2.3.1. Thermoresponsive Embolic Gels

Temperature-sensitive gelling systems have been developed recently to reduce cytotoxicity and gelation time. In a study, an injectable chemical and physical crosslinked N-isopropyl acrylamide (NIPAAm)-based gels for endovascular embolization ^[58]. These hydrogels are composed of the copolymers of NIPAAm and hydroxyethyl methacrylate (HEMA) with the functionalization of pentaerythritol tetrakis 3-mercapto propionate and olefins. This gelling system formed elastomeric hydrogels at pH 7.4. The cytotoxicity of this poly(NIPAAm-co-HEMA-acrylate) injectable gels was assessed using fibroblast by direct and indirect methods. Even though this material was not cytotoxic, it inhibited cell adhesion and proliferation on the gel surface. In another study, thermosensitive hydroxybutyl chitosan (HBC) hydrogel was developed for vascular occlusion ^[59]. Once this hydrogel was injected into the renal artery of a rat, a fast sol–gel transition converted the HBC solution into a hydrogel and tightly adhered to the inner wall of the blood vessel. As a result, the blood vessel was occluded immediately. Li et al. developed a thermoresponsive NIPAAm-N-propylacrylamide (NPAAm)-vinyl pyrrolidone (VP) terpolymers (PNINAVP) hydrogel for embolization application ^[60]. They added Iohexol (a radiopaque agent) to make it trackable for follow-up imaging. The reversible sol–gel transition occurred quickly within 1 min in response to temperature change. Then, the hydrogel solution was injected into the rete mirabiles (RM) of six swine. Angiographical data obtained immediately after the injection exhibited a complete occlusion of the RM, while no recanalization was reported in follow-up imaging after one month of operation. Moreover, histological results show no acute inflammatory damage inside the RM and the surrounding tissue of the animals. Chitosan has a high adhesion ability to a blood vessel but forms precipitation at pH 6.2, which often hinders its potential application for TAE ^[61]. To overcome this issue, a liquid embolic agent made of 2% chitosan and 56% b-glycerophosphate disodium salt (b-GP) was prepared for embolization ^[62]. This embolic hydrogel can be flowable in the physiological pH at low temperature and turn into a hydrogel at 37 °C in a thermoresponsive manner. This liquid embolic agent blocked the rabbit’s renal artery within eight weeks of treatment without any recanalization. A modified trackable hydrogel with the same composition of chitosan and b-GP was developed with an X-ray contrast reagent (i.e., Visipaque) for acute embolization of porcine spleen and gastric vessels ^[63]. Poloxamer 407 or poly(ethylene glycol)-poly(propylene glycol)-poly(ethylene glycol) is a thermoresponsive triblock copolymer that shows sol–gel transition upon temperature changes from 4 °C to 37 °C ^[64]. This material has been applied as a temporary embolic agent for the embolization of the arteries of animals. The results show successful embolization in the animal arteries while it caused recanalization of the vessels after some time. A composite hydrogel (PSHI-Ca²⁺) was developed consisting of poloxamer 407, hydroxymethyl cellulose, sodium alginate, iodixanol, and Ca²⁺ to solve this issue ^[65]. The alginate portion in this hydrogel enhances the retention rate of Ca²⁺ ions and prevents the erosion of the hydrogel by forming a stable three-dimensional structure in the water environment. This PSHI-Ca²⁺ hydrogel showed an excellent curative effect in VX2 liver tumors in rabbits by effectively blocking vessels around the tumor within 7 days of treatment. Although these temperature-sensitive hydrogels show potential in embolization, still, there is room to strengthen their mechanical properties. Such improvement will make them a suitable candidate for longer embolization as well.

2.3.2. pH-Responsive Gelling System

Although thermoresponsive hydrogel has the potential for embolization, early gel formation due to quick temperature change during injection is still a prime concern that needs attention ^[66]. Other physiological factors such as pH could be a salient parameter to design embolic hydrogels. In response to the changes in environmental pH, the pH-responsive hydrogel changes from a hydrophilic state to a hydrophilic state. pH-responsive hydrogels containing therapeutic agents could be transferred as a liquid at a controlled pH through a catheter and form gelation once it reaches the target lesion pH and subsequently releases the therapeutics ^[67]. Sulfamethazine (SM)-based hydrogels are typical examples of pH-responsive hydrogels that have been developed to treat vascular intervention therapy. A few examples of this kind of hydrogel are polyethylene glycol (PEG) and polyurethane sulphide sulfamethazine (PUSSM) copolymer or PEG-PUSSM, poly(e-caprolactone) (PCL), SM, PEG copolymer (PCL-PEG-SM), and the triblock copolymers made of poly(e-caprolactone-co-lactide)-poly(ethylene glycol)- poly(e-caprolactone-co-lactide) (PCLA-PEG-PCLA) and SM ^[68][69][70]. Sulfadimethazine-based pH-responsive hydrogels are ionized (SM part) and hydrophilic in nature at high pH, while at physiological pH, the SM portion of the hydrogels become deionized and hydrophobic. This means that the decrease in pH triggers the sol-to-gel transition and formation of a 3D gel network. Another pH-responsive hydrogel is hyperbranched poly(amino acid) (HPTTG), developed for noninvasive target embolization ^[71]. The sol–gel transition with reducing pH of HPTTG was regulated by adjusting the acidic amino acids in copolymers. The accumulation of HPTTG is mainly due to the acidic environment of tumors that triggers sol–gel transition. Despite using this polymer as an embolic for embolization of unresectable hypervascular tumors, it can be used combinedly with controlled-release, thermal ablation, trackability, and synergistic therapy. It has been reported that the unique pH-responsive property helps to achieve good performance in rabbit liver embolization and renal vasculature embolization ^[68].

