RepliCel Injects Their Final Subject in Their Tendon Repair Clinical Trial


RepliCel Life Sciences Inc., a biotechnology company based in Irvine, California, has reported the administration of the final injection in its phase 1 safety trial of their proprietary product RCT-01 in the treatment of patients with chronic Achilles tendinopathy.

RepliCel’s RCT-01 consists of cells taken from a patient’s own hair follicles. These “non-bulbar dermal sheath” or NBDS cell are isolated from the hair follicle sheath and expanded in culture.

nbds-cells-follicle

In this clinical trial, the NBDS cells are used to treat patients with chronic tendinosis, a condition caused by acute and chronic tendon overuse. RepliCel has received Health Canada Clearance and UBC Ethics approval to conduct its Phase 1/2 clinical trial for the treatment of chronic Achilles tendinosis. The RCT-01 chronic Achilles tendinosis clinical research study will take place at the University of British Columbia in Vancouver, BC.

RepliCel’s Phase 1/2 trial will enroll 28 subjects, all of whom suffer from chronic tendinosis and have failed traditional tendon treatments, but are, otherwise, in good health.

NBDS cells will be isolated from a small punch biopsy taken from the back of the scalp, expanded in culture and then reintroduced into the wounded tendons under the guidance of ultrasound. After these injections, all subjects will return to the clinic for assessments of safety, function and pain, as well as changes in tendon thickness, echotexture, interstitial tears and neovascularity.

Since the last patient has been injected with their own NBDS cells, the last scheduled patient visit to collect treatment follow-up data will be in late November. All data from this trial will be assessed for clinical safety of NBDS cells and six-month efficacy. These data should be un-blinded and made available for analysis and dissemination near the end of this year. year-end.

This trial is designed to ascertain the signs of efficacy but it is simply not statistically powerful enough to draw any strong conclusions about efficacy.

“What we are looking for is a convincing signal, in at least some of the treated patients, that the product has clinically relevant outcomes in terms of restoration of function, reduction of pain, and/or regeneration of the tendon structure as measured by ultrasound imaging,” said RepliCel’s Rolf Hoffmann.

Data from this trial, will, however, inform and guide RepliCel’s product development and clinical trial strategy not only for Achilles tendinopathy but also for several other tendon repair applications including the treatment of jumper’s knee, golfer’s elbow, tennis elbow, and rotator cuff.

RCT-01 contains, largely, type 1 collagen-expressing fibroblasts derived from the hair follicle. These NBDS fibroblasts have the potential to address many clinical conditions that result from a deficiency of active fibroblast cells, which are required for tissue remodeling and repair.

NBDS fibroblast cells, isolated from healthy hair follicles, are a rich source of fibroblasts unique in their high-level expression of the necessary proteins, such as Type I collagen, which can jump-start the stalled healing cycle.

RepliCel is in the process of developing a series of products from this platform that have the potential to address large commercial markets in the areas of musculoskeletal and skin-related conditions.

Phase I Clinical Trial of Fat-Based Mesenchymal Stem Cells for Severe Osteoarthritis


In the July 2016 edition of the journal Stem Cells Translational Medicine, a report has been published that lays out the results of a phase I clinical trial that used mesenchymal stem cells from a patient’s own fat tissues to treat osteoarthritis of the knee.  This study was not placebo controlled, but did examine the effects of escalated doses on the patient.  The main  investigator for this trial was Dr. Christian Jorgensen from Lapeyronie University Hospital in Montpellier, France.

Osteoarthritis (OA) is the most common musculoskeletal condition in adults and it can cause a good deal of pain and disability.

Joints like the knee consist of a junction between two or more bones.  The ends of these bones are capped by layer of cartilage called “hyaline cartilage” that serves as a shock absorber.  Larger joints like the knee, shoulder, and hip are encased in a sac called the “bursa” that is filled with lubricating synovial fluid.

Knee

OA involves damage and/or destruction of the cartilage caps at the ends of long bones, and erosion and ultimately permanent changes in the structure of bone that underlies the cartilage at the end of the bone. The knee loses its shock absorbers and lubricators and becomes a grinding, inflamed, painful caricature of its former self.

To treat OA, most orthopedic surgeons will replace the damaged knee with an artificial knee that is attached the upper (femur) and lower (tibia and fibula) bones of the leg.  This procedure, arthroplasty, reconstructs the knee with artificial materials that form synthetic joints.  Alternatively, some enterprising physicians have tried to use stem cells from bone marrow to repair eroded cartilage in the knees of OA patients.  Christopher Centeno and his colleagues at his clinic near Denver, CO and affiliated sites have pioneered procedures for OA patients.  However, Dr. Centeno remains skeptical of the ability of stem cells from fat to treat patients with OA.

In animal studies, OA of the knee can be induced by injected tissue-destroying enzymes.  If laboratory mice that received injectionof these enzymes into their knees are then treated with fat-based mesenchymal stem cells, the effects and symptoms of OA do not appear (ter Huurne M, et al. Arthritis Rheum 2012; 64:3604-3613).  In another study in rabbits, injections of 2-6 million fat-derived mesenchymal stem cells into the knee-joint of rabbits suffering from OA improved cartilage health and inhibited cartilage degradation.  These administered cells also reduced inflammation in the knee (Desando G., et al., Arthritis Res Ther 2013; 15:R22).  Therefore, fat-based mesenchymal stem seem to have some ability to ameliorate the effects and consequences of OA, at least in preclinical studies.  This trial is the beginnings of what will hopefully be a series of experiments that will assess the ability (or inability) to treat OA patients.

18 patients were enrolled from an initial pool of 48 candidates who all suffered from severe, symptomatic OA of the knee.  Six patients received 2 million mesenchymal stem cells isolated from their own fat, 6 others received ten million mesenchymal stem cells isolated from their own fat, and the final group of 6 OA patients received 50 million mesenchymal stem cells isolated from their own fat tissues.  These mesenchymal stem cells were isolated from the patient’s fat that was collected by means of liposuction.  The fat was then processed by means of a standard protocol that is used to isolated mesenchymal stem cells from human fat (see Bura A, et al., Cytotherapy 2014; 16:245-257).  All patients received their stem cells by means of injection into the knee-joint (inter-articular injections).

Because this is a Phase I clinical trial, assessing the safety of the procedure is one of the main goals of this study.  No adverse effects were associated with either the liposuction or the interarticular injections.  The article even states: “Laboratory tests, vital signs and electrocardiograms indicated no local or systemic safety concerns.”. Four patients experienced slight knee pain and joint effusion that either resolved by itself or with treatment with a nonsteroidal antinflammatory drug (think ibuprofen).  Therefore it seems fair to conclude that this procedure seems safe, but a larger, placebo-controlled study is still required to confirm this.

As to the patient’s clinical outcomes, 17 of the 18 patients elected to forego total knee replacement.  All patients showed improvement in pain and knee functionality at 1 week, 3 months and 6 months after the procedure.  However, only the low-dose group showed improvements that were statistically significant.

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WOMAC pain and function improvement during the study (WOMAC = Western Ontario and McMaster Universities Arthritis Index)

WOMAC pain and function improvement during the study. Abbreviation: WOMAC, Western Ontario and McMaster Universities Arthritis Index.

Seven of the patients treated in Germany (11 patients were treated in France and 7 were treated in Germany) were also examined with Magnetic Resonance Imaging (MRI) before and 4 months after the procedure.  Six of the seven patients showed what could be interpreted as improvements in cartilage.

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dGEMRIC and T1rho magnetic resonance imaging (MRI) of selected patients. The graphs on the left show the dGEMRIC (n = 6) and T1rho (n = 5) values before and 4 months after cell therapy. Increasing dGEmRIC and decreasing T1rho values are each known to correspond to increasing glycosaminoglycan/proteoglycan content and thus improved cartilage condition. On the right, the corresponding dGEMRIC and T1rho maps are shown as a color-coded overlay on an anatomical MRI for a patient receiving a low cell dose. The observed values in the cartilage change in the time course can be easily seen and correspond to an increase in cartilage condition. Abbreviation: dGEMRIC, delayed gadolinium-enhanced magnetic resonance imaging of cartilage.

Tissue biopsies of 11 of the 18 patients revealed an absence of significant inflammation, but some patients (4-5) showed signs of weak or moderate inflammation.  One patient showed what seemed to be a sheet of MSC cells on the surface of the cartilage.

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Histologic findings. (A): Vascular congestion and weak lymphocytic infiltrate of the synovial (case 8) (magnification, ×50). (B): Osteoarthritic cartilage OARSI grade >3 (case 4) (×25). (C): Toluidine blue staining (case 2) (magnification, ×100). (D): Stem cell stroma shows an Alcian blue depleted matrix compared with the strong staining of osteoarthritic cartilage (case 2) (magnification, ×100). (E): Weak PS100 staining of possible stem cells on the cartilage surface and strong PS100 staining of chondrocytes (case 2) (magnification, ×100). Abbreviations: OARSI, Osteoarthritis Research Society International.

