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David A. Steenblock, D.O. Inc

Personalized Regenerative Medicine

Stem cell therapy for osteoarthritis

The following pictures are from the website of the National Institute of Arthritis and

Musculoskeletal and Skin Diseases (NIAMS), part of the National Institutes of Health (NIH):

A Healthy Joint

In a healthy joint, the ends of bones are encased in smooth cartilage, which is protected by a jointcapsule lined with a synovial membrane which in turn produces synovial fluid. The capsule and

fluid protect the cartilage, the muscles, and the connective tissues.

A Joint With Severe Osteoarthritis

With osteoarthritis, the cartilage becomes worn away. Spurs grow out from the edge of the bone, and

synovial fluid increases. The joint therefore feels stiff and sore. From: NIAMS - National Institute of

Arthritis and Musculoskeletal and Skin Diseases.

In the new field of "tissue engineering", stem cell therapy offers a novel form of treatment for patientssuffering from osteoarthritis. Using the right type of stem cells, it is now possible to rebuild damaged

cartilage.

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Researchers at the Duke University Medical Center have "reprogrammed" adult stem cells by taking

small deposits of fat from behind the kneecap and developing these fat cells into cartilage and bone cellswhich may then be grown into replacement tissue for people suffering with osteoarthritis. Cellular

compatibility is guaranteed, and the possibility of immune rejection is eliminated since the stem cells are

derived from a person's own tissue. The particular stem cells that are used in this procedure, namely,stromal cells derived from adipose tissue, are obtained using a minimally invasive approach. Scientists

then treat the cells with a series of enzymes and, after centrifugal separation, the stromal cells are then

further treated with a biochemical "cocktail" of steroids and growth factors which induces the cells to

differentiate into multiple lineages. Adipose tissue has been shown to constitute a rich source ofprogenitor cells, and simply by controlling the biochemical environment in which the stem cells are

grown, researchers have been able to grow different types of cells from these adult stem cells.

Laboratory stem cell studies are often conducted by "infusing" the stem cells into a three-dimensionalmatrix, which resembles most closely the internal "topography" of the human joint. Utilizing such a

model, researchers at the University of Illinois at Chicago (UIC) have grown bone and cartilage from

adult stem cells, in a study conducted in December of 2003, thereby successfully forming the ballstructure of a joint that is found in the human jaw. The newly created joint, formed in the laboratory,

exhibits the same characteristic shape and tissue composition of the human original after which it was

patterned. The creation of this type of ball structure, known as an "articular condyle", marks an historic

milestone in a process which could ultimately be used to regenerate knees, hips, and other joints that aretypically damaged by osteoarthritis. Dr. Jeremy Mao, the director of the Tissue Engineering Laboratory

at UIC, and an associate professor of bioengineering and orthodontics, has stated that, "This represents

the first time a human-shaped articular condyle with both cartilage- and bone-like tissues was grownfrom a single population of adult stem cells. Our ultimate goal is to create a condyle that is biologically

viable - a living tissue construct that integrates with existing bone and functions like the natural joint."

Funded by multiple grants from the National Institutes of Health and the Whitaker Foundation, Dr. Maoused mesenchymal stem cells derived from the bone marrow of rats in the creation of this articular

condyle. It has been shown that mesenchymal stem cells, which are present in a variety of types of adult

tissue, are capable of differentiating into any kind of connective tissue, such as tendons, skeletal muscle,ligaments, cartilage, bone and teeth. With the addition of growth factors and other chemical substances,

these stem cells may be "engineered" to produce whatever specific type of tissue is desired. Such

custom-made tissues have been shown to replicate identically the characteristics of their naturallyoccurring counterparts, such as an extensive collage matrix with deposits of calcium salts, in the case ofbone, and collagen with large amounts of proteoglycans, in the case of cartilage. While additional

research is needed before tissue-engineered condyles are ready for the clinical treatment of patients

suffering from osteoarthritis, rheumatoid arthritis, injuries or congenital anomalies, Dr. Maonevertheless believes that, ultimately, the procedure could be adopted for total hip and knee

replacements. "Our findings represent a proof-of-concept for further development of tissue-engineered

condyles," Dr. Mao has said. (From the Journal of Dental Research). Adult bone marrow is aparticularly rich source of stem cells in this new field of tissue engineering. As the inner, spongy mass

that fills the core of long bones, bone marrow is easily accessible from such bones as the femur and tibia

of the legs.

Similarly, in November of 2004, researchers at the Israel Institute of Technology, Technion, succeededin building cartilage tissue in vivo, outside of the laboratory. Professor Joseph Mizrahi, chairman of

Technion's Biomedical Engineering Department, together with Dr. Dror Seliktar invented a new type of

bioreactor, which produces the mechanical stimulation that is necessary for building the tissue. As Dr.Mizrahi explains, "The basis is a polymer that serves as a scaffold within which we implant the cells.

