Injection Of Stem Cells Research Articles

Role of bone marrow-derived mesenchymal stem cells in treatment avascular necrosis of femoral head

Avascular necrosis (AVN) of the femoral head (FH) is a debilitating and painful disease with multiple etiologic risk factors head shows an increasing tendency and most commonly affects younger or middle-aged adults. Fifty patients (55 hips) with stage I, II or III avascular necrosis of femoral head were treated by autologous Bone marrow-derived mesenchymal stem cells injection. The patients were followed up clinically and radiologically for a minimum of 2 years at baseline, three, six, 12, and 24 months. The functional outcome was assessed in terms of Harris hip score, and disease progression was assessed radiologically by comparing the preoperative and follow-up MRI at the end of 2 years. On 2-year follow-up, there was considerable improvement in the hip function as measured by the Harris hip score (p = 0.041). On MRI, there was a decrease in the size of the lesion in group A (p = 0.03). Our findings showed that autologous Bone marrow-derived mesenchymal stem cells in avascular necrosis of femoral head is a safe and effective procedure and has better outcome.

Toxicity from a single injection of human umbilical cord mesenchymal stem cells into rat ovaries

Intraovarian injection of human umbilical cord mesenchymal stem cells (hUC-MSCs) has been applied and with promising therapeutic effects, but its toxicity and safety remain uncertain. This study evaluated the toxic effects and the affected target organs after a single injection of hUC-MSCs into bilateral rat ovaries. Sixty Sprague-Dawley rats were randomly divided into four groups and intraovarian injected with three different doses of hUC-MSC suspension. Toxicity-related manifestations occurred over the following 14 days postinjection. On day (D)5 and D15, we assessed the clinical pathology; immunotoxicity, including the cytokine IFN-γ, TNF-α, IL-4, and IL-6 levels; the immune organs, and the organ weights. On D5, inflammatory cells mainly infiltrated the ovaries of the low- and medium-dose groups, whereas inflammatory cells infiltrated the oviduct in the medium- and high-dose groups. On D15, inflammatory cells infiltrated the corpus luteal cysts, ovarian sacs and oviducts in each group. Body weights; organ weights; immunotoxicity; clinical pathology and histopathological examinations of the immune organs did not significantly differ among the groups. No obvious hUC-MSC-related clinical symptoms were observed except in the rats that died. The high-dose group exhibited significantly higher mortality than did the control and low-dose groups. Deaths in the high-dose group, who received approximately 50 times the standard clinical dose, were related to the intraovarian hUC-MSC injection. The maximum tolerated dose was approximately ten times the standard clinical dose. The ovary and oviduct may be the target organs for this toxicity. This report provides dosage references and guidance for clinical applications of intraovarian hUC-MSC injections.

In vitro analysis of genome-engineered muscle-derived stem cells for autoregulated anti-inflammatory and antifibrotic activity.

Traumatic muscle injury leads to chronic and pathologic fibrosis in skeletal muscles, primarily driven through upregulation of transforming growth factor-β1 (TGF-β1). Cell-based therapies, such as injection of muscle-derived stem cells (MDSCs),have shown promise in muscle repair. However, injected MDSCs in injured skeletal muscle can differentiate into myofibroblasts under the influence of TGF-β1, and contribute to the development of fibrosis, limiting their regenerative potential. In this study, we created a "smart" cell-based drug delivery system using CRISPR-Cas9 to genetically engineer MDSCs capable of sensing TGF-β1 and producing an antifibrotic biologic, decorin. These gene-edited smart cells, capable of inhibiting fibrosis in a dose-dependent and autoregulating manner, show anti-inflammatory and antifibrotic properties in vitro, without changing the expression of myogenic and stem cell markers as well as their cell proliferation and myogenic differentiation. Additionally, differentiation down a fibrotic lineage is reduced or eliminated in response to TGF-β1. Our results show that gene editing can be used to successfully create smart stem cells capable of producing biologic drugs with antifibrotic capabilities in a controlled and localized manner. This system provides a tool for cell-based drug delivery as the basis for a novel therapeutic approach for a variety of diseases.

