The science of Arthrosamid® (iPAAG)
A novel treatment for adults with knee osteoarthritis
Arthrosamid® is a non-absorbable, non-biodegradable, injectable, transparent, hydrophilic gel consisting of a backbone of firmly bound, non-biodegradable polyacrylamide (2.5%) and attached non-pyrogenic water (97.5%)
Arthrosamid® is supplied as a pre-filled, single use, sterile, 1 mL syringe, sealed with a luer lock fitting and a tip cap. It is intended to be injected intra-articularly in the knee joint with a sterile 21G x 2 inches (0.8 x 50mm) needle.
Figure 1 shows the three-dimensional structure of the polyacrylamide hydrogel. The tight uniform honeycomb structure provides a matrix for cell ingrowth.
Chemical description of polyacrylamide
As described above, the Arthrosamid® Hydrogel consists of 2.5% dry matter cross-linked polyacrylamide and 97.5% non-pyrogenic water. During the synthesis N,N, Methylene-bis-acrylamide polymerizes with acrylamide thus creating cross-links between polyacrylamide chains.
The cross-linked polyacrylamide hydrogel is synthesized in a polymerization process where repeating units of acrylamide are linked in a chain reaction.
The chain reaction involves a redox-initiator principle, where an ammonium persulfate (AMPS) initiator generates a free radical that adds an acrylamide monomer by obtaining an electron from the double bond in the acrylamide, thereby forming a single carbon-carbon bond with the acrylamide. This leaves an unshared electron for further addition of acrylamide monomers as depicted in Figure 2 to the right.
Branching of the linear carbon-carbon backbone of polyacrylamide will occur due to the presence of a cross-linking agent, N,N-methylene-bis-acrylamide monomer (MBAM) as depicted in Figure 3.
After branching of the backbone polyacrylamide chains, a three-dimensional network of cross-linked polyacrylamide is formed, rather than unconnected linear chains of polyacrylamide.
Arthrosamid® Materials and biocompatibility
Arthrosamid® does not incorporate a medicinal substance, tissues or blood products.
Materials used in Arthrosamid® are listed below (Table 2).
Device part |
Material |
Body contact |
|
|---|---|---|---|
Gel |
Hydrophilic gel consisting of approximately 2.5% cross-linked polyacrylamide and 97.5% non-pyrogenic water |
Knee joint |
|
Syringe |
barrel |
Polypropylene |
Skin* |
plunger |
Polycarbonate |
Skin* |
|
rubber stopper |
Silicone rubber |
Skin* |
|
lubricant |
Silicone oil |
Skin* |
|
tip cap |
Polypropylene |
Skin* |
|
Table 2. Device materials. *The syringe is handled by the user, who should wear protective gloves. Thus, normally neither the patient nor the user should come into contact with the syringe. The rubber stopper and the lubricant are non-exposed and thereby the risk of coming into contact with them is even lower than for the exposed syringe parts.
Biocompatibility testing has been performed in accordance with ISO 10993-1 for Contura’s existing hydrogel products and tests considered relevant for Arthrosamid® are summarized below (Table 3) and described in detail in the Biological Evaluation Report (BER) - Arthrosamid®.
