A Phase I Dose-Escalation Clinical Trial to Assess the Safety and Efficacy of Umbilical Cord-Derived Mesenchymal Stromal Cells in Knee Osteoarthritis.

Osteoarthritis (OA) is the most common degenerative joint disease. Mesenchymal stromal cells (MSC) are promising cell-based therapy for OA. However, there is still a need for additional randomized, dose-dependent studies to determine the optimal dose and tissue source of MSC for improved clinical outcomes. Here, we performed a dose-dependant evaluation of umbilical cord (UC)-derived MSC (Celllistem) in a murine model and in knee OA patients. For the preclinical study, a classical dose (200.000 cells) and a lower dose (50.000 cells) of Cellistem were intra-articularly injected into the mice knee joints. The results showed a dose efficacy response effect of Cellistem associated with a decreased inflammatory and degenerative response according to the Pritzker OARSI score. Following the same approach, the dose-escalation phase I clinical trial design included 3 sequential cohorts: low-dose group (2 × 106 cells), medium-dose group (20 × 106), and high-dose group (80 × 106). All the doses were safe, and no serious adverse events were reported. Nonetheless, 100% of the patients injected with the high-dose experienced injection-related swelling in the knee joint. According to WOMAC total outcomes, patients treated with all doses reported significant improvements in pain and function compared with baseline after 3 and 6 months. However, the improvements were higher in patients treated with both medium and low dose as compared to high dose. Therefore, our data demonstrate that the intra-articular injection of different doses of Cellistem is both safe and efficient, making it an interesting therapeutic alternative to treat mild and symptomatic knee OA patients. Trial registration ClinicalTrials.gov NCT03810521.

Analysis of vulnerability to reentry in acute myocardial ischemia using a realistic human heart model.

Electrophysiological alterations of the myocardium caused by acute ischemia constitute a pro-arrhythmic substrate for the generation of potentially lethal arrhythmias. Experimental evidence has shown that the main components of acute ischemia that induce these electrophysiological alterations are hyperkalemia, hypoxia (or anoxia in complete artery occlusion), and acidosis. However, the influence of each ischemic component on the likelihood of reentry is not completely established. Moreover, the role of the His-Purkinje system (HPS) in the initiation and maintenance of arrhythmias is not completely understood. In the present work, we investigate how the three components of ischemia affect the vulnerable window (VW) for reentry using computational simulations. In addition, we analyze the role of the HPS on arrhythmogenesis. A 3D biventricular/torso human model that includes a realistic geometry of the central and border ischemic zones with one of the most electrophysiologically detailed model of ischemia to date, as well as a realistic cardiac conduction system, were used to assess the VW for reentry. Four scenarios of ischemic severity corresponding to different minutes after coronary artery occlusion were simulated. Our results suggest that ischemic severity plays an important role in the generation of reentries. Indeed, this is the first 3D simulation study to show that ventricular arrhythmias could be generated under moderate ischemic conditions, but not in mild and severe ischemia. Moreover, our results show that anoxia is the ischemic component with the most significant effect on the width of the VW. Thus, a change in the level of anoxia from moderate to severe leads to a greater increment in the VW (40 ms), in comparison with the increment of 20 ms and 35 ms produced by the individual change in the level of hyperkalemia and acidosis, respectively. Finally, the HPS was a necessary element for the generation of approximately 17% of reentries obtained. The retrograde conduction from the myocardium to HPS in the ischemic region, conduction blocks in discrete sections of the HPS, and the degree of ischemia affecting Purkinje cells, are suggested as mechanisms that favor the generation of ventricular arrhythmias.

Umbilical Cord-Derived Mesenchymal Stromal Cells (MSCs) for Knee Osteoarthritis: Repeated MSC Dosing Is Superior to a Single MSC Dose and to Hyaluronic Acid in a Controlled Randomized Phase I/II Trial.

Knee osteoarthritis (OA) is a leading cause of pain and disability. Although conventional treatments show modest benefits, pilot and phase I/II trials with bone marrow (BM) and adipose-derived (AD) mesenchymal stromal cells (MSCs) point to the feasibility, safety, and occurrence of clinical and structural improvement in focal or diffuse disease. This study aimed to assess the safety and efficacy of the intra-articular injection of single or repeated umbilical cord-derived (UC) MSCs in knee OA. UC-MSCs were cultured in an International Organization for Standardization 9001:2015 certified Good Manufacturing Practice-type Laboratory. Patients with symptomatic knee OA were randomized to receive hyaluronic acid at baseline and 6 months (HA, n = 8), single-dose (20 × 106 ) UC-MSC at baseline (MSC-1, n = 9), or repeated UC-MSC doses at baseline and 6 months (20 × 106 × 2; MSC-2, n = 9). Clinical scores and magnetic resonance images (MRIs) were assessed throughout the 12 months follow-up. No severe adverse events were reported. Only MSC-treated patients experienced significant pain and function improvements from baseline (p = .001). At 12 months, Western Ontario and Mc Master Universities Arthritis Index (WOMAC-A; pain subscale) reached significantly lower levels of pain in the MSC-2-treated group (1.1 ± 1.3) as compared with the HA group (4.3 ± 3.5; p = .04). Pain Visual Analog scale was significantly lower in the MSC-2 group versus the HA group (2.4 ± 2.1 vs. 22.1 ± 9.8, p = .03) at 12 months. For total WOMAC, MSC-2 had lower scores than HA at 12 months (4.2 ± 3.9 vs. 15.2 ± 11, p = .05). No differences in MRI scores were detected. In a phase I/II trial (NCT02580695), repeated UC-MSC treatment is safe and superior to active comparator in knee OA at 1-year follow-up. Stem Cells Translational Medicine 2019;8:215&224.