Regeneration of Chronic Rotator Cuff Tear in a Rabbit Model: Synergetic Benefits of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells, Polydeoxyribonucleotides, and Microcurrent Therapy.

Objective To investigate synergic therapeutic effects of combined injection of intralesional mesenchymal stem cells derived from human umbilical cord blood (UCB-MSCs) and polydeoxyribonucleotide (PDRN) combined with microcurrent therapy (MIC) on full thickness rotator cuff tendon tear (FTRCTT) in rabbit models. Methods Thirty-two rabbit models were assigned to 4 different groups. FTRCTT in the supraspinatus tendon was created. After 6 weeks, 4 types of procedures (0.2 mL normal saline injection, group 1 (G1-NS); 0.2 mL SC injection, group 2 (G2-MSC); 0.2 mL SC and weekly four injections of 0.2 mL PDRN with sham MIC, group 3 (G3-MSC+PDRN+sham MIC); and 0.2 mL SC and weekly four injections of 0.2 mL PDRN with MIC for four weeks, group 4 (G4-MSC+PDRN+MIC)) were performed in FTRCTT. Gross morphologic and histological changes of proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF) and platelet endothelial cell adhesion molecule (PECAM-1) and motion analysis were performed. Results There was a significant difference in gross morphologic changes between baseline and week 4 posttreatment in group 4 compared to the other three groups (p = 0.01). In groups 3 and 4, all parameters of histochemical and motion analysis have been found to be significantly greater than the ones in groups 1 and 2 (p < 0.05). In group 4, PCNA-, VEGF-, and PECAM-1-stained cells, as well as walking distance, were significantly greater than the ones in group 3 (p < 0.05). Conclusion The treatment with UCB-MSCs and PDRN combined with MIC might be the most effective in rabbit models' traumatic FRTCTT.

Intramuscular Stem Cell Injection in Combination with Bioengineered Nerve Repair or Nerve Grafting Reduces Muscle Atrophy.

Peripheral nerve injuries represent a clinical challenge, especially when they are accompanied by loss of neural tissue. In this study, the authors attempted to attain a better outcome after a peripheral nerve injury by both repairing the nerve lesion and treating the denervated muscle at the same time. Rat sciatic nerves were transected to create 10-mm gaps. Repair was performed in five groups (n = 5 rats for each), as follows: group 1, nerve repair using poly-3-hydroxybutyrate strips to connect the proximal and distal stumps, in combination with control growth medium injection in the gastrocnemius muscle; group 2, nerve repair with poly-3-hydroxybutyrate strip seeded with Schwann cell-like differentiated adipose stem cells (differentiated adipose stem cell strip) in combination with growth medium intramuscular injection; group 3, differentiated adipose stem cell strip in combination with intramuscular injection of differentiated adipose stem cells; group 4, repair using autograft (reverse sciatic nerve graft) in combination with intramuscular injection of growth medium; and group 5, autograft in combination with intramuscular injection of differentiated adipose stem cells. Six weeks after nerve injury, the effects of the stem cells on muscle atrophy were assessed. Poly-3-hydroxybutyrate strips seeded with differentiated adipose stem cells showed a high number of βIII-tubulin-positive axons entering the distal stump and abundant endothelial cells. Group 1 animals exhibited more muscle atrophy than all the other groups, and group 5 animals had the greatest muscle weights and muscle fibers size. Bioengineering nerve repair in combination with intramuscular stem cell injection is a promising technique to treat nerve lesions and associated muscle atrophy. Nerve injuries and resulting muscle atrophy are a clinical challenge. To optimize functional recovery after a nerve lesion, the authors treated the nerve and muscle at the same time by using regenerative medicine with adipose stem cells and obtained encouraging results for future clinical applications.

