LITERATURE REVIEW

NeuraGen®

Nerve Guide

Integra®

NeuraGen® Nerve Guide

What is the NeuraGen® Nerve Guide?

NeuraGen® Nerve Guide is the most well-studied collagen nerve conduit and has been shown to be safe for the repair of peripheral nerve discontinuities.

NeuraGen was the first type 1 collagen conduit 510(k) cleared by the FDA in 20011. NeuraGen is made from Integra’s biocompatible Ultra Pure Collagen™ that allows for controlled resorption; the conduit’s precisely engineered porosity supports natural nerve regeneration by allowing Nerve Growth Factors and Schwann Cells to infiltrate. Since 2001, numerous studies have been conducted demonstrating the clinical safety and efficacy of NeuraGen used in peripheral nerve repair.

The NeuraGen Studies

The Development of NeuraGen

Joseph Nichols filed a patent for the first type I collagen nerve guide in October 1986.2 After further development to make the conduit more permeable to infiltration by neurotrophic proteins, this conduit became the product now known as the NeuraGen Nerve Guide.

First Primate Study:

Primate studies were performed to confirm the ability of NeuraGen to bridge nerve gaps safely, prior to clinical studies in humans. The first primate study of NeuraGen, published in 1990, showed excellent regeneration and functional recovery results (as determined by histology and electrophysiology) 14 months after the conduit was used to repair 2 cm ulnar nerve gaps.3

Second Primate Study:

In the second primate study, in which the functional efficacy of NeuraGen was compared to direct suture and nerve graft repair for 5 mm median/ulnar nerve gaps, all treatments provided equivalent functional reinnervation by the final follow-up assessment.4 This and other nonclinical histological studies demonstrated that the NeuraGen device is completely resorbed with no evidence of untoward inflammatory reaction.4,5

Pilot Clinical Study:

The first clinical implantation of NeuraGen was performed in Denmark as part of a pilot clinical study sponsored by Integra LifeSciences, which showed that the device was biocompatible and safe for human use. No adverse events were reported, and no neuroma formation was observed during follow-up.2

Randomized Controlled Trial:

The preliminary pilot data were followed up with an Integra-sponsored randomized, prospective multi-centered trial that compared the clinical efficacy of the NeuraGen nerve conduit to that of the gold standard, direct suture, for the repair of defects of the median/ulnar nerves.6 Boeckstyns et al. compared the clinical outcomes of 23 nerves treated with NeuraGen to 21 nerves treated through neurorrhaphy; electrophysiological and hand function outcomes were assessed as well as product safety. At the 24 month follow up, there was no difference in outcomes between the NeuraGen-treated patients and those who underwent direct suture repair. Furthermore, the study patients showed no adverse reactions to NeuraGen-treatment.6

Patient outcomes are important to you and your patients—NeuraGen has more published clinical data than any other collagen-based nerve conduit.*

* Including all publications that report the outcomes of more than 5 patients, as of April 1, 2019.

The NeuraGen Difference: An Investment in Data

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NeuraGen®

Nerve GuideAxoGuard®

Nerve Connector7

1 Study 1 Study0 Studies

18 Studies

NeuroFlex™

Flexible Collagen Nerve Cuff

NeuroMatrix™

Collagen Nerve Conduit

Author & Year Title NeuraGen

Conduits StudiedNerves Repaired

Huber et al. 20178 Recovery of mechanical detection thresholds after direct digital nerve repair versus conduit implantation 11 Digital

Krarup et al. 20179 Sensation, mechanoreceptor, and nerve fiber function after nerve regeneration 11* Median and Ulnar

Wilson et al. 20177 Lingual Nerve Microsurgery Outcomes Using 2 Different Conduits: A Retrospective Cohort Study 28 Lingual and Inferior

Alveolar

Klein et al. 201610 Collagen type I conduits for the regeneration of nerve defects 10 Radial and Ulnar

Krarup et al. 201611 Remodeling of motor units after nerve regeneration studied by quantitative electromyography 11* Median and Ulnar

Lohmeyer et al. 201412 Prospective clinical study on digital nerve repair with collagen nerve conduits and review of literature 49 Digital

Schmauss et al. 201413 Is nerve regeneration after reconstruction with collagen nerve conduits terminated after 12 months? the long-term follow-up of two prospective clinical studies. 20* Digital

Boeckstyns et al. 20136 Collagen conduit versus microsurgical neurorrhaphy: 2-year follow-up of a prospective, blinded clinical and electrophysiological multicenter randomized, controlled trial 23 Median and Ulnar

Diesntknecht et al. 201314 Type I collagen nerve conduits for median nerve repairs in the forearm 9 Median

Erakat et al. 201315 Interval Between Injury and Lingual Nerve Repair as a Prognostic Factor for Success Using Type I Collagen Conduit 22 Lingual

Haug et al. 201316 Sensory Recovery 1 Year After Bridging Digital Nerve. 45 Digital

Wolfe et al. 201317 Use of bioabsorbable nerve conduits as an adjunct to brachial plexus neurorrhaphy 10 Brachial Plexus

Taras et al. 201118 Reconstruction of digital nerves with collagen conduits 22 Digital

Wangensteen & Kalliainen. 201019 Collagen tube conduits in peripheral nerve repair: A retrospective analysis. 126

Digital, Radial, Medial, Ulnar, Median, etc.

