Review
A Physiology-Inspired Multifactorial Toolbox in Soft-to-Hard Musculoskeletal Interface Tissue Engineering

https://doi.org/10.1016/j.tibtech.2019.06.003Get rights and content

Highlights

  • Soft-to-hard interfaces exhibit unique compositional and structural gradients that are difficult to heal and have limited regenerative abilities.

  • From a biomimetic perspective, combining biological, biophysical, and biochemical cues is likely to enable the generation of physiologically relevant tissue engineered constructs emulating such complex multitissue transitions.

  • Progresses on cell sheet engineering are integrating cell patterning and mechanical stimulation, together with cells and their matrices as native orchestrators of tissue regeneration.

  • Advances in biomaterial design offer a precise tuning of architectural, topographical, and mechanical properties to recreate cell-specific niches.

  • Together with gradients of biochemical cues (including oxygen and growth factors), multifactorial strategies allow strategic control of stem cell differentiation along a single unit.

Musculoskeletal diseases are increasing the prevalence of physical disability worldwide. Within the body, musculoskeletal soft and hard tissues integrate through specific multitissue transitions, allowing for body movements. Owing to their unique compositional and structural gradients, injuries challenge the native interfaces and tissue regeneration is unlikely to occur. Tissue engineering strategies are emerging to emulate the physiological environment of soft-to-hard tissue interfaces. Advances in biomaterial design enable control over biophysical parameters, but biomaterials alone are not sufficient to provide adequate support and guide transplanted cells. Therefore, biological, biophysical, and biochemical tools can be integrated into a multifactorial toolbox, steering prospective advances toward engineering clinically relevant soft-to-hard tissue interfaces.

Section snippets

Musculoskeletal Interfaces and Regeneration Requirements: A Global Burden

Body tissues and organs are inherently composed of multiple tissues interfacing each other and allowing extremely complex biological functions to take place. In the musculoskeletal system, these tissue interfaces integrate extremely dissimilar tissues with distinctive characteristics, ranging from a hard and highly vascularized tissue with lightweight stiffness and strength, such as the bone, to extremely viscoelastic and avascular tissues, such as articular cartilage, or to tough, resilient,

A Multifactorial Toolbox for Designing Tissue Engineering Strategies

Based on the hierarchical organization of soft-to-hard tissue interfaces, various biomaterials-based approaches have been proposed over the past decade. For tendon/ligament–bone interface, scaffold design has long relied on the creation of stratified layers with or without minerals and reconstructed graft materials for interface repair [8]; however, this does not truly recreate the physiological structure. Therefore, multiphasic and gradient fiber-based scaffold designs, along with strategic

Concluding Remarks and Future Perspectives

Soft-to-hard tissue interfaces have primary mechanical roles. Thus, tissue engineering dedicates a considerable effort toward recapitulating these structures through biomaterial design. Nonetheless, the characteristic complexity of interfacial tissues requires integrative tissue engineering approaches that combine a set of tools (biological, biophysical, and biochemical) toward guiding native or transplanted cells.

Over the years, advances in biotechnological tools have refined TERM strategies.

Acknowledgments

The authors acknowledge the financial support from the European Union Framework Programme for Research and Innovation HORIZON2020 (TEAMING Grant agreement, No 739572 - The Discoveries CTR), the ERC Grant CoG MagTendon (nr 772817), Fundação para a Ciência e a Tecnologia (FCT) for the PhD grant of I.C. (PD/BD/128088/2016), and the Project NORTE-01-0145-FEDER-000021 through the European Regional Development Fund (ERDF).

Glossary

Biochemical cues
molecules involved in chemical reactions within living organisms that have the ability of initiating or modifying a biochemical or signaling cascade; such signals can be mimicked in vitro by culture supplementation or biofunctionalization.
Biofunctionalization
modification of a material surface for either specific or nonspecific immobilization of defined motifs or biomolecules that add biological functionality in addition to biocompatibility/tolerability by the body.

References (89)

  • Q. Liu

    Engineered tendon-fibrocartilage-bone composite and bone marrow-derived mesenchymal stem cell sheet augmentation promotes rotator cuff healing in a non-weight-bearing canine model

    Biomaterials

    (2019)
  • H. Takahashi

    Anisotropic cell sheets for constructing three-dimensional tissue with well-organized cell orientation

    Biomaterials

    (2011)
  • A.I. Gonçalves

    Tissue-engineered magnetic cell sheet patches for advanced strategies in tendon regeneration

    Acta Biomater.

    (2017)
  • A. Engler

    Matrix elasticity directs stem cell lineage specification

    Cell

    (2006)
  • R.I. Sharma et al.

