European Knee Meniscus Injury Pilot Trial to Evaluate Cytori Cell Therapy Begins


Cytori Therapeutics is a cell therapy company that is in the process of developing cell therapies from a patient’s own fat tissue that can potentially treat a variety of medical conditions. To date, the preclinical studies and clinical trials suggest that their Cytori Cell Therapy can improve blood flow, modulate the immune system, and facilitating wound repair.

Recently, Cytori has announced that it has enrolled its first patients in an ambitious clinical trial that will test their stem cell product in patients undergoing surgery for traumatic injuries to the meniscus of the knee.  The meniscus is a wedge of cartilage on either side of the knee joint that acts a a shock absorber between the femur and the head of the tibia.

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Ramon Cugat, who is the Co-Director of the Orthopedic Institute, Hospital Quiron Barcelona, Spain, is the principal investigator for this trial. Dr. Cugat serves as an orthopedic surgeon at Hospital Quiron Barcelona. This trial will test the ability of Cytori Cell Therapy to heal the meniscus and is being conducted in parallel with a similar trial that is testing the Cytori Cell Therapy as a treatment for anterior cruciate ligament (ACL) repairs. The patients treated with Cytori Cell Therapy for ACL repairs are still being evaluated, but to date, no safety related concerns have emerged and the patients seem to have improved. These preliminary results were presented at the Barcelona Knee Symposium in November 2014.

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“Dr. Cugat is a leading expert in treating traumatic knee injuries in elite athletes,” said Dr. Marc H. Hedrick, President and CEO of Cytori Therapeutics. “These trials are important to Cytori because, at minimal cost to us, they provide additional clinical evidence that our therapy can be safely used in treating a multitude of knee conditions.”

The meniscus trial is a two-center, phase I study that will assess the safety and efficacy of Cytori’s ECCM-50 adipose-derived regenerative cell therapy in meniscus repair. In this trial, up to 60 patients who have had meniscus surgery to repair the meniscus will receive injection of the cells directly into the meniscus. Each patient will be evaluated by several clinical read outs that assess the recovery of the patient after meniscus surgery. As in the case of the ACL repair study, the goal of this trial is to determine if Cytori Cell Therapy can be safely delivered to the meniscus and whether efficacy can be observed.

“Tears to the meniscus are problematic injuries for active individuals, particularly athletes. Based on the early results from a recent series of 20 patients treated for complete anterior cruciate ligament injuries, we are eager to evaluate whether augmentation surgery with Cytori Cell Therapy will lead to quicker and more complete healing,” said Dr. Cugat.

Injected patients will fill out a patient questionnaire that assesses knee pain, function and activity, This questionnaire is called the Knee Injury and Osteoarthritis Outcome Score (KOOS), but patients will also be physically examined to ascertain the extent of their knee function and the degree of their movement, with or without pain. Patients will be given a visual analogue score to assess knee pain, and knee function will be assessed by the Lysholm Knee Scoring Scale, Tegner Activity Scale, and the Lower Extremity Functional Scale. Each patient will also have their knees examined by Magnetic Resonance Imaging (MRI) in order to examine the structural integrity of their meniscus. These assessments will be taken before and 60, 90, 180 and 365 days after surgery and the MRIs will be done before and at 90, 180 and 365 days after surgery.

The preliminary results of the ACL study showed that the Cytori strategy was feasible and did not result in any significant safety issues above that seen with a standard small volume liposuction. All the injected patients recovered without any complications. The results of the ACL trial were compared to a historical control group of patients who had the same surgical procedure by the same surgical team but without other interventions. Overall, the patient’s recovery from pain and their ability to return to daily activities was accelerated as a result of the therapeutic enriched bone-patellar tendon-bone transplant. Both the patient questionnaires and serial MRI scans of the knees following cell therapy were consistent with accelerated healing of the graft. Presently, Dr. Cugat and his coworkers are obtaining one year follow-up information on the treated patients and they will report their data in a peer-reviewed journal in the future.

