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Tissue-engineered collagen grafts to treat large tendon defects

Keywords:  collagen • FEA • finite element analysis • suture technique • tendon • tendon graft • tissue engineering

Reconstruction of a tendon following rupture is surgically challenging as each end of the tendon retracts leaving a substantial gap so that direct repair is often not feasible. To restore function, a tendon graft is required to bridge this defect and different biological tissues have previously been used such as autografts, allografts or xenografts. Each of these grafts are prone to potential complications including donor site morbidity, immune rejection, poor biocompatibility or zoonosis, which may lead to graft necrosis and failure of tendon function [1] . The tissue-engineering approach has attempted to create artificial grafts derived from synthetic and natural polymers. Synthetic grafts such as polylactide, polyglycolide [2] , polylactide-co-glycolide loaded with mesenchymal stem cell [3] ; furthermore, a combination of polylactide-co-glycolide and degummed silk scaffold with bone marrow stromal cells [4] have mechanical properties similar to native biological tendons. However, the degradation process of these synthetic grafts and rate at which native matrix is deposited is key to long-term success in vivo. By contrast, natural polymers such as collagen I, the predominant structural protein in a tendon, have ideal biological properties. Using type I collagen in tissue engineering a tendon graft has inherent advantages as it is a natural polymer and is the most abundant and highly conserved protein in mammals. Recent technological advances in the rapid fabrication of reproducible tissue-engineered (TE) collagen grafts has highlighted the potential of this material in tendon repair.

10.2217/RME.14.15 © 2014 Future Medicine Ltd

There are various commercially available collagen products that have been tested for tendon replacement or repair in clinical studies, such as GraftJacket™ (Wright Medical Technology, Inc., TN, USA), BioBlanket™ (Kensey Nash Corporation, PA, USA) and Zimmer™ (Tissue Science Laboratories, IN, USA). The use of these grafts has shown improved mechanical properties and histology, but did not achieve the mechanical strength equivalent to the tendon [5] . Reports of repair of rotator cuff injuries in humans with porcine small intestine submucosa augmentation did not significantly improve tendon healing and, in a further study, reported re-tear of the tendon in ten out of 11 patients within 6 months [6,7] . We have reported using plastic compression of collagen I as a fabrication method for TE collagen graft. This artificial collagen graft embedded with allogeneic tendon cells has demonstrated favorable biomimetic qualities both in vitro and in vivo in a lapine subcutaneous model, proving its biocompatibility with the host tissues. [8,9] . The main limitation of using TE collagen grafts in vivo is that it is extremely weak under tensile loading. The break strength of the engineered collagen is 2.82 N compared with the break strength of rabbit posterior tibial tendon which is 261 N [10] . There are two options to overcome this problem: increase the mechanical properties of the TE collagen graft so that it is comparable to native tendon, or develop a surgical technique to mechanically support the TE graft until it becomes incorporated within

Regen. Med. (2014) 9(3), 249–251

Prasad Sawadkar University College London, Tissue Repair & Engineering Centre, Division of Surgery & Interventional Science, Stanmore Campus, London, HA7 4LP, UK

Susan Alexander University College London, Research Department of General Surgery, The Royal Free Hospital, Pond Street, London, NW3 2QG, UK

Vivek Mudera Author for correspondence: University College London, Tissue Repair & Engineering Centre, Division of Surgery & Interventional Science, Stanmore Campus, London, HA7 4LP, UK v.mudera@ ucl.ac.uk

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ISSN 1746-0751

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Editorial  Sawadkar, Alexander & Mudera the host tissue, because, in normal tendon repair, the repair strength of structure is directly proportional to the strength of the sutures [11] . Various techniques have been reported to improve the mechanical properties of a collagen graft, such as physical cross-linking under vacuum, UV radiation and dehydrothermal treatments; chemical cross-linking with riboflavin; enzymatic and nonenzymatic methods, which have shown increased collagen density and Young’s modulus of the scaffold. However, by adding these cross-linkers agents, biocompatibility of the scaffold was compromised [12–14] . Therefore, the compromise in increasing collagen cross-linking and mechanical strength comes with decreased biocompatibility.

“...by running core prolene sutures directly

through the entire length of the artificial collagen graft and interlocking the sutures onto itself at both ends in the native tendon, it was possible to increase the strength of the repair such that the graft may be able to withstand physiological loads in vitro and in situ.” Currently, the surgical gold standard for tendon repair is the modified Kessler suture technique [15] . In this method, sutures are placed through the middle of the cross section of both the tendons to appose the ends (core sutures). The repair is then reinforced by a continuous running suture at the periphery of the cross section, linking the two tendon ends. When this suture technique was applied to both ends of a TE collagen graft inserted into a tendon gap, it was unable to withstand physiological tensile loading and the repair failed. A novel modified suture technique was therefore developed to resolve this problem. Four core sutures were passed from the core of one native tendon end and through the core of the entire length of the TE graft, and into the core of the opposite tendon. These core sutures were interlocked onto the suture material itself at some distance away from each tendon end so that the strength of the repair was predominantly loaded through the suture itself and not the tendon or the graft. Nonabsorbable prolene sutures made from an isotactic crystalline stereoisomer of polypropylene, a synthetic References

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1

Sharifi P, Oryan A, Moshiri A. Advances in injured tendon engineering with emphasis on the role of collagen implants. Hard Tissue 1(2), 12 (2012).

