Fibrous Systems As Potential Solutions For Tendon and Ligament Repair, Healing, and Regeneration

REVIEW
www.advhealthmat.de
Fibrous Systems as Potential Solutions for Tendon and

Ligament Repair, Healing, and Regeneration
Chiara Rinoldi, Ewa Kijeńska-Gawrońska, Ali Khademhosseini, Ali Tamayol,
and Wojciech Swieszkowski*
1. Introduction
Tendon and ligament injuries caused by trauma and degenerative diseases are
frequent and affect diverse groups of the population. Such injuries reduce Tendons and ligaments are fibrous connec-
musculoskeletal performance, limit joint mobility, and lower people’s comfort. tive tissues, having the function of trans-
mitting loads in between muscle and bone,
Currently, various treatment strategies and surgical procedures are used to
and from one bone to another, respectively.
heal, repair, and restore the native tissue function. However, these strategies The tendon and ligament structures are de-
are inadequate and, in some cases, fail to re-establish the lost functionality. signed to carry loads and to guarantee suf-
Tissue engineering and regenerative medicine approaches aim to overcome ficient biomechanical performances, bear-
these disadvantages by stimulating the regeneration and formation of ing and reinforcing the joints as well as
preventing bone luxation.[1] Tendon and
neotissues. Design and fabrication of artificial scaffolds with tailored
ligaments are typically avascular and are
mechanical properties are crucial for restoring the mechanical function of mainly composed of extracellular matrix
tendons. In this review, the tendon and ligament structure, their physiology, (ECM) composed of collagen type I, III, V,
and performance are presented. On the other hand, the requirements are and X (75%), proteoglycans (e.g., decorin)
focused for the development of an effective reconstruction device. The most (20%), tenascin C, scleraxis, elastin (1%)
common fiber-based scaffolding systems are also described for tendon and and water. Progenitor cells, fibroblasts and
tenocytes, represent the cellular component
ligament tissue regeneration like strand fibers, woven, knitted, braided, and
of the tissues. The structure of tendons
braid-twisted fibrous structures, as well as electrospun and wet-spun and ligaments expands along their axes
constructs, discussing critically the advantages and limitations of their and shows a high hierarchical organization.
utilization. Finally, the potential of multilayered systems as the most effective The different organization levels are com-
candidates for tendon and ligaments tissue engineering is pointed out. posed of collagen molecules, collagen fib-
rils, collagen fibril bundles, collagen fib-
ril fascicles, proteoglycans, and elastin[2–4]
C. Rinoldi, E. Kijeńska-Gawrońska, W. Swieszkowski (Figure 1A,B). The highly organized structure and the tissue com-
Materials Design Division ponents influence their mechanical behavior.[5,6]
Faculty of Materials Science and Engineering
Warsaw University of Technology
Warsaw 02-507, Poland 1.1. Tendon and Ligament Mechanical Properties
E-mail: wojciech.swieszkowski@pw.edu.pl
E. Kijeńska-Gawrońska James et al. studied the mechanical properties of tendons, indi-
Centre for Advanced Materials and Technologies CEZAMAT viduating a triphasic behavior of the tissue when strain is applied
Warsaw University of Technology
Warsaw 02-822, Poland
(Figure 2A).[7,8] The first region (nonlinear or toe region) exhibits
A. Khademhosseini
low values of stress. In this phase, the force applied to the tissue
Department of Bioengineering, Department of Chemical is transferred to the collagen fibrils, inducing their contraction
and Biomolecular Engineering, Department of Radiology and rearrangement. The second region (linear region) is charac-
California NanoSystems Institute (CNSI) terized by a linear increase of stress and strain, due to the straight-
University of California ening and stretching of collagen molecules. The third phase dis-
Los Angeles CA 90095, USA
plays a flexion of the curve (microscopic failure). In this region,
A. Khademhosseini
Terasaki Institute for Biomedical Innovation (TIBI) the stress values slightly diminish until the defibrillation of colla-
Los Angeles CA 90024, USA gen fibers occurs, resulting in the macroscopic tissue rupture.[1,7]
A. Tamayol Ligament tissue showed a similar behavior when subjected to
Department of Biomedical Engineering tensile load (Figure 2B).[9] Depending on the type, the normal
University of Connecticut healthy tendon or ligament works between 7% and 40% failure
Farmington CT 06030, USA
load. Prosthetic implants for tendon and ligament replacement
The ORCID identification number(s) for the author(s) of this article or reinforcement are intended to match or exceed the mechan-
can be found under https://doi.org/10.1002/adhm.202001305 ical properties of the native tissue. However, some mechanical
DOI: 10.1002/adhm.202001305 parameters such as strength, stiffness, and elongation obtained
Adv. Healthcare Mater. 2021, 10, 2001305 2001305 (1 of 26) © 2021 Wiley-VCH GmbH
www.advancedsciencenews.com www.advhealthmat.de
Figure 1. Physiology and mechanical characteristics of tendon and ligament tissue. A) Tendon hierarchical structures. Reproduced with permission.[5]
Copyright 2015, Elsevier Inc. B) Ligament hierarchical structure. Reproduced with permission.[6] Copyright 2010, Elsevier Ltd.
Figure 2. Mechanical characteristics of tendon and ligament tissue. A) Representative stress–strain curve of tendon subjected to mechanical tensile
test. Reproduced with permission.[8] Copyright 2006, Elsevier Ltd. B) Representative stress–strain curve of ligament tissue failed in tension. Reproduced
with permission.[9] Copyright 1978, Wolters Kluwer Health.
for existing devices, still do not correspond to the physiological The cells start to produce and deposit collagen (mostly type I and
values.[2] III) during the remodeling phase, allowing the synthesis of ECM,
resulting in the regrowth of the tissue with low organization level
of the fibers.[16,17]
1.2. Injuries and Healing Process
Tendon and ligament injuries in the young population are de- 1.3. Treatment Strategies
rived mainly from sport activities including football, basketball,
and handball, while fall and lift of heavy weights are respon- Historically, since the 1980s, the tendon and ligament injury
sible for injuries in elderly population.[10] In addition to in- treatments included several approaches based on nonoperative
juries, chronic deterioration of the tissues often affects the old- treatments as well as various repair surgeries. Surgical proce-
est part of the population. Both tissue injuries and degenerative dures involve the implantation of natural or biological grafts,[11]
processes, result in reduced musculoskeletal functions, limiting autografts, allografts, and synthetic grafts.[18,19] Autografts and al-
people’s activities. Annually, just in the United States, approxi- lografts have been found to possess good mechanical strength
mately 300.000 surgical repairs of shoulders, foot, and ankles,[2] as well as correct architectural structure and chemical compo-
and around 350.000 anterior cruciate ligament (ACL) reconstruc- sition to promote cell proliferation and to stimulate new tis-
tive surgeries are performed,[11,12] costing around $30 billion.[13] sue growth.[1,20] The main concerns about autografts are the
When the injury occurs, the characteristic cascade of wound heal- donor site morbidity and limited graft availability. The use of ca-
ing takes place: the tissue inflammation phase is followed by cel- daver allografts carries a high probability of bacterial infection,
lular growth, with subsequent ECM restoration.[14,15] The first late biological incorporation, and transmission of blood-borne
stage is characterized by the formation of a blood clot on the in- diseases.[21,22] The failure of the grafts has higher incidence for
jured area due to the migration of monocytes, leukocytes, and elderly patients, people with tears of a large size or with severe
macrophages.[2] The proliferation phase provides the migration muscle atrophies and fatty infiltrations, and patients with sys-
and deposition of fibroblasts to form the vascular granular tissue. temic diseases.[3] For all these reasons, there is a need for the
development of new solutions. The fabrication and implantation production, and promoted adequate native tissue hierarchical
of scaffolds derived from biological sources or synthetic scaffolds organization.[50] The constant secretion of ECM can also im-
composed of biodegradable polymers are drawing noticeable at- prove the scaffold mechanical characteristics in terms of ten-
tention for the injury care of tendons and ligaments. sile properties, as well as its flexibility in the axial direction
In this article, we review the literature of fiber-based scaf- promoting mechanotransduction.[41,51] Mesenchymal stem cells
folds for tendon and ligament engineering. Fibrous constructs (MSCs) might also be used for tissue regeneration purposes.
including strand fibers, woven, knitted, braided and braid- Many studies have demonstrated their potential for differentia-
twisted, electro- and wet-spun structures are critically described tion into several cell types such as fibroblasts, osteoblasts, chon-
and analyzed, focusing on advantages and drawbacks of each drocytes, myoblasts, and tenocytes.[52–54] Moreover, the adminis-
approach.[23,24] Finally, the potential of engineered multi-layered tration of MSCs is reported to successfully promote healing and
systems as solutions for tendon and ligament regeneration is pre- regeneration of various musculoskeletal tissues (e.g., bones and
sented. ligaments).[11,49,55]
Growth factors (GF) stimulate tendon and ligament cells, in-
fluencing tissue homeostasis, repair, and healing.[11,22,56] They
2. Tendon and Ligament Tissue Engineering possess the ability to affect cellular growth and migration,
synthesis of different collagen types, as well as ECM protein
Tissue engineering (TE) is a multidisciplinary approach which secretion.[57,58] GFs such as basic Fibroblast Growth Factors
combines engineering, material science, chemistry, and biology (bFGFs), bone morphogenetic proteins (BMPs), transforming
to successfully regenerate damaged tissues, recreating their ar- growth factor beta (TGF-𝛽), and platelet-derived growth factors
chitecture, and restoring their functions. In the end of 1993, (PDGFs) are the most commonly used, due to their capability to
Robert Langer and Joseph Vacanti introduced the concept of TE, promote the tendon/ligament regeneration.[59–65]
describing the fundamental elements of tissue engineered sys-
tems defined as “a structural scaffold, a cell source, biological mod-
ulators and mechanical stimuli.”[25] According to this definition, 2.2. Scaffolds Used in Tendon and Ligament Tissue Engineering
TE of functional tendon and ligament requires the combination
of porous 3D matrix structures, which can enhance tissue re- The engineered scaffold functions as a support structure. Ideally,
generation as well as encapsulation of isolated cells and growth this kind of construct should be biocompatible, degradable, pro-
factors.[21,26] In this frame, the design of a proper scaffold degra- voke the least possible inflammatory reaction and should be easy
dation rate and matching the tissue mechanical properties are to implant.[29] It should act as a tissue growth support and ve-
considered the main challenges. Ideally, the substitute should hicle for the cells and growth factors, while the adhesion of sur-
support the tissue functionality, and favor tissue formation while rounded tissue should be avoided.[66] The scaffold is also sup-
degrading over time, permitting the total regeneration of the in- posed to recapitulate the mechanical features of the healthy tis-
jured site.[27,28] Moreover, the definition of the main factors which sue, guaranteeing the transmission of forces and strengthening
guide healing, as well as the detection of the mechanical, biolog- the joint, without risk of failure.[2] In order to design a proper
ical, and chemical patterns of stimuli are also considered among scaffold for tendon and ligament engineering, various natural
the most crucial aspects for a proper engineered tendon and lig- materials, biodegradable polymers, and composite biomaterials
ament tissue design.[27,29,30] have been considered.[67–76] Commercial materials used to pro-
duce and fabricate scaffolds for this application include synthetic
degradable, synthetic nondegradable, biological, and naturally
2.1. Role of Mechanical, Biological, and Chemical Stimulation in derived materials.[2] Synthetic biomaterials have the great ad-
Tendon and Ligament Regeneration vantage of improving tissue repair by sharing mechanical loads
with the host tissue. The possibility of utilization of a large vari-
The dynamic mechanical stimuli play a fundamental role in ten- ety of polymers and fabrication methods, as well as flexible de-
don and ligament development, homeostasis, repair, healing, signs, led researchers to optimize dimensions, mechanical prop-
and maintenance of strength.[31–33] The absence of the stimu- erties, biological characteristics, sterility, and degradation rates
lation pathways induces a loss in the mechanical properties of of biomaterials to better recapitulate the complexity of tendons
the tissues.[34–36] Timing, direction, and magnitude of the me- and ligaments.[77] Synthetic biomaterials carry a lower risk of
chanical stimulation affect cell integrin-mediated focal adhesion disease transmission in comparison to their natural counter-
and cytoskeleton orientation, influencing cellular growth, dif- parts when implanted in the host body.[11] Degradable synthetic
ferentiation, and ECM production.[37–43] Moreover, mechanical polymers including poly(caprolactone) (PCL), poly(lactic acid)
factors such as substrate stiffness, surface topography, and ge- (PLA), poly(glycolic acid) (PLG) and their copolymers and com-
ometry are expected to significantly affect cellular activity and posites, polydioxanone (PDO), poly (glycerol sebacate) (PGS),
functions.[21,44–46] and polyurethane (PU) have been explored as promising candi-
Biological stimulation is mainly promoted by various types date materials for the production of tendon and ligament engi-
of cells. Fibroblasts are the principal cell component of ten- neered scaffolds.[47,78–82] Nevertheless, they do not show the op-
don/ligament tissues and are involved in the synthesis, se- timal support for cellular adhesion, growth, and infiltration, or
cretion, deposition, and maintenance of the ECM.[47–49] Li new tissue formation. To improve the biological response of cells
et al. demonstrated that fibroblast cells cultured on scaffold’s cultured on the scaffolds, some research groups introduced the
surface showed a sufficient ECM deposition, proteoglycans use of biomaterials derived from natural sources like collagen,
alginate, chitosan, hyaluronic acid, gelatin, fibrin, heparin, and synovitis, and hypertrophy were also reported.[108,109] Moreover,
silk fibroin, which are reported to be more suitable for cell at- discomfort and the loss of knee mobility, and a consistent num-
tachment and proliferation.[52,57,60,83–88] Even though they are able ber of failure determined the limitation of carbon fiber use for
to improve the tissue healing process, their application is lim- tendon/ligament regeneration.[108,110] Even though carbon fibers
ited due to the poor suture retention and insufficient mechan- were produced “naked” in the beginning, many polymers and
ical properties[21,89] (except for silk fibroin which matched the copolymers have been utilized as their coatings or protection
tensile characteristics of native ligament[86] ). In order to over- agents. Synthetic polymers including PCL, PLA, PGA, and their
come these disadvantages, researchers started to consider syn- derived copolymers, as well as natural polymers such as gelatin
thetic polymers as reinforcement of naturally derived scaffolds, have been considered for this purpose.[18,107,111] Carbon fibers
exploring and designing different composites and multi-layered were incorporated into 3D printed polymeric structures in order
structures.[46,90–93] In the literature, many strategies are discussed to improve the cell colonization. Positive results demonstrated
for the design and fabrication of the scaffolds for tendon and lig- the scaffold’s potential application in tendon/ligament repair.[111]
ament regeneration purposes (Table 1). This review is focused Lately, strand fibers made of collagen via self-assembly or
on fiber-based approaches for scaffold fabrication, which mimics crosslinking technique have been investigated for reproducing
the fibrillar architecture of the native tissue and potentially direct the characteristic collagen fascicle structure of tendons and lig-
cellular organization and ECM deposition. aments. Collagen was selected due to its great porosity and ca-
pacity to mimic the proper microenvironment and structural fea-
tures of the native tissues, as well as its ability to act as elas-
3. Fiber-Based Engineered Scaffolds for Tendons tic energy storage in the tissue structure during locomotion.[112]
and Ligaments However, a study of Panas-Perez et al. showed that collagen
strand fibers had low mechanical properties and degraded within
Fibrous scaffolds produced using various fiber-based fabricating 2 months after implantation, increasing the risk of premature
techniques are recognized to be suitable for replacing anisotropic failure. In order to increase the mechanical characteristics and
tissues and to promote their healing.[94–99] The specific structure the degradation rate, they introduced silk fibroin and fabri-
enables them to mimic the collagen organization, to guarantee cated a composite scaffold made of 14% silk and 86% collagen
mechanical support and tissue infiltration during the regenera- fibers (v/v). The composite scaffold demonstrated ultimate ten-
tion process.[100–103] In this article, we have mainly focused on the sile stress comparable to native ligament and slow degradation
analysis of the utilization of fiber-based architectures including rate but not adequate physical resorption.[113] Additionally, im-
strand fibers, woven, knitted, braided, and braid-twisted fibrous munogenicity caused by bovine collagen and toxicity of chem-
structures as well as electrospun, wet-spun and multilayered fi- ical crosslinking agents have led researchers to consider other
brous constructs. alternatives. Recently, ultrahigh molecular weight polyethylene
(UHMWPE) strand fibers were incorporated into a hydrogel net-
work for tendon reinforcement. The authors reported the match-
3.1. Strand Fibers ing of mechanical properties with the native tissue, as well as in-
filtration and expression of tenogenic genes by tendon stem cells.
In the late 1970s, strand carbon fibers were one of the first ap- Additionally, collagen ingrowth was also observed in a rat model
proaches used for tendon and ligament replacement. Since car- in vivo.[114]
bon compounds are present in native tissues, grafts made of Strand fibers have the advantage of supporting collagen pro-
carbon elements, such as carbon fibers, were explored due to duction, infiltration, and orientation. However, fragmentation
their promising biocompatibility. Carbon fibers showed high ten- and degradation phenomena of carbon fibers induced discom-
sile strength and low elongation rate. Moreover, their character- fort, loss of knee mobility, and failure; while not sufficient me-
istics, such as the capability to induce infiltration, orientation, chanical properties and fast degradation rate of fibers composed
and production of collagen as well as biocompatibility and in- of collagen provoked their failure. Thus, the use of strand fibers
ertness made carbon fibers a considerable candidate for tissue as scaffold for tendon and ligament regeneration is now limited.
repair purposes.[104] Several studies on carbon fibrous grafts for
tendon/ligament showed that carbon fibers do not inhibit tissue
growth, become stronger over time and they may perform as a 3.2. Woven Fibrous Structures
scaffold for tissue regeneration.[18,105,106]
In the 1980s, carbon fibers became commercially avail- Common textile-based technologies such as weaving, knitting,
able from four different companies and clinically used in 20 braiding, and braid-twisting have also been applied for the fab-
countries.[107] Kumar et al. confirmed repair and regeneration of a rication of 3D fibrous architectures for tendon/ligament applica-
tendon tissue defect after 30 d from carbon fibrous graft implan- tions (Figure 3). In this frame, woven structures are obtained by
tation. Collagen and blood vessel organization were conformed interlacing two orthogonal sets of fibers, namely warp and weft,
similar to the normal healing process, proving that carbon bio- in a methodic and repetitive pattern. More specifically, weft fibers
logically acts as an inert material.[104] However, long-term follow perpendicularly cross warps fibers at each weaving step, result-
up showed fragmentation and erosion degradation phenomena ing in a regular 3D fiber-based structure (Figure 3A). The use
in the fibers, which provoked migration of the carbon particles of nondegradable synthetic constructs is one of the oldest strate-
in the synovium, hyaline cartilage, and menisci. Accumulation gies for tendon/ligament repair. Commercial woven fibrous de-
of the particles near lymph nodes, slight inflammatory reaction, vices made of poly(ethylene terephthalate) (PET) (e.g., Leeds-Keio
Table 1. Summary of selected fiber-based systems for tendon and ligaments TE.
Fabrication Scaffold material In vitro In vivo Clinical trial Stimulation Remarks Refs.
method
Strand fibers Carbon, silk, and • MSCs: cell adhesion, • Calve model: milder • Simple to – • Restoration of continuity [104,105,108–114]
collagen, viability and growth pain and exudation implant across the defect of the
UHMWPE • Tendon stem cells: cell as well as earlier • Well tolerated tendon
Adv. Healthcare Mater. 2021, 10, 2001305

