Safety and Efficacy of Bone Marrow-Derived Mesenchymal Stem Cells for Chronic Patellar Tendinopathy (With Gap >3 mm) in Patients: 12-Month Follow-up Results of a Phase 1/2 Clinical Trial.

Background: In a previous study, the authors found that at 6 months after treatment with a 20 × 106 dose of bone marrow-derived mesenchymal stem cells (BM-MSCs), patients showed improved tendon structure and regeneration of the gap area when compared with treatment using leukocyte-poor platelet-rich plasma (Lp-PRP). The Lp-PRP group (n = 10), which had not seen tendon regeneration at the 6-month follow-up, was subsequently offered treatment with BM-MSCs to see if structural changes would occur. In addition, the 12-month follow-up outcomes of the original BM-MSC group (n = 10) were evaluated. Purpose: To evaluate the outcomes of all patients (n = 20) at 12 months after BM-MSC treatment and observe if the Lp-PRP pretreated group experienced any type of advantage. Study Design: Cohort study; Level of evidence, 2. Methods: Both the BM-MSC and original Lp-PRP groups were assessed at 12 months after BM-MSC treatment with clinical examination, the visual analog scale (VAS) for pain during daily activities and sports activities, the Victorian Institute of Sport Assessment-Patella score for patellar tendinopathy, dynamometry, and magnetic resonance imaging (MRI). Differences between the 2 groups were compared with the Student t test. Results: The 10 patients originally treated with BM-MSCs continued to show improvement in tendon structure in their MRI scans (P < .0001), as well as in the clinical assessment of their pain by means of scales (P < .05). Ten patients who were originally treated with Lp-PRP and then with BM-MSCs exhibited an improvement in tendon structure in their MRI scans, as well as a clinical pain improvement, but this was not significant on the VAS for sports (P = .139). Thus, applying Lp-PRP before BM-MScs did not yield any type of advantage. Conclusion: The 12-month follow-up outcomes after both groups of patients (n = 20) received BM-MSC treatment indicated that biological treatment was safe, there were no adverse effects, and the participants showed a highly statistically significant clinical improvement (P < .0002), as well as an improvement in tendon structure on MRI (P < .0001). Preinjection of Lp-PRP yielded no advantages.

Effect of Autologous Expanded Bone Marrow Mesenchymal Stem Cells or Leukocyte-Poor Platelet-Rich Plasma in Chronic Patellar Tendinopathy (With Gap >3 mm): Preliminary Outcomes After 6 Months of a Double-Blind, Randomized, Prospective Study.

BACKGROUND: Patellar tendinopathy is common. The success of traditional management, including isometric or eccentric exercises combined with shockwave therapy and even surgery, is limited. Therefore, it is important to determine whether biological treatments such as ultrasound-guided intratendinous and peritendinous injections of autologous expanded bone marrow mesenchymal stem cells (BM-MSCs) or leukocyte-poor platelet-rich plasma (Lp-PRP) improve clinical outcomes in athletic patients with patellar tendinopathy. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: A prospective, double-blinded, randomized, 2-arm parallel group, active controlled, phase 1/2 single-center clinical study was performed in patients who had proximal patellar tendinopathy with a lesion >3 mm. A total of 20 participants (age 18-48 years) with pain for >4 months (mean, 23.6 months) and unresponsive to nonoperative treatments were randomized into 2 groups. Of these, 10 participants were treated with BM-MSC (20 × 106 cells) and 10 with Lp-PRP. Both groups performed the same postintervention rehabilitation protocol. Outcomes included the Victorian Institute of Sport Assessment for pain (VISA-P), self-reported tendon pain during activity (visual analog scale [VAS]), muscle function by dynamometry, tendon thickness and intratendinous vascularity by ultrasonographic imaging and Doppler signal, ultrasound tissue characterization (UTC) echo type changes, and magnetic resonance imaging (MRI) T2-weighted mapping changes. Participants were followed longitudinally for 6 months. RESULTS: The average VAS scores improved in both groups at all time points, and there was a significant reduction in pain during sporting activities (P < .05). In both groups, the average mean VISA-P scores at 6 months were significantly increased compared with baseline (66 BM-MSC group and 72.90 Lp-PRP group), with no significant differences in VAS or VISA-P scores between the groups. There were statistically significant greater improvements in tendon structure on 2-dimensional ultrasound and UTC in the BM-MSC group compared with the Lp-PRP group at 6 months. Similarly, the BM-MSC group demonstrated significant evidence of restoration of tendon structure on MRI compared with the Lp-PRP group at 6 months. Only the participants in the BM-MSC group showed evidence of normalization of tendon structure, with statistically significant differences between the groups on T2-weighted, fat-saturated sagittal and coronal scans and hypersignal in T2-weighted on spin-echo T2-weighted coronal MRI scan. Both treatments were safe, and no significant adverse events were reported in either group. CONCLUSION: Treatment with BM-MSC or Lp-PRP in combination with rehabilitation in chronic patellar tendinopathy is effective in reducing pain and improving activity levels in active participants. Participants who received BM-MSC treatment demonstrated greater improvement in tendon structure compared with those who received Lp-PRP. REGISTRATION: 2016-001262-28 (EudraCT identifier); NCT03454737 (ClinicalTrials.gov identifier).

