Osteoarthritis Stem Cell Therapy
(OA) also known as degenerative arthritis or degenerative joint disease or osteoarthrosis, is a group of mechanical abnormalities involving degradation of joints,including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion. A variety of causes—hereditary, developmental, metabolic, and mechanical—may initiate processes leading to loss of cartilage. When bone surfaces become less well protected by cartilage, bone may be exposed and damaged. As a result of decreased movement secondary to pain, regional muscles may atrophy, and ligaments may become more lax. Treatment generally involves a combination of exercise, lifestyle modification, and analgesics. If pain becomes debilitating, joint replacement surgery may be used to improve the quality of life. OA is the most common form of arthritis, and the leading cause of chronic disability in the United States. It affects about 8 million people in the United Kingdom and nearly 27 million people in the United States.
Signs and symptoms
Bouchard’s nodes and Heberden’s nodes may form in osteoarthritis
The main symptom is pain, causing loss of ability and often stiffness. “Pain” is generally described as a sharp ache, or a burning sensation in the associate muscles and tendons. OA can cause a crackling noise (called “crepitus”) when the affected joint is moved or touched, and patients may experience muscle spasm and contractions in the tendons. Occasionally, the joints may also be filled with fluid. Humid and cold weather increases the pain in many patients.
OA commonly affects the hands, feet, spine, and the large weight bearing joints, such as the hips and knees, although in theory, any joint in the body can be affected. As OA progresses, the affected joints appear larger, are stiff and painful, and usually feel better with gentle use but worse with excessive or prolonged use, thus distinguishing it from rheumatoid arthritis.
In smaller joints, such as at the fingers, hard bony enlargements, called Heberden’s nodes (on the distal interphalangeal joints) and/or Bouchard’s nodes (on the proximal interphalangeal joints), may form, and though they are not necessarily painful, they do limit the movement of the fingers significantly. OA at the toes leads to the formation of bunions, rendering them red or swollen. Some people notice these physical changes before they experience any pain.
OA is the most common cause of joint effusion, sometimes called water on the knee in lay terms, an accumulation of excess fluid in or around the knee joint.
Some investigators believe that mechanical stress on joints underlies all osteoarthritis, with many and varied sources of mechanical stress, including misalignments of bones caused by congenital or pathogenic causes; mechanical injury; overweight; loss of strength in muscles supporting joints; and impairment of peripheral nerves, leading to sudden or uncoordinated movements that overstress joints. However exercise, including running in the absence of injury, has not been found to increase one’s risk of developing osteoarthritis. Nor has cracking ones knuckles been found to play a role.
Primary osteoarthritis of the left knee. Note the osteophytes, narrowing of the joint space (arrow), and increased subchondral bone density (arrow).
Primary osteoarthritis is a chronic degenerative disorder related to but not caused by aging, as there are people well into their nineties who have no clinical or functional signs of the disease. As a person ages, the water content of the cartilage decreases as a result of a reduced proteoglycan content, thus causing the cartilage to be less resilient. Without the protective effects of the proteoglycans, the collagen fibers of the cartilage can become susceptible to degradation and thus exacerbate the degeneration. Inflammation of the surrounding joint capsule can also occur, though often mild (compared to what occurs in rheumatoid arthritis). This can happen as breakdown products from the cartilage are released into the synovial space, and the cells lining the joint attempt to remove them. New bone outgrowths, called “spurs” or osteophytes, can form on the margins of the joints, possibly in an attempt to improve the congruence of the articular cartilage surfaces. These bone changes, together with the inflammation, can be both painful and debilitating.
A number of studies have shown that there is a greater prevalence of the disease among siblings and especially identical twins, indicating a hereditary basis. Up to 60% of OA cases are thought to result from genetic factors.
Both primary generalized nodal OA and erosive OA (EOA. also called inflammatory OA) are sub-sets of primary OA. EOA is a much less common, and more aggressive inflammatory form of OA which often affects the DIPs and has characteristic changes on x-ray.
Diagnosis is made with reasonable certainty based on history and clinical examination. X-rays may confirm the diagnosis. The typical changes seen on X-ray include: joint space narrowing, subchondral sclerosis (increased bone formation around the joint), subchondral cyst formation, and osteophytes. Plain films may not correlate with the findings on physical examination or with the degree of pain. Usually other imaging techniques are not necessary to clinically diagnose osteoarthritis.
