Future Treatments

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. Promising trials have been done in cultured cells and in mice and horses. One of their papers can be found here.

Causeway Therapeutics is the company dedicated to developing and distributing TenoMiR™, which is the microRNA replacement therapy based on the Glasgow research. Their website states, "TenoMiR™ is unique in that it directly targets the key changes in collagen production associated with tendinopathy."

TenoMiR™ will be available as a single injection and will not require a biopsy to collect tissue from the patient like stem cell therapies do.

The company Celixir was developing a topical growth factor gel for the treatment of tendinopathy. The gel contained growth factors derived from platelet lysate, including PDGF-BB, VEGF, PDGF-AA, thrombospondin and angiopoietin. A successful Phase 2 Trial involved patients with chronic elbow tendinopathy who used the gel for 21 days and were followed for 3 months. Patients in the clinical trial were reported to experience an average 7o% improvement on the DASH disability scale and 74% improvement on the PRTEE scale.

Later, the Celixir company seemed to fall apart after accusations of dubious scientific/business practices. Perhaps the topical growth factor treatment concept will be researched by another company because it would be so much easier to administer than injection therapies, if it could be delivered topically in a formulation that reaches the tendon.

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, one source of information is "Gene Therapy and Tissue Engineering in Sports Medicine".[43]

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 tendinopathy.  Some researchers have looked at gene therapy delivery methods of growth factors to improve healing of injuries.

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. 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]

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.

CDMP2: 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.  (Presumably, they loaded both the controls and the treated injuries.)

TGFB-1: 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 tendinopathy, 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]