The Science of Arthrosamid® (2.5 iPAAG)

Migration potential of the polyacrylamide hydrogel has been studied comprehensively, as reviewed in the BER and in the report “Evaluation of Arthrosamid®Migration and Degradation Potential After Intraarticular Administration”. In short, in relation to intraarticular injection, it has been observed that small particles (8 µm or less) are subject to phagocytosis and will flow with the synovial fluid through the gap junctions in the synovial epithelium and eventually be distributed systemically, whereas larger particles (> 8-17 µm) are encapsulated over time and remain immobilized within soft tissues indefinitely. As described previously, Arthrosamid®/”Hydrogel” is made as a cross-linked matrix of polyacrylamide chains. The final material, as injected, has essentially no small particle components, and the smallest measurable particle size was measured to > 300 μm, which is well above the single micron particle size that has been reported to be physiologically mobile.

In studies of rabbits and horses, macrophages and giant cells associated with the hydrogel were observed, and there was no evidence of hydrogel particles within phagosomes in these cells (Christensen et al., 2016). Additional studies have been conducted that evaluated draining lymph nodes and tissue distant from soft tissue injection sites with no evidence of hydrogel in the local draining lymph nodes or in distant organs (Charles River, 2011). Migration potential of Contura’s polyacrylamide hydrogels is described and discussed extensively in the BER, where it - based on published literature and Arthrosamid® specific testing - is conclude that the polyacrylamide hydrogel will remain as a permanent implant in the subsynovial tissues.

In rabbits and horses the integration of the hydrogel has been followed for up to 2 years after injection. In horses 2 weeks post treatment, the hydrogel appeared as an inner layer within the synovial lining intermixed with proliferating synovial cells, similar to the histology seen in a rabbit model. At 1 month the synovial cells apparently relocated towards the surface, and at 3, 8 and 24 months a similar pattern of integration was observed (Christensen et al., 2016). The hydrogel was present as an integrated zone within the subsynovial interstitium with a fine vessel-bearing tissue network and very few inflammatory cells.

A prospective histopathological study has been performed on tissue removed from patients during total knee arthroplasty (TKA). The patients had received treatment with the hydrogel 5-33 months earlier. A similar histological pattern was seen in all seven cases: The hydrogel was found to be integrated in the synovial membrane and outer synovial lining cells had entered the gel and established a de novo lining layer. A similar pattern was described 9 months after TKA in a case study (Christensen and Daugaard, 2016) .

Contura’s hydrogels have been marketed since 2001 and a number of clinical studies with varying follow-up times have been conducted for various indications. Long-term data on the Contura polyacrylamide hydrogel is available from a 10 year follow-up study including 104 HIV-patients injected with an average of 6 ml of Aquamid® hydrogel for treatment of facial lipothrophy. At follow up (10 years) no patients presented with migration of the hydrogel and the majority of patients were “highly satisfied” (74.8%) or “satisfied” (23.4%) with the cosmetic result (Negredo et al., 2015). Stable appearance of hydrogel was also observed in an eight year follow-up study of 25 women with stress urinary incontinence who had been treated with Bulkamid® hydrogel, where all patients had visible polyacrylamide hydrogel deposits on vaginal ultrasonography (Mouritsen et al., 2014).

As described in this and the previous sections, pre-clinical studies have shown that Arthrosamid®/”Hydrogel” is biocompatible, non-absorbable, non-biodegradable and non-migratory (Bello et al., 2007; Charles River, 2011; Zarini et al., 2004). Long-term clinical data has confirmed this (Mouritsen et al., 2014; Negredo et al., 2015). It is therefore reasonable to conclude that Arthrosamid® is stable and safe for the lifetime of the device.

The intended purpose of Arthrosamid® is summarised below:

Table 6. Intended purpose of Arthrosamid®. Twelve months clinical follow-up data is presented for Arthrosamid® (see 5.4.1 and 5.4.4), whereas long-term clinical data is available for Contura’s hydrogels for other indications for up to 8 or 10 years (3.1.2.10), and it is therefore reasonable to believe that this permanent implant/hydrogel is stable and safe for the lifetime of the device (3.1.2.10).The recommended dosage of 6 ml is based on the total volume of gel injected in the “proof-of-concept” study (2 x 3 ml for the majority (96%) of the patients) and on data from the CON-OA study (5.4.4). One injection of 6 ml compared to 2 x 3 ml reduces the risk of infection, and prophylactic antibiotics are only given once.