infiltration, expression of restoration of tendon • Fibers bond • Discomfort and slight loss of
www.advancedsciencenews.com
tenogenic markers movements and directly to the movement of the knee

weight bearing bone without • Carbon particles appeared in
• Sheep model: fibrotic the regional lymph nodes
ingrowth of interposition • Carbon particles were found
fibroblastic tissue, • Debris, giant cell in the synovium, hyaline
collagen deposition, presence, cartilage and menisci
and alignment arthrofibrosis • Comparable or greater initial
• Rabbit model: ultimate tensile stress than
reduction in strength human ACL
and volume after 8 • Lobulation and hypertrophy
weeks
• Rat model: collagen
formation
Weaving PET, collagen I, silk • Preosteoblasts: • Rabbit model: tissue • Laxity • Mechanical • Signs of degenerative change [ 75,117,119,122–125,128–134]
fibroin and LAP, cytocompatibility, around the scaffold • Improvement of stretching • No development of functional
2001305 (5 of 26)
PCL, chitosan, osteogenic differentiation was highly cellular Lysholm and tissue
cellulose • Tendon-derived cells: cell and collagen fibrils Tegner score • Synovial reaction
nanocrystals, PLA elongations, alignment, were deposited • Enhancing of • Unsatisfactory long-term
expression of key • Rabbit model: knee stability results
tenogenic markers increase of stiffness, • Signs of pivot • Sufficient mechanical
• MSCs: cell alignment, collagen I deposition, shift properties
tenogenic differentiation tenomodulin • Unimodal • Poor cell infiltration
• MSCs/tenocytesumbilical expression distribution of • Osteointegration
vein endothelial cells • Rat model: formation collagen fibrils • Dynamic mechanical
coculture: expression of of mature collagen • Cases of failures stretching improves collagen
key tenogenic markers fibers, promotion of and ruptures expression and tenogenic
bone and differentiation
fibrocartilage tissue
formation,
enhancement of
biomechanical
properties
(Continued)
www.advhealthmat.de
© 2021 Wiley-VCH GmbH

Table 1. Continued.
method
Knitting Hyaluronan, PCL, • MSCs: cell proliferation, • Rabbit model: – – • Expression of important [52,78,135–137]
PLCL, PLGA and cell elongation; tendon-like ECM protein for scaffold

silk fibroin expression of CD44, expression, collagen interaction and typical

collagen I and III, fiber remodeling, ligament proteins
laminin, fibronectin, and neovascularization, • Toe region profile and elastic
actin; orientation along expression of modulus similar to ligaments
the direction of microfiber tenogenic markers • Sufficient biomechanical
alignment; deposition of properties
ECM secretion (collagen I • Tissue regeneration and
and III), expression of remodeling
specific tenogenic • Neovascularization
markers
Braiding Gore-Tex, PP, PLGA, • Fibroblasts and primary • Goat model: • Pain • Mechanical • Deterioration over time [ 115,116,141,142,144,145,147,148,102,140,149,150,152,153]
Suture threads, ACL cells: cell attachment improvement of • Increasing in stretching • Effusions and pain
GelMA and and proliferation mechanical degenerative • Mechanical properties
alginate, PGA, • Tendon-derived cells: cell properties, changes comparable to native
PLGA, PLLA, and migration and alignment inflammatory • Improvements in tendon/ligament
fibronectin, on the fiber axis; high reaction Lysholm scores, • Integration of the scaffold
2001305 (6 of 26)
silkworm gut expression of specific activity scores, • Normal joint laxity
tenogenic genes and arthrometry • Production of a collagen-rich
• MSCs: cell adhesion, values matrix
growth and tenogenic • Operative • Potential clinical efficacy
differentiation complication (combined with stem cells
• Improvement of therapies)
stability • Braiding angle affects the
• Decreasing of mechanical properties
pivot shift
Braid- PLLA, PEGDA • Fibroblasts: cell • Rabbit model: smaller – • Biochemical • Great porosity [139,154–157]
twisting proliferation, deposition cross-sectional area, stimulation • Mimicking the biomechanical

of ECM Sharpey’s fiber using BMP2 response and the mechanical
presence, formation characteristics of native ACL
of fibrocartilage • Osteointegration
• Resistance to fatigue
(Continued)
www.advhealthmat.de

Table 1. Continued.
method
PCL, PA6, and silica • Fibroblasts: cell • Rat model: cellular – • Biochemical • Scaffold implantation did not [ 41,45–47,56,62,67–69,71–73,79,80,91,162,165,170–175,177–183,225]
Electrospinningparticles, PEO, spreading, proliferation, infiltration and stimulation have negative effects
PLCL, and and matrix deposition, colonization, using bFGFs, • Sufficient mechanical
hyaluronic acid, aligned scaffolds guide improvement of insulin, properties for tendon repair
silk fibroin, PLGA, parallel orientation of glycosaminoglycans BMP-13 • Restoring biomechanical
PDO, PLLA and cells and higher collagen expression and • Mechanical strength

dextran, collagen production, expression of higher of collagen stretching • Aligned fibrous architectures
I, PLGA, PU, integrin organization showed anisotropic and

poly(trimethylene • MSCs: cells proliferation, • Rabbit model: no significantly higher
carbonate), zinc spreading and infiltration, improvement on mechanical characteristics
oxide, alginate, tenogenic differentiation, ultimate stress nor compared to randomly
gelatin, chitosan, ECM deposition Young’s modulus oriented fibers
cellulose • Human primary values, reinforcement • Aligned fibers can mimic
nanocrystals, tendon-derived cells: cell of tissue mechanical native tendon native
cellulose acetate attachment strength, architecture
antiadhesion effect • Adhesion prevention
• Rodent model: • Positive effect on tendon and
treated junctions ligaments healing
have higher Young’s • Aligned cells on the nanofiber
modulus structure are significantly
affected by stretching in axial
direction
• Regulation of mechanical
2001305 (7 of 26)
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
Wet- Chitosan, • Fibroblasts: cell adhesion • Rat model: increasing – • Mechanical • Great biological response [ 187–190]
spinning hyaluronan, and proliferation, of mechanical stretching • Stabilization of the joint

alginate, and collagen I expression properties and • Biochemical • Combination of biochemical
GelMA • MSCs: cell proliferation collagen I deposition stimulation and mechanical stimulation
and alignment, collagen I using promotes cell tenogenic
and III production, BMP-12 • Larger size of yarns leads to
specific tenogenic higher mechanical properties
markers expression (i.e., values of ultimate stress)
(Continued)
www.advhealthmat.de

Table 1. Continued.

method
PCL, gelatin, • MSCs: cell elongation in • Rat model: • Biochemical • Yield strain enhances during [ 74,76,90,176,192,193,194,195,196,197,198,199,200,201,202,203,204]
Multilayering chitosan, PLLA, the direction of the fiber improvement of the stimulation the culture time
PEO, scaffold, expression of structural and using • Tendon ECM used as scaffold
tendon-derived tenogenic phenotype, mechanical TGF-𝛽3, material might favor the
ECM, fibronectin, good metabolic activity, properties of tendon PDGF-BB, differentiation into tenogenic
PBS, PLGA, orientation on fiber injury repair, BMP-12, lines
heparin/fibrin, direction immunologic bFGF • Provide stable and integral
PA6, alginate, • Tenocytes: adhesion, compatibility, • Mechanical constructs easy to be handle
PDO, PGS, PLGA, viability and proliferation, tenogenic gene stretching during surgical procedures
PU, PLCL, ECM deposition expression of MSCs and in vivo implantations
polyethylene • Tendon stem/progenitor • Canine model: cells • Scaffold may release cells and
glycol, cells: spindle-shape remained viable in growth factors in vivo at the
poly-L-lysine, silk, morphology, cell the tendon repair same time
collagen, alignment, ECM environment, mild • Mechanical and biochemical
hyaluronic acid,
2001305 (8 of 26)
deposition immunoresponse stimulation improve cell
bioactive glasses • Fibroblasts: cell viability • Sheep model: no growth, align orientation, and
and proliferation excessive tenogenic differentiation
inflammation nor • Adhesion prevention
tissue adhesion • ECM deposition
• Rabbit model: • Cell growth and infiltration
formation of collagen • Vascularization
large fibrils and • Cell loading enhances tissue
aligned fibers, regeneration
increase of • Sufficient mechanical
biomechanical properties
properties • Tendon healing
• Chemotaxis
www.advhealthmat.de

Figure 3. Schematic illustration of fiber textile-based technologies and resulted 3D fibrous architectures: A) weaving; B) knitting; C) braiding; D) braid-
twisting. Partially based on.[97]
ligament or Ligament Advanced Reinforcement System) and by longitudinal fibers which possess resistance to fatigue and per-
stretched poly(tetrafluoroethylene) (Gore-Tex) have been widely mit cell infiltration. The extra-articular part is instead character-
implanted as tissue reinforcements and replacements.[115–120] ized by woven fibers, which offer strength and resist to elonga-
Conditionally approved by the Food and Drugs Administration tion. Left knee and right knee have clockwise and counterclock-
(FDA), they have the capacity to replace and protect the injured wise designs, respectively.[119] LARS artificial ligament showed a
tissue, preventing osteoarthritis and allowing the ingrowth of sufficient mechanical resistance of tension, flexion, and torsion
new tissue without risk of cross-infection, while restoring the loads. Moreover, it is not susceptible to torsional fatigue, wear,
joint stability.[121] The Leeds-Keio (LK) ligament (Neoligaments and tear events.[128] In their study, Gao et al. indicated a clinical
Ltd., UK), a cylindrical woven structure made of fibers of PET, was outcome of LARS failure of 4.4% and a very low complication rate
introduced and applied in the clinical practice in the 1980s and without significant evidence of synovitis, concluding good short
1990s, counting over 50 000 implantations all over the word. The and long term results of LARS implantation.[119] It has been also
graft provided strength, relatively low stiffness, and biological in- shown that LARS artificial ligament could induce the deposition
ertness, giving immediate stability and promoting the ingrowth of autologous collagen and neo tissue formation.[129] Since LARS
of collagen fibers.[122] Zaffagnini et al. studied intact LK liga- and LK are both made of the same material, their biocompatibility
ments after 20 years of implantation. Fibroblast migration and is similar, thus the autologous tissue ingrowth rate is not signif-
deposition of collagen tissue was proven by histologic and ultra- icantly different. Zaffagnini et al. demonstrated through in vitro
structural results. It has been reported, that the grafts were fully and in vivo studies the suitability of both LARS and LK surfaces
covered by autologous tissue, while collagen fibrils were physio- for fibroblast adhesion and proliferation.[123] Even though the wo-
logically orientated in the load direction.[123] However, long-term ven fibrous devices protected the injured tissues from axial split-
implantation outcome was only successful in about 60% of the ting and abrasive wear, guaranteeing sufficient extensibility and
patients.[124] An increase in laxity, loss of stability, and pivot shift- tissue infiltration, they generally failed due to the long-term me-
ing are reported in 50% of unsuccessful cases, while the device chanical phenomena such as creep, fatigue, stress shielding, and
failure rupture occurred in about 30%. Denti et al. demonstrated permanent deformation. Moreover, the contact with bone sharp
that the loss of stability is not time-dependent, and showed com- edges might induce abrasions, generating debris which could re-
parable results of short-term and long-term analysis of the im- sult in joint synovitis.[18,19] Recently, more biocompatible materi-
planted grafts.[125] Schroven et al. demonstrated that the high als (e.g., collagen) have been proposed for the production of wo-
rate of laxity led to a decrease in LK graft functions and tensile ven scaffolds.[130,131] Learn et al. proposed a type I collagen woven
mechanical properties during the implantation time.[126] For all system for tendon repair. The scaffold was seeded with MSCs and
these disadvantages, recent studies doubted the efficiency of LK tested in vivo in a rabbit model. Results showed an increment in
in the neoligament formation.[117] Another artificial nondegrad- stiffness, collagen deposition, and specific tenogenic protein ex-
able scaffold made of PET fibers for tendon and ligament replace- pression (i.e., tenomodulin).[132]
ment purposes is the Ligament Advanced Reinforcement System On the other hand, weaving textile technique using elec-
(LARS, France).[127] Its intra-articular structure is characterized trospun fibrous threads have also gained the interest of
researches.[133,134] In this frame, Laranjeira et al. fabricated a

