TABLE 1.

Advantages, disadvantages, and logistics of large animal models for articular cartilage injury and regeneration with MSC treatment, with parameters of relevant studies published within the last 5 years.

Animal model	Porcine	Goat	Sheep	Equine	Canine
Articular cartilage thickness	1–2 mm	1.5–2 mm	0.4–1.7 mm	1.5–2 mm	0.6–1.3 mm
Defect diameter	6–8 mm	6–10 mm	7–10 mm	6–20 mm	2–10 mm (4 mm most common)
Advantages	comparable biomechanics, comparable joint size	comparable biomechanics, comparable joint size, relatively inexpensive/easy to maintain	comparable biomechanics, comparable joint size, relatively inexpensive/easy to maintain	spontaneous OA, comparable biomechanics, comparable joint/cartilage size	spontaneous OA, relatively inexpensive/easy to maintain, compliant with postoperative exercise and loading regimens
Disadvantages	relatively late skeletal maturity, poor compliance with postoperative exercise/loading regimens, expensive and difficult to maintain	relatively late skeletal maturity, poor compliance with postoperative exercise/loading regimens, higher peak knee pressure	relatively late skeletal maturity, poor compliance with postoperative exercise/loading regimens	relatively late skeletal maturity, expensive and difficult to maintain, postoperative overloading, greater biomechanical load, strict licensing requirements	ethical concerns, limited noninvasive analysis methods
OA induction methods	ACL transection, partial/total meniscectomy, monosodium iodoacetate, chondral and osteochondral defect	partial/total meniscectomy, chondral and osteochondral defect	ACL transection, partial/total meniscectomy, chondral and osteochondral defect	spontaneous, osteochondral fragment, surgical impaction, chondral and osteochondral defect	spontaneous, ACL transection, partial/total meniscectomy, chondral and osteochondral defect
MSC Types	bMSCs, aMSCs, sMSCs, human bMSCs, human umMSCs	bMSCs, human umMSCs, human ubMSCs	bMSCs, aMSCs	bMSCs, sMSCs	bMSCs, aMSCs, umMSCs
MSC delivery route	Seeded onto implanted scaffolds, direct implantation	Intra-articular injection, seeded onto implanted scaffolds, direct implantation	Intra-articular injection, seeded onto implanted scaffolds, direct implantation	Seeded onto implanted scaffolds, direct implantation	Intra-articular injection
Injected MSC dose	n/a	25 million	2.5–50 million	n/a	1–10 million
Implanted MSC dose	0.4–30 million	1–60 million	2.5–30 million/ml	1–50 million	n/a
Length of Study	12–26 weeks	16–40 weeks	6–27 weeks	26–52 weeks	5–28 weeks
Treatment Outcomes	Lv et al. (2018): Improved gross/histological score, GAG content	Zhang et al. (2018a): Improved MRI/histological appearance, increased collagen II, compared to microfracture	Feng et al. (2018)—Improved MRI/histological scores, decreased synovial fluid inflammatory factors, thicker cartilage, allogenic MSC survival at least 14 weeks	Murata et al. (2022): improved radiographic defect filling, MRI/gross/histological scores	Li et al. (2018): improved radiographic defect filling, gross/histological scores
	Yamasaki et al. (2019): Improved MRI/histological score, increased radiographic defect filling	Zhang et al. (2020): Improved gross/MRI/histological appearance, higher GAG content and Young’s modulus, persistent xenogenic umMSCs in chondrocyte/MSC co-culture scaffold	Veronesi et al. (2022)—improved macroscopic/histological/synovial histological score, decreased local inflammatory markers, with stromal vascular fraction outperforming expanded MSCs		Zhang et al. (2018b): improved MRI X-ray appearance, thicker neocartilage, decreased circulating inflammatory markers
	Kondo et al. (2019): Improved gross/histological score, MRI appearance, only at study endpoint
	Tseng et al. (2018): Increased defect filling, histological appearance, decreased fibrous neotissue	Kim et al. (2022): Improved gross/X-ray score, lameness score	Keller et al. (2019)—No inflammatory cell infiltrate, comparable histological scores for matrix staining, superficial/mid/deep zone, and overall assessment to autograft, at end-point	Chu et al. (2018): Similar gross/MRI/histological score and fibrocartilage formation for nonexpanded bone marrow concentrate and microfracture	De Francesco et al. (2021): improved lameness and pain scores, trend towards reduced synovial inflammatory markers
	Wu et al. (2019): Improved gross appearance, histological score. HA increased proliferation and cartilage-specific gene expression	Wei et al. (2019): Improved gross/histological scores	Vahedi et al. (2019)—Increased gross defect filling with cartilaginous tissue, increased expression of collagen II, aggrecan, and SOX9, for MSCs with scaffold	Mancini et al. (2020): limited cartilaginous tissue formation and persistent hydrogel on histology, for both bilayer constructs
	Theruvath et al. (2021): Improved gross/MRI/histological score, collagen II content		Favreau et al. (2020)—Improved gross scores, MRI/histological appearance, regenerated cartilage surface area
	Bothe et al. (2019): Erosion of bone, decreased histological score with biphasic scaffold implantation		Di Bella et al. (2019)—improved gross/histological scores, for MSCs in in situ-printed scaffolds but not MSCs in pre-printed scaffolds