Low-dose mesenchymal stem cell therapy for discogenic pain: safety and efficacy results from a 1-year feasibility study.

Aim: To evaluate safety and efficacy of low dose autologous adipose-derived mesenchymal stem cells (ADMSCs) for treatment of disc degeneration resulting in low back pain (LBP). Methods: Nine participants with chronic LBP originating from single-level lumbar disc disease underwent intradiscal injection of 10 million ADMSCs with optional repetition after 6 months. Results: No unexpected or serious adverse events were recorded. Seven (78%) of participants reported reductions in pain 12 months after treatment. Five (56%) reported increased work capacity. Three (33%) reduced analgesic medication. Improvements in EQ-5D and Oswestry disability index results were observed. MRI demonstrated no further disc degeneration and improvements to annular fissures and disc protrusions. Conclusion: This study provides initial evidence of safety and efficacy of ADMSCs for discogenic LBP.

Real-world evidence of mesenchymal stem cell therapy in knee osteoarthritis: a large prospective two-year case series.

Objective: To evaluate the long-term safety and efficacy of adipose-derived mesenchymal stem cell (ADMSC) therapy in the treatment of knee osteoarthritis (OA). Methods: 329 participants with knee OA underwent intra-articular ADMSC therapy. Participants were followed up for 24 months and were separated based on radiological OA grade. Results: Treatment was well tolerated with no related serious adverse events. All participant groups reported clinically and statistically significant pain improvement. Clinical outcome was not influenced by patients' age or BMI. Conclusion: ADMSC therapy is an effective, safe and long-lasting treatment option for knee OA with the potential to delay total joint replacement. In addition to the observed clinical benefits, ADMSC therapy promises to reduce the global economic burden of OA. Trial registration number: ACTRN12617000638336.

The aim of this study was to assess the benefit of stem cell therapy in the treatment of mild to severe knee osteoarthritis. A total of 329 study participants with painful knee osteoarthritis undertook stem cell therapy and were followed up for two years. Stem cell therapy was well tolerated and safe. Significant pain and functional improvement were observed in all of the participant groups including those with severe bone-on-bone osteoarthritis. Participants' age and weight did not influence the clinical outcome. This study shows that stem cell therapy is an effective, safe and long-lasting treatment for knee osteoarthritis and greatly reduces knee pain and improves the function of the knee. Stem cell therapy may delay or prevent knee replacement surgery and result in significant global health and economic benefit.

Differentiation Potential of Early- and Late-Passage Adipose-Derived Mesenchymal Stem Cells Cultured under Hypoxia and Normoxia.

With an increasing focus on the large-scale expansion of mesenchymal stem cells (MSCs) required for clinical applications for the treatment of joint and bone diseases such as osteoarthritis, the optimisation of conditions for in vitro MSC expansion requires careful consideration to maintain native MSC characteristics. Physiological parameters such as oxygen concentration, media constituents, and passage numbers influence the properties of MSCs and may have major impact on their therapeutic potential. Cells grown under hypoxic conditions have been widely documented in clinical use. Culturing MSCs on large scale requires bioreactor culture; however, it is challenging to maintain low oxygen and other physiological parameters over several passages in large bioreactor vessels. The necessity to scale up the production of cells in vitro under normoxia may affect important attributes of MSCs. For these reasons, our study investigated the effects of normoxic and hypoxic culture condition on early- and late-passage adipose-derived MSCs. We examined effect of each condition on the expression of key stem cell marker genes POU5F1, NANOG, and KLF4, as well as differentiation genes RUNX2, COL1A1, SOX9, COL2A1, and PPARG. We found that expression levels of stem cell marker genes and osteogenic and chondrogenic genes were higher in normoxia compared to hypoxia. Furthermore, expression of these genes reduced with passage number, with the exception of PPARG, an adipose differentiation marker, possibly due to the adipose origin of the MSCs. We confirmed by flow cytometry the presence of cell surface markers CD105, CD73, and CD90 and lack of expression of CD45, CD34, CD14, and CD19 across all conditions. Furthermore, in vitro differentiation confirmed that both early- and late-passage adipose-derived MSCs grown in hypoxia or normoxia could differentiate into chondrogenic and osteogenic cell types. Our results demonstrate that the minimal standard criteria to define MSCs as suitable for laboratory-based and preclinical studies can be maintained in early- or late-passage MSCs cultured in hypoxia or normoxia. Therefore, any of these culture conditions could be used when scaling up MSCs in bioreactors for allogeneic clinical applications or tissue engineering for the treatment of joint and bone diseases such as osteoarthritis.