novel woven scaffold made of PLC, chitosan and cellulose
nanocrystals electrospun fibers, showing its potential for tendon
tissue engineering. The biological response was tested using two
different cells’ sources: human adipose-derived stem cells and
human tendon-derived cells. Results showed cell elongation and
alignment, while the expression of specific tenogenic markers
was detected. Moreover, cell infiltration and ECM oriented de-
position were reported.[134] In the same manner, Dong et al. pro-
posed the use of silk fibroin and laponite (LAP) wet-spun fibers to
fabricate a woven platform for ligament applications. The system
showed compatibility and osteogenic differentiation of mouse
pre-osteoblasts in vitro, as well as osteointegration and improve-
ment of mechanical properties in a rat model in vivo.[75]
Woven structures provided strength and stability while pro-
moting ingrowth of collagen fibers. However, these constructs do
not allow optimal cell infiltration which is essential for efficient
regeneration of the tissue. Moreover, fatigue and permanent de-
formation phenomena as well as laxity and pivot shifting repre-
sent big disadvantages of this approach.
3.3. Knitted Fibrous Structures
The knitting textile-based technology provides two sets of fibers

interlocked in a series of connected loops, creating a 3D structure
with knitted fibrous architecture (Figure 3B). The most interest-
ing characteristic of knitted fibrous structures is their ability to re-
produce the tendon/ligament toe region during tensile mechan-
ical tests. Additionally, knitting technology allows the fabrication
of less dense structures, which can be tailored and customized
for the desired size. The low-density structure shows internal in-
terconnected pores, useful for nutrient and gas transportation,
and tissue ingrowth. However, the high porosity does not permit
a homogeneous and controlled distribution of the seeded cells.
To solve this problem, different techniques such as cell encap-
sulation in hydrogel, elaboration of natural polymer fiber net-
work, cell sheet TE, silk microporous sponge, and nanofiber de-
position by electrospinning technique were developed.[78,135,136]
Cristino et al. seeded MSCs on a hyaluronan-based knitted com-
Figure 4. Morphological, biological, and mechanical properties of knit-
mercial scaffold for ligament regeneration (HYAFF). They re- ted fibrous structures: PLCL knitted scaffold coated by aligned electro-
ported homogeneous cell distribution, as well as cluster of dif- spun microfibers. A) SEM images of scaffold structure; B) Collagen type
ferentiation 44 (CD44), collagen I and III, laminin, fibronectin, I and III immunostaining after 14 d of culture; C) Stress–strain curves of
and actin expression, concluding that knitted HYAFF scaffold constructs coated and uncoated by aligned microfibers. Reproduced with
is not immunogenic and enables the new-tendon/ligament tis- permission.[78] Copyright 2010, Wiley Periodicals, Inc.
sue ingrowth.[52] Cai et al. proposed a PLC and silk fibroin/PLCL
knitted system for tendon engineering. In vitro biological per-
formances were evaluated seeding rabbit bone marrow stem proliferation and ECM secretion (mainly collagen I and III) (Fig-
cells, showing cell elongation, proliferation and expression of ure 4B).[78] Furthermore, stress–strain curves showed the charac-
tenogenic key markers. On the other hand, the scaffold was tested teristic triphasic profile, mimicking the mechanical behavior of
in vivo in a rabbit model, demonstrating sufficient biomechani- the native tendon (Figure 4C). Sahoo et al. proposed a poly(lactic-
cal properties, as well as tissue repair and regeneration.[137] More- co-glycolic acid) (PLGA) knitted scaffold coated with PLGA elec-
over, Vaquette et al. designed a novel poly(lactide-co-caprolactone) trospun nanofibers to recapitulate the native nanofibrous archi-
PLCL knitted scaffold coated by aligned electrospun microfibers, tecture of tendon/ligament ECM, as well as to guarantee cell ad-
to obtain a better spatial reproduction of cell microenvironment. hesion on a large biocompatible surface area.[138] The scaffold
Scanning Electron Microscope (SEM) images of the construct was seeded with the bone marrow stromal cells which expressed
are reported in Figure 4A. Cells seeded on the composite scaf- high level of specific tenogenic genes as collagen I, decorin, and
folds appeared uniformly distributed with spontaneous orienta- biglycan, proving its potential as system for tendon/ligament TE.
tion along the aligned microfibers. Immunostaining proved cell In another study, a silk knitted structure was combined with
a collagen sponge to fabricate ACL replacements. In vivo re- where LAD was implanted.[144] Additionally, histological analysis
sults in a rabbit model showed collagen fibers formation, neo- showed that 25% of the patients suffered from chronic inflam-
vascularization and expression of specific tenogenic markers of mation of synovium.[145]
stem/progenitor cells deposited on the construct.[135] Another braided nondegradable synthetic device is the Gore-
Even though the mechanical properties of basic knitted scaf- Tex ligament (W.L.Gore and Co., Flagstaff, Ariz.). It is a low-
folds seemed to be promising, the high porosity of this structure density braided poly(tetrafluoroethylene) (PTFE) structure com-
causes inadequate tissue ingrowth which restricts their use for posed of three multifilament beams.[146] The first PTFE scaffold
tendon and ligament replacement.[78] for ligament replacement was inserted in 1982 to rapidly mo-
bilize the knee, aiming to permanently substitute the injured
tissue.[147] Roolker et al. reported clinical outcomes of Gore-Tex
3.4. Braided Fibrous Structures prosthesis after 5 years of implantation showing that PTFE de-
vices led in 40% of the cases to better knee stability without pain.
The braiding textile technology creates an intertwined fibrous However, X-ray images indicated degenerative changes in 81% of
structure composed of three or more fibers, which diagonally the patients.[115] In another study, Ahlfeld et al. showed that the
interlace and overlap in a regular arrangement. The result is device improved knee stability in 87% of the patients, decreasing
a 3D fiber-based construct with a braided morphological struc- the pivot shifting. Pain decreased in 67% of the cases, but only
ture (Figure 3C), which can support high axial loads and pro- 30% of the patients had total pain alleviation. Moreover, in 70% of
vide extension and shear resistance. It possesses similar ten- the cases chondromalacia or articular cartilage defects occurred,
don/ligament stress–strain characteristics, as well as good resis- while 10% of the patients were not capable to perform normal
tance against abrasion, fatigue, and catastrophic failure.[139] By daily activities.[148] Dahlstedt et al. examined and compared the
optimizing the braiding angle, it is possible to fabricate struc- Gore-Tex graft and the Kennedy LAD, reporting the outcomes af-
tures with controlled geometry, pore diameter, porosity, yarn den- ter 36 months from the implantation. The LAD group showed
sity, and mechanical properties.[140,141] The oldest braided fibrous better results than the Gore-Tex group, which was affected from
devices were applied in the 1980s and were made of synthetic higher effusion and pain level. However, in both cases, the his-
nondegradable polymers such as polypropylene (PP) (e.g., Lig- tology demonstrated the presence of giant cells and microscopic
ament Augmentation Device) and Gore-Tex ligament. Kennedy foreign particles, while no significant difference in terms of com-
introduced the concept of a cylindrical diamond-braided graft pliance was registered.[116] Nowadays, these braided nondegrad-
made of PP: Ligament augmentation device (LAD) (3M, St. Paul, able synthetic fibrous devices are not considered optimal for the
Minn., USA). It consists of nine tows (or strands) of high-tenacity replacement of tendons and ligaments, due to the inflammatory
(8 gm per denier) PP yarn (180 fibers each) braided into a flat reaction, synovitis, and long-term fatigue phenomena they pro-
6mm construct.[142] Normally, LAD was implanted in associa- voke. For these reasons, their clinical use has been limited, cre-
tion with biological grafts, like the patella tendon, to enhance ating the need for a new generation of braided scaffolds which
knee stability. The LAD has the function to protect the biologi- are made of degradable polymers such as PGA, PLGA, PCL, and
cal graft from rapid degeneration and loss of strength.[18] LAD PLA. The studies showed interesting results in terms of cell at-
has also the capability to share forces with the biological graft, tachment, infiltration, and ECM production.[149–151] In another
allowing it to bear a portion of the load, as well as to prevent study, Yu et al. investigated the effect of air plasma treatment
potential long-term fatigue failure and laxity. The device could and fibronectin adsorption on PLLA braided constructs, revealing
carry 28-–45% of the load applied on the graft depending on the enhanced adhesion and proliferation of mesenchymal stem cells
type of tendon/ligament.[143] McPherson et al. evaluated the host seeded on treated matrices.[152] Pagán et al. proposed a braided fi-
body response to Kennedy LAD after 12 months from the im- brous structure made of natural-derived materials (i.e., silkworm
plantation, showing a significant collagen deposition within the gut), showing great biocompatibility in vitro as well as sufficient
yarns with oriented collagen fibers in the longitudinal direction mechanical properties for tendon and ligaments applications.[153]
2 years after implantation. Moreover, they showed that the aug- Cooper et al. examined the influence of different geometry on
mented anterior cruciate ligament reconstruction was stronger braid-twisted scaffold properties, showing that circular braided
after 2 years and just a limited local inflammatory response and geometry had significantly higher maximum tensile load com-
a low immunogenic response were reported.[144] Kdolsky et al. pared to the rectangular shape.[141] Additionally, Costa-Almeida
investigated the clinical long-term outcomes in terms of laxity et al. utilized the branding fabrication method for producing
of LAD implantation, examining the functionality and stability load-bearing hydrogel-based composite fibers made of braided
of the graft after 5 years from the implantation. They found that suture threads coated with cell-laden hydrogel for tendon regen-
97% of the patients had a standard knee laxity. Within this group, eration (Figure 5A).[102] The hydrogel component was loaded with
75% of the cases resulted in excellent recovery and patients could human tendon-derived cells which migrated through the hydro-
practice normal sport activities. On the other hand, 3% of the de- gel structure and aligned on the suture thread. Authors reported
vices failed, mostly because of the long-term fatigue phenomena. a higher expression of tendon specific markers such as scleraxis
However, it has been reported that LAD, as a foreign synthetic de- and tenascin C, as well as matrix remodeling related genes (i.e.,
vice, might provoke inflammatory reactions, infections, synovi- matrix metalloproteinase-1 and -2). Fluorescence images show
tis or eosinophilic, lymphocytic and plasma cell response in the that the encapsulated cells produced a collagen-rich matrix, prov-
host body, delaying the regeneration of the neo-tissue. After 12 ing the potential of the system as scaffolds for tendon TE (Fig-
months from the surgery, the histological evaluation of the graft ure 5B). Moreover, the effect of braiding pattern on the mechan-
showed the presence of giant cells and macrophages in the site ical properties of the constructs was investigated, concluding the
3.5. Braid-Twisted Fibrous Structures
The combination of branding technology with fiber twisting re-

