Biofabricated soft network composites for cartilage tissue engineering

Articular cartilage from a material science point of view is a soft network composite that plays a critical role in load-bearing joints during dynamic loading. Its composite structure, consisting of a collagen fiber network and a hydrated proteoglycan matrix, gives rise to the complex mechanical properties of the tissue including viscoelasticity and stress relaxation. Melt electrospinning writing allows the design and fabrication of medical grade polycaprolactone (mPCL) fibrous networks for the reinforcement of soft hydrogel matrices for cartilage tissue engineering. However, these fiber-reinforced constructs underperformed under dynamic and prolonged loading conditions, suggesting that more targeted design approaches and material selection are required to fully exploit the potential of fibers as reinforcing agents for cartilage tissue engineering. In the present study, we emulated the proteoglycan matrix of articular cartilage by using highly negatively charged star-shaped poly(ethylene glycol)/heparin hydrogel (sPEG/Hep) as the soft matrix. These soft hydrogels combined with mPCL melt electrospun fibrous networks exhibited mechanical anisotropy, nonlinearity, viscoelasticity and morphology analogous to those of their native counterpart, and provided a suitable microenvironment for in vitro human chondrocyte culture and neocartilage formation. In addition, a numerical model using the p-version of the finite element method (p-FEM) was developed in order to gain further insights into the deformation mechanisms of the constructs in silico, as well as to predict compressive moduli. To our knowledge, this is the first study presenting cartilage tissue-engineered constructs that capture the overall transient, equilibrium and dynamic biomechanical properties of human articular cartilage.

[1]  Jung Woo Lee,et al.  Soft network composite materials with deterministic and bio-inspired designs , 2015, Nature Communications.

[2]  I. Catelas 2.217 – Fibrin , 2011 .

[3]  E B Hunziker,et al.  Mechanical anisotropy of the human knee articular cartilage in compression , 2003, Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine.

[4]  P. Calvert Hydrogels for Soft Machines , 2009 .

[5]  Dietmar W. Hutmacher,et al.  A biomimetic extracellular matrix for cartilage tissue engineering centered on photocurable gelatin, hyaluronic acid and chondroitin sulfate. , 2014, Acta biomaterialia.

[6]  A. Waas,et al.  Ultrastrong and Stiff Layered Polymer Nanocomposites , 2007, Science.

[7]  W Herzog,et al.  Fluid pressure driven fibril reinforcement in creep and relaxation tests of articular cartilage. , 2008, Medical engineering & physics.

[8]  J. Malda,et al.  Effects of oxygen on zonal marker expression in human articular chondrocytes. , 2012, Tissue engineering. Part A.

[9]  A. Yoganathan,et al.  Heart valve function: a biomechanical perspective , 2007, Philosophical Transactions of the Royal Society B: Biological Sciences.

[10]  Giancarlo Pennati,et al.  Biomechanical properties of human articular cartilage under compressive loads. , 2004, Biorheology.

[11]  Dietmar W. Hutmacher,et al.  Enhancing structural integrity of hydrogels by using highly organised melt electrospun fibre constructs , 2015 .

[12]  Z. Pammer,et al.  The p–version of the finite–element method , 2014 .

[13]  C. Lim,et al.  Tensile testing of a single ultrafine polymeric fiber. , 2005, Biomaterials.

[14]  J. Buckwalter,et al.  Interspecies comparisons of in situ intrinsic mechanical properties of distal femoral cartilage , 1991, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[15]  J. Suh,et al.  Finite element formulation of biphasic poroviscoelastic model for articular cartilage. , 1998, Journal of biomechanical engineering.

[16]  R M Aspden,et al.  Fibre reinforcing by collagen in cartilage and soft connective tissues , 1994, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[17]  M. Yaremchuk,et al.  Cultured chondrocytes produce injectable tissue-engineered cartilage in hydrogel polymer. , 2001, Tissue engineering.

[18]  M. Oyen,et al.  Mechanical behaviour of electrospun fibre-reinforced hydrogels , 2014, Journal of Materials Science: Materials in Medicine.

[19]  Jos Malda,et al.  Reinforcement of hydrogels using three-dimensionally printed microfibres , 2015, Nature Communications.

