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. 2025 Jun;317(Pt 2):144756.
doi: 10.1016/j.ijbiomac.2025.144756. Epub 2025 May 29.

Chondroitin sulfate/hyaluronic acid/carboxymethylcellulose macroporous cryogels for controlled delivery of TGF-β1 and IGF-1 to induce chondrogenic differentiation of adipose-derived stem cells in cartilage tissue engineering

Chih-Hao Chen  1 , Chia-Jui Chang  2 , Chang-Yi Kuo  2 , Guan-Jie Luo  3 , Banendu Sunder Dash  2 , Darshan Tagadur Govindaraju  2 , Jyh-Ping Chen  4
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Chondroitin sulfate/hyaluronic acid/carboxymethylcellulose macroporous cryogels for controlled delivery of TGF-β1 and IGF-1 to induce chondrogenic differentiation of adipose-derived stem cells in cartilage tissue engineering

Chih-Hao Chen et al. Int J Biol Macromol. 2025 Jun.

Abstract

To repair articular cartilage defects using adipose-derived stem cells (ASCs), we aim to fabricate macroporous cryogel scaffolds from chondroitin sulfate (CS) and hyaluronic acid (HA), two of the most abundant glycosaminoglycans in cartilage extracellular matrix. Carboxymethylcellulose was blended with HA and CS and crosslinked with 1,4-butanediol diglycidyl ether to prepare a supramacroporous chondroitin sulfate/hyaluronic acid/carboxymethylcellulose (CHC) cryogel. The cryogel is biodegradable and has unique mechanical properties for use as a scaffold for cartilage tissue engineering. The transforming growth factor-β1 (TGF-β1) and insulin-like growth factor-1 (IGF-1) were bound to CS for prolonged presentation of these growth factors in the scaffolds, with controlled release extended to >21 days. The TGF-β1 and IGF-1 can act in combination to regulate chondrogenic differentiation of seeded ASCs. The CHC/TGF-β1/IGF-1 cryogel scaffold promotes the chondrogenesis over CHC/TGF-β1 from cell morphology, matrix and type II collagen production. From qRT-PCR analysis, it also upregulated the gene expression of SRY-box transcription factor 9 (SOX9), type II collagen (COL2A1), aggrecan (ACAN), and proteoglycan 4 (PRG4) while downregulated the gene expression of type X collagen (COL10A1) After in vitro culture ASCs in CHC/TGF-β1/IGF-1 cryogel for 14 days, the cell/scaffold constructs were implanted in rabbit knees to repair full-thickness articular cartilage defects. The regenerated neocartilage tissue on the surface of defect in the cellular group demonstrates similar morphological and histological features and comparable mechanical properties as the native cartilage. The CHC/TGF-β1/IGF-1 cryogel is an excellent scaffold for preparing tissue-engineered cartilage from ASCs in treating articular cartilage defects.

Keywords: Carboxymethylcellulose; Cartilage tissue engineering; Chondroitin sulfate; Cryogel; Glycoaminoglycans; Growth factors; Hyaluronic acid.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jyh-Ping Chen reports financial support was provided by Chang Gung Memorial Hospital Linkou Branch. Jyh-Ping Chen reports financial support was provided by Ministry of Science and Technology. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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