Bevacizumab Improves Achilles Tendon Repair in a Rat Model

Background/Aims: Effective wound-healing generally requires efficient re-vascularization after injury, ensuring sufficient supply with oxygen, nutrients, and various cell populations. While this applies to most tissues, tendons are mostly avascular in nature and harbor relatively few cells, probably contributing to their poor regenerative capacity. Considering the minimal vascularization of healthy tendons, we hypothesize that controlling angiogenesis in early tendon healing is beneficial for repair tissue quality and function. Methods: To address this hypothesis, Bevacizumab, a monoclonal antibody blocking VEGF-A signaling, was locally injected into the defect area of a complete tenotomy in rat Achilles tendon. At 28 days post-surgery, the defect region was investigated using immunohistochemistry against vascular and lymphatic epitopes. Polarization microscopy and biomechanical testing was used to determine tendon integrity and gait analysis for functional testing in treated vs non-treated animals. Results: Angiogenesis was found to be significantly reduced in the Bevacizumab treated repair tissue, accompanied by significantly reduced cross sectional area, improved matrix organization, increased stiffness and Young’s modulus, maximum load and stress. Further, we observed an improved gait pattern when compared to the vehicle injected control group. Conclusion: Based on the results of this study we propose that reducing angiogenesis after tendon injury can improve tendon repair, potentially representing a novel treatment-option.

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

The American Journal of Sports Medicine ◽

10.1177/0363546518814534 ◽

2018 ◽

Vol 47 (2) ◽

pp. 462-467 ◽

Cited By ~ 2

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.

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Biomechanical Effects of Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD), the Major Constituents of Cannabis, in a Sprague Dawley Rat Achilles Tendon Surgical Repair Model: A Pilot Study

The American Journal of Sports Medicine ◽

10.1177/03635465211016840 ◽

2021 ◽

pp. 036354652110168

Author(s):

Christopher M. Stauch ◽

Brittany Ammerman ◽

Diana Sepulveda ◽

Michael C. Aynardi ◽

Matthew R. Garner ◽

...

Keyword(s):

Pilot Study ◽

Achilles Tendon ◽

Tendon Repair ◽

Tendon Healing ◽

Tensile Load ◽

Control Group ◽

Sprague Dawley ◽

Load To Failure ◽

Strength And Stiffness ◽

Opioid Medications

Background: The use of cannabis is common among athletes and the US population at large. Cannabinoids are currently being evaluated as alternatives to opioid medications for chronic pain management. However, the effects of recreational and/or medical use of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on musculoskeletal injury and healing remain largely unknown. Hypothesis/Purpose: The purpose of this study was to evaluate the biomechanical effects of CBD and THC on tendon-to-tendon healing in a rat Achilles tendon repair model. The hypothesis was that rats administered CBD would demonstrate decreased tensile load to failure of surgically repaired Achilles tendons compared with the THC and control groups. Study Design: Controlled laboratory study. Methods: A total of 33 Sprague Dawley rats underwent Achilles tendon surgical transection and repair and were randomized to receive subcutaneous injection of THC, CBD, or vehicle once daily starting on the day of surgery and for 5 total days. After sacrifice, biomechanical tensile load-displacement testing was performed to determine Achilles tendon load to failure and stiffness. Data were analyzed by 1-way analysis of variance. Results: The THC group demonstrated the highest median load to failure, 18.7 N (95% CI, 15.3-19.2 N); the CBD group had the second highest at 16.9 N (95% CI, 15.1-19.8 N), and the control group had the lowest at 14.4 N (95% CI, 12.1-18.3 N). Stiffness was highest in the THC group at 4.1 N/mm (95% CI, 2.7-5.1 N/mm) compared with 3.6 N/mm (95% CI, 2.9-4.1 N/mm) for the CBD group and 3.6 N/mm (95% CI, 2.8-4.3 N/mm) for the control group. No statistically significant differences for strength and stiffness were observed between the groups. Conclusion: In this pilot study using an animal tendon-to-tendon repair model, neither THC nor CBD resulted in altered biomechanical characteristics compared to control. Clinical Relevance: Cannabinoids do not appear to adversely affect Achilles tendon healing.