In 1990, the American College of Rheumatology, using data from a multi-center study, developed a set of criteria for the diagnosis of hand osteoarthritis based on hard tissue enlargement and swelling of certain joints. These criteria were found to be 92% sensitive and 98% specific for hand osteoarthritis versus other entities such as rheumatoid arthritis and spondyloarthropathies.
Related pathologies whose names may be confused with osteoarthritis include pseudo-arthrosis. This is derived from the Greek words pseudo, meaning “false”, and arthrosis, meaning “joint.” Radiographic diagnosis results in diagnosis of a fracture within a joint, which is not to be confused with osteoarthritis which is a degenerative pathology affecting a high incidence of distal phalangeal joints of female patients.
Stem Cell Therapy
The large and expanding body of publications utilizing stem cell technology in orthopedic applications indicates that the infusion of stem cells and growth factors result in the modulation of T cell activity, decreased inflammatory chemicals and the stimulation of the chondocytes.
This combination of responses is probably the basis for the results seen in the referenced clinical trials. There clearly needs to be an increased utilization of the stem cell approach to safely address this condition. Unfortunately this is unlikely, as the use of expensive and risky pharmaceutical agents has taken the forefront. The limited options for this disorder suggest other avenues of treatment should preclude the surgeries that typical mark the end point of the disease process.
We at World Stem Cells, LLC feel strongly that the non-responders to conventional therapies should utilize a stem cell approach, prior to the use of the surgical and/or long-term steroidal or even non-steroidal medicinal applications.
Autologous Stem-Cell Transplant Phases :
After a review of your medical records and discussions with medical staff, a protocol is designed especially for you. Specifics of your condition are addressed along with any special needs. It may be similar to the one illustrated below:
· Day one: Arrive in Cancun and get settled
· Day two: Meet with our medical staff for an examination, discussion of the procedures and laboratory collections along with stem cell stimulation. Our staff video photographer may also interview you.
· Day three: Early morning procedures including a blood test and, dependent on the response to our therapy, additional stimulation or stem cell harvesting and re-implantation, if cellular numbers and viability are present at a high level. Potentially physical or occupational therapy, later in the day.
· Day four: Cellular re-implantation if not done on day 3. This will require a restful day and observation, including a post treatment examination. Additional physical or occupational therapy per the individual protocol.
· Day five: Meet with physician/s to reassess your condition and participate in physical/occupational therapy services. Discuss follow up and communications with both our services and the International Cellular Medicine Society. Suggest additional opportunities for maximizing the stem cell therapy.
· Day six: Return home or optionally there may be the use of additional ancillary therapies to enhance the procedure.
What makes our treatment different ? Our approach includes stimulation, prior to collection, processing and expansion of the cell along with the use of growth factors, together with an integrated medical approach. This maximizes the growth and implantation potentials yielding optimized potentials of making changes in your disease.
Our staff physicians are all board certified, in their field with years of experience. Your team includes both primary and ancillary care professionals devoted to maximizing your benefits from the procedures.
We enroll you in an open registry to track your changes independently, for up to 20 years. As our patient we also keep you abreast of the newest developments in stem cell research. This is an ongoing relationship to maintain and enhance your health.
Our promise is to provide you with travel and lodging support, access to bilingual staff members throughout the entire process and most importantly the best medical care possible.
Adv Biochem Eng Biotechnol. 2012 Mar 29.
Potential for Osteogenic and Chondrogenic
Differentiation of MSC.
Lavrentieva A, Institut für Technische Chemie, Leibniz Universität Hannover, Callinstrasse 5, 30167, Hannover, Germany, firstname.lastname@example.org.
The introduction of mesenchymal stem cells (MSC) into the field of tissue engineering for bone and cartilage repair is a promising development, since these cells can be expanded ex vivo to clinically relevant numbers and, after expansion, retain their ability to differentiate into different cell lineages. Mesenchymal stem cells isolated from various tissues have been intensively studied and characterized by many research groups. To obtain functionally active differentiated tissue, tissue engineered constructs are cultivated in vitro statically or dynamically in bioreactors under controlled conditions. These conditions include special cell culture media, addition of signalling molecules, various physical and chemical factors and the application of different mechanical stimuli. Oxygen concentration in the culture environment is also a significant factor which influences MSC proliferation, stemness and differentiation capacity. Knowledge of the different aspects which affect MSC differentiation in vivo and in vitro will help researchers to achieve directed cell fate without the addition of differentiation agents in concentrations above the physiological range.
