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Technical data Arthrosamid® (IPAAG).

A new treatment for adults with knee osteoarthritis

Arthrosamid® is a non-absorbable, non-biodegradable, injectable, transparent, hydrophilic gel consisting of a structure of firm, non-biodegradable polyacrylamide (2.5%) and non-pyrogenic water attached to it (97.5%)

Arthrosamid® is supplied as a pre-filled, sterile 1 mL single-use syringe sealed with a luer lock fitting and a sealing cap. The drug is intended to be injected intra-articularly into the knee joint with a 21G x 2 inch (0.8 x 50 mm) sterile needle.

Figure 1 shows the three-dimensional structure of the polyacrylamide hydrogel. The tight uniform honeycomb structure provides a grid for cell growth.

Figure 1. Electron microscopy images of cryofrozen and broken polyacrylamide hydrogel. The magnification is 1,600× on the left image and 6,000× on the right image.

Chemical description of Polyacrylamide

As described above, Arthrosamid®hydrogel consists of 2.5% dry matter crosslinked polyacrylamide and 97.5% non-pyrogenic water. During synthesis, N,N, methylene-bis-acrylamide polymerizes with acrylamide, forming cross-links between polyacrylamide chains.

The crosslinked polyacrylamide hydrogel is synthesized in a polymerization process in which repeating units of acrylamide are linked together in a chain reaction.

The chain reaction uses a redox initiator principle, in which an ammonium persulfate initiator (AMPS) generates a free radical that adds an acrylamide monomer by obtaining an electron from the double bond in the acrylamide, forming a single carbon-carbon bond with the acrylamide. This leaves an undivided electron for further addition of acrylamide monomers, as shown in Figure 2 on the right.

Branching of the linear carbon-carbon structure of polyacrylamide will occur due to the presence of a crosslinked agent, N,N-methylene-bis-acrylamide monomer (MBAM), as shown in Figure 3.

After branching of the polyacrylamide chains of the structure, a three-dimensional network of crossed polyacrylamide is formed, rather than non-coupled linear chains of polyacrylamide.

Arthrosamid® is supplied as a pre-filled, sterile 1 mL single-use syringe sealed with a luer lock fitting and a sealing cap. The drug is intended to be injected intra-articularly into the knee joint with a 21G x 2 inch (0.8 x 50 mm) sterile needle.

Figure 1 shows the three-dimensional structure of the polyacrylamide hydrogel. The tight uniform honeycomb structure provides a grid for cell growth.

Figure 2. Polymerization process of acrylamide monomers.

Fig 3. Example of branching between two polyacrylamide strands.

Materials and biocompatibility of Arthrosamid®

Arthrosamid® does not contain medicinal ingredients, tissues or blood products. The materials used in Arthrosamid® are listed below (Table 2).

Table 2. Device material. *The syringe is handled by the user, who must wear protective gloves. Thus, normally neither the patient nor the user should come into contact with the syringe. The rubber stopper and lubricant are not exposed and therefore the risk of coming into contact with them is even lower than for the exposed parts of the syringe.

Biocompatibility testing has been performed in accordance with ISO 10993-1 for Contura’s existing hydrogel products and tests considered relevant to Arthrosamid® are summarized below (Table 3) and described in detail in the Biological Evaluation Report (BER) Arthrosamid®.

Table 3. Biocompatibility studies (and implantation studies) performed on Contura hydrogel

Based on the tests conducted, Arthrosamid®is considered biocompatible and suitable for prolonged contact with the body.

Stability and longevity of Arthrosamid®

The stability of Contura’s polyacrylamide hydrogels is described and discussed in detail in the Biological Evaluation Report (BER) – Arthrosamid®, and a summary of the stability tests examining the potential hydrolysis, oxidative and physical loading of “hydrogel B” is given below (Table 5). As mentioned in the BER, the enzymatic degradation of polyacrylamide was tested in different enzymatic fermentation systems, but no degradation was observed.

Table 5. Stability studies performed on Contura’s hydrogel (“Hydrogel B”).

It was found that the polyacrylamide hydrogel is stable and does not degrade under the test conditions.

Stability Arthrosamid® - Migration

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

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

Arthrosamid® - Clinical and preclinical evidence of IPAAG

In rabbits and horses, uptake of the hydrogel was followed up to 2 years after injection. In horses, the hydrogel appeared 2 weeks after treatment as an inner layer in the synovial layer, mixed with multiplying synovial cells, similar to the histology seen in a rabbit model. After 1 month, the synovial cells apparently moved to the surface, and a similar uptake pattern was observed after 3, 8 and 24 months (Christensen et al., 2016). The hydrogel was present as an integrated zone in the subsynovial interstitium with a fine vascular tissue network and very few inflammatory cells.

A prospective histopathological study was performed on tissue removed from patients during total knee arthroplasty (TKA). The patients had been treated with hydrogel 5-33 months previously. A similar histologic pattern was seen in all seven cases: The hydrogel appeared to have been incorporated into the synovial membrane and the outer synovial coating cells had invaded the gel and formed a the new coating layer. A similar pattern was also described 9 months after TKA in a case study (Christensen and Daugaard, 2016).

Contura’s hydrogel has been marketed since 2001, and a number of clinical trials with varying follow-up times have been conducted for various indications. Long-term data on Contura’s polyacrylamide hydrogel are available from a 10-year follow-up study with 104 HIV patients who were injected with an average of 6 ml of Aquamid® hydrogel for the treatment of facial lipoatrophy. At follow-up (10 years), no patients presented with migration of the hydrogel and the majority of patients were “very satisfied” (74.8%) or “satisfied” (23.4%) with the cosmetic outcome (Negredo et al., 2015). A stable course of the 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, in which all patients had visible polyacrylamide hydrogel deposits on ultrasonography of the vagina (Mouritsen et al., 2014).

Conclusion - Stability and longevity of Arthrosamid®.

As described in this section and in previous sections, preclinical 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 have confirmed this (Mouritsen et al., 2014; Negredo et al., 2015) and Bliddal; et al. 10 year follow-up after intra-articular injections of 2.5% polyacrylamide hydrogel for knee osteoarthritis (presented WCO IOF-ESCEO 2025 Rome) Therefore, it is reasonable to conclude that Arthrosamid® is stable and safe for the lifetime of the device.

The intended purpose of Arthrosamid® is summarized below:

Table 6. Intended purpose of Arthrosamid® *Twelve months of clinical follow-up data are presented for Arthrosamid® (see 5.4.1 and 5.4.4), while long-term clinical data are available for hydrogels from Contura for other indications up to a maximum of 8 or 10 years (3.1.2.10), and it is therefore reasonable to assume that this permanent implant/hydrogel is stable and safe for the lifetime of the device (3.1.2.10).

**The recommended dose 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 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 administered only once.

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