sults in braid-twisted constructs (Figure 3D). More specifically,
this technique provides the twisting (e.g., clockwise or coun-
terclockwise twisted) of the fibers which are subsequently sub-
jected to the braiding process. Considering the large number
of fiber bundles which compose tendons and ligaments, some
research groups developed braid-twisted scaffolds to properly
mimic the physiological hierarchical organization and the biome-
chanical properties of the tissues. The introduction of twisted
fibers led to a significant improvement of the ultimate strain,
ultimate tensile strength, and a wider toe region. Moreover,
braid-twisted structures have higher porosity and quantity of
pores, as well as better abrasion resistance compared to braided
constructs.[139,154] The braid-twisted scaffolds are fabricated us-
ing synthetic biopolymers, like polyesters, as well as natural poly-
mers (e.g., silk fibroin) to support cells’ attachment, growth, and
proliferation.[86,155] Altman et al. were the first to design and pro-
duce twisted fibrous matrices for tendon and ligament regenera-
tion. They developed a structure consisting of six silk fibroin par-
allel twisted cords made of fiber bundled strands. Even though
the silk-fiber matrix was 80% less stiff compared to the paral-
lel fibroin fiber structure, in vivo studies demonstrated that it
was able to stabilize the injured joint.[86] To better reproduce the
viscoelastic properties of the tendon/ligament tissues, Freeman
et al. investigated the addition of 10% poly(ethylene glycol) diacry-
late (PEGDA) hydrogel in PLLA braid-twisted scaffolds.[139] The
incorporation of the hydrogel resulted in a decrease of pore sizes
and porosity and in a loss of ultimate tensile stress values. How-
ever, they demonstrate that PEGDA/PLLA twist-braided scaf-
folds maintained the typical stress–strain behavior and matched
the viscoelasticity of the native tissue in a better manner.[139,156]
The effect of braiding and twisting angle was further investi-
gated by evaluating the ultimate tensile strength and toe region
length. Authors concluded that scaffolds made of 4 braids with
60° twisted fibers and 72° twisted fiber bundles are the most suit-
able for tendon and ligament engineering purposes.[154] Meng-
steab et al. evaluated the in vivo response in terms of osteointe-
gration of PLLA braid-twisted scaffold in an ACL reconstruction
rabbit model. BMP-2 was injected in the bone tunnel through a
Figure 5. Morphological, biological, and mechanical properties of braided saline solution in order to enhance osteogenesis. Results revealed
fibrous structures: Suture threads coated with cell-laden hydrogel. A) SEM osteointegration (as demonstrated by the presence of Sharpey’s
images of coated and uncoated threads; B) Collagen type III and I depo- fibers), reduced bone tunnel cross-sectional area and formation
sition; C) Tensile stress–strain curves of differently braided constructs. of fibrocartilage, showing that the system is a potential candidate
Reproduced with permission.[102] Copyright 2017, John Wiley & Sons,
Ltd.
for ligament tissue engineering.[157]
The new generation of braid-twisted scaffolds shows good
abrasion resistance and sufficient mechanical properties, as well
as great porosity and larger number of pores, which promotes cell
infiltration, proliferation, and tissue ingrowth. However, these
1 × 1 biaxial structure ensures the higher tensile modulus (Fig- constructs do not assist 3D cell loading and oriented distribution.
ure 5C).
Braided constructs made of degradable polymers are consid-
ered potential candidates for tendon and ligament TE due to their 3.6. Electrospun Nanofibrous Meshes
capability of matching the mechanical behavior of native tissues,
while acting as an efficient cell vehicle. However, these structures Since the early 2000s, the electrospinning technique has been
can assess 3D cell encapsulation just if coated with hydrogel ma- considered for biomedical applications. It soon became an inter-
terials, and cannot properly recapitulate the tendon and ligament esting approach for the development and production of scaffolds
anisotropic features. for TE purposes.[158–160] The method permits the fabrication of
Figure 6. Morphological, biological, and mechanical properties of synthetic electrospun nanofibrous scaffolds: influence of fiber orientation (aligned
vs random). A) SEM images; B) Morphology of mesenchymal stem cells seeded on the scaffolds’ surface: SEM images; C) Stress–strain catachrestic
curves and derived tensile strength and Young’s modulus values. Reproduced with permission.[176] Copyright 2015, Elsevier Ltd.
very thin fibers when a polymer solution is flowing through a folds. Normally electrospun fibers are collected on a steady collec-
needle onto a collecting plate under electric field conditions.[161] tor to obtain randomly oriented nanofibers, which have isotropic
Scaffolds made of nanofibers possess important advantages com- mechanical properties. However, for applications which require
pared to differently fabricated scaffolds, including high surface anisotropic mechanical properties, aligned fibers were collected
area to volume ratio, small pore dimension, and large poros- on a rapidly rotating mandrel.[173] The scaffolds composed of
ity. Studies have reported that electrospun nanofibers can re- random nanofibers possess isotropic mechanical features which
produce the tissue ECM and offer a sufficient biomimetic envi- are considered convenient for the engineering of isotropic tis-
ronment for cell adhesion, growth, and differentiation, favoring sues or drug delivery systems. Nevertheless, because the me-
a better tissue regeneration.[158,162–164] Electrospinning parame- chanical function of tendon and ligaments is highly influenced
ters such as polymer concentration to be dissolved in the sol- by the collagen fiber anisotropic orientation, aligned nanofi-
vent solution, flow rate, voltage, working distance or ambience brous scaffolds appear to be more appropriate in this case.[174]
conditions can be manipulated to control fiber diameter, poros- Several studies demonstrated that the scaffold fiber organiza-
ity, and mechanical strength of the electrospun scaffold. It has tion could modulate the cellular response and regulate the scaf-
been demonstrated that nanofibrous constructs have greater me- fold properties. It has been shown that aligned fibers guide the
chanical properties than bulk polymer material and enhance cell cells into a preferential, longitudinal orientation, which mim-
proliferation, metabolic activity, and matrix expression.[165,166] ics the parallel arrangement of the cells in the native tissue.[47]
Fibrous scaffolds made through electrospinning show fiber di- The cells are led to attach along the nanofibers long axis, al-
ameters ranging from a few microns to less than 100 nm, aim- lowing better cell alignment, distribution, differentiation, and
ing to reproduce ECM structures, like collagen fibrils which size matrix deposition compared to the cells cultured on the ran-
ranges from 20 to 40 mm in vivo.[167] Considering those advan- dom fiber structures, which are typically polygonal and randomly
tages, electrospun nanofibers have been explored for the fabri- oriented.[176,177] This is also due to the great porosity (higher than
cation of constructs for engineering of musculoskeletal tissues, 80%) and high permeability of the structures, which affects the
including bones, cartilage, tendons, and ligaments.[168–171] The nutrient distribution, favoring the cell proliferation and tissue
introduction of biomaterials might accelerate new tissue forma- growth (Figure 6A,B). Full et al. demonstrated through nuclei
tion and, thanks to their biodegradability, a second surgery for re- staining that the number of attached cells on scaffolds made
moving the construct will be prevented. Synthetic polymers are of PLGA aligned nanofibers was significantly higher compared
normally used to fabricate scaffolds for tendon and ligament re- to random fibrous structures.[46] Additionally, numerous stud-
generation via electrospinning technique. Many studies proved ies reported that aligned scaffolds significantly improve the ten-
their biocompatibility, testing the fibroblast adhesion, prolifera- sile mechanical properties compared to random structures (Fig-
tion and infiltration on PCL,[158,172] PLA,[80] PLCL,[173] PLGA,[174] ure 6C).[176] PLGA aligned scaffolds have tensile Young modu-
PDO,[175] and PU[41] surfaces. lus that is 318% and tensile strength that is 324% higher com-
Nanofiber organization and alignment can be controlled dur- pared to randomly arranged ones.[174] PCL and PLCL aligned scaf-
ing the fabrication process, in order to tailor appropriate scaffolds showed the same behavior, having 214% and 400% higher
tensile Young modulus and 189% and 300% higher tensile cal properties and that its surface encourages human bone mar-
strength, respectively.[45,47,173] However, the produced electro- row stromal cells adhesion, migration and proliferation over 14
spun scaffolds appear to be significantly weaker, when compared d.[182] Electrospun composite scaffolds have also been investi-
to the tendon/ligament native tissues. gated to enhance the polymeric matrix’s response.[43,177] A study
In order to establish a stiffer alternative, Shang et al. proposed performed by Rinoldi et al. reported that the incorporation of
a new method to obtain thicker electrospun aligned nanofibrous silica nanoparticles into a bead-on-string fibrous structure could
scaffolds which are normally very thin and have relatively weak improve the wettability of the surface, favoring cell spreading and
mechanical properties. The scaffolds were obtained using an im- proliferation (Figure 7A–C).[165]
proved electrospinning fabrication method with a grounded wa- In order to modulate the cellular behavior and tissue growth,
ter bath which allows for the fabrication of about 200 µm aligned approaches such as seeding of stem cells on the scaffold
nanofibrous scaffolds. A significant increase in mechanical prop- surface[176] or the encapsulation of growth factors into the syn-
erties and structural stability of the constructs were reported.[178] thetic fibers, were developed.[56,67,183] bFGFs are generally se-
Following the same purpose, other studies reported the fabri- lected as representative growth factors that influence and en-
cation of 3D electrospun yarn bundles and nanoyarn-reinforced hance the tendon/ligament repair and healing, cellular differen-
scaffolds.[47,69,73,173] There devices showed higher tensile mechan- tiation, spreading, proliferation, and ECM production. Consid-
ical properties and were significantly stronger and stiffer than ering the mentioned growth factors’ advantages, Liu et al. in-
2D structures. Due to larger pores and greater porosity, the 3D corporated bFGFs into dextran glassy nanoparticles and electro-
scaffolds favor cell adhesion and migration, providing higher cell spun PLLA–dextran composite fibers (Figure 8A). The loaded
proliferation and infiltration (of approximately 500 µm[173] ). Fur- growth factors were maintaining their bioactivity for 30 d, re-
thermore, Erisken et al. and El Khatib et al. investigated the ef- leasing about 48.71 ± 13.53% and enhancing fibroblastic viabil-
fect of the scaffold’s structural properties, such as the fiber di- ity (Figure 8B), collagenase production, capillary endothelial cell
ameter, on cell response in vitro.[79,179] The influence, regulation, proliferation, and tissue regeneration.[56] However, the incorpo-
and material–cell interactions were investigated evaluating the ration of particles into the polymeric fibers may lead to a decrease
modulation on cell behavior on different scaffolds, which have in mechanical properties, due to the introduction of discontinu-
fibers with diameters of 320 nm, 680 nm, and 1.80 µm. It was ity, inhomogeneities, and defects in the fiber architecture (Fig-
reported that the scaffolds with fiber diameter of 320 nm show ures 7C and 8C). In another study, Zhao et al. tested bFGF-loaded
the highest cell adhesion, as well as collagen and glycosamino- PLGA electrospun fibrous membranes with a core–shell struc-
glycans (GAGs) expression, resulting in a better ECM produc- ture. It has been shown that bFGF–PLGA scaffold enhances col-
tion. On the other hand, the scaffolds with fiber diameter of 680 lagen organization and fibrocartilage formation. Moreover, the
nm promote the expression of collagen I, III, V, and tenomod- system showed higher mechanical properties such as ultimate
ulin (phenotypic markers of tendon fibroblasts), favoring cells load-to-failure and stiffness when compared to PLGA scaffolds.
to preserve their phenotype. Based on the obtained data, the The results demonstrated that bFGF bioactivity was preserved for
authors underlined the importance and difficulty of selecting 21 d, accelerating significantly tissue healing and remodeling.[62]
the best fiber diameter for the fabrication of scaffolds for ten- Additionally, electrospun nanofibers have been successfully
don/ligament regeneration.[79] applied as tendon biomimetic sheath or physical barrier, to pre-
The architecture and structure of electrospun scaffolds allow vent adhesion of surrounded tissues.[66] The local release of
the incorporation of natural components into the synthetic sys- bioactive agents loaded into the membranes can further improve
tem to improve its biological responses and tissue healing.[71,72] the antiadhesion effect and enhance tendon repair, as deeply de-
In order to enhance the biocompatibility of synthetic scaffolds, scribed by Alimohammadi et al.
the components of the ECM, e.g., collagen, can be added.[68,180] Overall, electrospun nanofibrous meshes have the great advan-
Even though collagen has high biocompatibility, its low mechan- tage of possessing nano/microsize diameter of the fibers, large
ical properties have suggested that it should be combined with porosity, and very high surface area to volume ratio. The nanofi-
synthetic polymers, which have superior mechanical behavior. brous structure is a promising alternative to produce a scaffold
The cospinning of synthetic materials with matrix proteins was for tendon and ligament regeneration, providing an adequate
considered by Full et al., who electrospun a solution of colla- microenvironment for biosignaling, supporting sufficient cell at-
gen I with PLGA and PU producing a 3D scaffold. It has been tachment and proliferation, as well as avoiding the adhesion of
demonstrated that the addition of collagen into the polymeric surrounded tissues. However, poor cell infiltration and lack of
structure enhanced cell response, while did not significantly de- cell biding sites have still been considered the main limitations
crease the mechanical properties of the scaffold. They concluded of those systems.
that collagen might blend with other synthetic polymers to fab-
ricate scaffolds with sufficient mechanical and biological proper-
ties for the required applications.[46] Due to the similar composi- 3.7. Wet-Spun Fibrous Constructs
tion and chemical structure of collagen, silk fibroin derived mate-
rials were also investigated. Advantages such as good biocompat- The wet-spinning technique provides a polymer solution flow-
ibility, biodegradability, no immunological activity, and high me- ing through a syringe into a liquid crosslinking bath, resulting
chanical properties made this natural polymer an excellent can- in fiber formation. This technique can be utilized for the fab-
didate for the fabrication of tendon and ligament scaffolds.[181] rication of randomly oriented fibers as well as parallel aligned
Jin et al. investigated electrospun silk fibroin-based fibrous scaf- fibrous systems.[184,185] A wide range of materials can be pro-
fold, showing that silk electrospun mat has sufficient mechani- cessed using the wet-spinning method, including natural-derived
Figure 7. Morphological, biological, and mechanical properties of bead-on-string composite electrospun nanofibrous scaffolds: incorporation of silica
nanoparticles into a polymeric matrix. A) SEM and AFM images, B) Spreading of L929 cells seeded onto PCL and silica composite mat (PCPAS): SEM
and acting staining images; C) Representative stress–strain curves of synthetic (PC, PCPA) versus composite structures (PCPAS). Reproduced with
permission.[165] Copyright 2018, Royal Society of Chemistry.
Figure 8. Morphological, biological, and mechanical properties of PLLA–dextran–bFGF composite electrospun nanofibrous scaffolds: loading of growth
factors into fibrous constructs. A) SEM images; B) Live and dead images of fibroblasts seeded on PLLA and PLLA composite scaffolds; C) Representative
stress–strain curves of synthetic versus composite structures. Reproduced with permission.[56] Copyright 2013, Elsevier Ltd.
polymers[186] as well as native ECM components.[187] The possi- over, authors investigated the influence of the mechanical static
bility of fabricating cell-laden highly biocompatible fibrous con- stretching and BMP-12 treatment on MSCs cultured within the
structs is most probably the greatest advantage of this technique constructs, showing an enhancement of specific tenogenic ma-
which avoids the use of toxic solvent during the spinning process. trix proteins expression.
Nowotny et al. applied the wet spinning technique to fabricate In another study, Funakoshi et al. applied the wet spinning
chitosan fibrous scaffolds for tendon regeneration.[188] Data re- technique to fabricate chitosan-based hyaluronan hybrid poly-
vealed that aligned architecture of the yarns significantly influ- mer fibrous scaffolds for ligament regeneration (Figure 10A).
ences human MSCs attachment and orientation in the direction The results revealed that hyaluronan presence significantly en-
of the fiber axis. The results are supported by a study of Rinoldi hanced the mechanical properties of the construct as well as fi-
et al. who biofabricated aligned hydrogel yarns loaded with MSCs broblasts adhesion, proliferation, and collagen I production (Fig-
via wet-spinning method, collecting the fibers on a rotating drum ure 10B).[189] However, even though it is shown that the cells pro-
to form a fibrous hydrogel bundle for tendon TE (Figure 9A–C). duced ECM proteins onto this kind of scaffolds, the mechanical
The highly aligned orientation of human bone marrow MSCs properties of these constructs decrease during the culture time,
on the fiber axis direction was observed (Figure 9B).[187] More- probably due to material degradation phenomena or because of
Figure 9. Morphological, biological, and mechanical properties of wet-spun fibrous constructs: cell-laden highly aligned hydrogel yarns. A) SEM images
of fiber bundle (left) and cross-section (right); B) Morphology of MSCs cultured for 14 d into mechanically stimulated fibers (actin staining); C) Rep-
resentative stress–strain curves of hydrogel yarns loaded with cells cultured in different conditions versus samples without cells, tested at day 0 (dash
line) and day 14 of culture (continuous line). Reproduced with permission.[187] Copyright 2019, Wiley-VCH GmbH.
the additional matrix remodeling effect exerted by the cells (Fig- For this reason, wet-spun fibers have been often braided (Fig-
ures 9C and 10C). Fibers fabricated via wet-spinning technique ure 11A), in order to form constructs with mechanical properties
have a direct relation between yarns dimension and ultimate comparable to the native tissues. In vitro test showed collagen
stress values;[188] however, do not always show sufficient mechan- I and III deposition on chitosan-hyaluronan wet-spun scaffolds
ical characteristics to match tendon/ligament performance.[186] (Figure 11B), while in vivo implantation in a rat model resulted in
Figure 10. Morphological, biological, and mechanical properties of wet-spun fibrous constructs: chitosan-hyaluronan fibrous scaffolds. A) SEM images
of fibers structures; B) Light micrograph of fibroblasts proliferated in the wet-spun structure after 14 d of culture; C) Tensile strength of samples after
different incubation times. Reproduced with permission.[189] Copyright 2005, Wiley Periodicals, Inc.
low toxicity and inflammation response, mechanically stabilizing ted structures. The scaffold implanted in a rat model revealed
the joint during the healing process (Figure 11C).[190] sufficient biomechanical properties and expression of tenogenic
Even though the wet-spinning technique has the ability of pro- markers by incorporated MSCs, promoting tissue repair and
cessing natural-derived materials, allowing the possibility of en- regeneration.[201] Jayasree et al. proposed a braided scaffold made
capsulating cells and directing their organization, the mechanical of PCL/collagen/bFBF layered with alginate hydrogel and sub-
properties of the wet-spun constructs are still considered insuffi- jected to dynamic mechanical stretching into a bioreactor sys-
cient for tendon applications. tem. Results revealed tenocyte viability, growth and expression
of tenogenic markers in vitro, while oriented collagen forma-
tion was observed in a rabbit model in vivo.[202] On the other
3.8. Multilayered Scaffolds hand, Chainani et al. fabricated a multilayered electrospun PCL
scaffold coated by tendon-derived matrix (TDM), and evaluated
Lately, multilayered approaches have gained attention as novel the biological response of human adipose-derived stem cells
methods for scaffold design.[191,192] Different layer-by-layer tech- (hASCs). They investigated the effect of the TDM layer, demon-
niques such as simultaneous wet electrospinning and cell- strating high cell infiltration and collagen production by his-
seeding, alternating layers of nanofibers and microfibers, vary- tological and immunofluorescence analysis, respectively. More-
ing polymers, or arranging electrospun layers coated with hy- over, the maintenance of mechanical properties during the cul-
drogels have been developed.[193–195] Systems combining electro- ture time was also reported, showing the stability of this kind of
spun fibrous mats with woven/knitted constructs in multilayered construct.[195] The results are supported by a study of Yang et al.,
scaffolds have been recently explored for tendon and ligament who showed homogeneous cell distribution and penetration
engineering.[78,138,196,197] Rashid et al. developed a system com- on multi-layered PCL/methacrylated gelatin (Figure 12A,B).[90]
posed of an inner layer of aligned electrospun PCL fibers and Moreover, the maintenance of mechanical properties during the
two outer layers of i) PDO woven structure and ii) electrospun culture time was also demonstrated (Figure 12C).[90] The novel
PDO fibrous meshes. In vivo testing in a sheep model showed multilayered scaffolds also have the ability to simultaneously load
infiltration of cells (mostly tendon fibroblasts) and the develop- and deliver cells and growth factors, preserving their viability
ment of blood vessels onto the electrospun layer. Non-excessive and bioactivity, respectively. Manning et al. designed a multilay-
inflammatory reaction nor adhesion of surrounded tissue were ered scaffold consisting of interchanging layers of heparin/fibrin-
reported.[196] On the other hand, knitted silk constructs were based hydrogels and PLGA electrospun nanofibers. Additionally,
coated with PU/collagen electrospun matrix in order to improve authors encapsulated platelet-derived growth factor BB (PDGF-
the biological response of the knitted structure.[198] BB) and ASCs into the hydrogel delivery system. In vitro and
Recently, the electrospinning technique has also been com- in vivo studies showed the homogeneous distribution of cells
bined with 3D printing technology, creating fibrous meshes lay- into the hydrogel structure, their viability, and the continuous re-
ered with printed structures.[76] In this frame, Touré et al. directly lease of growth factors.[203] In another study, authors proposed
electrospun PCL/PGS nanofibers onto 3D printed PCL/PGS con- a twisted PLLA electrospun fibrous bundle surrounded by thin
struct loaded with bioactive glasses for tendon/ligament applica- PLLA electrospun layer coated with chitosan hydrogel to recapit-
tions. Results revealed that the presence of bioactive glasses im- ulate the native tendon ECM. Results showed good biocompat-
proved the biocompatibility in vitro, while sufficient mechanical ibility in terms of attachment and growth of tenocytes seeded
properties (i.e., Young modulus) were reported.[76] onto the scaffold. Moreover, a low protein absorption was de-
Additionally, layer-by-layer scaffolds, where electrospun, knit- tected, revealing the scaffold potential for preventing adhesion
ted or braided structures are layered with hydrogels, are also con- of surrounded tissues in vivo.[74] Rinoldi et al. proposed 3D
sidered promising alternatives for reproducing the native char- multi-layered composite scaffolds composed of synthetic elec-
acteristic of tendon/ligament tissues.[90,102,139,199,200] Zhao et al. trospun nanofibers coated with layers of hydrogel loaded with
fabricated a multilayered system made of fibrin gel loaded with MSCs (Figure 13A).[204] The electrospun matrix was made of
bFGF and MSCs sheet sandwiched between two PLGA knit- PCL and polyamide 6 (PA6) and it was proven to provide the
approach synergizes the properties of different source-materials,

