Temporary Embolic Agents

Embolic agents and their use in therapeutic vascular occlusion have advanced considerably since the emergence of these procedures in the mid-1960s. The earliest embolic agents included muscle tissue and Gelfoam used for the treatment of traumatic carotid-cavernous fistula in 1965 and 1966, respectively. ^{1 2} Other early embolizations employed permanent agents such as 1.5- and 3-mm stainless steel pellets administered for the treatment of arteriovenous malformation ³ and lead pellets for the treatment of spinal cord hemangioma, both in 1968. ⁴

Pharmacologic agents such as epinephrine and propranolol were also being investigated for their occlusive effects by Czech radiologist, Dr. Josef Rösch in 1970. ⁵ These embolization procedures differed in that they capitalized on image guidance to identify and occlude distant vessels, specifically for the treatment of gastrointestinal hemorrhage. Rösch's ground-breaking publication prompted an editorial note in Gastroenterology titled “Turned Off Bleeders” which cautioned against unchecked enthusiasm for minimally invasive procedures, ^{6 7} but early interventionalists were not swayed.

With influence from Rösch, American radiologist Dr. Charles Dotter administered an autologous clot to treat gastrointestinal hemorrhage shortly thereafter. ⁸ In the coming years, embolic agents for gastrointestinal hemorrhage were further explored in canine models with physical agents, like Gelfoam, outperforming pharmacologic vasoconstrictors. ⁹ By the 1980s, Gelfoam became the favored agent for temporary occlusion in gynecologic hemorrhage, presurgical devascularization, and hemoptysis. ^{10 11} Other temporary embolic agents studied in animal models included Oxycel and Surgicel, ¹² with polyvinyl alcohol (Ivalon), silicone, and cyanoacrylates rounding out the permanent embolic agents. As the application of therapeutic embolization grew, so did the arsenal of embolic agents, each with unique advantages and drawbacks. One of the major distinguishing factors for embolic agents is whether they provide temporary or permanent occlusion.

This review article will focus on the temporary embolic agents in use today, namely: Gelfoam, autologous blood clots (ABCs), and Avitene. Their preparation, indication, and specific limitations will be discussed in addition to advances in embolic bioengineering with the emergence of on-demand degradation, shape memory polymers (SMP), and drug-eluting beads.

Embolization Procedure

Embolization procedures employ the modified Seldinger technique which was developed in 1953 by Swedish radiologist Dr. Sven Ivar Seldinger. The original Seldinger technique is performed by inserting a hollow needle into a vessel under ultrasound guidance and advancing a guidewire through it. The guidewire is manually compressed within the vessel while the hollow needle is subsequently removed. To complete the procedure, a catheter is threaded over the guidewire and into the vessel, providing a hollow conduit for interventions. The modified Seldinger technique, also called the catheter-over-needle approach, is also available. This involves threading a fine catheter over the needle prior to its removal, without the need for a guidewire intermediate.

After access is obtained, embolization procedures rely on angiography for visualization of internal vasculature. Once the vessel of choice is located, the appropriate embolic agent is selected, prepared, and administered through the intravascular catheter. Selecting an ideal embolic agent is crucial, and “first principles” must be taken into account:

1. Whether the embolization is proximal or distal.

2. Whether the desirable occlusion is temporary or permanent.

3. Whether tissue necrosis or viability is favored. ¹³

Temporary agents should be administered when short-term occlusion is sought. ¹¹ The biodegradable nature of temporary embolics allows for reintervention into previously embolized vessels, ¹³ which is favorable if multiple treatments are anticipated. Temporary embolic agents are also indicated in cases of trauma when selective arterial embolization is not possible. ¹⁴ In these cases, temporary occlusion of a larger vessel may be necessary to stabilize the patient, slow down hemorrhage, and preserve long-term organ function. ^{13 15}

Temporary Embolic Agents

Autologous Blood Clot

ABC was first administered as a temporary embolic agent for the treatment of gastrointestinal hemorrhage in the early 1970s by Dr. Charles Dotter and his team at the Oregon Health Sciences University. ⁸

