The development of NASHA was based on three basic considerations:
• Pure hyaluronic acid.
• Synthesis to obtain the desired physical form and sufficient residence time in the various clinical applications.
• Safety, no side effects, so that this synthetic hyaluronic acid is virtually identical to native hyaluronic acid without contaminants.
Starting material
The hyaluronic acid used in the manufacture of NASHA is biosynthesized from a proprietary non-animal source. The molecular weight is ~1 million. Higher molecular weights are not needed as the hyaluronic acid is “stabilized”, polymerized in a particular viscous form.
The raw material for NASHA is manufactured with a very high order of product purity though a proprietary process from non-animal cells. The presence of potentially harmful components such as viruses, proteins and endotoxins, those of animal origin in particular, is excluded.
Stabilization and manufacturing
The manufacturing of NASHA is by Q-Med AB, Uppsala, Sweden and includes stabilization of hyaluronic acid to form NASHA, polymerization into a continuous 3-dimensional molecular network by a proprietary process that maintains the ultimate tolerance of native hyaluronic acid; in this way a gel of any shape and form can be produced. Gel particles of defined sizes are produced depending on the intended application so that a defined polymer is produced with a physical form that suits the intended use, improves shelf life, and produces appropriate the residence time
following injection from a few days to many months depending on the specific degree of polymerization.
The products are steam-sterilized to a high sterility assurance level so that the probability of finding a 5 ml syringe of NASHA gel containing a microorganism is less than 1 in 1 million.
The modification needed to obtain the stabilized NASHA is presented in figures 19 and 20:
Figure 19. A hyaluronic acid molecule with the flexible molecular network entangles with its neighbors. This entanglement strongly hampers the movement of the molecules sideways.
However, individual molecules are capable of moving within the flexible molecular network at a remarkable speed by means of a snake-like movement called reptation.
Figure 20. In the NASHA products, the hyaluronic acid molecules are stabilized to a minor degree. The stabilization is accomplished using a compound that does not cause any significant biological reaction. Due to the high molecular weight of the starting material (1 million) minute amounts of stabilization are needed to obtain a few permanent linkages that
join all the hyaluronic acid molecules in the solution, thus forming a continuous gel.
Therefore, very low amounts of stabilizer are needed.
Biocompatibility
The biocompatibility of NASHA has been extensively tested both in vitro and in vivo following the guidelines in the ISO (International Organization for
Standardization) 10993 standard on “Biological Evaluation of Medical Devices”.
These biocompatibility tests have demonstrated that NASHA:
• is neither cytotoxic nor genotoxic
• does not give rise to any acute, subacute, or chronic effects
• does not give rise to any hypersensitivity reactions Residence time of NASHA
The turnover of endogenous hyaluronic acid is very fast and efficient. In most tissues the half-life varies from half a day to a few days so that exogenous hyaluronic acid implanted into a tissue will disappear within this short time. The residence time may be slightly modified by changing the molecular size or concentration of
hyaluronic acid, or by the modifying the method of application. However, modification of the hyaluronic acid molecular weight will increase the residence time only slightly, by a factor <2.
In healthy tissue, the extracellular degradation of NASHA is by free radicals, present in very low concentrations in normal tissue resulting in very slow degradation of NASHA with slow release of free hyaluronic acid chains, which are catabolised by the same mechanism as the endogenous hyaluronic acid described above. As a consequence of the mild stabilization in NASHA, the residence time in e.g. the skin has been increased from a few days to many months, sometimes almost up to a year100-102.
The residence time of non-animal stabilized hyaluronic acid, NASHA, is
dependent on the size of the gel particles, the concentration of stabilized hyaluronic acid, and the existence of inflammatory reactions in the area. The smaller the gel particle size, the easier it will escape from its place of residence. Too large gel particles will rupture the tissue and cause reparative inflammatory reactions that will speed up the degradation. Hence a careful match of gel size to tissue is essential.
Gels of any shape and form
The NASHA gel can be manufactured to almost any shape and form. Depending on the clinical demand, the gels can be thick or thin, dense or loose as well as
containing big or small gel particles. For the purpose of tissue augmentation, the size of the gel particles has to match the density of the tissue. For facial augmentation e.g. several products with different size of the gel particles have been developed.
Clinical use of NASHA
NASHA™ has been successfully used for treatment of knee and hip osteoarthritis103-105or facial tissue augmentation106-108, for treatment of vesico-ureteral reflux in children109,110, and for treatment of urinary stress incontinence in women
111-113.