Induced Collagen Cross-Links Enhance Cartilage Integration

Athens, Aristos A.; Makris, Eleftherios; Hu, Jerry C.

doi:10.1371/journal.pone.0060719

Cited by 47 publications

(55 citation statements)

References 37 publications

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“…Previously, in articular cartilage-neocartilage integration, a tensile test demonstrated lysyl oxidase induced an apparent interfacial stiffness of 1.5 MPa when treated two weeks prior to and during one week of integration [9]. In this study, detected by a pushthrough test, which assesses primarily shear mechanics, an interfacial stiffness of 17 MPa was measured with lysyl oxidase, CuSO 4 and hydroxylysine treatment, following eight weeks integration.…”

Section: Discussionmentioning

confidence: 63%

“…During collagen formation and repair, lysyl oxidase oxidizes amino groups on collagen's lysine residues to form reactive aldehydes, which react with others, condensing to form covalent pyridinoline cross-links [20], a reaction that is dependent upon molecular oxygen and copper ion. Previously, lysyl oxidase has been shown to enhance collagen cross-links towards improving integration of neocartilage and native hyaline cartilage [9]. Following two weeks integration in vitro, lysyl oxidase induced 2-2.2 times increase in apparent stiffness across the cartilage interface in both neocartilage-to-native cartilage and native-to-native cartilage interfaces [9].…”

Section: Introductionmentioning

confidence: 99%

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Neocartilage integration in temporomandibular joint discs: physical and enzymatic methods

Murphy

Arzi

Prouty

et al. 2015

J. R. Soc. Interface.

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Integration of engineered musculoskeletal tissues with adjacent native tissues presents a significant challenge to the field. Specifically, the avascularity and low cellularity of cartilage elicit the need for additional efforts in improving integration of neocartilage within native cartilage. Self-assembled neocartilage holds significant potential in replacing degenerated cartilage, though its stabilization and integration in native cartilage require further efforts. Physical and enzymatic stabilization methods were investigated in an in vitro model for temporomandibular joint (TMJ) disc degeneration. First, in phase 1, suture, glue and press-fit constructs were compared in TMJ disc intermediate zone defects. In phase 1, suturing enhanced interfacial shear stiffness and strength immediately; after four weeks, a 15-fold increase in stiffness and a ninefold increase in strength persisted over press-fit. Neither suture nor glue significantly altered neocartilage properties. In phase 2, the effects of the enzymatic stabilization regimen composed of lysyl oxidase, CuSO 4 and hydroxylysine were investigated. A full factorial design was employed, carrying forward the best physical method from phase 1, suturing. Enzymatic stabilization significantly increased interfacial shear stiffness after eight weeks. Combined enzymatic stabilization and suturing led to a fourfold increase in shear stiffness and threefold increase in strength over press-fit. Histological analysis confirmed the presence of a collagen-rich interface. Enzymatic treatment additionally enhanced neocartilage mechanical properties, yielding a tensile modulus over 6 MPa and compressive instantaneous modulus over 1200 kPa at eight weeks. Suturing enhances stabilization of neocartilage, and enzymatic treatment enhances functional properties and integration of neocartilage in the TMJ disc. Methods developed here are applicable to other orthopaedic soft tissues, including knee meniscus and hyaline articular cartilage.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Neocartilage integration in temporomandibular joint discs: physical and enzymatic methods

Murphy

Arzi

Prouty

et al. 2015

J. R. Soc. Interface.

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“…[41][42][43] These results support the value of strategies using exogenous treatments such as lysyl oxidase to strengthen the collagen network by increasing collagen cross-link precursors and to prevent the swelling evident in this study. 44 In prior studies of this model system, 45 it had been suggested that the higher deposition of GAG might inhibit collagen deposition, possibly due to a steric effect. Histological stains from this study support this hypothesis (Fig.…”

Section: Discussionmentioning

confidence: 93%

Matrix Production in Large Engineered Cartilage Constructs Is Enhanced by Nutrient Channels and Excess Media Supply