The primary outcome of this study – the safety of interarticular injections of fat0-based mesenchymal stem cells – seems to have been satisfied.  This is similar to the safety profiles of such cells in clinical trials that have used fat-based mesenchymal stem cells to treat fistulae in inflammatory bowel disease (Bura A, et al., Cytotherapy 2014; 16: 245-257) or critical limb ischemia (Lee WY and others, Stem Cells 2013; 31:2575-2581).  Also, patients showed improvements in pain and functionality.  Even though there was no placebo in this study, a double-blinded, placebo-controlled study that examined the use of efficacy of interarticular hyaluronic acid injections showed a smaller decreased in pain score that what was observed in this case (22.9 ± 1.4 vs 30.7 ± 10.7).  It is doubtful that the injected mesenchymal stem cells made much cartilage but instead quelled inflammation and stimulated resident stem cell populations to repair damage in the knee.

This study is small and is not placebo controlled, however, the hopeful results do warrant a larger, phase 1/2 placebo-controlled study that is apparently already underway.

An even more intriguing project might be to prime the isolated mesenchymal stem cells to make cartilage and then use live fluoroscopy to overlay the cells on the actual cartilage lesions.  While this is a more exacting procedure, it is the way Centeno and his group are using stem cells to treat their patients, and a true head-to-head study of the efficacy of fat-based mesenchymal stem cells versus bone marrow-based mesenchymal stem cells would be immensely useful.

RepliCel Skin Rejuvenation and Tendon Repair Trials With Hair Follicle Stem Cells Underway


RepliCel Life Sciences has enrolled subjects for their skin rejuvenation and tendon repair trial.  The primary goal of these trials is to determine the safety of their cell therapeutic products.

NBDS-Cells-Follicle

In the first trial will test a product called RCS-01, which consists of cells derived from non-bulbar dermal sheath (NBDS) cells, which are taken from the outer regions of hair follicles.  NBDS cells express type 1 collagen, a protein that is steadily degraded in aged skin (hence the formation of wrinkles).  Therefore, RepliCel is confident that RCS-01 injections underneath the skin has the potential to rejuvenate aged or damaged skin.  The trial will examine male and female subjects, between 50-65 years old, and will address the inherent deficit of active fibroblasts required for the production of type 1 collagen, elastin and other critical extracellular dermal matrix components found in youthful skin. The trial will be conducted at the IUF Leibniz-Institut für umweltmedizinische Forschung GmbH in Dusseldorf, Germany.  Originally, RepliCel wished to enrolled 15 men and 15 women, but the large number of female subjects and paucity of men persuaded the company to move forward with the trial despite only enrolling a few men and all the projected women.

The second trial will test the safety and efficacy of RCT-01 in the repair of damaged Achilles tendons.  RCT-01 also consists of NBDS cells and this trial is a phase 1/2 clinical trial that examines the ability of NBDS cells to treat chronic tendinosis caused by acute and chronic tensile overuse.  This trial will take place at the University of British Columbia in Vancouver, BC, and will only treat 10 subjects.  Even though RepliCell wishes to originally test 28 participants, the company shorted the trial in order to have safety data by the end of 2016.

Darrell Panich, RepliCel Vice President of Clinical Affairs, said that the company had a late start on its trials, and therefore truncated the recruitment process in order to have safety data for analysis by the end of 2016.  Despite the small size of these trials (and they are small), the company is hopeful that their safety data will provide the impetus for moving forward with larger phase 2 trials.

Panich said, “We have adjusted our plans for the RCT-01 clinical trial in part because it started later in 2015 and enrolled slower than originally anticipated. While the trial did not meet projected enrollment targets, we are confident the safety and preliminary efficacy data obtained by year-end will provide a signal of the product’s potential to regenerate chronically injured tendon that has failed to respond to other treatments. This will allow our teams to effectively plan larger phase 2 trials in 2017 which are powered to be statistically significant for clinical efficacy (evidence the product works as intended).”

“Future trials involving products from our non-bulbar dermal sheath (NBDS) platform will be designed to investigate the efficacy of these products at different dose levels and treatment frequencies while continuing to collect other data that will be used to support eventual RCS-01 and RCT-01 marketing applications by our commercial partners.”

“The delivery of clinical data when promised is important to management”, said R. Lee Buckler, President & CEO, RepliCel Life Sciences Inc. “We have made critical decisions to keep our commitment to the financial community and we believe the data from these trials will facilitate us closing a licensing and co-development deal on one or both of these products similar to the kind we have in place with Shiseido Company for our RCH-01 product,” he added.

RepliCel is confident that their NBDS fibroblast platform will address numerous indications where impaired tissue healing has been stalled due to a paucity of active fibroblasts, which are required for tissue remodeling and repair.  NBDS fibroblasts, isolated from the hair follicles of healthy individuals, are a rich source of fibroblasts and are unique in their ability to express high levels of type 1 collagen and elastin to push-start the healing process.

RepliCel is also developing products from this same platform to address larger commercial markets in the areas of musculoskeletal and skin-related conditions.

Cartilage Cells from Cow Knee Joints Grow New Cartilage Tissue in Laboratory


A research team from Umeå University in Sweden has used cartilage cells isolated from the knee joints of cows engineer joint-specific cartilage. Such a technique might lead to a novel stem cell-based tissue engineering treatment for osteoarthritis.

Hyaline cartilage is a specific type of cartilage found at joints where bones come together. Hyaline cartilage is a tough, pliable shock absorber, but because it is poorly supplied by blood vessels its capacity to regenerate is also poor. Knee injuries and the everyday wear-and-tear wear down cartilage tissue and might lead to a condition called osteoarthritis. In Sweden along, 26.6 percent of all people age 45 years or older were diagnosed with osteoarthritis. According to the Centers for Disease Control, in the United States, osteoarthritis affects 13.9% of adults aged 25 years and older and 33.6% (12.4 million) of those older than 65 in 2005; an estimated 26.9 million US adults in 2005 up from 21 million in 1990 (believed to be conservative estimate). Serious osteoarthritis cases can involve the loss of practically the entire cartilage tissue in the joint. Osteoarthritis causes pain and immobility in patients, but it also burdens society with accumulated medical costs.

“There is currently no good cure for osteoarthritis,” says Janne Ylärinne, doctoral student at the Department of Integrative Medical Biology. “Surgical treatments may help when the damage to the cartilage is relatively minor, whereas joint replacement surgery is the only available solution for people with larger cartilage damage. However, artificial joints only last for a couple of decades, making the surgery unsuitable for young persons. So we need a more permanent solution.”

Fortunately, tissue engineering might provide way to successfully treat osteoarthritis. Ylärinne and his colleagues developed new methods to produce cartilage-like “neotissues” in the laboratory.

Normally, tissue engineering methods that grow cartilage use cartilage-making cells, signaling molecules such a growth factors, and some sort of three-dimensional scaffold that acts as an artificial support system that makes the culture system more realistic for the cells. Unfortunately, such protocols are difficult, inexact, and generate respectable variation in what they produce. Consequently, it is also unclear whether stem cells or primary cells are best suited for cartilage tissue engineering experiments.

In these experiments, Ylärinne and others used primary cow chondrocytes (cartilage-making cells from cows) to which they successfully devised improved methods for growing cartilage tissue in a laboratory environment. The cartilage made by Ylärinne and others is similar to that normally present in the human joints.

Bovine cartilage made in laboratory

In the future, protocols like this one might help the development of neocartilage production for actual cartilage repair. If this protocol or others like it can be adapted to stem cells rather than primary cartilage cells, then perhaps these cells can be grown to provide unlimited amount of material for tissue engineering. However, despite the hopefulness of this research, more research is needed to improve the tissue quality and make it more structurally similar to the hyaline cartilage found at human joints.

Making Cartilage from Umbilical Cord Stem Cells Without Growth Factors


Loïc Reppel and his colleagues at CNRS-Université de Lorraine in France have found that mesenchymal stem cells from human umbilical cord can not only be induced to make cartilage, but that these remarkable cells can make cartilage without the use of exogenous growth factors.

Mesenchymal stromal/stem cells from bone marrow (BM-MSC) have, for some time, been the “all stars” for cartilage regeneration. In fact, a very innovative clinic near Denver, CO has pioneered the use of BM-MSCs for patients with cartilage injuries. Chris Centeno, the mover and shaker, of this clinic has carefully documented the restoration of articular cartilage in many patients in peer-reviewed articles.

