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Towards surgical use of matrix metalloproteinase biology
Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Matrix metalloproteinases (MMPs), such as collagenases, are a family of enzymes capable of degrading most constituents of the extracellular matrix. MMPs are thought to be involved in the aetiopathogenesis of tendon rupture. Additionally, failure of healing has in some instances been associated with elevated levels of MMPs. We have studied (a) the effects of the MMP-inhibitor doxycycline on healing of tendons and intestines in experimental models and (b) systemic levels of MMPs and their endogenous inhibitors (TIMPs) in patients with tendon rupture.

In the first study, systemic doxycycline treatment lead to weakened rat Achilles tendons during healing after injury.

Subsequently, systemic doxycycline was shown to improve biomechanical properties of tendon suture fixation in the rat Achilles tendon. Sutures were also coated with doxycycline, leading to similar improvement in mechanical strength of the suture construct during healing.

In the third study, doxycycline-coated sutures improved the strength of healing intestinal anastomoses in an experimental model.

Finally, we showed that patients with a history of Achilles tendon rupture had elevated levels of MMP-2, MMP-7 and TIMP-2 in serum. In addition, MMP-7 correlated inversely to mechanical strength of the tendon during healing.

In conclusion, MMP-inhibitors can be administered systemically and locally to manipulate healing of tendons and intestines. Generalised alterations in the MMP-TIMP system may be involved in the pathogenesis of Achilles tendon rupture and associated with differences in outcome of healing.

Place, publisher, year, edition, pages
Linköping University Electronic Press, 2008. , 61 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1057
Keyword [en]
Achilles tendon, colon, tetracyclines, tissue inhibitor of metalloproteinases (TIMP), wound healing., colorectal surgery, extracellular matrix, humans, matrix metalloproteinases (MMPs), rats, surgical anastomosis, sutures, tendon injuries
National Category
Surgery
Identifiers
URN: urn:nbn:se:liu:diva-11489ISBN: 978-91-7393-931-7 (print)OAI: oai:DiVA.org:liu-11489DiVA: diva2:17919
Public defence
2008-05-09, Linden, Hälsonuniversitetet, Linköping, 13:30 (English)
Opponent
Supervisors
Available from: 2008-05-07 Created: 2008-05-07 Last updated: 2015-11-19
List of papers
1. Doxycycline impairs tendon repair in rats
Open this publication in new window or tab >>Doxycycline impairs tendon repair in rats
2006 (English)In: Acta Orthopaedica Belgica, ISSN 0001-6462, Vol. 72, no 6, 756-760 p.Article in journal (Refereed) Published
Abstract [en]

Doxycycline exhibits various effects apart from its antimicrobial activity, such as inhibition of matrix metalloproteinases (MMPs). MMPs, mainly collagenases and gelatinases, are capable of degrading virtually all constituents of the extracellular matrix and are critical to connective tissue remodelling and healing. We therefore hypothesised that doxycycline would negatively influence the rat tendon healing process and impede tendon regeneration. The Achilles tendon of 60 Sprague Dawley rats was transected transversely. The animals were treated with doxycycline, 130 mg/kg body weight/day. The healing tendons were evaluated mechanically at 5, 8 and 14 days. Doxycycline significantly decreased force at failure (p < 0.005) and energy uptake (p < 0.001). Doxycycline serum concentration was 3.4 (SD 1.0) µg/ml. In conclusion, tendon healing can be affected by doxycycline at clinically relevant serum concentrations. This observation might be of relevance to further studies exploring effects of MMP-inhibitors on tendon tissue.

Place, publisher, year, edition, pages
Bruxelles: Acta Medica Belgica, 2006
Keyword
tendon repair ; doxycycline ; matrix metalloproteinase (MMP)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13148 (URN)17260615 (PubMedID)
Available from: 2008-05-07 Created: 2008-05-07 Last updated: 2013-10-28Bibliographically approved
2. Doxycycline-coated sutures improve the suture-holding capacity of the rat Achilles tendon
Open this publication in new window or tab >>Doxycycline-coated sutures improve the suture-holding capacity of the rat Achilles tendon
Show others...
2007 (English)In: Acta Orthopaedica, ISSN 1745-3674, Vol. 78, no 5, 680-686 p.Article in journal (Refereed) Published
Abstract [en]