When anticipating the use of ABC, approximately 10 to 15 mL of the patient's blood should be drawn into a non-additive sterile container prior to the beginning of a procedure and administration of heparin. The time for collected blood to clot varies from patient to patient, but typically occurs between 15 and 90 minutes based on the patient's coagulation profile. This process can be augmented by shaking the blood sample, heating the blood with steam, or adding clotting factors. Once the supernatant is removed, ABC can be fragmented and injected to cause mechanical occlusion of selected vessels. Vessel recanalization is expected within hours to days as a result of in vivo fibrinolysis. The use of an ABC as an embolic agent is desirable for a multitude of reasons including wide availability, ease of production, cost-effectiveness, and biocompatibility. ¹⁶

Gelfoam

Gelatin foam, commercially sold as Gelfoam, was first administered as an embolic agent in the mid-1960s for cavernous-carotid fistula. ^{2 17 18} Gelfoam is a water-insoluble biologic made from purified porcine skin gelatin that has been used in a variety of clinical scenarios, initially as a hemostatic agent during surgical procedure. ^{13 16 17 19} During its manufacturing, nitrogen is bubbled into the Gelfoam sponge giving it a porous structure. When injected in the bloodstream, Gelfoam causes a mechanical obstruction, reducing blood flow and allowing platelet aggregation in its porous element inducing the clotting cascade. ^{16 17 19} Eventually, it is internally degraded by collagenase and trypsin enzymes ²⁰ and provides complete recanalization within weeks. ^{16 17 21} However, Gelfoam can elicit a strong inflammatory response with dense packing, resulting in permanent occlusion in some cases. ^{13 22}

There are many advantages to the use of Gelfoam as an embolic agent including cost-effectiveness, wide availability, safety profile, efficacy, and versatility of use. ^{10 17} Its main limitations are variability in size of the particles as the embolic agent is created by the operator. ¹⁸ Its temporary action can be augmented by adding aminocaproic acid for longer lasting and potentially permanent embolization. ¹⁶ Gelfoam is commercially available as sterile sheets or powder in 1-g vials which can be administered as pledgets, slurry, or powder based on the desired embolic location.

Gelatin Pledgets

Gelfoam should be administered as pledgets when a proximal arterial embolization is desirable. ¹⁶ To prepare pledgets, Gelfoam sheets are flattened between the thumb and fingers before being cut into smaller, uniform pieces with a scalpel or scissors. The pledgets are then placed into the back of a sterile saline syringe with the plunger removed. Dilute contrast is mixed into the syringe to permit identification of the embolic agent before being attached to the angiocatheter. The larger size of the pledgets allows for more proximal vessel embolization with insignificant variation in the size of particles.

Gelatin Slurry

Gelfoam should be administered as slurry for embolization of medium-sized vessels. ¹⁶ A slurry is produced by pumping gelatin pledgets and dilute contrast back and forth between two syringes through a three-way stop cock prior to its injection into the angiocatheter.

Gelatin Powder

Gelfoam powder is available in sterile 1-g vials and is indicated for distal arteriolar embolization. ¹⁶ It is produced by mixing dilute contrast with a vial of Gelfoam powder until a semi-liquid suspension (applesauce consistency) is achieved. Notably, there is a higher probability of ischemia with the use of gelatin powder to distal embolization due to its small size, ¹⁷ and some sources suggest its embolization effect is more permanent due to the inflammatory effect it has on small vessels with subsequent necrosis. ²³

Microfibrillar Collagen (Avitene)

Microfibrillar collagen, commercially sold as Avitene, was approved in 1976 with multiple form factors coming to market shortly thereafter. ²⁴ Avitene, derived from bovine hide collagen, is available in multiple forms including flour, sheets, pliable sponge, and pre-loaded syringes. ^{16 25} Avitene acts as a potent thrombogenic agent that causes occlusion by mechanical means, but unlike gelatin sponge, it has been demonstrated to cause granulomatous arteritis. This is followed by fibrosis as inflammation subsides with recanalization beginning at 1 week and lasting up to 8 weeks. Avitene is prepared by mixing microfibrillar collagen with dilute contrast to form a semi-liquid suspension (applesauce consistency).

Advantages and Disadvantages of Currently Available Agents

Once the decision is made to use a temporary embolic, interventionalists are tasked with choosing between a variety of available agents. This section provides direction for choosing a temporary embolic agent based on the clinical scenario and current research. Findings are summarized in Table 1 .

Table 1. Comparison of temporary embolic agents and some clinical uses and limitations.