However, there is another “kid’ on the cartilage-regeneration block; mesenchymal stromal/stem cells from Wharton’s jelly (WJ-MSC). The advantages of these cells are their low immunogenicity and large cartilage-making potential. In this paper, which was published in Stem Cell Research and Therapy, Reppel and others evaluated the ability of WJ-MSCs to make cartilage in three-dimensional culture systems.

Reppell and his coworkers embedded WJ-MSCs isolated from the umbilical cords of new-born babies in alginate/hyaluronic acid hydrogel and grew them for over 28 days. These hydrogels were constructed by the spraying method. The hydrogel solution (for those who are interested, it was 1.5 % (m/v) alginate and hyaluronic acid (ratio 4:1) dissolved in 0.9 % NaCl) was sprayed an airbrush connected to a compressor. The solution was seeded with WJ-MSCs and then sprayed on a sterile glass plate. The hydrogel was made solid (gelation) in a CaCl 2 bath (102 mM for 10 minutes). Then small cylinders were cut (5 mm diameter and 2 mm thickness) with a biopsy punch. Then Reppel and others compared the chondrogenic differentiation of WJ-MSC in these three-dimensional scaffolds, without adding growth factors with BM-MSC.

Illustration of protocol steps used to perform scaffold construct and chondrogenic differentiation. After monolayer expansion, MSC were seeded at 3× 10 6 cells/mL of Alg/HA hydrogel. Hydrogel was sprayed, gelated, and cut into 5 mm diameter cylinders; scale bar = 5 mm. Scaffolds were cultivated in a 48-well plate in differentiation medium for 28 days. Alg/HA alginate/hyaluronic acid, MSC mesenchymal stromal/stem cells, P3 passage 3
Illustration of protocol steps used to perform scaffold construct and chondrogenic differentiation. After monolayer expansion, MSC were seeded at 3× 10 6 cells/mL of Alg/HA hydrogel. Hydrogel was sprayed, gelated, and cut into 5 mm diameter cylinders; scale bar = 5 mm. Scaffolds were cultivated in a 48-well plate in differentiation medium for 28 days. Alg/HA alginate/hyaluronic acid, MSC mesenchymal stromal/stem cells, P3 passage 3

After 3 days in culture, WJ-MSCs seemed nicely adapted to their new three-dimensional culture system without any detectable damage. From day 14 – 28, the proportion of WJ-MSC cells that expressed all kinds of cell surface proteins characteristic of MSCs (i.e., CD73, CD90, CD105, and CD166) decreased significantly. This suggests that these cells were differentiating into some other cell type.

After 28 days in this scaffold culture, both WJ-MSCs and BM-MSCs showed strong upregulation of cartilage-specific genes. However, WJ-MSCs exhibited greater type II collagen synthesis than BM-MSCs, and these differences were evident at the RNA and protein levels. Collagen II is a very important molecule when it comes to cartilage synthesis because chondrogenesis, otherwise known as cartilage production, occurs when MSCs differentiate into cartilage-making cells known as chondroblasts that begins secreting aggrecan and collagen type II that form the extracellular matrix that forms cartilage. Unfortunately, in order to complete the run to mature cartilage formation, the chrondrocytes must enlarge (hypertrophy), and express the transcription factor Runx2 and secrete collagen X. Unfortunately, WJ-MSCs expressed Runx2 and type X collagen at lower levels than BM-MSCs in this culture system.

Matrix synthesis detected after 28 days of chondrogenic induction. Proteoglycans and total collagen were stained by Alcian blue and Sirius red (a), respectively. To explore the synthesis of various collagens in depth, immunofluorescence (b) and immunohistochemistry staining (c) were performed and detected using fluorescence microscopy and light microscopy, respectively; scale bar = 100 μm. BM-MSC bone marrow-derived mesenchymal stromal/stem cells, WJ-MSC Wharton’s jelly-derived mesenchymal stromal/stem cells
Matrix synthesis detected after 28 days of chondrogenic induction. Proteoglycans and total collagen were stained by Alcian blue and Sirius red (a), respectively. To explore the synthesis of various collagens in depth, immunofluorescence (b) and immunohistochemistry staining (c) were performed and detected using fluorescence microscopy and light microscopy, respectively; scale bar = 100 μm. BM-MSC bone marrow-derived mesenchymal stromal/stem cells, WJ-MSC Wharton’s jelly-derived mesenchymal stromal/stem cells

These experiments only examined cells in culture, which is not the same as placing cells in a living animal, but it is a start. Thus, when they are seeded in the hydrogel scaffold, WJ-MSCs and BM-MSCs, after 4 weeks, were able to adapt to their environment and express specific cartilage-related genes and matrix proteins in the absence of growth factors. In order to properly make cartilage in clinical applications, WJ-MSCs must go the full way and express high levels of Runx2 and collagen X. However, these experiments show that WJ-MSCs, which in the past were medical waste, are a potential alternative source of stem cells for cartilage tissue engineering.

Reppel and his colleagues note in their paper that to improve cartilage production from WJ-MSCs, it might be important to mimic the physiological environment in which chondrocytes normally find themselves. For example, they could apply mechanical stress or even a low-oxygen culture system. Additionally, Reppel and others could apply stratified cartilage tissue engineering. Reppel thinks that they could adapt their spraying method to design new stratified engineered tissues by applying progressive cells and spraying hydrogel layers one at a time.

All in all, cartilage repair based with WJ-MSC embedded in Alginate/Hyaluronic Acid hydrogel will hopefully be tested in laboratory animals and then, perhaps, if all goes well, in clinical trials.

Stem Cell-Based Cartilage Regeneration Could Decrease Knee and Hip Replacements


Work by Chul-Won Ha, director of the Stem Cell and Regenerative Medicine Institute at Samsung Medical Center and his colleagues illustrates the how stem cell treatments might help regrow cartilage in patients with osteoarthritis or have suffered from severe hip or knee injuries.

A 2011 report from the American Academy of Orthopedic Surgeons showed that approximately one million patients in the US alone (645,000 hips and 300,000 knees) have had joint replacements in the U.S. alone. Most joint replacements occur with few complications, artificial joints can only last for a certain period of time and some will even eventually require replacement. Also these procedures require extensive rehabilitation and are, in general, quite painful. A goal for regenerative medicine is the regenerate the cartilage that was worn away to prevent bones from eroding each other and obviate the need for artificial joint replacement procedures.

Extensive research from the past two decades from a whole host of laboratories in the United States, Europe, and Japan have shown that mesenchymal stem cells (MSCs) have the ability to make cartilage, and might even have the capability to regenerate cartilage in the joint of a living organism. MSCs have the added benefit of suppressing inflammation, which is a major contributor to the pathology of osteoporosis. Additionally, MSCs are also relatively easy to isolate from tissues and store.

“Over the past several years, we have been investigating the regeneration potential of human umbilical cord blood- derived MSCs in a hyaluronic acid (HA) hydrogel composite. This has shown remarkable results for cartilage regeneration in rat and rabbit models. In this latest study we wanted to evaluate how this same cell/HA mixture would perform in larger animals,” said Ha.

Ha collaborated with researchers from Ajou University, which is also in Seoul, and Jeju University in Jeju, Korea. Ha and his team used pigs as their model system, which is a better system than rodents for such research.

The stem cells for this project were isolated from human umbilical cord blood that was obtained from a cord blood bank. They isolated MSCs from the umbilical cord blood and grew them in culture to establish three different human Umbilical Cord Blood MSC lines. Then they pelleted the cells and mixed them with the HA solution and applied them to the damaged knee joints of pigs.

“After 12 weeks, there was no evidence of abnormal findings suggesting rejection or infection in any of the six treated pigs. The surface of the defect site in the transplanted knees was relatively smooth and had similar coloration and microscopic findings as the surrounding normal cartilage, compared to the knees of a control group of animals that received no cells. The borderline of the defect was less distinct, too,” said the study’s lead investigator, Yong-Beom Park, who is a colleague of Ha’s at the SungKyunKwan University’s Stem Cell and Regenerative Medicine Institute.

“This led us to conclude that the transplantation of hUCB-MSCs and 4 percent HA hydrogel shows superior cartilage regeneration, regardless of the species. These consistent results in animals may be a stepping stone to a human clinical trial in the future,” Dr. Ha noted.

“These cells are easy to obtain, can be stored in advance and the number of potential donors is high,” said Anthony Atala, M.D., Editor of STEM CELLS Translational Medicine and Director of the Wake Forest Institute for Regenerative Medicine. “The positive results in multiple species, including the first study of this treatment in large animals, are certainly promising for the many patients requiring treatments for worn and damaged cartilage.”

