Nanotheranostics 2018; 2(4):347-359. doi:10.7150/ntno.26119

Research Paper

Hyaluronic Acid-Based Optical Probe for the Diagnosis of Human Osteoarthritic Cartilage

Shuxin Li1, Wei Cong1,2, Amirhossein Hakamivala1, YiHui Huang1, Joseph Borrelli Jr1, Liping Tang1,3✉

1. Department of Bioengineering, University of Texas at Arlington, Arlington, TX 76019, USA
2. Department of Oral Anatomy, College of Stomatology, Dalian Medical University, Dalian, Liaoning, 116044, China
3. Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
Li S, Cong W, Hakamivala A, Huang Y, Borrelli J Jr, Tang L. Hyaluronic Acid-Based Optical Probe for the Diagnosis of Human Osteoarthritic Cartilage. Nanotheranostics 2018; 2(4):347-359. doi:10.7150/ntno.26119. Available from

File import instruction


Osteoarthritis is typically caused by cartilage injury, followed by localized inflammatory responses and tissue deterioration. Early treatment of osteoarthritis is often impossible due to the lack of diagnostic options. Recent studies have supported that different imaging probes can be used for arthritis detection in mice. However, none of these diagnostic tools have been tested on human articular cartilage. To fill this gap, an optical imaging probe was developed to target activated macrophages and the accumulation of imaging probes on tissue was used to assess the severity of human osteoarthritis.

Methods: The probe was fabricated using hyaluronic acid (HA) particles conjugated with near-infrared dye and folic acid (FA). The ability of the FA-HA probes to detect activated macrophages and quantify cartilage injury was evaluated using a cell culture model in vitro and human osteoarthritic cartilage explants ex vivo.

Results: Our cell study results supported that the FA-HA probes are cell compatible (up to 0.5mg/mL) and can detect activated macrophages in 30 minutes. Using human articular cartilage, we verified the existence of activated macrophages on osteoarthritic cartilage with highly up-regulated expression of folate receptors (~13 folds by comparison with healthy control). In addition, we found that FA-HA probes had higher binding amounts (~3 folds) to osteoarthritic tissue than healthy ones. Histological analyses confirmed that there was a strong linear relationship (R=0.933) between the fluorescent intensity of tissue-associated probe and the extent of folate receptors on osteoarthritic cartilage. Finally, the co-localization of the imaging probe, folate receptors and cartilage degeneration on the tissue sections indicated the extraordinary accuracy and efficiency of this osteoarthritis diagnostic probe.

Conclusions: Our results support the probe as an effective diagnostic tool to detect the area and severity of osteoarthritic human articular cartilage.

Keywords: osteoarthritis, diagnosis, optical probes, hyaluronic acid, folate receptor, human explant.