The polymer solidifies, thus enabling transfer of mechanical loads to the cells, which then begin to

create protein. Eventually, this protein replaces the polymer scaffold which wears away." Dr. Seliktaradds that the "scaffold" is engineered to degrade during the dynamics of the protein production, since,

"The scaffold becomes superfluous when the protein is created," he explains. The research was

conducted in collaboration with Dr. Jennifer Elisseeff from The Johns Hopkins University in the

Baltimore, MD, who succeeded in growing fetal stem cells in goat tissue in such a manner that bone cell

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development is simulated. "We want to direct the basic, primitive cell to develop into a cartilage cell or

a bone cell," explains Prof. Mizrahi. "We are researching if existing environmental conditions cause the

cell to become a cartilage or bone cell."

It is commonly understood that the naturally regenerative ability of cartilage tissue when damaged is

extremely limited and virtually non-existent in adults. Several independent researchers have found thatstem cells from muscle can also be coaxed to repair cartilage, however. As previously described,

damage to articular cartilage (cartilage covering the ends of bones where they meet in a joint) is a

frequent occurrence due to injury, illness and natural aging, and is a common cause of degenerative

osteoarthritis. While conventional treatments are problematic, the new field of stem cell therapy has

shown repeated success in the targeted repair of specific sites of damaged articular cartilage.

Numerous studies also indicate that muscle tissue constitutes a previously unrecognized source of stem

cells that can be "reprogrammed" to develop into a variety of cells, including cartilage and bone cells. Ina study published in the February 2006 issue of Arthritis and Rheumatism, researchers designed a study

in which muscle-derived stem cells (MDSCs) were engineered with a therapeutic protein in order to

repair articular cartilage defects in rats. The research was led by Johnny Huard, PhD, director of theGrowth and Development Laboratory at Children's Hospital of Pittsburgh and an associate professor in

the departments of Orthopaedic Surgery and Molecular Genetics and Biochemistry and Bioengineering

at the University of Pittsburgh School of Medicine. The study involved the use of 12-week-old rats,

demonstrating that skeletal muscle is a readily available and promising source of stem cells which candifferentiate into cartilage. As Dr. Huard describes, "The MDSCs used here served as good carriers of a

therapeutic gene and enabled the delivery of appropriate amounts of BMP-4 protein to the injury site."

The findings show great promise in the repair of articular cartilage. (From, "Cartilage Repair UsingBone Morphogenetic Protein 4 and Muscle-Derived Stem Cells," Ryosuke Kuroda, Arvydas Usas, Seiji

Kubo, Karin Corsi, Hairong Peng, Tim Rose, James Cummins, Freddie H. Fu, Johnny Huard, Arthritis

and Rheumatism, February 2006; 54:2; pp. 433-442).

In an accompanying editorial in the same issue, Dr. Mary B. Goldring, of the New England Baptist Boneand Joint Institute and Harvard Medical School in Boston, Massachusetts, points out the significance of

Dr. Huard's study as the first to investigate enriched stem cells from muscle in the treatment of damaged

cartilage. Dr. Goldring also acknowledged that the study "provides proof-of-principle for performingMDSC implantation in cartilage of adult humans, since 12-week-old rats are considered to be young

adults." Although other studies have suggested that the tissue lining the space between joints (the

synovium) might also be a source of stem cells, obtaining these cells is more invasive than musclebiopsies. Dr. Goldring also notes that patients could potentially serve as their own donors, although she

agrees that, "Further work is warranted to determine the chondroprogenitor potential of MDSCs in adult

humans and their capacity to form cartilage in vivo." (From, "Are Bone Morphogenetic ProteinsEffective Inducers of Cartilage Repair? Ex Vivo Transduction of Muscle-Derived Stem Cells," Mary B.

Goldring, Arthritis and Rheumatism, February 2006; 54:2; pp. 387-389).

While stem cells derived from muscle represent some of the newer areas of research in cartilage repair,

stem cells derived from fat, bone marrow and cord blood have long-established and well documentedhistories in the successful repair and regeneration of cartilage. The richest stem cell source of all,however, remains cord blood, which logically exhibits the greatest capacity for the repair and

regeneration of any tissue.

With stem cell therapy, it is now possible for entire joints to be relined with new cartilage that has beenbio-engineered to specific parameters. Sufferers of osteoarthritis may now regain their strength and

mobility, free of pain, with newly developed methods of stem cell treatment.

According to the website of the National Institute of Arthritis and Musculoskeletal and Skin Diseases

(NIAMS), a division of the National Institutes of Health (NIH),

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"In 2004, NIAMS and other institutes and offices of the NIH began recruiting participants for the

Osteoarthritis Initiative (OAI). The OAI is a collaboration that pools the funds and expertise of the NIHand industry to hasten the discovery ofosteoarthritis biomarkers: physical signs or biological substances

that indicate changes in bone or cartilage. Researchers are collecting images and specimens from

approximately 5,000 people at high risk of having osteoarthritis as well as those at high risk ofprogression to severe osteoarthritis during the course of the study. Scientists are following participants

for 5 years, collecting biological specimens (blood, urine, and DNA), images (X-rays and magnetic

resonance imaging scans), and clinical data annually. For updates on this initiative, go to

www.niams.nih.gov/ne/oi."