Partial Repair of Full-Thickness Rotator Cuff Tears By Guided Application of Umbilical Cord Blood Mesenchymal Stem Cells


Baseball players, weight lifters, tennis players, basketball players, and other athletes have experienced the pain and frustration of a rotator cuff injury. The rotator cuff is the capsule that surrounds the shoulder joint, in combination with the fused tendons that support the arm at the shoulder joint. A tear in any of these tendons constitute a rotator cuff tear, and it is painful, and debilitating. Furthermore, rotator cuff tears are notoriously slow healing, if they heal at all.

The main option for a rotator cuff tear is microsurgical repair of the tendon. However, as Christopher Centeno at the Regenexx blog points out, sewing together atrophied tissue does not make a lot of sense, and consequently, rotator cuff repairs by means of microsurgery can have a high percentage of re-tearing. Is there a better way?

In the journal Stem Cells and Translational Medicine, Dong Rak Kwon and his two colleagues, Gi-Young Park and Sang Chui Lee, from the Catholic University of Daugu School of Medicine in Daegu, Korea have reported the results of treating whole-thickness rotator cuff tears in rabbits with human umbilical cord blood mesenchymal stem cells (UCB-MSCs). The results are quite interesting.

Kwon and his colleagues broke a colony of New Zealand White rabbits into three groups and surgically subjected all animals to full-thickness tears in the subscapularis tendon. Because rabbits are four-legged creatures, such tears severely compromise their ability to walk, and Kwon and his team measured the ability of these rabbits to walk and the speed at which they walked. All three groups of rabbits showed about the same ability to walk: they walked at about the same speed at for the same distance before giving up.

Human umbilical cord blood-derived mesenchymal stem cell (MSC) and ultrasound images. (A): Human umbilical cord blood-derived MSCs. (B): Injection was made in the left shoulder subscapularis (SCC) full-thickness tears under ultrasound guidance. (C): Longitudinal ultrasound image showed the needle (arrows) in the left shoulder SCC of the rabbit. Abbreviations: S, mesenchymal stem cell; T, tendon.
Human umbilical cord blood-derived mesenchymal stem cell (MSC) and ultrasound images. (A): Human umbilical cord blood-derived MSCs. (B): Injection was made in the left shoulder subscapularis (SCC) full-thickness tears under ultrasound guidance. (C): Longitudinal ultrasound image showed the needle (arrows) in the left shoulder SCC of the rabbit. Abbreviations: S, mesenchymal stem cell; T, tendon.

The first group of rabbits received injections of UCB-MSCs into their rotator cuffs. These injections were guided by ultrasound so that Kwon and his colleagues were able to place the stem cells directly on the damaged tendons. The second group of rabbits received injections of hyaluronic acid (HA), which is a component of connective tissue and the synovial fluid within bursal sacs that surround and lubricated some our joints. The third group received injections of sterile saline into their joints. The animals were then examined four weeks later.

shoulder-joint

The HA- and saline-injected animals showed few changes, but the UCB-MSC-injected animals were able to walk almost twice as far as the other rabbits and almost twice as fast. When the joint tissue of these animals was examined in detail, the HA and saline-injected animals still had full-thickness rotator cuff tears, although the HA-injected animals showed more healing that then the saline-injected rabbits. When the UCB-MSC-injected animals were examined, seven of the ten animals have rotator cuffs that had healed so that the tears could be classified as partial-thickness tears rather than full-thickness tears. Furthermore, a more detailed examination of these joint revealed that they showed regeneration of the tendon and the production of tough, high-quality collagen I.

Gross morphological (A–F) and histological (G–I) findings of the subscapularis tendons in groups 1, 2, and 3. The polygon in each of the first six images depicts the area of the full-thickness subscapularis tendon tear. (A–C): Pretreatment images. (D–F): Posttreatment images. (G): Parallel arrangement of hypercellular fibroblastic bundles (arrow) was noted in group 1. (H, I): Histological findings in groups 2 and 3 showed absence of fiber bundles. Group 1 received a 0.1-ml injection of MSCs; group 2, 0.1 ml of HA; group 3, 0.1 ml of saline. Hematoxylin-and-eosin stain, ×40. Abbreviations: MSC, human umbilical cord blood-derived mesenchymal stem cell; HA, hyaluronic acid; SSC, subscapularis muscle.
Gross morphological (A–F) and histological (G–I) findings of the subscapularis tendons in groups 1, 2, and 3. The polygon in each of the first six images depicts the area of the full-thickness subscapularis tendon tear. (A–C): Pretreatment images. (D–F): Posttreatment images. (G): Parallel arrangement of hypercellular fibroblastic bundles (arrow) was noted in group 1. (H, I): Histological findings in groups 2 and 3 showed absence of fiber bundles. Group 1 received a 0.1-ml injection of MSCs; group 2, 0.1 ml of HA; group 3, 0.1 ml of saline. Hematoxylin-and-eosin stain, ×40. Abbreviations: MSC, human umbilical cord blood-derived mesenchymal stem cell; HA, hyaluronic acid; SSC, subscapularis muscle.

Collagen I is the tough material that makes tendon. When rotator cuff surgeries fail, it can be for a variety of reasons, such as poor blood supply, intrinsic tendon degeneration, fatty infiltration, or muscle atrophy (see UG Longo, et al., British Medical Bulletin 2011, 98:31-59).

Histological micrographs of tissue from group 1 rabbits. (A): Newly regenerated tendons are shown in the blue-stained fibers (black arrow; Masson’s trichrome stain; magnification, ×12.5). (B): Regenerated tendon fibers (yellow arrowhead; Masson’s trichrome stain; magnification, ×250) are connected to adjacent M fibers. (C): The regenerated tendon fibers (black arrow) stained with anti-type 1 collagen antibody. The defect was reconstructed with human umbilical cord blood-derived mesenchymal stem cells (magnification, ×100). Abbreviation: M, muscle.
Histological micrographs of tissue from group 1 rabbits. (A): Newly regenerated tendons are shown in the blue-stained fibers (black arrow; Masson’s trichrome stain; magnification, ×12.5). (B): Regenerated tendon fibers (yellow arrowhead; Masson’s trichrome stain; magnification, ×250) are connected to adjacent M fibers. (C): The regenerated tendon fibers (black arrow) stained with anti-type 1 collagen antibody. The defect was reconstructed with human umbilical cord blood-derived mesenchymal stem cells (magnification, ×100). Abbreviation: M, muscle.

However, tendon failures after surgery usually result from the production of collagen III, which is mechanically weaker than collagen I, instead of collagen I (see MF Pittenger, et al., Science 1999, 284: 143-147; V Rocha, et al., New England Journal of Medicine 2000, 342: 1846-1854). None of the animals in the other groups showed any sign of collagen I production.

This experiment shows that full thickness tears in the subscapularis tendon of the rotator cuff of rabbits, which is functionally similar to the supraspinatus in humans (see figure below), can be partially healed by the ultrasound-guided infusion of UCB-MSCs.

th48RY4PHI

If larger numbers of UCB-MSCs were implanted, it is possible that the tears would have been completely repaired. Also, it is possible that partial tears can be completely repaired by this procedure, but clearly more work is required.

Other questions also remain besides the optimal dose of the cells. What sized tears can be regenerated by this procedure? What immobilization procedures are appropriate after the stem cell injections and for how long? What are the most effective rehabilitation techniques after the surgery? These are all questions that are amenable to research so take heart athletes; a better cure is slowly, but surely on its way.

The Ideal Recipe for Cartilage from Stem Cells


Researchers at Case Western Reserve and Harvard University will use a 5-year, $2-million NIH grant to build a microfactory that bangs out the optimal formula for joint cartilage. Such an end product could one day potentially benefit many of the tens of thousands of people in the United States who suffer from cartilage loss or damage.

Joint cartilage or articular cartilage caps the ends of long bones and bears the loads, absorbs shocks and, in combination with lubricating synovial fluid, helps knees, hips, shoulders, and other joints to smoothly bend, lift, and rotate. Unfortunately, this tissue has little capacity to regenerate, which means that there is a critical need for new therapeutic strategies.

Artificial substitutes cannot match real cartilage and attempts to engineer articular cartilage have been stymied by the complexities of directing stem cells to differentiate into chondrocytes and form the right kind of cartilage.

Stem cells are quite responsive to the environmental cues presented to them from their surroundings. What this research project hopes to determine are those specific cue that drive stem cells to differentiate into chondrocytes that make the right kind of cartilage with the right kind of microarchitecture that resembles natural, articular cartilage. To do this, they will engage in a systematic study of the effects of cellular micro-environmental factors that influence stem cell differentiation and cartilage formation.

