Novel strategies in tendon and ligament tissue engineering: Advanced biomaterials and regeneration motifs

Tendon and ligaments have poor healing capacity and when injured often require surgical intervention. Tissue replacement via autografts and allografts are non-ideal strategies that can lead to future problems. As an alternative, scaffold-based tissue engineering strategies are being pursued. In this review, we describe design considerations and major recent advancements of scaffolds for tendon/ligament engineering. Specifically, we outline native tendon/ligament characteristics critical for design parameters and outcome measures, and introduce synthetic and naturally-derived biomaterials used in tendon/ligament scaffolds. We will describe applications of these biomaterials in advanced tendon/ligament engineering strategies including the utility of scaffold functionalization, cyclic strain, growth factors, and interface considerations. The goal of this review is to compile and interpret the important findings of recent tendon/ligament engineering research in an effort towards the advancement of regenerative strategies.

[1]  J. Paul Robinson,et al.  Tensile mechanical properties of three-dimensional type I collagen extracellular matrices with varied microstructure. , 2002, Journal of biomechanical engineering.

[2]  Hongbin Fan,et al.  Anterior cruciate ligament regeneration using mesenchymal stem cells and silk scaffold in large animal model. , 2009, Biomaterials.

[3]  Natalia Juncosa-Melvin,et al.  Effect of scaffold material, construct length and mechanical stimulation on the in vitro stiffness of the engineered tendon construct. , 2008, Journal of biomechanics.

[4]  Joseph W Freeman,et al.  Collagen self-assembly and the development of tendon mechanical properties. , 2003, Journal of biomechanics.

[5]  A. Chhabra,et al.  GDF‐5 deficiency in mice delays Achilles tendon healing , 2003, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[6]  Stavros Thomopoulos,et al.  bFGF and PDGF-BB for Tendon Repair: Controlled Release and Biologic Activity by Tendon Fibroblasts In Vitro , 2010, Annals of Biomedical Engineering.

[7]  J. Wolff.  Das Gesetz der Transformation der Knochen , 1893 .

[8]  S. Woo,et al.  Tensile properties of the human femur-anterior cruciate ligament-tibia complex , 1991, The American journal of sports medicine.

[9]  D. Cheresh,et al.  Arginine-glycine-aspartic acid binding leading to molecular stabilization between integrin alpha v beta 3 and its ligand. , 1991, The Journal of biological chemistry.

[10]  D. Carter,et al.  Relationships between loading history and femoral cancellous bone architecture. , 1989, Journal of biomechanics.

[11]  Marcos Garcia-Fuentes,et al.  Silk fibroin/hyaluronan scaffolds for human mesenchymal stem cell culture in tissue engineering. , 2009, Biomaterials.

[12]  S. Woo,et al.  On the viscoelastic properties of the anteromedial bundle of the anterior cruciate ligament. , 1993, Journal of biomechanics.

[13]  M. Raspanti,et al.  Structural aspects of the extracellular matrix of the tendon: an atomic force and scanning electron microscopy study. , 2002, Archives of histology and cytology.

[14]  Ivan Martin,et al.  Silk matrix for tissue engineered anterior cruciate ligaments. , 2002, Biomaterials.

[15]  J. Goh,et al.  In vivo study of anterior cruciate ligament regeneration using mesenchymal stem cells and silk scaffold. , 2008, Biomaterials.

[16]  Joseph W Freeman,et al.  Fiber-based tissue-engineered scaffold for ligament replacement: design considerations and in vitro evaluation. , 2005, Biomaterials.

[17]  K. Fujikawa,et al.  Tensile Load and the Metabolism of Anterior Cruciate Ligament Cells , 1998, Clinical orthopaedics and related research.

[18]  Oliver H. Lowry,et al.  THE DETERMINATION OF COLLAGEN AND ELASTIN IN TISSUES, WITH RESULTS OBTAINED IN VARIOUS NORMAL TISSUES FROM DIFFERENT SPECIES , 1941 .