Agent	Representative clinical uses	Limitations
Autologous blood clot	High-flow priapism, biopsy tract embolization, iatrogenic pseudoaneurysm formation	Recanalization within hours to days
Gelfoam (pledgets and slurry)	Traumatic hemorrhage, gastrointestinal hemorrhage, preoperative embolization, uterine artery embolization, biopsy tract embolization	Migration, non-target embolization, possible recanalization
Gelfoam (powder)	Selective arterial embolization, preoperative embolization	Distal occlusion, small vessel ischemia
Microfibrillar collagen (Avitene)	Tumor embolization, biopsy tract embolization	Small vessel ischemia

Autologous Blood Clot

As previously mentioned, ABC was pioneered as a transcatheter embolic agent to temporize gastrointestinal bleeding in the 1960s. Although ABC is not routinely used by interventionalists for embolization of gastrointestinal bleeding at present, it is desirable in certain clinical scenarios including the treatment of high-flow priapism (HFP), biopsy tract embolization, and in the correction of iatrogenic pseudoaneurysm formation. Specifically, ABC should be chosen when vessel recanalization is to be achieved within days. ¹⁶

In a retrospective study by Kim et al, 27 patients underwent superselective embolization of the cavernous artery for HFP. This study compared the use of ABC and gelatin sponge embolic agents in the treatment of HFP. The conclusion drawn from this retrospective study found no significant difference in repeat embolization or change in quality of erection between ABC and gelatin sponge. ²⁶ Similar findings were noted during a retrospective review conducted by Numan et al. In this study, 11 patients who had undergone superselective embolization of nonischemic HFP from 2002 to 2006 were identified. Follow-up examination at 12 months postoperative revealed that 10 of 11 had restoration of full erectile capacity without recurrence of priapism. These studies, along with numerous published case reports, demonstrate the efficacy of ABC in treating HFP. The body's innate spontaneous lysis of ABC in a short period of time after embolization of the cavernous artery for HFP allows for restoration of normal blood flow without catastrophic side effects of ischemia, making this agent an appealing choice for treatment. ²⁷

An additional use for ABC is in the setting of biopsy tract embolization after lung biopsy. A prospective randomized control trial conducted by Malone et al compared biopsy tract embolization with ABC against a control of non-embolization following CT-guided percutaneous lung biopsy. This study found that ABC biopsy tract embolization significantly reduced post-biopsy pneumothorax requiring chest tube placement from 18 to 9% ( p  = 0.048). The overall rate of pneumothorax after biopsy was also reduced in the ABC group, but this was not statistically significant from the control group ( p  = 0.12). ²⁸ In another study performed by Maybody et al, 407 patients who underwent CT-guided percutaneous lung biopsy were randomly selected to receive ABC or hydrogel plug for biopsy tract embolization to assess each agent's effectiveness in decreasing the rate of pneumothorax. Conclusions drawn from this analysis showed that ABC was noninferior to hydrogel in reducing the rate of pneumothorax. ²⁹

Gelfoam

Of the temporary embolic agents discussed, Gelfoam has been explored for a variety of conditions including traumatic hemorrhage, gastrointestinal hemorrhage, preoperative embolization, uterine artery embolization, and biopsy tract embolization.

As aforementioned, temporary embolic agents are favorable in cases of traumatic hemorrhage due to the eventual recanalization of vessels with restoration of blood flow. Gelfoam is frequently chosen for embolization in trauma cases, especially when the patient is unstable, requiring nonselective embolization of large vessels. ²³ Notably, Gelfoam powder should be used only when selective arterial embolization is possible; its use in nonselective vessel embolization can precipitate distal occlusion and undesirable ischemia of small vessels.

A specific emergency for which Gelfoam is indicated is postpartum hemorrhage. This is especially favorable in patients who wish to avoid emergent hysterectomy to preserve future fertility. Gelfoam embolization of the uterine artery via the internal iliac can promote cessation of hemorrhage in the majority of patients, with some requiring the addition of a permanent embolic agent to avoid hysterectomy. ³⁰ According to a recent meta-analysis, Gelfoam particles 500 to 1,000 μm in diameter are considered safe. ³¹ Additional obstetric and gynecologic conditions in which Gelfoam embolization can be of benefit include symptomatic uterine arteriovenous shunt secondary to obstetric complications ³² and uterine fibroids in which Gelfoam alone has similar efficacy to Gelfoam plus a permanent embolic agent. ³³

Other emergencies that can be treated with Gelfoam embolization include acute gastrointestinal hemorrhage. In a recent systematic review, Gelfoam was a popular choice for embolization agent, second only to permanent coils. ³⁴ Gelfoam carries the risk of migration and non-target embolization for this indication, while coils can cause permanent occlusion of non-target vessels if deployed incorrectly. Studies that directly compare the efficacy and safety of these agents are required to determine which one is superior.