morphologies, and fabrication technologies resulting in compos-
ite structures which can potentially make the most in terms of
biological response as well as mechanical and structural proper-
ties. Moreover, the possibility of loading and releasing bioactive
molecules is also enabled.
4. Fiber-Based Scaffolds for Tissue Interfaces

Engineering of tissue interfaces has always been considered a
great challenge. The main difficulty in this field is the design of
gradient scaffolds with zonal structure, architectures, composi-
tions, and mechanical properties. However, this aspect is crucial
to develop systems which can guarantee the physiological bio-
functionality of the tissue.[205]
Herein, fiber-based scaffolding approaches for engineering
tendon/ligament-bone and tendon-muscle interfaces are de-
scribed and discussed.
4.1. Constructs for Tendon/Ligament-to-Bone Engineering
The main requirement for engineering tendon/ligament-bone

junction is developing a single scaffold with gradient mineralized
and nonmineralized regions, various collagen interlacing and
hard-to-soft mechanical characteristics. More specifically, three
different tissue regions should be designed: tendon/ligament, fi-
brocartilage interface and bone.[206]
In case of injuries, due to the poor regeneration properties
of the tissue, a lack of gradient characteristics occurs at the in-
terface, where mainly unorganized scar tissue is formed. This
phenomenon can create a considerable properties mismatch
between tendon/ligament and bone regions, often leading to
refailure.[206]
In literature, scaffolds for tendon/ligament-to-bone engineer-
ing are commonly designed combining various phases (e.g.,
Figure 11. Morphological, biological, and mechanical properties of wet- biphasic, triphasic) or continuous gradients. Several fiber-based
spun fibrous constructs: chitosan-hyaluronan 3D wet-spun fibers. A) SEM platforms have been developed for this application, including
images of the final construct (after braiding); B) In vitro collagen I and knitted, braided, electrospun, and multilayered systems.[206–208]
III deposition; C) In vivo mechanical properties of rabbit rotator cuff de- In this frame, the knitting technology was applied to fabricate
fect models treated with the proposed scaffolds (CSS: cell seeded scaffold,
a silk construct, further combined with aligned collagen fibers.
NCSS: nonseeded scaffold). Reproduced with permission.[190] Copyright
2007, SAGE Publications. The authors presented bone marrow stem cells adhesion and
osteogenic differentiation in vitro, while adequate biomechan-
ical properties were detected in vivo.[208] On the other hand,
mechanical properties and bear the whole construct. On the other the braiding technique was used to produce triphasic braided
hand, the hydrogel layers were composed of gelatin methacry- scaffolds made of PLA. The different braided regions showed
loyl (GelMA) and alginate and mimic a micro-environment suit- zonal mechanical characteristics, recapitulating the tissue junc-
able for cell encapsulation and growth (Figure 13B,C). Constructs tion properties.[206]
were mounted and cultured into a custom-built bioreactor, where Electrospinning of scaffolds composed of synthetic (e.g., PCL,
mechanical and biochemical stimulation was applied. The ad- PLGA), naturally based (e.g., collagen, silk) and composite (e.g.,
dition of BMP-12 was optimized in terms of concentration, to PLGA/hydroxyapatite) biomaterials have also been reported for
promote the tenogenic differentiation of MSCs. In vitro results engineering of tendon/ligament–bone interface.[207,209,210] The
showed the positive effect of the combined stimuli in terms of multiple-phased scaffolds have been obtained by varying the
proliferation, alignment (Figure 13B), as well as tenogenic differ- orientation, architecture and distribution of electrospun fibers
entiation of MSCs.[204] in district regions.[211] Electrospinning of aligned-to-random fi-
Multilayered scaffolds appear the most promising candidates brous constructs was implemented in order to reproduce the
for tendon TE due to the great advantage of combining the bene- collagen fiber distribution and orientation in tendon-to-bone
ficial properties of each layer in the final engineered system. This junction.[212] Cells seeded on the biphasic construct reported
Figure 12. Morphological, biological, and mechanical properties of multi-layered scaffolds: PCL electrospun aligned mat layered with methacrylated
gelatin. A) Scaffold morphology: Fluorescent and SEM images; B) Cell distribution onto the scaffold: actin staining image; C) Anisotropic mechanical
properties of the scaffold (on the left-hand side, cross vs longitudinal direction); modulus of crosslinked (CC), not crosslinked (NC) and alternative
layers (PC) constructs during culture time (on the right-hand side). Reproduced with permission.[90] Copyright 2016, Elsevier Ltd.
zonal morphological differences, showing oriented versus unor- Distinctive signs of progress have been recently reported on
ganized cell distribution in aligned and random fibrous regions, the development of fiber-based scaffolds for tendon/ligament–
respectively.[212,213] Electrospun constructs loaded with growth bone interface. However, issues related to loading and delivery of
factors have also been proposed by Reifenrath et al.[214] Gradient cells in vivo as well as mismatching of mineral gradient distribu-
profiles in terms of growth factor and mineral distribution were tion remain still unsolved.
additionally achieved on aligned-to-random scaffolds by Chen
and co-workers. The development of a BMP-2 and nanohydroxya-
patite (nanoHA) graded electrospun matrix resulted in a gradient 4.2. Systems for Tendon–Muscle Junction
differentiation of bone marrow stem cells cultured onto the con-
structs. Consistently, higher expression of osteogenic markers The design of the tendon–muscle interface requires great efforts
was detected in areas with higher content of BMP-2/nanoHA.[215] due to the significant difference in properties between the two tis-
Similarly, Jiang et al. fabricated mineral graded silk scaffolds, sues. Indeed, muscles are mainly composed of cells, while ECM
showing gradient characteristics in terms of mechanical proper- is the primary tendon component. This results in a mismatch
ties and stem cells differentiation.[216] of tissue vascularization and consequent metabolic demand. Me-
Additionally, multilayered systems have been proposed for chanical properties are also distinct: tendons have higher me-
tendon/ligament-to-bone applications, including electrospun chanical characteristics in terms of stiffness, while muscles are
meshes combined with woven structures and films.[217,218] Zhang compliant and more elastic.[221] The tissue interface involves
et al. produced a PCL electrospun mat loaded with BMP-7 and three components: tendon, myotendinous junction (MTJ), and
rolled on a PET woven construct, resulting in a degradable– muscle.[222]
nondegradable hybrid structures. The scaffolds showed good When the interface is damaged or injured, restoring the gradi-
biocompatibility, sufficient mechanical properties in vivo and ent architecture of the myotendinous junction is crucial to guar-
induced osteogenesis.[217] Constructs formed from different antee the transferring of loads from muscle to tendon and to en-
electrospun layers have also been developed for tendon–bone sure the proper tissue functionalities.
interface.[219] Li et al. designed a dual-layered electrospun ma- Zonal changes related to extracellular matrix, cell component,
trix made of PLLA and PLLA/nanoHA composite;[220] while Cai and mechanical features should be considered while engineer-
et al. obtained a dual-layered silk/PLCL fibrous scaffold by de- ing MTJs.[223] Fiber-based scaffolding systems for this applica-
positing random fibers on previously spun aligned fibers.[219] Re- tion have not been widely explored, and just a few studies are
sults showed oriented collagen formation and tissue regenera- published on this topic.[224] Ladd et al. fabricate synthetic elec-
tion. trospun matrices made of PCL and PLLA–collagen for MTJ
Figure 13. Morphological, biological, and mechanical properties of multilayered scaffolds: PCL-PA6 electrospun matrix coated by hydrogel layers formed
from 10% GelMA and different concentrations of alginate. A) SEM images of electrospun core (left) and edge of the scaffold (right); B) Fluorescence
images of cell cytoskeleton (nonstimulated vs stimulated samples); C) Tensile and compressive moduli of the scaffolds. Reproduced with permission.[204]
Copyright 2019, American Chemical Society.
Table 2. Summary of advantages and disadvantages of fiber-based scaffolds.
Fiber-based scaffold Degradability Mechanical Possibility of cell encapsulation Collagen deposition Fatigue phenomena and synovitis
properties
Strand fibers ± + – + +
Woven fibers – + – + +
Knitted fibers + + – + +
Braided fibers ± + + + +
Braid-twisted fibers + + – + –
Electrospun fibers + + – + –
Wet-spun fibers + – + + –
Multilayered fibers + + + + –
applications. The authors simultaneously spun the two electro- tendons/ligaments. For these reasons, the combination of differ-
spinning solutions obtaining a three-region platform. The bio- ent techniques is considered crucial to produce scaffolds which
compatibility along with adhesion of myoblasts and fibroblasts can recapitulate the native tissue properties and promote tissue
seeded on the construct was demonstrated, while the formation regeneration. Thus, multilayered systems, where each compart-
of myotubes was observed.[224] Additionally, different mechani- ment can be independently produced and tailored, have emerged
cal profiles were detected, successfully mimicking the MTJ trend as the most effective alternatives for tendon and ligament TE. Po-
characteristics. tentially, these constructs might combine the advantages of dif-
Up to date, not many fiber-based studies are focused on MTJ ferent platforms produced with distinct techniques, combining
applications; however, it is expected that the field of fibrous sys- synthetic and natural polymers, and simultaneously providing
tems for this application will exponentially grow in the near fu- mechanical support and biocompatible microenvironments (Ta-
ture. ble 2).
3D multilayered scaffolds may soon be used for the treatment
5. Concluding Remarks and Future Directions of tendon injuries. This approach can create gradient multilay-
ered scaffolds that can potentially regenerate tissue interfaces
The highly organized hierarchical fibrous structure of tendons and eventually favor the integration of the developed systems as
and ligaments is designed to carry loads and to supply the biome- well as functional recovery. Most probably, fabrication methods
chanical functions, such as sustaining, bearing, and reinforcing and strategies for obtaining more compact and stable multilay-
the joints. The production of fiber-based scaffolds composed of ered scaffolds will be developed in the near future, to minimize
biomaterials derived from biological or synthetic sources is con- delamination phenomena which may occur between layers, re-
sidered a great approach to reproduce the collagen fibrous ori- sulting in the failure of the implants.
entation and to promote the repair and regeneration of tendon
and ligament tissues. In this review strand fiber, woven, knit-
ted, braided, and braid-twisted fibrous structures, as well as wet- Acknowledgements
and electrospun fibrous scaffolds were described and discussed. The authors thank the funding from the National Center for Research and
Although strand, woven, and braided fibrous scaffolds provided Development (STRATEGMED1/233224/10/NCBR/2014, project START).
immediate stability after the implantation as well as collagen de- A.T. acknowledges financial support from National Institutes of Health
position, they caused inflammatory reaction, synovitis, and long- (GM126831, AR073822).
term fatigue phenomena, limiting their clinical use. In order to
overcome these disadvantages, a new generation of braid-twisted
scaffolds was developed. Their good abrasion resistance and ade- Conflict of Interest
quate mechanical properties as well as their great porosity which The authors declare no conflict of interest.
promotes cell infiltration, proliferation, and tissue infiltration,
make the braid-twisted structures a promising candidate for ten-
don and ligament regeneration purposes. Nevertheless, the elec- Keywords
trospinning method allows the control of fiber diameter, poros-
ity, and mechanical properties to reproduce the natural physiol- fiber-based fabrication technologies, fibrous scaffolds, ligament tissue en-
gineering, tendon tissue engineering
ogy of the tissues. However, the small pore size of the nanofi-
brous constructs might not permit an optimal cell infiltration
Received: July 24, 2020
and tissue ingrowth. On the other hand, the wet-spinning ap- Revised: October 19, 2020
proach allowed the fabrication of 3D cell-laden structures, pro- Published online: February 12, 2021
viding fibrous systems which can mimic the ECM features. Even
though wet-spun aligned fibrous systems might guide cell ori-
entation, the mechanical properties of those natural hydrogel-
based scaffolds often do not match the mechanical properties of [1] C. T. Laurencin, J. W. Freeman, Biomaterials 2005, 26, 7530.
[2] A. Ratcliffe, D. L. Butler, N. A. Dyment, P. J. Cagle, C. S. Proctor, S. [33] M. Skutek, M. Griensven, J. Zeichen, N. Brauer, U. Bosch, Eur. J.
S. Ratcliffe, E. L. Flatow, Ann. Biomed. Eng. 2015, 43, 819. Appl. Physiol. 2001, 86, 48.
[3] N. Andarawis-Puri, E. L. Flatow, L. J. Soslowsky, J. Orthop. Res. 2015, [34] M. T. Galloway, A. L. Lalley, J. T. Shearn, J. Bone Jt. Surg. Am. 2013,