179 Clinical Outcomes From a Single-Site Phase I Study of Neural Stem Cell Transplantation for Chronic Spinal Cord Injury

INTRODUCTION: We previously reported safe implantation and improvement in motor and sensory scores using neural stem cell line (NSC) NSI-566 in chronic thoracic complete spinal cord injury (SCI) patients. METHODS: A total of four subjects received NSI-566 spinal cord implantation. All subjects tolerated the procedure well with no serious adverse events in the immediate post-procedure period. Prospective data have been collected including ISNCSCI scores, functional and pain surveys, SCIM scores, electromyography (EMG), Brain Motor Control Assessment (BMCA), and serial MRI. RESULTS: Two patients experienced improvements in neurological level of injury (NLI), motor score, and sensory score. BMCA showed newly developed muscle responsiveness in lower limbs to reinforcement maneuvers in one patient. Three subjects experienced new EMG activity in lower muscle groups. Two patients had overall decreased pain scores post-operatively, which included both discomfort and allodynia in the transition zone, surgical site pain, and neuropathic and nociceptive pain elsewhere. MR imaging showed no radiographical evidence of immediate or delayed complications after the stem cell injections. CONCLUSION: Our current clinical data demonstrate that spinal grafting of the human NSI-566 cell line in chronic spinal trauma patients is safe with no detectable side effects identified at 60 months after cell delivery. Despite the small sample size, the key strengths of the study are the extensive follow-up period and the timeline of treatment. Like other Phase I studies, this study was intended to provide proof of safety and tolerability and proof of concept data that will justify the next cohort.

411 Mesenchymal Stem Cells for Shoulder Tendon Injury and Osteoarthritis

Abstract Introduction In recent years there has been a boom in the advancements and research in mesenchymal stem cells (MSCs) injections for tissue regeneration. This has led to commercial products and early adoption of the technology. High profile cases, media and internet prominence of stem cell therapies have led to a patient demand for the treatment for numerous traumatic and degenerative musculoskeletal conditions. Aim In this article we aim to review the evidence for mesenchymal stem cell therapy so far, focusing on its use in osteoarthritis and specifically tendon repair within the shoulder. Method Through the database PubMed, the search included all animal models and clinical trials assessing the use of mesenchymal stem cells for treatment of osteoarthritis or rotator cuff pathology, up to the year 2018. Results We identified 20 animal studies (95% positive findings) and 17 human studies (94% positive findings) for Osteoarthritis (OA) (399 patients assessed), however all therapy was targeted at the knee. Rotator cuff tear studies yielded 8 animal studies findings and 3 human studies (100% positive findings in both) (106 patients assessed). Conclusions There is a reasonable body of evidence to support its use for the early stages of OA and as such phase III trials should be implicated. Evidence to support use of MSCs for rotator cuff tendon pathology is still in early stages with variable significance, but promising. More trials need to be done to assess its efficacy for injection both at the point of surgical repair and in non-surgical patients.

Should Degenerated Intervertebral Discs of Patients with Modic Type 1 Changes Be Treated with Mesenchymal Stem Cells?

Low back pain (LBP) has been among the leading causes of disability for the past 30 years. This highlights the need for improvement in LBP management. Many clinical trials focus on developing treatments against degenerative disc disease (DDD). The multifactorial etiology of DDD and associated risk factors lead to a heterogeneous patient population. It comes as no surprise that the outcomes of clinical trials on intradiscal mesenchymal stem cell (MSC) injections for patients with DDD are inconsistent. Intradiscal MSC injections have demonstrated substantial pain relief and significant disability-related improvements, yet they have failed to regenerate the intervertebral disc (IVD). Increasing evidence suggests that the positive outcomes in clinical trials might be attributed to the immunomodulatory potential of MSCs rather than to their regenerative properties. Therefore, patient stratification for inflammatory DDD phenotypes may (i) better serve the mechanisms of action of MSCs and (ii) increase the treatment effect. Modic type 1 changes—pathologic inflammatory, fibrotic changes in the vertebral bone marrow—are frequently observed adjacent to degenerated IVDs in chronic LBP patients and represent a clinically distinct subpopulation of patients with DDD. This review discusses whether degenerated IVDs of patients with Modic type 1 changes should be treated with an intradiscal MSC injection.

Comparative results of 3 treatments for medial femoral condyle subchondral cystic lesions in Thoroughbred racehorses.

