scholarly journals Different gene response to mechanical loading during early and late phases of rat Achilles tendon healing

2017 ◽  
Vol 123 (4) ◽  
pp. 800-815 ◽  
Author(s):  
M. Hammerman ◽  
P. Blomgran ◽  
A. Dansac ◽  
P. Eliasson ◽  
P. Aspenberg
Keyword(s):  
Transcription Factors ◽  
Achilles Tendon ◽  
Mechanical Loading ◽  
Tendon Healing ◽  
Treadmill Running ◽  
Inflammatory Phase ◽  
Gene Response ◽  
Healing Phase ◽  
Two Phases ◽  
The Right

Mechanical loading stimulates tendon healing both when applied in the inflammatory phase and in the early remodeling phase of the process, although not necessarily via the same mechanisms. We investigated the gene response to mechanical loading in these two phases of tendon healing. The right Achilles tendon in rats was transected, and the hindlimbs were unloaded by tail suspension. The rats were exposed to 5 min of treadmill running 3 or 14 days after tendon transection. Thereafter, they were resuspended for 15 min or 3 h until euthanasia. The controls were suspended continuously. Gene analysis was first performed by microarray analysis followed by quantitative RT-PCR on selected genes, focusing on inflammation. Fifteen minutes after loading, the most important genes seemed to be the transcription factors EGR1 and C-FOS, regardless of healing phase. These transcription factors might promote tendon cell proliferation and differentiation, stimulate collagen production, and regulate inflammation. Three hours after loading on day 3, inflammation was strongly affected. Seven inflammation-related genes were upregulated according to PCR: CCL20, CCL7, IL-6, NFIL3, PTX3, SOCS1, and TLR2. These genes can be connected to macrophages, T cells, and recruitment of leukocytes. According to Ingenuity Pathway Analysis, the recruitment of leukocytes was increased by loading on day 3, which also was confirmed by histology. This inflammation-related gene response was not seen on day 14. Our results suggest that the immediate gene response after mechanical loading is similar in the early and late phases of healing but the late gene response is different. NEW & NOTEWORTHY This study investigates the direct effect of mechanical loading on gene expression during different healing phases in tendon healing. One isolated episode of mechanical loading was studied in otherwise unloaded healing tendons. This enabled us to study a time sequence, i.e., which genes were the first ones to be regulated after the loading episode.

Response of the Injured Tendon to Growth Factors in the Presence or Absence of the Paratenon

2018 ◽  
Vol 47 (2) ◽  
pp. 462-467 ◽  
Author(s):  
Sebastian A. Müller ◽  
Nicholas P. Quirk ◽  
Julia A. Müller-Lebschi ◽  
Patricia E. Heisterbach ◽  
Lutz Dürselen ◽  
...  
Keyword(s):  
Growth Factors ◽  
Achilles Tendon ◽  
Platelet Rich Plasma ◽  
Tendon Repair ◽  
Tendon Healing ◽  
Cross Sectional ◽  
Autologous Conditioned Serum ◽  
Injured Tendon ◽  
The Right ◽  
Exogenous Growth Factors

Background: The paratenon is important for Achilles tendon healing. There is much interest in the use of exogenous growth factors (GFs) as potential agents for accelerating the healing of damaged Achilles tendons. Purpose/Hypothesis: The present study used a rat model to study the responses of the injured Achilles tendon to GFs in the presence or absence of the paratenon. The hypothesis was that responses of the injured tendon to GFs would be lower in the absence of a paratenon. Study Design: Controlled laboratory study. Methods: A 4-mm defect was created in the right Achilles tendon of 60 skeletally mature rats, which were treated with a validated combination of GFs (bFGF, BMP-12, and TGF-β1). Animals were randomly assigned to the intact paratenon (IP) group or resected paratenon (RP) group. Healing was studied anatomically, mechanically, and histologically after 1, 2, and 4 weeks. Results: IP tendons showed improved healing compared with RP tendons. IP tendons were significantly stronger (32.2 N and 48.9 N, respectively) than RP tendons (20.1 N and 31.1 N, respectively) after 1 and 2 weeks. IP tendons did not elongate as much as RP tendons and had greater cross-sectional areas (18.0 mm2, 14.4 mm2, and 16.4 mm2, respectively) after 1, 2, and 4 weeks compared with RP tendons (10.5 mm2, 8.4 mm2, and 11.9 mm2, respectively). On histology, earlier collagen deposition and parallel orientation of fibrils were found for IP tendons. Conclusion: The paratenon is essential for efficient Achilles tendon healing. Healing with GFs in this Achilles tendon defect model was superior in the presence of the paratenon. Clinical Relevance: Biological approaches to tendon engineering using GFs are in vogue and have been shown to improve healing of the rat Achilles tendon, most likely by inducing progenitor cells located within the paratenon. Clinically, resection or incision of the paratenon has been proposed for wound closure. Our data demonstrate the fundamental importance of the paratenon, which therefore should be preserved during Achilles tendon repair, especially if augmented with products such as platelet-rich plasma or autologous conditioned serum that are rich in GFs.

