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Response to mechanical loading in healing tendons
Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Ruptured tendons heal faster if they are exposed to mechanical loading. Loading creates deformation of the extracellular matrix and cells, which give rise to intracellular signalling, increased gene expression and protein synthesis. The effects of loading have been extensively studied in vitro, and in intact tendons in vivo. However, the response to loading in healing tendons is less known.

The general aim of this thesis was to understand more about the response to mechanical loading during tendon healing. The specific aims were to find out how short daily loading episodes could influence tendon healing, and to understand more about genes involved in tendon healing.

The studies were performed using rat models. Unloading of healing tendons resulted in a weaker callus tissue. This could be reversed to some extent by short daily loading episodes. Loading induced more matrix production, making the tendons thicker and stronger, but there was no improvement in the material properties of the matrix. Lengthening is one potential adversity with early loading, during tendon healing in patients. This was also seen with continuous loading in the rat models. However, short loading episodes did not result in any lengthening, not even when loading was applied during the inflammatory phase of healing. It also appeared as loading once daily was enough to make healing tendons stronger, while loading twice daily with 8 hours interval did not give any additional effect. The strongest gene expression response to one loading episode was seen after 3 hours. The gene expression changes persisted 12 hours after the loading episode but had disappeared by 24 hours. Loading appeared to regulate genes involved in inflammation, wound healing and coagulation, angiogenesis, and production of reactive oxygen species. Inflammation-associated genes were regulated both by continuous loading and by one short loading episode. Inflammation is an important part of the healing response, but too much can be harmful. Loading might therefore have a role in fine-tuning the inflammatory response during healing.

In conclusion, these studies show that short daily loading episodes during early tendon healing could potentially be beneficial for rehabilitation. Loading might have a role in regulating the inflammatory response during healing.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2011. , 86 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1247
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-70774ISBN: 978-91-7393-166-3 (print)OAI: oai:DiVA.org:liu-70774DiVA: diva2:441502
Public defence
2011-09-09, Nils-Holger salen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2011-09-16 Created: 2011-09-16 Last updated: 2012-03-27Bibliographically approved
List of papers
1. Tissue memory in healing tendons: short loading episodes stimulate healing
Open this publication in new window or tab >>Tissue memory in healing tendons: short loading episodes stimulate healing
2009 (English)In: JOURNAL OF APPLIED PHYSIOLOGY, ISSN 8750-7587, Vol. 107, no 2, 417-421 p.Article in journal (Refereed) Published
Abstract [en]

Intact tendons adapt slowly to changes in mechanical loading, whereas in healing tendons the effect of mechanical loading or its absence is dramatic. The longevity of the response to a single loading episode is, however, unknown. We hypothesized that the tissue has a "memory" of loading episodes and that therefore short loadings are sufficient to elicit improved healing. The Achilles tendon of 70 female rats was transected and unloaded by tail suspension for 12 days (suspension started on day 2 after surgery). Each day, the rats were let down from suspension for short daily training episodes according to different regimes: 15 min of cage activity or treadmill running for 15, 30, 60, or 2 x 15 min. Rats with transected Achilles tendons and full-time cage activity served as controls. The results demonstrated that full-time cage activity increased the peak force over three times compared with unloading. Short daily loading episodes (treadmill running) increased the peak force about half as much as full-time activity. Prolongation of treadmill running above 15 min or dividing the daily training in two separate episodes had minimal further effect. This mechanical stimulation increased the cross-sectional area but had no effect on the mechanical properties of the repair tissue. The findings indicate that once the tissue had received information from a certain loading type and level, this is "memorized" and leads to a response lasting many hours. This suggests that patients might be allowed early short loading episodes following, e. g., an Achilles tendon rupture for a better outcome.

Keyword
hindlimb suspension, immobilization, Achilles tendon, tendon healing, mechanical stimulation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19914 (URN)10.1152/japplphysiol.00414.2009 (DOI)
Available from: 2009-08-14 Created: 2009-08-14 Last updated: 2012-03-27
2. Achilles tendon healing in rats is improved by intermittent mechanical loading during the inflammatory phase
Open this publication in new window or tab >>Achilles tendon healing in rats is improved by intermittent mechanical loading during the inflammatory phase
2012 (English)In: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 30, no 2, 274-279 p.Article in journal (Refereed) Published
Abstract [en]

