Do Stem Cell Treatments Work? Answers by SkyGen

How do Stem Cell Treatments Work?

Information for Medical Professionals

1.0 Do Stem Cell Treatments Work? An Introduction

This document is intended to inform and update clinical professionals on the current treatment options for patients presenting with osteoarthritis of appendicular and axial synovial joints, armed with the question “How do stem cell treatments work?”.
As an attention-demanding focus within the field of Regenerative Medicine, cell based therapies (including Stem Cells and, to a lesser degree, platelet rich plasma; PRP) have been demonstrated to provide therapeutic benefit to patients presenting with chondral defects resulting from non-rheumatoid degenerative diseases such as idiopathic/age-associated osteoarthritis.
Along with bone marrow, subcutaneous adipose tissue is a rich source of adult stem cells. These cells have an ability to differentiate into cell types that regenerate cartilage and other connective/supportive tissues in and around the spine and peripheral joints. In the primary clinical care setting, patients can be advised of these benefits in the context of standard risk assessment for autologous cell transplants.
Adipose derived stem cells may improve symptomatic arthritis by:
• reducing local inflammation (monocyte suppression-mediated)
• assisting innate healing mechanisms (macrophage-mediated)
• reconstituting damaged cartilage and/or ligamentous/tendinous tissue
It is important to note that the responsible promotion of stem cell therapy to patients in Australia necessitates full disclosure that these therapies are considered experimental.

Not all patients assessed as candidates are approved for stem cell therapy, especially by SkyGen’s partnered clinics. Further, primary care clinicians can be assured that the screening process for all patients, and the appropriate benefit:risk ratio is thoroughly discussed with each patient following referral to/engagement with SkyGen and its accredited hospitals and clinics.

2.0 Background

Osteoarthritis impacted 1.3 million patients (young and old), families and workplaces in 2013. The resultant consultations with medical professionals, referrals to public specialists and enrolment on public waiting lists for orthopaedic surgery is currently no less dramatic than any other medical condition crippling the Australian Public Healthcare System.

Due to its crippling effect on patient lifestyle, work place participation and the dependency on hospital and primary health care services, osteoarthritis (OA) has been declared a National Health Priority Area in Australia. A decade ago, it was estimated that the cost of arthritis to the Australian economy was greater than $23.9 billion each year (Peat, McCarney et al., 2001; Gupta, Hawker et al., 2005). In the context of an ageing population, conservative estimates suggest a 58% rise in the incidence of symptomatic OA by 2032. Worldwide, osteoarthritis is considered to be the fourth leading cause of disability (Fransen et al., 2011).

Current medical treatment strategies for osteoarthritis are aimed at pain reduction/symptom management rather than disease treatment. These current pharmacological therapies are limited and can compound patients with unwanted side effects (Bagga, Burkhardt et al., 2006; Abraham et al., 2007). Viscosupplement/hyaluronic acid intra-articular injections are used to treat symptoms of mild to moderate OA. However, their mechanism of action is uncertain, with some studies suggesting little improvement beyond that achieved with placebo injections (Baltzer, Moser et al. 2009). Furthermore, important conservative interventions including exercise and weight loss are inherently futile, evidenced by the lack of compliance and adherence to these interventions as a part of treatment programs for obesity and diabetes.

Unlike isolated obesity and/or diabetes, osteoarthritis dramatically restricts a patient’s ability to exercise and perform many tasks necessary to maintain a physically and mentally sound body. Oftentimes, the comorbidities of advanced OA are obesity and diabetes and are in themselves contraindications for many forms of surgery. This is often particularly catastrophic for surgeries planned to be performed by privately operating surgeons on patients reliant on private healthcare. Obesity and associated metabolic disorders, even as the result of the primary ailment, can exclude patients for coverage by many private health insurers.
The currently accepted treatment option for prosthetic joint replacement is (Total Knee Replacement – TKR. From 2000 to 2010 total knee replacement increased from 85.2 procedures per 100,000 population to 1453; total hip replacement increased from 71.2 procedures per 100,000 population to 94.1). The Australian National Joint Replacement Registry Report of 2013 documented more than 100,000 knee joint arthroplasties in the last year (Aus Orthopaedic Association). This was an approximate 10% increase on the prior year. It is also estimated that approximately 600,000 TKR procedures are performed annually in the United States (Cram et al. 2012). Alarmingly – and perhaps reflecting increased rates of obesity – an increasing proportion of patients who undergo a TKR are under the age of 65 (Swedish Knee Arthroplasty Registry). Further revision rates of primary TKR are 25 times higher in patients under 65yrs of age (Carr et al, 2013). Not surprisingly it is estimated that the number of annual total knee revision operations performed will grow by over 600% between the years 2005 and 2030 (Kurtz et al. 2007).

