Hyaluronic Acid Supplement as a Chondrogenic Adjuvant in Promoting the Therapeutic Efficacy of Stem Cell Therapy in Cartilage Healing

Chin-Chean Wong; Shi-Da Sheu; Pei-Chun Chung; Yi-Yen Yeh; Chih-Hwa Chen; Yen-Wei Chang; Tzong-Fu Kuo

doi:10.3390/pharmaceutics13030432

Hyaluronic Acid Supplement as a Chondrogenic Adjuvant in Promoting the Therapeutic Efficacy of Stem Cell Therapy in Cartilage Healing

Pharmaceutics. 2021 Mar 23;13(3):432. doi: 10.3390/pharmaceutics13030432.

Authors

Chin-Chean Wong^{1

2

3

4

5}, Shi-Da Sheu⁶, Pei-Chun Chung⁷, Yi-Yen Yeh⁸, Chih-Hwa Chen^{1

3

8

9}, Yen-Wei Chang¹⁰, Tzong-Fu Kuo¹¹

Affiliations

¹ Department of Orthopedics, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan.
² Department of Orthopedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
³ Research Center of Biomedical Devices, Taipei Medical University, Taipei 11031, Taiwan.
⁴ International Ph.D. Program for Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
⁵ Non-Invasive Cancer Therapy Research Institute of Taiwan, Taipei 10489, Taiwan.
⁶ Department of Chinese Medicine, E-Da Cancer Hospital, Kaohsiung 82405, Taiwan.
⁷ School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan.
⁸ School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan.
⁹ School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
¹⁰ Office of Physical Education, Asia University, Taichung 41354, Taiwan.
¹¹ Department of Post-Baccalaureate Veterinary Medicine, Asia University, Taichung 41354, Taiwan.

Abstract

The main aim of this study is to investigate the therapeutic efficacy of direct intra-articular injection of bone-marrow-derived stem/stromal cells (BMSCs) and the adjuvant role of hyaluronic acid (HA) in facilitating rabbit articular cartilage repair. First, rabbit BMSCs were treated with a medium containing different concentrations of HA. Later, HA's influence on BMSCs' CD44 expression, cell viability, extracellular glycosaminoglycan (GAG) synthesis, and chondrogenic gene expression was evaluated during seven-day cultivation. For the in vivo experiment, 24 rabbits were used for animal experiments and 6 rabbits were randomly allocated to each group. Briefly, chondral defects were created at the medial femoral condyle; group 1 was left untreated, group 2 was injected with HA, group 3 was transplanted with 3 × 10⁶ BMSCs, and group 4 was transplanted with 3 × 10⁶ BMSCs suspended in HA. Twelve weeks post-treatment, the repair outcome in each group was assessed and compared both macroscopically and microscopically. Results showed that HA treatment can promote cellular CD44 expression. However, the proliferation rate of BMSCs was downregulated when treated with 1 mg/mL (3.26 ± 0.03, p = 0.0002) and 2 mg/mL (2.61 ± 0.04, p = 0.0001) of HA compared to the control group (3.49 ± 0.05). In contrast, 2 mg/mL (2.86 ± 0.3) of HA treatment successfully promoted normalized GAG expression compared to the control group (1.88 ± 0.06) (p = 0.0009). The type II collagen gene expression of cultured BMSCs was significantly higher in BMSCs treated with 2 mg/mL of HA (p = 0.0077). In the in vivo experiment, chondral defects treated with combined BMSC and HA injection demonstrated better healing outcomes than BMSC or HA treatment alone in terms of gross grading and histological scores. In conclusion, this study helps delineate the role of HA as a chondrogenic adjuvant in augmenting the effectiveness of stem-cell-based injection therapy for in vivo cartilage repair. From a translational perspective, the combination of HA and BMSCs is a convenient, ready-to-use, and effective formulation that can improve the therapeutic efficacy of stem-cell-based therapies.

Keywords: bone marrow stem cells; cartilage; hyaluronic acid; injection; repair.

Abstract

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