The Healing Effects on Tendons or Ligaments - Essay Example

The Healing Effects on Tendons or Ligaments ABSTRACT Objective: To review research related to IGF-1 and the ability to improve the healing effects on tendons or ligaments. Design: This is a systematic review of Longitudinal studies done on the healing possibilities of IGF-I on tendons and ligaments. Methods: Research was included from databases to March 2010: Science Direct, Web of Knowledge, Medline, Ebscohost, and ProQuest, and the National Research Register. One reviewer selected studies meeting the inclusion criteria. That reviewer then reviewed each article for quality of information and collected articles to be used in this literature review after reading and cross referencing data. ResultsTen studies were kept as part of the review and all ten studies showed varying positive effects of IGF-I on the improvement of healing in tendons and ligaments. Only two of these ten studies were actually conducted using human ligaments or tendons. Most of the studies used between 6 and 10 subjects or tendon sets. : Studies showed positive results on tendon and ligament healing with IGF-1. Conclusion: All of the studies indicate positive results in the healing process for tendons as well as ligaments. There are still many unknowns. The healing effect has been shown but not clearly in live tendons or human tendons. There is also a continued need for further well-defined study in the form of human clinical trials with a larger number of participants. These trials should be specific to tendon and ligament injury. Introduction Tendon and ligament injury can be devastating. Healing can be long and arduous and even when healed there may be scar tissue that prevents full use of the tendon or ligament, preventing the patient from being able to support the amount of loading in that area that was allowed before. This review of research is to determine if IGF-1 is able to improve the method of healing in such a way that the process is improved and faster providing for less scar tissue and allowing better use of the tendon or ligament after healing. IGF-1 is a natural molecular structure similar to insulin (insulin-like-growth-factor-1). As a natural growth hormone, it is produced by the body allowing children to grow. It consists of a number of interconnected amino acids that make up a single chain and that chain is called IGF-1. The primary purpose of this hormone is to stimulate cell growth and many kinds of cells are affected. The interest of this research is to determine if the cells of tendons and ligaments are affected in such a positive manner to allow those cells to be repaired. Tendons have shown an ability to adapt to changes in mechanical loading and injury. They consist of what is seen as a dense extracellular matrix that has collagen as the major protein. IGF-1 is one substance that is promising in the mediation of the effects of the tendon to produce collagen. If collagen is effectively produced at the time of the tendon or ligament injury, it is supposed that the tendon might heal better. IGF-1 has been shown to be highly effective during the inflammatory phase of a healing process in studies using animal and human tendons but what about the healing phase? It also has shown to aid in the proliferation and migration of fibroblasts and to subsequently increase collagen production. [1] Studies with rats, such as the one done by Scott (2008), shows that IGF-1 may be a potent stimulator that is available for many kinds of tissues. In increasing the amount of collagen produced, it adapts itself well to the possibility of healing without scaring. The principles of tendon healing are somewhat different than healing of other tissues. Most tendons have the ability to heal themselves but when they do there is a great deal of scar tissue that leads to the tendon being less effective than prior to injury. [1] The use of surgery and other methods of healing tendons have been less than effective for many years. This has led to much research based on the search for an effective way to heal quicker and without scar tissue build up. The understanding of the mechanism of use in IGF-1 is very important in the future of this research. It is known at this time that injured tissues that are lacking in IGF-1 are somewhat disadvantaged in healing. This can occur for many reasons. Some of the activities that IGF show during the healing process are stimulation of the migration as well as increased numbers of fibroblasts, and then increase the production of collagens and other extracellular matrix structures as well as stimulating cells to produce this collagen. [1] There have been many recent studies on different types of injuries as well as tendons and ligaments of different kinds. This paper will discuss the