Gelfoam, often in combination with permanent agents, is also favorable for preoperative embolization to decrease intraoperative blood loss, transfusion, and postoperative complications. Preoperative embolization is especially beneficial for the resection of musculoskeletal lesions due to their high risk of intraoperative bleeding. According to a recent literature review, the most common embolic agents for these procedures include Gelfoam, coils, N-butyl-cyanoacrylate, ethylene–vinyl alcohol (onyx), and polyvinyl alcohol ³⁵ with several sites reporting the use of Gelfoam in combination with other permanent agents to achieve desirable occlusion. ^{36 37} Gelfoam powder has also been used as an adjunct to coils and permanent microspheres for preoperative portal vein embolization to induce lobar hypertrophy prior to hepatectomy. ³⁸ Since Gelfoam is cheaper than engineered microspheres, this likely contributed to decreased cost. An additional use for Gelfoam powder lies in the preoperative embolization of the internal maxillary artery prior to resection of nasopharyngeal carcinoma. ³⁹

Gelfoam for biopsy tract embolization has variable utility based on the sampled organ and patient risk factors. Recent randomized control trials suggest Gelfoam slurry significantly decreases pneumothorax, hospital admissions, ⁴⁰ and chest tube placement ⁴¹ following CT-guided lung biopsy. Gelfoam slurry for liver biopsy tract embolization is associated with significantly fewer bleeding-related adverse events, ⁴² though it may incur additional costs with little benefit for patients with low risk of bleeding. ⁴³ Gelfoam sponge was the cheapest agent ($19.06) of those studied which included Avitene ($77.31), though ABC is assumed to be the most cost-effective of temporary agents.

Microfibrillar Collagen (Avitene)

Microfibrillar collagen (Avitene) may be used as a temporary embolic agent for tumor embolization and biopsy tract embolization. Of the temporary embolic agents discussed, Avitene precipitates granulomatous arteritis and has the longest time to recanalize, making it a useful agent when significant, long-term occlusion is sought.

In a retrospective study performed by Gaba et al, the safety and efficacy of gelatin foam and microfibrillar collagen was compared in liver tract embolization after islet cell transplantation. During their retrospective study, they identified 37 patients who underwent islet cell transplantation and compared the rates of post-embolization bleeding. Post-embolization bleeding was not identified in the two patients who underwent Avitene liver tract embolization compared to nine bleeding events in the remaining patients who underwent Gelfoam embolization of the liver tract. ⁴⁴ Further studies are warranted to determine which agent is more effective for this indication.

Avitene also has utility as an embolic agent in the interventional suite for tumor and skin/biopsy tract embolization. Of note, Avitene, similar to Gelfoam powder, should be avoided in controlling gastrointestinal bleeding as distal, small vessel occlusion by Avitene can lead to end-organ ischemia with catastrophic consequences. ¹⁶

Limitations of Agents

These agents have been used successfully for many decades in various settings. However, little is known about the duration of occlusion of these “temporary” embolic agents. Early animal model reports on Gelfoam demonstrated differing vessel recanalization time occurring within 2 months by Light and Prentice ⁴⁵ compared to 4 months by Barth et al. ⁴⁶ Furthermore, literature by Jander and Russinovich that highlights permanent vessel occlusion with Gelfoam by follow-up angiogram performed between 1 and 4 months suggests that Gelfoam embolization can have an unintended consequence. ¹⁰ This might be related in part to the way Gelfoam is prepared or administered by the operator. The smaller the embolic agent, the greater likelihood for distal embolization and vascular occlusion. Similarly, the greater the volume of embolic administered, the greater the density of embolic material and lower likelihood for vessel recanalization.