Improved Healing of Transected Rabbit Achilles Tendon after a Single Injection of Cartilage-Derived Morphogenetic Protein-2

2003 ◽  
Vol 31 (4) ◽  
pp. 555-559 ◽  
Author(s):  
Carina Forslund ◽  
Per Aspenberg
Keyword(s):  
Achilles Tendon ◽  
Single Injection ◽  
Rabbit Model ◽  
Tendon Healing ◽  
Radiographic Examination ◽  
Morphogenetic Protein ◽  
Tendon Ruptures ◽  
The Right ◽  
Callus Size ◽  
Positive Effect

Background Achilles tendon ruptures in humans might be treated more efficiently with the help of a growth factor. Cartilage-derived morphogenetic protein-2 has been shown to induce formation of tendon-like tissue. Hypothesis Cartilage-derived morphogenetic protein-2 has a positive effect on mechanical parameters for tendon healing in a rabbit model with Achilles tendon transection. Study Design Controlled laboratory study. Methods The right Achilles tendon of 40 rabbits was transected without tendon suture. Cartilage-derived morphogenetic protein-2 (10 μg) or vehicle control (acetate buffer) was injected locally 2 hours postoperatively. All tendons were tested biomechanically at 8 and 14 days, and treated tendons were histologically and radiographically evaluated at 56 days. Results At 14 days, both failure load and stiffness of treated tendons were increased by 35%. The treated tendons had significantly larger callus size at 8 and 14 days. Histologic and radiographic examination showed no signs of ossification in the treated tendons after 56 days. Conclusions A single injection of cartilage-derived morphogenetic protein-2 led to a stronger and stiffer tendon callus than that in the controls without inducing bone formation. Clinical Relevance Similar results from a larger animal model would suggest a possible future use of cartilage-derived morphogenetic protein-2 in the treatment of human Achilles tendon ruptures.

Rat Achilles tendon healing: mechanical loading and gene expression

2009 ◽  
Vol 107 (2) ◽  
pp. 399-407 ◽  
Author(s):  
Pernilla Eliasson ◽  
Therese Andersson ◽  
Per Aspenberg
Keyword(s):  
Achilles Tendon ◽  
Mechanical Loading ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Lysyl Oxidase ◽  
Late Phase ◽  
Tendon Healing ◽  
Transforming Growth Factor Β1 ◽  
Tenascin C ◽  
Transverse Area

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-α transforming growth factor-β1, 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.

scholarly journals Response to mechanical loading in rat Achilles tendon healing is influenced by the microbiome

PLoS ONE ◽  
2020 ◽  
Vol 15 (3) ◽  
pp. e0229908
Author(s):  
Franciele Dietrich-Zagonel ◽  
Malin Hammerman ◽  
Pernilla Eliasson ◽  
Per Aspenberg
Keyword(s):  
Achilles Tendon ◽  
Mechanical Loading ◽  
Tendon Healing

Tissue memory in healing tendons: short loading episodes stimulate healing

2009 ◽  
Vol 107 (2) ◽  
pp. 417-421 ◽  
Author(s):  
Therese Andersson ◽  
Pernilla Eliasson ◽  
Per Aspenberg
Keyword(s):  
Achilles Tendon ◽  
Mechanical Loading ◽  
Achilles Tendon Rupture ◽  
Peak Force ◽  
Treadmill Running ◽  
Female Rats ◽  
Full Time ◽  
Time Activity ◽  
Cage Activity ◽  
Daily Training

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 × 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.

scholarly journals Diminishing effects of mechanical loading over time during rat Achilles tendon healing

2020 ◽  
Author(s):  
Hanifeh Khayyeri ◽  
Malin Hammerman ◽  
Mikael J Turunen ◽  
Parmis Blomgran ◽  
Thomas Notermans ◽  
...  
Keyword(s):  
Achilles Tendon ◽  
Mechanical Loading ◽  
Biological Activities ◽  
Tendon Healing ◽  
Early Time ◽  
Peripheral Region ◽  
Sprague Dawley ◽  
Post Injury ◽  
Normal Loading ◽  
Over Time