affects of that increase in collagen and healing effect by review of some of the research done on both animal and human tendons. Methods The databases of MEDLINE, CINAHL, National Research Register, Web of Knowledge and Science Direct, ProQuest, and EbscoHost, were searched. There were no date restrictions placed on any of the searches. The databases were searched up to March of 2010. One reviewer screened and reviewed the articles and studies using the inclusion and exclusion criteria. Those that met the inclusion criteria were copied for review. The same reviewer reviewed each article and collected data related to this study. The studies that were eliminated were related to other types of tissue such as cancer or chronic muscle disease. Table 1 Selection Criteria Inclusion Criteria Population Tendons from animals or human that have been injured in study or naturally Interventions Use of IGF-1 for enhanced healing Outcome Measures Any relevant studied outcome. Study design Systematic cross-sectional research Exclusion Criteria Population None Intervention IGF-1 combined with gene therapy, exercise therapy Outcome Measures Those studies that show an end result whether positive or negative Study designs Studies without control group and random allocation Study List Study Design Population Outcome Methods Anima/Human 1. Olesen, Heinemeier, Langberg, 2006 Longitudinal N=12 IGF-1 shows improvement in natural tendon repair RNA and IGF-1 were determined by optical density studies Human, male, 6 caucasion, 6 black, postmortem 2. Provenzana, Osario, Grorud, 2007 Longitudinal N=12 IGF-1 showed positive results in improving healing of tendons Studied tendons that had been electrically stimulated Animal Rats and dogs with hind quarter injuries. 3. Scott, Cook, Hart, 2007 Longitudinal N=6 IGF-1 shows positive results in improving healing of exhausted tendon Ran rats down hill over time, exhausting tendon, removal of tendons for RNA and IGF-I study Animal, Rats 4. Hyde, Hollier, Anderson 2004 Longitudinal N=6 + DNA synthesis with addition of IGF-1` Tendon surgical damage tested with addition of IGF-1. Animal, Rats 5. Olesen, Heinemeier, Haddad 2006 Longitudinal N=12 + increase in fibroblast and collagen stimulation with addition of IGF-1 Tendons that were reseted were tested for RNA and IGF-1 and stimulation of collagen. Animal, Rats 6. Dahlgren, Mohammed and Nixon 2008 Longitudinal N=14 + tendon healing shown with IGF-1 by increasing collagen production Induced injury in forelimbs. Removal of tendons and studied improvement with IGF-1 Animal, Horses 7. Heinemeier, Olesen, Haddad 2008 Longitudinal N=6 +results shown in healing with use of IGF-1 Induced injury, harvested tendons after injury for study Animal, Rats 8. Dahlgren, vander Meulen, Bertram 2002 Longitudinal N=8 Reduced size of lesions created on tendons within 4 weeks. Induced surgical injury to forelimbs of horses and treated over time with IGF-1. Horses treated with IGF-I showed the best healing. Animal, Horses 9. Doessing, 2007 Longitudinal N=6 IGF-1 improved collagen synthesis needed for healing. IGF-1 was given to live humans to test improvement in inflamed and injured tendons. Control group was used with saline injection Human, healthy, young with tendon injuries. 10. Kjaer, Langberg, Heinemeier 2009 Longitudenal N=6 IGF-1 improved collagen synthesis in stressed tendons Placed overload on tendons, injuring and studied response to IGF-1 and control Animal, dogs Search Results Results Olesen, Heinemeier, and Langberg et.al. (2006) [1] used human Achilles tendons in their research. The objective was to determine the presence and response of IGF-1 in the human tendon whether or not it has been injured. This study magnifies the potential of IGF-1 in the healing process of tendons and ligaments, demonstrating its effectiveness, and demonstrating the need for continued study. Olesen, et.al. (2006), chose to use post mortem Achilles tendons of forensic autopsies for study of the effect of IGF-1 on tendon healing. Six patients were used, all men, three black and three Caucasian. The cause of death had nothing to do with the tendons so there was no immediate injury to them. The Achilles tendons were removed from the body within twenty four hours of death and frozen. RNA was removed from the frozen samples as well as IGF-1. RNA concentration was determined by an optical density and IGF-I was measured using an immunohistochemical technique. The result showed that there was, in fact, both transcription and translation of IGF-1 that took place in the Achilles tendon and that IGF-1 encouraged the fibroblasts. The goal was to measure the concentration of RNA and IGF-1. The results showed that IGF-1 was concentrated near the fibroblast with every study. The IGF-1 peptide came from the translation of the IGF-1 