Tendons adapt to changes in mechanical loading, and numerous animal studiesshow that immobilization of a healing tendon is detrimental to the healingprocess. The present study addresses whether the effects of a few episodes ofmechanical loading are different during different phases of healing. Fifty femalerats underwent Achilles tendon transection, and their hind limbs were unloadedby tail suspension on the day after surgery. One group of 10 rats was taken downfrom suspension to walk on a treadmill for 30 minutes per day, on days 2-5 aftertransection. They were euthanized on day 8. Another group underwent similartreadmill running on days 8-11 and was euthanized on day 14. Completelyunloaded groups were euthanized on day 8 and 14. Tendon specimens were thenevaluated mechanically. The results showed that just 4 loading episodesincreased the strength of the healing tendon. This was evident irrespective of thetime-point when loading was applied (early or late). The positive effect on earlyhealing was unexpected, considering that the mechanical stimulation was appliedduring the inflammatory phase, when the calluses were small and fragile. Ahistological study of additional groups with early loading also showed someincreased bleeding in the loaded calluses. Our results indicate that a smallamount of early loading may improve the outcome of tendon healing. This couldbe of interest to clinical practice.

Place, publisher, year, edition, pages
Wiley Online Library, 2012
Keyword
Early loading, tail-suspension, unloading, mechanical testing, cell differentiation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-70772 (URN)10.1002/jor.21511 (DOI)000298581200016 ()
Note

funding agencies|Swedish National Centre for Research in Sports||Swedish Research Council| VR 2009-6725 |Ostergotland County Council||

Available from: 2011-09-16 Created: 2011-09-16 Last updated: 2017-12-08Bibliographically approved
3. Rat Achilles tendon healing: mechanical loading and gene expression
Open this publication in new window or tab >>Rat Achilles tendon healing: mechanical loading and gene expression
2009 (English)In: JOURNAL OF APPLIED PHYSIOLOGY, ISSN 8750-7587, Vol. 107, no 2, 399-407 p.Article in journal (Refereed) Published
Abstract [en]

Injured tendons require mechanical tension for optimal healing, but it is unclear which genes are upregulated and responsible for this effect. We unloaded one Achilles tendon in rats by Botox injections in the calf muscles. The tendon was then transected and left to heal. We studied mechanical properties of the tendon calluses, as well as mRNA expression, and compared them with loaded controls. Tendon calluses were studied 3, 8, 14, and 21 days after transection. Intact tendons were studied similarly for comparison. Altogether 110 rats were used. The genes were chosen for proteins marking inflammation, growth, extracellular matrix, and tendon specificity. In intact tendons, procollagen III and tenascin-C were more expressed in loaded than unloaded tendons, but none of the other genes was affected. In healing tendons, loading status had small effects on the selected genes. However, TNF-alpha transforming growth factor-beta 1, and procollagens I and III were less expressed in loaded callus tissue at day 3. At day 8 procollagens I and III, lysyl oxidase, and scleraxis had a lower expression in loaded calluses. However, by days 14 and 21, procollagen I, cartilage oligomeric matrix protein, tenascin-C, tenomodulin, and scleraxis were all more expressed in loaded calluses. In healing tendons, the transverse area was larger in loaded samples, but material properties were unaffected, or even impaired. Thus mechanical loading is important for growth of the callus but not its mechanical quality. The main effect of loading during healing might thereby be sought among growth stimulators. In the late phase of healing, tendon-specific genes (scleraxis and tenomodulin) were upregulated with loading, and the healing tissue might to some extent represent a regenerate rather than a scar.

Keyword
unloading, tendon healing, inflammation, extracellular matrix, mechanobiology
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19899 (URN)10.1152/japplphysiol.91563.2008 (DOI)
Available from: 2009-08-14 Created: 2009-08-14 Last updated: 2012-03-27
4. Mechanical load and BMP signaling during tendon repair: A role for follistatin?
Open this publication in new window or tab >>Mechanical load and BMP signaling during tendon repair: A role for follistatin?
2008 (English)In: Clinical Orthopaedics and Related Research, ISSN 0009-921X, E-ISSN 1528-1132, Vol. 466, no 7, 1592-1597 p.Article in journal (Refereed) Published
Abstract [en]

