Table 1.

Summary of selected fiber-based systems for tendon and ligaments TE.

Fabrication method	Scaffold Material	In vitro	In vivo	Clinical trial	Stimulation	Remarks	Reference
Strand fibers	Carbon, silk, and collagen, UHMWPE	• MSCs: cell adhesion, viability and growth • Tendon stem cells: cell infiltration, expression of tenogenic markers	• Calve model: milder pain and exudation as well as earlier restoration of tendon movements and weight bearing • Sheep model: ingrowth of fibroblastic tissue, collagen deposition, and alignment • Rabbit model: reduction in strength and volume after 8 weeks • Rat model: collagen formation	• Simple to implant • Well tolerated • Fibers bond directly to the bone without fibrotic interposition • Debris, giant cell presence, arthrofibrosis	--	• Restoration of continuity across the defect of the tendon • Discomfort and slight loss of movement of the knee • Carbon particles appeared in the regional lymph nodes • Carbon particles were found in the synovium, hyaline cartilage and menisci • Comparable or greater initial ultimate tensile stress than human ACL • Lobulation and hypertrophy	• [104], [105], [108], [109] [110], [111], [113], [114]
Weaving	PET, collagen I, silk fibroin and LAP, PCL, chitosan, cellulose nanocrystals, PLA	• Pre-osteoblasts: cytocompatibility, osteogenic differentiation • Tendon-derived cells: cell elongations, alignment, expression of key tenogenic markers • MSCs: cell alignment, tenogenic differentiation • MSCs/tenocytesumbilical vein endothelial cells co-culture: expression of key tenogenic markers	• Rabbit model: tissue around the scaffold was highly cellular and collagen fibrils were deposited • Rabbit model: increase of stiffness, collagen I deposition, tenomodulin expression • Rat model: formation of mature collagen fibers, promotion of bone and fibrocartilage tissue formation; enhancement of biomechanical properties	• Laxity • Improvement of Lysholm and Tegner score • Enhancing of knee stability • Signs of pivot shift • Unimodal distribution of collagen fibrils • Cases of failures and ruptures	• Mechanical stretching	• Signs of degenerative change • No development of functional tissue • Synovial reaction • Unsatisfactory long-term results • Sufficient mechanical properties • Poor cell infiltration • Osteointegration • Dynamic mechanical stretching improves collagen expression and tenogenic differentiation	• [75], [117], [119], [122], [123], [124], [125], [128], [129], [130], [131], [132], [133] [134]
Knitting	Hyaluronan, PCL, PLCL, PLGA and silk fibroin	• MSCs: cell proliferation, cell elongation; expression of CD44, collagen I and III, laminin, fibronectin, and actin; orientation along the direction of microfiber alignment; deposition of ECM secretion (collagen I and III), expression of specific tenogenic markers	• Rabbit model: tendon-like ECM expression; collagen fiber remodelling, neovascularization, expression of tenogenic markers	--	--	• Expression of important protein for scaffold interaction and typical ligament proteins • Toe region profile and elastic modulus similar to ligaments • Sufficient biomechanical properties • Tissue regeneration and remodelling • Neovascularization	• [52], [78], [135], [136], [137]
Braiding	Gore-Tex, PP, PLGA, Suture threads, GelMA and alginate, PGA, PLGA, PLLA, and fibronectin, silkworm gut	• Fibroblasts and primary ACL cells: cell attachment and proliferation • Tendon-derived cells: cell migration and alignment on the fiber axis; high expression of specific tenogenic genes • MSCs: cell adhesion, growth and tenogenic differentiation	• Goat model: improvement of mechanical properties; inflammatory reaction	• Pain • Increasing in degenerative changes • Improvements in Lysholm scores, activity scores, and arthrometry values • Operative complication • Improvement of stability • Decreasing of pivot shift	• Mechanical stretching	• Deterioration over time • Effusions and pain • Mechanical properties comparable to native tendon/ligament • Integration of the scaffold • Normal joint laxity • Production of a collagen-rich matrix • Potential clinical efficacy (combined with stem cells therapies) • Braiding angle affects the mechanical properties	• [115], [116], [141], [142], [144], [145], [147], [148], [102], [140], [149], [150], [152], [153]
Braid-twisting	PLLA, PEGDA	• Fibroblasts: cell proliferation, deposition of ECM	• Rabbit model: smaller cross-sectional area, Sharpey’s fiber presence, formation of fibrocartilage	--	• Biochemical stimulation using BMP2	• Great porosity • Mimicking the biomechanical response and the mechanical characteristics of native ACL • Osteointegration • Resistance to fatigue	• [139], [154], [155], [156], [157]