To compare 3 different methods for treatment of medial femoral condyle (MFC) subchondral cystic lesions in Thoroughbred horses <24 months old based on the criterion of ability to race post-treatment. Retrospective cohort study. Thoroughbreds (n = 107, age < 24 months) diagnosed with MFC subchondral cystic lesions. Medical records between January 2004 and December 2017 were reviewed. Three treatment methods were used in these horses during that time frame: arthroscopic debridement, intralesional autologous mesenchymal stem cell (MSC) injection, and intralesional corticosteroid injection. The outcome evaluated was the ability to compete in a pari-mutuel race. Seventy-eight of 107 Thoroughbreds (73%) raced post-treatment; 41/57 (72%) of horses treated by arthroscopic debridement raced; 16/19 (84%) of horses treated with intralesional MSCs raced; 21/31 (68%) of horses treated with intralesional corticosteroids raced. There was no difference between groups in the ability to start a race. Sex, limb affected, and lesion size also had no effect on the ability to start a race. There was a trend for increasing lesion size reducing the probability of racing. Seventy-three percent of the horses raced, but there was no difference in the ability of unraced Thoroughbreds to race after treatment of MFC subchondral cystic lesions with arthroscopic debridement, intralesional mesenchymal stem cells, or intralesional corticosteroids. The 3 reported treatment options may be considered for treatment of MFC subchondral cystic lesions with a good prognosis for racing post-treatment. Owners should be advised that increasing lesion size decreases the probability of racing.

Icariin-Loaded Hydrogel Regulates Bone Marrow Mesenchymal Stem Cell Chondrogenic Differentiation and Promotes Cartilage Repair in Osteoarthritis.

Intra-articular injection of mesenchymal stem cells is a potential therapeutic strategy for cartilage protection and symptom relief for osteoarthritis (OA). However, controlling chondrogenesis of the implanted cells in the articular cavity remains a challenge. In this study, hydrogels containing different concentrations of icariin were prepared by in situ crosslinking of hyaluronic acid and Poloxamer 407. This injectable and thermoresponsive hydrogel, as a 3D cell culture system, showed good biocompatibility with chondrocytes and bone marrow mesenchymal stem cells (BMSCs), as well as promoted proliferation and chondrogenesis of BMSCs through the Wnt/β-catenin signaling pathway. Intra-articular injection of this kind of BMSC-loaded composite hydrogel can significantly prevent cartilage destruction by inducing chondrogenic differentiation of BMSCs, and relieve pain through regulating the expression of inflammatory cytokines (e.g., IL-10 and MMP-13) in the OA model. Incorporating BMSCs into this novel icariin-loaded hydrogel indicates a more superior efficacy than the single BMSC injection, which suggests a great potential for its application in OA.

Stem Cell Injection for Complex Refractory Perianal Fistulas in Crohn's Disease: A Single Center Initial Experience.

From 30 to 70% of patients with Crohn's disease (CD) may develop perianal fistulas during their lifetime. The medical and surgical management of this complication is challenging, and its treatment still gives unsatisfactory results. However, recent studies on adipose-derived mesenchymal stem cells have proven their anti-inflammatory and immuno-modulatory potential, representing a new promising tool in the treatment of such stubborn disease. We report our initial experience with three patients who had recurrent perianal CD treated with local infiltration of stem cell darvadstrocel (Alofisel). All the patients had a long history of perianal disease refractory to multiple medical and surgical treatments. The preoperative workup included transperineal ultrasound (TP-US), pelvic MRI, and colonoscopy that ruled out active proctitis in all the patients. The post-treatment follow-up included clinical assessment at 1, 3, and 6 months with repeated MRI and TP-US at 6 months. At 6 months, 2 patients had a clinical response despite radiological persistence of fistula tracts, while one patient presented perianal fistula recurrence complicated by perianal abscess. Although our experience is limited to 3 patients and a short follow-up, our results confirm that darvadstrocel injection is a safe procedure, with a good clinical response in most of the patients, but that it apparently had no effect on the anatomical modification of the fistula tracts. Long-term results, with a rigorous assessment of anatomical lesions, are still needed to support the promising data of the literature.

