Preclinical Translation of Therapeutic Interventions for Tendon Injury

Links

URL: https://udspace.udel.edu/handle/19716/28852

Abstract

The burden of injury to tendon and the attachment between tendon and bone (i.e., the tendon-bone attachment) on quality of life, disability, health care, and the economy is significant. Unfortunately, current therapeutic interventions have high reinjury rates and do not restore the optimized multiscale structure and function of the healthy tendon or attachment. Investigations are needed to further develop and validate methods to prevent re-injury and improve tendon and attachment healing. The overall goal of this dissertation was to improve the preclinical translation of therapeutic interventions for tendon and attachment injury. The body of work in this dissertation helps to translate therapeutic interventions for tendon and attachment injury by establishing (1) an improved animal model of attachment injury, (2) success criteria for preclinical translation of hydrogels for tendon repair, (3) the safety and efficacy of a clinically available therapy, and (4) biomarkers of tendon injury.

The first aim of this research was to develop and validate a rat model of localized and partial-thickness attachment injury. The first part of this aim established the multiscale biomechanical properties of the attachment with and without localized defects ex vivo. Biomechanical tests validated that strain concentrations localize at the defect site, suggesting that defects may propagate in vivo. The final part of this aim established the cellular, structural, and biomechanical healing capacity of the attachment in vivo. Collectively, this aim established that the attachment has limited healing capacity and validated this animal model for continued preclinical translation of therapeutic interventions for improving the healing capacity of the attachment.

A weak scar tissue forms following tendon and attachment injury due to poor cell-mediated repair. Engineered cell-instructive cues within synthetic hydrogels are promising therapeutic strategies for tissue regeneration. However, the soft mechanical integrity of hydrogels raises concern about the functional application of hydrogels in mechanically demanding environments like tendon and attachment repair. In the second aim, we developed rigorous success criteria for preclinical testing of hydrogels in mechanically demanding environments by systematic review of the literature. Subsequently, using our success criteria, we demonstrated the preclinical efficacy of multi-functional synthetic hydrogels for tendon repair. This aim indicated the promise for continued preclinical translation of synthetic hydrogels for tissue regeneration.

Therapeutic interventions that alter the normal cellular response to injury may cause undesired effects in vivo. Therefore, in vivo investigations are needed to validate the safety and efficacy of cell-targeted therapies. The third aim of this dissertation evaluated the preclinical safety and efficacy of near-infrared light therapy during both tendon maturation and following injury in vivo. This aim showed that light therapy may be a beneficial therapy for tendon injury because it mildly improved the biomechanical properties of tendon healing without any adverse effects.

Prognostic biomarkers of tendon injury may help to improve clinical decisions for treatment. Currently, several biomarkers of tendon injury exist, however a need exists to determine whether biomarkers are pathological or necessary adaptations to injury. The final aim investigated metabolic biomarkers following mature tendon injury in comparison to normal tendon growth. In this aim, we identified several biomarkers of tendon injury that were not expressed during normal tendon growth.

This dissertation is significant in that I not only advanced knowledge of the characteristics of attachment healing but also helped to advance the preclinical translation of therapeutic interventions for tendon healing and repair. In summary, in my dissertation work, I aimed to answer fundamental questions about therapeutic interventions for tendon injury to increase the likelihood for successful preclinical translation and to ultimately reduce the time from bench to bedside.

Cited Works (18)

Year	Entry
2000	Butler DL, Goldstein SA, Guilak F. Functional tissue engineering: the role of biomechanics. J Biomech Eng. December 2000;122(6):570-575.
2012	Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez J-Y, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A. Fiji: an open-source platform for biological-image analysis. Nat Methods. June 28, 2012;9(7):676-682.
2010	Raggatt LJ, Partridge NC. Cellular and molecular mechanisms of bone remodeling. J Biol Chem. August 13, 2010;285(33):25103-25108.
1996	Soslowsky LJ, Carpenter JE, DeBano CM, Banerji I, Moalli MR. Development and use of an animal model for investigations on rotator cuff disease. J Shoulder Elbow Surg. September–October 1996;5(5):383-392.
2009	Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. July 21, 2009;6(7):e1000097.
2003	Silver FH, Freeman JW, Seehra GP. Collagen self-assembly and the development of tendon mechanical properties. J Biomech. October 2003;36(10):1529-1553.
1990	Komi PV. Relevance of in vivo force measurements to human biomechanics. J Biomech. 1990;23(suppl 1):23-34.
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.
2006	Hadjidakis DJ, Androulakis II. Bone remodeling. Annals NY Acad Sci. December 2006;1092(1):385-396.
1999	Maganaris CN, Paul JP. In vivo human tendon mechanical properties. J Physiol. November 15, 1999;521(1):307-313.
2006	Benjamin M, Toumi H, Ralphs JR, Bydder G, Best TM, Milz S. Where tendons and ligaments meet bone: attachment sites (‘entheses’) in relation to exercise and/or mechanical load. J Anat. April 2006;208(4):471-490.
2006	Thomopoulos S, Marquez JP, Weinberger B, Birman V, Genin GM. Collagen fiber orientation at the tendon to bone insertion and its influence on stress concentrations. J Biomech. 2006;39(10):1842-1851.
2009	Lake SP, Miller KS, Elliott DM, Soslowsky LJ. Effect of fiber distribution and realignment on the nonlinear and inhomogeneous mechanical properties of human supraspinatus tendon under longitudinal tensile loading. J Orthop Res. December 2009;27(12):1596-1602.
1998	Benjamin M, Ralphs JR. Fibrocartilage in tendons and ligaments: an adaptation to compressive load. J Anat. 1998;193(4):481-494.
1996	Berenson MC, Blevins FT, Plaas AHK, Vogel KG. Proteoglycans of human rotator cuff tendons. J Orthop Res. July 1996;14(4):518-525.
2004	Gimbel JA, Van Kleunen JP, Mehta S, Perry SM, Williams GR, Soslowsky LJ. Supraspinatus tendon organizational and mechanical properties in a chronic rotator cuff tear animal model. J Biomech. May 2004;37(5):739-749.
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.
2005	Discher DE, Janmey P, Wang Y-l. Tissue cells feel and respond to the stiffness of their substrate. Science. November 18, 2005;310(5751):1139-1143.