There is evidence of high matrix metalloproteinase (MMP) activity around sutures inserted into tendons. This probably results in tissue breakdown, allowing the suture to cut through the tendon, and thus contributes to repair-site elongation and gap formation. We therefore hypothesized that treatment with the MMP inhibitor doxycycline would improve the sutureholding capacity of tendon. Animals, methods and results In the first sub-study, rats received a suture in the Achilles tendon. One group was treated with systemic doxycycline and the other received no treatment. At 3, 5, and 7 days, suture-holding capacity was measured mechanically. The pull-out force and energy were reduced in all tendons, at 3 days compared to freshly inserted sutures, but no further reduction was detected at later time points. Doxycycline- treated tendons showed improved suture-holding capacity as measured by higher energy uptake than in untreated tendons. Force at failure showed a trend towards improvement. The effect was most evident on day 3. In the second sub-study, sutures were coated with doxycycline. At 3 days, local doxycycline treatment caused improved suture-holding capacity—as measured by higher force at failure and higher energy uptake.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13149 (URN)10.1080/17453670710014392 (DOI)
Available from: 2008-05-07 Created: 2008-05-07 Last updated: 2009-08-20
3. Doxycycline-coated sutures improve mechanical strength of intestinal anastomoses
Open this publication in new window or tab >>Doxycycline-coated sutures improve mechanical strength of intestinal anastomoses
Show others...
2008 (English)In: International Journal of Colorectal Disease, ISSN 0179-1958, Vol. 23, no 3, 271-276 p.Article in journal (Refereed) Published
Abstract [en]

Background and aims: After resection and repair of the intestines, tissue degradation leads to weakening of the repair site and a risk of postoperative leakage. Matrix metalloproteinases (MMPs) are thought to be responsible for collagenolysis in the direct vicinity of surgical sutures in many tissues. Several experimental studies show that MMP-inhibitors administered systemically alleviate postoperative weakening of intestinal anastomoses. We hypothesised that local delivery of MMP-inhibitors would achieve a similar effect.

Methods: Implementing a novel method for the coating of biomaterials, we coated sutures with a crosslinked fibrinogen film and bound the MMP-inhibitor doxycycline into this film. The sutures were then used in a standard rat model for evaluating mechanical properties of colonic anastomoses 3 days after surgery.

Results: The breaking strength of the anastomoses on the critical third day after operation was 17 % higher with doxycycline-coated sutures compared to controls (P=0.026). Energy uptake at failure was enhanced by 20 % (P=0.047).

Conclusion: Drug delivery by means of MMP-inhibitor-coated sutures appears to improve tissue integrity during anastomotic repair and may reduce postoperative complications.

Keyword
colon, matrix metalloproteinase (MMP), wound dehiscence, anastomotic leakage, suture
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-11695 (URN)10.1007/s00384-007-0401-0 (DOI)
Note
The original publication is available at www.springerlink.com: Björn Pasternak, Martin Rehn, Line Andersen, Magnus S. Ågren, Anne-Marie Heegaard, Pentti Tengvall and Per Aspenberg, Doxycycline-coated sutures improve mechanical strength of intestinal anastomoses, 2008, International Journal of Colorectal Disease, (23), 271-276 http://dx.doi.org/10.1007/s00384-007-0401-0. Copyright: Springer, www.springerlink.comAvailable from: 2008-09-01 Created: 2008-09-01 Last updated: 2009-08-20
4. Elevation of systemic matrix metalloproteinase-2 and -7 and tissue inhibitor of metalloproteinases-2 in patients with a history of Achilles tendon rupture
Open this publication in new window or tab >>Elevation of systemic matrix metalloproteinase-2 and -7 and tissue inhibitor of metalloproteinases-2 in patients with a history of Achilles tendon rupture
2010 (English)In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 38, 308-317 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: To compare serum levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) between patients with a history of Achilles tendon rupture and blood donor controls, and to relate MMPs and TIMPs to mechanical properties of the tendons during healing.

Methods: More than three years after injury, we measured serum levels of MMP-1, -2, -3, -7, -8, -9 and -13 and TIMP-1 and -2 in eight patients who had suffered Achilles tendon rupture. Twelve blood donors served as controls. During the early phase of healing, the tendon modulus of elasticity was calculated from radiostereometric data and tendon cross-sectional area.

Results: Patients with a history of Achilles tendon rupture had increased levels of MMP-2 (median difference (m.d.) 10 %; p = 0.01), MMP-7 (m.d. 15 %; p = 0.02) and TIMP-2 (m.d. 36%; p = 0.02), as compared to controls. Levels of MMP-7, measured three years after injury, correlated inversely to tendon modulus of elasticity (rs = -0.83; p = 0.02), and positively to tendon elongation (rs = 0.74; p = 0.05) during the early phase of healing. There was a trend towards positive correlation between MMP-7 and cross-sectional area during the early phase of healing (rs = 0.67; p = 0.08).

Conclusions: Patients with a history of Achilles tendon rupture appear to have elevated levels of MMP-2, MMP-7 and TIMP-2 in serum. These pilot data support the view that the MMP-TIMP system is involved in tendinopathy and suggest that disturbances in proteolytic control might be generalised.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13151 (URN)10.1136/bjsm.2008.049411 (DOI)
Available from: 2008-05-07 Created: 2008-05-07 Last updated: 2012-03-27

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