Vascularization and biocompatibility of poly(ε-caprolactone) fiber mats for rotator cuff tear repair

Autoři: Sarah Gniesmer aff001;  Ralph Brehm aff003;  Andrea Hoffmann aff002;  Dominik de Cassan aff005;  Henning Menzel aff005;  Anna Lena Hoheisel aff002;  Birgit Glasmacher aff002;  Elmar Willbold aff002;  Janin Reifenrath aff002;  Nils Ludwig aff008;  Ruediger Zimmerer aff001;  Frank Tavassol aff001;  Nils-Claudius Gellrich aff001;  Andreas Kampmann aff001
Působiště autorů: Department of Oral and Maxillofacial Surgery, Hannover Medical School, Hannover, Germany aff001;  NIFE—Lower Saxony Centre for Biomedical Engineering, Implant Research and Development, Hannover, Germany aff002;  Institute for Anatomy, University of Veterinary Medicine Hannover, Hannover, Germany aff003;  Department of Orthopedic Surgery, Laboratory for Biomechanics and Biomaterials, Graded Implants and Regenerative Strategies, Hannover Medical School, Hannover, Germany aff004;  Institute for Technical Chemistry, Braunschweig University of Technology, Braunschweig, Germany aff005;  Institute of Multiphase Processes, Leibniz University Hannover, Hannover, Germany aff006;  Department of Orthopedic Surgery, Hannover Medical School, Hannover, Germany aff007;  Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America aff008
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0227563


Rotator cuff tear is the most frequent tendon injury in the adult population. Despite current improvements in surgical techniques and the development of grafts, failure rates following tendon reconstruction remain high. New therapies, which aim to restore the topology and functionality of the interface between muscle, tendon and bone, are essentially required. One of the key factors for a successful incorporation of tissue engineered constructs is a rapid ingrowth of cells and tissues, which is dependent on a fast vascularization. The dorsal skinfold chamber model in female BALB/cJZtm mice allows the observation of microhemodynamic parameters in repeated measurements in vivo and therefore the description of the vascularization of different implant materials. In order to promote vascularization of implant material, we compared a porous polymer patch (a commercially available porous polyurethane based scaffold from Biomerix) with electrospun polycaprolactone (PCL) fiber mats and chitosan-graft-PCL coated electrospun PCL (CS-g-PCL) fiber mats in vivo. Using intravital fluorescence microscopy microcirculatory parameters were analyzed repetitively over 14 days. Vascularization was significantly increased in CS-g-PCL fiber mats at day 14 compared to the porous polymer patch and uncoated PCL fiber mats. Furthermore CS-g-PCL fiber mats showed also a reduced activation of immune cells. Clinically, these are important findings as they indicate that the CS-g-PCL improves the formation of vascularized tissue and the ingrowth of cells into electrospun PCL scaffolds. Especially the combination of enhanced vascularization and the reduction in immune cell activation at the later time points of our study points to an improved clinical outcome after rotator cuff tear repair.

Klíčová slova:

Biomaterial implants – Macrophages – Medical implants – Polymers – Porous materials – Tendons – Tissue repair – White blood cells


1. Yamamoto A, Takagishi K, Osawa T, Yanagawa T, Nakajima D, Shitara H, et al. Prevalence and risk factors of a rotator cuff tear in the general population. J Shoulder Elb Surg. 2010;19(1):116–20.

2. Lähteenmäki HE, Virolainen P, Hiltunen A, Heikkilä J, Nelimarkka OI. Results of early operative treatment of rotator cuff tears with acute symptoms. J Shoulder Elb Surg. 2006 Mar;15(2):148–53.

3. Gerber C, Meyer DC, Schneeberger AG, Hoppeler H, von Rechenberg B. Effect of tendon release and delayed repair on the structure of the muscles of the rotator cuff: an experimental study in sheep. J Bone Joint Surg Am. 2004;

4. Gerber C, Meyer DC, Frey E, von Rechenberg B, Hoppeler H, Frigg R, et al. Neer Award 2007: Reversion of structural muscle changes caused by chronic rotator cuff tears using continuous musculotendinous traction. An experimental study in sheep. J Shoulder Elb Surg. 2009;18:163.