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EP.FRI.154 Could Antiangiogenic Drugs be the Solution to Tendon Injury? A Literature Review on the use of Antiangiogenic Drugs for Tendon Regeneration

British Journal of Surgery ◽

10.1093/bjs/znab312.031 ◽

2021 ◽

Vol 108 (Supplement_7) ◽

Author(s):

Chris Kirchhoff

Keyword(s):

Literature Review ◽

Surgical Intervention ◽

Healing Process ◽

Intervention Group ◽

Tendon Healing ◽

Flow Diagram ◽

Current Evidence ◽

Control Group ◽

Cross Sectional ◽

Antiangiogenic Drugs

Abstract Background Tendinopathy accounts for more than half of reported musculoskeletal injuries worldwide. The subsequent healing process results in a disorganised tendon structure secondary to neovascularisation, forming a bulky tendon with overall reduced strength. Current treatment options remain controversial as re-rupture rates following surgical intervention are high. It has been proposed that the use of anti-vascular endothelial growth factors could improve tendon healing. Methods This literature review employed a systematic approach. The search strategy incorporated an adjusted PICO format and PRISMA flow diagram. Search findings were critically appraised using the CASP tool checklist. Identified studies investigated the effect of injectable anti-angiogenic drugs on tendon healing. Results Three final studies were identified. Tempfer et al. showed a reduction in cross sectional tendon area in the intervention group (5.6mm²+1.8), comparatively to the control group (9.1mm² +2.0), and increased tendon strength in the intervention group (47.7N+6.41) comparatively to the control group(32.41N+9.23). Dallaudiere (2014) et al. showed reduced cross-sectional area in the intervention group (0.95mm²+0.01) compared with the control group (0.75mm²+0.01). Dallaudiere (2013) et al. also showed reduced cross sectional areas in the intervention group (1.10mm²+0.01) compared with the control group (1.11mm²+0.03). Conclusion All studies supported the use of anti-angiogenic drugs to support tendon healing. The use of injectable anti-angiogenic drugs may potentially serve in conjunction with surgical intervention or as an alternative minimally invasive intervention to improve tendon rehabilitation. This review recommends that further randomised control studies will be needed to strengthen the current evidence.

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Patients with Achilles Tendon Rupture Have a Degenerated Contralateral Achilles Tendon: An Elastography Study

BioMed Research International ◽

10.1155/2018/2367615 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Qianru Li ◽

Qi Zhang ◽

Yehua Cai ◽

Yinghui Hua

Keyword(s):

Achilles Tendon ◽

Axial Strain ◽

Achilles Tendon Rupture ◽

Cross Sectional Area ◽

Control Group ◽

Computer Assisted ◽

Study Group ◽

Sectional Area ◽

Cross Sectional ◽

The Mean

Purpose. To evaluate differences of Achilles tendon (AT) hardness and morphology between asymptomatic tendons in patients with acute AT ruptures on the contralateral side and asymptomatic tendons in healthy people by using computer-assisted quantification on axial-strain sonoelastography (ASE). Methods. The study consisted of 33 asymptomatic tendons in 33 patients (study group) and 34 tendons in 19 healthy volunteers (control group). All the tendons were examined by both ASE and conventional ultrasound. Computer-assisted quantification on ASE was applied to extract hardness variables, including the mean (Hmean), 20th percentile (H20), median (H50) and skewness (Hsk) of the hardness within tendon, and the ratio of the mean hardness within tendon to that outside tendon (Hratio) and three morphological variables: the thickness (THK), cross-sectional area, and eccentricity (ECC) of tendons. Results. The Hmean, Hsk, H20, H50, and Hratio in the proximal third of the tendon body in study group were significantly smaller than those in control group (Hmean: 0.43±0.09 vs 0.50±0.07, p=0.001; Hsk: -0.53±0.51 vs -1.09±0.51, p<0.001; H20: 0.31±0.10 vs 0.40±0.10, p=0.001; H50: 0.45±0.10 vs 0.53±0.08, p<0.001; Hratio: 1.01±0.25 vs 1.20±0.23, p=0.003). The THK and cross-sectional area of tendons in the study group were larger than those in the control group (p<0.05). Conclusions. As a quantitative objective method, the computer-assisted ASE reveals that the asymptomatic ATs contralateral to acute rupture are softer than those of healthy control group at the proximal third and the asymptomatic tendons in people with rupture history are thicker, larger, and rounder than those of normal volunteers especially at the middle and distal thirds of AT body.