On August 1st of 2006, the NIH issued a press release informing the public that the first set of data from

the OAI is now available. A description of the study may be viewed at the website of the Johns Hopkins

Arthritis Center, and data on participants is accessible on the website of the University of California at

San Francisco (UCSF).

Although The United Nations, the World Health Organization and 37 countries have proclaimed 2000 to

2010 as the "Bone and Joint Decade", individual countries have also proclaimed their own decades inwhich extra research would be dedicated to bone and joint health. In the United States, 2002 to 2011 was

declared the "National Bone and Joint Decade." In proclaiming this Decade, President George W. Bush

made the following declaration:

"Bones, joints and connective tissue are the structure upon which all other systems of the body depend.

They give us strength, mobility, protection and stability. Our musculoskeletal structure is a complexsystem of tissue and bone that is regularly subjected to trauma, metabolic and genetic processes, and the

gradual wear and tear of an active life. In the U.S., musculoskeletal disorders are a leading cause of

physical disability. Such conditions also affect hundreds of millions of people around the world."

"The National Bone and Joint Decade, 2002-2011, envisions a series of international initiatives amongphysicians, health professionals, patients, and communities, working together to raise awareness about

musculoskeletal disorders and promoting research and development into therapies, preventative

measures, and cures for these disorders. Advances in the prevention, diagnosis, treatment, and research

of musculoskeletal conditions will greatly enhance the quality of life of our aging population."

"The National Institutes of Health, the National Institute of Arthritis and Musculoskeletal and Skin

Diseases, and other Federal agencies support many bone and joint studies. Industry and privateprofessional and voluntary agencies support other initiatives. This work involves scientists examining

the possible genetic causes of bone and joint diseases and studying how hormones, growth factors, and

drugs regulate the skeleton. Other researchers are studying bone density, quality, and metabolism, and

other ways to increase the longevity of joint replacements for those whose daily activities have becomepainful, difficult, or even impossible. These research efforts can help relieve pain and suffering and give

countless children and adults the opportunity for a better life. Thanks to the hard work of these dedicated

researchers, we have made great progress in understanding and treating musculoskeletal disorders. I

commend their efforts and encourage them to pursue diligently further research that will help thosesuffering from these disorders. And I hope that all Americans will learn more about musculoskeletal

problems, their long- and short-term effects, and the therapies and treatments available to help them."

From the website of the White House.

Musculoskeletal diseases such as osteoarthritis are recognized internationally not only as problems thatimpact individual lives, but also as problems that impact national economies. Such a global call for the

effective treatment of these diseases represents an important political policy today, but it will acquire a

tone of increasing urgency as the global population continues to age.

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In the treatment of all forms of arthritis, especially osteoarthritis, stem cells offer a potentially useful

therapy.

Increased knee cartilage volume in degenerative joint disease using

percutaneously implanted, autologous mesenchymal stem cells.

Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D.

Abstract

BACKGROUND: The ability to repair tissue via percutaneous means may allow interventional pain

physicians to manage a wide variety of diseases including peripheral joint injuries and osteoarthritis.

This review will highlight the developments in cellular medicine that may soon permit interventionalpain management physicians to treat a much wider variety of clinical conditions and highlight an

interventional case study using these technologies

OBJECTIVE: To determine if isolated and expanded human autologous mesenchymal stem cells could

effectively regenerate cartilage and meniscal tissue when percutaneously injected into knees.

DESIGN: Case Study

SETTING: Private Interventional Pain Management practice.

METHODS: An IRB approved study with a consenting volunteer in which mesenchymal stem cells

were isolated and cultured ex-vivo from bone marrow aspiration of the iliac crest. The mesenchymalstem cells were then percutaneously injected into the subject's knee with MRI proven degenerative joint

disease. Pre- and post-treatment subjective visual analog pain scores, physical therapy assessments, and

MRIs measured clinical and radiographic changes.

RESULTS: At 24 weeks post-injection, the patient had statistically significant cartilage and meniscus

growth on MRI, as well as increased range of motion and decreased modified VAS pain scores.

CONCLUSION: The described process of autologous mesenchymal stem cell culture and percutaneous

injection into a knee with symptomatic and radiographic degenerative joint disease resulted in

significant cartilage growth, decreased pain and increased joint mobility in this patient. This has

significant future implications for minimally invasive treatment of osteoarthritis and meniscal injury.

PMID: 18523506 [PubMed - indexed for MEDLINE]Free Article

Tel:(949) 367-8870 ~ Fax:(949) 367-9779 ~ Toll Free: 1-800-900-1063

26381 Crown Valley Parkway, Suite 130 ~ Mission Viejo, California 92691 ~ WWW.STEMCELL.MD

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Centeno%20CJ%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Busse%20D%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Kisiday%20J%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Keohan%20C%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Freeman%20M%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Karli%20D%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Karli%20D%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Freeman%20M%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Keohan%20C%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Kisiday%20J%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Busse%20D%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Centeno%20CJ%22%5BAuthor%5D