Dendrimer-modified gelatin methacrylate hydrogels carrying adipose-derived stromal/stem cells promote cartilage regeneration

BackgroundCartilage defects pose a significant burden on medical treatment, leading to an urgent need to develop regenerative medicine approaches for cartilage repair, such as stem cell therapy. However, the direct injection of stem cells can result in insufficient delivery or inaccurate differentiation. Hence, it is necessary to choose appropriate stem cell delivery scaffolds with high biocompatibility, injectability and chondral differentiation induction ability for cartilage regeneration.MethodsIn this study, the photocrosslinked gelatin methacrylate (GelMA) hydrogel with high cell affinity and plasticity was selected and strengthened by incorporating methacrylic anhydride-modified poly(amidoamine) (PAMAM-MA) to fabricate an adipose-derived stromal/stem cells (ASCs) delivery scaffold for cartilage repair. The physiochemical properties of the GelMA/PAMAM-MA hydrogel, including the internal structure, stability and mechanical properties, were tested. Then, ASCs were encapsulated into the hydrogels to determine the in vitro and in vivo chondrogenic differentiation induction abilities of the GelMA/PAMAM-MA hydrogel.ResultsCompared with the GelMA hydrogel, the GelMA/PAMAM-MA hydrogel exhibited more uniform structure, stability and mechanical properties. Moreover, on the basis of good biocompatibility, the hybrid hydrogel was proven to exert a sufficient ability to promote cartilage regeneration by in vitro three-dimensional (3D) culture of rASCs and in vivo articular cartilage defect repair.ConclusionsThe injectable photocrosslinked GelMA/PAMAM-MA hydrogel was proven to be a capable stem cell carrier for cartilage repair and provides new insight into the design strategy of stem cell delivery scaffolds.

P407 A Phase IB/IIA study of remestemcel-L, an allogeneic bone marrow derived mesenchymal stem cell product, for the treatment of medically refractory ulcerative colitis: An interim analysis

Abstract Background Direct injection of mesenchymal stem cells (MSCs) have been used for the treatment of perianal Crohn’s fistulizing disease. However, no studies have looked at the direct injection of MSCs for luminal ulcerative colitis (UC). Methods Following screening and informed consent, patients with medically refractory UC were randomized in a, 2:1 fashion to receive remestemcel-L, an ex vivo expanded allogeneic bone marrow derived MSC product, at a dose of, 150 or, 300 million MSCs versus placebo delivered via direct injection using a, 23 G sclerotherapy needle at the time of colonoscopy. Patients were included if they had medically refractory UC defined as an established diagnosis for at least, 6 months prior to study enrollment and had lost response to at least one monoclonal antibody in the past. Patients were evaluated with validated clinical and endoscopic scoring systems at, 2 weeks, 6 weeks, and, 3 months post MSC delivery. Patients randomized to control crossed over at, 3 months to receive MSC treatment and followed the same schedule for post MSC evaluation. Results A total of six patients were enrolled and treated;, 4 were randomized to treatment and, 2 to placebo. All had been on prior anti-TNF or anti integrin-therapy. There were no adverse and serious adverse events related to investigational product. In the treatment group (n=4), the Mayo score and Mayo endoscopic severity score decreased in all patients by two weeks after MSC delivery. By six weeks post MSC treatment, all treated patients had achieved clinical and endoscopic remission as defined by the Mayo score and Mayo endoscopic severity score. Patient reported number of daily bowel movements decreased as did urgency and presence of blood in the stool. With regard to patient reported outcomes, at three months, based on the inflammatory bowel disease patient reported treatment impact (IBD-PRTI), all patients were extremely satisfied or satisfied with their MSC treatment. Treated response was described as excellent or good in all patients. In the control group (n=2), the Mayo score did not decrease. Patient reported number of daily bowel movements increased as did the number reporting blood in their stool; urgency remained unchanged. With regard to patient reported outcomes, at three months, based on the IBD-PRTI, one patient was neutral, and one patient was dissatisfied. Treated response was described as poor or unchanged in control patients. Conclusion MSCs offer a safe alternative therapeutic for the treatment of medically refractory UC. Early data suggests improved clinical and endoscopic scores by as early as two weeks following MSC delivery.

