Clinical Safety In Application
Both in vitro and in vivo studies have taken place, designed to generate data on the safety of Arthramid Vet and to support regulatory submissions for market authorisation. Most current OA treatments are focused on reducing symptoms, and there are few effective treatments that address the underlying cause of the disease . 1Besides, some treatments are associated with significant toxicities and contra-indications, and their use is restricted because of competition and welfare concerns. 1, 2 Multiple studies have now shown that 2.5% PAAG is safe for use in animals and humans. 1, 3, 4, 5, 6, 7, 8,9
A neurotoxic mode of action would require the presence of acrylamide monomer in the joint. No sources of acrylamide are present due to extensive washing and autoclaving through the manufacturing process and is validated at lot release testing of each batch. Any potential cytotoxic effects of Arthramid Vet have also been independently tested using cell growth analysis via BCA-Staining. This method represents one of the easiest methods to determine any possible detrimental effects of substances, and cell culture techniques also allow a rapid yet sensitive diagnosis of the biological reactivity of materials. 10, 11The BCA-Staining test predicts cytotoxic or necrotic effects of medical devices or materials with good correlation to animal experiments and high sensitivity. 12, 13 Under this testing model it has been shown that no cytotoxic or banned substances are released from 2.5% PAAG.
The active substance used to manufacture 2.5% PAAG is the same as the finished product, i.e. cross-linked polyacrylamide hydrogel (CAS No. 9003-05-8). The product is known to be exceptionally stable, and extensive washing occurs during the manufacturing process to remove any potential contaminants. In contrast, monomers of acrylamides are known to be neurotoxic to animals and humans, whereas polyacrylamides are non-toxic14. More than 500,000 humans have been treated with Contura 2.5% PAAG medical devices worldwide, with no evidence of neurotoxicity.
Furthermore, any possible toxic effects of residual monomers from manufacturing have been calculated using recommendations from the United States Environmental Protection Agency (2007). 15Levels did not raise biological safety concerns, either in data-derived or worst-case scenarios. The European Medical Agency (EMA) likewise recently ruled that 2.5%PAAG as not falling within the scope of regulation concerning residues for veterinary medicinal products. 16
In vivo, studies investigating the safety of Arthramid Vet at 1x, 2x, and 5x the standard recommended dose have been performed for regulatory purposes with follow up examinations done at Days 1, 3, 7, and 14 after treatment. The safety of the product was evaluated using physical examination, (including joint health and mobility), and evaluation of complete blood haematology, serum biochemistry and acute phase proteins (SAA). While results showed mild variations between individuals and groups, they were unrelated to the treatment and consistent with normal variations due to breed, exercise, diet, climate, and history. This finding aligns with numerous other published clinical studies where no adverse reactions have been recorded with Arthramid®Vet. 2, 3, 4, 5, 6, 7
Tnibar (2017)7 also investigated any potential neurotoxic effects by studying the nerve endings in the synovial membrane of 2.5% PAAG treated goats. The nerve endings were seen intact with normal morphology and in normal numbers, regardless of the clinical result and the same as saline treated controls.
In conclusion, 2.5% PAAG has had widespread use in human medicine for many years and together these studies are consistent in their findings that it is safe, non-pyrogenic and neuro-innocuous.
- 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.
- Kynch, H., Vidal, M., Chouicha, N., Mitchell, M., Kass, P., Cytokine, catabolic enzyme and structural matrix gene expression in synovial fluid following intra-articular administration of triamcinolone acetonide in exercised horses. Equine Vet J. 2017; 49: 107-115.
- 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 2014b.
- 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. Equine Vet J; [Online] 2019. https://www.sciencedirect.com/science/article/pii/S0737080618307615?dgcid=rss_sd_all
- 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.
- 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.
- Tnibar, A., Persson, A.B., Jensen, H.E., Mechanisms of action of an intraarticular 2.5% polyacrylamide hydrogel (Arthramid Vet) in a goat model of osteoarthritis: Preliminary Observations. SM J Biomed Eng. 2017; 3: 1022.
- 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.
- Henriksen, M., Overgaard, A., Bliddal, H., Initial estimates of efficacy of intra-articular 2.5% polyacrylamide hydrogel for the treatment of knee osteoarthritis: An observational proof-of-concept study [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10).
- Guess, W.L., Autian, J., Toxicity evaluation of Lexan, Kyonar, Rilsan, short-term studies. J Oral Ther Pharmacol. 1966; 3(2): 116-123.
- Stark, D.M., Shopsis, C., Borenfreund, E., Babich, H., Progress and problems in evaluating and validating alternative assays in toxicology. Fd Chem Toxic. 1986; 24: 449-455.
- Autian, J., Dillingham, E.O., Overview of general toxicity testing with emphasis on special tissue culture tests. In: Berky, J., Seherrod, C., editors. In vitro toxicity testing. The Franklin University Press. Philadelphia, 1978; 21-49.
- Wilsnack, R.E., Quantitative cell culture biocompatibility testing of medical devices to animal tests. Bio-materials. 1976; 4: 235-261.
- Narins, R.S. and Schmidt, R., Polyacrylamide hydrogel differences: Getting rid of the confusion. J Drugs Dermatol. 2011; 10(12): 1370-1375.
- ‘United States Environmental Protection Agency, 2007. IRIS Toxicological Review of Acrylamide. [Online]
Available at: http://ofmpub.epa.gov/eims/eimscomm.getfile?p_download_id=495149
- European Medical Agency. 2019. Substances considered as not falling within the scope of Regulation (EC) No. 470/20091, with regard to residues of veterinary medicinal products in foodstuffs of animal origin Available at; https://www.ema.europa.eu/documents/regulatory-procedural-guideline/substances-considered-not-falling-within-scope-regulation-ec-no-470/20091-regard-residues-veterinary-medicinal-products-foodstuffs-animal-origin_.pdf
Arthramid Vet New Zealand
Registered in New Zealand to: Innovative Medical Solutions Limited NZBN: 9429041325544, 32 Hill Road, Cambridge 3494, New Zealand. Registered pursuant to the ACVM Act 1997 Number A11596. See www.foodsafety.govt.nz for registration conditions.