Migliore and Granata More than ten years have passed since the original expla- nation by Balazs and Denlinger (1993) that the favorable effects of IA HA therapy in OA was related only to the resto- ration of SF rheological properties (Goldberg and Buckwalter 2005). Many subsequent studies have supported that IA HA therapy is a symptom-modifying approach that has been found to be safe and effective for reducing pain due to OA of the knee and furthermore may also signiﬁcantly decrease the rate of deterioration of joint structure. This statement stems from different evidences. First of all, the complex biochemi- cal effects of HAs in the synovium and extracellular matrix of the articular cartilage, including interactions between exogenously administered HA and articular cartilage, sub- chondral bone, matrix proteoglycans, and collagens. In the second place, the effects of HA administration in animal models of OA, including total or partial meniscectomy and anterior cruciate ligament transectomy. Thirdly, the results of clinical trials using one HA, Hyalgan (sodium hyaluronate, molecular weight 500–730 kDa) that evaluated structural outcomes, such as joint-space width, chondrocyte density and vitality, and arthroscopic evaluation of chondropathy. Localized severe acute inﬂammatory reactions reported with repeated treatment in some patients are not a class effect but may be linked to physicochemical characteristics of hylan- based treatment (Arrich et al 2005; Pagnano and Westrich 2005; Goldberg and Buckwalter 2005). Studies on the effects of HAs of different molecular weight (MW) on speciﬁc receptors have shown that the results can vary depending on the size of the HA molecules used. For example low MH HA fragments generated during joint inﬂammation may promote chemokine gene expression by macrophages. Ohkawara and colleagues (2000) noticed that HA preparation of MW 0.2 × 106 Da was more effec- tive in maintaining the survaival of blood eosinophils than HA with an MW of 3 × 106 −6 × 106 Da, proposing that the effect derived from the increased expression of granulocyte macrophage colony-stimulating factor after CD44 activation (Ohkawara et al 2000). Table 1 Molecular weights of hyaluronic acid (HA) products Trade name Molecular weight Hyalgan 500–730 KDa Hyalubrix 1500 KDa Artz (Supartz) 800–1170 KDa Synovial (Jointex) 800–1200 KDa HA Synvisc 6000 KDa Durolane 90 millions Da Euﬂexxa 2.400–3.600 kDa 366 Different HA products Presently, there are several different HA products available for injection. However, the source of hyaluronic acid var- ies. Some products are extracted from rooster combs but a contraindication to treatment would be an allergy to eggs or chicken. Hyaluronic acid is available in a variety of products with different molecular weight ranging from 500 KD to more than 90 millions D (Table 1). Hylans are cross-linked hyaluronic acids, which gives them a higher molecular weight and increased elastoviscous properties. HA products in the intra-articular treatment of knee OA The ﬁrst studies on the use of HA in human knee OA were carried out in the 1970s by Rydell and Balasz (1971) and Peyron and Balasz (1974). In 1974, Peyron injected 1, 2, or 3 ml of HA (Healon) in 23 knees and obtained positive responses in pain and function in 74% of patients. The treat- ment with two injections of 2 ml HA each appeared to have the best outcome. Recent papers have reviewed clinical trials published in the last years using different HA preparation and the results of these trials are summarized in Table 2. Data support the beneﬁt and safety of repeated treatment with IA HA. Many trials indicate that sodium hyaluronate (molecular weight [MW] 500–730 kDa) is well tolerated and as effective after multiple courses of treatment as it is after a single course (Pagnano and Westrich 2005). Other data state that viscosupplementation is an effective treatment for patients with knee OA who have ongoing pain or are unable to tolerate conservative treatment or joint replacement. Viscosupplementation appears to have a slower onset of action than intra-articular steroids, but the effect seems to last longer (Wang et al 2004). HA not only relieves the symptoms of OA but also modiﬁes the structure of the diseased joint and the rate of Source HA extracted from rooster combs Fermentative HA HA extracted from rooster combs Fermentative HA HA extracted from rooster combs Synthetic HA Fermentative HA Mg/ml 20 mg/2 ml 30 mg/2 ml 25 mg/2.5 ml 16 mg/ml 16 mg/2 ml 20 mg/ 3 ml 20 mg/2 ml Clinical Interventions in Aging 2008:3(2)