Similarly, time to vessel recanalization with Avitene varies in the literature. In a study by Sniderman et al, selective catheterization and embolization was performed of eight mongrel dogs. Arteriography and histologic evaluation after sacrifice demonstrated partially recanalized vessels at 2 weeks, which were fully recanalized after 2 months. ⁴⁷ The intrinsic quality of Avitene inducing a granulomatous arteritis reaction would suggest a more permanent vascular occlusion or, at the very least, an unpredictable time to vessel recanalization.

It is imperative for the operator to visualize their target for embolization and the administration of their embolic agent of choice. None of the temporary embolic agents' innate properties allow for detection by fluoroscopy, and even with the nuanced preparation of Gelfoam and Avitene with contrast dye, the visualization on angiography is limited. ¹³ This makes it challenging to determine when the embolization endpoint has been met or to assess if there has been migration or non-target embolization.

Advancements in Embolic Technology

Current temporary embolic agents have their limitations, including non-target embolization due to migration of the agent, nuanced preparation of the embolic or the catheter, limited visualization on angiography, ¹³ and unpredictable degradation timeframes. ⁴⁸ Development of a more favorable embolic could have positive outcomes and economic implications for both the hospital and the patient, warranting their investigation. Temporary embolic agents currently in development include the following: Thermogel, Embogel and Emboclear, Borate glass microspheres, poly(D,L-lactic acid), and imipenem–cilastatin (IPM-CS). Their properties are outlined in Table 2 .

Table 2. Summary of temporary embolic agents in development with respect to their strengths, limitations, and intended clinical uses.

Agent	Strengths	Limitations	Intended clinical use	Citation
Thermogel	Radiopaque, storage	Recanalization at 1 h		49
Embogel/Emboclear	On-demand degradation			53
Shape memory polymers	Phase change, complete occlusion, limited distal migration, radiopaque	Unknown recanalization and tissue response		55
Borate glass microspheres	Uniform degradation	Incomplete recanalization		48
Starch microspheres			UAE, epicondylitis	52
Biodegradable DEB	Sustained drug release and targeted drug accumulation	Partial, incomplete degradation	Interventional oncology	56 57
Imipenem–cilastatin	Peripheral ischemia (when desirable)		Knee OA, finger OA	58 59 60 61

Abbreviations: UAE, uterine artery embolization; DEB, drug-eluting beads; OA, osteoarthritis.

Thermogel is a liquid embolic agent composed of polyethylene glycol-poly lactic acid copolymers. ⁴⁹ It can be stored at room temperature and combined with iopamidol for X-ray visualization, making it easy to access and visualize during procedures. It also overcomes some of the limitations of Onyx, the only liquid embolic agent currently approved by the FDA. Onyx is a permanent agent composed of ethylene vinyl alcohol in dimethyl sulfoxide (DMSO) which requires slow infusion via specific catheters. This also necessitates an upper limit to how much agent can be injected, and it requires pre-mixing with tantalum powder for 20 minutes prior to administration. ⁵⁰ Thermogel, on the other hand, is a temporary agent that can be administered through conventional catheters with no known upper limit and no pre-mixing. However, recanalization observed 1 hour post-embolization requires further engineering to capitalize on these benefits. ⁴⁹

PEG microspheres have also been cross-linked to poly(lactic-co-glycolic acid) (PLGA), forming resorbable embolization microspheres which have been investigated in uterine artery embolization. ⁵¹ They are degraded into monomer subunits and excreted in the urine.

Degradable starch microspheres (Sperex, Kristianstad, Sweden) have also been investigated for the purpose of temporarily occluding the uterine artery ⁵² as they are degraded via host a-amylase. With further study, these temporary embolic agents may overcome the limitations of permanent ones which are thought to produce chronic inflammatory responses, collateral development, and irreversible damage.

Another area of research involves embolic agents that can be degraded on-demand. This technology was first developed and patented under the name Embogel and Emboclear from a group at Johns Hopkins University. ⁵³ They successfully complexed biodegradable alginate with iohexol which polymerizes into a hydrocoil. The embolic agent can be degraded following the administration of alginate lyase and ethylenediaminetetraacetic acid (EDTA). A second alginate-based gel has been used to form microspheres when complexed with ultra-small superparamagnetic iron oxide clusters and coagulated with CaCl2. ⁵⁴ The administration of EDTA acts as a calcium chelator, effectively sequestering the calcium cross-links and degrading the microspheres in vitro and in vivo . On-demand degradation could reverse non-target embolization, especially in the case of embolic agents advancing beyond the target area and occluding downstream vessels.