in the Achilles tendon. This study confirms that IGF-1 is very important in the natural repair of tendons and ligaments. Provenzano, Alejandro-Osorio, and Grorud (2007) [2] further illustrated that IGF-1 played a crucial role in wound healing and tissue repair. They believed there was a direct connection between healing of ligaments and IGF-1. They used rats and other animals with hind limb injury to the extent of not being able to use the limb. They split their participants into three groups. The first was ambulatory sham control, the second ambulatory-healing, and the third hind limb unloaded-healing. The medial lateral ligaments of the knees were surgically altered. The control group was given saline injections, the study group was given IGF-1 and a second study group was given IGF-1+GH. Three weeks later they studied these same animals for tendon healing. [2] The amount of healing was noted in each of the groups as the three weeks passed and the data was recorded. The results were that the ligaments that were treated with IGF-1 alone healed faster and stronger than the other two groups. There were several methods of study used throughout this experiment. They were biomechanical testing, histology, and immunohistochemistry as well as multiphoton laser scanning microscopy, western blot analysis, and statistical analysis. Scott, Cook, and Hart et.al. (2007) performed a study that was quite similar in results. They felt that they could show an increase in IGF-1 in an over exercised and exhausted tendon. They accomplished the exhaustion by running a group of rats downhill, exhausting them to the point of causing tendon injury. They ran down hill at 1 km per hours for 1 hour per day for several weeks. These tendons were then harvested for study at 4, 8, 12, and 16 weeks. Processing was then done using brightfield, polarized light, or transmission electron microscopy. [3] IGF-1 expression was determined by computer-assisted quantification of immunchistochemical reaction. The results of the study showed that tendinosis was present at the end of 12 week time period. There was also an increased IGF-1 expression. This study indicates to the researchers that tendon injury does naturally increase the amount of IGF-1 to help increase tendon repair. [3] It was a strong, well conducted study done over time in such a way as to allow information to be generated over the full injury as well as the full healing process of these tendons. Hyde C., Hollier B., Anderson A. et.al. (2004) discovered that IGF-1 proved to be effective in DNA synthesis and regulated cell proliferation and differentiation. [4]. This process with IGF-1, they felt must also increased healing. The insulin effects of IGF-1 in this study also affected cell mobility, allowing the active promotion of active polymerization at the leading edge of the migrating cell. During this study they exposed the tendon tissues to IGF-1 in the study group, saline in the control group and IGF-2 in the second study group. The IGF-1 group improved faster and healed stronger than the other two groups. Throughout the study they used cell cultures, protein synthesis assay, attachment assay, migration assay, and statistical analysis. This study supports the work of Provenzano [2] as well as Olesen and Heinemeier. [5] Olesen J., Heinemeier K., and Haddad F. et.al. (2006). [5] Contended that IGF-1 stimulates a collagen like production of fibroblasts and helps to bind proteins to heal tendons. There have been some earlier studies showing this descriptive behavior of IGF-1 but it has not been in human tendon tissue. Increased loading occurs in the tendon to produce collagen and this is increased by the IGF-1. It then becomes a potent stimulator of protein. Dahlgren, Mohanned, and Nixon (2006) supported this by showing that IGF-1 must be present during mechanical loading in order to increase DNA content. [6] In animals, it is known that IGF-1 stimulates collagen production which is then expressed inn tendons with binding proteins. This causes an increased loading of fibroblasts which is increased by the introduction of IGF-1. This increased loading of fibroblasts and increasing collagen in turn increases healing. Dahlgren, et.al. (2006) showed by increasing tenocyte cultures that IGF-1 increased RNA content. The increased numbers of fibroblasts were tracked as the tendon healing occurred. In animals and humans collagen produced by fibroblasts is expressed in tendons. This study was performed on rested animal tendons shows that indeed the healing process is increased in both animal and human tendons. Dahlgren et.al. (2008) further followed this up by studying the treatment of overused tendons that acquired injuries in an attempt to return an athlete to function. The study was conducted on 14 horse tendons. Realizing