DOP31 Efficacy and safety of bone marrow-derived mesenchymal stem cells in refractory perianal fistulae in Crohn’s Disease: Results from a prospective monocentric study

Abstract Background Anoperianal lesions affect up to 30% of patients with Crohn’s disease (CD). Long-term fistula healing is challenging with conventional biotherapies. Although recent studies demonstrated the efficacy of local injections of adipose tissue-derived stem cells with 50 % of fistulae closure without abscess at one year, this treatment is not available in routine. The primary aim of this study was to evaluate the safety and the feasibility of the injection of bone marrow-derived mesenchymal stem cells isolated and prepared in a local university laboratory of cell therapy for perianal fistulizing CD. The second aim was to evaluate the efficacy of this treatment and his impact on the quality of life of the patients. Methods A prospective observational study was performed in the CHU of Liège from October 2019 till October 2021. All CD patients with perianal fistula and seton placement for at least 6 months were eligible. PRO, clinical examination, CRP, fecal calprotectine, CDAI, Short health scale (SHS) and MRI were performed at weeks 0, 12 and 48. PDAI was calculated at inclusion and at Week 48. Efficacy was defined as closure of all treated external openings at clinical examination without abscess at MRI. Results Sixteen patients with a median age of 49 years old and a median duration of perianal CD of 8 years were included. Eleven (69%) patients were on anti-TNF. CDAI and PDAI at inclusion were 97,5 ± 48,8 et 5 ± 4,4 respectively. Four (25%) patients reported adverse events the week after the injection (local pain 3/16, mild bleeding 1/16), all of them quickly resolutive. Ten (63%) and 8 (50%) patients had a closure of all the external opening at week 12 and 48 respectively. Five out of 6 patients with 2 external openings had at least 1 opening closed at Week 48. One abscess was observed during the follow-up. The median PDAI was numerically lower at the end of the study (3 versus 5 at the inclusion). The quality of life improved with a regression of the SHS from 10 to 7.5 at the end of the follow-up. At MRI, MAGNIFI-CD score and Van Assche index were similar for each patients at the inclusion and at the end of the study. Conclusion Injection of locally prepared bone marrow-derived mesenchymal stem cells seems safe and effective in refractory perianal fistulae in Crohn’s disease with 50% of closure at 1 year. The treatment is associated with an improvement of the perianal activity scores and the quality of life scores but not with the MRI scores.

Evaluation of the Usefulness of Human Adipose-Derived Stem Cell Spheroids Formed Using SphereRing® and the Lethal Damage Sensitivity to Synovial Fluid In Vitro.

Osteoarthritis (OA) is an irreversible degenerative condition causing bone deformation in the joints and articular cartilage degeneration with chronic pain and impaired movement. Adipose-derived stem cell (ADSC) or crushed adipose tissue injection into the joint cavity reportedly improve knee function and symptoms, including pain. Stem cell spheroids may be promising treatment options due to their anti-inflammatory and enhanced tissue regeneration/repair effects. Herein, to form human ADSC spheroids, we used first SphereRing® (Fukoku Co., Ltd., Ageo, Japan), a newly developed rotating donut-shaped tube and determined their characteristics by DNA microarray of mRNA analysis. The variable gene expression cluster was then identified and validated by RT-PCR. Gene expression fluctuations were observed, such as COL15A1 and ANGPTL2, related to vascular endothelial cells and angiogenesis, and TNC, involved in tissue formation. In addition, multiplex cytokine analysis in the medium revealed significant cytokines and growth factors production increase of IL-6, IL-10, etc. However, ADSC administration into the joint cavity involves their contact with the synovial fluid (SF). Therefore, we examined how SF collected from OA patient joint cavities affect 2D-culture ADSCs and ADSC spheroids and observed SF induced cell death. ADSC spheroids could become promising OA treatment options, although studying the administration methods and consider their interaction with SF is essential.

