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.

Picture cryo-frozen and fractured polyacrylamide hydrogel
Figure 1. Electron microscopy images of cryo-frozen and fractured polyacrylamide hydrogel. Magnification on left image is x1.600 and x6.000 on the right.

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.

Fig 2
Figure 2. Polymerization process of acrylamide monomers.
Fig 3
Figure 3. Example of branching between two polyacrylamide strands

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
APR21

Pass

Sensitization

ISO 10993-10: 2010

Assessment of Contact Hypersensitivity in Guinea Pig (Maximization-Test) Local Lymph Node Assay in Mice

No. 517557

2017
APR26

Pass

Hydrogel B: Local Lymph Node Assay (Skin sensitization)

No. 77691)

2017
MAR23

Irritation or intracutaneous reactivity

ISO 10993-10: 2010

Intracutaneous Reactivity Test in the Rabbit

No. 77693

2017
MAR23

Pass

Systemic toxicity (acute)

ISO 10993-11: 2017 /

10993-12: 2012 USP 151

Material Mediated Pyrogenicity Test

No. APS-GZJ009-ST01

2018
APR04

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
JUL31

Pass

Genotoxicity

ISO 10993-3: 2014

Bacterial Reverse Mutation Assay (Ames test)

No. 16/368-007M

2017
MAR31

Pass

In vitro mammalian Chromosomal Aberration test

No. 16/368-020C

2017
JUN06

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
JUL31

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.

ConditionTestResultTest Reference
Hydrolysis and oxidative stressDuplicate 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).

Arthrosamid® - Principles of operation

Arthrosamid® is injected into the knee cavity and provides lubrication. It subsequently integrates into the synovial tissue of the inner joint capsule and decreases joint stiffness, thereby diminishing pain and improving function of the knee affected by osteoarthritis (OA). Arthrosamid® forms a cushion-like membrane comprising the hydrogel incorporated in a matrix of fine tissue network covered by a synovial lining. The non-absorbable, non-biodegradable and non-migratory characteristics of Arthrosamid® provide cushioning of the inner joint capsular tissue (Christensen, 2019; Christensen et al., 2016; Tnibar et al., 2017).

Although the exact mechanism by which Arthrosamid® reduces OA symptoms has not been elucidated completely, there is experimental evidence that the hydrogel stabilises OA progression and improves joint elasticity (Tnibar et al., 2017). Equine studies have shown decreasing joint effusion following hydrogel injection in joints indicating reduction in inflammation (Tnibar et al., 2015). Initial human data indicate significant decrease in pain and stiffness (Henriksen et al., 2018).

A major complaint from patients with knee OA is persistent pain, and recent findings suggest that the synovial membrane might contribute to the pathogenesis of OA and pain (Belluzzi et al., 2019).

The histologically synovium in OA patients is characterised by the synovial lining hyperplasia, sublining fibrosis and with abundant influx of inflammatory cells (Mathiessen and Conaghan, 2017) which play a role in the progress of the joint destruction. Interestingly, following polyacrylamide hydrogel (Arthrosamid®) injection histological observations in both animal and human joints have demonstrated a considerable increase of the synovial membrane thickness (Christensen, 2019; Christensen et al., 2016). However, in contrast to a high concentration of inflammatory cells, often associated with fibrosis in an OA knee, macrophages in a hydrogel incorporated synovial lining are scarce. Hence, the Arthrosamid® hydrogel may decrease the signalling between macrophages as well as other immune cells like neutrophils, by physically increasing the distance for chemokines and cytokines to move between cells. The effect of the hydrogel would be to decrease the inflammatory processes without damaging the normal immune defence. The gel may therefore decrease the flow rate of chemokines and cells into the joint without losing the general signal pathways.

As synovium inflammation is related to pain and potentially also contributes to cartilage degradation (Mathiessen and Conaghan, 2017), a modification of the preexisting inflammation by “diluting” inflammatory cells via increased thickness of the synovial membrane could be a plausible mechanism of action for the hydrogel.

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:

  • If an active skin disease or infection is present at or near the injection site
  • If the joint is infected or severely inflamed
  • If a degradable intra-articular injectable such as hyaluronic acid is present, it must be expected to be absorbed according to the manufacturer’s information for the specific product, before injection with Arthrosamid®
  • If the patient has previously received treatment with a different non-absorbable injectable/implant
  • If the patient has received a knee arthroplasty or has any foreign material in the knee
  • If the patient has undergone knee arthroscopy within the last 6 months
  • In hemophilia patients or in patients in uncontrolled anticoagulant treatment

Warnings

  • Arthrosamid® must not be injected intra-vascularly, extra-articularly or in the synovial tissue or capsule
  • Do not inject corticosteroids along with Arthrosamid®

Precautions required by the manufacturer

  • Arthrosamid® should be used with caution in patients with e.g. autoimmune disorders and uncontrolled diabetes as well as in patients undergoing major dental work or surgery
  • Prophylactic antibiotic treatment must be administered prior to injection
  • Usual precautions associated with invasive joint procedures should be followed
  • Pharmaceuticals or biological substances should not be injected into the hydrogel
  • Safety and effectiveness have not been established in patients under 18 years, in pregnant or lactating women, or in patients having foreign material implanted in the knee
  • Only use Arthrosamid® if the packaging and products are intact and undamaged. Do not re-sterilize Arthrosamid®.


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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