Table 4.

Biodistribution after intramuscular and intraarticular administration of MSCs in animal models.

Article	Model	Disease (Number of Animals)	Route of Administration (Source of Cells)	Cell-Marking Technique	Detection Time and Outcome	Comments
Hamidian Jahromi et al. [63] (2017)	Mice	Carrageenan-induced plantar inflammation	Intramuscular (contralateral to plantar inflammation) (xenogenic MSCs—Human MSCs)	MSCs were labelled with Gaussia Luciferase. Bioluminescence imaging, qPCR and histology techniques were used to assess biodistribution.	Bioluminescence was performed at 24 h, 48 h and up to 33 days. No MSCs were found to distribute to other organs. MSCs were detectable in the muscle up to 33 days after injection.	MSCs were able to reduce the contralateral inflammation and to lower the TNF-alfa serum levels without distributing systemically.
Creane et al. [61] (2017)	Mice	Healthy mice (10 animals)	Intramuscular (xenogenic MSCs—Human MSCs)	Human MSCs were injected and quantitative PCR for Alu sequences was performed in different tissue samples.	Ex vivo analysis was performed 3 months after injection. No MSCs were detected in any organ, including heart, lung, brain, liver, kidney and spleen. MSCs were detected in the thigh and calf samples, where MSCs were injected.	Intramuscular MSCs do not seem to remain viable and/or distribute 3 months after injection.
Hamidian Jahromi et al. [65] (2019)	Rats and mice (Review)	Different diseases	Intramuscular (different sources of MSCs)	Different techniques.	MSCs do not seem to distribute after intramuscular injection. MSCs seem to remain or spread locally, without systemic biodistribution.	Intramuscular MSCs do not seem to distribute systemically.
Cai et al. [64] (2017)	Rats	Healthy rats	Intramuscular (allogenic MSCs)	Melanin-based gadolinium3+ (Gd3+)-chelate nanoparticles were used to label MSCs. MRI was used to assess biodistribution.	MRI was performed on days 1, 4, 7, 14, 21, and 28. MSCs were found in the muscle up to 28 days after injection. No systemic biodistribution was observed.	Intramuscular MSCs do not seem to distribute systemically
Markides et al. [70] (2019)	Sheep	Osteochondral injury	Intraarticular (autogenic MSCs)	MSCs were labelled with Nanomag, and using a cell-penetrating technique, glycosaminoglycan-binding enhanced transduction (GET). Evaluation was performed with ex vivo MRI and histologic tests.	Ex vivo MRI and histology was performed 7 days after injection. MSCs were detected in the synovium, and not in the osteochondral defect.	MSCs are capable to home in the synovium, whereas they do not seem to be able to enter the joint to reach the osteochondral defect.
Yang et al. [74] (2019)	Mice	Supraspinatus tendon tear	Intraarticular (allogenic MSCs)	MSCs were labeled with quantum dots with near-infrared properties. Near-infrared fluorescence imaging was used to assess biodistribution.	Imaging was performed at days 1, 3, 7, 11, 14, and 17. MSCs did not distribute systemically. MSCs tended to migrate from the joint to the place of the lesion.
Satué et al. [75] (2019)	Rats	Patellofemoral cartilage defect	Intraarticular (allogenic MSCs)	MSCs expressing heat stable human placental alkaline phosphatase were used. Histological and immuno-histochemical analyses were performed in joint tissue and distant organs (heart, spleen, kidney, liver and lung)	Ex vivo analysis was performed at 1 day, 1 week, 1, 2 and 6 months. Injected MSCs remained in the synovial cavity, engrafted within the cartilage lesion, and were detectable up to 1 month post-injection. No systemic distribution was observed, apart from 1 case of MSCs in the lung.
Li et al. [67] (2016)	Mice	Osteoarthritis	Intraarticular (xenogenic MSCs—human MSCs)	MSCs were labeled with DiD fluorescent dye. In vivo bioluminescence imaging, and ex vivo quantitative PCR were performed to assess biodistribution.	Ex vivo imaging was performed up to day 70. PCR was performed at day 14 and 70 in heart, liver, spleen, lung, kidney, brain, muscle adjacent to the joint, and the whole injected knee join. MSCs were detected in the injected joint up to day 70 in diseased mice. In healthy mice, MSCs were detected up to day 21. No systemic distribution of MSCs was found.	MSCs seem to stand long times in the injected joint with no systemic distribution.