Intra-articular injection of culture-expanded adipose tissue-derived stem cells for knee osteoarthritis: Assessments with clinical symptoms and quantitative measurements of articular cartilage volume

BackgroundIntra-articular administration of adipose tissue-derived stem cells (ADSC) is an alternative treatment option for knee osteoarthritis (OA) after conventional treatment fails; however, the clinical results related to the severity of OA grade and changes of cartilage volumes after the administration of ADSC is unknown. This study aimed to determine 1) clinical outcomes after the ADSC administration in knee OA with consideration of radiographic OA grades and 2) changes in cartilage volumes after ADSC administration. MethodsThis observational study included 86 knees from 51 patients who underwent intra-articular administration of cultured ADSC; 47 patients (80 knees) completed follow-up for 6 months (follow-up rate: 93%). The Knee injury and Osteoarthritis Outcome Scores (KOOS) were reported at baseline and 1, 3, and 6 months after the administration. The efficacy rate in the Outcome Measures in Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) was evaluated using the KOOS. Cartilage volume of the knee joint was measured using quantitative 3-dimensional magnetic resonance imaging (3D-MRI) software at baseline and 6 months in 52 knees in 31 patients (follow-up rate: 61%). ResultsAll items on the KOOS except “sports/recreation” improved significantly at 6 months with more significance in knees with a Kellgren–Lawrence (KL) grade 2 or 3 compared with KL grade 4 knees. The OMERACT-OARSI responder at 6 months was significantly greater in knees with KL grade 2 or 3 (64%) than in knees with KL grade 4 (42%, p = 0.045). Cartilage volume changes varied among patients and were not related to the changes in KOOS after ADSC administration. ConclusionsIntra-articular administration of ADSC in knee OA improved KOOS at 6 months. The effects were more significant in knees with KL grade 2 or 3 than with KL grade 4. Changes in KOOS were not related to change in cartilage volumes after ADSC administration.

A randomized controlled trial of stem cell injection for tendon tear

Tendons have limited reparative ability and perform a relatively simple mechanical function via the extracellular matrix. Thus, the injured tendon might be treated successfully by stem cell transplantation. We performed a randomized, controlled study to investigate the effects of mesenchymal stem cell injection for treating partial tears in the supraspinatus tendon. We enrolled 24 patients with shoulder pain lasting more than 3 months and partial tears in the supraspinatus tendon. Participants were assigned to three groups: stem cells in fibrin glue, normal saline/fibrin glue mixture, and normal saline only, with which intra-lesional injection was performed. Pain at activity and rest, shoulder function and tear size were evaluated. For safety measures, laboratory tests were taken and adverse events were recorded at every visit. Participants were followed up at 6, 12 weeks, 6, 12 months and 2 years after injection. The primary outcome measure was the improvement in pain at activity at 3 months after injection. Twenty-three patients were included in the final analysis. Primary outcome did not differ among groups (p = 0.35). A mixed effect model revealed no statistically significant interactions. Only time significantly predicted the outcome measure. All participants reported transient pain at the injection site. There were no differences in post-injection pain duration or severity. Safety measures did not differ between groups, and there were no persistent adverse events. Stem cell injection into supraspinatus partial tears in patients with shoulder pain lasting more than 3 months was not more effective than control injections.ClinicalTrials.gov Identifier: NCT02298023

Non-polar metabolites of green beans (Phaseolus vulgaris L.) potentiate the antidiabetic activity of mesenchymal stem cells in streptozotocin-induced diabetes in rats.

Green beans (Phaseolus vulgaris L.) are consumed as pods or mature seeds (common beans). The pods were extracted with 95% ethanol and processed to prepare non-polar and polar fractions. Comparing the antihyperglycemic activity of both fractions, non-polar fraction (NPF, 200mgkg-1 day-1 ) lowered blood glucose in streptozotocin diabetic rats by 65% compared to 57% for the polar fraction at the same dose. When NPF treatment was combined with injection of mesenchymal stem cells (MSC) a 4.4-fold increase in serum insulin and a 73.6% reduction in blood glucose were observed compared to untreated control. Additionally, a significant decrease in malondialdehyde (76.2%), nitric oxide (68.2%), cholesterol (76.1%), and triglycerides (69.5%) and a 1.75-fold increase in HDL concentrations were observed in the group treated with this combination compared to diabetic animals. Interestingly, NPF increased homing of MSC in pancreas potentiating their antidiabetic activity. Finally, 26 compounds were identified in NPF using LC/MS analysis and four were isolated in pure form. The isolated compounds namely calotroproceryl acetate, fridelin, calotroproceryl A, and stigmasterol showed good inhibitory activity against pancreatic lipase with IC50 at 1.93, 1.07, 1.34 and 1.44-1μg/ml, respectively. Additionally, these compounds inhibited α-amylase, albeit at higher concentration, with IC50 at 248, 212, 254, and 155μg/ml for calotroproceryl acetate, fridelin, calotroproceryl A, and stigmasterol, respectively. Our results suggest that green beans extract can potentiate effect of MSC in diabetes directly due to its own antidiabetic effect and indirectly by increasing MSC homing in pancreatic tissues. PRACTICAL APPLICATIONS: It has been suggested in this study that green beans can improve hyperglycemia, oxidative balance in diabetes, so green beans can be promoted as a healthy nutrient for diabetic patients. Green beans also can enhance homing and differentiation of mesnchymal stem cells in the pancreas for future stem cell therapy of type I diabetes.