2

Guo Z, Chen JJ, Zhang PH. A knitted scaffold for tendon engineering using poly(lactic acid) fibers. Adv. Mater. Res. 197–198, 164–167 (2011).

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linear polyolefin, were used. Size 3–0 was used for the core interlocking sutures and a smaller 6–0 was used for the peripheral sutures. To test this repair technique, lapine tendons were isolated and a 15-mm section was excised from the middle of the tendon and replaced with a 15-mm-long TE collagen graft and secured using the technique described above [10] . Tensile testing of this construct demonstrated that the modified suture technique failed at 50.62 N compared with the traditional Kessler repair, which failed at 12.49 N. This new technique was validated by repeating the experiment with the tendon in situ using a cadaveric lapine hind leg. The break strength of the repair was 24.60 N, which was twice as strong compared with traditional repairs, which failed at 13.98 N. It was not possible to directly measure the force passing through either the TE collagen graft or the force applied at the interlocking suture points, thus a finite element analysis computational model was used to predict these forces. The mechanical force passing through the TE collagen graft using the modified technique was 20-times less than the Kessler repair and the interlocking suture points were able to load twice as much stress as compared with Kessler repairs. Interestingly, the strain on the collagen graft was 10%, which was also measured during mechanical testing. In conclusion, by running core prolene sutures directly through the entire length of the artificial collagen graft and interlocking the sutures onto itself at both ends in the native tendon, it was possible to increase the strength of the repair such that the graft may be able to withstand physiological loads in vitro and in situ. The next stage will be to determine whether this novel technique is mechanically robust enough to be used in vivo and, ultimately, this can facilitate the incorporation of a TE collagen graft by native tissue so that it is regenerated into the host tendon. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. 3

Ouyang HW, Goh JC, Thambyah A, Teoh SH, Lee EH. Knitted poly-lactide-co-glycolide scaffold loaded with bone marrow stromal cells in repair and regeneration of rabbit Achilles tendon. Tissue Eng. 9(3), 431–439 (2003).

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Sahoo S, Lok Toh S, Hong Goh JC. PLGA nanofiber-coated silk microfibrous scaffold for connective tissue engineering. J. Biomed. Mater. Res. B Appl. Biomater. 95B(1), 19–28 (2010).

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Tissue-engineered collagen grafts to treat large tendon defects 

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Longo UG, Lamberti A, Maffulli N, Denaro V. Tendon augmentation grafts: a systematic review. Br. Med. Bull. 94, 165–188 (2010).

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Iannotti JP, Codsi MJ, Kwon YW, Derwin K, Ciccone J, Brems JJ. Porcine small intestine submucosa augmentation of surgical repair of chronic two-tendon rotator cuff tears. A randomized, controlled trial. J. Bone Joint Surg. Am. 88(6), 1238–1244 (2006).

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Sclamberg SG, Tibone JE, Itamura JM, Kasraeian S. Sixmonth magnetic resonance imaging follow-up of large and massive rotator cuff repairs reinforced with porcine small intestinal submucosa. J. Shoulder Elbow Surg. 13(5), 538–541 (2004).

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Levis HJ, Brown RA, Daniels JT. Plastic compressed collagen as a biomimetic substrate for human limbal epithelial cell culture. Biomaterials 31(30), 7726–7737 (2010).

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Mudera V, Morgan M, Cheema U, Nazhat S, Brown R. Ultra-rapid engineered collagen constructs tested in an in vivo nursery site. J. Tissue Eng. Regen. Med. 1(3), 192–198 (2007).

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10

Sawadkar P, Alexander S, Tolk M et al. Development of a surgically optimized graft insertion suture technique to accommodate a tissue-engineered tendon in vivo. Biores. Open Access 2(5), 327–335 (2013).

11

Ketchum LD. Suture materials and suture techniques used in tendon repair. Hand Clin. 1(1), 43–53 (1985).

12

Kanungo BP, Gibson LJ. Density-property relationships in collagen–glycosaminoglycan scaffolds. Acta Biomater. 6(2), 344–353 (2010).

13

Weadock KS, Miller EJ, Bellincampi LD, Zawadsky JP, Dunn MG. Physical crosslinking of collagen fibers: comparison of ultraviolet irradiation and dehydrothermal treatment. J. Biomed. Mater. Res. 29(11), 1373–1379 (1995).

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Reiser K, Mccormick RJ, Rucker RB. Enzymatic and nonenzymatic cross-linking of collagen and elastin. FASEB J. 6(7), 2439–2449 (1992).

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Schneppendahl J, Thelen S, Schek A et al. Initial stability of two different adhesives compared with suture repair for acute Achilles tendon rupture – a biomechanical evaluation. Int. Orthop. 36(3), 627–632 (2012).

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