TABLE 1.

Functional motifs applications for cartilage tissue engineering.

Growth factor	Function	Motif sequence	Selection mechanism	Carrier	Modification	Cell/Species	Results	Reference
TGF-β	Promote differentiation of MSCs into chondrocytes Blumenfeld et al. (1997)	ANVAENA (CM-1)	Microstructure simulation	—	—	Rat	CM1 improved the thickness of neotissue and collagen secretion in mouse wound model	El-Sakka et al. (1997)
	Improve cartilage matrix synthesis, such as collagen typeⅡand proteoglycans Garbuzenko et al. (2009)			—	—	hMSCs	CM1 improved the GAGs production, independent of dosage	Renner and Liu (2013)
	Reduce the activity of cytokines related to cartilage injury, such as interleukin-1 Sellers et al. (1997)	LIAEAK (CM-2)	Microstructure simulation	—	—	hMSCs	CM2 improved the GAGs production, independent of dosage	Renner and Liu (2013)
				CX-HA	Covalent bond	hPLSCs	Chemically crosslinked CM2 showed stabler release and better GAGs deposition, compared with physically mixed into HA hydrogel	Park et al. (2019)
		LIANAK (CM-10)	Microstructure simulation	FNF-HMS	Covalent bond	BMSCs	Safranin O, Von kossa and immunohistochemical stains showed better deposition of GAGs and collagen, with little calcification	Zhang et al. (2015a)
						Rat
				—	—	Rat	CM10 induced early epithelialization and vascularization of skin wound, so as to strengthen the collagen deposition and tissue reconstruction	Basu et al. (2009)
BMHP	Recruitment of MSCs to cartilage defect areas Liu et al. (2013)	PFSSTKT	Highly repetitive conserved sequences	—	—	MNSCs	PFSSTKT recruited NSCs to local tissue, and the cell behaviors were stable, compared with Matrigel	Gelain et al. (2006)
				SAP hydrogel	Covalent bond	BMSC	RAD/PFS hydrogel did favor to the adhesion of rabbit BMSCs	Lu et al. (2018)
						Rabbit	Better reconstruction of articular cartilage was found after implanting RAD/PFS/ACM composite scaffold into rabbit knee cartilage defect
		SKPPGTSS	Highly repetitive conserved sequences	—	—	MNSCs	SKPPGTSS recruited NSCs to local tissue, and the cell behaviors were stable, compared with Matrigel	Gelain et al. (2006)
				HX	Covalent bond	BMSC	BMSCs stayed healthy on different scaffolds	Sun et al. (2018)
						Rabbit	RAD/SKP/PFS group showed ideal neocartilage at rabbit knee cartilage defect area
BMP	Drive the development of cartilage	KIPKASSVPTELSAISTYL	Phage Display technology	—	—	hMSCs	BMP-mimetic peptide significantly strengthened the secretion of GAGs in hMSCs	Renner and Liu (2013)
	Induce the differentiation of mesenchymal precursor cell into chondrocytes Yang et al. (2011)			—	—	hMSCs	BMP-mimetic peptide did favor for cartilage matrix deposition	Renner et al. (2012)
	Induce BMSCs to generate cartilage matrix both in vitro and in vivo Raducanu et al. (2009)						BMP-mimetic peptide reduced the secretion of collagen type X and the ALP activity of hMSCs
		SYED (CK2.1)	Phage Display technology	—	—	Rat	CK2.1 increased the regeneration of cartilage but decreased the expression of collagen type X and osteocalcin	Akkiraju et al. (2017a)
				HGP	Covalent bond	Rat	CK2.1-HGP improved the cartilage restoration in mice but showed no evidence of hypertrophy, and lower deposition of collagen type X	Akkiraju et al. (2017b)
N-Cadherin	Mediate the aggregation and condensation of progenitor cells and MSCs Tavella et al. (1994)	HAV	Highly repetitive conserved sequences	MeHA hydrogel	Covalent bond	hMSCs	The productions of GAGs and collagen in HVA group were increased than other groups in vitro and in vivo	Bian et al. (2013)
						Rat
				E-PA	Covalent bond	hMSCs	Cells adhered the HAV/E-PA network well	Eren Cimenci et al. (2019)
							Cells cultured on the HAV/E-PA scaffold secreted more GAGs, and showed higher expression of chondrogenic markers