Healing of the rat Achilles tendon is sensitive to mechanical loading, and the callus strength is reduced by 3/4 after 14 days, if loading is prevented. Exogenous GDFs stimulate tendon healing. This response is influenced by loading: without loading, cartilage and bone formation is initiated. This implies BMP signaling is crucial during tendon healing and influenced by mechanical loading. We therefore asked if mechanical loading influences the gene expression of the BMP signaling system in intact and healing tendons, and how the BMP signaling system changes during healing. The genes were four BMPs (OP-1/BMP-7, GDF-5/CDMP-1/BMP-14, GDF-6/CDMP2/BMP-13, and GDF-7/CDMP-3/BMP-12), two receptors (BMPR1b and BMPR2), and the antagonists follistatin and noggin. The Achilles tendon was transected in rats and left to heal. Half of the rats had one Achilles tendon unloaded by injection of Botox in the calf muscles. Ten tendons were analyzed before transection and for each of four time points. All genes except noggin were expressed at all points, but followed different patterns during healing. Loading strongly decreased the expression of follistatin, which could lead to increased signaling. The BMP system appears involved in tendon maintenance and healing, and may respond to mechanical loading.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-45883 (URN)10.1007/s11999-008-0253-0 (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13
5. Myostatin in tendon maintenance and repair
Open this publication in new window or tab >>Myostatin in tendon maintenance and repair
Show others...
2009 (English)In: Growth Factors, ISSN 0897-7194, Vol. 27, no 4, 247-254 p.Article in journal (Refereed) Published
Abstract [en]

Myostatin, a negative regulator of muscle growth, has recently been found to be expressed in tendons. Myostatin-deficient mice have weak and brittle tendons, which suggest that myostatin could be important for tendon maintenance. Follistatin expression in the callus tissue after tendon transection is influenced by loading. We found that follistatin antagonises myostatin, but not GDF-5 or OP-1 in vitro. To study if myostatin might play a physiological role in soft tissue, we transected 64 rat Achilles tendons and studied the gene expression for myostatin and its receptors at four different time-points during healing. Intact tendons were also studied. All samples were studied with or without mechanical loading. Unloading was achieved with botulinum toxin injections in the calf muscles. The expression of the myostatin gene was more than 40 times higher in intact tendons than in the callus tissue during tendon healing. The expression of myostatin was also influenced by loading status in both intact and healing tendons. Thereafter, we measured the mechanical properties of healing tendons after local myostatin administration. This treatment increased the volume and the contraction of the callus after 8 days, but did not improve its strength. Our results indicate that myostatin plays a positive role in tendon maintenance and that exogenous protein administration stimulates proliferation and growth of early repair tissue. However, no effect on further development towards connective tissue formation was found.

Keyword
GDF-8; myostatin; follistatin; gene expression; mechanical loading; Achilles tendon
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20180 (URN)10.1080/08977190903052539 (DOI)
Available from: 2009-09-02 Created: 2009-08-31 Last updated: 2012-03-27Bibliographically approved
6. Influence of a single loading episode on gene expression in healing rat Achilles tendons
Open this publication in new window or tab >>Influence of a single loading episode on gene expression in healing rat Achilles tendons
2012 (English)In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 112, no 2, 279-288 p.Article in journal (Refereed) Published
Abstract [en]

Mechanical loading stimulates tendon healing via mechanisms that are largely unknown. Genes will be differently regulated in loaded healing tendons, compared to unloaded, just because of the fact that healing processes have been changed. In order to avoid such secondary effects and study the effect of loading per se, we therefore studied the gene expression response shortly after a single loading episode in otherwise unloaded healing tendons.

The Achilles tendon was transected in 30 tail suspended rats. The animals were let down from the suspension to load their tendons on a treadmill for 30 min once, 5 days after tendon transection. Gene expression was studied by Affymetrix microarray before, and 3, 12, 24 and 48 h after loading. The strongest response in gene expression was seen 3 hours after loading, when 150 genes were up- or down-regulated (fold change≥ 2, p≤0.05). 12 hours after loading, only 3 genes were up-regulated, while 38 were down-regulated. Less than 7 genes were regulated after 24 and 48 hours. Genes involved in the inflammatory response were strongly regulated at 3 and 12 hours after loading; this included up-regulation of iNOS, PGE synthase, and IL-1β. Also genes involved in wound healing/coagulation, angiogenesis and production of reactive oxygen species were strongly regulated by loading. Microarray results were confirmed for 14 selected genes in a repeat experiment (N=30 rats) using real-time PCR. It was also confirmed that a single loading episode on day 5 increased the strength of the healing tendon on day 12. The fact that there were hardly any regulated genes 24 h after loading suggests that optimal stimulation of healing requires a mechanical loading stimulus every day.

Place, publisher, year, edition, pages
AMER PHYSIOLOGICAL SOC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA, 2012
Keyword
Gene expression, tendons, healing
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-70773 (URN)10.1152/japplphysiol.00858.2011 (DOI)000299318400006 ()
Note
funding agencies|Board of Research at the Karolinska Institute||Research Committee at the Karolinska Hospital||Swedish Research Council| 2009-6725 |Swedish National Centre for Research in Sports||King Gustaf V and Queen Victoria Free Mason Foundation||Available from: 2011-09-16 Created: 2011-09-16 Last updated: 2017-12-08Bibliographically approved

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