TKR surgery is not without risks of significant complications. As many as 20% of patients will continue to experience knee pain and other problems post TKR (Bourne et al. 2010). Further, significant complications such as death, pulmonary embolism and infections requiring re-admission to hospital occur in up to 2% of patients (SooHoo et al. 06). These rates increase with revision procedures. The average cost of a TKR is greater than $20,000 with total cost to the private healthcare industry being $500 Million in 2012-2013 (Private Healthcare Aus). The health and economical implications of TKR are significant cause for exploring an alternative therapy.

In hyaline-coated synovial joints, chondrocytes, which line the bone and become embedded, albeit sparsely, in the cartilaginous matrix, not only produce the matrix of collagen, glycosaminoglycans and hyaluronic acid, but also normally induce homeostatic turnover through lytic and degradative enzymes with subsequent regeneration. In terms of OA pathology, the clear generic problem is lack of, or damage to, articular cartilage. This can be triggered by acute injury or chronic wear and tear, eventually leading to sub-chondral bone aggravation as a precedent to OA, which itself is graded I to IV based on severity; grade IV is often aptly referred to as “bone on bone” (Kellgren et al, 1957). Depending on the age of the patient and the presented health of the joint, there is the potential for some degree of spontaneous repair and cartilage rejuvenation due to the presence of viable chondrocytes within the cartilage matrix. However, these cells are only found in relatively low abundances and the process is severely compromised by the lack of vasculature which would otherwise allow for better perfusion of the cartilage plate.

In attempts to address the avascular nature of chondral tissue, several surgical treatment methods aimed at assisting repair of articular cartilage lesions – including surgical osteochondral grafts, microfracture and chondrocyte plantation – have been explored. These methods however are limited to the repair of focal lesions only and not for diffuse degenerative OA.

During OA, disease progression results from a cytokine imbalance between pro-inflammatory molecules (eg 1. tumour necrosis factor; TNF) and anti-inflammatory cytokines including interleukin-4 and interleukin-10 (Goldring et al., 2000). This cytokine imbalance is thought to activate proteolytic enzymes, leading to the destruction of cartilage with elevated levels of degradative enzymes that override normal repair processes. This leads to synovitis, degeneration of articular cartilage, loss of extracellular matrix and ultimately the progressively compromised cartilage surface.

Given the severe impact that OA has on the patient’s quality of life through pain, drastic pain management and impaired mobility, it is not surprising that great efforts and resources have been invested in developing clinical solutions to address the paucities in the current therapeutic landscape.
Recent advancement in our global understanding of the pathological disease process of osteoarthritis has seen increased interest in the area of biological cell-based therapies including those leveraging the mechanistic action of mesenchymal stem cells (MSCs). Haemopoietic stem cells (HSC) have been demonstrated to acheive remarkable clinical success for over 40 years in the area of bone marrow transplantation, and thus served as an important proof of concept for cell based therapies. The most comprehensively researched regenerative cell type and therapeutic procedure demonstrating the most reliable clinical results are those procured by mini-liposuction and found in the stromal vascular fraction of adipose tissue; these cells are often referred to as multi-potent mesenchymal stromal cells (MSCs) or, simply, adipose-derived mesenchymal stem cells. Note: The former definition is more appropriate due to the inherent heterogeneity of the cellular fractions used in the therapies documented in clinical research and practise.