ACL and meniscus tears are among the most common sports-related knee injuries and unfortunately, these two injuries often are sustained simultaneously. According to the American Academy of Orthopedic Surgeons, ACL injuries have an annual incidence of more than 200,000 cases with nearly half undergoing surgical reconstruction. Further, an estimated 850,000 patients undergo surgical procedures to address meniscus injuries each year.

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3-D Printed Meniscus Regenerated Meniscus in Sheep


Within the knee-joint, on either side, is a cartilage shock absorber called the meniscus. Tears to this structure can cause pain and swelling in the knee and erosion of the meniscus can lead to bone-on-bone joints that abrade the bone and cause further inflammation and osteoarthritis. Because the meniscus is made of cartilage, and since cartilage can be grown in the laboratory, it should be possible, in theory, to make a new meniscus. Researchers at Columbia University Medical Center have succeeded in using 3-D printing to do that just.

The laboratory of Jeremy Mao used made personalized 3-D implants made from a scaffold infused with human growth factors. When implanted into the knee, these growth factors stimulate the body to regenerate the meniscus on its own. Mao and his coworkers successfully tested their treatment strategy in sheep. Their procedure could provide the first effective and long-lasting way to repair of damaged menisci, which occur in millions of Americans each year and can lead to debilitating arthritis. This work from the Mao lab was published in Science Translational Medicine.

“At present, there’s little that orthopedists can do to regenerate a torn knee meniscus,” said Mao, who is the Edwin S. Robinson Professor of Dentistry (in Orthopedic Surgery) at the Medical Center. “Some small tears can be sewn back in place, but larger tears have to be surgically removed. While removal helps reduce pain and swelling, it leaves the knee without the natural shock absorber between the femur and tibia, which greatly increases the risk of arthritis.”

Heavily damaged menisci can be replaced with a meniscal transplant that utilizes tissue from other parts of the body or from cadavers. Such transplants, however, have a low success rate and carries significant risks. Approximately one million meniscus surgeries are performed in the United States each year.

Mao and his colleagues began with MRI scans of the intact meniscus in the undamaged knee. Special computer software then converts these high-resolution scans in to a 3D image. Data from these images are then used to drive a 3D printer, which produces a scaffold in the exact shape of the meniscus, all the way down to a resolution of 10 microns, which is less than the width of a human hair. The scaffold takes about 30 minutes to print and is made from an organic polymer called polycaprolactone, which is the same biodegradable polymer used to make surgical sutures.

The printed scaffold is infused with two recombinant human proteins: connective growth factor (CTGF) and transforming growth factor β3 (TGFβ3). In earlier work, Mao’s team discovered that sequential delivery of these two proteins attracts resident stem cells from the body and induces them to form meniscal tissue.

In order for a meniscus to properly form, these growth factors must be released from specific areas of the scaffold and in a specific order. To accomplish this, the growth factors were encapsulated in two types of slow-dissolving polymeric microspheres. The first of these microspheres released CTGF, which stimulates the production of the outer meniscus. The second microspheres release TGFβ3, which induces the production of the inner meniscus. Finally, this protein-infused scaffold is inserted into the knee so that it can direct the generation of a new meniscus. When these printed, growth factor-infused scaffolds were implanted into the knees of sheep, the meniscus regenerated in approximately four to six weeks. The implanted, biodegradable scaffold eventually disintegrates.

“This is a departure from classic tissue engineering, in which stems cells are harvested from the body, manipulated in the laboratory, and then returned to the patient—an approach that has met with limited success,” said Mao. “In contrast, we’re jumpstarting the process within the body, using factors that promote endogenous stem cells for tissue regeneration.”

“This research, although preliminary, demonstrates the potential for an innovative approach to meniscus regeneration,” said co-author Scott Rodeo, sports medicine orthopedic surgeon and researcher at Hospital for Special Surgery in New York City. “This would potentially be applicable to the many patients who undergo meniscus removal each year.”