Bone marrow- and fat-derived mesenchymal stem cells have been differentiated into cartilage-making chondrocytes in the laboratory. These two stem cell populations are distinct, however, and required different conditions in order to drive them to differentiate into chondrocytes. This research group, however, has designed new materials with unique physical properties, cell adhesive capabilities, and have the capacity to deliver bioactive molecules.

By controlling the presentation of these signals to cells, independently and in combination with mechanical cues, this group hopes to identify those most important cues for driving cells to differentiate into chondrocytes.

Ali Khademhosseini specializes in microfabrication and micro-and nano-scale technologies to control cell behavior. He and his team will develop a microscale high-throughput system at his laboratory that will accelerate the testing and analysis of materials engineered in another laboratory.

This research cooperative hopes to test and analyze more than 3,000 combinations of factors that may influence cell development, including differentiation, amounts of biochemicals, extracellular matrix properties, compressive stresses, and more. Khademhosseini and his colleagues hope to begin testing comditions identified from these studies in animal models by the of the grant term.

Non-Randomized Stem Cell Study for Knee Osteoarthritis Yields Positive Results


A peer-reviewed study that was neither placebo-controlled nor randomized, but did examine 840 patients, has shown that the use of a patient’s own bone marrow stem cells are both safe and effective.

Christopher Centeno and his colleagues, who pioneered the Regenexx protocol, use live-imaging to guide the application of stem cells to the site in need of healing. Centeno and others have established several clinics around the United States that utilize the Regenexx system, and the data published in this paper came from these clinics, in addition to Chris Centeno’s own clinic in the Denver, Colorado area.

In this study, patients self-rated their lower extremity functional using a lower extremity functional scale (LEFS), and their knee pain by using a numerical pain scale (NPS). Patients had bone marrow extracted through a bone marrow aspiration. These bone marrow cells were isolated and concentrated, and then prepared for reinvention. In addition, platelet rich plasma (PRP) and platelet lysate (PL) were prepared from the patient’s own blood and these, with the bone marrow cells, were injected into the knee under guided imaging. The frequency and types of adverse events (AE) were also recorded by the physicians.

Some of these patients had fat overlaid on their knee lesions in addition to their bone marrow cells. Of the 840 procedures that were performed, 616 had treatment without additional fat, and 224 had treatment with the fat graft. This was to determine if the use of fat, with its resident stem cell population, augmented healing of the arthritic knee.

When the LEFS scores before and after the Regenexx procedure were compared, an increase of 7.9 and 9.8 in the two groups (out of 80) was observed. The mean NPS score decreased from 4 to 2.6 and from 4.3 to 3 in the two groups. AE rates were 6% and 8.9% in the two groups. An examination of these data showed that pre- and posttreatment improvements were statistically significant. However, the differences between the fat- and fat+ groups were statistically insignificant.

The patients in this study suffered from osteoarthritis. Consequently, they were experiencing significant knee pain and many were candidates for a knee replacement. Many of these patients were able to avoid knee replacement by undergoing the Regenexx procedure.

The study concluded that there was no advantage of adding fat to the joint over the bone marrow cells. Safety in both groups (with and without fat) was excellent compared to knee replacement.

This study used data from patients who were part of the Regenexx registry. Therefore, this study was not a randomized, controlled study, like the kind that are used to test drugs. Randomized controlled trials are being conducted by Centeno and his colleagues at the various Regenexx centers. A knee osteoarthritis study is being studied in Chicago, another study regarding shoulder rotator cuff tears, and a third study examining ACL tears are in progress.

Cartilage Repair Using Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Embedded in Hyaluronic Acid Hydrogel in a Minipig Model


Cartilage shows lousy regenerative capabilities. Fortunately, it is possible to regenerate cartilage with human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) that have been embedded in a hyaluronic acid (HA) hydrogel composite. In fact, such a combination has shown remarkable results in rat and rabbit models.

In this present study, published in Stem Cells Translational Medicine, Yong-Geun Park and his colleagues from SungKyunKwan University School of Medicine, in Seoul, South Korea sought to confirm the efficacy of this protocol in a in a pig model using three different hUCB-MSC cell lines.

Park and his coworkers generated full-thickness cartilage injuries in the trochlear groove of each knee in 6 minipigs. Three weeks later, an even larger cartilage defect, 5 mm wide by 10 mm deep, was created, followed by an 8-mm-wide and 5-mm-deep boring. In short, the knee cartilages of these minipigs were very messed up.

Trochlear-groove

To these knee cartilages, a mixture (1.5 ml) of hUCB-MSCs (0.5 × 107 cells per milliliter) and 4% HA hydrogel composite were troweled into was then cartilage defects of the right knee. The left knee served as an untreated control. Each cell line was used in two minipigs.

Macroscopic findings of the osteochondral defects of the porcine knees. At 12 weeks postoperatively, the defects of both knees had produced regenerated tissues that were pearly white and firm. These new tissues, which resembled articular cartilage, appeared adherent to the adjacent cartilage and had restored the contour of the femoral condyles (smooth articular surfacewithout depression). The regenerated tissue of the control knee (left knee) looked fibrillated. Grossly, no differencewas seen in the quality of the repaired tissue in the transplanted knee (right knee) among the three groups with different cell lines. (A): Group A. (B): Group B. (C): Group C. Abbreviations: HA, hyaluronic acid; hUCB-MSCs, human umbilical cord blood-derived mesenchymal stem cells.
Macroscopic findings of the osteochondral defects of the porcine knees. At 12 weeks postoperatively, the defects of both
knees had produced regenerated tissues that were pearly white and firm. These new tissues, which resembled articular cartilage, appeared adherent to the adjacent cartilage and had restored the contour of the femoral condyles (smooth articular surface without depression). The regenerated tissue of the control knee (left knee) looked fibrillated. Grossly, no difference was seen in the quality of the repaired tissue in the transplanted knee (right knee) among the three groups with different cell lines. (A): Group A. (B): Group B. (C): Group C. Abbreviations: HA, hyaluronic acid; hUCB-MSCs, human umbilical cord blood-derived mesenchymal stem cells.

12 weeks after surgery, the pigs were sacrificed, and the degree of subsequent cartilage regeneration was evaluated by gross and more detailed microscopic analysis of the knee tissue. The transplanted knee showed superior and more complete joint-specific (hyaline) cartilage regeneration compared with the control knee. The microscopic characteristics of the knee cartilage showed that those animals that received the hUCB-MSCs had greater rates of cell proliferation and cells that differentiated into cartilage-making cells.

Microscopic findings of the regenerating osteochondral defects on porcine articular cartilage (safranin O and fast green staining). At 12 weeks postoperatively, the surface of the repairing tissue in the control knee (left knee) was poorly stained for glycosaminoglycan. In the transplanted knee (right knee), both the regenerated tissue and the adjacent cartilage to which it had become adherent exhibited the normal orthochromatic staining properties with safranin O. (A): Group A. (B): Group B. (C): Group C. Scale bars = 2 mm. Abbreviations: HA, hyaluronic acid; hUCB-MSCs, human umbilical cord blood-derived mesenchymal stem cells.
Microscopic findings of the regenerating osteochondral defects on porcine articular cartilage (safranin O and fast green staining). At 12 weeks postoperatively, the surface of the repairing tissue in the control knee (left knee) was poorly stained for glycosaminoglycan. In the transplanted knee (right knee), both the regenerated tissue and the adjacent cartilage to which it had become adherent exhibited the normal orthochromatic staining properties with safranin O. (A): Group A. (B): Group B. (C): Group C. Scale bars = 2 mm. Abbreviations: HA, hyaluronic acid; hUCB-MSCs, human umbilical cord blood-derived mesenchymal stem cells.

These data show consistent cartilage regeneration using composites of hUCB-MSCs and HA hydrogel in a large animal model. These experiments could be a stepping stone to a human clinical trial in the future that treats osteoarthritis of the knees with hUCB-MSCs embedded in HA hydrogel.

Cartilage-Making Stem Cells from Joints


Chiharo Akazawa from the Tokyo Medical and Dental University and his colleagues have tested two types of mesenchymal stem cells from human patients for their ability to make bone, cartilage, or fat. Their tests illustrated what has been shown several time before; mesenchymal stem cells tend to differentiate into the tissues that most closely resemble their tissue of origin.

Akazawa and his colleagues previously discovered a way to effectively isolated mesenchymal stem cells from bone marrow, which is no small feat because mesenchymal stem cells (MSCs) are a minority of the cells in bone marrow (Mabuchi and others (2013), Stem Cell Reports 1: 152-165). In a recent paper in the journal PLoS ONE, Akazawa and others used this technique to isolate MSCs from bone marrow and from synovial membrane – the fluid-filled sac that encases joints. In large joints, this synovium is large and called a “bursa.”.