Tissue Eng. 2006 Jul;12(7):1787-98.
Maturation of tissue engineered cartilage implanted in injured and osteoarthritic human knees.
Hollander AP, Dickinson SC, Sims TJ, Brun P, Cortivo R, Kon E, Marcacci M, Zanasi S, Borrione A, De Luca C, Pavesio A, Soranzo C, Abatangelo G.
University of Bristol Academic Rheumatology, Department of Clinical Science at North Bristol, Avon Orthopaedic Centre, Southmead Hospital, Bristol, United Kingdom.
The regeneration of damaged organs requires that engineered tissues mature when implanted at sites of injury or disease. We have used new analytic techniques to determine the extent of tissue regeneration after treatment of knee injury patients with a novel cartilage tissue engineering therapy and the effect of pre-existing osteoarthritis on the regeneration process. We treated 23 patients, with a mean age of 35.6 years, presenting with knee articular cartilage defects 1.5 cm2 to 11.25 cm2 (mean, 5.0 cm2) in area. Nine of the patients had X-ray evidence of osteoarthritis. Chondrocytes were isolated from healthy cartilage removed at arthroscopy. The cells were cultured for 14 days, seeded onto esterified hyaluronic acid scaffolds (Hyalograft C), and grown for a further 14 days before implantation. A second-look biopsy was taken from each patient after 6 to 30 months (mean, 16 months). After standard histological analysis, uncut tissue was further analyzed using a newly developed biochemical protocol involving digestion with trypsin and specific, quantitative assays for type II collagen, type I collagen, and proteoglycan, as well as mature and immature collagen crosslinks. Cartilage regeneration was observed as early as 11 months after implantation and in 10 out of 23 patients. Tissue regeneration was found even when implants were placed in joints that had already progressed to osteoarthrosis. Cartilage injuries can be effectively repaired using tissue engineering, and osteoarthritis does not inhibit the regeneration process.
Comment: Its interesting to note that as early as 2006 researchers were noting the resiliency of the cartilaginous tissues with the use of autologous stem cells.
Autologous bone marrow mesenchymal stem cells implantation for cartilage defects: two cases report.
Kasemkijwattana C, Hongeng S, Kesprayura S,Rungsinaporn V, Chaipinyo K, Chansiri K. J Med Assoc Thai. 2011 Mar;94(3):395-400. Department of Orthopedics, Faculty of Medicine, HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakhrinwirot University, Nakhon Nayok, Thailand. email@example.com
The authors reported the results of autologous bone marrow mesenchymal stem cells (BM-MSCs) implantation in two patients with large traumatic cartilage defects of the knee.
MATERIAL AND METHOD:
Two patients with grade 3-4 according to the International Cartilage Repair Society Classification System were performed autologous bone marrow mesenchymal stem cells (BM-MSCs) implantation on December 2007 and January 2008. The bone marrow aspiration was performed in the outpatient visit under local anesthesia and sent to the laboratory for BM-MSCs isolation and expansion. The BM-MSCs were re-implanted into the defects with the three-dimensional collagen scaffold. The patients were clinical evaluated preoperatively and postoperatively with Knee and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee Score (IKDC Score) and arthroscopic examination. The duration of follow-up was 30-31 months.
There was no postoperative complication. The clinical evaluation with Knee and Osteoarthritis Outcome Score (KOOS) and International Knee Documentation Committee Score (IKDC Score) showed significant improvement.The arthroscopic assessment showed the good defect fill, stiffness and incorporation to the adjacent cartilage.
The autologous bone marrow mesenchymal stem cells implantation showed the potential for the treatment of large cartilage defects. The one-stage procedure is the advantage over the conventional autologous chondrocytes implantation. The long-term follow-up with long last hyaline-like cartilage is required.
Adult autologus SCs were used in this study. At the World Stem cells Clinic we activate the stem cells with platelet derived growth factors that are combined for implantation. this combination has significantly better response than a singular approach.
Chondrogenic potential of human adult mesenchymal stem cells is independent of age or osteoarthritis etiology.
NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.