2.3.3. Self-Healing Embolic Gels

Self-healing hydrogels show autorepair ability under physiological conditions. Hence, these hydrogels exhibit their potential as an embolization material. For example, a self-healing hydrogel made of glycol chitosan, dibenzaldehyde-terminated PEG, and carbazochrome was prepared for chemoembolization ^[72]. In this hydrogel, Schiff-base bonding helps self-healing by uncoupling and recoupling imine linkages. The gelation of this hydrogel occurred within 3 min, while Carbazochrome was released from the hydrogel continuously for 6 h as a hemostatic agent to block blood flow. This hydrogel was developed initially for in vivo renal artery chemoembolization in a rat model.

2.3.4. Shear-Thinning Hydrogels

In recent years, shear-thinning hydrogels have drawn great attention in endovascular embolization. These hydrogels are self-healable, easily injectable, and capable of delivering therapeutic agents and growth factors ^[73]. They are ideal for facilitating injection during transcatheter delivery due to decreased viscosity at an enhanced strain rate. For instance, a shear-thinning biomaterial (STB) was developed using gelatin (type A) and silicate nanoplatelets (Laponite^TM XLG) to use as a hemostatic agent for embolization ^[74][75]. The positively charged gelatin interacts with silicate due to anisotropic charge distribution. As a result, they self-assemble, form dynamically, and show the shear-thinning property. Furthermore, silicate nanoplatelets trigger coagulation by concentrating clotting factors. The STB shows hemostatic behavior due to the intrinsic coagulation of gelatin and silicate nanoplatelets. STBs exhibited excellent results in arterial embolization in small and large animals. This material blocked the blood flow immediately after being injected into a pig’s left external iliac artery. A pig’s iliac artery has a high flow rate of 100 cm s⁻¹ like human iliac arteries. Hence, STB shows the potential to provide stable and complete occlusion.

2.3.5. Other Potential Polymeric Embolic Agents

Besides the above-mentioned established polymer-based emerging embolic agents, some new polymeric embolics have also been developed in recent years. For instance, the PPODA–QT polymer composite was developed in the basic environment (NaOH) from liquid organic monomers poly(propylene glycol) diacrylate (PPODA) and pentaerythritol tetrakis 3-mercapto propionate (QT) ^[76]. This composite material transforms into gels to form a network through crosslinking by a Michael-type addition in a time-dependent manner. The mixture can be delivered through a catheter before being transformed into fully crosslinked gels. Furthermore, high pH, presence of surfactant, and premixing time all trigger faster gelation kinetics of the PPODA–QT system. The type of contrast agent used in the system also alters the gelation kinetics. For example, rapid gelation occurs when the Conray contrast medium (Mallinckrodt, St Louis, MO, USA) is used, while the Omnipaque system slightly slows down the gelation kinetics of the PPODA–QT system ^[77]. There is a risk of uncontrollable and unpredictable swelling after embolization because it possibly overstresses weak blood vessels. Additionally, experimental evidence suggests that its biocompatibility and long-term stability make this system a potential candidate for embolization treatment (e.g., aneurysm). In a study, a new injectable embolic gel (PCLA-PUSSM) was developed with radiopacity property using poly(e-caprolactone-co-lactide) (PCLA), poly(urethane sulfide sulfamethazine) (PUSSM), and poly(ethylene glycol) (PEG) ^[70]. The gelation conditions (temperature/pH) of this hydrogel were 25 °C/8.5 (sol) to 37 °C/6.6 (gel), respectively. An in vivo experiment showed that the 25 wt% PCLA-PUSSM exhibited successful gelation at the target site in a rabbit hepatic tumor model. No significant washout of the polymers into the bloodstream was noticed in the test. Such dual responsive injectable radiopaque polymer gels may have the potential to be used for chemoembolization targeting unresectable hepatic carcinoma, cerebral aneurysms, and other diseases. In another study, Lym et al. developed a pH-responsive PCL–PEG–SM copolymer that experienced a sol–gel transition from pH 8.0 to pH 7.4 at 37 °C ^[69]. This copolymer solution could be intra-arterially administrated in a rabbit VX2 liver tumor model at pH 8.0 for embolic application. Huynh et al. developed a dual responsive hydrogel made of poly(amino ester urethane) (PAEU) block copolymer that demonstrated its potential as a stimuli-responsive embolic agent in TAE application ^[78].