Development of Nanofiber Scaffolds With Controllable Structure and Mineral Content for Tendon-to-Bone Repair

Rotator cuff tears are common and lead to significant pain and disability. Effective repair of torn rotator cuff tendons requires healing of tendon to bone. Unfortunately, healing does not reproduce the structural and compositional features of the natural tendon-to-bone bone attachment that are necessary for effective load transfer, and surgical repairs often rupture.

Recent efforts for improving tendon-to-bone healing have focused on tissue engineering approaches. Scaffolds, cells, and/or growth factors are implanted at the repair site to guide the healing process and improve outcomes. To that end, a polymer-mineral tissue engineered scaffold was developed for this thesis which mimics two of the primary features of the tendonto-bone insertion: aligned nanofibers and hydroxyapatite mineral crystals. The nanofibrous component was created by electrospinning poly lactic-co-glycolic acid to create non-woven mats. The bone-like mineral was then deposited onto the nanofibers using mineralizing solutions. The structure (alignment and crimp microstructure) and composition (mineral content and morphology) of the scaffolds were modulated to understand their influence on scaffold mechanics. Experimental and modeling results demonstrated that: (1) the orientation distribution of the nanofibers was a major determinant of modulus, strength, and anisotropy, (2) crimp microstructure was a major determinant of low strain non-linear mechanical behavior, (3) mineral content positively correlated with modulus and strength and negatively correlated with toughness, (4) mineral morphology was a significant determinant of its stiffening effect, and (5) scaffold-level stiffening by mineral was due to mineral cross-bridges between nanofibers, not due to stiffening of individual nanofibers. Scaffolds were tested in a rotator cuff tendon-to-bone animal model in an effort to improve healing, but were found to be ineffective; the scar-mediated wound healing response dominated over any effects from the scaffold. In summary, a number of mechanisms driving nanofiber mechanics were defined, but further study is needed to effectively apply these scaffolds in the setting of tendon-to-bone repair.

Year	Entry
1974	Reilly DT, Burstein AH, Frankel VH. The elastic modulus for bone. J Biomech. May 1974;7(3):271-275.
1978	Kastelic J, Galeski A, Baer E. The multicomposite structure of tendon. Connect Tissue Res. 1978;6(1):11-23.
2003	Lynch HA, Johannessen W, Wu JP, Jawa A, Elliott DM. Effect of fiber orientation and strain rate on the nonlinear uniaxial tensile material properties of tendon. J Biomech Eng. October 2003;125(5):726-731.
2005	Sharma P, Maffulli N. Tendon injury and tendinopathy: healing and repair. J Bone Joint Surg. January 2005;87A(1):187-202.
1982	Gilmore RS, Katz JL. Elastic properties of apatites. J Mater Sci. 1982;17:1131-1141.
2002	Erickson GR, Gimble JM, Franklin DM, Rice HE, Awad H, Guilak F. Chondrogenic potential of adipose tissue-derived stromal cells in vitro and in vivo. Biochem Biophys Res Commun. January 18, 2002;290(2):763-769.
2003	Thomopoulos S, Williams GR, Gimbel JA, Favata M, Soslowsky LJ. Variation of biomechanical, structural, and compositional properties along the tendon to bone insertion site. J Orthop Res. May 2003;21(3):413-419.
2012	Alexander B, Daulton TL, Genin GM, Lipner J, Pasteris JD, Wopenka B, Thomopoulos S. The nanometre-scale physiology of bone: steric modelling and scanning transmission electron microscopy of collagen-mineral structure. J R Soc Interface. August 7, 2012;9(73):1774-1786.
1988	Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA. Novel regulators of bone formation: molecular clones and activities. Science. December 16, 1988;242(4885):1528-1534.
2006	Eppell SJ, Smith BN, Kahn H, Ballarini R. Nano measurements with micro-devices: mechanical properties of hydrated collagen fibrils. J R Soc Interface. February 22, 2006;3(6):117-121.
1999	Maganaris CN, Paul JP. In vivo human tendon mechanical properties. J Physiol. November 15, 1999;521(1):307-313.
2007	Bi Y, Ehirchiou D, Kilts TM, Inkson CA, Embree MC, Sonoyama W, Li L, Leet AI, Seo B-M, Zhang L, Shi S, Young MF. Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat Med. October 2007;13(10):1219-1227.
2007	Nerurkar NL, Elliott DM, Mauck RL. Mechanics of oriented electrospun nanofibrous scaffolds for annulus fibrosus tissue engineering. J Orthop Res. August 2007;25(8):1018-1028.
2002	Hansen KA, Weiss JA, Barton JK. Recruitment of tendon crimp with applied tensile strain. J Biomech Eng. February 2002;124(1):72-77.
1993	Woo SL-Y, Johnson GA, Smith BA. Mathematical modeling of ligaments and tendons. J Biomech Eng. November 1993;115(4B):468-473.
1963	Hashin Z, Shtrikman S. A variational approach to the theory of the elastic behaviour of multiphase materials. J Mech Phys Solids. March–April 1963;11(2):127-140.
2007	Baker BM, Mauck RL. The effect of nanofiber alignment on the maturation of engineered meniscus constructs. Biomaterials. April 2007;28(11):1967-1977.
2003	Thomopoulos S, Williams GR, Soslowsky LJ. Tendon to bone healing: differences in biomechanical, structural, and compositional properties due to a range of activity levels. J Biomech Eng. February 2003;125(1):106-113.
2007	Thurner PJ, Erickson B, Jungmann R, Schriock Z, Weaver JC, Fantner GE, Schitter G, Morse DE, Hansma PK. High-speed photography of compressed human trabecular bone correlates whitening to microscopic damage. Eng Fract Mech. 2007;74(12):1928-1941.
1999	Currey JD. The design of mineralised hard tissues for their mechanical functions. J Exp Biol. December 1999;202(23):3285-3294.