SMP may similarly prevent non-target embolization and provide a customizable material for temporary occlusion. In preliminary studies, poly (D,L-lactide-co-glycolide) (PLGA) was coated in cross-linked polyethylene glycol diacrylate (PEGDA) with radiopaque filler, producing a plug prototype that can be administered via microcatheters. ⁵⁵ The PLGA-PEGDA blend can be heated into an amorphous phase that allows for its administration. Once within the vessel, the plug displays complete embolization by cooling to body temperature, swelling with the absorption of water, and obtaining its final, crystalline structure. Degradation of the PLGA-PEGDA plug occurs via solubilization and hydrolysis of acrylate esters, and notable mass loss was observed in vitro over a period of 10 weeks. Complete occlusion was observed within 120 seconds in vivo , and only one subject was observed to have distal migration of the embolic agent after administration to the carotid artery.

Borate glass microspheres have also been proposed as temporary agents for TAE due to their uniform degradation. However, their administration requires a prototype, three-way stopcock for delivery, further complicated by incomplete recanalization despite their degradation, ⁴⁸ likely due to natural thrombus formation. This requires further investigation over a longer time period to determine the efficacy of borate glass microspheres for temporary embolic use.

In addition to clinical use for TAE, temporary embolic agents are being developed for TACE. Poly(D,L-lactic acid) (PDLLA) is an emerging temporary DEB which can load and distribute chemotherapeutic drugs thanks to its porosity. ⁵⁶ PDLLA microspheres exhibit partial degradation with significant releases of sorafenib and cisplatin in vitro . PLGA microspheres have also been investigated as biodegradable DEBs loaded with sorafenib and 2,3,5-triiodobenzoic acid for visualization. ⁵⁷ In vitro and in vivo studies exhibit sustained drug release, observable degradation, and targeted drug accumulation compared to oral intake of sorafenib. Biodegradable embolic agents could prevent late inflammatory responses to permanent foreign material and provide an avenue for reintervention if necessary, making them favorable over permanent occlusives in some cases. Longitudinal studies are required to determine whether these biodegradable agents are in fact temporary.

The clinical applications of temporary embolic agents continue to evolve as well. IPM-CS, which forms <40-μm particles when mixed, is being investigated as an alternative to permanent polyvinyl alcohol and microsphere agents for the treatment of joint conditions such as osteoarthritis. ⁵⁸ The agent is thought to produce peripheral ischemic changes, and the GAUCO study protocol will elucidate its efficacy compared to permanent embolic agents for knee osteoarthritis. ⁵⁹ IPM-CS has also been proposed for the treatment of finger osteoarthritis ⁶⁰ and biodegradable gelatin agents are being adapted for the treatment of lateral epicondylitis. ⁶¹

Conclusion

Embolic agents and their application in therapeutic vascular occlusion have advanced considerably since their emergence in the mid-1960s, and choosing an appropriate agent becomes increasingly important as additional agents arise. Temporary embolic agents such as ABCs, Gelfoam, and Avitene have emerged as indispensable tools in the interventionalist's arsenal, providing effective occlusion while allowing for vessel recanalization and potential reintervention. The choice of embolic agent is guided by various factors including clinical indication and desired occlusion duration. Gelfoam has the most extensive clinical utility with efficacy in treating traumatic hemorrhage, gastrointestinal hemorrhage, preoperative embolization, uterine artery embolization, and biopsy tract embolization. ABC is also indicated for biopsy tract embolization in addition to HFP and iatrogenic pseudoaneurysm embolization. Avitene has utility in tumor and biopsy tract embolization.

Challenges remain, specifically regarding non-target embolization and unpredictable degradation timeframes. However, ongoing research into novel technologies such as Thermogel, SMP, and on-demand degradable agents hold promise for addressing these limitations and further enhancing the safety and efficacy of embolization procedures. From the earliest use of muscle tissue and lead pellets to the latest developments in embolic technology, the field of embolization has witnessed significant progress driven by the same innovative spirit that Dr. Charles Dotter possessed during the first image-guided embolization procedure and every pioneering interventionalist who followed.