Mesenchymal stem cell therapy combined with arthroscopic abrasion arthroplasty regenerates cartilage in patients with severe knee osteoarthritis: a case series.

Aim: To evaluate the safety and efficacy of adipose-derived mesenchymal stem cell (ADMSC) therapy in combination with arthroscopic abrasion arthroplasty (AAA) in advanced knee osteoarthritis (OA). Materials & methods: 27 patients with Grade IV OA of the knee underwent AAA and ADMSC therapy (50 × 106 ADMSCs at baseline and 6 months). Clinical outcome was assessed over 36 months. Structural change was determined using MRI. Results: Treatment was well tolerated with no serious adverse events. Clinically significant improvements in pain and function were observed. Reproducible hyaline-like cartilage regeneration was seen in all participants. Conclusion: ADMSC therapy combined with AAA in Grade IV OA results in reproducible pain, functional and structural improvements. This represents a joint preservation technique for patients with advanced OA of the knee. Trial registration number: ACTRN12617000638336.

Evaluation of autologous adipose-derived mesenchymal stem cell therapy in focal chondral defects of the knee: a pilot case series.

Aim: To evaluate the safety, pain, functional and structural improvements after autologous adipose-derived mesenchymal stem cell (ADMSC) therapy in combination with arthroscopic abrasion arthroplasty in focal chondral defects of the knee. Methods: Eight patients with a focal full thickness chondral defect of the knee underwent arthroscopic abrasion arthroplasty followed by postoperative intra-articular injections of autologous ADMSCs (50 × 106 ADMSCs at baseline and 6 months). Clinical outcome was assessed using numeric pain rating scale, Knee Injury and Osteoarthritis Outcome Score and the Western Ontario and McMaster Universities Osteoarthritis Index. Structural outcome was determined by magnetic resonance imaging. Outcome was assessed over 24 months. Results: No serious adverse events occurred. Participants observed clinically significant improvement in pain and function. Magnetic resonance imaging analysis showed cartilage regeneration with T2 mapping values comparable to hyaline cartilage. Conclusion: Arthroscopic abrasion arthroplasty in combination with intra-articular ADMSC therapy results in reproducible pain, functional and structural improvements with regeneration of hyaline-like cartilage. Trial registration number: ACTRN12617000638336.

Mesenchymal stem cell use in acute respiratory distress syndrome: a potential therapeutic application.

Acute respiratory distress syndrome (ARDS) is a condition of acute respiratory failure resulting from noncardiogenic pulmonary edema. It may occur as a consequence of lung infection, sepsis, trauma, aspiration or drug reaction. The pathogenesis of ARDS is understood to be an unregulated inflammatory cascade with both endothelial and epithelial layer damage leading to alveolar fluid collection and pulmonary edema. Despite improved understanding of the cause of ARDS, treatment remains supportive with a mortality rate ranging from 25-40%. Preclinical and early phase clinical trials have highlighted the potential role of mesenchymal stem cells in combating the inflammatory cascade through immunomodulatory mechanisms and assisting in tissue repair.

Effect of autologous adipose-derived mesenchymal stem cell therapy in combination with autologous platelet-rich plasma in the treatment of elbow tendinopathy.