The Effect of CD 90 Expression after Intrasclera Limbal Mesenchymal Stem Cell Injection in Form Deprivation Myopia Animal Model

Purpose: To investigate the capability of limbal mesenchymal stem cells (LMSCs) in increasing CD 90 expression as marker that become new fibroblast to potentially reduce myopia progression in form deprivation myopia animal model. Method: This study using cultured LMSC from rabbit (Oryctolagus cuniculus) and isolated using modification of semienzimatic methods. 24 animal model divided into three groups, consists of control group, form deprivation myopia group (FDM), and form deprivation myopia group with LMSCs injection (FDM+LMSCs). Myopia model was made by monocular occlusion for six weeks. LMSCs was injected intrasclera after fourth week of occlusion. Enucleation was performed in sixth week. CD 90 expression of posterior sclera were evaluated using immunohistochemistry. The results between groups were analyzed using Kruskal-Wallis and Mann-Whitney with 95% confidence interval (p<0,05). Result: After four weeks of deprivation, all eyes became more myopic. LMSCs injection was done 2,5 mm posterior from limbus and two week-evaluation showed LMSCs had migrated on posterior region of the sclera. CD 90 expression showed significant differences between control and FDM+LMSCs group also FDM and FDM+LMSCs group (p<0,05). Conclusion: LMSCs has potential role in myopia control in form deprivation eye animal model by increasing CD 90 expression and lead to additional new scleral fibroblast cells.

Intra-Articular Injection of Umbilical Cord Mesenchymal Stem Cells Loaded With Graphene Oxide Granular Lubrication Ameliorates Inflammatory Responses and Osteoporosis of the Subchondral Bone in Rabbits of Modified Papain-Induced Osteoarthritis.

AimThis study is to investigate the effects of umbilical cord mesenchymal stem cells (UCMSCs) loaded with the graphene oxide (GO) granular lubrication on ameliorating inflammatory responses and osteoporosis of the subchondral bone in knee osteoarthritis (KOA) animal models.MethodsThe KOA animal models were established using modified papain joint injection. 24 male New Zealand rabbits were classified into the blank control group, GO group, UCMSCs group, and GO + UCMSCs group, respectively. The concentration in serum and articular fluid nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), type II collagen (COL-II), and glycosaminoglycan (GAG) was detected using ELISA, followed by the dissection of femoral condyles and staining of HE and Micro-CT for observation via the microscope.ResultsGO granular lubrication and UCMSCs repaired the KOA animal models. NO, IL-6, TNF-α, GAG, and COL-II showed optimal improvement performance in the GO + UCMSCs group, with statistical significance in contrast to the blank group (P <0.01). Whereas, there was a great difference in levels of inflammatory factors in serum and joint fluid. Micro-CT scan results revealed the greatest efficacy of the GO + UCMSCs group in improving joint surface damage and subchondral bone osteoporosis. HE staining pathology for femoral condyles revealed that the cartilage repair effect in GO + UCMSCs, UCMSCs, GO, and blank groups were graded down.ConclusionUCMSCs loaded with graphene oxide granular lubrication can promote the secretion of chondrocytes, reduce the level of joint inflammation, ameliorate osteoporosis of the subchondral bone, and facilitate cartilage repair.