33, 780. 95, 1620.
[4] S. Rathbone, S. Cartmell, in Tissue Engineering for Tissue and Organ [35] T. Wang, Z. Lin, R. E. Day, B. Gardiner, E. Landao-Bassonga, J.
Regeneration (Ed: D. Eberli), InTech, London 2011, pp. 131–162. Rubenson, T. B. Kirk, D. W. Smith, D. G. Lloyd, G. Hardisty, A. Wang,
[5] C. T. Thorpe, H. L. Birch, P. D. Clegg, H. R. C. Screen, in Tendon Re- Q. Zheng, M. H. Zheng, Biotechnol. Bioeng. 2013, 110, 1495.
generation: Understanding Tissue Physiology and Development to En- [36] K. Il Lee, J. S. Lee, J. G. Kim, K. T. Kang, J. W. Jang, Y. B. Shim, S. H.
gineer Functional Substitutes, (Eds: M. E. Gomes) R. L. Rei, M. T. Ro- Moon, J. Biomed. Mater. Res., Part A 2013, 101, 3152.
drigues) Academy Press, Boston 2015, p. 3. [37] D. W. Youngstrom, J. G. Barrett, Stem Cells Int. 2015, 2016, 3919030.
[6] S. P. Reese, S. A. Maas, J. A. Weiss, J. Biomech. 2010, 43, 1394. [38] P. Sawadkar, D. Player, L. Bozec, V. Mudera, J. Tissue Eng. Regener.
[7] R. James, G. Kesturu, G. Balian, A. B. Chhabra, J. Hand Surg. 2008, Med. 2020, 14, 135.
33, 102. [39] A. Sensini, L. Cristofolini, A. Zucchelli, M. L. Focarete, C. Gualandi,
[8] J. H. C. Wang, J. Biomech. 2006, 39, 1563. A. D. E. Mori, A. P. Kao, M. Roldo, G. Blunn, G. Tozzi, J. Microsc.
[9] D. L. Butler, E. S. Grood, F. R. Noyes, R. F. Zernicke, Exercise Sport 2020, 277, 160.
Sci. Rev. 1978, 6, 125. [40] T. Tetsunaga, T. Furumatsu, N. Abe, K. Nishida, K. Naruse, T. Ozaki,
[10] B. D. Beynnon, B. C. Fleming, J. Biomech. 1998, 31, 519. J. Biomech. 2009, 42, 2097.
[11] T. Nau, World J. Orthop. 2015, 6, 127. [41] C. H. Lee, H. J. Shin, I. H. Cho, Y. M. Kang, I. A. Kim, K. D. Park, J.
[12] M. M. Murray, B. C. Fleming, J. Orthop. Res. 2013, 31, 1501. W. Shin, Biomaterials 2005, 26, 1261.
[13] T. Wang, B. S. Gardiner, Z. Lin, J. Rubenson, T. B. Kirk, A. Wang, J. [42] T.-W. Qin, Y.-L. Sun, A. R. Thoreson, S. P. Steinmann, P. C. Amadio,
Xu, D. W. Smith, D. G. Lloyd, M. H. Zheng, Tissue Eng., Part B 2013, K.-N. An, C. Zhao, Biomaterials 2015, 51, 43.
19, 133. [43] A. R. Tomás, A. I. Goncalves,
˛ E. Paz, P. Freitas, R. M. A. Domingues,
[14] N. D. Weiss, Yale J. Biol. Med. 1991, 64, 194. M. E. Gomes, Nanoscale 2019, 11, 18255.
[15] S. Saghazadeh, C. Rinoldi, M. Schot, S. S. Kashaf, F. Sharifi, E. Jalil- [44] E. W. Yates, A. Rupani, G. T. Foley, W. S. Khan, S. Cartmell, S. J.
ian, K. Nuutila, G. Giatsidis, P. Mostafalu, H. Derakhshandeh, K. Anand, Stem Cells Int. 2012, 2012, 438125.
Yue, W. Swieszkowski, A. Memic, A. Tamayol, A. Khademhosseini, [45] H. M. Pauly, D. J. Kelly, K. C. Popat, N. A. Trujillo, N. J. Dunne, H.
Adv. Drug Delivery Rev. 2018, 127, 138. O. McCarthy, T. L. Haut Donahue, J. Mech. Behav. Biomed. Mater.
[16] N. A. Dyment, J. L. Galloway, Curr. Mol. Biol. Rep. 2015, 1, 124. 2016, 61, 258.
[17] A. Viidik, in Biomechanics of Diarthrodial Joints (Ed: A. Ratcliffe), [46] S. M. Full, C. Delman, J. M. Gluck, R. Abdmaulen, R. J. Shemin, S.
Springer-Verlag, New York 1990, pp. 4–38. Heydarkhan-Hagvall, J. Biomed. Mater. Res., Part B 2015, 103, 39.
[18] C. Chaput, N. Duval, in Ligaments and Ligamentoplasties (Ed: L’H. [47] L. A. Bosworth, N. Alam, J. K. Wong, S. Downes, J. Mater. Sci.: Mater.
Yahia), Springer, Berlin 1997, p. 143.[CrossRef ] Med. 2013, 24, 1605.
[19] U. G. Longo, A. Lamberti, N. Maffulli, V. Denaro, Br. Med. Bull. 2010, [48] J. A. Cooper, L. O. Bailey, J. N. Carter, C. E. Castiglioni, M. D. Kofron,
94, 165. F. K. Ko, C. T. Laurencin, Biomaterials 2006, 27, 2747.
[20] A. N. Shirazi, W. Chrzanowski, A. Khademhosseini, F. Dehghani, [49] J. Chen, J. Moreau, R. Horan, A. Collette, D. Bramano, V. Volloch,
in Engineering Mineralized and Load Bearing Tissues (Eds: L. E. J. Richmond, G. Vunjak-Novakovic, D. L. Kaplan, G. H. Altman, in
Bertassoni, P. G. Coelho), Springer International Publishing, Cham, Culture of Cells for Tissue Engineering, (Eds: G. Vunjak-Novakovic, R.
Switzerland 2015, pp. 161–186. I. Freshney) Wiley, New York 2005, p. 191.
[21] N. L. Leong, F. A. Petrigliano, D. R. McAllister, J. Biomed. Mater. Res., [50] F. Li, B. Li, Q. M. Wang, J. H. C. Wang, Cell Motil. Cytoskeleton 2008,
Part A 2014, 102, 1614. 65, 332.
[22] M. T. Rodrigues, R. L. Reis, M. E. Gomes, J. Tissue Eng. Regener. Med. [51] J. H.-C. Wang, G. Yang, Z. Li, W. Shen, J. Biomech. 2004, 37, 573.
2013, 7, 673. [52] S. Cristino, F. Grassi, S. Toneguzzi, a Piacentini, B. Grigolo, S. Santi,
[23] C. Yilgor, P. Yilgor Huri, G. Huri, Stem Cells Int. 2011, 2012, 374676. M. Riccio, E. Tognana, A. Facchini, G. Lisignoli, J. Biomed. Mater.
[24] G. Vunjak-Novakovic, G. Altman, R. Horan, D. L. Kaplan, Annu. Rev. Res., Part A 2005, 73, 275.
Biomed. Eng. 2004, 6, 131. [53] P. P. Yee Lui, Stem Cells Cloning: Adv. Appl. 2015, 8, 163.
[25] R. Langer, J. P. Vacanti, Science 1993, 260, 920. [54] R. Costa-Almeida, I. Calejo, M. E. Gomes, Int. J. Mol. Sci. 2019, 20,
[26] R. M. Nerem, Medical Sciences - Volume II, (Eds: B.P. Mansourian) 3002.
A. Wojtezak, B. McA. Sayers Encyclopedia of Life Support Systems, [55] A. I. Gonçalves, R. Costa-Almeida, P. Gershovich, M. T. Rodrigues, R.
Oxford, United Kingdom) 2009, 27. L. Reis, M. E. Gomes, in Tendon Regeneration: Understanding Tissue
[27] N. Celikkin, C. Rinoldi, M. Costantini, M. Trombetta, A. Rainer, W. Physiology and Development to Engineer Functinal Substitutes (Eds:
Świeszkowski,
˛ Mater. Sci. Eng., C 2017, 78, 1277. M. E. Gomes, R. L. Reis, M. Rodrigues), Academic Press, Boston
[28] M. Costantini, S. Testa, C. Rinoldi, N. Celikkin, J. Idaszek, C. Colosi, 2015, pp. 187–203.
A. Barbetta, C. Gargioli, W. Świeszkowski,
˛ in Biofabrication 3D Tissue [56] S. Liu, M. Qin, C. Hu, F. Wu, W. Cui, T. Jin, C. Fan, Biomaterials 2013,
Modelling, The Royal Society of Chemistry, London 2019, pp. 184– 34, 4690.
215. [57] S. Thomopoulos, R. Das, S. Sakiyama-Elbert, M. J. Silva, N. Charl-
[29] J. Idaszek, E. Kijeńska, M. Łojkowski, W. Swieszkowski, Appl. Surf. ton, R. H. Gelberman, Ann. Biomed. Eng. 2010, 38, 225.
Sci. 2016, 388, 762. [58] S. E. Sakiyama-Elbert, R. Das, R. H. Gelberman, F. Harwood, D.
[30] Y. J. No, M. Castilho, Y. Ramaswamy, H. Zreiqat, Adv. Mater. 2020, Amiel, S. Thomopoulos, J. Hand Surg. 2009, 33, 1548.
32, 1904511. [59] O. Evrova, G. M. Burgisser, C. Ebnother, A. Adathala, M. Calcagni,
[31] J. Lee, V. Guarino, A. Gloria, L. Ambrosio, G. Tae, Y. H. Kim, Y. E. Bachmann, J. G. Snedeker, C. Scalera, P. Giovanoli, V. Vogel, J.
Jung, S.-H. Kim, S. H. Kim, J. Biomater. Sci., Polym. Ed. 2010, 21, Buschmann, Biomaterials 2019, 232, 119722.
1173. [60] S. Thomopoulos, R. Das, M. J. Silva, S. Sakiyama-Elbert, F. L. Har-
[32] N. Davarinos, B. J. O’Neill, W. Curtin, C. W. Davarinos N, B. J. wood, E. Zampiakis, H. M. Kim, D. Amiel, R. H. Gelberman, J. Or-
O’Neill, B. J. O. Neill, W. Curtin, Adv. Orthop. Surg. 2014, 2014, 1. thop. Res. 2009, 27, 1209.
[61] S. C. Fu, Y. P. Wong, B. P. Chan, H. M. Pau, Y. C. Cheuk, K. M. Lee, [89] S. Chaudhury, C. Holland, M. S. Thompson, F. Vollrath, A. J. Carr, J.
K.-M. Chan, Life Sci. 2003, 72, 2965. Shoulder Elbow Surg. 2012, 21, 1168.
[62] S. Zhao, J. Zhao, S. Dong, X. Huangfu, B. Li, H. Yang, J. Zhao, W. [90] G. Yang, H. Lin, B. B. Rothrauff, S. Yu, R. S. Tuan, Acta Biomater.
Cui, Int. J. Nanomed. 2014, 9, 2373. 2016, 35, 38.
[63] S. P. Roth, W. Brehm, C. Gross, P. Scheibe, S. Schubert, J. Burk, Int. [91] M. S. Kim, G. Kim, Carbohydr. Polym. 2014, 114, 213.
J. Mol. Sci. 2019, 20, 5474. [92] H.-J. Shao, C. S. Chen, Y.-T. Lee, J.-H. Wang, T.-H. Young, J. Biomed.
[64] R. James, S. G. Kumbar, C. T. Laurencin, G. Balian, A. B. Chhabra, Mater. Res., Part A 2010, 93, 1297.
Biomed. Mater. 2011, 6, 025011. [93] D. P. Pacheco, L. Zorzetto, P. Petrini, in Biomedical Composites,
[65] J. E. Moreau, J. Chen, R. L. Horan, D. L. Kaplan, G. H. Altman, Tissue Woodhead Publishing, Sawston, UK 2017, p. 59.
Eng. 2005, 11, 1887. [94] A. Fallahi, A. Khademhosseini, A. Tamayol, Trends Biotechnol. 2016,
[66] M. Alimohammadi, Y. Aghli, O. Fakhraei, A. Moradi, M. 34, 683.
Passandideh-Fard, M. H. Ebrahimzadeh, A. Khademhosseini, [95] A. Fallahi, I. K. Yazdi, L. Serex, E. Lesha, N. Faramarzi, F. Tarlan, H.
A. Tamayol, S. A. Mousavi Shaegh, ACS Biomater. Sci. Eng. 2020, 6, Avci, R. Costa-Almeida, F. Sharifi, C. Rinoldi, M. E. Gomes, S. R. Shin,
4356. A. Khademhosseini, M. Akbari, A. Tamayol, ACS Biomater. Sci. Eng.
[67] D. M. Ramos, S. Abdulmalik, M. R. Arul, S. Rudraiah, C. T. Laurencin, 2019, 6, 1112.
A. D. Mazzocca, S. G. Kumbar, Polym. Adv. Technol. 2019, 30, 1205. [96] Y. Wu, Y. Han, Y. S. Wong, J. Y. H. Fuh, J. Tissue Eng. Regener. Med.
[68] A. Sensini, C. Gualandi, A. Zucchelli, L. A. Boyle, A. P. Kao, G. C. 2018, 12, 1798.
Reilly, G. Tozzi, L. Cristofolini, M. L. Focarete, Sci. Rep. 2018, 8, [97] M. Akbari, A. Tamayol, S. Bagherifard, L. Serex, P. Mostafalu, N.
17167. Faramarzi, M. H. Mohammadi, A. Khademhosseini, Adv. Healthcare
[69] D. Olvera, R. Schipani, B. N. Sathy, D. J. Kelly, Biomed. Mater. 2019, Mater. 2016, 5, 751.
14, 035016. [98] M. B. Guner, A. D. Dalgic, A. Tezcaner, A. Yilanci, D. Keskin, Biomed.
[70] C. Gabler, J. O. Saß, S. Gierschner, T. Lindner, R. Bader, T. Tischer, Mater. 2020, 15, 065014.
Biomed Res. Int. 2018, 2018, 6432742. [99] S. Yang, X. Shi, X. Li, J. Wang, Y. Wang, Y. Luo, Biomaterials 2019,
[71] J. C. Y. Liao, M. He, A. W. T. Gan, F. Wen, L. P. Tan, A. K. S. Chong, J. 207, 61.
Biomed. Mater. Res., Part B 2018, 106, 2605. [100] M. Akbari, A. Tamayol, V. Laforte, N. Annabi, A. H. Najafabadi, A.
[72] D. Sheng, J. Li, C. Ai, S. Feng, T. Ying, X. Liu, J. Cai, X. Ding, W. Jin, Khademhosseini, D. Juncker, Adv. Funct. Mater. 2015, 24, 4060.
H. Xu, J. Chen, S. Chen, J. Mater. Chem. B 2019, 7, 4801. [101] A. Tamayol, A. H. Najafabadi, B. Aliakbarian, E. Arab-Tehrany, M.
[73] H. Almeida, R. M. A. Domingues, S. M. Mithieux, R. A. Pires, A. I. Akbari, N. Annabi, D. Juncker, A. Khademhosseini, Adv. Healthcare
Gonçalves, M. Gómez-Florit, R. L. Reis, A. S. Weiss, M. E. Gomes, Mater. 2015, 4, 2146.
ACS Appl. Mater. Interfaces 2019, 11, 19830. [102] R. Costa-Almeida, R. M. A. Domingues, A. Fallahi, H. Avci, I. K. Yazdi,
[74] M. Nivedhitha Sundaram, S. Deepthi, U. Mony, K. T. Shalumon, J. M. Akbari, R. L. Reis, A. Tamayol, M. E. Gomes, A. Khademhosseini,
P. Chen, R. Jayakumar, Int. J. Biol. Macromol. 2019, 122, 37. J. Tissue Eng. Regener. Med. 2017, 12, 1039.
[75] Q. Dong, J. Cai, H. Wang, S. Chen, Y. Liu, J. Yao, Z. Shao, X. Chen, [103] N. Saveh-Shemshaki, L. S. Nair, C. T. Laurencin, Acta Biomater.
Acta Biomater. 2020, 106, 102. 2019, 94, 64.
[76] A. B. R. Touré, E. Mele, J. K. Christie, Nanomaterials 2020, 10, 626. [104] N. Kumar, a K. Sharma, G. R. Singh, P. Gupta, J. Vet. Med., A 2002,
[77] R. Hortensius, L. Mozdzen, B. Harley, in Tendon Regeneration: Un- 49, 161.
derstanding Tissue Physiology and Development to Engineer Functional [105] D. H. Jenkins, B. McKibbin, J. Bone Jt. Surg. Br. Vol. 1980, 62-B, 497.
Substitutes (Eds: M. E. Gomes, R. L. Reis, M. T. B. T.-T. R. Rodrigues), [106] M. Blazewicz, Eur. Cell Mater. 2001, 2, 21.
Academic Press, Boston 2015, p. 349. [107] J. A. Albright, E. M. Keating, A. A. Marino, Schumpert Med. 1984, 3,
[78] C. Vaquette, C. Kahn, C. Frochot, C. Nouvel, J. L. Six, N. De Isla, L. H. 16.
Luo, J. Cooper-White, R. Rahouadj, X. Wang, J. Biomed. Mater. Res., [108] D. H. Jenkins, J. Bone Jt. Surg., Br. Vol. 1978, 60-B, 520.
Part A 2010, 94, 1270. [109] U. Dasar, S. Gursoy, M. Akkaya, O. Algin, C. Isik, M. Bozkurt, J. Or-
[79] C. Erisken, X. Zhang, K. L. Moffat, W. N. Levine, H. H. Lu, Tissue thop. Surg. 2016, 24, 188.
Eng., Part A 2012, 19, 519. [110] U. K. Debnath, J. A. Fairclough, R. L. Williams, Knee 2004, 11, 259.
[80] D. C. Surrao, S. D. Waldman, B. G. Amsden, Acta Biomater. 2012, 8, [111] J. P. García-Ruíz, A. D. Lantada, Materials 2017, 11, 23.
3997. [112] F. H. Silver, J. W. Freeman, G. P. Seehra, J. Biomech. 2003, 36, 1529.
[81] O. Hakimi, P.-A. Mouthuy, A. Carr, Int. J. Exp. Pathol. 2013, 94, 287. [113] E. Panas-Perez, C. J. Gatt, M. G. Dunn, J. Mater. Sci.: Mater. Med.
[82] P. Deniz, S. Guler, E. Çelik, P. Hosseinian, H. M. Aydin, Mater. Sci. 2013, 24, 257.
Eng., C 2020, 106, 110293. [114] Y. J. No, S. Tarafder, B. Reischl, Y. Ramaswamy, C. Dunstan, O.
[83] D. I. Zeugolis, S. T. Khew, E. S. Y. Yew, A. K. Ekaputra, Y. W. Tong, L.-Y. Friedrich, C. H. Lee, H. Zreiqat, ACS Biomater. Sci. Eng. 2020, 6,
L. Yung, D. W. Hutmacher, C. Sheppard, M. Raghunath, Biomaterials 1887.
2008, 29, 2293. [115] W. Roolker, T. W. Patt, C. N. van Dijk, M. Vegter, R. K. Marti, Knee
[84] A. Gigante, E. Cesari, A. Busilacchi, S. Manzotti, K. Kyriakidou, F. Surg. Sports Traumatol. Arthrosc. 2000, 8, 20.
Greco, R. Di Primio, M. Mattioli-Belmonte, J. Orthop. Res. 2009, 27, [116] L. Dahlstedt, N. Dalén, U. Jonsson, Acta Orthop. Scand. 1990, 61,
826. 217.
[85] T. Majima, T. Funakosi, N. Iwasaki, S. T. Yamane, K. Harada, S. Non- [117] A. W. Murray, M. F. Macnicol, Knee 2004, 11, 9.
aka, A. Minami, S. I. Nishimura, J. Orthop. Sci. 2005, 10, 302. [118] N. Davarinos, B. J. O. Neill, W. Curtin, Adv. Orthop. Surg. 2014, 2014,
[86] G. H. Altman, R. L. Horan, H. H. Lu, J. Moreau, I. Martin, J. C. Rich- 1.
mond, D. L. Kaplan, Biomaterials 2002, 23, 4131. [119] K. Gao, S. Chen, L. Wang, W. Zhang, Y. Kang, Q. Dong, H. Zhou, L.
[87] N. Contessi Negrini, P. Tarsini, M. C. Tanzi, S. Farè, J. Appl. Polym. Li, Arthroscopy 2010, 26, 515.
Sci. 2019, 136, 47104. [120] M. Leciejewski, A. Królikowska, P. Reichert, Polym. Med. 2019, 48,
[88] J. Chen, G. H. Altman, V. Karageorgiou, R. Horan, A. Collette, V. Vol- 53.
loch, T. Colabro, D. L. Kaplan, J. Biomed. Mater. Res., Part A 2003, [121] C. Legnani, A. Ventura, C. Terzaghi, E. Borgo, W. Albisetti, Int. Or-
67, 559. thop. 2010, 34, 465.