5. Meyer DC, Hoppeler H, von Rechenberg B, Gerber C. A pathomechanical concept explains muscle loss and fatty muscular changes following surgical tendon release. J Orthop Res. 2004;22:1004. doi: 10.1016/j.orthres.2004.02.009 15304272

6. Rodeo SA. Biological augmentation of rotator cuff tendon repair. J Shoulder Elb Surg. 2007;16:191S.

7. Santoni BG, McGilvray KC, Lyons AS, Bansal M, Turner AS, Macgillivray JD, et al. Biomechanical analysis of an ovine rotator cuff repair via porous patch augmentation in a chronic rupture model. Am J Sports Med. 2010;38:679. doi: 10.1177/0363546510366866 20357402

8. Seiberl W, Seppel G, Plath JE, Vo C. Long-term Results After Arthroscopic Repair of Isolated Subscapularis Tears. Am J Sport Med Mon. 2017;45:759.

9. Nho SJ, Delos D, Yadav H, Pensak M, Romeo AA, Warren RF, et al. Biomechanical and Biologic Augmentation for the Treatment of Massive Rotator Cuff Tears. Am J Sports Med. 2009 Sep 23;38(3):619–29. doi: 10.1177/0363546509343199 19776339

10. Lovett M, Lee K, Edwards A, Kaplan DL. Vascularization strategies for tissue engineering. Tissue Eng Part B Rev. 2009 Sep [cited 2018 Feb 27];15(3):353–70. doi: 10.1089/ten.TEB.2009.0085 19496677

11. Kannan RY, Salacinski HJ, Sales K, Butler P, Seifalian AM. The roles of tissue engineering and vascularisation in the development of micro-vascular networks: a review. Biomaterials. 2005 May 1 [cited 2018 Feb 27];26(14):1857–75. doi: 10.1016/j.biomaterials.2004.07.006 15576160

12. Font Tellado S, Balmayor ER, Van Griensven M. Strategies to engineer tendon/ligament-to-bone interface: Biomaterials, cells and growth factors. Adv Drug Deliv Rev. 2015 Nov 1 [cited 2018 Feb 27];94:126–40. doi: 10.1016/j.addr.2015.03.004 25777059

13. Lam CXF, Hutmacher DW, Schantz J, Woodruff MA. Evaluation of polycaprolactone scaffold degradation for 6 months in vitro and in vivo. J Biomed Mater Res—Part A. 2008;906.

14. Venugopal J, Ma LL, Yong T, Ramakrishna S. In vitro study of smooth muscle cells on polycaprolactone and collagen nanofibrous matrices. Cell Biol Int. 2005;

15. Jing X., Mi H.-Y., Wang X.-C., Peng L-ST X.-F. Shish-kebab-structured poly(ε-caprolactone) nanofibers hierarchically decorated with chitosan-poly(ε-caprolactone) copolymers for bone tissue engineering. ACS Appl Mater interfaces 7. 2015;12:6955.

16. Wang X, Salick MR, Wang X, Cordie T, Han W, Peng Y, et al. Poly(ε-caprolactone) nanofibers with a self-induced nanohybrid shish-kebab structure mimicking collagen fibrils. Biomacromolecules. 2013;14(10):3557. doi: 10.1021/bm400928b 24010580

17. Wang F, Mohammed A, Li C, Wang L. Promising Poly (? -caprolactone) Composite Reinforced with Weft-Knitted Polyester for Small-Diameter Vascular Graft Application. Adv Mater Sci Eng. 2014;2014:9.

18. Chim H, Hutmacher DW, Chou AM, Oliveira AL, Reis RL, Lim TC, et al. A comparative analysis of scaffold material modifications for load-bearing applications in bone tissue engineering. Int J Oral Maxillofac Surg. 2006;35(10):928–34. doi: 10.1016/j.ijom.2006.03.024 16762529

19. Malikmammadov E, Tanir TE, Kiziltay A, Hasirci V, Hasirci N. PCL-TCP wet spun scaffolds carrying antibiotic-loaded microspheres for bone tissue engineering. J Biomater Sci Polym Ed. 2018 Jun 13;29(7–9):805–24. doi: 10.1080/09205063.2017.1354671 28705112

20. Li W-J, Danielson KG, Alexander PG, Tuan RS. Biological response of chondrocytes cultured in three-dimensional nanofibrous poly(ϵ-caprolactone) scaffolds. J Biomed Mater Res Part A. 2003 Dec 15;67A(4):1105–14.