Marquina et al. [104] (2017)	Rats	Intraarticular chondrocyte trasplantation	Intraarticular, intravenous, intraperitoneal (allogenic MSCs)	MSCs were labeled with luciferase. Bioluminescence imaging was performed to assess biodistribution.	Imaging was performed at 2 h, 24 h, 2, 4 and 5 days. After intraarticular injection, no distribution of MSCs was detected. After intravenous injection, most MSCs were trapped in the lungs and disappeared within 24 h. After intraperitoneal injection, MSCs were localized in the injection site without distribution up to 5 days.
Li et al. [68] (2017)	Rats	Osteoarthritis	Intraarticular (xenogenic MSCs—human MSCs)	MSCs were labeled with DiD fluorescent dye. In vivo bioluminescence imaging and ex vivo histologic examinations were performed.	In vivo imaging was performed up to 70 weeks. MSCs were detected in the injected join up to 9 weeks. No systemic distribution was observed.	MSCs seem to stand long times in the injected joint with no systemic distribution.
Meseguer-Olmo et al. [21] (2017)	Rabbits	Healthy animals	Intraarticular and intravenous (xenogenic MSCs—human MSCs)	MSCs were labeled with99mTc-HMPAO. Scintigraphic images and qPCR in tissues (liver, kidney, heart, lung, bladder, knee, gallbladder) were used for assessing biodistribution.	Images were taken every 30 s during 25 min. qPCR was performed at 24 h. Intravenous MSCs distributed mainly to the lungs. Intraarticular MSCs did not distributed.
Toupet et al. [66] (2015)	Mice	Osteoarthritis and arthritis (unknown number)	Intravenous and intraarticular (xenogenic MSCs—human MSCs)	Human MSCs were infused, Quantitative assays for human DNA and mRNA were used to evaluate the distribution in 13 different organs.	Necropsies were performed at different times (1, 10, 30, 42) and PCR was performed. After intravenous infusion, MSCs were only detected in lungs in day 1. No MSCs were detected in day 10. After intra-articular injection, MSCs were detected for at least 10 days in osteo-arthritic knee joints. No MSCs were detected in other organs after in these mice.	After intra-articular injection, MSCs do not seem to distribute to other organs or tissues.
Shim et al. [73] (2015)	Mice	Osteoarthritis and healthy models	Intraarticular and intravenous (xenogenic MSCs—human MSCs)	Human MSCs were injected and qPCR tests were used to assess biodistribution in the different organs.	At 15 min and 8 h after injection, samples were collected from eight organs (spleen, kidney, liver, lymph nodes, muscle, lung, heart, brain). Blood concentrations were also monitored. After intravenous injection MSCs were detected immediately in blood, with a progressive decrease. After intraarticular injection, MSCs were detected in blood with a peak at 8 h. No systemic distribution was observed after intraarterial delivery. After intravenous injection, most MSCs were trapped in the lungs.	After intraarterial injection, MSCs are detectable in blood with a peak at 8 h. However, no systemic distribution is observed.
Delling et al. [69] (2015)	Sheep	Osteoarthritis	Intraarticular (autogenic MSCs)	MSCs were labelled with SPION particles. MRI and histological analyses were performed.	MR images were acquired at injection and at 1, 4, 8, and 12 weeks. Ex vivo histological examination was performed at 12 weeks. MSCs were found in the joint up to 12 weeks, without systemic distribution.
Ikuta et al. [76] (2015)	Rats	Healthy and cartilage defect models	Intraarticular (a magnet was used for selective accumulation of MSCs) and intravenous (xenogenic MSCs—human MSCs)	MSCs were labeled with DiR fluorescent dye and iron nanoparticles. MRI and fluorescent imaging were used to assess biodistribution. Histological exams were also performed.	Bioluminescence imaging was performed immediately and 1, 3, 7, 14, 21, and 28 days after cell transplantation. At day 28, organs were collected for ex vivo analyses. After intraarticular injection, MSCs remained in the joint. The use of the magnet led to magnetic MSCs accumulation in the target lesion.	The use of a magnet during magnetic-labeled MSCs transplantation can lead to selective accumulation of cells into the cartilage defects.