Article Text

SAT0319 Development of Crosslinked Hydrogels of Recombinant Hyaluronic Acid for Osteoarthritis Applications
  1. B. M. Malle1,
  2. M. Mellergaard1,
  3. S. Poulsen1
  1. 1Application Development, Novozymes Biopharma A/S, Bagsvaerd, Denmark


Background Hyaluronic acid (HA), a natural linear polysaccharide, is ubiquitous in human and animal tissues, where it exhibits significant structural, rheological, physiological, and biological functions.1 HA is widely used in the treatment of inflammatory and degenerative joint diseases (viscosupplementation), as it mimics the viscoelastic properties of synovial fluids. Existing treatments of osteoarthritis (OA) are mainly symptomatic and consist of the systemic administration of analgesics, nonsteroidal anti-inflammatory drugs, and selective cyclooxygenase 2 inhibitors in the early stages of the disease. Intra-articular injections of glucocortocoids and HA are prescribed at more advanced stages of the illness2. While these various treatments are somewhat effective, there is still a major unmet need for efficacious pain treatment with long-lasting effects.

Objectives In this work HA has been crosslinked with divinyl sulfone (DVS) to produce hydrogels especially targeted towards osteoarthritis treatment. The objective was to evaluate the dependence of the crosslinking degree and specific composition of the formulation on the resulting viscoelastic properties of the crosslinked hydrogels.

Methods HA was produced by Novozymes Biopharma DK A/S by fermentation of Bacillus subtilis with the average molecular weight of 0.85 MDa. Crosslinked hydrogels were produced according to the method described in the patent with variation of DVS/HA weight ratios.3 The crosslinked HA hydrogels were swollen in PBS buffer, pH 7.4, yielding hydrogels with final HA concentration in the range of 1.4 to 2.0 w/w%. The viscoelastic properties were evaluated on a rotational rheometer (Gemini, Bohlin Instruments, UK) using a parallel plate geome-try.

Results Novozymes proprietary technology for preparation of crosslinked HA is based on a reproducible and safe process, which results in transparent hydrogels with modular viscoelastic properties. The results show that the elastic properties of the hydrogels are constant over the range of frequencies tested. The approach to develop formulations for treatment of OA based on combining native HA and crosslinked HA in one product formulation is demonstrated. In this way the final formulation properties as elasticity, viscosity and injectability are fine-tuned to target both disease-modifying properties and long-lasting pain relief.

Conclusions In this work, novel hydrogels of crosslinked hyaluronic acid have successfully and reproducibly been prepared with different HA starting concentrations, crosslinking degrees and formulation compositions. The viscoelastic properties of these novel hydrogels can be tailor-made to produce materials with improved and well-defined rheological characteristics to target osteoarthritis treatment.


  1. Liao. Y.-H; Jones, S.A.; Forbes, B.; Martin, G.P.; Brown, M.B. Drug Delivery 2005, 12, 327-342.

  2. Gerwin et al., Advanced drug delivery reviews, 2006, 58, 226–242.

  3. Longin, F.; Schwach-Abdellaoui, K., WO/2006/056204.

Disclosure of Interest None Declared

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