21. Huang H, Oizumi S, Kojima N, Niino T, Sakai Y. Avidin–biotin binding-based cell seeding and perfusion culture of liver-derived cells in a porous scaffold with a three-dimensional interconnected flow-channel network. Biomaterials. 2007;28(26):3815–23. doi: 10.1016/j.biomaterials.2007.05.004 17544499

22. Serrano-Aroca Á, Vera-Donoso CD, Moreno-Manzano V. Bioengineering Approaches for Bladder Regeneration. Int J Mol Sci. 2018 Jun 17;19(6):1796.

23. Dubský M, Kubinová Š, Širc J, Voska L, Zajíček R, Zajícová A, et al. Nanofibers prepared by needleless electrospinning technology as scaffolds for wound healing. J Mater Sci Mater Med. 2012 Apr;23(4):931–41. doi: 10.1007/s10856-012-4577-7 22331377

24. Daud MFB, Pawar KC, Claeyssens F, Ryan AJ, Haycock JW. An aligned 3D neuronal-glial co-culture model for peripheral nerve studies. Biomaterials. 2012;33(25):5901–13. doi: 10.1016/j.biomaterials.2012.05.008 22656449

25. Beason DP, Connizzo BK, Dourte LM, Mauck RL, Soslowsky LJ, Steinberg DR, et al. Fiber-aligned polymer scaffolds for rotator cuff repair in a rat model. J Shoulder Elb Surg. 2012 Feb 1 [cited 2018 Feb 27];21(2):245–50.

26. Gniesmer S, Brehm R, Hoffmann A, de Cassan D, Menzel H, Hoheisel A-L, et al. In vivo analysis of vascularization and biocompatibility of electrospun polycaprolactone fiber mats in the rat femur chamber. J Tissue Eng Regen Med. 2019 Apr 26;0(ja).

27. Ricchetti ET, Aurora A, Iannotti JP, Derwin KA. Scaffold devices for rotator cuff repair. J Shoulder Elb Surg. 2012 Feb 1 [cited 2018 Feb 27];21(2):251–65.

28. Rücker M, Laschke MW, Junker D, Carvalho C, Schramm A, Mülhaupt R, et al. Angiogenic and inflammatory response to biodegradable scaffolds in dorsal skinfold chambers of mice. Biomaterials. 2006 Oct 1 [cited 2018 Feb 27];27(29):5027–38. doi: 10.1016/j.biomaterials.2006.05.033 16769111

29. Encalada-Diaz I, Cole BJ, Macgillivray JD, Ruiz-Suarez M, Kercher JS, Friel NA, et al. Rotator cuff repair augmentation using a novel polycarbonate polyurethane patch: preliminary results at 12 months’ follow-up. J shoulder Elb Surg. 2011 Jul [cited 2018 Feb 27];20(5):788–94.

30. Becker A, Zernetsch H, Mueller M, Glasmacher B. A novel coaxial nozzle for in-process adjustment of electrospun scaffolds fiber diameter. Curr Dir Biomed Eng. 2015;1(1):104–7.

31. de Cassan D, Sydow S, Schmidt N, Behrens P, Roger Y, Hoffmann A, et al. Attachment of nanoparticulate drug-release systems on poly(ε-caprolactone) nanofibers via a graftpolymer as interlayer. Colloids Surfaces B Biointerfaces. 2018 Mar 1 [cited 2018 Aug 27];163:309–20. doi: 10.1016/j.colsurfb.2017.12.050 29329076

32. Cole BJ, Gomoll AH, Yanke A, Pylawka T, Lewis P, MacGillivray JD, et al. Biocompatibility of a polymer patch for rotator cuff repair. Knee Surgery, Sport Traumatol Arthrosc. 2007 Apr 30 [cited 2018 Feb 27];15(5):632–7.

33. Schumann P, von See C, Kampmann A, Lindhorst D, Tavassol F, Kokemüller H, et al. Comparably accelerated vascularization by preincorporation of aortic fragments and mesenchymal stem cells in implanted tissue engineering constructs. J Biomed Mater Res Part A. 2011 Jun 15 [cited 2018 Feb 27];97A(4):383–94.

34. Lehr H-A, Leunig M, Menger MD, Nolte D, Messmer K. Dorsal Skinfold Chamber Technique for Intravital Microscopy in Nude Mice. Am J Pathol. 1993 [cited 2018 Feb 27];143(4).