AbstractMechanical loading affects tendon healing and recovery. However, our understanding about how physical loading affects recovery of viscoelastic functions, collagen production and tissue organisation is limited. The objective of this study was to investigate how different magnitudes of loading affects biomechanical and collagen properties of healing Achilles tendons over time.Achilles tendon from female Sprague Dawley rats were cut transversely and divided into two groups; normal loading (control) and reduced loading by Botox (unloading). The rats were sacrificed at 1, 2- and 4-weeks post-injury and mechanical testing (creep test and load to failure), small angle x-ray scattering (SAXS) and histological analysis were performed.The effect of unloading was primarily seen at the early time points, with inferior mechanical and collagen properties (SAXS), and reduced histological maturation of the tissue in unloaded compared to loaded tendons. However, by 4 weeks no differences remained. SAXS and histology revealed heterogeneous tissue maturation with more mature tissue at the peripheral region compared to the center of the callus. Thus, mechanical loading advances Achilles tendon biomechanical and collagen properties earlier compared to unloaded tendons, and the spatial variation in tissue maturation and collagen organization across the callus suggests important regional (mechano-) biological activities that require more investigation.

Effects of Exercise on Achilles Tendon Healing in a Rat Model

1998 ◽  
Vol 19 (9) ◽  
pp. 598-603 ◽  
Author(s):  
George A.C. Murrell ◽  
Daniel Jang ◽  
Xiang-Hua Deng ◽  
Jo A. Hannafin ◽  
Russell F. Warren
Keyword(s):  
Achilles Tendon ◽  
Internal Control ◽  
Rat Model ◽  
Detrimental Effect ◽  
Functional Performance ◽  
Tendon Healing ◽  
Exercise Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
The Right

The effects of motion, or lack of it, on Achilles tendon healing are not well defined. We have recently shown that immobilization has a detrimental effect on tendon healing in a rat model. The aim of this experiment was to determine whether enforced exercise had an additional beneficial effect on the mechanical and functional recovery of divided Achilles tendons in rats. Male Sprague-Dawley rats were randomly allocated into a nonexercise and an exercise group (N = 10 for each group). In both groups the right Achilles tendon was surgically transected. The left, uninjured lower limb served as an internal control. Both groups of animals were housed under identical conditions with the exception that the exercise group swam for 15 minutes per day. Functional performance was determined from the measurement of hindpaw prints of walking rats preoperatively and on alternate postoperative days. On day 15, the animals were killed and weighed, and biomechanical evaluations were performed on both the injured and uninjured Achilles tendon constructs. There were no differences in weight at time of death. All animals had an initial functional deficit that returned to near-normal by day 15. There were significant differences in the morphological and the mechanical properties of the healing Achilles tendon constructs at day 15 when comparing the injured with the uninjured Achilles tendon constructs. Supplemental exercise, however, had no effect on the functional or mechanical recovery of injured or uninjured Achilles tendons in the rat model.

scholarly journals Diminishing effects of mechanical loading over time during rat Achilles tendon healing

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0236681
Author(s):  
Hanifeh Khayyeri ◽  
Malin Hammerman ◽  
Mikael J. Turunen ◽  
Parmis Blomgran ◽  
Thomas Notermans ◽  
...  
Keyword(s):  
Achilles Tendon ◽  
Mechanical Loading ◽  
Biological Activities ◽  
Tendon Healing ◽  
Early Time ◽  
Peripheral Region ◽  
Sprague Dawley ◽  
Post Injury ◽  
Normal Loading ◽  
Over Time

Mechanical loading affects tendon healing and recovery. However, our understanding about how physical loading affects recovery of viscoelastic functions, collagen production and tissue organisation is limited. The objective of this study was to investigate how different magnitudes of loading affects biomechanical and collagen properties of healing Achilles tendons over time. Achilles tendon from female Sprague Dawley rats were cut transversely and divided into two groups; normal loading (control) and reduced loading by Botox (unloading). The rats were sacrificed at 1, 2- and 4-weeks post-injury and mechanical testing (creep test and load to failure), small angle x-ray scattering (SAXS) and histological analysis were performed. The effect of unloading was primarily seen at the early time points, with inferior mechanical and collagen properties (SAXS), and reduced histological maturation of the tissue in unloaded compared to loaded tendons. However, by 4 weeks no differences remained. SAXS and histology revealed heterogeneous tissue maturation with more mature tissue at the peripheral region compared to the center of the callus. Thus, mechanical loading advances Achilles tendon biomechanical and collagen properties earlier compared to unloaded tendons, and the spatial variation in tissue maturation and collagen organization across the callus suggests important regional (mechano-) biological activities that require more investigation.

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