3.0 Mesenchymal Stromal Cells

Recent work has demonstrated that MSCs are capable of differentiating into cartilage and/or bone, supporting their potential applications in the treatment in OA (Diekman et al. 2010; Kern et al. 2006). Research highlighting the pro-inflammatory cytokines involved in the destruction of hyaline cartilage and resultant development of degenerative osteoarthritis (Goldring. 2000) has also highlighted the potential of MSCs as a pathology modifying agent due to their immunomodulatory/anti-inflammatory properties.

Mesenchymal stem cells were first identified and described within the stroma of bone marrow. They display a multipotent phenotype i.e. are able to differentiate down osteogenic, chondrogenic and adipogenic lines. MSCs also play an intrinsic role in tissue repair and regeneration (Caplan et al. 2011). Similar cells have been shown to be present in other tissues including peripheral blood, cord blood, skeletal muscle, heart and adipose tissue. The presence of these cells within other tissues has meant that they are perhaps more accurately described as mesenchymal multipotential stromal cells (MSCs).

Whilst evidence of the capacity of MSCs to differentiate along a chosen cell lineage represents great promise in the area of regenerative medicine it is postulated that their beneficial effect is also achieved through an immunomodulatory and paracrine mechanism and hence manipulation of the disease process (Caplan et al. 2009). MSCs are observed to suppress inflammatory T-cell proliferation, and inhibit maturation of monocytes and myeloid dendritic cells resulting in an immunomodulatory and anti-inflammatory effect. They also produce essential cytokines such as TGF-beta, Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor (EGF) and secrete an array of bioactive molecules that stimulate local tissue repair (Nakagomi et al. 2006; Caplan 1991; Caplan and Correa. 2011).

MSCs are a heterogenous population of stromal cells that lack a specific and unique marker. They are characterized by their adherent properties and expression of several surface antigens including CD105, CD90 and CD73 and their absence of the haematopoetic markers CD34 and CD45 (Dominici et al., 2006). The MSCs’ capacity to respond to a wide variety of extracellular cues in their local environment and carry out a number of the therapeutic outcomes observed (Lo Surdo et al. 2012) has been attributed, in part, to the functional heterogeneity of the cellular fractions from which they are derived.

3. 1 Do Stem Cell Treatments Work? Evidence of MSC Efficacy

Effective reconstitution of cartilage has been demonstrated in animal models with cartilage defects after treatment with MSCs (Dragoo et al., 2007, Cui et al., 2009). Further, Black and colleagues have published two randomised control trials showing a significant improvement in lameness and range of motion (ROM) in dogs following intra-articular stromal cellular injections (Black et al., 2007; 2008).

Evidenced by the clinical literature, there is growing support of MSC efficacy. In 2006 and 2008, a large clinical group published single case studies looking at the effect of expanded bone marrow-derived mesenchymal stromal stem cells on hip and knee OA respectively. They showed a marginal improvement in pain for hip osteoarthritis and a clinically significant decrease in pain for knee osteoarthritis (Centeno et al., 2006, Centeno et al, 2008). More convincingly in their 2011 case series of 339 patients, the same group reported that 69% of patients treated were candidates for knee replacement but after treatment with MSCs only 6.9% still required TKR. Sixty percent of patients reported 50% pain relief and 40% reported >75% pain relief at 11 months (Centeno et al., 2011). Further indication of efficacy has been highlighted by several other case study reports whereby intra-articular stromal cell injections have resulted in clinically significant improvement in function and reduction in pain (Pak, 2011; Davachi et al., 2011; Emadedin et al., 2011).

Importantly, there is now abundant evidence that confirms the ability of MSCs therapies to, not only improve pain and function, but also influence the structure of cartilage and therefore have disease-modifying properties. Kuroda and colleagues (2007) successfully treated a femoral condyle cartilage defect with autologous bone marrow stromal cells showing repair with hyaline-like tissue at follow-up arthroscopy and biopsy. Furthermore, Jo and colleagues have successfully shown regeneration of cartilage using a high dose (100 million cells) expanded autologous MSC preparation (Jo et al, 2014). Additionally, recent preliminarily released results by Cao and colleagues have also shown regrowth of cartilage using high dose preparations of MSC (Cao et al, 2014).

