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Not all hydrogels are the same

In 2011, Narin’s and Schmitd(1) published an article titled 'Polyacrylamide differences; Getting rid of the confusion'. The article outlined the significant differences between the numerous polyacrylamide hydrogels (PAAG) available. Polymer hydrogels have been used for many years in European and Asian countries in humans and these products are often considered to be the same material in different packaging. This however was not the case. With the increasing use and awareness now of PAAG hydrogels in the veterinary field we felt it time to raise this discussion again. 

Hydrogel products, although often considered equal, have clear differences in composition, manufacturing and injection technique, as well as their ability to interact with surrounding tissues. Characteristics that ultimately determine the safety and efficacy profiles of each of these gels. 

Arthramid® Vet, a 2.5% PAAG, is manufactured by Contura A/S, Denmark. It is produced by a patented technology called In-line Cross-Linking Technology (ILX Technology), forcing water molecules between the cross- linked polymers of polyacrylamide (CAS No. 9003-05-8), that provides the gel with exceptional molecular stability and the ability to retain its viscoelastic properties in situ. Arthramid® Vet is hydrophilic, due to its chemical structure, and has an irreversible and steady-state backbone, with lightly bound water molecules that can interchange with water molecules of surrounding tissue. 

The human equivalent hydrogel was first approved and CE-marked in Europe in 2001 for soft tissue augmentation in humans. Having undergone extensive analysis for safety, efficacy, toxicology, and manufacturing, Arthramid® Vet was first approved by regulators in New Zealand in mid 2019 for veterinary treatment of joint lameness in horses. Australia soon followed in early 2020, and the FDA in the United States approved the product in the middle of 2020. Contura’s 2.5% PAAG’s are now approved for multiple uses across both veterinary and human medical fields in multiple countries and jurisdictions around the world. 

Arthramid® Vet 2.5% polyacrylamide hydrogel is proven to be a stable, non-degradable, cross-linked hydrogel with 2.5% wt-% dry matter. Each batch is analysed for consistency and compliance with product specification including narrow tolerances of elasticity modulus, pH, impurities and degradation products from the polymerization reaction before batch release.  

Tissue cells have been found to grow well in the 2.5% PAAG gel and it allows vessel in-growth from adjacent tissues, likely due to the unique pore size between molecules. Its biocompatibility in soft tissues has been demonstrated and histopathological studies of subcutaneous tissues from mice, rats, rabbits, pigs, horses and humans have shown it supports cell growth and tissue integration and possesses a permanent, stable augmentation effect due to constant molecular water exchange with its host tissue (2,3,4,5). Multiple experimental studies have shown that the integration process will begin immediately after injection and takes four up to six weeks to have an effect (2). 

Harder (high visco-elastic) hydrogels do not integrate with the surrounding tissues. Instead they become covered with a thin fibrous membrane that completely surrounds the hydrogel. Therefore, implantation of these hydrogels has been associated with higher incidence of complications such as late onset infections, granulomas, and hydrogel displacement. Some hydrogels are banned from certain countries due to such complications. Arthramid® Vet is a softer (low visco-elastic) hydrogel so can also be injected using smaller gauge needles (typically a 20-23g in horses) and is known to fully integrate into the synovium and joint capsule within 2 to 4 weeks, minimising the risk of encapsulation, migration, and other late onset complications such as bio-film assisted infection. 

The safety and performance of Arthramid® Vet has been evaluated in multiple clinical studies (6,7,8,9,10,11). The literature shows little evidence of performance or safety of other PAAG products, but a widespread and largely indiscriminate use of these in some countries has caused serious long-term complications, mainly infection and granulomatous reactions, that have been described in several reports during the past 10 years. Reports on a 4% PAAG hydrogel (12) (Noltrex) used only an improvement in lameness score as a measure of clinical success. In comparison studies on Arthramid® Vet 2.5% PAAG have consistently used ‘complete resolution of lameness’ as a measure of success. Ultimately from a clinician’s and owner’s point of view horses are either sound and can continue in work, or are still lame and require other treatments, reassessment of the diagnosis or prolonged periods of rest. 

Serious long-term complications have rarely been reported in these clinical trials, probably where products have been used under tight control and according to intended use. However as with any other product when used incorrectly some safety concerns may arise. Arthramid® Vet comes in a sterile pre-loaded luer lock syringe that reduces the risk of infection and increases safety even further. 