[19]  Michael Kjaer,et al.  Role of extracellular matrix in adaptation of tendon and skeletal muscle to mechanical loading. , 2004, Physiological reviews.

[20]  F. Silver,et al.  Structural and mechanical assessment of developing chick tendon , 1988 .

[21]  T. Paulalbear,et al.  Mechanical Comparison of 10 Suture Materials before and after in Vivo Incubation , 2004 .

[22]  Zi Yin,et al.  Ligament regeneration using a knitted silk scaffold combined with collagen matrix. , 2008, Biomaterials.

[23]  A. K. S. Chong Mbbs Mrcs MMed.  Optimization of Flexor Tendon Tissue Engineering With a Cyclic Strain Bioreactor , 2009 .

[24]  Young-Mi Kang,et al.  Nanofiber alignment and direction of mechanical strain affect the ECM production of human ACL fibroblast. , 2005, Biomaterials.

[25]  M. Bonnin,et al.  Fgf4 positively regulates scleraxis and tenascin expression in chick limb tendons. , 2002, Developmental biology.

[26]  K. Spindler,et al.  Collagen-Platelet Composites Improve the Biomechanical Properties of Healing Anterior Cruciate Ligament Grafts in a Porcine Model , 2009, The American journal of sports medicine.

[27]  J. McCarthy,et al.  Uniaxial mechanical strain: an in vitro correlate to distraction osteogenesis. , 2007, The Journal of surgical research.

[28]  Marian F Young,et al.  Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche , 2007, Nature Medicine.

[29]  R. Tucker,et al.  Connective tissues: signalling by tenascins. , 2004, The international journal of biochemistry & cell biology.

[30]  Natalia Juncosa-Melvin,et al.  Mechanical stimulation of tissue engineered tendon constructs: effect of scaffold materials. , 2007, Journal of biomechanical engineering.

[31]  Sambit Sahoo,et al.  Development of hybrid polymer scaffolds for potential applications in ligament and tendon tissue engineering , 2007, Biomedical materials.

[32]  J. Iannotti,et al.  Porcine Small Intestine Submucosa as a Flexor Tendon Graft , 2004, Clinical orthopaedics and related research.

[33]  S. Teoh,et al.  Characterization of anterior cruciate ligament cells and bone marrow stromal cells on various biodegradable polymeric films , 2002 .

[34]  Joseph W Freeman,et al.  Tissue engineering of the anterior cruciate ligament using a braid-twist scaffold design. , 2007, Journal of biomechanics.

[35]  J. Feijen,et al.  Interaction of cultured human endothelial cells with polymeric surfaces of different wettabilities. , 1985, Biomaterials.

[36]  J. Ralphs,et al.  Tendon cells in vivo form a three dimensional network of cell processes linked by gap junctions. , 1996, Journal of anatomy.

[37]  R. F. Ker,et al.  Mechanical properties of various mammalian tendons , 1986 .

[38]  G. Lichtwark,et al.  In vivo mechanical properties of the human Achilles tendon during one-legged hopping , 2005, Journal of Experimental Biology.

[39]  D. Butler,et al.  Tensile stimulation of murine stem cell-collagen sponge constructs increases collagen type I gene expression and linear stiffness. , 2009, Tissue engineering. Part A.

[40]  M. Benjamin,et al.  Structure‐function relationships in tendons: a review , 2008, Journal of anatomy.

[41]  G. Murrell,et al.  Early Inflammatory Reaction after Rotator Cuff Repair with a Porcine Small Intestine Submucosal Implant , 2005, The American journal of sports medicine.

[42]  Volker Musahl,et al.  The use of porcine small intestinal submucosa to enhance the healing of the medial collateral ligament—a functional tissue engineering study in rabbits , 2004, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[43]  C. Tabin,et al.  Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments. , 2001, Development.

[44]  J. P. Paul,et al.  Tensile properties of the in vivo human gastrocnemius tendon. , 2002, Journal of biomechanics.

[45]  M. Tsukada,et al.  Physico-chemical properties of silk fibroin membrane as a biomaterial. , 1990, Biomaterials.