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Growth Factor and Intense Pulse Light in Flexor Tendon Repair: A Biomechanical Study at Strength and Gap Resistance

The Journal of Hand Surgery (Asian-Pacific Volume) ◽

10.1142/s2424835518500431 ◽

2018 ◽

Vol 23 (04) ◽

pp. 463-468

Author(s):

Rohit Singh ◽

Jihad Alzyoud ◽

Ryan Trickett ◽

Peter Thomas ◽

Peter Theobald ◽

...

Keyword(s):

Growth Factor ◽

Flexor Tendon ◽

Tendon Repair ◽

Tendon Healing ◽

Lead Author ◽

Control Group ◽

Intense Pulse Light ◽

Vast Number ◽

Collagen Formation ◽

Pulse Light

Background: Flexor tendon injuries are extremely common and they are usually the result of incised traumatic glass or knife injury. The process of tendon healing is a complicated and exceptionally-regimented mechanism that is originated and monitored by a vast number of diverse molecules. One of the most pivotal groups of mediators that are crucial to the healing process are growth factors (GF). Intense pulse light (IPL) can lead to evidence of new collagen formation with associated clinical improvement in tissue healing. The biological benefit of Intense pulse light (IPL) relies on judicious photothermolysis, where heat driven radiation is dissipated and focused at the cellular level. The aims of this study is to set out the effect of growth factor and IPL on healing following a tendon repair. Methods: Bovine common digital extensor tendons (CDET) were used as an ex vivo model. 44 tendon repairs were performed by the lead author using 2.5 × magnification loupes and standard instruments. Clamped tendons were assigned into the following groups; control, IPL, GF, IPL and GF. After culturing, biomechanical testing was carried out using monotonic tensile testing with displacement-controlled uniaxial tension to failure. Results: The mean values for ultimate tensile stress (UTS) for the control group was 53.51 N, for IPL it was 51.15 N, for growth factor was 70.10 N and for combined growth factor and IPL it was 75.16 N. Conclusions: This study showed significant improvement in UTS when repaired tendons were cultured with growth factor compared to control and IPL. This would suggest a biomechanical advantage for tendon healing.

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Strength of Braided Polyblend Polyethylene Sutures versus Braided Polyester Sutures in Achilles Tendon Repair

Journal of the American Podiatric Medical Association ◽

10.7547/1000185 ◽

2010 ◽

Vol 100 (3) ◽

pp. 185-188 ◽

Cited By ~ 7

Author(s):

Keith D. Cook ◽

Greg Clark ◽

Eric Lui ◽

Gaurav Vajaria ◽

George F. Wallace

Keyword(s):

