Discoveries
Regenerative Medicine for Orthopedics
More than 500 million people worldwide live with osteoarthritis, a degenerative joint disease that causes severe, debilitating pain and often requires surgery or joint replacement. Cedars-Sinai is pioneering breakthroughs in regenerative medicine that offer hope for far less invasive and nonsurgical procedures for treating the condition. Investigators aim to bring the long-awaited promise of stem cell or platelet-rich plasma injections to life to reduce inflammation and pain, promote healing in joints and the spine, and generate new tissue to replace worn and torn tendons and ligaments.
“There is an epidemic of back pain and rotator cuff tears. It is so disabling, and the burden to our society is huge,” said orthopedic surgeon Bert Mandelbaum, MD, vice chair of the department of Orthopaedic Surgery at Cedars-Sinai and co-director of the Regenerative Orthobiologic Center at the Cedars-Sinai Board of Governors Regenerative Medicine Institute. “Our focus is on developing a family of orthobiologics that can improve symptoms and increase function and lifespan.”
Patients are already seeking regenerative medicine care for orthopedics more than for any other condition. With so many promising applications, the field is predicted to grow significantly in coming years.
Can Stem Cells Fix Back Pain?
Disc degeneration is a common cause of chronic back pain, and existing treatments can be invasive and ineffective.
“The difficulty is that even with sophisticated imaging equipment, it can be hard to identify the source of the pain,” said Dmitriy Sheyn, PhD, a research scientist at the Regenerative Medicine Institute. “Sometimes surgeons will remove multiple discs, because they do not know which one is causing the problem.”
Sheyn’s laboratory is working to develop biomarkers to help surgeons more accurately identify the source of discogenic pain. But the ultimate goal, he says, is to develop an injectable therapy that eliminates the need for surgery.
More than 500 million people worldwide are affected by osteoarthritis. It’s such a burden to our society.”
— Dr. Bert Mandelbaum
To that end, Sheyn is engineering induced pluripotent stem cells (iPSCs) to become the cells that compose the disc.
“The idea is to put these young cells into old discs, enabling regeneration,” he said.
The laboratory has had success injecting the iPSCs into small animals and is now conducting research in larger animal models that provide a better comparison to human physiology.
The team has also developed biobehavioral tests—similar to neurological tests for people—to help determine whether the treatment improves an animal’s pain.
“It is an exciting and important tool,” said Sheyn, “because we currently rely on imaging to determine if the problem is repaired. However, getting feedback from the animal would have much greater value.”
Less Invasive Treatments for OA and Beyond
About 1 in 5 U.S. adults have some form of arthritis—most commonly osteoarthritis (OA), which usually impacts the knees as people age. More than half of those with OA in their knees will undergo total knee replacements.
Platelet-rich plasma (PRP) is becoming increasingly popular as a treatment for OA in the knees and other orthopedic injuries such as torn muscles, tendons and ligaments. The problem, according to Sheyn, is that there is a lack of scientific evidence for PRP’s efficacy and mechanisms of action.
To better understand and guide the development of PRP therapy, Sheyn’s laboratory conducted a trial of 30 participants with knee OA.
“We performed cellomics and proteomics on the PRP to sift through which components may be beneficial and which might actually have an adverse effect,” he said.
The study provided insights into the detrimental effect of certain immune cells and the positive effect of some proteins in PRP, but a larger study is needed to get more actionable answers. Now, the Cedars-Sinai Board of Governors Regenerative Medicine Institute has partnered with the Cleveland Clinic and the Mayo Clinic to gather PRP samples from about 1,000 patients. Sheyn’s laboratory will analyze the samples to see if this larger cohort can shed light on which proteins in PRP are most effective at reducing pain and symptoms and improving quality of life.
In addition, Sheyn’s laboratory is using iPSC treatments to prevent a particular form of knee OA that can develop later in life after early knee injuries—a syndrome often experienced by athletes.
“We differentiate iPSCs into anti-inflammatory macrophages,” he explained. “We think that if we treat the knee right after an injury or reconstruction with these macrophages, we can in turn suppress inflammation faster and prevent later-onset arthritis.”
Read: Soothing Joints
Making New Tendons and Ligaments
Tendon and ligament injuries, such as torn rotator cuffs, anterior cruciate ligaments (ACLs) and Achilles tendons, make up about 50% of musculoskeletal injuries. Stem cell technology holds great promise for restoring them.
Surgically repaired tendons develop fibrosis, or scar tissue, which is not as flexible as a true tendon.
“The repaired tendon will not allow the body to perform as before, and it has a high chance of re-tearing,” Sheyn said.
His laboratory is working to build new replacement tendons by differentiating iPSCs into tendon cells, or iTenocytes.
The work is delicate, since a tendon’s qualities are challenging to re-create, and since tendons play different roles based on their location in the body.
“If it is too elastic, then the muscle will move the tendon, but it will not move the bone,” said Sheyn. “And if it is too stiff, then range of motion may be insufficient.”
There Is No Time to Waste
Orthopedic applications for regenerative medicine lag behind a number of other medical fields, Mandelbaum said. Cell therapies are already approved by the U.S. Food and Drug Administration to treat some blood cancers and autoimmune-related diseases, and clinical trials are testing the use of stem cells in disorders of the nervous system and Type 1 diabetes.
Mandelbaum feels optimistic that orthopedic patients will have more options within the decade.
“I think within the next five years, maybe seven, we will have treatments and clinical studies ready to go,” he said.