ahead of time that there are several kinds of receptors, binding proteins, and proteases, the objective was to attempt to bring a tendon back to use as in an athlete. They created induced lesions in the tensile region of the forelimbs. The tendons were then harvested from euthanized horses [6] every other week until week 24. The protein expression was noted using Western ligand blot. The tendons showed increasing IGF-1 over the period of healing time. This is an important study because the data was well monitored and can help create a protocol for the proper timing to use IGF-1 for tendon healing. It is also important because it shows healing in athletic tendons. Finally, Heinemeier, Olesen, and Haddad et.al. (2008), managed a study on the expression of collagen as it relates to rat tendon repair and skeletal muscle. It is clear that acute exercise induces collagen synthesis in tendons, muscles and connective tissues but how this mechanism works is still unknown. [7] Different contraction types sometimes affect the needs of those tendons, muscles, and connective tissue as to the collagen synthesis that must take place for repair. IGF-1 improves the production of that synthesis but it is not thoroughly understood how. They used the Achilles tendon of rats to study. The rats were anesthsized and the muscles were strained by applying electric current to the rats muscles while sleeping. The sciatic nerve was stimulated during each bout. Twenty four hours after the last bout, the rats were killed and the Achilles tendon was dissected and studied. IGF-1 was then used in one group and the second group was studied for natural IGF-1 being present because of injury. The findings supported the view that IGF-1 is present to improve the healing of tendons damaged by overuse. IGF-1 according to this study helps to build the collagen level, improving healing. Dahlgren, van der Meulen, Marjolein et.al. (2002), investigated the effects of IGF-1 on the healing process in a debilitating tendinitis caused in elite and recreational athletes. They used an equine model for tendinitis. Collagenase induced lesions were created in the tensile region of the forelimbs of eight horses. The horses were then euthanized and the tendons were harvested and DNA, hydoxyproline and glycosaminoglycan content determined. [8] Local soft tissue swelling was reduced in the IGF-1 treated limbs. The lesion size in these limbs was also smaller 3 and 4 weeks after the treatment with IGF-1. Overall the healing process was much stronger in the IGF-1 treated tendons. [8] Doessing (2010) tested the hypothesis that IGF-1 increased collagen and mRNA expression in the injured tendon creating an increased healing process. [9] He tested his hypothesis by giving recombinant human GH and IGF-1 to healthy young volunteers. The IGF-1 was injected directly into live tendon on part of the volunteers and saline was used on the other group. Tendon collagen in those participants that had the IGF-1 showed increased synthesis and muscle collagen. The conclusion of the study was very important and done in February of this year. In this case the collagen production was definitely increased when the participant was given IGF-1 and compared to GH which was given to the second group, and compared to saline which was given to the second group. The final long term results of this study will not be out until July of this year. Kjaer, Langberg, and Heinemeier et.al. (2009), agreed that the adoptive response of tendons and ligaments to loading that was required of them required an increase in the synthesis of proteins and collagen for best healing. They felt that as injury escalates in a tendon or ligament, so does the amount of IGF-1 needed to increase collagen available for the healing process. IGF-1 was found to be increased in tendon and ligament damage. The increase in IGF-1 and procollagen expression showed a similar response. [10] It was also noted by them, that the size and the mechanical use of the tendon or ligament may have some effect on the response of IGF-1 as well as the collagen building process that occurs. Those tendons that are worked the hardest may very well be able to use the IGF-1 the best. This is good news when evaluated for the use of athletic tendon injury. Discussion This review has explored the effectiveness of IGF-1 in the improvement of tendon and ligament healing. After exploring these studies it is apparent that there is more work to be done , however, after the evaluation of these studies, it is noted that IGF-1 does increase the healing in tendons and ligaments. It appears that IGF-1 may have an exciting future. It appears to have multiple uses in improving healing, including the rested and the exercised tendon. Exercise wears out tendons and ligaments and acute exercise can literally