Engineering Tendon: Scaffolds, Bioreactors, and Models of Regeneration

Abstract

Tendons bridge muscle and bone, translating forces to the skeleton and increasing the safety and efficiency of locomotion. When tendons fail or degenerate, there are no effective pharmacological interventions. The lack of available options to treat damaged tendons has created a need to better understand and improve the repair process, particularly when suitable autologous donor tissue is unavailable for transplantation. Cells within tendon dynamically react to loading conditions and undergo phenotypic changes in response to mechanobiological stimuli. Tenocytes respond to ultrastructural topography and mechanical deformation via a complex set of behaviors involving force-sensitive membrane receptor activity, changes in cytoskeletal contractility, and transcriptional regulation. Effective ex vivo model systems are needed to emulate the native environment of a tissue and to translate cell-matrix forces with high fidelity. While early bioreactor designs have greatly expanded our knowledge of mechanotransduction, traditional scaffolds do not fully model the topography, composition, and mechanical properties of native tendon. Decellularized tendon is an ideal scaffold for cultivating replacement tissue and modeling tendon regeneration. Decellularized tendon scaffolds (DTS) possess high clinical relevance, faithfully translate forces to the cellular scale, and have bulk material properties that match natural tissue. This review summarizes progress in tendon tissue engineering, with a focus on DTS and bioreactor systems.

Exposure to buffer solution alters tendon hydration and mechanics

“…Another limitation is that we used grip strain, rather than optically measured strains, which could contribute to variability in mechanical measurements. Finally, this study was designed to maintain the “hydration” environment and mechanical properties and did not intend to replicate in vivo environment, where buffer solutes are just one of the several factors that are involved (Youngstrom and Barrett, 2016). …”

Hierarchical electrospun tendon‐ligament bioinspired scaffolds induce changes in fibroblasts morphology under static and dynamic conditions

“…Thanks to the possibility to obtain nanoscale fibres with different spatial arrangements, electrospun scaffolds have demonstrated enhancement of cellular orientation in the fibres direction (Bosworth & Downes, 2011;Denchai et al, 2018). Furthermore, several studies have confirmed the possibility to speed up cell proliferation and elongation on the electrospun scaffolds with a simplified shape, such as flat mats, bundles or yarns, by uniaxially stretching the constructs in a bioreactor (Bosworth et al, 2014;Xu et al, 2014;Youngstrom & Barrett, 2016;Wu et al, 2017). These simple designs allow for convenient documentation of changes in cellular shape using standard techniques, such as scanning electron microscopy (SEM), fluorescent microscopy or histology.…”

Creating homogenous strain distribution within 3D cell‐encapsulated constructs using a simple and cost‐effective uniaxial tensile bioreactor: Design and validation study

“…Uniaxial tensile strain bioreactors for mechanical loading of musculoskeletal cells have emerged to be an important tool for tissue engineering to study cellular biochemical responses and signaling pathways triggered by the synergistic effect of mechanical and micro-environmental cues (Berry et al, 2003;Brown et al, 1998;Seliktar et al, 2000;Skutek et al, 2001). However, most of the current custom-built and commercial bioreactors for loading 3D cellular constructs are limited by the generation of non-linear strain profiles over the length of the construct (Riehl et al, 2012;Youngstrom and Barrett, 2016). The bioreactors also tend to be complex in operation and maintenance and require handling of constructs which may risk the structural integrity of the construct (Altman et al, 2002;Garvin et al, 2003;Puk et al, 2006;Woon et al, 2011).…”

“…Most of such bioreactors employ nylon mesh or foam anchors as grips onto which the collagen solution is poured and allowed to polymerize to minimize the risk of construct disintegration during mechanical loading (Birla et al, 2007;Garvin et al, 2003;Riehl et al, 2012). It is observed that only a narrow uniform strain region near the center of the construct is obtained, while wide variation in strain magnitudes are seen near the ends of the construct (Riehl et al, 2012;Wang et al, 2012b;Youngstrom and Barrett, 2016). However, this actuation and gripping system can typically lead to nonhomogenous strain distribution within the collagen construct where the strain experienced by the cells inside the construct vary significantly based on their spatial location.…”

“…However, this actuation and gripping system can typically lead to nonhomogenous strain distribution within the collagen construct where the strain experienced by the cells inside the construct vary significantly based on their spatial location. It is observed that only a narrow uniform strain region near the center of the construct is obtained, while wide variation in strain magnitudes are seen near the ends of the construct (Riehl et al, 2012;Wang et al, 2012b;Youngstrom and Barrett, 2016). Thus, there is a persistent demand for uniaxial tensile strain bioreactors that can produce enlarged area of homogenous strain distribution within 3D cellular constructs along with the minimal risk of construct disintegration.…”