Autologous bone marrow expanded mesenchymal stem cells in patellar tendinopathy: protocol for a phase I/II, single-centre, randomized with active control PRP, double-blinded clinical trial.

INTRODUCTION: Patellar tendon overuse injuries are common in athletes. Imaging may show a change in tissue structure with tendon thickening and disruption of the intratendinous substance. We wish to test the hypothesis that both autologous bone marrow expanded mesenchymal stem cells and autologous leukocyte-poor platelet-rich plasma (LP-PRP) implanted into the area of the disrupted tendinopathic patellar tendon will restore function, but tendon regeneration tissue will only be observed in the subjects treated with autologous bone marrow expanded mesenchymal stem cells. METHODS AND ANALYSIS: This is a single-centre, pilot phase I/II, double-blinded clinical trial with randomisation with active control. Twenty patients with a diagnosis of patellar tendinopathy with imaging changes (tendon thickening and disruption of the intratendinous substance at the proximal portion of the patellar tendon) will be randomised in a 1:1 ratio to receive a local injection of either bone-marrow autologous mesenchymal stem cells (MSC), isolated and cultured under GMP at The Institute of Biology and Molecular Genetics (IBGM) (Spain) or P-PRP. The study will have two aims: first, to ascertain whether a clinically relevant improvement after 3, 6 and 12 months according to the visual analogue scale (VAS), Victorian Institute of Sport Assessment for patellar tendons (VISA-P) and dynamometry scales (DYN) will be achieved; and second, to ascertain whether the proposed intervention will restore tendon structure as determined by ultrasonography (US), Doppler ultrasonography (DUS), and innovative MRI and ultrasound techniques: Magnetic Resonance T2 FAT SAT (UTE, Ultrashort Echo TE) sequence and Ultrasound Tissue Characterization (UTC). Patients who are randomised to the P-PRP treatment group but do not achieve a satisfactory primary endpoint after 6 months will be offered treatment with MSC. TRIAL REGISTRATION: NCT03454737.

Terapia celular en las lesiones deportivas: dónde estamos y a dónde vamos / Cell therapy in sports injuries: Where we are and where we're headed

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Final results of a phase I-II trial using ex vivo expanded autologous Mesenchymal Stromal Cells for the treatment of osteoarthritis of the knee confirming safety and suggesting cartilage regeneration.

BACKGROUND: Cellular therapies have shown encouraging results in the treatment of chronic osteoarthritis (OA). Herein, we present the final results of a phase I-II clinical trial assessing the feasibility, safety and efficacy of ex vivo expanded autologous bone marrow Mesenchymal Stromal Cells (MSC, XCEL-M-ALPHA), infused intra-articularly, in patients with knee OA. METHODS: Fifteen patients (median age=52years) with grade II(9) or III(6) gonarthrosis (Kellgren & Lawrence classification) and chronic pain were treated with an intra-articular infusion of 40.9×10(6)±0.4×10(6) MSCin a phase I-II prospective, open-label, single-dose, single-arm clinical trial. Endpoints were safety and tolerability. Efficacy was measured by the Visual Analogue Scale for pain, algofunctional Health Assessment Questionnaire, Quality of Life (QoL) SF-36 questionnaire, Lequesne functional index and WOMAC score. Cartilage integrity was assessed by Magnetic Resonance Imaging and quantitative T2-mapping at 0, 6 and 12months. RESULTS: The cell-based product was well tolerated with few reported Adverse Events (mild arthralgia and low back pain). There was a relevant decrease in the intensity of pain since day 8 after the infusion, that was maintained after 12months. The SF-36 QoL test showed improvement of parameters including bodily pain, role physical and physical functioning at month 12. The health assessment questionnaire revealed a significant decrease of incapacity. Moreover, T2 mapping showed signs of cartilage regeneration in all patients at 12months post-treatment. CONCLUSIONS: Single intra-articular infusion of XCEL-M-ALPHA is a safe and well-tolerated cell-based product, associated with a long-lasting amelioration of pain, improvement of QoL (up to four years), and signs of cartilage repair.