3.1.1 Clinic-specific Treatment History

Although the current orthopaedic and neural components of the Intellihealth Plus clinic’s complete patient treatment history will remain confidential until mid-2015, the most recently publicised figures from 2012 detail over 1,750 patients treated for a range of conditions including aplastic anaemia, osteoarthritis and neuronal diseases. Of the specialised therapies performed at the clinic, treatments of osteoarthritis with MSCs have one of the most impressive therapeutic profiles with approximately 75% of treatments achieving significant therapeutic outcomes (i.e. significant pain relief, range of motion improvements and cartilage reconstitution) and the remaining 25% of treatments achieving partial improvements (either improvement in only one parameter or marginal improvements in all parameters). In contrast to other clinics with reports of up to 40% of patients receiving either partial or no improvement, Intellihealth Plus provides either significant or partial improvements in 100% of patients treated with their patented technologies, protocols and supportive therapies (0% of patients receive no improvement).

3.2 MSC Safety

There are now over 367 trials using MSCs registered with the National Institutes of Health; over 30 of these are focused on musculoskeletal disease and most of these are treating osteoarthritis. Importantly, based upon the outcomes of previous and current clinical trials, MSC therapy is safe. A recent systematic review and meta-analysis of trials involving a total of 1,012 participants receiving intravascular autologous, allogeneic and expanded/cultured MSCs for various clinical conditions (including ischaemic stroke, Crohn’s disease, cardiomyopathy, ischaemic heart disease and graft versus host disease) did not identify any significant adverse events other than transient hyperthermia (Lalu et al, 2012). Patients were followed up in some studies for over 90 months. This evidence of safety was further confirmed with a systematic review of intra-articular injections of expanded stem cells (Peeters et al. 2013). Importantly, no association has been made between MSC therapy and adverse events such as infection, death or malignancy. The typical risks inherent in injectable therapies are noted to apply to cell based therapies due to their administration route. However, the incidence of these complications has not yet been documented or evidenced in the current literature.

3.3 Adipose Derived Mesenchymal Stromal Cells

The preliminary research into MSC-based therapies was performed using bone marrow-derived cells. Bone marrow harvest procedures are however painful and yield relatively low numbers of MSCs (Pittenger et al. 1999). An alternative source of autologous adult MSCs, due to its abundance and ease of harvest (through mini-liposuction), is adipose tissue (De Ugarte et al. 2003; Kern et al. 2006). In order to harvest adipose-derived stromal cells, an abdominal lipoharvest procedure (liposuction) is performed. The lateral abdominal region is anaesthetised using tumescent fluid comprised of local anaesthetic and adrenalin suspended in a saline solution. Using a specialised lipoaspiration canula and adapted non-traumatic surgical techniques, adipose tissue is aspirated and collected within a sterile medical-grade tissue sample collection bag.

3.4 Isolation of Cells

Despite the expansion of autologous mesenchymal stem cells being safe, long term in vitro expansion (using up to 20 passages) has shown evidence of DNA disruption and loss of cellular mesenchymal specificity. This indicates that, in order to retain the multi-potent properties of these cells, the use of expansion protocols should be limited (Safwani et al., 2012).

The Intellihealth Plus Clinic avoids any expansion when processing the stromal vascular fraction. The isolation of cells is performed, rather, by ultrasonic cavitation using a closed system patented technology licensed by the global biotechnology company Stem Cells 21. This procedure produces far cleaner isolations with a significantly higher cellular content with high mesenchymal specificity.

Following the mini-liposuction procedure performed by a fully-qualified plastic surgeon, the lipoaspirate is rapidly transferred through an inter-theatre sample transfer unit (sterile sample pass box) to be processed in a sterile class 100,000 laboratory environment in a Biological Safety Cabinet (BSC) Class II, using strict aseptic techniques. All relevant equipment used is qualified and validated for aseptic processing of samples intended for clinical transplantation. All materials used in this process are sterile and validated for clinical use.

