Everything you need to know about this novel intra-articular therapy

Osteoarthritis (OA) is one of the more serious performance-altering and potentially career-ending maladies to affect horses. Equine practitioners and researchers make great efforts to seek out effective treatments. What started decades ago as palliative care using intra-articular corticosteroid (triamcinolone acetonide, or TA) and/or hyaluronic acid (HA) intra-articular injections has more recently transformed into therapeutic use of regenerative therapies with biologic agents such as IRAP (interleukin-1 receptor antagonist protein), platelet-rich plasma, and stem cells within a joint.

A new treatment approach has come to the forefront that holds promise for improving the health and comfort of ailing joints: polyacrylamide gel, or PAAG, which is designed to restore joint capsule elasticity and synovial (joint) fluid viscosity and improve lubrication. In this article we’ll review the mechanisms of action and science behind two types of PAAG on the market: 2.5% and 4%.

What Is 2.5% PAAG?

Florent David, DVM, MS, Dipl. ACVS, ECVS, ACVSMR, ECVSMR, ECVDI, associate and senior surgeon at the Equine Veterinary Medical Center, in Doha, Qatar, has been part of the vanguard of practitioners using PAAG regularly to treat OA in sport and racehorses. He describes 2.5% PAAG as a nontoxic gel that retains viscoelastic properties through cross-linking technology. He says the gel integrates with water molecules and surrounding tissue to form a bioscaffold, and that the ­material incorporates into the synovium (the joint lining) about four weeks post-injection and can persist up to two years in OA-affected and control joints. In his experience, he adds, orthopedic shoeing and modified exercise programs help maximize the duration of improvement.

“I see many cases injected on multiple occasions with corticosteroids yet with far too short an interval between injections,” says David. “Response to corticosteroids often lessens or fails to achieve improvement by the time I see the horse. I prefer to catch joint damage early in its course to avoid having to use other intra-articular therapies. In some instances it may be appropriate to use PAAG joint injections in horses as young as 1 to 4 years old, depending on breed and activity. Early implementation of PAAG is particularly appropriate for horses where a conformational issue has been identified as a ticking time bomb for joint degeneration.”

He adds that combining orthopedic shoeing and PAAG can help stave off joint degeneration in young horses entering an intense sport with conformation faults that would otherwise result in unmanageable joint damage.

“PAAG is beneficial for established OA or its precursor and early stages,” David says. “Based on the study results with 2.5% PAAG (TheHorse.com/183011), 60-70% of the cases returned to soundness after one PAAG injection for the joints tested—coffin, pastern, fetlock, and knees. It seems to be slightly less efficient in managing severe or chronic cases, with only 10% reduction in the chance of returning horses to soundness. As yet, we don’t have a large-scale study comparing the outcome at various stages of ­osteoarthritis.”

He says he likes to use PAAG to provide a therapeutic effect when horses have three to four weeks before their next competition or when corticosteroids are contraindicated for joint or metabolic health or banned due to competition testing requirements. “Because this medication needs time to elicit its benefit in a joint, it is not appropriate to use it at the last minute in an attempt to push a lame horse through a competition that might risk a more serious injury,” he stresses.

Label directions recommend transitioning horses back to work slowly over two weeks to allow time for the gel to incorporate into the synovium and to reduce the chance of a joint flare. If a veterinarian injects a joint with 2.5% PAAG for preventive or maintenance purposes, David says the horse might only need 48 hours of rest following treatment.

“For a horse that is visibly lame, it is beneficial to reduce the exercise level for at least two weeks until the effect becomes noticeable,” he says. “If stopping the horse from exercise is not an option, or if this period is targeted for ­conditioning, then swimming or underwater treadmill exercise is useful to accomplish cardiovascular exercise with a reduced load on the musculoskeletal system.”

Lauren Luedke, DVM, Dipl. ACVS-L, a surgeon at Manor Equine Hospital, in Monkton, Maryland, explains the two-week course of rest following PAAG injection is based on the timing of effect for PAAG to begin to integrate into the synovial lining.

“Continued cellular infiltration occurs until four to six weeks after the injection,” she says. “Horses are significantly improved after two weeks, although on a cellular level, it takes four to six weeks for peak effect.”

How 2.5% PAAG Works

Luedke explains that 2.5% PAAG integrates with the synovial lining to support synoviocytes (cells in the joint lining) while integrating into the cells to form a network of vascular and fibrous tissue. “This is thought to allow greater joint capsule elasticity to achieve positive symptom-modifying effects,” she says.