Lohmeyer et al 200920 The clinical use of artificial nerve conduits for digital nerve repair: a prospective cohort study and literature review 15 Digital

Bushnell et al. 200821 Early clinical experience with collagen nerve tubes in digital nerve repair 12 Digital

Farole and Jamal, 200822 A bioabsorbable collagen nerve cuff (NeuraGen) for repair of lingual and inferior alveolar nerve injuries: a case series 9 Lingual and Inferior

Alveolar

Ashley et al. 200623 Collagen nerve guides for surgical repair of brachial plexus birth injury 5 Brachial Plexus

TOTAL: 438

Approximately 400 Nerves Repaired in 18 Clinical Studies

• 10+ years of clinical evidence

• 16 centers

• Gap lengths up to 2.7 cm

• Mostly traumatic nerve injuries

* Follow up of repairs previously studied.

Integra®

NeuraGen® Nerve Guide

USA 800-654-2873 n 888-980-7742 faxInternational +1 609-936-5400 n +1 609-750-4259 faxintegralife.com

United States, Canada, Asia, Pacific, Latin America

Availability of these products might vary from a given country or region to another, as a result of specific local regulatory approval or clearance requirements for sale in such country or region. n Non contractual document. The manufacturer reserves the right, without prior notice, to modify the products in order to improve their quality.n Warning: Applicable laws restrict these products to sale by or on the order of a physician.n Consult product labels and inserts for any indication, contraindications, hazards, warnings, precautions, and instructions for use.

For more information or to place an order, please contact:

NeuraGen, Integra and the Integra logo are registered trademarks of Integra LifeSciences Corporation or its subsidiaries in the United States and/or other countries. ©2019 Integra LifeSciences Corporation. All rights reserved. Printed in USA. 1349403-1-EN