At critical milestones of the cell purification process, cell count and cell viability are performed by a trained clinical cell biologist.
Cells are characterised and their viability is assessed by flow cytometry (FACS) using Muse Analyser technology following isolation of samples from each patient. Dosages containing 40-100 million autologous MSCs each (according to the prescribed treatment protocol) are individually cryostored in sterile cryovials in approved cell safe cryoprotectant media by a validated control rate freezing technique and stored in liquid nitrogen until required (Martinello et al., 2011; Goh et al., 2007).

Upon commencement of treatment, a single dose of cells is thawed at 37o C in a sterile water bath and centrifuged to remove cryoprotectant media. The pelleted cells are then mixed with 3mls of sterile clinical grade injectable normal saline and injected into the knee, hip, shoulder, spine, elbow, hand, wrist, ankle or foot of the patient. This step is repeated as per the elected treatment protocol, spanning days, months or years.

4.0 Research and Development

The Medical Director and associated medical staff at Intellihealth Plus have been involved in large-scale clinical trials using stem cells to reconstitute a range of tissues and treat a variety of diseases (performed independently to the clinic). Although the clinic intends to conduct trials of chronic disease treatments in the future, the clinic maintains a satisfaction with the current abundance of data supporting the use of MSCs in the treatment of osteoarthritis. The clinic and its staff are actively involved in sharing their developments with the international medical fraternity both in Australia and abroad at conferences and meetings. However, the intellectual property possessed by the clinic and its group of owners prohibit the dissemination of the specialised skills and protocols affording the clinic and its patients its reputable history and successful future.

5.0 References

Australian Orthopaedic Association, National Joint Replacement Registry: Supplementary Report 2013, https://
aoanjrr.dmac.adelaide.edu.au/documents/10180/127369/Revision%20of%20Hip%20%26%20Knee%20Arthroplasty

Abraham, NS, El-Serag, et al. (2007). Cyclooxygenase2 selectivity of non-steroidal anti-inflammatory drugs and the risk of myocardial infarction and cerebrovascular accident. Aliment Pharmacol Ther 25(8): 913-924.

Bagga, H., Burkhardt, D., et al. (2006). Longterm effects of intraarticular hyaluronan on synovial fluid in osteoarthritis of the knee. J Rheumatol 33(5): 946-950.

Baltzer, AW., Moser, C., et al. (2009). Autologous conditioned serum (Orthokine) is an effective treatment for knee osteoarthritis. Osteoarthritis Cartilage 17(2): 152-160,

Beurskens, A, de Vet, H., et al. (1996). Responsiveness of functional status in low back pain: a comparison of different instruments. Pain 65(1): 71-76.

Black, L., Gaynor, J., Adams, C., et al. (2008) Effect of intraarticular injection of autologous adipose derived mesenchymal stem and regenerative cells on clinical signs of chronic osteoarthritis of the elbow joint in dogs. Vet Ther; 9:192-200.

Bourne, RB, Chesworth, BM., et al (2010). Patient satisfaction after total knee arthroplasty: who is satisfied and who is not. Clin Orthop Relat; 468: 57–63,

Caplan, A. (2009) What are MSCs therapeutic? New data: new insight. Pathol 217: 318-324

Caplan, A. I., & Correa, D. (2011). The MSC: an injury drugstore. Cell Stem Cell, 9(1), 11-15.

Caplan, A. I. (2005). Review: mesenchymal stem cells: cell-based reconstructive therapy in orthopedics. Tissue engineering, 11(7-8), 1198-1211.

Carr, A., Robertsson, O., et al. (2012). Knee Replacement. Lancet; 379:1331-1340

Centeno, C., Busse, D., Kisiday, J., et al. (2008) Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician; 11 (3): 343-353.

Centeno, C., Kisiday, J., Freeman, M, et al. (2006) Partial regeneration of the human hip via autologous bone marrow nucleated cell transfer: A case study. Pain Physician; 9:253-256

Centeno, C., Schultz, J., Cheever, M. (2011) Safety and Complications Reporting on the ReImplantation of Culture Expanded Mesenchymal Stem Cells Using Autologous Platelet Lysate Technique. Current Stem Cell; 5(1): 81-93.