[20]  Ivo Babuška,et al.  The p-Version of the Finite Element Method for Parabolic Equations. Part 1 , 1981 .

[21]  Dietmar W Hutmacher,et al.  Direct Writing By Way of Melt Electrospinning , 2011, Advanced materials.

[22]  Gerard A Ateshian,et al.  The role of interstitial fluid pressurization in articular cartilage lubrication. , 2009, Journal of biomechanics.

[23]  Q. Fu,et al.  Strong and tough micro/nanostructured poly(lactic acid) by mimicking the multifunctional hierarchy of shell , 2014 .

[24]  A. Abbas,et al.  Unconfined compression properties of a porous poly(vinyl alcohol)-chitosan-based hydrogel after hydration. , 2009, Acta biomaterialia.

[25]  Young Ha Kim,et al.  In vitro chondrocyte culture in a heparin-based hydrogel for cartilage regeneration. , 2010, Tissue engineering. Part C, Methods.

[26]  C. Werner,et al.  FGF-2 and VEGF functionalization of starPEG-heparin hydrogels to modulate biomolecular and physical cues of angiogenesis. , 2010, Biomaterials.

[27]  Guillermo A. Gomez,et al.  The effect of time-dependent deformation of viscoelastic hydrogels on myogenic induction and Rac1 activity in mesenchymal stem cells. , 2014, Biomaterials.

[28]  T. Quinn,et al.  Anisotropic hydraulic permeability in compressed articular cartilage. , 2006, Journal of biomechanics.

[29]  J M Mansour,et al.  The permeability of articular cartilage under compressive strain and at high pressures. , 1976, The Journal of bone and joint surgery. American volume.

[30]  James C. Weaver,et al.  Hydrogels with tunable stress relaxation regulate stem cell fate and activity , 2015, Nature materials.

[31]  C. Werner,et al.  Defined Polymer–Peptide Conjugates to Form Cell‐Instructive starPEG–Heparin Matrices In Situ , 2013, Advanced materials.

[32]  K. Athanasiou,et al.  Biomechanical topography of human ankle cartilage , 1995, Annals of Biomedical Engineering.

[33]  D. Hutmacher,et al.  Effect of preculture and loading on expression of matrix molecules, matrix metalloproteinases, and cytokines by expanded osteoarthritic chondrocytes. , 2013, Arthritis and rheumatism.

[34]  Ali Khademhosseini,et al.  Fiber-reinforced hydrogel scaffolds for heart valve tissue engineering , 2014, Journal of biomaterials applications.

[35]  Farshid Guilak,et al.  A biomimetic three-dimensional woven composite scaffold for functional tissue engineering of cartilage. , 2007, Nature materials.

[36]  Federica Chiellini,et al.  Polycaprolactone Scaffolds Fabricated via Bioextrusion for Tissue Engineering Applications , 2009, International journal of biomaterials.

[37]  R. Ritchie,et al.  Bioinspired structural materials. , 2014, Nature materials.

[38]  M. Woodruff,et al.  Tailoring Hydrogel Viscoelasticity with Physical and Chemical Crosslinking , 2015 .

[39]  A. Yoganathan,et al.  Heart valve function: a biomechanical perspective , 2008, Philosophical Transactions of the Royal Society B: Biological Sciences.

[40]  Kyriacos A Athanasiou,et al.  Hydrostatic pressure in articular cartilage tissue engineering: from chondrocytes to tissue regeneration. , 2009, Tissue engineering. Part B, Reviews.

[41]  K. Bowman Mechanical Behavior of Materials , 2003 .

[42]  I. Zein,et al.  Fused deposition modeling of novel scaffold architectures for tissue engineering applications. , 2002, Biomaterials.

[43]  J S Jurvelin,et al.  Volumetric changes of articular cartilage during stress relaxation in unconfined compression. , 2000, Journal of biomechanics.

[44]  X. Edward Guo,et al.  Mechano-electrochemical properties of articular cartilage: their inhomogeneities and anisotropies. , 2002, Annual review of biomedical engineering.