In culture, the bone marrow-derived MSCs from several different human donors showed a marked tendency to form bone, but they did not make good cartilage or fat. The synovial MSCs, on the other hand, did not do so well at making bone, but made very good fat and cartilage. These differentiation trends were observed in MSCs culture for several different human donors. All cells were collected during arthroscopic surgery.

Since the synovial membrane of patients suffering from osteoarthritis undergoes, increased cell division, it is possible that the number of stem cells also increases. Alternatively, using MSCs from healthy donors who do not have arthritis may be even more preferable. Nevertheless, MSCs from synovial membrane show excellent cartilage-making potential and they may be a suitable source of cell for cartilage regeneration.

Mesoblast Phase Degenerative Disc Disease Treatment Receives Positive Feedback from European Regulatory Agencies


Mesoblast Limited announced that European Medicines Agency has approved expansion of their Phase 3 clinical program of its product candidate MPC-06-1D for degenerative disc disease.

Mesoblast’s Phase 3 program for this product candidate is currently in the process of enrolling patients in the United States under an Investigational New Drug (IND) application filed with the US Food and Drug Administration (FDA).  Having received general agreement from EMA on the target patient population, trial size, primary composite endpoint, and comparators in the control population, Mesoblast now intends to additionally enroll patients across multiple European sites.

The discussions with EMA occurred as part of combined scientific and reimbursement advice under an EU pilot program known as Shaping European Early Dialogues (SEED). The SEED pilot program was established to facilitate early dialogue between EMA, European Health Technology Assessment reimbursement bodies, and selected companies with late-stage clinical development programs. Mesoblast’s product candidate MPC-06-ID is one of only seven medicines accepted for the SEED program.

Mesoblast and SEED representatives discussed key clinical trial aspects of the development of MPC-06-ID including the safety database, mechanisms of action, patient population and trial size, composite endpoints, and comparators. The discussions also focused on access to EU markets and pharmacoeconomic endpoints that may lead to reimbursement.

The guidance from the meeting with SEED representatives may result in a final comprehensive EU development and commercialization program that has an increased likelihood of producing data that will be acceptable for both registration and reimbursement review in multiple European countries.

High-Quality Cartilage Production from Pluripotent Stem Cells


High-quality cartilage has been produced from pluripotent stem cells by workers in the laboratory of Sue Kimber and her team in the Faculty of Life Sciences at The University of Manchester. Such success might be used in the future to treat the painful joint condition osteoarthritis.

Kimber and her colleagues used strict laboratory conditions to grow and transform embryonic stem cells into cartilage cells known as chondrocytes.

Professor Kimber said: “This work represents an important step forward in treating cartilage damage by using embryonic stem cells to form new tissue, although it’s still in its early experimental stages.” Kimber’s research was published in Stem Cells Translational Medicine.

During the study, the team analyzed the ability of embryonic stems cells to become cartilage precursor cells. Kimber and her colleagues then implanted these pre-chrondrocytes into cartilage defects in the knee joints of rats. After four weeks, the damaged cartilage was partially repaired and following 12 weeks a smooth surface, which looked very similar to normal cartilage, was observed. More detailed studied of this newly regenerated cartilage demonstrated that cartilage cells from embryonic stem cells were still present and active within the tissue.

Developing and testing this protocol in rats is the first step in generating the information required to run such a study in people with arthritis. Before such a clinical trial can be run, more data will need to be collected in order to check that this protocol is effective and that there are no toxic side-effects.

However, Kimber and her coworkers say that this study is very promising as not only did this protocol generate new, healthy-looking cartilage but also importantly there were no signs of any side-effects such as growing abnormal or disorganized, joint tissue or tumors. Further work will build on this finding and demonstrate that this could be a safe and effective treatment for people with joint damage.

Chondrocytes created from adult stem cells are being used on an experimental basis, but, to date, they cannot be produced in large amounts, and the procedure is expensive.

With their huge capacity to proliferate, pluripotent stem cells such as embryonic stem cells and induced pluripotent stem cells can be manipulated to form almost any type of mature cell. Such cells offer the possibility of high-volume production of cartilage cells, and their use would also be cheaper and applicable to a greater number of arthritis patients, the researchers claim.

“We’ve shown that the protocol we’ve developed has strong potential for developing large numbers of chondrogenic cells appropriate for clinical use,” added Prof Kimber. “These results thus mark an important step forward in supporting further development toward clinical translation.”

Osteoarthritis affects more than eight million people in the UK alone, and is a major cause of disability. It and occurs when cartilage at the ends of bones wears away causing joint pain and stiffness.

Director of research at Arthritis Research UK Dr Stephen Simpson added: “Current treatments of osteoarthritis are restricted to relieving painful symptoms, with no effective therapies to delay or reverse cartilage degeneration. Joint replacements are successful in older patients but not young people, or athletes who’ve suffered a sports injury.

“Embryonic stem cells offer an alternative source of cartilage cells to adult stem cells, and we’re excited about the immense potential of Professor Kimber’s work and the impact it could have for people with osteoarthritis.”

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.

meniscus

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.

knee_joint

“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.

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.”

Human articular cartilage defects can be treated with nasal septum cells


A report from collaborating research teams from the University and the University Hospital of Basel specifies that cells isolated from the nasal septum cartilage can adapt to the environment the knee and repair articular cartilage defects. The ability of nasal cartilage cells to self-renew and adapt to the joint environment is associated with the expression of genes know as HOX genes. This research was published in the journal Science Translational Medicine in combination with reports of the first patients treated with their own nasal cartilage.

Lesions in articular or joint-specific cartilage is a degenerative that tends to occur in older people or younger athletes who engage in impact-heavy sports. Sometimes people who have experienced accidents can also suffer from cartilage lesions. Cartilage lesions present several challenges for orthopedic surgeons to repair. These surgeries are often complicated, and the recovery times are also long. However, Prof. Ivan Martin, professor of tissue engineering, and Prof. Marcel Jakob, Head of Traumatology, from the Department of Biomedicine at the University and the University Hospital of Basel have presented a new treatment option for cartilage lesions that includes the use of nasal cartilage cells to replace cartilage cells in joints.

When grown in cell culture, cartilage cells extracted from the nasal septum (also known as nasal chondrocytes) have a remarkable ability to generate new cartilage tissue after their growth in culture. In an ongoing clinical study, the Basal research group have taken small biopsies (6 millimeters in diameter) from the nasal septa of seven of 25 patients below the age of 55 years. After isolating the cartilage cells from these cartilage samples, they cultured these cells and expanded them and applied them to a three-dimensional scaffold in order to engineer a cartilage graft with a specific size (30 x 40 millimeters).

Martin and his colleagues used these very cartilage grafts to treat the cartilage lesions in human patients. After removing the damaged cartilage tissue from the knee of several patients, their knees were treated with the engineered, tailored tissue from their noses.

Two previous experiments demonstrated the potential efficacy of this procedure. First, a previous clinical study conducted in cooperation with plastic surgeons and the Basel group used the same method to successfully reconstruct nasal wings affected by tumors.

Secondly, a preclinical study with goats whose knees were implanted with nasal cartilage cells showed that these cells were not only compatible with the knee-joint, but also successfully reconstituted the joint cartilage. Lead author of this study, Karoliina Pelttari, and her colleagues were quite surprised that the implanted nasal cartilage cells, which originate from a completely different set of embryonic cell types than the knee-joint were compatible. Nasal septum cells develop from neuroectodermal cells, which also form the nervous system and their self-renewal capacity is attributed to their lack of expression of some homeobox (HOX) genes. However, these same HOX genes are expressed in articular cartilage cells that are formed by mesodermal cells in the embryo.

“The findings from the basic research and the preclinical studies on the properties of nasal cartilage cells and the resulting engineered transplants have opened up the possibility to investigate an innovative clinical treatment of cartilage damage,” says Prof. Ivan Martin about the results. Several studies have confirmed that human nasal cells maintain their capacity to grow and form new cartilage despite the age of the patient. This means that older people could also benefit from this new method, as could patients with large articular cartilage defects.

The primary target of the ongoing clinical study at the University Hospital of Basel is to confirm the safety, efficacy and feasibility of nasal cartilage grafts transplanted into joints, the clinical effectiveness of this procedure, from the data presently in hand, is highly promising.

Stem Cell Treatments to Repair Cartilage Defects in the Knee


Erosions of the cartilage that covers the surfaces at the ends of our leg bones has motivated several laboratories to undertake clinical studies to test new techniques to heal lost cartilage, particularly at the knee. Many of these techniques have their share of drawbacks and advantages, but the number of clinical trials to deal with cartilage lesions of the knee are increasing. Unfortunately, more work remains to be done, but much more is known about several of these techniques than before. This article will summarize many of these techniques.