Osteoarthritis (OA) is a multifactorial disease strongly correlated with history of joint trauma, joint dysplasia, and advanced age. Mesenchymal stem cells (MSCs) are promising cells for biological cartilage regeneration. Conflicting data have been published concerning the availability of MSCs from the iliac crest, depending on age and overall physical fitness. Here, we analyzed whether the availability and chondrogenic differentiation capacity of MSCs isolated from the femoral shaft as an alternative source is age- or OA etiology-dependent. MSCs were isolated from the bone marrow (BM) of 98 patients, categorized into three OA-etiology groups (age-related, joint trauma, joint dysplasia) at the time of total hip replacement. All BM samples were characterized for cell yield, proliferation capacity, and phenotype. Chondrogenic differentiation was studied using micromass culture and analyzed by histology, immunohistochemistry, and quantitative reverse transcriptase-polymerase chain reaction. Significant volumes of viable BM (up to 25 ml) could be harvested from the femoral shaft without observing donor-site morbidity, typically containing >10(7) mononuclear cells per milliliter. No correlation of age or OA etiology with the number of mononuclear cells in BM, MSC yield, or cell size was found. Proliferative capacity and cellular spectrum of the harvested cells were independent of age and cause of OA. From all tested donors, MSCs could be differentiated into the chondrogenic lineage. We conclude that, irrespective of age and OA etiology, sufficient numbers of MSCs can be isolated and that these cells possess an adequate chondrogenic differentiation potential. Therefore, a therapeutic application of MSCs for cartilage regeneration of OA lesions seems feasible.
Immunosuppressive properties of mesenchymal stem cells: advances and applications.
Mesenchymal stem cells (MSCs) have been isolated from a variety of tissues, such as bone marrow, skeletal muscle, dental pulp, bone, umbilical cord and adipose tissue. MSCs are used in regenerative medicine mainly based on their capacity to differentiate into specific cell types and also as bioreactors of soluble factors that will promote tissue regeneration from the damaged tissue cellular progenitors. In addition to these regenerative properties, MSCs hold an immunoregulatory capacity, and elicit immunosuppressive effects in a number of situations. Not only are they immunoprivileged cells, due to the low expression of class II Major Histocompatibilty Complex (MHC-II) and costimulatory molecules in their cell surface, but they also interfere with different pathways of the immune response by means of direct cell-to-cell interactions and soluble factor secretion. In vitro, MSCs inhibit cell proliferation of T cells, B-cells, natural killer cells (NK) and dendritic cells (DC), producing what is known as division arrest anergy. Moreover, MSCs can stop a variety of immune cell functions: cytokine secretion and cytotoxicity of T and NK cells; B cell maturation and antibody secretion; DC maturation and activation; as well as antigen presentation. It is thought that MSCs need to be activated to exert their immunomodulation skills. In this scenario, an inflammatory environment seems to be necessary to promote their effect and some inflammation-related molecules such as tumor necrosis factor-α and interferon-γ might be implicated. It has been observed that MSCs recruit T-regulatory lymphocytes (Tregs) to both lymphoid organs and graft. There is great controversy concerning the mechanisms and molecules involved in the immunosuppressive effect of MSCs. Prostaglandin E2, transforming growth factor-β, interleukins- 6 and 10, human leukocyte antigen-G5, matrix metalloproteinases, indoleamine-2,3-dioxygenase and nitric oxide are all candidates under investigation. In vivo studies have shown many discrepancies regarding the immunomodulatory properties of MSCs. These studies have been designed to test the efficacy of MSC therapy in two different immune settings: the prevention or treatment of allograft rejection episodes, and the ability to suppress abnormal immune response in autoimmune and inflammatory diseases. Preclinical studies have been conducted in rodents, rabbits and baboon monkeys among others for bone marrow, skin, heart, and corneal transplantation, graft versus host disease, hepatic and renal failure, lung injury, multiple sclerosis, rheumatoid arthritis, diabetes and lupus diseases. Preliminary results from some of these studies have led to human clinical trials that are currently being carried out. These include treatment of autoimmune diseases such as Crohn’s disease, ulcerative colitis, multiple sclerosis and type 1 diabetes mellitus; prevention of allograft rejection and enhancement of the survival of bone marrow and kidney grafts; and treatment of resistant graft versus host disease. We will try to shed light on all these studies, and analyze why the results are so contradictory.
Comment: This is an excellent example of a literature review and then subsequent inquiry into some of the known and as yet to be found pathways that allow the stem cells their ability to positively impact diseases. I think it’s interesting that “mother nature’ allows these cells such a pervasive impact on the inflammatory processes. Great design…