Adipose Tissue-Derived Stem Cells with PRP In Joints
Adipose Tissue-Derived Stem Cells with PRP In Joints
Our results show that autologous and uncultured ADSCs/PRP therapy in the form of SVF could be considered to be safe when used as percutaneous local injections.
ADSCs were extracted using collagenases, which were later removed by washing the ADSCs with D5LR solution three times. After all three washings, the total amount of collagenase contained in the ADSCs was undetectable (data not shown). Therefore, it would be very doubtful if such undetectable amount of collagenase would have caused swelling and pain of the joints. However, it can be assumed that some of the cells injected into the joints, including red blood cells and ADSCs, would not have survived, as previously reported. Probably such non-viable cells surmount an inflammatory reaction, causing pain and swelling. A recent report supports this notion. Such pain and swelling subside gradually with oral intakes of NSAIDs and cold compression. The frequency of these complications was more than that of other report using culture-expanded bone marrow-derived MSCs.
After 6–8 weeks of ADSCs and PRP injection of knee joints, some elderly patients complained of knee pain secondary to tenosinovitis and tendonitis. These symptoms usually occurred in elderly patients over the age of 60 (15 of 22 patients), as previously described. These symptoms improved with NSAIDs and resolved with trigger point injections with triamcinolone at third or fourth months. The exact cause of these symptoms is not clear. It can be postulated that knee posture may be the cause. Cartilage regeneration, decreased mobility during the procedure, or increased mobility after the procedure may cause the positioning of the knee joint to be changed, resulting the tendons and ligament to strain, as previously reported.
One patient experienced a localized rash around the injected site of the knee. Another patient experienced a hemorrhagic stroke. Although the percentage of these complications is greater than 1% of the total patient population of this group, these two are more of co-incidences. The likely causative agent in case of the localized rash would be the synthetic hyaluronic acid that was injected as a scaffold material. As for the hemorrhagic stroke, no other patient experienced such symptoms in the other patient group treated after the year 2010. Further, in the case of hemorrhagic stroke, it is difficult to assume that any form of cells injected locally with PRP were re-absorbed or transferred to blood stream, causing hemorrhagic stroke. In addition, recent research by Horie et al. demonstrated that MSCs implanted in a joint remain localized to the transplant site.
According to the results of the analysis of pain scores and telephone questionnaires from 100 joints, there has been no report of tumor formation at the implant sites. Further, there was no evidence of tumor formation in 27 joints that were imaged by MRI. This study is the first report on ADSCs safety in clinical applications. While it is possible that tumors may still form at some time beyond the average follow-up period presented in our data, this possibility decreases at an exponential rate. MSCs replicate every 2–4 days in vitro expansion. Thus, if a tumor were to form at the implanted site, it might have been discernible within few months by a high field MRI.
Patients' VAS after the ADSCs/PRP treatment improved 50–60%, and this was statistically significant (Figure 1). The pain improvement can be attributed to the probable regeneration of the damaged tissues that have been documented by MRI in some of the patients. However, no patient reported 100% resolution of the pain. Many possibilities exist for the explanation of incomplete resolution of the pain. One of the reasons would be the fact that the extent of the regeneration was achieved only partially. Another possible rationale for the incomplete resolution of the pain is probably the fact that the osteoarthritis and AVN are joint disorders as a whole, not just degeneration of only cartilage and bone, respectively.
The two low back and the two ankle patients reported minimal clinical improvement. Many reasons exist for possible rationale of the minimal pain improvement. Also, quantity and quality of MSCs are important. Another important factor is properly targeting the site for injection, especially if the target site has limited space. With regards to low backs, uncertainty exists if ADSCs were correctly and properly placed in the disc. As for the ankle, the quantity and quality of ADSCs injected in the limited joint space could be questioned.
Overall, this study with 100 joint injections of ADSCs, in the form of SVF, with PRP shows that ADSCs/PRP treatment is safe and provides long-term pain improvement. However, this study only shows a glimpse of the possibility of using ADSCs in the field of regenerative medicine. All patients were offered the third month post-procedure MRIs, but some patients refused to undergo post-procedure MRIs due to symptom improvement and/or financial reasons. Therefore, the longer-term (more than 3 months) follow-ups were conducted based on telephone questionnaires. The measurement of PRP concentration and the assessment of viable ADSCs' quantity and quality are necessary. Also, randomized, double blind, and placebo-controlled studies are needed to confirm the efficacy of ADSCs in various joint diseases.