Nims

Cigáň

Albro

et al. 2015

Tissue Engineering Part C: Methods

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Cartilage tissue engineering is a promising approach to resurfacing osteoarthritic joints. Existing techniques successfully engineer small-sized constructs with native levels of extracellular matrix (glycosaminoglycans [GAG] or collagen). However, a remaining challenge is the growth of large-sized constructs with properties similar to those of small constructs, due to consumption and transport limitations resulting in inadequate nutrient availability within the interior of large constructs. This study employed system-specific computational models for estimating glucose requirements of large constructs, with or without channels, to enhance nutrient availability. Based on glucose requirements for matrix synthesis in cartilage constructs, computational simulations were performed to identify the media volume (MV) and the number of nutrient channels (CH) needed to maintain adequate glucose levels within tissue constructs over the 3-day period between media replenishments. In Study 1, the influence of MV (5, 10, 15 mL/construct) and number of nutrient channels (CH: 0, 3, 7, 12 per construct) on glucose availability was investigated computationally for B10 · 2.34 mm cylindrical constructs. Results showed that the conventionally used MV 5 led to deleterious glucose depletion after only 40 h of culture, and that MV 15 was required to maintain sufficient glucose levels for all channel configurations. Study 2 examined experimentally the validity of these predictions, for tissue constructs cultured for 56 days. Matrix elaboration was highest in MV 15/CH 12 constructs (21.6% -2.4%/ww GAG, 5.5% -0.7%/ww collagen, normalized to wet weight (ww) on day 0), leading to the greatest amount of swelling (3.0 -0.3 times day-0 volume), in contrast to the significantly lower matrix elaboration of conventional culture, MV 5/CH 0 (11.8% -1.6%/ww GAG and 2.5% -0.6%/ww collagen, 1.6 -0.1 times day-0 volume). The computational analyses correctly predicted the need to increase the conventional media levels threefold to support matrix synthesis in large channeled engineered constructs. Results also suggested that more elaborate computational models are needed for accurate predictive tissue engineering simulations, which account for a broader set of nutrients, cell proliferation, matrix synthesis, and swelling of the constructs.

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“…Increased neocartilage-to-native cartilage interfacial properties, such as tensile stiffness and strength, were observed after LOX treatment. Longer durations of treatment resulted in statistically higher interfacial tensile properties, 2.2 times that of the untreated control [100].…”

Section: Lox-mediated Enhancement Of Cartilage Integrationmentioning

confidence: 85%

Harnessing Biomechanics to Develop Cartilage Regeneration Strategies

Athanasiou

Responte²,

Brown

et al. 2015

Journal of Biomechanical Engineering

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laboratory over the past 25 years. The prevalence and severity of degeneration of articular cartilage, a tissue whose main function is largely biomechanical, have motivated the development of cartilage tissue engineering approaches informed by biomechanics. This article provides a review of important steps toward regeneration of articular cartilage with suitable biomechanical properties. As a first step, biomechanical and biochemical characterization studies at the tissue level were used to provide design criteria for engineering neotissues. Extending this work to the single cell and subcellular levels has helped to develop biochemical and mechanical stimuli for tissue engineering studies. This strong mechanobiological foundation guided studies on regenerating hyaline articular cartilage, the knee meniscus, and temporomandibular joint (TMJ) fibrocartilage. Initial tissue engineering efforts centered on developing biodegradable scaffolds for cartilage regeneration. After many years of studying scaffold-based cartilage engineering, scaffoldless approaches were developed to address deficiencies of scaffold-based systems, resulting in the self-assembling process. This process was further improved by employing exogenous stimuli, such as hydrostatic pressure, growth factors, and matrix-modifying and catabolic agents, both singly and in synergistic combination to enhance neocartilage functional properties. Due to the high cell needs for tissue engineering and the limited supply of native articular chondrocytes, costochondral cells are emerging as a suitable cell source. Looking forward, additional cell sources are investigated to render these technologies more translatable. For example, dermis isolated adult stem (DIAS) cells show potential as a source of chondrogenic cells. The challenging problem of enhanced integration of engineered cartilage with native cartilage is approached with both familiar and novel methods, such as lysyl oxidase (LOX). These diverse tissue engineering strategies all aim to build upon thorough biomechanical characterizations to produce functional neotissue that ultimately will help combat the pressing problem of cartilage degeneration. As our prior research is reviewed, we look to establish new pathways to comprehensively and effectively address the complex problems of musculoskeletal cartilage regeneration.

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Induced Collagen Cross-Links Enhance Cartilage Integration

Cited by 47 publications

References 37 publications

Neocartilage integration in temporomandibular joint discs: physical and enzymatic methods

Neocartilage integration in temporomandibular joint discs: physical and enzymatic methods

Matrix Production in Large Engineered Cartilage Constructs Is Enhanced by Nutrient Channels and Excess Media Supply

Harnessing Biomechanics to Develop Cartilage Regeneration Strategies

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