[122] M. F. Macnicol, I. D. Penny, L. Sheppard, J. Bone. Joint. Surg. Br. [155] J. W. Freeman, M. D. Woods, D. A. Cromer, L. D. Wright, C. T. Lau-
1991, 73, 377. rencin, J. Biomater. Sci., Polym. Ed. 2009, 20, 1709.
[123] S. Zaffagnini, G. M. Marcheggiani Muccioli, V. Chatrath, A. Bondi, V. [156] S. Madhavarapu, R. Rao, S. Libring, E. Fleisher, Y. Yankannah, J. W.
De Pasquale, D. Martini, B. Bacchelli, M. Marcacci, Knee Surg. Sports Freeman, Technology 2017, 05, 98.
Traumatol. Arthrosc. 2008, 16, 1026. [157] P. Y. Mengsteab, P. Conroy, M. Badon, T. Otsuka, H. M. Kan, A. T.
[124] D. J. Dandy, A. J. R. Gray, J. Bone Jt. Surg. Br. Vol. 1994, 76, 193. Vella, L. S. Nair, C. T. Laurencin, PLoS One 2020, 15, e0227181.
[125] M. Denti, M. Bigoni, G. Dodaro, M. Monteleone, A. Arosio, Knee [158] A. Nasajpour, S. Mandla, S. Shree, E. Mostafavi, R. Sharifi, A.
Surg. Sports Traumatol. Arthrosc. 1995, 3, 75. Khalilpour, S. Saghazadeh, S. Hassan, M. J. Mitchell, J. Leijten,
[126] I. T. J. Schroven, S. Geens, L. Beckers, W. Lagrange, G. Fabry, Knee X. Hou, A. Moshaverinia, N. Annabi, R. Adelung, Y. K. Mishra,
Surg. Sports Traumatol. Arthrosc. 1994, 2, 214. S. R. Shin, A. Tamayol, A. Khademhosseini, Nano Lett. 2017, 17,
[127] S. D. S. Newman, H. D. E. Atkinson, C. A. Willis-Owen, Int. Orthop. 6235.
2013, 37, 321. [159] A. Chlanda, E. Kijeńska, C. Rinoldi, M. Tarnowski, T. Wierzchoń, W.
[128] T. Nau, P. Lavoie, N. Duval, J. Bone Jt. Surg. Br. 2002, 84, 356. Swieszkowski, Micron 2018, 107, 79.
[129] S.-B. Yu, R.-H. Yang, Z.-N. Zuo, Q.-R. Dong, Int. J. Clin. Exp. Med. [160] F. Hejazi, H. Mirzadeh, N. Contessi, M. C. Tanzi, S. Faré, J. Biomed.
2014, 7, 2511. Mater. Res., Part A 2017, 105, 1535.
[130] M. Younesi, A. Islam, V. Kishore, J. M. Anderson, O. Akkus, Adv. [161] E. Kijeńska, W. Swieszkowski, in Electrospun Materials for Tissue Engi-
Funct. Mater. 2014, 24, 5762. neering and Biomedical Application (Eds: T. Uyar, E. Kny), Woodhead
[131] A. Islam, M. S. Bohl, A. G. Tsai, M. Younesi, R. Gillespie, O. Akkus, Publishing, Sawston, UK 2017, pp. 43–56.
Clin. Biomech. 2016, 30, 669. [162] A. Nasajpour, S. Ansari, C. Rinoldi, A. S. Rad, T. Aghaloo, S. R.
[132] G. D. Learn, P. E. McClellan, D. M. Knapik, J. L. Cumsky, V. Webster- Shin, Y. K. Mishra, R. Adelung, W. Swieszkowski, N. Annabi, A.
Wood, J. M. Anderson, R. J. Gillespie, O. Akkus, J. Biomed. Mater. Khademhosseini, A. Moshaverinia, A. Tamayol, Adv. Funct. Mater.
Res., Part B 2019, 107, 1864. 2018, 28, 1703437.
[133] S. Wu, Y. Wang, P. N. Streubel, B. Duan, Acta Biomater. 2017, 62, [163] E. Kijeńska-Gawrońska, T. Bolek, M. Bil, W. Swieszkowski, J. Mater.
102. Chem. B 2019, 7, 4509.
[134] M. Laranjeira, R. M. A. Domingues, R. Costa-Almeida, R. L. Reis, M. [164] C. E. Campiglio, N. C. Negrini, S. Farè, L. Draghi, Materials 2019, 12,
E. Gomes, Small 2017, 13, 1700689. 2476.
[135] D. Ruan, T. Zhu, J. Huang, H. Le, Y. Hu, Z. Zheng, C. Tang, Y. Chen, [165] C. Rinoldi, E. Kijeńska, A. Chlanda, E. Choinska, N. Khenoussi, A.
J. Ran, X. Chen, Z. yin, S. Qian, D. Pioletti, B. C. Heng, W. Chen, W. Tamayol, A. Khademhosseini, W. Swieszkowski, J. Mater. Chem. B
Shen, H.-W. Ouyang, ACS Biomater. Sci. Eng. 2019, 5, 5412. 2018, 6, 3116.
[136] W. Zhang, Y. Yang, K. Zhang, T. Luo, L. Tang, Y. Li, J. Biomater. Tissue [166] R. James, U. S. Toti, C. T. Laurencin, S. G. Kumbar, in Biomedical
Eng. 2017, 7, 571. Nanotechnology Methods and Protocols (Ed: S. J. Hurst), Humana
[137] J. Cai, X. Xie, D. Li, L. Wang, J. Jiang, X. Mo, J. Zhao, Biomater. Sci. Press, Totowa, NJ 2011, pp. 243–258.
2020, 8, 4413. [167] S. Agarwal, J. H. Wendorff, A. Greiner, Polymer 2008, 49, 5603.
[138] S. Sahoo, H. Ouyang, J. C.-H. Goh, T. E. Tay, S. L. Toh, Tissue Eng. [168] R. L. Mauck, B. M. Baker, N. L. Nerurkar, J. a. Burdick, W.-J. Li, R. S.
2006, 12, 91. Tuan, D. M. Elliott, Tissue Eng., Part B 2009, 15, 171.
[139] J. W. Freeman, M. D. Woods, D. a. Cromer, E. C. Ekwueme, T. Andric, [169] A. Sensini, C. Gualandi, M. L. Focarete, J. Belcari, A. Zucchelli, L.
E. a. Atiemo, C. H. Bijoux, C. T. Laurencin, J. Biomech. 2011, 44, 694. Boyle, G. C. Reilly, A. P. Kao, G. Tozzi, L. Cristofolini, Biofabrication
[140] S. K. Czaplewski, T. L. Tsai, S. E. Duenwald-Kuehl, R. Vanderby, W. J. 2019, 11, 035026.
Li, Biomaterials 2014, 35, 6907. [170] M. S. Peach, R. James, U. S. Toti, M. Deng, N. L. Morozowich, H.
[141] J. A. Cooper, H. H. Lu, F. K. Ko, J. W. Freeman, C. T. Laurencin, Bio- R. Allcock, C. T. Laurencin, S. G. Kumbar, Biomed. Mater. 2012, 7,
materials 2005, 26, 1523. 045016.
[142] F. R. Noyes, S. D. Barber-Westin, Arthroscopy 1994, 10, 371. [171] X. Li, H. Chen, S. Xie, N. Wang, S. Wu, Y. Duan, M. Zhang, L. Shui,
[143] K. Kumar, N. Maffulli, Arthroscopy 1999, 15, 422. Int. J. Nanomed. 2020, 15, 6373.
[144] G. K. McPherson, H. V. Mendenhall, D. F. Gibbons, H. Plenk, W. [172] D. P. Beason, B. K. Connizzo, L. M. Dourte, R. L. Mauck, L. J.
Rottmann, J. B. Sanford, J. C. Kennedy, J. H. Roth, Clin. Orthop. Relat. Soslowsky, D. R. Steinberg, J. Bernstein, J. Shoulder Elbow Surg.
Res. 1985, 186. 2012, 21, 245.
[145] R. Kdolsky, O. Kwasny, R. Schabus, Clin. Orthop. Relat. Res. 1993, [173] C. Yang, G. Deng, W. Chen, X. Ye, X. Mo, Colloids Surf., B 2014, 122,
183. 270.
[146] D. Johnson, Oper. Tech. Sports Med. 1995, 3, 173. [174] K. L. Moffat, A. S.-P. Kwei, J. P. Spalazzi, S. B. Doty, W. N. Levine, H.
[147] G. W. Bowyer, S. J. Matthews, J. R. Army Med. Corps 1991, 137, 69. H. Lu, Tissue Eng., Part A 2009, 15, 115.
[148] S. K. Ahlfeld, R. L. Larson, H. R. Collins, Am. J. Sports Med. 1987, 15, [175] O. Hakimi, R. Murphy, U. Stachewicz, S. Hislop, a. J. Carr, Eur. Cells
326. Mater. 2012, 24, 344.
[149] H. H. Lu, J. A. Cooper, S. Manuel, J. W. Freeman, M. A. Attawia, F. [176] C. Zhang, H. Yuan, H. Liu, X. Chen, P. Lu, T. Zhu, L. Yang, Z. Yin, B.
K. Ko, C. T. Laurencin, Biomaterials 2005, 26, 4805. C. Heng, Y. Zhang, H. Ouyang, Biomaterials 2015, 53, 716.
[150] J. A. J. Cooper, J. S. Sahota, W. J. 2nd Gorum, J. Carter, S. B. Doty, C. [177] R. M. A. Domingues, S. Chiera, P. Gershovich, A. Motta, R. L. Reis,
T. Laurencin, Proc. Natl. Acad. Sci. USA 2007, 104, 3049. M. E. Gomes, Adv. Healthcare Mater. 2016, 5, 1364.
[151] M. Gwiazda, S. Kumar, W. Świeszkowski, S. Ivanovski, C. Vaquette, [178] S. Shang, F. Yang, X. Cheng, X. Frank Walboomers, J. A. Jansen, Eur.
J. Mech. Behav. Biomed. Mater. 2020, 104, 103631. Cells Mater. 2010, 19, 180.
[152] X. Yu, P. Y. Mengsteab, G. Narayanan, L. S. Nair, C. T. Laurencin, [179] M. El Khatib, A. Mauro, M. Di Mattia, R. Wyrwa, M. Schweder, M.
Engineering 2020, https://doi.org/10.1016/j.eng.2020.02.010., . Ancora, F. Lazzaro, P. Berardinelli, L. Valbonetti, O. Di Giacinto,
[153] A. Pagán, S. D. Aznar-Cervantes, J. Pérez-Rigueiro, L. Meseguer- A. Polci, C. Cammà, M. Schnabelrauch, B. Barboni, V. Russo, Cells
Olmo, J. L. Cenis, J. Biomed. Mater. Res., Part B 2019, 107, 2209. 2020, 9, 1207.
[154] J. W. Freeman, M. D. Woods, C. T. Laurencin, J. Biomech. 2007, 40, [180] T. Tu, Y. Shen, X. Wang, W. Zhang, G. Zhou, Y. Zhang, W. Wang, W.
2029. Liu, Appl. Mater. Today 2020, 18, 100495.
[181] T. Ni, P. Senthil-Kumar, K. Dubbin, S. D. Aznar-Cervantes, N. Datta, [202] A. Jayasree, S. Kottappally Thankappan, R. Ramachandran, M. N.
M. A. Randolph, J. L. Cenis, G. C. Rutledge, I. E. Kochevar, R. W. Sundaram, C. H. Chen, U. Mony, J. P. Chen, R. Jayakumar, ACS Bio-
Redmond, Lasers Surg. Med. 2012, 44, 645. mater. Sci. Eng. 2019, 5, 1476.
[182] H.-J. Jin, J. Chen, V. Karageorgiou, G. H. Altman, D. L. Kaplan, Bio- [203] C. N. Manning, a. G. Schwartz, W. Liu, J. Xie, N. Havlioglu, S. E.
materials 2004, 25, 1039. Sakiyama-Elbert, M. J. Silva, Y. Xia, R. H. Gelberman, S. Thomopou-
[183] Y. Maghdouri-White, S. Petrova, N. Sori, S. Polk, H. Wriggers, R. los, Acta Biomater. 2013, 9, 6905.
Ogle, R. Ogle, M. Francis, Biomed. Phys. Eng. Express 2018, 4, [204] C. Rinoldi, A. Fallahi, I. Yazdi, J. Campos Paras, E. Kijeńska-
025013. Gawrońska, G. Trujillo-de Santiago, A. Tuoheti, D. Demarchi, N.
[184] R. M. A. Domingues, A. I. Gonçalves, R. Costa-almeida, M. T. Ro- Annabi, A. Khademhosseini, W. Swieszkowski, A. Tamayol, ACS Bio-
drigues, R. L. Reis, M. E. Gomes, Tendon Regeneration: Understand- mater. Sci. Eng. 2019, 5, 2953.
ing Tissue Physiology and Development to Engineer Functional Substi- [205] L. Rossetti, L. A. Kuntz, E. Kunold, J. Schock, K. W. Müller, H. Grab-
tutes, Elsevier Inc., Amsterdam 2015. mayr, J. Stolberg-Stolberg, F. Pfeiffer, S. A. Sieber, R. Burgkart, A. R.
[185] Y. Yang, J. Sun, X. Liu, Z. Guo, Y. He, D. Wei, M. Zhong, L. Guo, H. Bausch, Nat. Mater. 2017, 16, 664.
Fan, X. Zhang, Regener. Biomater. 2017, 4, 299. [206] H. Ramakrishna, T. Li, T. He, J. Temple, M. W. King, A. Spagnoli,
[186] H. Y. Wu, F. Zhang, X. X. Yue, J. F. Ming, B. Q. Zuo, Mater. Lett. 2014, Biomater. Res. 2019, 23, 11.
135, 63. [207] Y. Lin, L. Zhang, N. Q. Liu, Q. Yao, B. Van Handel, Y. Xu, C. Wang,
[187] C. Rinoldi, M. Costantini, E. Kijeńska, M. Heljak, C. Monika, R. Buda, D. Evseenko, L. Wang, Int. J. Nanomed. 2019, 14, 5831.
J. Baldi, S. Cannata, J. Guzowski, C. Gargioli, A. Khademhosseini, W. [208] S. Qian, Z. Wang, Z. Zheng, J. Ran, J. Zhu, W. Chen, Med. Sci. Monit.
Swieszkowski, Adv. Healthcare Mater. 2019, 8, 1801218a. 2019, 25, 269.
[188] J. Nowotny, D. Aibibu, J. Farack, U. Nimtschke, M. Hild, M. Gelinsky, [209] P. V. Kolluru, J. Lipner, W. Liu, Y. Xia, S. Thomopoulos, G. M. Genin,
P. Kasten, Ch. Cherif, et al., J. Biomater. Sci., Polym. Ed. 2016, 27, I. Chasiotis, Acta Biomater. 2013, 9, 9442.
917. [210] W. Liu, Y.-C. Yeh, J. Lipner, J. Xie, H.-W. Sung, S. Thomopoulos, Y.
[189] T. Funakoshi, T. Majima, N. Iwasaki, S. Yamane, T. Masuko, A. Mi- Xia, Langmuir 2011, 27, 9088.
nami, K. Harada, H. Tamura, S. Tokura, S. Nishimura, J. Biomed. [211] S. Samavedi, P. Vaidya, P. Gaddam, A. R. Whittington, A. S. Gold-
Mater. Res., Part A 2005, 74A, 338. stein, Biotechnol. Bioeng. 2014, 111, 2549.
[190] T. Majima, T. Irie, N. Sawaguchi, T. Funakoshi, N. Iwasaki, K. Harada, [212] J. Xie, X. Li, J. Lipner, C. N. Manning, A. G. Schwartz, S. Thomopou-
A. Minami, S. Nishimura, Proc. Inst. Mech. Eng., Part H 2007, 221, los, Y. Xia, Nanoscale 2010, 2, 923.
537. [213] S. Font Tellado, W. Bonani, E. R. Balmayor, P. Foehr, A. Motta, C.
[191] L. Sardelli, D. P. Pacheco, L. Zorzetto, C. Rinoldi, W. Świeszkowski,
˛ P. Migliaresi, M. Van Griensven, Tissue Eng., Part A 2017, 23, 859.
Petrini, J. Appl. Biomater. Funct. Mater. 2019, 17, 228080001878285. [214] J. Reifenrath, M. Wellmann, M. Kempfert, N. Angrisani, B. Welke, S.
[192] C. Liu, S. Tian, J. Bai, K. Yu, L. Liu, G. Liu, R. Dong, D. Tian, Int. J. Gniesmer, A. Kampmann, H. Menzel, E. Willbold, Int. J. Mol. Sci.
Nanomed. 2020, 15, 927. 2020, 21, 1046.
[193] X. Liu, C. Laurent, Q. Du, L. Targa, G. Cauchois, Y. Chen, X. Wang, [215] P. Chen, L. Li, L. Dong, S. Wang, Z. Huang, Y. Qian, C. Wang, W.
N. de Isla, J. Biomed. Mater. Res., Part A 2018, 106, 3042. Liu, L. Yang, ACS Biomater. Sci. Eng. 2020, https://doi.org/10.1021/
[194] X. Liu, A. Baldit, E. de Brosses, F. Velard, G. Cauchois, Y. Chen, X. acsbiomaterials.9b01683.
Wang, N. de Isla, C. Laurent, Polymers 2020, 12, 2163. [216] N. Jiang, J. He, W. Zhang, D. Li, Y. Lv, Mater. Sci. Eng. C 2020, 110,
[195] A. Chainani, K. J. Hippensteel, A. Kishan, N. W. Garrigues, 110711.
D. S. Ruch, F. Guilak, D. Little, Tissue Eng., Part A 2013, 19, [217] P. Zhang, F. Han, T. Chen, Z. Wu, S. Chen, Biomater. Sci. 2020, 8,
2594. 871.
[196] M. Rashid, J. Dudhia, S. G. Dakin, S. J. B. Snelling, R. De Godoy, P. [218] F. Han, P. Zhang, T. Chen, L. Chao, W. Xuejun, P. Zhao, Int. J.
A. Mouthuy, R. K. W. Smith, M. Morrey, A. J. Carr, Sci. Rep. 2020, 10, Nanomed. 2019, 14, 9159.
4754. [219] J. Cai, J. Wang, K. Ye, D. Li, C. Ai, D. Sheng, W. Jin, X. Liu, Y. Zhi, J.
[197] O. Hakimi, P. A. Mouthuy, N. Zargar, E. Lostis, M. Morrey, A. Carr, Jiang, J. Chen, X. Mo, S. Chen, Int. J. Nanomed. 2018, 13, 3481.
Acta Biomater. 2015, 26, 124. [220] X. Li, R. Cheng, Z. Sun, W. Su, G. Pan, S. Zhao, J. Zhao, W. Cui, Acta
[198] M. Sharifi-Aghdam, R. Faridi-Majidi, M. A. Derakhshan, A. Chegeni, Biomater. 2017, 61, 204.
M. Azami, Proc. Inst. Mech. Eng., Part H 2017, 231, 652. [221] K. W. VanDusen, L. M. Larkin, Regenerative Engineering of Muscu-
[199] Z. Zheng, J. Ran, W. Chen, Y. Hu, T. Zhu, X. Chen, Z. Yin, B. C. Heng, loskeletal Tissues and Interfaces, Elsevier Ltd, Amsterdam 2015.
G. Feng, H. Le, C. Tang, J. Huang, Y. Chen, Y. Zhou, P. Dominique, [222] C. Arrigoni, D. Petta, S. Bersini, V. Mironov, C. Candrian, M. Moretti,
W. Shen, H.-w. Ouyang, Acta Biomater. 2017, 51, 317. Biofabrication 2019, 11, 032004.
[200] S. Jiang, H. Yan, D. Fan, J. Song, C. Fan, Int. J. Mol. Sci. 2015, 16, [223] M. A. Barajaa, L. S. Nair, C. T. Laurencin, Regener. Eng. Transl. Med.
6932. 2020, 6, 451.
[201] T. Zhao, Y. Qi, S. Xiao, J. Ran, J. Wang, E. P. Ghamor-Amegavi, X. [224] M. R. Ladd, S. J. Lee, J. D. Stitzel, A. Atala, J. J. Yoo, Biomaterials
Zhou, H. Li, T. He, Z. Gou, Q. Chen, K. Xu, J. Mater. Chem. B 2019, 2011, 32, 1549.
7, 2201. [225] E. D. Taylor, J. Bone Jt. Surg. 2010, 92, 170.
Wojciech Świeszkowski
˛ obtained his Ph.D. in mechanical engineering at Warsaw University of Tech-
nology (WUT), Poland and he completed a four year postdoctoral fellowship at TU Delft, the Nether-
lands. He obtained his habilitation at the Faculty of Materials Science and Engineering at WUT, where
he is professor and leader of the Biomaterials group. He visited several universities abroad, includ-
ing Harvard University and TU Wien. His research interests involve the design of advanced bioma-
terials for engineering cartilage, bone, tendon and nerve tissues, development of 3D-printing and
bioprinting technologies, computer modeling and characterization of biomaterials, and development
of drug delivery systems.