[45]  David J Mooney,et al.  The tensile properties of alginate hydrogels. , 2004, Biomaterials.

[46]  Robert E. Guldberg,et al.  Analysis of cartilage matrix fixed charge density and three-dimensional morphology via contrast-enhanced microcomputed tomography , 2006, Proceedings of the National Academy of Sciences.

[47]  Carsten Werner,et al.  A star-PEG-heparin hydrogel platform to aid cell replacement therapies for neurodegenerative diseases. , 2009, Biomaterials.

[48]  Marcia Simon,et al.  Hydrogels for Regenerative Medicine , 2016 .

[49]  Frank Baaijens,et al.  A knitted, fibrin-covered polycaprolactone scaffold for tissue engineering of the aortic valve. , 2006, Tissue engineering.

[50]  Saso Ivanovski,et al.  Effect of culture conditions and calcium phosphate coating on ectopic bone formation. , 2013, Biomaterials.

[51]  R. Ritchie,et al.  Tough, Bio-Inspired Hybrid Materials , 2008, Science.

[52]  K. Kiick,et al.  Heparin-functionalized polymeric biomaterials in tissue engineering and drug delivery applications. , 2014, Acta biomaterialia.

[53]  G. Mayer,et al.  Rigid Biological Systems as Models for Synthetic Composites , 2005, Science.

[54]  F. J. Dzida,et al.  Comparative study of the intrinsic mechanical properties of the human acetabular and femoral head cartilage , 1991, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[55]  A Shirazi-Adl,et al.  Nonlinear analysis of cartilage in unconfined ramp compression using a fibril reinforced poroelastic model. , 1999, Clinical biomechanics.

[56]  D. Hutmacher,et al.  Periosteum tissue engineering in an orthotopic in vivo platform. , 2017, Biomaterials.

[57]  Seyed Meysam Hashemnejad,et al.  Strain stiffening and negative normal stress in alginate hydrogels , 2016 .

[58]  E. Rank,et al.  High order finite elements for shells , 2005 .

[59]  K. Anseth,et al.  Biophysically Defined and Cytocompatible Covalently Adaptable Networks as Viscoelastic 3D Cell Culture Systems , 2014, Advances in Materials.

[60]  Gerard A. Ateshian,et al.  Interstitial Fluid Pressurization During Confined Compression Cyclical Loading of Articular Cartilage , 2000, Annals of Biomedical Engineering.

[61]  A Shirazi-Adl,et al.  A fibril reinforced nonhomogeneous poroelastic model for articular cartilage: inhomogeneous response in unconfined compression. , 2000, Journal of biomechanics.

[62]  Hinrich Wiese,et al.  Long-term stable fibrin gels for cartilage engineering. , 2007, Biomaterials.

[63]  A. Palmqvist Synthesis of ordered mesoporous materials using surfactant liquid crystals or micellar solutions , 2003 .

[64]  Y. Oaki,et al.  Bioinspired stiff and flexible composites of nanocellulose-reinforced amorphous CaCO3 , 2014 .

[65]  L. P. Li,et al.  A human knee joint model considering fluid pressure and fiber orientation in cartilages and menisci. , 2011, Medical engineering & physics.

[66]  A Shirazi-Adl,et al.  Strain-rate dependent stiffness of articular cartilage in unconfined compression. , 2003, Journal of biomechanical engineering.

[67]  Marc A. Meyers,et al.  Biological materials: Functional adaptations and bioinspired designs , 2012 .

[68]  A. Shirazi-Adl,et al.  The role of fibril reinforcement in the mechanical behavior of cartilage. , 2002, Biorheology.

[69]  T. Woodfield,et al.  Stage-specific embryonic antigen-4 is not a marker for chondrogenic and osteogenic potential in cultured chondrocytes and mesenchymal progenitor cells. , 2013, Tissue engineering. Part A.

[70]  Joachim Aigner,et al.  Alginate as a chondrocyte-delivery substance in combination with a non-woven scaffold for cartilage tissue engineering. , 2002, Biomaterials.

[71]  V. Mow,et al.  Biphasic creep and stress relaxation of articular cartilage in compression? Theory and experiments. , 1980, Journal of biomechanical engineering.