35. Zimmerer RM, Ludwig N, Kampmann A, Bittermann G, Spalthoff S, Jungheim M, et al. CD24 + tumor-initiating cells from oral squamous cell carcinoma induce initial angiogenesis in vivo. Microvasc Res. 2017 Jul 1 [cited 2018 Feb 27];112:101–8. doi: 10.1016/j.mvr.2017.03.006 28344048

36. Willbold E, Kalla K, Bartsch I, Bobe K, Brauneis M, Remennik S, et al. Biocompatibility of rapidly solidified magnesium alloy RS66 as a temporary biodegradable metal. Acta Biomater. 2013;9(10):8509–17. doi: 10.1016/j.actbio.2013.02.015 23416472

37. Laschke MW, Harder Y, Amon M, Martin I, Farhadi J, Ring A, et al. Angiogenesis in Tissue Engineering: Breathing Life into Constructed Tissue Substitutes. 2006 [cited 2018 Feb 27];

38. Gerald Williams BR Jr, Rockwood CA Jr, Bigliani LU, Iannotti JP, Stanwood W. Why Do We Repair Them?*. J BONE Jt Surg. 2004;86–A:2764.

39. Tavassol F, Kampmann A, Lindhorst D, Schumann P, Kokemü H, Bormann K-H, et al. Prolongated Survival of Osteoblast-Like Cells on Biodegradable Scaffolds by Heat Shock Preconditioning. Tissue Eng Part A. 2011;17:1935. doi: 10.1089/ten.TEA.2010.0603 21417712

40. Agrawal CM, Ray RB. Biodegradable polymeric scaffolds for musculoskeletal tissue engineering. J Biomed Mater Res. 2001;55:141. doi: 10.1002/1097-4636(200105)55:2<141::aid-jbm1000>;2-j 11255165

41. Ribeiro JCV, Vieira RS, Melo IM, Araújo VMA, Lima V. Versatility of Chitosan-Based Biomaterials and Their Use as Scaffolds for Tissue Regeneration. ScientificWorldJournal. 2017 [cited 2018 Feb 27];2017:8639898. doi: 10.1155/2017/8639898 28567441

42. McCormack RA, Shreve M, Strauss EJ. Biologic augmentation in rotator cuff repair should we do it, who should get it, and has it worked? Bull NYU Hosp Jt Dis. 2014;

43. Johnson KE, Wilgus TA. Vascular Endothelial Growth Factor and Angiogenesis in the Regulation of Cutaneous Wound Repair. Adv wound care. 2014 Oct 1;3(10):647–61.

44. Harada Y, Mifune Y, Inui A, Sakata R, Muto T, Takase F, et al. Rotator cuff repair using cell sheets derived from human rotator cuff in a rat model. J Orthop Res. 2017 Feb 1;35(2):289–96. doi: 10.1002/jor.23289 27171575

45. Zumstein MA, Rumian A, Tr F, Lesbats V, Schaer M, Boileau P. Increased vascularization during early healing after biologic augmentation in repair of chronic rotator cuff tears using autologous leukocyte- and platelet-rich fibrin (L-PRF): a prospective randomized controlled pilot trial. J Shoulder Elb Surg. 2014;23(1):3–12.

46. Fealy S, Adler R, Drakos M, Kelly A, Allen A, Cordasco F, et al. Patterns of Vascular and Anatomical Response After Rotator Cuff Repair. Am J Sports Med. 2006 Feb 1;34:120–7. doi: 10.1177/0363546505280212 16260468

47. Kuboki Y, Jin Q, Takita H. Geometry of Carriers Controlling Phenotypic Expression in BMP-induced osteogenesis and chondrogenesis. J BONE Jt Surg. 2001;83–A:S1–105.

48. Blakeney BA, Tambralli A, Anderson JM, Andukuri A, Lim D-J, Dean DR, et al. Cell infiltration and growth in a low density, uncompressed three-dimensional electrospun nanofibrous scaffold. Biomaterials. 2011 Feb [cited 2018 Feb 27];32(6):1583–90. doi: 10.1016/j.biomaterials.2010.10.056 21112625

49. Pham QP, Sharma U, Mikos AG. Electrospun Poly (E -caprolactone) Microfiber and Multilayer Nanofiber / Microfiber Scaffolds: Characterization of Scaffolds and Measurement of Cellular Infiltration. 2006;2796–805.

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