**5. Conclusions**

Although pharmacological treatments of OA are rapid and effective for symptomatic relief in regular clinical practice, the long-term use is restricted by the associated adverse effects. IAHA has been conditionally recommended for long-term treatment of knee OA with a favorable safety profile over repeated IA corticosteroid. At and beyond 12 weeks of treatment, it may have the beneficial effects on pain [57]. Nutraceuticals are safe candidates for long-term supplementation to provide persistent effect as treatment adjuvant [58]. In fact, many nutraceutical products have been extensively used for OA pain and their active compounds were identified for potential drug development [59]. In conclusion, the evidence and safety profiles observed in these surgically-induced OA rats sugges<sup>t</sup> that long-term oral SNO supplement can be used as an effective adjuvant for IAHA treatment to enhance the symptomatic relief and delay the disease progression in clinical practice.

**Author Contributions:** (1) I.-J.C., contributes to formal analysis, investigation, methodology, and writing—original draft. (2) C.-S.W., contributes to conceptualization, funding acquisition, supervision, writing—review & editing and approval of the submitted and final versions. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study was supported in the form of a contract from Universal Integrated Corp. to evaluate the effect of the product SheaFlex75 on our well-established OA animal model. The Article Processing Charge was funded by Cathy General Hospital.

**Acknowledgments:** We thank our laboratory assistants Ching-Pai Wang and Tsou-Mei Liu for performing oral gavage, the knee width and weight bearing measurements. Thanks to the Taiwan Animal Consortium for technical service in tissue embedding/sectioning and the biochemical analysis, and the Instrument Center of National Defense Medical Center for providing the slide scanner service.

**Conflicts of Interest:** The authors declare no conflict of interest. The sponsors had no role in the design, execution, interpretation, or writing of the study.