Fibrous Systems As Potential Solutions For Tendon and Ligament Repair, Healing, and Regeneration

Uploaded by

Copyright:

Available Formats

Fibrous Systems As Potential Solutions For Tendon and Ligament Repair, Healing, and Regeneration

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Fibrous Systems As Potential Solutions For Tendon and Ligament Repair, Healing, and Regeneration

Uploaded by

Copyright:

Available Formats

REVIEW

Fibrous Systems as Potential Solutions for Tendon and

Adv. Healthcare Mater. 2021, 10, 2001305

tenogenic markers movements and directly to the movement of the knee

© 2021 Wiley-VCH GmbH

Adv. Healthcare Mater. 2021, 10, 2001305

silk ﬁbroin expression of CD44, expression, collagen interaction and typical

twisting proliferation, deposition cross-sectional area, stimulation • Mimicking the biomechanical

© 2021 Wiley-VCH GmbH

Adv. Healthcare Mater. 2021, 10, 2001305

I, PLGA, PU, integrin organization showed anisotropic and

spinning hyaluronan, and proliferation, of mechanical stretching • Stabilization of the joint

© 2021 Wiley-VCH GmbH

Adv. Healthcare Mater. 2021, 10, 2001305

© 2021 Wiley-VCH GmbH

researches.[133,134] In this frame, Laranjeira et al. fabricated a

3.3. Knitted Fibrous Structures

The knitting textile-based technology provides two sets of ﬁbers

3.5. Braid-Twisted Fibrous Structures

The combination of branding technology with ﬁber twisting re-

approach synergizes the properties of diﬀerent source-materials,

4. Fiber-Based Scaﬀolds for Tissue Interfaces

4.1. Constructs for Tendon/Ligament-to-Bone Engineering

The main requirement for engineering tendon/ligament-bone

Table 2. Summary of advantages and disadvantages of ﬁber-based scaﬀolds.

You might also like

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.