Cram, P, Lu, , et al (2012) Total knee arthroplasty volume, utilization, and outcomes among medicare beneficiaries, 1991-2010″ JAMA 308 (12): 1227-1236

Davatchi, F, Sadeghi Abdollahi, B., Mohyeddin, M, et al. (2011) Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients. Int Rhem dis; 14(2): 211-215.

Deyo, RA, Battie, M, et al. (1998). Outcome Measures For Low Back Pain. Spine 23(18): 2003-2013.

Diekman, B., Rowland, C., Lennon, D. et al. (2010). Chondrogenesis of adult stem cells from adipose tissue and bone marrow: Induction by growth factors and cartilage-derived matrix. Tissue Eng Part A; 16(2): 523-533.

Dominici, M, Le Blanc, K, et al. (2006) Minimal criteria for defining mulipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy; 8(4): 315-317

Dworkin, R., Turk, D., et al. (2005). Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 112(1-2): 1-2.

Emadedin, M, Aghdami, N, Taghiyar, L, et al. (2012) Intraarticular injection of Autologous Mesenchymal Stem Cells in Six Patients with Knee Osteoarthritis. Arch Iran Med; 15(7): 422-428.

Ferrer, M, Pellisé, F, et al. (2006). Validation of a minimum outcome core set in the evaluation of patients with back pain. Spine 31(12): 1372-1379.

Fransen, M, Bridgett, L, March, L, et al. The epidemiology of osteoarthritis in Asia. Int J Rheum Dis; 14(2): 113-121

Gupta, S, Hawker, GA, et al. (2005). The economic burden of disabling hip and knee osteoarthritis (OA) from the perspective of individuals living with this condition. Rheumatology (Oxford) 44(12): 1531-1537

Hamer, R, Simpson, P (2009). Last observation carried forward versus mixed models in the analysis of psychiatric clinical trials. American Journal of Psychiatry 166(6): 639-641.

Helmhout, P, Staal, J., et al. (2008). Exercise therapy and low back pain: insights and proposals to improve the design, conduct, and reporting of clinical trials. Spine; 33(16): 1782-1788.

Jo, CH, Lee, Y, et al. (2014). Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: A proof of concept clinical trial. Stem Cells; Doi: 10.1002/stem.1634

Kellgren, J., Lawrence, J. (1957). Radiological assessment of osteoarthrosis.” Annals of Rheumatic Diseases 16(4): 494-502.

Kelly, S. (2014) News Release : http://globenewswire.com/news-release/2014/02/24/612749/10069672/en/Cellular-Biomedicine-Group-Announces-Updated-Results-From-Phase-I-IIa-Clinical-Trial-for-ReJoin-TM-Treatment-of-Knee-Osteoarthritis-KOA.html

Kern, S., Eichler, H., Stoeve, J., Kluter, H. and Bieback, K. (2006) Comparative analysis of mesenchymal stem cells from bone marow, umbilical cord blood or adipose tissue. Stem Cells; 24(5): 1294-1301.

Krueger, C. and Tian, L., (2004). A comparison of the general linear mixed model and repeated measures ANOVA using a dataset with multiple missing data points. Biol Res Nurs 6(2): 151-157.

Kuroda, R, Ishida, K, et al. Treatment of a full-thickness articular cartilage defect in the femoral condyle of an athlete with autologous bonemarrow stromal cells. Osteoarthritis Cartilage. 2007; 15:22631.

Kurtz, S, Ong, K, et al (2007). Projections of primary and revision hip and knee arthroplasty in the united states from 2005 to 2030. Bone Jt Surg Am, 89(4): 780-785

Linton, S. and Boersma, K, (2003). Early identification of patients at risk of developing a persistent back problem: the predictive validity of the Orebro musculoskeletal pain questionnaire.” Clinical Journal of Pain 192): 80-86.

