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Stimulation of tendon repair by platelet concentrate, CDMP-2 and mechanical loading in animal models
Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Orthopaedic Centre, Department of Orthopaedics Linköping.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Growth factor delivery may be useful to accelerate the rate of tendon healing. We studied Platelet Concentrate, which in effect can be regarded as a cocktail of growth factors relevant for tendon healing. In a rat Achilles tendon transection model, one postoperative injection of Platelet Concentrate resulted in increased strength even 3 weeks later.

Mechanical stimulation improves the repair of ruptured tendons. We studied the effects of platelets upon Achilles tendon regenerates in rats 3, 5 and 14 days after transection, either unloaded or mechanically stimulated. At 14 days, physical activity and platelets increased repair independently. Unloading decreased the mechanical properties of the repair tissue to less than half of normal. Moreover, the platelets had no effect without loading.

Thrombin, which we used for platelet activation, improved healing of the rat Achilles tendon by itself. Conversely, continuous inhibition of thrombin by low molecular weight heparin (LMWH) inhibited tendon repair. However, intermittent inhibition, similar to clinical thromboprophylaxis, had no effect on tendon healing.

Cartilage Derived Morphogenetic Protein-2 (CDMP-2) can improve tendon healing in loaded defect models. We now studied unloaded repair in a rabbit patellar tendon model. Two hours postoperative, the rabbits received CDMP-2 injected into the haematoma. The healing tendon became 65 % stronger than controls. We then studied Achilles tendon healing with CDMP-2 injections in sheep, to get a bigger animal model. There was an unexpectedly high variation of repair in these animals, and the study turned out to be underpowered. Spontaneous ruptures in humans have a more variable geometry than in our sheep model, so humans can also be expected to vary a lot in mechanical characteristics of Achilles tendon repair. This accentuates the importance of individualized rehabilitation programs.

In conclusion, both platelet concentrate and CDMP-2 injections might be of interest for clinical use as a complement to surgical or conservative treatment of tendon ruptures. Platelet treatment for tendon ruptures should probably be combined with early physiotherapy.

Place, publisher, year, edition, pages
Institutionen för nervsystem och rörelseorgan , 2007. , 34 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1005
Keyword [en]
Achilles tendon, injuries, physiology, Blood platelets, tendon injuries, physiopathology, therapy, wound healing
National Category
Surgery
Identifiers
URN: urn:nbn:se:liu:diva-11264ISBN: 978-91-85831-88-3 (print)OAI: oai:DiVA.org:liu-11264DiVA: diva2:17676
Public defence
2007-06-07, Aulan, Hälsans Hus, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2009-08-22
List of papers
1. Platelet concentrate injection improves Achilles tendon repair in rats
Open this publication in new window or tab >>Platelet concentrate injection improves Achilles tendon repair in rats
2004 (English)In: Acta Orthopaedica Scandinavica, ISSN 1745-3674, Vol. 75, no 1, 93-99 p.Article in journal (Refereed) Published
Abstract [en]

Background:Blood platelets release a cocktail of growth factors when activated, some of which are thought to initiate and stimulate repair.

Experiment and findings: We studied whether a platelet concentrate injection would improve Achilles tendon repair in an established rat model. The Achilles tendon was transected and a 3 mm segment removed. After 6h, a platelet concentrate was injected percutaneously into the hematoma. This increased tendon callus strength and stiffness by about 30 % after 1 week, which persisted for as long as 3 weeks after the injection. At this time, the mechanical testing indicated an improvement in material characteristics - i.e., greater maturation of the tendon callus. This was confirmed by blinded histological scoring.

Interpretation: Platelet concentrate may prove useful for the treatment of Achilles tendon ruptures.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13012 (URN)10.1080/759369155 (DOI)
Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2009-08-17
2. Independent and additive stimulation of tendon repair by thrombin and platelets
Open this publication in new window or tab >>Independent and additive stimulation of tendon repair by thrombin and platelets
2006 (English)In: Acta Orthopaedica, ISSN 1745-3674, Vol. 77, no 6, 960-966 p.Article in journal (Refereed) Published
Abstract [en]

Background Platelet concentrate application with added thrombin improves Achilles tendon repair in the rat. Upon tissue injury, platelets are activated by thrombin, which has many biological properties in common with growth factors. We wanted to differentiate the effect of platelets from that of thrombin.

Methods The Achilles tendon was transected in 50 rats. Platelet gel was prepared from the blood of 10 other rats. The rats were given either platelet gel with active or neutralized thrombin implanted into the defect during the operation, or a local injection 6h postoperatively with 50 μL of either platelet concentrate, thrombin or saline. The rats were killed after 14 days and the tendons were mechanically tested.

Results Compared to saline, platelet gel caused a 42% increase in force at failure, a 90% increase in energy, and a 61% increase in ultimate stress. Platelet gel with neutralized thrombin caused a 22% increase in force at failure, and energy and stress were less elevated. Injected platelet concentrate caused a 24% increase in force at failure, and thrombin caused a 10% increase. These effects and the differences between treatments were statistically significant.