Endpoint of biological evaluation |
Standard reference |
Test and test number |
Report Date |
Result |
|---|---|---|---|---|
Cytotoxicity |
ISO 10993-5:2009 USP 29 |
Hydrogel B: In Vitro Cytotoxicity Test No. 16/368-030C |
2017 |
Pass |
Sensitization |
ISO 10993-10: 2010 |
Assessment of Contact Hypersensitivity in Guinea Pig (Maximization-Test) Local Lymph Node Assay in Mice No. 517557 |
2017 |
Pass |
Hydrogel B: Local Lymph Node Assay (Skin sensitization) No. 77691) |
2017 |
|||
Irritation or intracutaneous reactivity |
ISO 10993-10: 2010 |
Intracutaneous Reactivity Test in the Rabbit No. 77693 |
2017 |
Pass |
Systemic toxicity (acute) |
ISO 10993-11: 2017 / 10993-12: 2012 USP 151 |
Material Mediated Pyrogenicity Test No. APS-GZJ009-ST01 |
2018 |
Pass |
Subchronic toxicity (subacute toxicity) |
ISO 10993-6:2007 |
Systemic toxicity endpoints for subchronic toxicity were examined in the Two-Year Implantation Study in Sheep No. 285465 |
2017 |
Pass |
Genotoxicity |
ISO 10993-3: 2014 |
Bacterial Reverse Mutation Assay (Ames test) No. 16/368-007M |
2017 |
Pass |
In vitro mammalian Chromosomal Aberration test No. 16/368-020C |
2017 |
|||
In vivo Mammalian Erythrocyte Micronucleus Test No. 16/368-013E |
2017 APR07 |
|||
Implantation |
ISO 10993-6:2007 |
Two-Year Implantation Study in Sheep No. 285465 |
2017 |
Pass |
Table 3. Biocompatibility studies (and implantation study) performed on Contura’s hydrogel
Based on the performed testing, Arthrosamid® is considered biocompatible and suitable for long term contact with the body.
Stability and lifetime of Arthrosamid®
The stability of Contura’s polyacrylamide hydrogels is described and discussed extensively in the Biological Evaluation Report (BER) – Arthrosamid®, and a summary of stability tests investigating potential hydrolysis, oxidative and physical stress on “Hydrogel B” is given below (Table 5). As reviewed in the BER, enzymatic degradation of polyacrylamide has been tested in various enzymatic fermentation systems, but no degradation was observed.
| Condition | Test | Result | Test Reference |
|---|---|---|---|
| Hydrolysis and oxidative stress | Duplicate Hydrogel B samples were incubated 24 hours at 370C in non-oxidative, moderate oxidative and extreme oxidative hypotonic and isotonic solvents. pH 2 adjusted and non-adjusted neutral solvents were compared. The samples were analyzed by HPLC. | Hydrogel B did not show any tendency of forming monomeric acrylamide under non-oxidative and oxidative and aggressive hydrolytic acidic test conditions. | ChemPilot 2018 |
| Physical stress | An experimental setup exposed the hydrogel to an extreme mechanical shear stress in a knife blending procedure. | Extreme mechanical stress did not lead to degradation of the hydrogel into acrylamide monomers. Extreme mechanical stress, as knife blending, is not experienced during physiological conditions. | Contura (011.INR.00025) |
Table 5. Stability studies performed on Contura’s hydrogel (“Hydrogel B”).
It is seen that the polyacrylamide hydrogel is stable and does not degrade under the test conditions.
Arthrosamid® stability - Migration
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.
Arthrosamid® - Clinical and pre-clinical evidence of iPAAG
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).
Conclusion – Stability and lifetime of Arthrosamid®
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:
Intended purpose of Arthrosamid® |
|
Indication |
Arthrosamid® is intended to be used for symptomatic treatment of knee osteoarthritis in adults. |
Disease to be treated |
Knee osteoarthritis. |
Patient population |
Adult patients diagnosed with osteoarthritis. |
Intended application |
Arthrosamid® is intended to be injected intra-articularly in the knee joint. |
Intended user |
Arthrosamid® is intended to be used by a qualified physician familiar with intra-articular injection procedures, such as orthopaedic surgeons or rheumatologists. |
Effect on the human body |
Arthrosamid® diminishes pain and improves function of the knee affected by osteoarthritis. |
Tissues in contact with the device |
Knee joint. |
Duration of use |
Long-term (>30 days)*. |
Contact with mucosal membranes |
Arthrosamid® is in contact with the synovial membrane of the knee joint. |
Invasive / non-invasive |
Invasive. |
Implantable / non-implantable |
Implantable. |
Single use / reusable |
Single use. |
Recommended dose |
6 ml**. |
Contraindications |
Arthrosamid® should not be injected:
|
Warnings |
|
Precautions required by the manufacturer |
|
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.
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