Stem Cells for Augmenting Tendon Healing

Future Treatments

Researchers are investigating how to improve the slow, poor healing process of injured tendons and ligaments. Stem cell therapy and growth factor therapies are already being offered in some places (see links in text below). These treatments have not reached mainstream practice yet, but they may be more widely available if they prove to be successful in enough cases. We don’t know yet if these treatments will be helpful, so you should know that many doctors urge caution when it comes to trying unproven strategies.

Local Injection of Mesenchymal Stem Cells

Stem cells are progenitor cells found in embryos and also in some tissues of adults; these special cells can differentiate into cells for many different kinds of tissue such as bone, fat, cartilage, tendon, nerve, blood, brain, or muscle. Embryonic stem cells can differentiate into more tissue types than adult stem cells, but adult cells are more available and avoid the ethical and political issues associated with the use of embryonic cells. Adult stem cells have been found in many parts of the body, for example in fat, bone marrow, and skin.

One kind of stem cell is the mesenchymal stem cell or MSC; this type of cell can differentiate into various kinds of connective tissue. Adult bone marrow and fat are two sources for MSCs. Researchers are exploring how to use MSCs to repair tissues such as bone, tendon, ligament, and cartilage.[47]

In several early tendon studies, researchers surgically created one-centimeter-long gap defects in rabbit tendons and then implanted composites of stem cells suspended in Type I collagen gel into the injuries.[2,3,15] In one study, the MSC treated tendons were twice as strong as the untreated tendons after 4, 8, and 12 weeks.[15] The treated tendons also had larger cross-sectional area and better aligned collagen fibers. The authors concluded, “The results indicate that delivering mesenchymal stem cell-contracted, organized collagen implants to large tendon defects can significantly improve the biomechanics, structure and probably the function of tendon after injury.”[15]

Although these early studies looked at acute surgically-created tendon injuries, this research was then extended to look at chronic tendon injuries. Instead of surgically implanting MSCs into tendon gaps, MSCs were injected directly into the area of chronic injury. The MSCs are healthy cells uninjured by repetitive motion, and they can, in theory, go to work creating new healthy collagen to slowly repair the area of failed healing.

A 2012 study followed up on eight patients who had undergone stem cell therapy for patellar tendinopathy five years prior; seven of the eight had good results and were still happy with the procedure after five years. [57]

Stem cell injections are being offered at a few clinics such as The Institute of Regenerative and Molecular Orthopaedics in Florida, Regenexx in Colorado, and StemGenex in California. Sometimes stem cell therapy is combined with plasma-rich platelet injections and growth factors to try to maximize the results.

More research is needed, but stem cell treatments appear promising. The companies mentioned above offer stem cells to treat numerous medical and cosmetic concerns, and not much research into efficacy exists yet for tendinosis. Another related therapy, described in the section below, is currently being researched and offered specifically for tendinosis: injecting autologous tenocyte or fibroblast cells instead of injecting mesenchymal stem cells.

Local injection of Fibroblasts and Tenocytes

Rather than injecting stem cells, researchers have also tried injecting fibroblasts into the tendinosis region. Fibroblasts are cells in tissue, such as skin and tendon, that produce collagen and the extracellular matrix. (For more on the differences between stem cells and fibroblasts, see studies such as ”Fibroblasts share mesenchymal phenotypes with stem cells, but lack their differentiation and colony-forming potential,” Biol Cell. 2011 Apr;103(4):197–208. doi: 10.1042/BC20100117.)

Initial studies have shown promise for injecting dermal fibroblasts (what these studies call tenocyte-like cells) in elbows and knees with tendinosis. [55, 56]

This type of autologous cell treatment is being offered in Australia through Ortho Cell. In September/October 2013, Ortho Cell reported that a clinical study of autologous tenocyte therapy for lateral epicondylitis was successful. The study was published in the December 2013 American Journal of Sports Medicine. [59] Patients can go to clinics that work with Ortho Cell; the patient has an initial appointment during which a tendon biopsy is collected from a healthy tendon and sent to Ortho Cell for processing, and then later the patient returns for an injection of the tenocyte cells isolated and grown from the biopsy.

A Canadian company, Replicel, is starting a clinical trial (Sept 2014) of their new autologous cell therapy treatment for tendinosis. They will be injecting Achilles tendinosis injuries with fibroblasts collected from the dermal sheath of patients’ hair follicles. Replicel reports that these fibroblasts derived from hair follicles produce five times more Type I collagen than skin-derived fibroblasts.