				KLD hydrogel	Covalent bond	hMSCs	With stimulation of HAVDI, the secretion of GAGs and gene expression of chondrogenesis were upgraded	Li et al. (2017a)
							The subcellular localization changed
				—	—	hMSCs	HAV strengthened the expressions of early chondrogenic markers, depending on the dosage strongly	Kwon et al. (2018)
Integrin	Promote the adhesion between cells and ECM Place et al. (2009)	RGD	Highly repetitive conserved sequences	PEG hydrogel	Covalent bond	hPDC	Supplemented by RGD, cells survived and proliferated better	Kudva et al. (2018)
	Participate in the mechanical signal transduction pathway of chondrocytes Hajos et al. (2008)						The upregulation of cell spreading and downregulation of cell circularity confirmed the satisfying cell adhesion
				Au-NPs	Covalent bond	hMSCs	Au-RGD1400 stimulation exhibited higher deposition of GAGs	Li et al. (2017b)
				PEG hydrogel	Covalent bond	Chondrocytes	RGD sequence was chemically crosslinked with PEG, resulting in more secretion of GAGs. A trend of hypertrophy in chondrocytes was found after stimulation of peptide RGD.	Zhang et al. (2015b)
				PEG hydrogel	Covalent bond	Chondrocytes	The risk of chondrocyte dedifferentiation tended to decrease when the microscopic distance were over 70nm, indicating more beneficial to maintain the normal phenotype of chondrocytes	Li et al. (2015)
				PEG hydrogel	Non-covalent bond	Chondrocytes	Without dynamic load, RGD had a negative effect on the phenotype of chondrocytes. Under dynamic compression, the expression of chondrogenic genes increased with the increase of RGD concentration	Villanueva et al. (2009)
		GRGDY	Highly repetitive conserved sequences	Calcium alginate hydrogel	Covalent bond	Chondrocytes	Formation of ectopic cartilage on the back of rats	Alsberg et al. (2002)
						Rat
		CPENFFGGRGDSG	Highly repetitive conserved sequences	PEG hydrogel	Covalent bond	hMSCs	Enzymatically cleaved CPENFFGRGDSG showed limited long-term influence on cell viability. With stimulation of CPENFFGRGDSG, the secretion of GAGs was significantly improved	Salinas and Anseth (2008)
IGF	Induce the proliferation and chondrogenic differentiation of MSCs Trippel, (1995)	GRVDWLQRNANFYDWFVAELG	Phage Display technology	—	—	hMSCs	Insulin-derived peptide of 0.1 μM improved the deposition of GAGs, with the presence of TGF-β3	Renner and Liu (2013)
PTH	Induce MSCs to differentiate into chondrocytes, but counteracting hypertrophic differentiation, so as to maintain the phenotype of chondrocyte Jiang et al. (2008)	PtHrP	Highly repetitive conserved sequences	—	—	BMSC	The content ratio of collagen type II to collagen type I was significantly improved by PTHrP	Kafienah et al. (2007)
		(1–34)					The expression of collagen type X was significantly downregulated by PTHrP
				—	—	MSCs, hAC Rat	PTHrP inhibited the ALP activity and gene expression of Indian hedgehog and collagen type X	Fischer et al. (2014)
				—	—	MSCs	The deposition of proteoglycan and collagen type II was promoted, and decreased expression trend of collagen type X was found	Rajagopal et al. (2021)
				—	—	MSCs	PtHrP supplementation from day 4 significantly increased the expression of chondrogenic markers compared with day 14	Zhang et al. (2013)
				—	—	BMSC	PTHrP improved the chondrogenic matrix deposition of proteoglycan and collagen type II.	Kim et al. (2008)
						ADSC	The markers of endochondral osteogenesis were inhibited
				—	—	NC, MSC	Implanted cell pellets that treated with PTHrP showed improved Safranin-O staining and anti-collagen type I/II IF staining results after 3 weeks	Johnstone et al. (1998)
						Rat	Weakly positive stains of Alizarin Red S and anti-collagen type X/CD31 IF staining were found
		PTHrP (1–40)	Highly repetitive conserved sequences	—	—	Rabbit	The time window between 4 and 6 weeks for PTHrP injection benefited the rat knee cartilage repair better	Anderson-Baron et al. (2021)