Electrospinning	PCL, PA6 and silica particles, PEO, PLCL and hyaluronic acid, silk fibroin, PLGA, PDO, PLLA and dextran, collagen I, PLGA, PU, poly(trimethylene carbonate), zinc oxide, alginate, gelatin, chitosan, cellulose nanocrystals, cellulose acetate	• Fibroblasts: cell spreading, proliferation, and matrix deposition, aligned scaffolds guide parallel orientation of cells and higher collagen production, expression of integrin • MSCs: cells proliferation, spreading and infiltration, tenogenic differentiation, ECM deposition • Human primary tendon-derived cells: cell attachment	• Rat model: cellular infiltration and colonization, improvement of glycosaminoglycans expression and higher of collagen organization • Rabbit model: no improvement on ultimate stress nor Young’s modulus values, reinforcement of tissue mechanical strength; antiadhesion effect • Rodent model: treated junctions have higher Young’s Modulus	--	• Biochemical stimulation using bFGFs, insulin, BMP-13 • Mechanical stretching	• Scaffold implantation did not have negative effects • Sufficient mechanical properties for tendon repair • Restoring biomechanical strength • Aligned fibrous architectures showed anisotropic and significantly higher mechanical characteristics compared to randomly oriented fibers • Aligned fibers can mimic native tendon native architecture • Adhesion prevention • Positive effect on tendon and ligaments healing • Aligned cells on the nanofiber structure are significantly affected by stretching in axial direction • Regulation of mechanical properties and biological response (e.g. cell growth, differentiation, and matrix deposition) can be performed by varying the fiber diameter • Deposition of tendon-mimetic ECM • The fiber orientation can influence cell proliferation, differentiation, and immunomodulation	• [41], [45], [46], [47], [56], [62], [67], [68], [69], [71], [72], [73], [80], [79], [91], [162], [165], [170], [171], [172], [173], [174], [175], [177], [178], [179], [180], [181], [182], [183], [225]
Wet-spinning	Chitosan, hyaluronan, alginate, and GelMA	• Fibroblasts: cell adhesion and proliferation, collagen I expression • MSCs: cell proliferation and alignment, collagen I and III production, specific tenogenic markers expression	• Rat model: increasing of mechanical properties and collagen I deposition	--	• Mechanical stretching • Biochemical stimulation using BMP-12	• Great biological response • Stabilization of the joint • Combination of biochemical and mechanical stimulation promotes cell tenogenic • Larger size of yarns leads to higher mechanical properties (i.e. values of ultimate stress)	• [187], [188], [189], [190]
Multi-layering	PCL, gelatin, chitosan, PLLA, PEO, tendon-derived ECM, fibronectin, PBS, PLGA, heparin/fibrin, PA6, Alginate, PDO, PGS, PLGA, PU, PLCL, polyethylene glycol, poly-L-lysine, silk, collagen, hyaluronic acid, bioactive glasses	• MSCs: cell elongation in the direction of the fiber scaffold, expression of tenogenic phenotype, good metabolic activity, orientation on fiber direction • Tenocytes: adhesion, viability and proliferation, ECM deposition • Tendon stem/progenitor cells: spindle-shape morphology, cell aligment, ECM deposition • Fibroblasts: cell vialibily and proliferation	• Rat model: improvement of the structural and mechanical properties of tendon injury repair, immunologic compatibility; tenogenic gene expression of MSCs • Canine model: cells remained viable in the tendon repair environment, mild immunoresponse • Sheep model: no excessive inflammation nor tissue adhesion • Rabbit model: formation of collagen large fibrils and aligned fibers, increase of biomechanical properties		• Biochemical stimulation using TGF-β3, PDGF-BB, BMP-12, bFGF • Mechanical stretching	• Yield strain enhances during the culture time • Tendon ECM used as scaffold material might favour the differentiation into tenogenic lines • Provide stable and integral constructs easy to be handle during surgical procedures and in vivo implantations • Scaffold may release cells and growth factors in vivo at the same time • Mechanical and biochemical stimulation improve cell growth, align orientation, and tenogenic differentiation • Adhesion prevention • ECM deposition • Cell growth and infiltration • Vascularization • Cell loading enhances tissue regeneration • Sufficient mechanical properties • Tendon healing • Chemotaxis	• [74], [76], [90], [176], [192], [193], [194], [195], [196], [197], [198], [199], [200],[201], [202], [203], [204]