David adds that shock absorption from viscoelastic properties is a possible—though not yet proven—mechanism of action. He believes this could explain the relatively immediate response in some cases. “That said, a sufficient volume is necessary to cover the entire cartilage bed in order to achieve such an effect,” he says.

In one study Tnibar et al. showed improved elastance (a measure of the tendency of a structure to return to its original form after removal of a deforming force) reduced joint stiffness. Improved joint elasticity is an important feature of how PAAG modulates discomfort and lameness, says Luedke. Other speculated mechanisms of action include covering subchondral mechanoreceptors (cells that respond to stimuli) to prevent nerve stimulation.

David notes this is unproven and that “it is hard to believe that such a thick gel composed of large molecules could travel through entire cartilage tissue to reach and block subchondral ­mechanoreceptors.”

A possible mechanism of action, in light of recent findings with 4% PAAG, is the gel’s adhering properties to cartilage lesions and a subsequent reduction in friction between cartilage surfaces. However, he says there’s no evidence of 2.5% PAAG coating cartilage to facilitate fibrocartilaginous healing.

Luedke says when she has performed arthroscopic surgery on some horses previously injected with PAAG, she’s noticed visual evidence of PAAG within the joint. She describes what she sees as clumps of clear “saran-wrap-like material” that are free floating or adhered to the synovium. “I can’t say that is necessarily a negative effect; however, it is concerning for cases that become infected following injection or have joint flare,” she says. “It is ­unknown if PAAG has the capacity to harbor bacteria and support the formation of biofilm.”

For these reasons Luedke says she only injects joints with PAAG if they’ve been clear of infection for at least three months.

Duration of Action of 2.5% PAAG

David’s group recently completed a study (de Clifford et al., 2021) indicating PAAG can provide relief for up to 12 weeks, although the researchers didn’t follow the study horses beyond that. In other studies researchers have noted the presence of 2.5% PAAG in synovial membrane for two years after injection, with improved lameness and joint effusion throughout that duration.

Luedke tends to use 2.5% PAAG for treating end-stage joints that have developed a fair amount of OA, especially in older horses no longer helped by corticosteroid-hyaluronic acid or IRAP injections. “Because I typically use PAAG in more advanced OA cases … the joint needs more support (higher and more frequent doses),” she says. “Therefore, I am injecting those horses every 10 to 12 months.”

Luedke and David point out that there is no published dose/volume response data for PAAG. “It is reasonable to consider that the same volume of PAAG likely has a more profound effect in a smaller volume joint, such as the fetlock, compared to the voluminous femoropatellar joint of the stifle,” says Luedke. “More volume can be used in larger joints; however, this can be cost-prohibitive.”

One might wonder whether 2.5% PAAG injections potentially interfere with the efficacy of other treatments. “The duration of action of triamcinolone is 14 days, and product reports suggest safety when injecting other products simultaneously,” Luedke says. “Yet, it is probably best to be cautious and wait two to three months between TA and PAAG injection.”

David says follow-up with another treatment is possible in case of treatment failure or if the horse experiences only a partial response to PAAG. “For a horse that responds partially, I prefer not to combine different intra-articular treatments but, instead, try to stick to the product selected as Option A,” he explains. “In these cases the horse is either given additional time for recovery along with reshaping the rehab program or the joint is re-injected with a higher dose of PAAG before turning to Option B.”

David recommends veterinarians base follow-up injections for joints that respond well to PAAG on the horse’s competition schedule and rider or trainer feedback.

What Is 4% PAAG, and How Does It Work?

Polyacrylamide gel is also available in a 4% form, which is completely different than the 2.5% product, says Scott McClure, DVM, PhD, Dipl. ACVS, ACVSMR, of Midwest Equine, in Boone, Iowa.

“You can take a bucket of water and have 5% volume of yarn,” he explains. “The yarn can be tightly woven, loosely woven, knitted in circles or squares. You still have 5% yarn and 95% water. The differences in percentage of ­polyacrylamide—2.5% versus 4%—should not be confused with how they are ‘knitted together.’ ” The 4% acts as a surface lubricant, he says.