Discussion
Our results show that autologous and uncultured ADSCs/PRP therapy in the form of SVF could be considered to be safe when used as percutaneous local injections.
ADSCs were extracted using collagenases, which were later removed by washing the ADSCs with D5LR solution three times. After all three washings, the total amount of collagenase contained in the ADSCs was undetectable (data not shown). Therefore, it would be very doubtful if such undetectable amount of collagenase would have caused swelling and pain of the joints. However, it can be assumed that some of the cells injected into the joints, including red blood cells and ADSCs, would not have survived, as previously reported. Probably such non-viable cells surmount an inflammatory reaction, causing pain and swelling. A recent report supports this notion. Such pain and swelling subside gradually with oral intakes of NSAIDs and cold compression. The frequency of these complications was more than that of other report using culture-expanded bone marrow-derived MSCs.
After 6–8 weeks of ADSCs and PRP injection of knee joints, some elderly patients complained of knee pain secondary to tenosinovitis and tendonitis. These symptoms usually occurred in elderly patients over the age of 60 (15 of 22 patients), as previously described. These symptoms improved with NSAIDs and resolved with trigger point injections with triamcinolone at third or fourth months. The exact cause of these symptoms is not clear. It can be postulated that knee posture may be the cause. Cartilage regeneration, decreased mobility during the procedure, or increased mobility after the procedure may cause the positioning of the knee joint to be changed, resulting the tendons and ligament to strain, as previously reported.
One patient experienced a localized rash around the injected site of the knee. Another patient experienced a hemorrhagic stroke. Although the percentage of these complications is greater than 1% of the total patient population of this group, these two are more of co-incidences. The likely causative agent in case of the localized rash would be the synthetic hyaluronic acid that was injected as a scaffold material. As for the hemorrhagic stroke, no other patient experienced such symptoms in the other patient group treated after the year 2010. Further, in the case of hemorrhagic stroke, it is difficult to assume that any form of cells injected locally with PRP were re-absorbed or transferred to blood stream, causing hemorrhagic stroke. In addition, recent research by Horie et al. demonstrated that MSCs implanted in a joint remain localized to the transplant site.
According to the results of the analysis of pain scores and telephone questionnaires from 100 joints, there has been no report of tumor formation at the implant sites. Further, there was no evidence of tumor formation in 27 joints that were imaged by MRI. This study is the first report on ADSCs safety in clinical applications. While it is possible that tumors may still form at some time beyond the average follow-up period presented in our data, this possibility decreases at an exponential rate. MSCs replicate every 2–4 days in vitro expansion. Thus, if a tumor were to form at the implanted site, it might have been discernible within few months by a high field MRI.
Patients' VAS after the ADSCs/PRP treatment improved 50–60%, and this was statistically significant (Figure 1). The pain improvement can be attributed to the probable regeneration of the damaged tissues that have been documented by MRI in some of the patients. However, no patient reported 100% resolution of the pain. Many possibilities exist for the explanation of incomplete resolution of the pain. One of the reasons would be the fact that the extent of the regeneration was achieved only partially. Another possible rationale for the incomplete resolution of the pain is probably the fact that the osteoarthritis and AVN are joint disorders as a whole, not just degeneration of only cartilage and bone, respectively.
The two low back and the two ankle patients reported minimal clinical improvement. Many reasons exist for possible rationale of the minimal pain improvement. Also, quantity and quality of MSCs are important. Another important factor is properly targeting the site for injection, especially if the target site has limited space. With regards to low backs, uncertainty exists if ADSCs were correctly and properly placed in the disc. As for the ankle, the quantity and quality of ADSCs injected in the limited joint space could be questioned.
Overall, this study with 100 joint injections of ADSCs, in the form of SVF, with PRP shows that ADSCs/PRP treatment is safe and provides long-term pain improvement. However, this study only shows a glimpse of the possibility of using ADSCs in the field of regenerative medicine. All patients were offered the third month post-procedure MRIs, but some patients refused to undergo post-procedure MRIs due to symptom improvement and/or financial reasons. Therefore, the longer-term (more than 3 months) follow-ups were conducted based on telephone questionnaires. The measurement of PRP concentration and the assessment of viable ADSCs' quantity and quality are necessary. Also, randomized, double blind, and placebo-controlled studies are needed to confirm the efficacy of ADSCs in various joint diseases.
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