Interpretation Platelets and thrombin had independent and additive stimulatory effects on tendon repair. The clinical relevance is so far unknown.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13013 (URN)10.1080/17453670610013295 (DOI)
Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2009-06-08
3. How can one platelet injection after tendon injury lead to a stronger tendon after 4 weeks?: Interplay between early regeneration and mechanical stimulation
Open this publication in new window or tab >>How can one platelet injection after tendon injury lead to a stronger tendon after 4 weeks?: Interplay between early regeneration and mechanical stimulation
2006 (English)In: Acta Orthopaedica, ISSN 1745-3674, Vol. 77, no 5, 806-812 p.Article in journal (Refereed) Published
Abstract [en]

Background Mechanical stimulation improves the repair of ruptured tendons. Injection of a platelet concentrate (platelet-rich plasma, PRP) can also improve repair in several animal models. In a rat Achilles tendon transection model, 1 postoperative injection resulted in increased strength after 4 weeks. Considering the short half-lives of factors released by platelets, this very late effect calls for an explanation.

Methods We studied the effects of platelets on Achilles tendon regenerates in rats 3, 5 and 14 days after transection. The tendons were either unloaded by Botulinum toxin A (Botox) injections into the calf muscles, or mechanically stimulated in activity cages. No Botox injections and ordinary cages, respectively, served as controls. Repair was evaluated by tensile testing.

Results At 14 days, unloading (with Botox) abolished any effect of the platelets and reduced the mechanical properties of the repair tissue to less than half of normal. Thus, some mechanical stimulation is a prerequisite for the effect of platelets at 14 days. Without Botox, both activity and platelets increased repair independently of each other. However, at 3 and 5 days, platelets improved the mechanical properties in Botox-treated rats.

Interpretation Platelets influence only the early phases of regeneration, but this allows mechanical stimulation to start driving neo-tendon development at an earlier time point, which kept it constantly ahead of the controls.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13014 (URN)10.1080/17453670610013033 (DOI)
Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2009-06-08
4. Low Molecular Weight Heparin impairs tendon repair
Open this publication in new window or tab >>Low Molecular Weight Heparin impairs tendon repair
2008 (English)In: Journal of Bone and Joint Surgery, ISSN 0301-620X, E-ISSN 2044-5377, Vol. 90-B, no 3, 388-392 p.Article in journal (Refereed) Published
Abstract [en]

Thrombin has many biological properties similar to those of growth factors. In a previous study, we showed that thrombin improves healing of the rat tendo Achillis. Low molecular weight heparin (LMWH) inhibits the activity and the generation of thrombin. We therefore considered that LMWH at a thromboprophylactic dose might inhibit tendon repair.

Transection of the tendo Achillis was carried out in 86 rats and the healing tested mechanically. Low molecular weight heparin (dalateparin) was either injected a few minutes before the operation and then given continuously with an osmotic mini pump for seven days, or given as one injection before the operation. In another experiment ,we gave LMWH or a placebo by injection twice daily. The anti-factor Xa activity was analysed.

Continuous treatment with LMWH impaired tendon healing. After seven days, this treatment caused a 33% reduction in force at failure, a 20% reduction in stiffness and a 67% reduction in energy uptake. However, if injected twice daily, LMWH had no effect on tendon healing. Anti-factor Xa activity was increased by LMWH treatment, but was normal between intermittent injections.

Low molecular weight heparin delays tendon repair if given continuously, but not if injected intermittently, probably because the anti-factor Xa activity between injections returns to normal, allowing sufficient thrombin stimulation for repair. These findings indicate the need for caution in the assessment of long-acting thrombin and factor Xa inhibitors.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13015 (URN)10.1302/0301-620X.90B3.19493 (DOI)
Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2017-12-13
5. CDMP-2 injection improves early tendon healing in a rabbit model for surgical repair
Open this publication in new window or tab >>CDMP-2 injection improves early tendon healing in a rabbit model for surgical repair
2005 (English)In: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, Vol. 15, no 4, 260-264 p.Article in journal (Refereed) Published
Abstract [en]

This study examines the hypothesis that cartilage-derived morphogenic protein-2 (CDMP-2) can improve tendon healing after surgical repair. We have previously found improved tendon healing by applying CDMP-2 in models for conservative treatment with mechanically loaded Achilles tendon defects in rats and rabbits. In this study, the patellar tendon was unloaded by patello- tibial cerclage and cut transversely in 40 rabbits. Two hours post-operative, the rabbits received a dose of 20 μg of CDMP-2 or vehicle injected into the hematoma. Specimens were harvested after 14 and 28 days and evaluated by biomechanical testing, radiography and histology. At 14 days, CDMP-2 caused a 65% increase in force at failure, a 50% increase in ultimate stress and a 57% increase in stiffness, as compared with controls. There was no effect on callus size. At 28 days, no differences between the treatment groups could be demonstrated. No bone or cartilage was found in any tendon or regenerated tissue at any time point. Thus, early tendon repair can be stimulated by CDMP-2 in an unloaded model. These results suggest that CDMP-2 might be of interest for clinical use as a complement to surgical treatment of tendon ruptures.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13016 (URN)10.1111/j.1600-0838.2005.00462.x (DOI)
Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2009-06-08
6. Early Achilles tendon repair in sheep
Open this publication in new window or tab >>Early Achilles tendon repair in sheep
Manuscript (Other academic)
Identifiers
urn:nbn:se:liu:diva-13017 (URN)
Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2010-01-13

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Virchenko, Olena

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