Tendinopathy is a common condition of both the athletic and general population and can be associated with significant pain and disability. The ability of mesenchymal stem cells (MSCs) to differentiate along a mesodermal cell lineage, including tenocytes, and secrete various bioactive regenerative and anti-inflammatory molecules has seen them considered as a future reparative therapy for tendinopathy. Preclinical trials with MSCs have shown promising positive functional and structural outcomes in several connective tissue related conditions. A 52-year-old male professional masters golfer presents with a clinical history of common extensor origin tendinopathy of the elbow. Subsequent formal ultrasound showed evidence of a large intrasubstance tear. The patient underwent intratendinous autologous adipose-derived MSC therapy in combination with autologous platelet-rich plasma. Following treatment, the patient reported progressive improvement as measured by the validated Numeric Pain Rating Scale and Patient-Rated Tennis Elbow Evaluation score. Repeat imaging showed successful regeneration of tendon-like tissue.

Effect of autologous adipose-derived mesenchymal stem cell therapy in the treatment of an osteochondral lesion of the ankle.

Osteochondral lesions (OCLs) of the talus are rare but can be associated with significant morbidity and may lead to the development of osteoarthritis. An improved understanding of the action of mesenchymal stem cells (MSCs) has seen renewed interest in their role in cartilage repair, with early preclinical and clinical research showing benefits in symptomatic and structural improvement. A 42-year-old man presented with an unstable OCL of the talus and onset of early osteoarthritis with a history of multiple previous ankle arthroscopies for ankle impingement. The patient underwent arthroscopic removal of the OCL in combination with adipose-derived MSC therapy. The patient reported progressive improvement as measured by the validated Foot and Ankle Disability Index. Repeat MRI with additional T2 mapping techniques showed successful regeneration of hyaline-like cartilage. This case is the first to show the successful use of MSC therapy in the management of an ankle OCL. Trial registration: Australian New Zealand Clinical Trials Registry - ACTRN12617000638336.

Effect of autologous adipose-derived mesenchymal stem cell therapy in the treatment of acromioclavicular joint osteoarthritis.

The aim of this case report is to evaluate the efficacy of mesenchymal stem cell (MSC) therapy in the treatment of small joint osteoarthritis (OA). Acromio-clavicular (AC) joint OA is an under-diagnosed and yet frequent source of shoulder pain. MSCs have shown evidence of benefit in the treatment of knee OA. This is the first report to describe the use of MSC therapy in OA of the upper limb. A 43-year-old patient presents with painful AC joint OA and undergoes MSC therapy. The patient reported pain and functional improvement as assessed by the Disability of Arm, Shoulder and Hand Score and Numeric Pain Rating Scale. Imaging at 12 months showed structural improvement with reduction in subchondral oedema, synovitis and subchondral cysts. This case is the first to show the benefit of MSC therapy in the treatment of small joint arthropathy and also of the upper limb.Trial registration number: Australian New Zealand Clinical Trials Registry (ACTRN12617000638336).

Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: a randomized controlled trial.

Aim: To evaluate the efficacy of autologous adipose-derived mesenchymal stem cell (ADMSC) therapy on pain, function and disease modification in knee osteoarthritis. Methods: 30 participants with symptomatic knee osteoarthritis were randomized into three groups. Two treatment groups received intra-articular ADMSC therapy consisting of either a single injection (100 × 106 ADMSCs) or two injections (100 × 106 ADMSCs at baseline and 6 months). The third group served as control and continued conservative management. Results: No serious adverse events were observed. Both treatment groups receiving ADMSCs showed clinically significant pain and functional improvement at completion of follow-up at 12 months. Radiological analysis using the Magnetic Resonance Imaging Osteoarthritis Knee Score indicated modification of disease progression. Conclusion: Autologous ADMSC therapy appears to be a safe and effective therapy for knee osteoarthritis and may have the potential to prevent disease progression. Trial registration number: ACTRN12614000814673.

High tibial osteotomy in combination with arthroscopic abrasion arthroplasty and autologous adipose-derived mesenchymal stem cell therapy in the treatment of advanced knee osteoarthritis.