Achilles Tendon ◽

Suture Material ◽

Tendon Repair ◽

Contralateral Side ◽

Suture Technique ◽

Materials Testing ◽

Suture Materials ◽

Cross Sectional ◽

The Mean ◽

The Right

Background: Various techniques may be used to repair Achilles tendon ruptures; however, we contend that using the strongest suture with the least amount of suture material is ideal. Methods: To compare the strength of 2-0 FiberLoop (Arthrex Inc, Naples, Florida) and #2 Ethibond (Ethicon Inc, Somerville, New Jersey) suture materials in Achilles tendon repairs, 12 Achilles tendons were harvested from cadavers aged 18 to 62 years (median age, 42 years). The tendons were transected and repaired using a modified Krackow suture technique. All of the right limbs were repaired with 2-0 FiberLoop, and the contralateral side was repaired with #2 Ethibond. The specimens were mounted to a materials testing system, and the repairs were pulled to failure in an anatomical direction. Results: The mean ± SD yield loads of 2-0 FiberLoop and #2 Ethibond were 233 ± 48 N and 134 ± 34 N, respectively (P = .002). The mean ± SD ultimate load of 2-0 FiberLoop was 282 ± 58 N, and that of #2 Ethibond was 135 ± 33 N (P < .001). The cross-sectional area of one pass of 2-0 FiberLoop was calculated to be 0.21 mm2, and one pass of #2 Ethibond was 0.28 mm2. Conclusions: The smaller-caliber 2-0 FiberLoop was significantly stronger than #2 Ethibond. This study suggests that there is no advantage to using the traditional larger suture material for Achilles tendon repairs; however, further clinical testing is needed to determine the optimal repair technique. (J Am Podiatr Med Assoc 100(3): 185–188, 2010)

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Bone Marrow Derived Mesenchymal Stem Cell Augmentation of Rabbit Flexor Tendon Healing

Hand Surgery ◽

10.1142/s0218810415500343 ◽

2015 ◽

Vol 20 (03) ◽

pp. 421-429 ◽

Cited By ~ 10

Author(s):

Min He ◽

Aaron Wei Tat Gan ◽

Aymeric Yu Tang Lim ◽

James Cho Hong Goh ◽

James Hoi Po Hui ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Flexor Tendon ◽

Tendon Repair ◽

Tendon Healing ◽

Control Group ◽

High Dose ◽

Positive Staining ◽

Flexor Tendon Repair

Background: This study investigated the effect of mesenchymal stem cell implantation on flexor tendon healing using a rabbit model of flexor tendon repair. Specifically, we compared the difference between autologous and allogeneic stem cells. The influence of cell number on the outcome of flexor tendon healing was also investigated. Methods: Repaired tendons on the rear paws of rabbits were randomly assigned into four groups: control group, 1 million autologous cells, 1 million allogeneic cells, and 4 million allogeneic cells. Rabbits were sacrificed at 3 or 8 weeks after surgery. Results: Implantation of 4 million stem cells resulted in a significant increase in range of motion compared with control group at three weeks after surgery. The positive staining of collagen I in healing tendons was enhanced in stem cell treated groups three weeks after surgery. However, stem cells did not improve biomechanical properties of flexor tendons. Conclusions: High dose stem cells attenuated adhesions in the early time point following flexor tendon repair. Further work is needed determine the value of stem cell therapy in flexor tendon healing in humans.

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1298 Could Antiangiogenic Drugs Be the Solution to Tendon Injury? A Literature Review on The Use of Antiangiogenic Drugs for Tendon Regeneration

British Journal of Surgery ◽

10.1093/bjs/znab259.1043 ◽

2021 ◽

Vol 108 (Supplement_6) ◽

Author(s):

C Kirchhoff

Keyword(s):