Microfracture is a procedure in which several small holes are drilled into the end of the bone to enhance the migration of mesenchymal stem cells from the bone marrow to the site of the cartilage defect. These MSCs then differentiate into chondrocytes and make cartilage that fills the lesion with new cartilage. Unfortunately, the cartilage made in these cases is fibrocartilage and not hyaline cartilage. Fibrocartilage lacks the biomechanical strength and durability of hyaline cartilage and it typically deteriorates 18-24 months after surgery. When used to treat large lesions, 20-50% of all cases develop intralesional osteophytes and the sclerotic bone increases the failure rate of autologous chrondrocyte implantation 3-7X. Thus microfractionation is only performed under very specific conditions and only in young patients, since this technique does not work in older patients.

Microfracture

Autologous Chondrocyte Implantation or ACI uses a full-thickness punch biopsy from a low-weight-bearing region of the joint taken during an arthroscopic surgery. This biopsy contains chondrocytes that are grown in cell culture to a population of about 12-48 million chondrocytes, which are troweled into the lesion during a second arthroscopic surgery. Clinical trials have established that ACI is safe and effective for large knee lesions. Peterson and others and Minas and others have established that even after 10 years, patients who have been treated with ACI show good relief of pain and increased knee function.

In the Peterson study, questionnaires were sent to 341 patients. 224 of 341 patients replied to the questionnaires, and of these respondents, 74% of the patients reported their status as better or the same as the previous years 10-20 years after the procedure (mean, 12.8 years).  92% were satisfied and would have ACI again.  Knee function and pain levels were significantly better after the procedure than before.  From this study, Peterson and others concluded that ACI is an effective and durable solution for the treatment of large full-thickness cartilage and osteochondral lesions of the knee-joint, and that the clinical and functional outcomes remain high even 10 to 20 years after the implantation.

Minas and others analyzed data from 210 patients treated with ACI who were followed for more than 10 years. ACI provided durable outcomes with a survivorship of 71% at 10 years and improved function in 75% of patients with symptomatic cartilage defects of the knee at a minimum of 10 years after surgery. A history of prior marrow stimulation as well as the treatment of very large defects was associated with an increased risk of failure.
In comparison studies by Bentley and others, ACI produced superior results to mosaicplasty (osteochondral transplantation or cylinders of bone drilled form low-weight-bearing parts of the knee that are implanted in a mosaic fashion into the knee).  In the Bentley study, 10 of 58 ACI patients had failed grafts after 10 years, but 23 of 42 mosaicplasty patients had failed cartilage repair.  According to studies by Based and others, and Saris and others, ACI is also superior to microfractionation in the repair of large cartilage lesions (>3 cubic cm), but seems to provide the same outcomes as microfracture for smaller lesions, according to Knudsen and others.  There are drawbacks to ACI.  The tissue flap used to seal the cartilage implant sometimes becomes pathologically enlarged.  Other materials have been used to seal the patch, such as hyaluronic acid, or collagen types I and III, but the use of these materials increases the expense of the procedure and the likelihood that the immune system will response to the covering.  Also, ACI outcomes vary to such an extent that the procedure is simply too unstandardized at the present time to be used consistently in the clinic.

Autologous Cartilage Implantation

In an attempt to standardize ACI, several orthopedic surgeons have tried to add a supportive scaffold of some sort to the chondrocytes harvested from the patient’s body.  Several studies in tissue culture have shown that chondrocytes not only divide better, but also keep their identities as chondrocytes better in a three-dimensional matrix (see Grigolo et al, Biomaterials (2002) 23: 1187-1195 and Caron et al, Osteoarthritis Cartilage (2012) 20; 1170-1178).  Therefore, ACI has given way to MACI or Matrix-Induced Autologous Chondrocyte Implantation, which seeds the chondrocytes on an absorbable porcine-derived mixed collagen (type I and III) prior to implantation.  The implant is then secured into the debrided cartilage lesion by means of a fibrin cover.

Several case studies have shown that MACI has substantial promise, but individual case studies are the weakest evidence available.  To prove its superiority over ACI or microfracture surgery, MACI must be compared in controlled studies.  In the few studies that have been conducted, the superiority of MACI remains unproven to date.  Patients who received MACI or ACI showed similar clinical outcomes in two studies (Bartlett and others, Journal of Bone and Joint Surgery (2005) 87: 640-645; and Zeifang et al, American Journal of Sports Medicine (2010) 38: 924-933), although those who received MACI showed a significantly lower tendency for the graft to enlarge.  MACI is clearly superior to microfracture surgery (Basad, et al., Knee Surgery, Sports Traumatology and Arthroscopy (2010) 18: 519-527), but longer-term studies are needed to establish the superiority of MACI over other treatment options.

A slight variation of the MACI theme is to embed the chondrocytes in a gel-like material called hyaluronic acid (HA).  HA-embedded chondrocytes have been shown to promote the formation of hyaline cartilage in patients (Maracci et al., Clinical Orthopedics and Related Research (2005) 435: 96-105).  Even though the outcomes are superior for patients treated with HA-MACI, the recovery period is longer (Kon E, et al., American Journal of Sports Science (2011) 39: 2549-2567).  MACI is available in Europe but not the US to date.  FDA approval is supposedly pending.  Long-term follow-up studies are required to establish the efficacy of this procedure.

Future prospects for treating knee cartilage lesions include culturing collagen-seeded chondrocytes for a longer period of time than the three days normally used for MACI.  During these longer culture periods, the seeded chondrocytes mature, and make their own scaffolds, which ensure higher-quality cartilage and better chondrocyte engraftment (see Khan IM and others, European Cell Materials (2008) 16: 26-39).  Alternatively, joint cartilage responds to stress by undergoing cell proliferating and increasing in density.  This response is due to the production of growth factors such as Transforming Growth Factor-β1 and -β3 (TGF-β1 and TGF-β3).  This motivated some enterprising tissue engineers to use recombinant forms of these growth factors to grow cartilage in bioreactors under high-stress conditions.  Such a strategy has given rise to NeoCart, a tissue-engineered product that has gone through Phase I and II trials and has been shown in two-year follow-up studies to be safe and more effective than microfracture surgery (Crawford DC and others, Journal of Bone and Joint Surgery, American Volume. 2012 Jun 6;94(11):979-89 and Crawford DC, and others, Am J Sports Med. 2009 Jul;37(7):1334-43).

Mesenchymal stem cells (MSCs) from bone marrow and other sites have also been used to successfully treat cartilage lesions.  These types of treatments are less expensive than ACI and MACI, and do not require two surgeries as do ACI and MACI.  The studies that have been published using a patient’s own MSCs have been largely positive, although some pain associated with the site of the bone marrow aspiration is a minor side effect (see Centeno and others, Pain Physician (2008) 11:343-353; Emadedin, et al., Arch Iran Med (2012) 15: 422-428; Wong RL, et al., Arthroscopy (2013) 29: 2020-2028).  Fat-based MSCs have been tested as potential cartilage-healers in elderly patients (Koh YG, et al., Knee Surgery, Sports Traumatology, and Arthroscopy (Dec 2013, published on-line ahead of print date).  While these initial results look promising,, fat-based, MSCs have only just begun to be tested for their ability to regenerate cartilage.  Fat-based MSCs show different properties than their bone-marrow counterparts, and it is by no means guaranteed that fat-based MSCs can regenerate cartilage as well as MSCs from bone marrow.

Fresh cartilage grafts from donors (aka – cartilage allografts) use transplanted cartilage that has been freshly collected from a donor.  Fresh cartilage allografts have had positive benefits for young, active patients and the grafts have lasted 1-25 years (Gross AE, et al., Clinical Orthopedics and Related Research (2008) 466: 1863-1870).  Particulate cartilage allografts takes minced cartilage and lightly digests it with enzymes to liberate some of the cartilage-synthesizing chondrocytes, and then pats this material into the cartilage lesion, where it is secured with a fibrin glue plug.  The cartilage provides an excellent matrix for the synthesis of new cartilage, and the chondrocytes make new cartilage while seeded onto this cartilage scaffold.  Clinical experience with this technique includes a two-year follow-up in which MRI evidence showed good filling of the lesions (Bonner KF, Daner W, and Yao JQ, Journal of Knee Surgery 2010 23: 109-114 and Farr J, et al., Journal of Knee Surgery 2012 25: 23-29).  A variation on this technique uses a harvested hyaline cartilage plug that is glued into an absorbable scaffold before transplantation into the cartilage lesion.  This procedure had the same safety profile as microfracture surgery, but resulted in better clinical outcomes, high quality cartilage, and fewer adverse side effects (Cole JB et al., American Journal of Sports Medicine 2011 39: 1170-1179).  A clinical trial that tested this procedure remains uncompleted after the company suspended the trial because of conflicts with the FDA (Clinical Trial NCT00881023).