The companies mentioned in the previous section on mesenchymal stem cells are trying stem cell therapy on many diverse medical and cosmetic conditions without much research to go on. It is good to see Ortho Cell and Replicel conducting research and trials specifically with tendinosis so that perhaps these tenocyte and fibroblast treatments will be more targeted and more effective. The Replicel tenocyte method has the added benefit of not requiring a tendon biopsy from a healthy tendon.

Improving Collagen Type I to Type III Ratio

A team at the University of Glasgow is researching a possible way to correct the imbalance in Types I and III collagen that occurs during the failed healing of tendinopathy. They discovered that a microRNA called miR-29a can up-regulate the production of type I collagen relative to type III to restore collagen to pre-injury levels. Trials have been done in cultured cells and in mice, and horses will be next. One of their papers can be found here.

Manipulating Growth Factors

Growth factors (also called cytokines) are proteins, glycoproteins, and peptides that can stimulate cell proliferation and differentiation. Some growth factors can help normal uninjured tendon fibroblasts proliferate and synthesize more collagen and proteoglycans. Since growth factors play an important role in tissue healing, researchers have wondered if they could be used to improve the healing of tendons and ligaments. When it comes to healing, there are both good and bad cytokines; some enhance healing but others cause inflammation. Researchers are looking at ways to maximize the helpful cytokines and minimize the inflammatory cytokines.

Research into growth factor treatments is difficult because the effects of growth factors can be very different in vivo than in vitro and because fibroblast cells injured by repetitive motion can react differently to growth factors than normal cells.[1] In a study of carpal tunnel syndrome, wrist ligament cells from injured and uninjured people were exposed to four growth factors, including transforming growth factor beta (TGF-beta).[1] The cells from the injured patients produced abnormally high amounts of Type III collagen and low amounts of Type I collagen when exposed to the growth factors, as compared to the controls. The cells in the injured patients seemed to have been altered by the injury so that their response to growth factors was different. Therefore, studies that use growth factors to improve healing of acute tendon injuries might not apply to healing of tendinosis injuries.

If growth factor treatments don’t seem to produce a good response from cells injured by repetitive motion, autologous stem cell or fibroblast cell treatment could be combined with growth factor treatment; the stem cells or fibroblast cells would provide normal uninjured cells for the growth factors to stimulate, and the growth factors could stimulate them to produce healthy tendon/ligament collagen. See the previous sections on this page for more information about stem cell and fibroblast cell therapy.

Another obstacle with growth factor therapy is that a fine line could exist between too little and too much of the growth factor; too little could cause inability to heal and too much could cause abnormal healing, scar formation, or other negative effects. When wounds and acute injuries heal normally, the body provides the correct balance of growth factors at the correct time in sequence as healing progresses from one stage to the next. More research is needed to investigate whether we can control the timing and the amount of added growth factors well enough to optimize healing. Researchers will need to investigate how the effects of various growth factors depend on the dose, the injury site, the stage in the healing process, and the interactions with other growth factors.

Various delivery methods for growth factors have been tried. Growth factors can be injected directly into the site of injury, but they tend to break down quickly and not maintain constant enough levels. Other researchers have tried implanting controlled-release polymer matrices or microspheres into the injury site to slowly release growth factors into the tissue; these methods could be appropriate for some acute injuries, but a non-surgical method is better for tendinosis. Some researchers have looked at gene therapy delivery methods of growth factors to improve healing of injuries. The Florida clinic mentioned in the stem cell section above is giving growth factors in oral form as part of the stem cell treatment protocol.

The following list of growth factors describes some of the studies that have been done to determine whether these substances can be used to help improve the healing of tendon and ligament injuries.