Researcher Larry Bonassar, PhD, and his team at Cornell University’s Meinig School of Biomedical Engineering, in Ithaca, New York, recently discovered that 4% PAAG lowers the friction coefficient (the lower the coefficient, the less friction) of neonatal bovine cartilage in a lab model by nearly 50%—a significant amount considering the dynamic range of friction during joint movement, he adds. Bonassar says 4% PAAG’s direct association with the cartilage tissue might explain how it provides lubrication.

“The 4% material was designed with properties to mimic hyaluronic acid,” McClure explains. “This product persists on the cartilage surface for at least a month. Ultimately, the synovial membrane phagocytizes (engulfs) any free material and removes it. Still, the 4% PAAG may persist on the cartilage for many months. The 4% adheres to the cartilage surface likely due to ionic bonding based on the way it stays on the surface of damaged cartilage through friction testing.”

Duration of Action of 4% PAAG

In his research Bonassar has discovered the gel stays present under conditions in which other viscosupplements wash away. The association with tissue not only continues but is enhanced, particularly in cartilage that has been damaged prior to applying the gel, says McClure. In Bonassar’s study, he and colleagues reviewed the effects of 4% PAAG on neonatal bovine femoral condyles in various states in the laboratory: healthy cartilage; induction of mechanical injury; or cytokine injury to elicit biochemical inflammation. He found:

• In cases with calibrated amounts of mechanical injury, the 4% PAAG gel was delivered quickly to surfaces of cartilage fibrillation and cracking.
• For cases with biochemical inflammation via cytokines that elicited cellular responses and tissue damage, PAAG associated (bonded) strongly with the cartilage.
• PAAG associated most strongly with tissues affected by mechanical damage.
• The lower friction coefficient results achieved in damaged tissue were comparable to friction coefficients seen in healthy tissue.

The friction coefficient of cartilage from many species behaves similarly, says Bonassar. This includes neonatal and adult bovine tissue, as well as equine and human tissue. He used bovine neonatal tissue in his study because it is readily available and reproducible.

The duration of time 4% PAAG remains in synovial fluid is a critical feature of its efficacy, says Bonassar. While HA often clears quickly, in this study 4% PAAG persisted for months.

“It may be more important as to ‘when’ versus ‘how much’ is cleared,” he says. “Previous dogma has believed that the mechanical effect occurs on the same time scale as clearance. However, if the therapeutic material is in the right place, it may still have an enduring effect even if some material has been cleared.”

“Safety data show that 4% PAAG can be injected four times at 45-day intervals with no adverse effects,” says McClure. As for prophylactic (preventive) use, he says, “Horses in a number of equestrian disciplines have at-risk joints, so it makes sense to protect the cartilage when we can. It’s best to have the horse on down time after treatment, so it’s opportune to treat when these athletes have a break from competition.”

Other Uses of PAAG Besides Joints

Luedke says some vets have used 2.5% PAAG to treat tendons successfully. “­Appropriate diagnosis is key,” she says. “A horse with tendon sheath effusion due to a tear in the DDFT (deep digital flexor tendon) needs treatment aimed at the tendinopathy rather than synovitis. It is also important to ensure that PAAG won’t predispose to adhesion formation in the tendon sheath, especially based on the end result of PAAG integration into the synovium as a layer of fibrouslike tissue.”

She adds that 2.5% PAAG might have an appropriate use in treating navicular bursitis (inflammation of the navicular bursa, or the sac cushioning the navicular bone from the DDFT); it also has potential value for cervical facet arthritis.

McClure says he has used 4% PAAG to treat cases of chronic navicular bursitis and DDFT pathology at the navicular bursa with favorable responses.

Still, “more studies need to come to a better understanding of the PAAG mechanism of action, dosage and volume injected per joint, and dosage needed to address specific disease severity or chronicity,” David adds. “We also need studies investigating the combination of other IA medications with PAAG and whether these are beneficial and synergistic or if they work antagonistically. Research also is important to determine if mixing PAAG with other potential doping products like corticosteroids might affect drug withdrawal times for equine competition.”

Take-Home Message

David believes PAAG is a true game-changer for managing osteoarthritis when used properly. “It should prolong the athletic career of elite athletes and make a difference in their overall performance,” he says.

Says McClure, “I’ve seen some cases in which we were able to maintain performance levels that I could not accomplish without polyacrylamide.”

For retired arthritic horses dealing with metabolic issues such as pituitary pars intermedia dysfunction or equine metabolic syndrome, says David, PAAG can improve their daily comfort safely without resorting to corticosteroid injections that could put them at risk of developing laminitis.