Literature Review ◽

Intervention Group ◽

Tendon Healing ◽

Tendon Injury ◽

Cross Sectional Area ◽

Control Group ◽

Sectional Area ◽

Cross Sectional ◽

Surgical Interventions ◽

Antiangiogenic Drugs

Abstract Aim Tendinopathy accounts for more than half of reported cases of musculoskeletal injuries worldwide. The subsequent healing process results in a disorganised tendon structure secondary to increased neovascularisation, forming a bulky tendon with overall reduced strength. Current treatment options remain controversial as re-rupture rates following surgical interventions are high. It has been proposed that the use of anti-vascular endothelial growth factors could improve tendon healing. Method This literature review employed a systematic approach. The search strategy incorporated an adjusted PICO format and PRISMA flow diagram. Search findings were critically appraised using the CASP tool checklist. Identified studies investigated the effects of injectable anti-angiogenic drugs following tendon injury. Results Three final studies were identified. Tempfer et al. showed a reduction in cross sectional tendon area in the intervention group (5.6mm² +1.8), comparatively to the control group (9.1mm² +2.0), and increased tensile tendon strength in the intervention group (47.7N+6.41) comparatively to the control group(32.41N+9.23). Dallaudiere (2014) et al. showed a reduced cross-sectional area in the intervention group (0.95mm²+0.01) compared with the control group (0.75mm²+0.01). Dallaudiere (2013) et al. also showed a reduced cross-sectional area in the intervention group (1.10mm²+0.01) compared with the control group (1.11mm²+0.03). Conclusions All studies supported the use of anti-angiogenic drugs to support tendon healing. The use of injectable anti-angiogenic drugs may potentially serve in conjunction with surgical interventions or as an alternative minimally invasive intervention to improve tendon rehabilitation. This review recommends that further randomised control studies could be used to strengthen the current promising evidence base.

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The Role of the Paratenon in Achilles Tendon Healing: A Study in Rats

The American Journal of Sports Medicine ◽

10.1177/0363546518756093 ◽

2018 ◽

Vol 46 (5) ◽

pp. 1214-1219 ◽

Cited By ~ 14

Author(s):

Sebastian A. Müller ◽

Christopher H. Evans ◽

Patricia E. Heisterbach ◽

Martin Majewski

Keyword(s):

Achilles Tendon ◽

Tendon Healing ◽

Cross Sectional Area ◽

Sectional Area ◽

Sprague Dawley ◽

Cross Sectional ◽

Collagen Formation ◽

Tendon Defect ◽

Tear Resistance

Background: The role of the paratenon in tendon healing is unknown. The present study compares healing in the presence or absence of the paratenon in an Achilles tendon defect model in rats. Hypothesis: Resection of the paratenon impairs tendon healing. Study Design: Controlled laboratory study. Methods: Sixty skeletally mature Sprague Dawley rats were randomly assigned to either a resected paratenon (RP) group or an intact paratenon (IP) group. In all animals, a 4-mm portion of the Achilles tendon was resected in the midsubstance. In the RP group, the paratenon was resected completely. In the IP group, the paratenon was opened longitudinally and closed again after the tendon defect had been created. One, 2, and 4 weeks after surgery, 7 animals per group were tested biomechanically and 3 animals per group examined histologically. Results: The recovery of mechanical strength was much more rapid in IP tendons. Tear resistance was significantly increased for IP tendons (41.3 ± 8.8 N and 47.3 ± 14.1 N, respectively) compared with RP tendons (19.3 ± 9.1 N and 33.2 ± 6.4 N, respectively) after 1 and 2 weeks. The cross-sectional area was larger in the IP group after 1 and 2 weeks (8.2 ± 2.3 mm2 and 11.3 ± 3.1 mm2 vs 5.0 ± 2.4 mm2 and 5.9 ± 2.0 mm2, respectively) compared with the RP group. Tendon stiffness was greater in the IP group after 1 week (10.4 ± 1.9 N/mm vs 4.5 ± 1.6 N/mm, respectively) compared with the RP group. In comparison, normal contralateral tendons had a maximal tear resistance of 56.6 ± 7.2 N, a cross-sectional area of 3.6 ± 0.7 mm2, and stiffness of 17.3 ± 3.8 N/mm. Hematoxylin and eosin staining revealed slightly delayed healing of RP tendons. Early collagen formation was seen in the IP group already after 1 week, whereas in the RP group, this only occurred after 2 weeks. After 4 weeks, the IP tendons showed more collagen crimp formation than the RP tendons. Conclusion: An intact paratenon promotes healing of the Achilles tendon. Clinical Relevance: Although incision or resection of the paratenon has been advocated when repairing injured or degenerative tendons, our data suggest that the integrity of the paratenon should be preserved.

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