So while polymer hydrogels might seem at first glance to be the same material in different packaging clear differences become evident on closer inspection. These differences appear in composition, manufacturing processing and control, injection technique and tissue interaction. Each of these parameters has the potential to greatly affect the safety and performance of the product as highlighted in the discussion above. In conclusion polymer products including different PAAG hydrogel product should therefore not be used interchangeably. The level of evidence for safety and performance varies greatly from product to product and the lack of safety and performance data for some polymeric hydrogels hinders accurate comparison between the products. This means that only the Arthramid® Vet 2.5% PAAG product with a proven and adequate safety profile should be used under strict regulations for intended use. 

Dr Jason Lowe BVSc, Cert EP, MBA

References 

1. Narins, R.S. and Schmidt, R., Polyacrylamide hydrogel differences: Getting rid of the confusion. J Drugs Dermatol. 2011; 10(12): 1370-1375. 
2. Christensen, L., Camitz, L., Illigen, K.E., Hansen, M., Sarvaa, R., Conaghan, P.G., Synovial incorporation of polyacrylamide hydrogel after injection into normal and osteoarthritic animal joints. Osteoarthritis Cartilage. 2016; 24: 1999-2002. 
3. Christensen, L.H., Nielsen, J.B., Mouritsen, L., Sorensen, M., Lose, G., Tissue integration of polyacrylamide hydrogel: An experimental study of periurethral, perivascular, and mammary gland tissue in the pig. Dermatol Surg. 2008; 34: 68-77. 
4. Christensen, L.H., Breiting, V.B., Aasted, A., Jorgensen, A., Kebuladze, I., Long-term effects of polyacrylamide hydrogel on human breast tissue. Plast Reconstr Surg. 2003; 111(6): 1883-1889. 
5. Zarini, E., Supino, R., Pratesi. G., Laccabue, D., Tortoreto, M., Scanziani, E., Ghisleni, G., Paltrinieri, S., et al. Biocompatability and tissue interactions of a new filler material for medical use. Plast Reconstr Surg. 2004; 114: 934-942. 
6. Tnibar, A., Schougaard, H., Koene, M., Christensen, L.H., Markussen, B., A controlled clinical trial on the efficacy of an intra-articular polyacrylamide hydrogel in horses with osteoarthritis. 23rd Annual Scientific Meeting of the European College of Veterinary Surgeons (ECVS), Copenhagen, July 2014. 
7. De Clifford, L.T., Lowe, J.N., McKellar, C.D., Chambers, M., David, F., A single site, double-blinded, prospective study on the comparative efficacy of a 2.5% polyacrylamide hydrogel in horses with inter- carpal joint lameness. Journal Equine Vet Science; [Online] 2019. https://www.sciencedirect.com/ science/article/pii/S0737080618307615?dgcid=rss_ sd_all 
8. Tnibar, A., Persson, A., Jensen, H.E., Svalastoga, E., Westrup, U., McEvoy, F., Evaluation of a polyacrylamide hydrogel in the treatment of induced osteoarthritis in a goat model: A pilot randomized controlled Study [abstract]. Osteoarthritis Cartilage. 2014; 22: 477. 
9. Tnibar, A., Schougaard, H., Camitz, L., Rasmussen, J., Koene, M., Jahn, W., Markussen, B., An international multi-centre prospective study on the efficacy of an intrarticular polyacrylamide hydrogel in horses with osteoarthritis: a 24 month follow up. Acta Vet Scand. 2015; 57: 20-27. 
10. Janssen, I., Koene, M., Lischer, C., Intra-articular use of a polyacrylamide hydrogel as a treatment for osteoarthritis in the distal interphalangeal joint: a case series of 12 horses. Pferdeheilkunde. 2012; 28: 650-656. 
11. Bathe, A.P., Read, R., Briggs, C., Intra-articular polyacrylamide hydrogel for the treatment of 20 horses with non-responsive osteoarthritis of the interphalangeal joints: a prospective study [abstract]. Veterinary Orthopaedic Society 43rd Annual Conference, USA. 2016; 4-5. 
12. McClure, S.R. and Wang, C., A preliminary field evaluating the efficacy of 4% polyacrylamide hydrogel in horses with osteoarthritis. J Equine Vet Sci. 2017; 54: 98-102.