[46]  Y. Shimabukuro,et al.  Regeneration of periodontal tissues by basic fibroblast growth factor. , 1999, Journal of periodontal research.

[47]  Stephen B Doty,et al.  Novel nanofiber-based scaffold for rotator cuff repair and augmentation. , 2009, Tissue engineering. Part A.

[48]  Guoping Chen,et al.  Application of PLGA-collagen hybrid mesh for three-dimensional culture of canine anterior cruciate ligament cells , 2004 .

[49]  Hiromi Yamada,et al.  Preparation of undegraded native molecular fibroin solution from silkworm cocoons , 2001 .

[50]  L. Soslowsky,et al.  Influence of decorin and biglycan on mechanical properties of multiple tendons in knockout mice. , 2005, Journal of biomechanical engineering.

[51]  A. Yamanaka,et al.  Silk protein, sericin, inhibits lipid peroxidation and tyrosinase activity. , 1998, Bioscience, biotechnology, and biochemistry.

[52]  H. Iwata,et al.  Surface modification of poly(ethylene-co-vinyl alcohol): hydroxyapatite immobilization and control of periodontal ligament cells differentiation. , 2004, Biomaterials.

[53]  Joseph W Freeman,et al.  Anterior cruciate ligament regeneration using braided biodegradable scaffolds: in vitro optimization studies. , 2005, Biomaterials.

[54]  W. Stanish,et al.  Is there significant variation in the material properties of four different allografts implanted for ACL reconstruction , 2009, Knee Surgery, Sports Traumatology, Arthroscopy.

[55]  Stephen F Badylak,et al.  Degradation and remodeling of small intestinal submucosa in canine Achilles tendon repair. , 2007, The Journal of bone and joint surgery. American volume.

[56]  Siew Lok Toh,et al.  Cyclic uniaxial strains on fibroblasts-seeded PLGA scaffolds for tissure engineering of ligaments , 2005, International Conference on Experimental Mechanics.

[57]  S. Arnoczky,et al.  Anatomy of the anterior cruciate ligament: a blueprint for repair and reconstruction. , 1994, Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association.

[58]  H. Nakagawa,et al.  Elastin in the Human Posterior Longitudinal Ligament and Spinal Dura A Histologic and Biochemical Study , 1994, Spine.

[59]  Albert J Banes,et al.  Ligament cells stretch-adapted on a microgrooved substrate increase intercellular communication in response to a mechanical stimulus. , 2005, Journal of biomechanics.

[60]  Chisa Shukunami,et al.  Scleraxis positively regulates the expression of tenomodulin, a differentiation marker of tenocytes. , 2006, Developmental biology.

[61]  N. Tran,et al.  Effect of uniaxial stretching on rat bone mesenchymal stem cell: Orientation and expressions of collagen types I and III and tenascin‐C , 2008, Cell biology international.

[62]  F. Luyten,et al.  Multipotent mesenchymal stem cells from adult human synovial membrane. , 2001, Arthritis and rheumatism.

[63]  S. C. Cowin,et al.  Bone remodeling due to continuously applied loads , 2006, Calcified Tissue International.

[64]  Siew Lok Toh,et al.  The interaction between a combined knitted silk scaffold and microporous silk sponge with human mesenchymal stem cells for ligament tissue engineering. , 2008, Biomaterials.

[65]  G. Murrell,et al.  The Roles of Growth Factors in Tendon and Ligament Healing , 2003, Sports medicine.

[66]  B. Seedhom,et al.  Effect of cyclic tensile strain on proliferation of synovial cells seeded onto synthetic ligament scaffolds--an in vitro simulation. , 2005, Bone.

[67]  P. Delmas,et al.  Racemization and isomerization of type I collagen C-telopeptides in human bone and soft tissues: assessment of tissue turnover. , 2000, The Biochemical journal.

[68]  A. Mikos,et al.  Electrospinning of polymeric nanofibers for tissue engineering applications: a review. , 2006, Tissue engineering.