destroy them as we have seen during many of these studies. It appears, however, that increasing collagen related to IGF-1 therapy can provide what is needed to heal these over used tendons, or at least to improve them. This certainly begs for attention for sports injuries as well as childhood injuries. It appears from the outcomes of these studies that IGF-1 has a vital fucntion during the early and intermedicate stages of healing, at which time it ads in the migration and proliferation of fibroblasts and stimulates extracellular matrix synthesis that then improves the healing process. It is involved in many kinds of reactions during this process that stimulates the healing process. There was a much improved healing effect when IGF-1 was applied in each of these studies. There has already been some success shown in the use of IGF-1 as a therapeutic and a variety of delivery techniques have been used including direct injection, surgical implant and collagen or gel vehicles. In many of the studies, the application of very few molecules seems to generate a result which seems to boost the healing signal. Longitudinal studies were used which provides more information over time of the tendon healing. This information is extremely important when considering the numbers of debilitating tendon injuries that occur, not only in elite athletes but in many other human injuries. The stimulation of collagen that is shown in each of the studies is also important both in tendon and ligament injuries but in many other kinds of tissue injuries. This is a method of helping the tendon succeed in healing without leaving behind scar tissue that then limits the use of the limb. This review has shown IGF-1 to be an effective addition to improving healing in tendons and ligaments. Review of this research leaves no doubt that IGF-1 helps in tendon and ligament healing and answers the original research question. The next step is where do we go from here? What dose should be used and how often? Is injection directly into the tendon the right method or is there another. What other kinds of tissues will benefit from its use? The answer to the original question brings more questions which, under the circumstances brings the necessity of further research. Reference List 1. Olesen J., Heinemeier K., Langberg H., et.al. Expression, content, and localization of insulin-like growth factor I in human Achilles tendon. C Tiss Re. 2006: 47. 200-206. 2. Provenzano P., Alejandra-Osorio A., Grorud K. Systemic administration of IGF-1 enhances healing in collagenous extracellular matrices: evaluation of loaded and unloaded ligaments. BMC Physiology. 2007: 7(2). 2-24. 3. Scott A., Cook J., Hart D. et.al. Tenocyte responses to mechanical loading in vivo; a role for local insulin-like growth factor 1 signaling in early tendinosis in rats. Arthritis and Rheumatism. 2007:56930. 871-881. 4. Hyde C., Hollier B., Anderson A., et.al. Insulin-like growth factors and IGF binding proteins bound to vitronectin enhance keratinocyte protein synthesis and migration. J Invest Derm. 2004. 122. 1198-1206. 5. Olesen J., Heinemeier K., Haddad F. et.al. Expression of insulin-like growth factor 1, insulin-like growth factor-binding proteins, and collagen mRNA in mechanically loaded plantaris tendon. J. Appl Physiol. 2006: 101 183-188 6. Dahlgren LA, Mohammed HO, Nixxon AJ. Expression of insulin-like growth factor binding proteins in healing tendon lesions. J Orthop Res. 2008: 24(2). 183-192. 7. Heinemeier K., Olesen J., Haddad F. Expression of collagen and related growth factors in rat tendon and skeletal muscle in response to specific contraction types. Inst of Spts Med. 2008; 28. 430-438. 8. Dahlgren L., van der, Meulen M., Bertram J. et.al. Insulin-like growth factor-1 improves cellular and molecular aspects of healing a collagenase-induced model of flexor tendinitis. Journal of Orthopaedic Research. 2002. 20(5). 910. 9. Doessing, S. IGF-1 therapy; new IGF-1 therapy data have been reported by researchers at University of Copenhagen, Institute of Sports Medicine. Hematology Week. 601. 10. Kjaer M., Langberg H., Heinemeier K. et.al. From mechanical loading to collagen synthesis, structural changes and function in human tendon. Scandinavian Journal of medicine and Science. 2009. Oxford: 19(4). 500 Appendix-Computer database search strategy 1. Insulin like growth factor heals tendons, ligaments (1586171) 2. Growth factor and tendon repair (61, 148) 3. IGF-1 and healing tendons (16,148) 4. IGF-1 and tendon healing (9,772) 5. IGF-1 (52, 408) 6. Tendon repair (16, 356) 7. IGF-1 and tendons (532) 8. IGF-I and healing (92) 9. Role of Insulin growth factor in tendon healing (0) 10. Tendon healing and IGF-1 (0) 11. IGF-I and ligaments (5) 12. IGF-I and tendon repair (38) 13. IGF-I and ligament repair (41) Read More