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Evidence indicates that hyaluronic acid (HA) mitigates tendinopathy, but the effect of molecular weight is unclear. We investigated the effects of different concentrations and different molecular weights of HA (350 kDa, 1500 kDa, and 3000 kDa) on matrix metalloproteinase (MMP)-1 and -3 expression in IL-1β-stimulated rat tenocytes, and on their dynamic expression in peritendinous effusion from patients with long head of biceps (LHB) tendinopathy after high-molecular-weight (HMW)-HA treatments. Reverse transcription PCR, real-time PCR, and ELISA were used to determine MMP-1 and -3expression. Because CD44 was clearly expressed in the plasma membranes of cultured tenocytes, OX-50, a CD44 antagonist, was used to inhibit CD44 to evaluate the HA mechanism. HA (3000 kDa) significantly (p < 0.001) downregulated the mRNA and protein expression of MMP-1 and -3 in IL-1β-stimulated tenocytes. Its attenuating effects were dose-dependent (p < 0.01). In OX-50-pretreated cells, the mRNA expression of CD44 was not significantly altered, but the mRNA expression of MMP-1 and -3 was significantly upregulated. Visual analogue scale scores were significantly lower, and MMP-1 and -3 expression was significantly (p < 0.05) lower one month posttreatment. HMW-HA attenuated tendinopathy by downregulating MMP-1 and -3 expression. Inhibiting CD44 blocked the effects of HMW-HA.

Hyaluronate (HA) is therapeutic for tendinopathy, but an intratendinous HA injection is usually painful; thus, it is not suggested for clinical practice. However, there are no studies on the histopathological changes after an intratendinous HA injection. We hypothesized that an HA injection would induce more-acute inflammation than that induced by an injection of phosphate buffered saline (PBS). Thirty-two rats were randomly divided into 4 post-injection groups (n = 8): day 3, day 7, day 28, and day 42. HA (0.1 c.c.) was, using ultrasound guidance, intratendinously injected into each left Achilles tendon, and PBS (0.1 c.c.) into each right one. For each group, both Achilles tendons of 3 control-group rats (n = 6) were given only needle punctures. The histopathological score, ED1+ and ED2+ macrophage densities, interleukin (IL)-1β expression, and the extent of neovascularization were evaluated. In both experimental groups, each Achilles tendon showed significant histopathological changes and inflammation compatible with acute tendon injury until day 42. The HA group showed more-significant (p < 0.05) histopathological changes, higher ED1+ and ED2+ macrophage density, and higher IL-1β expression than did the PBS group. The neovascularization area was also significantly (p < 0.05) greater in the HA group, except on day 3. Both HA and PBS induced acute tendon injury and inflammation, sequential histopathological changes, ED1+ and ED2+ macrophage accumulation, IL-1β expression, and neovascularization until post-injection day 42.HA induced more-severe injury than did PBS. Therefore, an intratendinous HA injection should be avoided.

Post-laminectomy/laminotomy epidural fibrosis (EF) has been implicated as an important cause of failed back syndrome (FBS). The various clinical approaches used to control EF yield mixed outcomes. Cross-linked hyaluronic acid hydrogel (cHA) was synthesized to increase mechanical stability and residence time. We evaluated the therapeutic attenuation of proliferative EF in laminectomy/laminotomy groups treated and not treated with cHA. A bilateral T11-L1 total laminectomy or unilateral T12 laminotomy was done on four groups (n = 10 each) of Sprague-Dawley rats and then histologically examined 2 months post-surgery: (I) laminectomy group treated with and (II) not treated with cHA, (III) laminotomy group treated with and (IV) not treated with cHA. The grade of EF, the diameters within the spinal canal, dura mater thickness, and the area of the epidural space, subarachnoid space, and conus medullaris space were assessed. The cHA-treated subgroups (I, III) had a significantly lower grade of EF, thinner dura mater, and larger epidural and subarachnoid spaces than did the control subgroups (II, IV) (p < 0.05). The cHA formed a solid interpositional membrane barrier that prevented invasive fibrosis, and also helped reduce pathological changes to the adjacent structures. In conclusion, topically applied cHA is effective for reducing EF., (© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Hyaluronan (HA) is well known for its biocompatibility and has widespread clinical use. To change its mechanical and physiologic properties to adapt to specific clinical scenarios, HA is crosslinked with chemically reactive linker molecules, most of which are toxic chemical reagents. Adverse events related to clinical use of crosslinked HA have been documented. Although approved by the FDA as dermal filler, the safety of perineural application of 1,4-butanediol diglycidyl ether (BDDE)-crosslinked HA has not been assessed critically. Concern exists owing to the vulnerability of neural tissues, because of their elongated morphology, high ratio of membrane surface area to cell volume, and complicated electrophysiologic properties. In this study, we systematically investigated the toxicity profile of BDDE-crosslinked HA, using in vitro and in vivo experiments in a rat model. The in vivo experiments included the evaluation of aspects of histopathology, electrophysiology, and neurobehavior. There were no significant changes in the treatment group compared with the control group in all aspects of the experiments, except for the increased epineurial vascular formation in the 0.5% crosslinked HA-treated group during 2 weeks of observation. Further studies involving perineural application of BDDE-crosslinked HA can be done based on our findings, which ruled out the safety concern of cytotoxicity and adverse changes in electrophysiology and neurobehavior., (© 2014 Wiley Periodicals, Inc.)