Year

Entry

1974

Reilly DT, Burstein AH, Frankel VH. The elastic modulus for bone. J Biomech. May 1974;7(3):271-275.

1978

Kastelic J, Galeski A, Baer E. The multicomposite structure of tendon. Connect Tissue Res. 1978;6(1):11-23.

2003

Lynch HA, Johannessen W, Wu JP, Jawa A, Elliott DM. Effect of fiber orientation and strain rate on the nonlinear uniaxial tensile material properties of tendon. J Biomech Eng. October 2003;125(5):726-731.

2005

Sharma P, Maffulli N. Tendon injury and tendinopathy: healing and repair. J Bone Joint Surg. January 2005;87A(1):187-202.

1982

Gilmore RS, Katz JL. Elastic properties of apatites. J Mater Sci. 1982;17:1131-1141.

2002

Erickson GR, Gimble JM, Franklin DM, Rice HE, Awad H, Guilak F. Chondrogenic potential of adipose tissue-derived stromal cells in vitro and in vivo. Biochem Biophys Res Commun. January 18, 2002;290(2):763-769.

2003

Thomopoulos S, Williams GR, Gimbel JA, Favata M, Soslowsky LJ. Variation of biomechanical, structural, and compositional properties along the tendon to bone insertion site. J Orthop Res. May 2003;21(3):413-419.

2012

Alexander B, Daulton TL, Genin GM, Lipner J, Pasteris JD, Wopenka B, Thomopoulos S. The nanometre-scale physiology of bone: steric modelling and scanning transmission electron microscopy of collagen-mineral structure. J R Soc Interface. August 7, 2012;9(73):1774-1786.

1988

Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA. Novel regulators of bone formation: molecular clones and activities. Science. December 16, 1988;242(4885):1528-1534.

2006

Eppell SJ, Smith BN, Kahn H, Ballarini R. Nano measurements with micro-devices: mechanical properties of hydrated collagen fibrils. J R Soc Interface. February 22, 2006;3(6):117-121.

1999

Maganaris CN, Paul JP. In vivo human tendon mechanical properties. J Physiol. November 15, 1999;521(1):307-313.

2007

Bi Y, Ehirchiou D, Kilts TM, Inkson CA, Embree MC, Sonoyama W, Li L, Leet AI, Seo B-M, Zhang L, Shi S, Young MF. Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat Med. October 2007;13(10):1219-1227.

2007

Nerurkar NL, Elliott DM, Mauck RL. Mechanics of oriented electrospun nanofibrous scaffolds for annulus fibrosus tissue engineering. J Orthop Res. August 2007;25(8):1018-1028.

2002

Hansen KA, Weiss JA, Barton JK. Recruitment of tendon crimp with applied tensile strain. J Biomech Eng. February 2002;124(1):72-77.

1993

Woo SL-Y, Johnson GA, Smith BA. Mathematical modeling of ligaments and tendons. J Biomech Eng. November 1993;115(4B):468-473.

1963

Hashin Z, Shtrikman S. A variational approach to the theory of the elastic behaviour of multiphase materials. J Mech Phys Solids. March–April 1963;11(2):127-140.

2007

Baker BM, Mauck RL. The effect of nanofiber alignment on the maturation of engineered meniscus constructs. Biomaterials. April 2007;28(11):1967-1977.

2003

Thomopoulos S, Williams GR, Soslowsky LJ. Tendon to bone healing: differences in biomechanical, structural, and compositional properties due to a range of activity levels. J Biomech Eng. February 2003;125(1):106-113.

2007

Thurner PJ, Erickson B, Jungmann R, Schriock Z, Weaver JC, Fantner GE, Schitter G, Morse DE, Hansma PK. High-speed photography of compressed human trabecular bone correlates whitening to microscopic damage. Eng Fract Mech. 2007;74(12):1928-1941.

1999

Currey JD. The design of mineralised hard tissues for their mechanical functions. J Exp Biol. December 1999;202(23):3285-3294.

Year	Entry
2017	Boyle J. Accurate Determination and Application of Local Strain for Studying Tissues With Gradients in Mechanical Properties [PhD thesis]. St. Louis, MO: Washington University in St. Louis; December 2017.

Year

Entry

2017

Boyle J. Accurate Determination and Application of Local Strain for Studying Tissues With Gradients in Mechanical Properties [PhD thesis]. St. Louis, MO: Washington University in St. Louis; December 2017.