  • IGF-1
  • Insulin-like growth factor 1, or IGF-1, is a growth factor that is important for tissue healing. It can stimulate an increase in Type I collagen when added to normal fibroblasts.
  • One study showed that tenocytes from healthy equine tendon made more Type I collagen relative to Type III collagen when treated with IFG-1 in vitro.[31] The tendon samples had “greater numbers of larger and more metabolically active fibroblasts,” and IGF-1 enhanced collagen synthesis in a dose dependant manner. The authors suggest that IGF-1 might help treat horses with tendinosis.
  • Several other studies showed that a combination of IGF-1 and platlet-derived growth factor increased the rupture force, stiffness, and breaking energy in rat medial collateral ligaments.[32,33] Also, one study showed that treating injured rat Achilles tendons with IGF-1 reduced the “maximal functional deficit” and the “time to functional recovery.”[34] Another study showed that IGF-1 and IGF-II stimulated collagen, proteoglycan, and DNA synthesis in a dose-dependent manner in rabbit flexor tendon in vitro.[35]
  • IGF-1 was not one of the growth factors tried in the previously mentioned carpal tunnel syndrome study[1], so it would be interesting to discover its effect on cells from tendinosis patients.
  • GDF-5
  • Growth and differentiation factor 5, or GDF-5, has been linked to tendon healing in several studies. One study showed that the tensile strength of healing rat tendons increased in a dose-dependent manner when treated with GDF-5.[36] Another study showed that GDF-5 deficiency caused mouse tail tendon to have a 17% increase in the proportion of medium diameter collagen fibrils at the expense of larger diameter fibrils, as well as a 33% increase in irregularly-shaped polymorphic fibrils.[37] These structural differences did not cause major differences in biomechanical properties of the tendon, but did cause the fibers to relax 11% more slowly than controls during time-dependent stress/relaxation tests. More research would be needed to see if GDF-5 could play a role in the treatment of tendinosis.
  • CDMP-2
  • One research group has investigated the potential for treating tendon injuries with cartilage derived morphogenetic protein, or CDMP-2.[25] This protein is a member of the TGF-beta super family. The researchers treated injured rat Achilles tendons with injections of CDMP-2 and found that the treated tendons were 39% stronger than controls after 8 days. The tendons were also mechanically loaded during healing because the researchers suspected that loading would help the CDMP-2 induce tendon-like tissue instead of bone or cartilage tissue. (The abstract didn’t say if the control tendons were also mechanically loaded; if not, the improved healing could be from the loading rather than from the CDMP-2. Presumably, they loaded both the controls and the treated injuries.)
  • TGF-beta1
  • Transforming growth factor beta1, or TGF-beta1, is a growth factor important in wound and tissue healing. It has been associated with excessive scar tissue formation in some cases. A group of researchers studied the effect of reducing TGF-beta1 because they were looking for a way to reduce the adhesions and scar tissue that commonly form between the site of injured hand flexor tendon and the surrounding tissues.[26,27] These adhesions reduce normal range of motion. Injured rabbit flexor tendons treated with neutralizing antibody to TGF-beta1 had approximately twice as much range of motion as the controls after 8 weeks of healing. This research might not have direct implications for treating tendinosis, but it does show that sometimes lowering growth factors can lead to better healing; more is not always better when it comes to growth factors.
  • BMP-12
  • Bone morphogenic protein 12, or BMP-12, has been shown to improve tendon healing; researchers found that in vivo gene therapy delivery of BMP-12 caused a two-fold increase in tissue strength and stiffness of healing chicken tendons.[38]

Gene Therapy

The science of gene therapy is in its early stages and it is hard to know if it will ever become a part of tendinosis treatment protocol. Gene therapy involves delivering a desired gene into cells and tissues in the patient’s body to achieve therapeutic results. It can mean replacing a defective gene, or adding a gene that will cause cells to make beneficial proteins, or adding a gene that will cause cells to make proteins that will block harmful proteins. When applied to the healing of injuries, gene therapy could deliver a gene that encodes for a protein that would enhance the healing process, such as a growth factor. This method could work better than simply injecting the growth factor directly into the injury because delivery via gene therapy allows the level of the growth factor to be maintained for the long periods of time required for tissue healing. One of the biggest challenges facing gene therapy researchers is finding effective and safe ways to carry the desired gene into the targeted cell. We may never see this type of therapy in actual practice, but research in this area can still contribute to our understanding and could help advance other types of treatments.

For more information about gene therapy, see “Gene Therapy and Tissue Engineering in Sports Medicine”.[43]

Nitric Oxide Synthase

Nitric oxide synthase, or NOS, is an enzyme that reacts with L-arginine (an amino acid) to produce nitric oxide. Researchers found that the three NOS isoforms are up-regulated following tendon injury and that inhibiting NOS activity with oral drugs reduces the cross-sectional area and failure load of healing Achilles tendon in rats.[28,29,30] Further study showed that the three isoforms are expressed by fibroblasts “in a coordinated temporal sequence during tendon healing.”[30] The authors of the third study suggest that each NOS isoform might play a different role in healing and that these substances might be able to be manipulated to achieve therapeutic effects.[30] We don’t know whether any of the NOS isoforms are somehow inhibited in the failed healing process of tendinosis, so the potential of NOS as a therapeutic agent is unknown, but researchers have begun to look at it. One study showed that nitric oxide patches decreased pain and increased range of motion.[58] Some dermal patches are available that can provide NOS to the injured area.


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