    Biochemical and biomechanical gradients for directed bone marrow stromal cell differentiation toward tendon and bone

    Biomaterials

    (2010)
  • S.Q. Liu

    Biomimetic hydrogels for chondrogenic differentiation of human mesenchymal stem cells to neocartilage

    Biomaterials

    (2010)
  • M. Darnell

    RNA-seq reveals diverse effects of substrate stiffness on mesenchymal stem cells

    Biomaterials

    (2018)
  • M. Ni

    Engineered scaffold-free tendon tissue produced by tendon-derived stem cells

    Biomaterials

    (2013)
  • P.P.Y. Lui

    Transplantation of tendon-derived stem cells pre-treated with connective tissue growth factor and ascorbic acid in vitro promoted better tendon repair in a patellar tendon window injury rat model

    Cytotherapy

    (2016)
  • M.Y. Koh et al.

    Passing the baton: the HIF switch

    Trends Biochem. Sci.

    (2012)
  • S.K.M. Perikamana

    Graded functionalization of biomaterial surfaces using mussel-inspired adhesive coating of polydopamine

    Colloids Surf. B Biointerface

    (2017)
  • C. Stüdle

    Spatially confined induction of endochondral ossification by functionalized hydrogels for ectopic engineering of osteochondral tissues

    Biomaterials

    (2018)
  • P. Provenzano et al.

    Collagen fibril morphology and organization- implications for force transmission in ligament and tendon

    Matrix Biol.

    (2006)
  • H. Fujie et al.

    Effects of low tangential permeability in the superficial layer on the frictional property of articular cartilage

    Biosurf. Biotribol.

    (2015)
  • E.B. Hunziker

    Quantitative structural organization of normal adult human articular cartilage

    Osteoarthr. Cartil.

    (2002)
  • J. Rieppo

    Changes in spatial collagen content and collagen network architecture in porcine articular cartilage during growth and maturation

    Osteoarthr. Cartil.

    (2009)
  • K.M. Ferlin

    Influence of 3D printed porous architecture on mesenchymal stem cell enrichment and differentiation

    Acta Biomater.

    (2016)
  • J.-M. Lee et al.

    SOX trio-co-transduced adipose stem cells in fibrin gel to enhance cartilage repair and delay the progression of osteoarthritis in the rat

    Biomaterials

    (2012)
  • C.J. Needham

    Osteochondral tissue regeneration through polymeric delivery of DNA encoding for the SOX trio and RUNX2

    Acta Biomater.

    (2014)
  • S.R. Goldring et al.

    Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage–bone crosstalk

    Nat. Rev. Rheumatol.

    (2016)
  • L. Rossetti

    The microstructure and micromechanics of the tendon–bone insertion

    Nat. Mater.

    (2017)
  • A.M. Briggs

    Musculoskeletal health conditions represent a global threat to healthy aging: a report for the 2015 World Health Organization World Report on Ageing and Health

    Gerontologist

    (2016)
  • S.N. Sambandam

    Rotator cuff tears: an evidence based approach

    World J. Orthop.

    (2015)
  • J. Chen

    Scaffolds for tendon and ligament repair: review of the efficacy of commercial products

    Expert Rev. Med. Devices

    (2009)
  • D. Bicho

    Commercial products for osteochondral tissue repair and regeneration

    Adv. Exp. Med. Biol.

    (2018)
  • Y. Li

    The horizon of materiobiology: a perspective on material-guided cell behaviors and tissue engineering

    Chem. Rev.

    (2017)
  • B.S. Kim

    Human collagen-based multilayer scaffolds for tendon-to-bone interface tissue engineering

    J. Biomed. Mater. Res. A

    (2014)
  • G.X. Huang

    Modeling and validation of multilayer poly(lactide-co-glycolide) scaffolds for in vitro directed differentiation of juxtaposed cartilage and bone

    Tissue Eng. Part A

    (2015)
  • M. Perikamana

    Harnessing biochemical and structural cues for tenogenic differentiation of adipose derived stem cells (ADSCs) and development of an in vitro tissue interface mimicking tendon-bone insertion graft

    Biomaterials

    (2018)
  • S.F. Tellado

    Heparin functionalization increases retention of TGF-β2 and GDF5 on biphasic silk fibroin scaffolds for tendon/ligament-to-bone tissue engineering

    Acta Biomater.

    (2018)
  • F. Gao

    Direct 3D printing of high strength biohybrid gradient hydrogel scaffolds for efficient repair of osteochondral defect

    Adv. Funct. Mater.

    (2018)
  • R.F. Canadas

    Biochemical gradients to generate 3D heterotypic-like tissues with isotropic and anisotropic architectures

    Adv. Funct. Mater.

    (2018)
  • F. Wang

    Scaffold-free cartilage cell sheet combined with bone-phase BMSCs-scaffold regenerate osteochondral construct in mini-pig model

    Am. J. Transl. Res.

    (2018)
  • C. Liu

    Light-induced cell alignment and harvest for anisotropic cell sheet technology

    ACS Appl. Mater. Interfaces

    (2017)
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