Osteoarthritis is a progressive and debilitating condition. An increasing number of total knee replacements are being performed under the age of 65. Improved understanding of the action of mesenchymal stem cells (MSC) has seen renewed interest in their role in cartilage repair. A 43-year-old man presented with grade IV medial compartment knee osteoarthritis. The patient underwent high tibial osteotomy (HTO) and arthroscopic abrasion arthroplasty in combination with adipose-derived MSC therapy. The patient reported improvement in pain and function as measured by validated outcome scores. Repeat MRI including T2 mapping techniques showed hyaline-like cartilage regeneration. This case highlights the potential benefit of surgical interventions including HTO in combination with MSC therapy in early-onset severe osteoarthritis. This technique may considerably delay or prevent the need for total knee replacement in young patients. Further controlled trials are needed to confirm the reproducibility of this outcome.

Effect of autologous adipose-derived mesenchymal stem cell therapy in the treatment of a post-traumatic chondral defect of the knee.

Isolated chondral defects have a limited capacity to heal and predispose to the development of osteoarthritis. Current surgical management can be unpredictable in outcome. Improved understanding of the action of mesenchymal stem cells (MSCs) has seen renewed interest in their role in cartilage repair. A 26-year-old athlete presented with a post-traumatic, isolated patella chondral defect. The patient underwent an arthroscopy with removal of a chondral loose body. After failure to symptomatically improve 12 months following surgery, the patient received intra-articular autologous adipose-derived mesenchymal stem cell (ADMSC) therapy.

The effect of autologous adipose derived mesenchymal stem cell therapy in the treatment of a large osteochondral defect of the knee following unsuccessful surgical intervention of osteochondritis dissecans - a case study.

BACKGROUND: A prospective analysis of the effect of autologous adipose derived mesenchymal stem cell (MSC) therapy in the treatment of an osteochondral defect of the knee with early progressive osteoarthritis following unsuccessful surgical intervention of osteochondritis dissecans (OCD). CASE PRESENTATION: After failed conventional management of OCD a patient undergoes intra-articular MSC therapy. Patient outcome measures included the Numeric Pain Rating Scale (NPRS), the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and the Knee Injury and Osteoarthritis Outcome Score (KOOS). Structural outcome was assessed using MRI with the novel technique of T2 mapping used to indicate cartilage quality. Following MSC therapy the patient reported improvement in pain and function as measured by NPRS, WOMAC and KOOS. Repeat MRI analysis showed regeneration of cartilage. MRI T2 mapping indicated hyaline like cartilage regrowth. CONCLUSION: In this report, the use of MSCs, after unsuccessful conventional OCD management, resulted in structural, functional and pain improvement. These results highlight the need to further study the regenerative potential of MSC therapy. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry Number - ACTRN12615000258550 (Date registered 19/03/2015 - retrospectively registered).

Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy - a review.

Osteoarthritis is a leading cause of pain and disability across the world. With an aging population its prevalence is likely to further increase. Current accepted medical treatment strategies are aimed at symptom control rather than disease modification. Surgical options including joint replacement are not without possible significant complications. A growing interest in the area of regenerative medicine, led by an improved understanding of the role of mesenchymal stem cells in tissue homeostasis and repair, has seen recent focused efforts to explore the potential of stem cell therapies in the active management of symptomatic osteoarthritis. Encouragingly, results of pre-clinical and clinical trials have provided initial evidence of efficacy and indicated safety in the therapeutic use of mesenchymal stem cell therapies for the treatment of knee osteoarthritis. This paper explores the pathogenesis of osteoarthritis and how mesenchymal stem cells may play a role in future management strategies of this disabling condition.

Adipose derived mesenchymal stem cell therapy in the treatment of isolated knee chondral lesions: design of a randomised controlled pilot study comparing arthroscopic microfracture versus arthroscopic microfracture combined with postoperative mesenchymal stem cell injections.