Is computed tomography an accurate and reliable method for measuring total knee arthroplasty component rotation?

PURPOSE: Computed tomography (CT) is widely used to assess component rotation in patients with poor results after total knee arthroplasty (TKA). The purpose of this study was to simultaneously determine the accuracy and reliability of CT in measuring TKA component rotation. METHODS: TKA components were implanted in dry-bone models and assigned to two groups. The first group (n = 7) had variable femoral component rotations, and the second group (n = 6) had variable tibial tray rotations. CT images were then used to assess component rotation. Accuracy of CT rotational assessment was determined by mean difference, in degrees, between implanted component rotation and CT-measured rotation. Intraclass correlation coefficient (ICC) was applied to determine intra-observer and inter-observer reliability. RESULTS: Femoral component accuracy showed a mean difference of 2.5° and the tibial tray a mean difference of 3.2°. There was good intra- and inter-observer reliability for both components, with a femoral ICC of 0.8 and 0.76, and tibial ICC of 0.68 and 0.65, respectively. CONCLUSIONS: CT rotational assessment accuracy can differ from true component rotation by approximately 3° for each component. It does, however, have good inter- and intra-observer reliability.

Effect of cyclic tension on the biomechanical properties of flexor tendon grafts. Results of an ex-vivo porcine study.

BACKGROUND: Autologous flexor tendons are widely used for anterior cruciate ligament (ACL) reconstruction. Pretension of the graft before fixation has been described as part of the surgical technique, nevertheless there is no consensus on the type and amount to tension needed to increase the stiffness without affecting its biomechanical properties.Our hypothesis is cyclic tension increases flexor tendon stiffness without affecting its ultimate failure at maximum loads (UFML). METHODS: Forty-five flexor digitorum profundus tendons harvested from domestic pigs (Sus scrofa domestica) were randomly divided into three groups: E1 (n=15), E2 (n=15) and C (n=15). Groups E1 and E2 were subjected to 50 cyclic loads at a 1 Hz frequency, at 70N and 100N respectively, group C was not intervened. The three groups were then tested for UFML. Cyclic loads and measurements were performed using a Stress-Strain machine (SST 1.0 Kinetecnic). Results were analyzed using GrapgPad statistical software. Groups were compared using Mann-Whitney test with a 95% confidence interval. RESULTS: Significant increased stiffness for group E1 (p=0.02) and group E2 ( p<0.01) when compared to group C. The stiffness of group E2 was also significantly higher than E1 (p=0.03). There was a significant reduction on the UFML between group E2 and C (p<0.01), which was not observed when comparing groups E1 and C. CONCLUSION: Cyclic loads at 70N result in an increased stiffness of flexor tendons without affecting its ultimate failure at maximum loads. Cyclic loads at higher tensions might cause a deleterious effect on the biomechanical properties of flexor tendon grafts.

Treatment of patellofemoral chondropathy with the Bandi tibial tubercle osteotomy More than 10years follow-up.

Isolated degenerative patellofemoral chondropathy is a prevalent disease. There is still controversy regarding its ideal type of management. A retrospective study was performed to assess the outcomes of 28 patients with a minimum of 10-year follow-up, in whom the Bandi tibial tubercle osteotomy was performed. The Bentley score was applied pre and postoperatively to evaluate the clinical results. Preoperatively, 21 (67%) patients were rated as fair and seven (33%) as poor according to the Bentley functional scale for patellofemoral osteoarthritis. At 5 years of follow-up, one case was rated as excellent, 23 (81%) cases as good, three as fair and one as poor. At 10 years of follow-up no cases were rated as excellent, 17 (61%) cases as good, four (14%) as fair and seven (25%) as poor. The difference in terms of poor results evaluated at five and 10 years after the surgery was statistically significant (p<0.05). We concluded that excellent and good short-term results can be expected with the use of the Bandi tibial tubercle osteotomy in patients with isolated degenerative patellofemoral chondropathy; however, such outcomes tend to deteriorate over the time, especially in patients with advanced chondromalacia, making its indication controversial.

Effects of platelet concentrate and a bone plug on the healing of hamstring tendons in a bone tunnel.

PURPOSE: The purpose of this study was to determine if the use of platelet concentrate (PC) and bone plug (BP) does accelerate the healing process in anterior cruciate ligament (ACL) reconstruction. METHODS: One hundred and eight patients requiring ACL reconstruction were prospectively randomized into 4 groups: control (27 patients), PC (26 patients), BP (28 patients), and a combination of PC and BP (27 patients). Magnetic resonance imaging (MRI) studies were carried out at both 3 and 6 months postsurgery. Maturation of the graft was evaluated at the femoral tunnel using MRI maturation criteria defined by a low-intensity signal, absence of osteoligamentous interface, and no widening of the femoral tunnel. RESULTS: Three months after surgery, no differences were found among the groups regarding MRI maturation criteria. Six months postsurgery, 78% of the patients in the control group had a low-intensity signal, while in the PC group the low-intensity signal was present in 100% of the patients (P = .036). No statistical differences were observed regarding the osteoligamentous interface between the various groups. Finally, tunnel widening was seen in 11% of the patients of the BP group versus 41% of the patients in the control group (P = .047), but no statistical difference was seen with the other groups. CONCLUSIONS: The use of PC had an enhancing effect on the graft maturation process evaluated only by MRI signal intensity, without showing any significant effect in the osteoligamentous interface or tunnel widening evolution. The use of a BP effectively prevented tunnel widening. The BP and PC combination did not show a synergic effect as compared to PC or BP individually. LEVEL OF EVIDENCE: Level II, lesser quality randomized controlled trial.