Lo surdo, J. Bauer, SR. (2012). Quantitative approaches to detect done and passage differences in adipogenic potential and clonogenicity in human bone marrow derived mesenchymal stem cells. Tiss Eng; 18(11): 1-13.

Lalu, ML, McIntyre, L, et al. (2012) Safety of cell therapy with mesenchymal stromal cells (safe cell: A systematic review and metaanalysis of clinical trials. PLOS One; 71 O, open access e47559

Nakagami, H., Morishita, R, et al. (2006). Adipose tissue derived stromal cells as a novel option for regenerative cell therapy. J Atherosclerosis and Thrombosis; 13(2), 77.

Ornetti, P, Dougados, M, et al. (2011). Validation of a numerical rating scale to assess functional impairment in hip and knee osteoarthritis: comparison with the WOMAC function scale. Ann Rheum Dis 70(5): 740-746.

Pak, J. (2011). Regeneration of human bones in hip osteonecrosis and human cartilage in knee osteoarthritis with autologous adipose-tissue-derived stem cells: a case series. J Med Case Reports; 5:296

Paterson, C. and Britten, N, 2005). A narrative review shows the unvalidated use of self-report questionnaires for individual medication as outcome measures. Journal of Clinical Epidemiology 58(10): 967-973.

Peat, G., McCarney, R, et al. (2001). Knee pain and osteoarthritis in older adults: a review of community burden and current use of primary health care. Ann Rheum Dis; 60(2): 91-97.

Peeters, CM, Leijs, M., et al. (2013) Safety of intraarticular cell therapy with culture expanded stem cells in humans: a systematic literature review Osteo Cartilage; 21(10): 1465-1473.

Pittenger, MF, Mackay, AM, et al. (1999). Multilineage potential of adult human mesenchymal stem cells. Science; 284: 193

Private Healthcare Australia (2014), Variations in Care – Hip and Knee Replacement https://www.privatehealthcareaustralia.org.au/news/stats_and_data/variations-in-care-hip-and-knee-replacement/

Robinson, K. and Dennison, C. (2007). Systematic review identifies number of strategies important for retaining study participants. Journal of Clinical Epidemiology 60(8): 757-765.

Roos, E., Roos, H., et al. (1999). WOMAC Osteoarthritis Index: additional dimensions for use in post-traumatic osteoarthritis of the knee. Osteoarthritis Cartilage 7(3): 216-221.

Roos, E., Roos, H., et al. (1998). Knee Injury and Osteoarthritis Outcome Score (KOOS)-development of a self-administered outcome measure. J Orthop Sports Phys Ther; 28(2): 88-96.

Saw, KY, et al. (2013). Articular cartilage regeneration with autologous peripheral blood stem cells versus hyaluroninc acid: a randomised controlled trial. Arthroscopy; 29(4): 684-694

Sanchez, M, E. Anitua, et al. (2008). Intraarticular injection of an autologous preparation rich in growth factors for the treatment of knee OA: a retrospective cohort study. Clin Exp Rheumatol; 26(5): 910-913.

SooHoo, N, Lieberman, J., et al. (2006). Factors predicting complication rates following total knee replacement. Bone Jt Surg Am; 88(3): 480-485

Thompson, W, N. Gordon, et al. (2009). American College of Sports Medicine Guidelines for Exercise Testing and Prescription. Philadelphia, Wolters Kluwer.

*Please read: Although the information provided on this page may describe a particular patient experience and/or outcome, readers must understand that each patient presents with a unique medical history and may be recommended a different treatment/surgery by their surgeon to that described above. Individual results may vary between surgery centre/hospital, surgeon, surgery type and patient. Although SkyGen agrees to share all updates from patients at their request, SkyGen does not endorse any physical activities attempted by patients following surgery which do not follow the explicit instructions provided by their surgeon. SkyGen encourages all patients to discuss the risks of such activities with medical professionals before attempting these themselves.

Written by SkyGen Public Relations

This content is copyright and property of SkyGen Spinal & Orthopaedic. It was written to educate our patients in making informed decisions regarding their own healthcare. SkyGen is Australia's largest international collaboration between world class regenerative medicine clinics and orthopaedic hospitals.