INTRODUCTION: The management of intra-articular chondral defects in the knee remains a challenge. Inadequate healing in areas of weight bearing leads to impairment in load transmission and these defects predispose to later development of osteoarthritis. Surgical management of full thickness chondral defects include arthroscopic microfracture and when appropriate autologous chondrocyte implantation. This latter method however is technically challenging, and may not offer significant improvement over microfracture. Preclinical and limited clinical trials have indicated the capacity of mesenchymal stem cells to influence chondral repair. The aim of this paper is to describe the methodology of a pilot randomised controlled trial comparing arthroscopic microfracture alone for isolated knee chondral defects versus arthroscopic microfracture combined with postoperative autologous adipose derived mesenchymal stem cell injections. METHODS AND ANALYSIS: A pilot single-centre randomised controlled trial is proposed. 40 participants aged 18-50 years, with isolated femoral condyle chondral defects and awaiting planned arthroscopic microfracture will be randomly allocated to a control group (receiving no additional treatment) or treatment group (receiving postoperative adipose derived mesenchymal stem cell treatment). Primary outcome measures will include MRI assessment of cartilage volume and defects and the Knee Injury and Osteoarthritis Outcome Score. Secondary outcomes will include further MRI assessment of bone marrow lesions, bone area and T2 cartilage mapping, a 0-10 Numerical Pain Rating Scale, a Global Impression of Change score and a treatment satisfaction scale. Adverse events and cointerventions will be recorded. Initial outcome follow-up for publication of results will be at 12 months. Further annual follow-up to assess long-term differences between the two group will occur. ETHICS AND DISSEMINATION: This trial has received prospective ethics approval through the Latrobe University Human Research Ethics Committee. Dissemination of outcome data is planned through both national and international conferences and formal publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: Australia and New Zealand Clinical Trials Register (ANZCTR Trial ID: ACTRN12614000812695).

To evaluate the effect of combining photo-activation therapy with platelet-rich plasma injections for the novel treatment of osteoarthritis.

OBJECTIVE: To evaluate the effect of combining photo-activation therapy with platelet-rich plasma injections for the novel treatment of osteoarthritis. DESIGN: We present a case report of osteoarthritis of the knee treated with photo-activated platelet-rich plasma injections (PAPRP). METHODS: After utilising conventional osteoarthritis treatment methods a patient underwent a course of PAPRP injections. The patient outcome was measured using the numerical pain rating scale (NPRS) and the Western Ontario and McMaster Universities Arthritis (WOMAC) Index. RESULTS: Following treatment the patient reported improvements in both pain and function as measured by the NPRS and WOMAC Index, respectively. The patient was followed up for 18 weeks, at which time no significant complications were noted. CONCLUSIONS: In this case report of osteoarthritis, with strict control of conventional therapy variables, PAPRP injections demonstrated improvement in all recorded outcome measures. The results of this case report highlight the need to further investigate the use of PAPRP in the treatment of symptomatic knee osteoarthritis.

Photoactivated platelet-rich plasma therapy for a traumatic knee chondral lesion.

To evaluate the effect of combining photoactivation therapy with platelet-rich plasma injections in the treatment of a traumatic chondral lesion of the knee. A 38-year-old man presented with left-knee pain and swelling following a basketball injury. MRI demonstrated a full-thickness lateral tibial plateau chondral flap with subchondral cyst formation and marrow oedema. The patient underwent a course of photoactivated platelet-rich plasma (PAPRP) injections. Patient outcome measures included the numerical pain rating scale and the Western Ontario and McMaster Universities Arthritis Index 3.0 (WOMAC). Following treatment, the patient reported improvement in both pain and function as measured by the numerical pain-rating scale and WOMAC. MRI showed resolution of subchondral bone marrow bruising/oedema. No complications were noted. In this case report, PAPRP injections demonstrated improvement in all recorded outcome measures. Recognising the limitations of a single case report, the results highlight the need for more formal controlled trials to determine the potential use of PAPRP in the treatment of chondral lesions.