Discussion
Pain, non-atherosclerotic PAD, CLI, amputation, amputations, pain, ill, major amputations, ulcer
LIMB ISCHEMIA, DISEASE, MINOR, SECONDARY, ISCHEMIC ULCERS, ULCERATION, ULCER, COMPLICATIONS
In ischemic lesions in CLI patients, normal vascular regeneration mechanisms, including angiogenesis and arteriogenesis, do not take place [No clinical research has documented the safety and effectiveness of utilizing P-MSCs to treat patients with non-atherosclerotic PAD. Therefore, in this primary clinical trial, we assessed the safety, feasibility, and tolerability of prenatal MSCs as potential treatments for patients with CLI. Our findings demonstrated that, following cell injection, physical function and clinical complications improved significantly in all participants. Most of the recovered patients had a dramatic response—2 to 3 month after the first MSC injection that persisted during the 6-month follow-up assessment. Despite the small patient population, the efficacy outcomes for some patients with advanced disease stages are highly encouraging.In this dose-escalation phase I experiment, two cell doses (20 million and 60 million MSCs) were tested until the MTD was established, as the optimal number of cells required for angiogenesis remains unknown. Few studies on cell doses have been conducted, and such studies will be critical for optimizing the administration of enlarged populations of stem cells or marker-selected stem cell populations MTD was established. MTD was not achieved following P-MSC therapy because no occurrences of DLT or AEs leading to P-MSC treatment discontinuation were recorded in this experiment. All dosages of P-MSCs, including the highest tested dose of 60 × 10We selected appropriate patient populations for the transplantation of stem cells in this clinical study, as there is a great deal of diversity in the capacity of patients to establish significant vascular repairs [We utilized IM injection in this trial because it effectively conveys a large number of cells to ischemic sites, as reported in preexisting cell-based treatments for CLI [Although this trial was not powered for effectiveness criteria measures, we found clinically substantial improvements in limb blood circulation and severity of limb ischemia. This was demonstrated by a substantial improvement in rest pain, blood flow, and maximum walking distance after P-MSC implantation. Pain scores showed a decreasing trend after treatment with P-MSCs in both dose groups, up to a decrease of 4.5 units. ABI, which is considered a marker of tissue perfusion, increased over the first trimester. However, this increasing trend was not significant in the second trimester after the injection (mean baseline ABI: 1.04; 3-month mean ABI: 1.12; 6-month mean ABI: 1.08.4, In this trial, all patients showed improved symptoms on the QoL questionnaire and reduced analgesic usage. Interestingly, one patient experienced dramatic improvement in the injected leg despite major amputation before the end of the follow-up period. It is worth emphasizing that all patients acknowledged and were informed of the significant clinical benefits of the treated limb.In this clinical trial, angiographic evaluation was performed before and after cell infusion and revealed that collateral vessel formation scores were elevated. However, these changes were not significant (One of the main outcomes of effectiveness in this study was the prevention of major limb amputation. We were able to avoid or perform minor amputations rather than major amputations in the patients with CLI. In the study by Gupta et al., the number of ulcer healings and amputations was comparable in both groups (placebo and BM-MSC). It is possible that allogeneic BM-MSC treatment did not provide significant benefit to severely ill patients who were facing amputation owing to the advanced form of their condition [In addition, considerable improvement or complete healing was observed in all patients with ischemic ulcers. Even when we had to perform minor amputations in a few patients before or after P-MSC implantation, the wounds healed after amputation, and the measurement of the total wound area was greatly reduced.Our study had a number of caveats and limitations. This study was not powerful enough to determine whether high doses of P-MSCs were more effective than low doses of P-MSCs.ABI improvement was the primary outcome of several stem cell studies on CLI; however, there was no noticeable difference between baseline and follow-up. Yet, other secondary endpoints, such as amputation-free interval extension, wound healing, and rest pain, showed substantial improvements [In this trial, the collateral vessel formation scores changes were not significant. Part of the reason is the small number of patients in this study. The other part could be the low resolution of the angiography method used in this clinical trial. It should be mentioned that there is a need for more accurate methods to check the collateralization, such as magnetic resonance angiography (MRA) and digital subtraction angiography (DSA), which can show the formation of new vessels with higher accuracy [Because the number of injected limbs was insufficient to conduct a statistical analysis, data on the amputation-free survival rate and ulcer healing were reported descriptively.Despite the immunomodulatory and anti-inflammatory characteristics of MSCs, there are emerging concerns regarding their tumorigenic potential owing to their innate predisposition to migrate to injured tissues and inflammatory regions [In this study, we followed the patients for 6 months in terms of clinical and preclinical outcomes, which seems to be short, since some criteria such as the results of angiogenesis, ABI, relief of rest pain, healing of ulceration, and prevention of major amputation in the target limb may change in the long term. In other words, most of the results will be more accurate during a more thorough follow-up.