Mao and others tested their procedure in 11 sheep. Even though they are four-legged creatures, sheep knees closely resemble that of humans, and therefore, as an excellent model system for orthopedic research. These animals were randomized to have part of their knee meniscus replaced with a protein-infused 3D scaffold (the treatment group) or a 3D scaffold that was not infused with growth factors (the nontreatment group). After three months, the treated animals all walked normally. A postmortem analysis of the treated animals demonstrated that the regenerated meniscus in the treatment group had structural and mechanical properties very similar to those of natural meniscus. Mao’s laboratory is now conducting studies to determine whether the regenerated tissue is long-lasting.

“We envision that personalized meniscus scaffolds, from initial MRI to 3D printing, could be completed within days,” said Mao. The personalized scaffolds will then be shipped to clinics and hospitals within a week. The researchers hope to begin clinical trials once funding is in place.

“These studies provide clinically valuable information on the use of meniscal regeneration in the knees of patients with torn or degenerate menisci,” said co-author Lisa Ann Fortier, professor of large animal surgery at Cornell University College of Veterinary Medicine in Ithaca, N.Y. “As a veterinary orthopedic surgeon-scientist on this multi-disciplinary team, I foresee the added bonus of having new techniques for treating veterinary patients with torn knee meniscus.”

Stem Cell Therapy Following Meniscus Knee Surgery Reduces Pain and Regenerates Meniscus


According to a new study published in the January issue of the Journal of Bone and Joint Surgery (JBJS), a single stem cell injection after meniscus knee surgery can provide pain relief and aid in meniscus regrowth.

In the US alone, over one million knee arthroscopy procedures are performed each year. These surgeries are usually prescribed to treat tears to the wedge-shaped piece of cartilage on either side of the knee called the “meniscus.” The meniscus acts as an important shock absorber between the thighbone (femur) and the shinbone (tibia) at the knee-joint.

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This novel study, “Adult Human Mesenchymal Stem Cells (MSC) Delivered via Intra-Articular Injection to the Knee, Following Partial Medial Meniscectomy,” examined 55 patients who had undergone a surgical removal or all or part of a torn meniscus (known as a partial medial meniscectomy). Each patient was randomly assigned to one of three treatment groups: Groups A, B and C. The 18 patients in group A received a “low-dose” injection of 50 million stem cells within seven to 10 days after their meniscus surgery. Another 18 patients in group B received a higher dose of 150 million stem cells seven to ten days after their knee surgery. The controls group consisted of 19 patients who received injections of sodium hyaluronate only (no stem cells). All patients were evaluated to determine the safety of the procedure, the degree of meniscus regeneration (i.e. with MRI and X-ray images), the overall condition of the knee-joint, and the clinical outcomes through two years. Most of the patients enrolled in this study had some arthritis, but patients with severe (level three or four) arthritis, were excluded from the study.

Most of the patients who had received stem cell treatments reported a significant reduction in pain. 24 percent of the patients in one MSC group and 6 percent of the other showed at least a 15 percent increase in meniscal volume at one year. Unfortunately, there was no additional increase in meniscal volume at year two.

“The results demonstrated that high doses of mesenchymal stem cells can be safely delivered in a concentrated manner to a knee-joint without abnormal tissue formation,” said lead study author C. Thomas Vangsness, Jr., MD. “No one has ever done that before.” In addition, “the patients with arthritis got strong improvement in pain” and some experienced meniscal regrowth.

The key findings of this study are that there no abnormal (ectopic) tissue formation or “clinically important” safety issues identified. Also, 24 percent of the patients in the low-dose injection group (A) and six percent of the high-dose injection group (B) at one year showed “significantly increased meniscal volume,” as determined by an MRI, and this increase did not continue into the second year, but remained stable (should future studies try a second injection of MSCs?). Third, none of the patients in the control group (non-MSC group) showed significant meniscus regrowth. Finally, patients with osteoarthritis experienced a reduction in pain in the stem cell treatment groups, but there was no reduction in pain in the control (non-MSC group).

“The results of this study suggest that mesenchymal stem cells have the potential to improve the overall condition of the knee joint,” said Dr. Vangsness. “I am very excited and encouraged” by the results. With the success of a single injection, “it begs the question: What if we give a series of injections?”