AMIC or Autologous Matrix-Induced Chondrogenesis is a cell-free treatment option in which the cartilage lesion is cleaned and filled subjected to microfracture, after which the lesion is filled with a mixed collagen matrix that is glued or stitched to the cartilage lesion.  The MSCs released by the microfracture procedure now move into a scaffold-laden cartilage lesion that induces the formation of hyaline cartilage.  This technique appears to aid the filling of full-thickness cartilage defects, and follow-up examinations have revealed that after 5 years, patients showed substantial improvements in knee function, pain relief and MRI analyses of knee cartilage showed high-quality cartilage in repaired lesion (Kusano T, et al., Knee Surgery, Sports Traumatology, and Arthroscopy 2012 20: 2109-2115; Gille J, et al., Archives of Orthopedic Trauma Surgery 2013 133: 87-93; Gille J, et al., Knee Surgery, Sports Traumatology, and Arthroscopy 2010 18: 1456-1464).

These are just a few of the new treatments of cartilage lesions of the knee and other joints.  As you can see, all of this will lead to greater repair of knee lesions and it is all being done without embryonic stem cells or destroying embryos.

Bone Therapeutics Cleared to Test ALLOB in Spinal Fusion Trial


Bone Therapeutics is a biotechnology company that specializes in regenerative therapies for orthopaedic conditions. Founded in 2006, Bone Therapeutics is headquartered in Gosselies, Belgium. One of the products developed by Bone Therapeutics is called ALLOB, which is a bone making (osteoblastic) cell product that has the ability to regenerate bone, and has been developed for the treatment of bone diseases. ALLOB is meant to be an off-the-shelf product that can be used to treat patients with various types of bone diseases.

Bone Therapeutics has recently announced that it has received approval from the Belgium regulatory agencies for a phase II proof-of-concept study to assess the safety and efficacy of ALLOB in spinal fusion procedures that are commonly used to treat degenerative lumbar disc disease. The hope is that this clinical trial will demonstrate that ALLOB improves spinal fusion surgery outcomes. Bone Therapeutics hopes to market ALLOB as an off-the-shelf treatment for spinal fusion surgery.

In previous studies, ALLOB has shown that it can enhance bone formation, and that it is a safe product in laboratory animals. Currently ALLOB is being evaluated in a phase I/IIa trial for delayed-union fractures. This is a pilot proof-of-concept study that examines 16 patients with symptomatic degenerative lumbar disc disease, all of whom require interbody vertebral fusion. These patients will be treated with a single dose of ALLOB mixed with bioceramic granules to promote bone formation and fusion at the within the degenerative discs. The bioceramic scaffold in this trials promotes bone formation by guiding bone growth in three dimensions and restoring a healthy bone environment. Patients will be enrolled in this trial at four different centres. The safety and efficacy of the treatment will be monitored over 12 months by clinical and radiological means. Additionally, there will be a 24-month post-study follow-up.

Back pain is a widespread medical disorder in industrialized societies that sometimes requires spinal surgery. Around 1.3 million spinal fusions are performed each year in Europe and the USA, the majority of which are to address degenerative lumbar disc disease. Despite the frequency of this surgery, non-union of bone and persistent pain following the intervention is still somewhat common. Further improvements to this procedure would be most welcome to patients and medical practitioners alike.

Enrico Bastianelli, CEO of Bone Therapeutics commented, “This new clinical trial clearance from the Competent Authorities in Belgium is an important milestone in the development of ALLOB® and further validates Bone Therapeutics’ clinical, regulatory and manufacturing capabilities.”

The Australian Football League Approves Regeneus’ Fat-Based HiQCell Stem Cell Therapy for Injured Players


The regenerative medicine company Regeneus Ltd announced this week that the Australian Football League or AFL has decided to approve, on a case-by-case basis, the use of its innovative HiQCell stem cell therapy as an optional treatment for injured AFL players. Football (soccer) players tend to suffer from impact-related osteoarthritis and tendonitis.

Regeneus’ Commercial Development Director for Human Health, Steve Barbera, said, “It’s pleasing that HiQCell has been approved under the new AFL Prohibited Treatments List released in March 2014. HiQCell also received clearance as an approved therapy from the Australian Sports Anti-Doping Authority (ASADA) for use with athletes who participate in sporting competitions subject to the WADA Anti-Doping Code, including the AFL. This recent decision by the AFL demonstrates a further level of compliance, specifically for players within that sporting code.”

Regeneus’ HiQCell treatment is the only stem cell treatment for osteoarthritis that has been subjected to the highest level of clinical scrutiny. A double-blind placebo-controlled safety trial is the gold standard for clinical trials. The particular clinical trial to which HiQCell treatments were subjected showed that HiQCell is safe and it reduces pain and halts cartilage degradation in arthritic joints. Additionally, the ongoing effects of HiQCell are being tracked in over 380 patients in an independent ethics-approved registry. A recent registry update demonstrated that patients are maintaining significant improvements 2 years after their treatment.

HiQCell has already been used to treat several high-profile athletes across several sporting codes, including the National Rugby League, which was announced on May 7th, 2014. It is encouraging for Regeneus that elite sports patients can use their HiQ therapy to much quickly return to sports from hard-to-treat injuries and continue their playing careers after receiving this innovative therapy.

Dr Phil Bloom, a Melbourne based Specialist Sports and Exercise Physician and HiQCell treating medical practitioner, said, “permission from the AFL for HiQCell treatment is a positive progression as it allows for an additional option for players with conditions that are unresponsive to existing treatments”.

The HiQCell treatment uses stem cells harvested from a small amount of a patient’s fat. After separating and concentrating these regenerative cells, they are re-injected in osteoarthritic-affected joints such as knees, hips and ankles. The HiQCell treatment reduces inflammation and repairs damaged tissue when it is carried out under the supervision of a medical practitioner.

Mesenchymal Stem Cells from Fat Relieve Arthritis Pain for Up to Two Years


Regeneus is an Australian regenerative that has developed an experimental treatment for arthritis called HiQCells.  HiQCell is a stem cell treatment made from the patient’s own adipose (fat) tissue, and is subsequently injected into an affected joint or tendon. Regeneus has tested their HiQCell treatment in an independent clinical study that examined the efficacy of injections of HiQCells into the joints of patients with osteoarthritis of the knee.  The study examined 40 patients with knee osteoarthritis.  Half of these patients received the placebo and half HiQCell in a double-blinded study.  When asked about their pain levels six months after the procedure, patients in the placebo and HiQCell group ~45% of patients reported less pain and by 12 months after treatment 55% of patients in both groups reported less pain.  Thus both treatments relieved pain to a similar degree.  However, when the progression of the disease was examined, a very different result was observed.  As osteoarthritis progresses, some of the breakdown products of joint cartilage appear in urine and blood.  By collecting urine and blood samples from osteoarthritis patients, the progression of the disease can be readily tracked.  Blood and urine testing showed significantly less cartilage breakdown in the HiQCell group and significantly more breakdown in the patients in the placebo group who had advanced cartilage damage. Thus, even though the patients who received placebo had about the same level of pain reduction over the six-month period, it seems that their cartilage breakdown progressed at a faster rate.

Now a follow-up examination of these and other subjects who participated in this initial clinical study has revealed something surprising.  According to Regeneus, as of July 21, 2014, from a collection of 386 patients: 1) Pain has continued to decrease two years post-treatment; 2) One year after treatment, 63 of 86 patients reported more than a 30% reduction in pain;
3) Two years after treatment, 14 of 17 patients reported more than a 30 % reduction in pain and 14 patients experienced an average pain reduction of 84% at two years post-treatment; 4) Patients also reported significant improvements from pre-treatment in knee-function, sleep quality and reduced pain medications.  Finally, it is clear from these results that HiQCell is a safe therapy and well tolerated by patients, since the frequency and severity of adverse effects of patients who received HiQCell treatments were no different from those received the placebo.

The HiQCell Joint Registry established by Regeneus is the first of its kind in that the patients who participate in this study are subjected to long-term follow-up and undergo stem cell therapy using the patient’s own fat-derived stem cells. The HiQCell study has been approved by a human research ethics committee.  These 386 patients included in the Joint Registry will continue to be followed for up to 5 years with analysis updated regularly.

Professor Graham Vesey, CEO of Regeneus, comments: “The registry data is demonstrating that HiQCell has a therapeutic benefit for longer than 2 years. We are now also beginning to see very encouraging data from patients that have had cells frozen for future injections. This combination of the long-term effect from HiQCell and the successful storage of cells for repeat injections in the future, means that HiQCell can be used to treat joint pain for many years. This is particularly important for patients that are too young for joint replacement or are simply looking to delay joint replacement.”