Collagen Scaffolds Incorporating Coincident Gradations of Instructive Structural and Biochemical Cues for Osteotendinous Junction Engineering

Caliari, Steven R.; Weisgerber, Daniel W.; Grier, William K.; Mahmassani, Ziad; Boppart, Marni D.; Harley, Brendan A.C.

doi:10.1002/adhm.201400809

Cited by 58 publications

(65 citation statements)

References 51 publications

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“…This has motived the development of tissue engineering (TE) strategies for ligament regeneration [8,9]. A number of studies have attempted to engineer stable fibrocartilaginous tissue or a mineral gradient to interface between the calcified region and the main body of the engineered ligament [10][11][12][13][14], although the ideal solution has yet to be identified.…”

Section: Introductionmentioning

confidence: 99%

Modulating microfibrillar alignment and growth factor stimulation to regulate mesenchymal stem cell differentiation

et al. 2017

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The ideal tissue engineering (TE) strategy for ligament regeneration should recapitulate the bonecalcified cartilage -fibrocartilage -soft tissue interface. Aligned electrospun-fibers have been shown to guide the deposition of a highly organized extracellular matrix (ECM) necessary for ligament TE.However, recapitulating the different tissues observed in the bone-ligament interface using such constructs remains a challenge. This study aimed to explore how fiber alignment and growth factor stimulation interact to regulate the chondrogenic and ligamentous differentiation of mesenchymal stem cells (MSCs). Without growth factor stimulation, MSCs on aligned-microfibers showed higher levels of tenomodulin (TNMD) and aggrecan gene expression compared to MSCs on randomlyoriented fibers. MSCs on aligned-microfibers stimulated with transforming growth factor β3 (TGFβ3) formed cellular aggregates and underwent robust chondrogenesis, evidenced by increased type II collagen expression and sulphated glycosaminoglycans (sGAG) synthesis compared to MSCs on randomly-oriented scaffolds. Bone morphogenetic protein 2 (BMP2) and type I collagen gene expression were higher on randomly-oriented scaffolds stimulated with TGFβ3, suggesting this substrate was more supportive of an endochondral phenotype. In the presence of connective tissue growth factor (CTGF), MSCs underwent ligamentous differentiation, with increased TNMD expression on aligned compared to randomly aligned scaffolds. Upon sequential growth factor stimulation, MSCs expressed types I and II collagen and deposited higher overall levels of collagen compared to scaffolds stimulated with either growth factor in isolation. These findings demonstrate that modulating the alignment of microfibrillar scaffolds can be used to promote either an endochondral, chondrogenic, fibro-chondrogenic or ligamentous MSC phenotype upon presentation of appropriate biochemical cues.

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Section: Introductionmentioning

confidence: 99%

Modulating microfibrillar alignment and growth factor stimulation to regulate mesenchymal stem cell differentiation

et al. 2017

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“…Furthermore, given clinical concerns regarding limited expansion of terminally-differentiated cells as well as secondary wound site creation, many efforts are beginning to develop biomaterials to drive mesenchymal stem cell (MSC) differentiation down osteotendinous lineages in a spatially-selective manner. [9] However, in addition to biomaterial-based cues, the function of the native osteotendinous insertion suggests applied tensile strain may be a particularly important instructional signal. Applied strain has previously been shown to alter cell alignment within biomaterials, [10] and in the TBJ is known to underlie initial development of the enthesis.…”

Section: Introductionmentioning

confidence: 99%

“…We showed anisotropic scaffolds containing structural alignment cues can enhance alignment, proliferation and transcriptomic stability of equine tenocytes, [15, 16] while also selectively activate mechanotransduction paths and MSC tenogenic differentiation in the absence of growth factors supplementation. [9, 17, 18] We have separately demonstrated a hydroxyapatite mineralized CG scaffold that enhanced MSC differentiation towards an osteogenic lineage, again in the absence of conventional osteogenic supplements. [18, 19] We have recently described a method to generate multi-compartment scaffolds that contain discrete scaffold regions connected by a continuous interface.…”

Section: Introductionmentioning

confidence: 99%

“…[18, 19] We have recently described a method to generate multi-compartment scaffolds that contain discrete scaffold regions connected by a continuous interface. [9] This approach provides orthogonal means to control both the degree of mineralization across the scaffold but also the degree of structural alignment (aligned, non-aligned). This capacity inspires significant questions regarding how cells within a graded scaffold architecture respond to applied strain.…”

Section: Introductionmentioning

confidence: 99%

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The Effect of Gradations in Mineral Content, Matrix Alignment, and Applied Strain on Human Mesenchymal Stem Cell Morphology within Collagen Biomaterials

Mozdzen

Thorpe

Screen

et al. 2016

Adv Healthcare Materials

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The tendon-bone junction (TBJ) is a unique, mechanically dynamic, structurally graded anatomical zone which transmits tensile loads between tendon and bone. Current surgical repair techniques rely on mechanical fixation and can result in high re-failure rates. We have recently described a new class of collagen biomaterial that contains discrete mineralized and structurally aligned regions linked by a continuous interface to mimic the graded osteotendinous insertion. Here we report the combined influence of graded biomaterial environment and increasing levels of applied strain (0 – 20%) on MSC orientation and alignment. In osteotendinous scaffolds, which contain opposing gradients of mineral content and structural alignment characteristic of the native osteotendinous interface, MSC nuclear and actin alignment was initially dictated by the local pore architecture, while applied tensile strain enhanced cell alignment in the direction of strain. Comparatively, in layered scaffolds that did not contain any structural alignment cues, MSCs were randomly oriented in the unstrained condition, then became oriented in a direction perpendicular to applied strain. These findings provide an initial understanding of how scaffold architecture can provide significant, potentially competitive, feedback influencing MSC orientation under applied strain, and forms the basis for future tissue engineering efforts to regenerate the osteotendinous enthesis.

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“…Culver et al used laser writing of adhesive peptides to instruct multicellular organization for the fabrication of vascular networks within hydrogels (102). Further, gradient biomaterials that present biochemical ligands in a spatially defined fashion have been used to recapitulate osteochondral and osteotendinous interfaces (103,104).…”

Section: From Bioinert To Biocomplexmentioning

confidence: 99%

Progress in material design for biomedical applications

Tibbitt

Rodell

Burdick

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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138

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Biomaterials that interface with biological systems are used to deliver drugs safely and efficiently; to prevent, detect, and treat disease; to assist the body as it heals; and to engineer functional tissues outside of the body for organ replacement. The field has evolved beyond selecting materials that were originally designed for other applications with a primary focus on properties that enabled restoration of function and mitigation of acute pathology. Biomaterials are now designed rationally with controlled structure and dynamic functionality to integrate with biological complexity and perform tailored, high-level functions in the body. The transition has been from permissive to promoting biomaterials that are no longer bioinert but bioactive. This perspective surveys recent developments in the field of polymeric and soft biomaterials with a specific emphasis on advances in nano-to macroscale control, static to dynamic functionality, and biocomplex materials.biomaterials | soft materials | feature control | dynamics | biocomplex

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Collagen Scaffolds Incorporating Coincident Gradations of Instructive Structural and Biochemical Cues for Osteotendinous Junction Engineering

Cited by 58 publications

References 51 publications

Modulating microfibrillar alignment and growth factor stimulation to regulate mesenchymal stem cell differentiation

Modulating microfibrillar alignment and growth factor stimulation to regulate mesenchymal stem cell differentiation

The Effect of Gradations in Mineral Content, Matrix Alignment, and Applied Strain on Human Mesenchymal Stem Cell Morphology within Collagen Biomaterials

Progress in material design for biomedical applications

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