[69]  R. Tuan,et al.  Spatiotemporal protein distribution of TGF‐βs, their receptors, and extracellular matrix molecules during embryonic tendon development , 2008, Developmental dynamics : an official publication of the American Association of Anatomists.

[70]  Thomas L. Smith,et al.  A naturally derived, cytocompatible, and architecturally optimized scaffold for tendon and ligament regeneration. , 2007, Biomaterials.

[71]  R. Schweitzer,et al.  Recruitment and maintenance of tendon progenitors by TGFβ signaling are essential for tendon formation , 2009, Development.

[72]  Ivan Martin,et al.  The FASEB Journal express article 10.1096/fj.01-0656fje. Published online December 28, 2001. Cell differentiation by mechanical stress , 2022 .

[73]  Jiake Xu,et al.  Porcine small intestine submucosa (SIS) is not an acellular collagenous matrix and contains porcine DNA: possible implications in human implantation. , 2005, Journal of biomedical materials research. Part B, Applied biomaterials.

[74]  Natalia Juncosa-Melvin,et al.  Chondroitin‐6‐sulfate incorporation and mechanical stimulation increase MSC‐collagen sponge construct stiffness , 2010, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[75]  T. Yamamuro,et al.  Elastin in the human intervertebral disk , 1986, Archives of orthopaedic and traumatic surgery.

[76]  B. Mikic,et al.  Sexual dimorphism in the effect of GDF‐6 deficiency on murine tendon , 2009, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[77]  Y. Tabata,et al.  Regeneration of anterior cruciate ligament by biodegradable scaffold combined with local controlled release of basic fibroblast growth factor and collagen wrapping. , 2008, Tissue engineering. Part C, Methods.

[78]  K. Sung,et al.  Ligament tissue engineering using synthetic biodegradable fiber scaffolds. , 1999, Tissue engineering.

[79]  D. Noonan,et al.  Neutrophils as a key cellular target for angiostatin: implications for regulation of angiogenesis and inflammation , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[80]  Sambit Sahoo,et al.  Bioactive nanofibers for fibroblastic differentiation of mesenchymal precursor cells for ligament/tendon tissue engineering applications. , 2010, Differentiation; research in biological diversity.

[81]  S. Woo,et al.  Biomechanics of knee ligaments: injury, healing, and repair. , 2006, Journal of biomechanics.

[82]  J. Spring,et al.  Tenascin-C expression by fibroblasts is elevated in stressed collagen gels , 1994, The Journal of cell biology.

[83]  J. Goh,et al.  Characterization of a novel polymeric scaffold for potential application in tendon/ligament tissue engineering. , 2006, Tissue engineering.

[84]  Jianguo Huang,et al.  Tensile behavior and morphology of differently degummed silkworm (Bombyx mori) cocoon silk fibres , 2006 .

[85]  J. Zhou,et al.  Morphology and adhesion of human fibroblast cells cultured on bioactive polymer grafted ligament prosthesis , 2007, 2007 29th Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[86]  Su A Park,et al.  Biological responses of ligament fibroblasts and gene expression profiling on micropatterned silicone substrates subjected to mechanical stimuli. , 2006, Journal of bioscience and bioengineering.

[87]  Kai-Ming Chan,et al.  Sports Medicine, Arthroscopy, Rehabilitation, Therapy & Technology , 2009 .

[88]  Jeffrey P Spalazzi,et al.  Mechanoactive Scaffold Induces Tendon Remodeling and Expression of Fibrocartilage Markers , 2008, Clinical orthopaedics and related research.

[89]  A. R. Baker,et al.  Commercial extracellular matrix scaffolds for rotator cuff tendon repair. Biomechanical, biochemical, and cellular properties. , 2006, The Journal of bone and joint surgery. American volume.

[90]  Albert J Banes,et al.  Novel system for engineering bioartificial tendons and application of mechanical load. , 2003, Tissue engineering.

[91]  Rocky S Tuan,et al.  Mechanoactive tenogenic differentiation of human mesenchymal stem cells. , 2008, Tissue engineering. Part A.