Efficacy of autologous platelet-rich plasma for the treatment of muscle rupture with haematoma: a multicentre, randomised, double-blind, placebo-controlled clinical trial.

BACKGROUND: The goals of the treatment of muscle injuries are to shorten the time of healing and to avoid relapses. The aim of this study was to assess the efficacy of autologous platelet-rich plasma (PRP) in the healing of muscle injuries. MATERIALS AND METHODS: A multicentre, randomised, double-blind, parallel, controlled clinical trial was conducted in 71 patients (81.8% males) aged 45.6 (SD=10.0) years with muscle tears in the legs and haematoma. The haematoma was evacuated in all patients. Thirty-three patients were randomised to a single dose of autologous PRP and 38 patients to simulation of PRP administration. The primary end-point was time to complete recovery of muscle injury. Secondary end-points were pain, relapses, ultrasound parameters, and adverse events. The total follow-up per patient was 12 months. RESULTS: Time to complete recovery after the treatment was 31.63 days (SD=15.38) in the PRP group, and 38.43 days (SD=18.58) in the control group (p=0.261). Pain decreased over time in both groups without statistical differences between them. Eight patients relapsed (seven in the control group, and one in the PRP group). There were no adverse effects related to the interventions. DISCUSSION: Autologous PRP did not significantly improve the time to healing compared to that in the control group.

Treatment of Knee Osteoarthritis With Allogeneic Bone Marrow Mesenchymal Stem Cells: A Randomized Controlled Trial.

BACKGROUND: Osteoarthritis is the most prevalent joint disease and a common cause of joint pain, functional loss, and disability. Conventional treatments demonstrate only modest clinical benefits without lesion reversal. Autologous mesenchymal stromal cell (MSC) treatments have shown feasibility, safety, and strong indications for clinical efficacy. We performed a randomized, active control trial to assess the feasibility and safety of treating osteoarthritis with allogeneic MSCs, and we obtain information regarding the efficacy of this treatment. METHODS: We randomized 30 patients with chronic knee pain unresponsive to conservative treatments and showing radiological evidence of osteoarthritis into 2 groups of 15 patients. The test group was treated with allogeneic bone marrow MSCs by intra-articular injection of 40 × 10(6) cells. The control group received intra-articular hyaluronic acid (60 mg, single dose). Clinical outcomes were followed for 1 year and included evaluations of pain, disability, and quality of life. Articular cartilage quality was assessed by quantitative magnetic resonance imaging T2 mapping. RESULTS: Feasibility and safety were confirmed and indications of clinical efficacy were identified. The MSC-treated patients displayed significant improvement in algofunctional indices versus the active controls treated with hyaluronic acid. Quantification of cartilage quality by T2 relaxation measurements showed a significant decrease in poor cartilage areas, with cartilage quality improvements in MSC-treated patients. CONCLUSIONS: Allogeneic MSC therapy may be a valid alternative for the treatment of chronic knee osteoarthritis that is more logistically convenient than autologous MSC treatment. The intervention is simple, does not require surgery, provides pain relief, and significantly improves cartilage quality.

Peripheral nerve regeneration after experimental section in ovine radial and tibial nerves using synthetic nerve grafts, including expanded bone marrow mesenchymal cells: morphological and neurophysiological results.