References: 1. Kehoe S, Zhang XF, Boyd D. FDA approved guidance conduits and wraps for peripheral nerve injury: a review of materials and efficacy. Injury. 2012 May 1;43(5):553-72. 2. Archibald, Simon. “Nervenwiederherstellung mittels Tuben (Röhrchen).” In Plastische Chirurgie, pp. 47-62. Springer, Berlin, Heidelberg, 2017. 3. Mackinnon SE, Dellon AL. A study of nerve regeneration across synthetic (Maxon) and biologic (collagen) nerve conduits for nerve gaps up to 5 cm in the primate. Journal of Reconstructive Microsurgery. 1990 Apr;6(02):117-21. 4. Archibald SJ, Shefner J, Krarup C, Madison RD. Monkey median nerve repaired by nerve graft or collagen nerve guide tube. Journal of Neuroscience. 1995 May 1;15(5):4109-23. 5. Li ST, Archibald SJ, Krarup C, Madison RD. Peripheral nerve repair with collagen conduits. Clinical Materials. 1992 Jan 1;9(3-4):195-200. 6. Boeckstyns ME, Sørensen AI, Viñeta JF, Rosén B, Navarro X, Archibald SJ, Valss-Solé J, Moldovan M, Krarup C. Collagen conduit versus microsurgical neurorrhaphy: 2-year follow-up of a prospective, blinded clinical and electrophysiological multicenter randomized, controlled trial. The Journal of Hand Surgery. 2013 Dec 1;38(12):2405-11. 7. Wilson MT, Chuang SK, Ziccardi VB. Lingual nerve microsurgery outcomes using 2 different conduits: A retrospective cohort study. Journal of Oral and Maxillofacial Surgery. 2017 Mar 1;75(3):609-15. 8. Huber JL, Maier C, Mainka T, Mannil L, Vollert J, Homann HH. Recovery of mechanical detection thresholds after direct digital nerve repair versus conduit implantation. Journal of Hand Surgery (European Volume). 2017 Sep;42(7):720-30. 9. Krarup C, Rosén B, Boeckstyns M, Ibsen Sørensen A, Lundborg G, Moldovan M, Archibald SJ. Sensation, mechanoreceptor, and nerve fiber function after nerve regeneration. Annals of neurology. 2017 Dec;82(6):940-50. 10. Klein S, Vykoukal J, Felthaus O, Dienstknecht T, Prantl L. Collagen type I conduits for the regeneration of nerve defects. Materials. 2016;9(4):219. 11. Krarup C, Boeckstyns M, Ibsen A, Moldovan M, Archibald S. Remodeling of motor units after nerve regeneration studied by quantitative electromyography. Clinical Neurophysiology. 2016 Feb 1;127(2):1675-82. 12. Lohmeyer JA, Kern Y, Schmauss D, Paprottka F, Stang F, Siemers F, Mailaender P, Machens HG. Prospective clinical study on digital nerve repair with collagen nerve conduits and review of literature. Journal of Reconstructive Microsurgery. 2014 May;30(04):227-34. 13. Schmauss D, Finck T, Liodaki E, Stang F, Megerle K, Machens HG, Lohmeyer JA. Is nerve regeneration after reconstruction with collagen nerve conduits terminated after 12 months? The long-term follow-up of two prospective clinical studies. Journal of Reconstructive Microsurgery. 2014 Oct;30(08):561-8. 14. Dienstknecht T, Klein S, Vykoukal J, Gehmert S, Koller M, Gosau M, Prantl L. Type I collagen nerve conduits for median nerve repairs in the forearm. The Journal of Hand Surgery. 2013 Jun 1;38(6):1119-24. 15. Erakat MS, Chuang SK, Shanti RM, Ziccardi VB. Interval between injury and lingual nerve repair as a prognostic factor for success using type I collagen conduit. Journal of Oral and Maxillofacial Surgery. 2013 May 1;71(5):833-8. 16. Haug A, Bartels A, Kotas J, Kunesch E. Sensory recovery 1 year after bridging digital nerve defects with collagen tubes. The Journal of Hand Surgery. 2013 Jan 1;38(1):90-7. 17. Wolfe SW, Strauss HL, Garg R, Feinberg J. Use of bioabsorbable nerve conduits as an adjunct to brachial plexus neurorrhaphy. The Journal of Hand Surgery. 2012 Oct 1;37(10):1980-5. 18. Taras JS, Jacoby SM, Lincoski CJ. Reconstruction of digital nerves with collagen conduits. The Journal of Hand Surgery. 2011 Sep 1;36(9):1441-6. 19. Wangensteen KJ, Kalliainen LK. Collagen tube conduits in peripheral nerve repair: a retrospective analysis. Hand. 2010 Sep;5(3):273-7. 20. Lohmeyer JA, Siemers F, Machens HG, Mailänder P. The clinical use of artificial nerve conduits for digital nerve repair: a prospective cohort study and literature review. Journal of Reconstructive Microsurgery. 2009 Jan;25(01):055-61. 21. Bushnell BD, McWilliams AD, Whitener GB, Messer TM. Early clinical experience with collagen nerve tubes in digital nerve repair. The Journal of Hand Surgery. 2008 Sep 1;33(7):1081-7. 22. Farole A, Jamal BT. A bioabsorbable collagen nerve cuff (NeuraGen) for repair of lingual and inferior alveolar nerve injuries: a case series. Journal of Oral and Maxillofacial Surgery. 2008 Oct 1;66(10):2058-62. 23. Ashley WW, Weatherly T, Park TS. Collagen nerve guides for surgical repair of brachial plexus birth injury. Journal of Neurosurgery: Pediatrics. 2006 Dec 1;105(6):452-6. 24. Lee JY, Giusti G, Friedrich PF, Archibald SJ, Kemnitzer JE, Patel J, Desai N, Bishop AT, Shin AY. The effect of collagen nerve conduits filled with collagen-glycosaminoglycan matrix on peripheral motor nerve regeneration in a rat model. JBJS. 2012 Nov 21;94(22):2084-91.

Stryker NeuroFlex Study: Gould JS, Naranje SM, McGwin Jr G, Florence M, Cheppalli S. Use of collagen conduits in management of painful neuromas of the foot and ankle. Foot & Ankle International. 2013 Jul;34(7):932-40.

NeuraGen® Nerve GuideIndications for Use: NeuraGen Nerve Guide is indicated for the repair of peripheral nerve discontinuities where gap closure can be achieved by flexion of the extremity.Contraindications: NeuraGen Nerve Guide is not designed, sold or intended for use expect as described in the indications for use and is contraindicated for patients with a known hypersensitivity to bovine derived materials.

The Next Generation of Nerve Repair

“The surgical techniques and technologic advances currently used [in nerve repair] have made it possible to consistently expect vast improvement in the lives of patients, but there remains room for continued advancement... the focus of nerve repair [has shifted] toward manipulation of the biological environment within the conduit on a molecular level, with the result that many new materials are being added as substrates within the conduit.” – Wilson et al.7

Integra is investing in the development of a next generation collagen nerve conduit filled with a matrix of collagen and chondroitin-6-sulfate.

Results of a study, conducted in a rat model of peripheral nerve repair, showed that the collagen conduit filled with a matrix of collagen and chondroitin-6-sulftate (c6s) was more effective in achieving functional motor recovery than a hollow conduit. Axon counts in the collagen/c6s matrix filled conduit were comparable with those in a reversed autograft at 12 weeks after repair.24

Development of Integra’s next generation collagen nerve conduit includes the collection of clinical evidence to demonstrate the device’s safety and efficacy. Thus, an Integra-sponsored pilot study of the collagen and chondroitin-6-sulfate filled conduit is currently ongoing.

Axons in autograft24

Axons in hollow conduit24

Axons in conduit filled with collagen/c6s matrix24