The standard treatment of peripherical nerve injuries with substance gap is to introduce the nerve free extremes in a biodegradable tube which, as a biocamera, allows the continuity of the nerve, promote the neuroconduction and save the lesion from the surrounding fibrosis. However, this procedure has not any direct effect on the neuroregeneration nor to resolve high severe lesions. The mesenchymal stem cells (MSC) can derivate "in vitro" in different lineages, including Schwann cells. Different studies have shown MSC can promote the nerve regeneration in rodents, dogs and primates. Moving to the human clinical application requires the procedure standardization, including the optimal cell dose which we have to use. In the sheep model animal we performed a study of 1 cm. nerve section-ressection and repair with a Neurolac™ biocamera, in whose gap we applied between 30 to 50×10(6) MSC from cancellous bone, all of them selected and cultured with GMP procedures. The results were compared with controls (saline serum ± platelet-rich plasma). We used radial nerve (sensitive) and tibial nerve (motor) from 7 sheep. In the first step we performed the surgical lesion and bone marrow aspiration, and in 3 weeks we performed the surgical repair. 3 sheep were sacrificed in 3 months, and 4 sheep in 6 months. In all surgeries we performed a neurophysiological register. When we obtained the tissue samples, we performed an histological, immunohistiquimical and morphometrical study. The recovery percentage was defined comparing the axonal density from the proximal and distal lesion margins. The 3 months samples results were wrong. In 6 months samples results we observed a significative myelined nervous fibers and conduction increasing, in front of controls, both radial and tibial nerves. These results suggest the MSC application in biodegradable scaffold in nerve injuries promotes good results in terms of regeneration and functional recovery.

Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study.

BACKGROUND: Osteoarthritis is the most prevalent joint disease and a frequent cause of joint pain, functional loss, and disability. Osteoarthritis often becomes chronic, and conventional treatments have demonstrated only modest clinical benefits without lesion reversal. Cell-based therapies have shown encouraging results in both animal studies and a few human case reports. We designed a pilot study to assess the feasibility and safety of osteoarthritis treatment with mesenchymal stromal cells (MSCs) in humans and to obtain early efficacy information for this treatment. METHODS: Twelve patients with chronic knee pain unresponsive to conservative treatments and radiologic evidence of osteoarthritis were treated with autologous expanded bone marrow MSCs by intra-articular injection (40×10 cells). Clinical outcomes were followed for 1 year and included evaluations of pain, disability, and quality of life. Articular cartilage quality was assessed by quantitative magnetic resonance imaging T2 mapping. RESULTS: Feasibility and safety were confirmed, and strong indications of clinical efficacy were identified. Patients exhibited rapid and progressive improvement of algofunctional indices that approached 65% to 78% by 1 year. This outcome compares favorably with the results of conventional treatments. Additionally, quantification of cartilage quality by T2 relaxation measurements demonstrated a highly significant decrease of poor cartilage areas (on average, 27%), with improvement of cartilage quality in 11 of the 12 patients. CONCLUSIONS: MSC therapy may be a valid alternative treatment for chronic knee osteoarthritis. The intervention is simple, does not require hospitalization or surgery, provides pain relief, and significantly improves cartilage quality.

Intratendinous gouty tophus mimics patellar tendonitis in an athlete.

We describe the imaging and pathologic features of a case of intratendinous patellar gouty tophus incidentally discovered in a patient with knee pain. The possibility of intratendinous gouty tophus must be kept in mind by sports physicians, especially in the management of patellar tendinopathy in athletes. It may be associated with other injuries, such as enthesopathies or partial tendon tears.

Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study.

BACKGROUND: Degenerative disc disease may cause severe low-back pain, a large public health problem with significant economic and life quality impact. Chronic cases often require surgery, which may lead to biomechanical problems and accelerated degeneration of the adjacent segments. Cell-based therapies may circumvent these problems and have exhibited encouraging results in vitro and in animal studies. We designed a pilot study to assess feasibility and safety and to obtain early indications on efficacy of treatment with mesenchymal stem cells (MSC) in humans. METHODS: Ten patients with chronic back pain diagnosed with lumbar disc degeneration with intact annulus fibrosus were treated with autologous expanded bone marrow MSC injected into the nucleus pulposus area. Clinical evolution was followed for 1 year and included evaluation of back pain, disability, and quality of life. Magnetic resonance imaging measurements of disc height and fluid content were also performed. RESULTS: Feasibility and safety were confirmed and strong indications of clinical efficacy identified. Patients exhibited rapid improvement of pain and disability (85% of maximum in 3 months) that approached 71% of optimal efficacy. This outcome compares favorably with the results of other procedures such as spinal fusion or total disc replacement. Although disc height was not recovered, water content was significantly elevated at 12 months. CONCLUSIONS: MSC therapy may be a valid alternative treatment for chronic back pain caused by degenerative disc disease. Advantages over current gold standards include simpler and more conservative intervention without surgery, preservation of normal biomechanics, and same or better pain relief.