Tema 1

Biomaterials 32 (2011) 7411e7431
Contents lists available at ScienceDirect
Biomaterials
journal homepage: www.elsevier.com/locate/biomaterials
Review
The knee meniscus: Structureefunction, pathophysiology, current repair

techniques, and prospects for regeneration
Eleftherios A. Makris, Pasha Hadidi, Kyriacos A. Athanasiou*
Department of Biomedical Engineering, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA
a r t i c l e i n f o a b s t r a c t
Article history: Extensive scientific investigations in recent decades have established the anatomical, biomechanical, and
Received 27 May 2011 functional importance that the meniscus holds within the knee joint. As a vital part of the joint, it acts to
Accepted 17 June 2011 prevent the deterioration and degeneration of articular cartilage, and the onset and development of
Available online 18 July 2011
osteoarthritis. For this reason, research into meniscus repair has been the recipient of particular interest
from the orthopedic and bioengineering communities. Current repair techniques are only effective in
Keywords:
treating lesions located in the peripheral vascularized region of the meniscus. Healing lesions found in
Knee meniscus
the inner avascular region, which functions under a highly demanding mechanical environment, is
Meniscus pathology
Meniscal repair
considered to be a significant challenge. An adequate treatment approach has yet to be established,
Tissue engineering though many attempts have been undertaken. The current primary method for treatment is partial
Scaffolds meniscectomy, which commonly results in the progressive development of osteoarthritis. This drawback
has shifted research interest toward the fields of biomaterials and bioengineering, where it is hoped that
meniscal deterioration can be tackled with the help of tissue engineering. So far, different approaches
and strategies have contributed to the in vitro generation of meniscus constructs, which are capable of
restoring meniscal lesions to some extent, both functionally as well as anatomically. The selection of the
appropriate cell source (autologous, allogeneic, or xenogeneic cells, or stem cells) is undoubtedly
regarded as key to successful meniscal tissue engineering. Furthermore, a large variation of scaffolds for
tissue engineering have been proposed and produced in experimental and clinical studies, although
a few problems with these (e.g., byproducts of degradation, stress shielding) have shifted research
interest toward new strategies (e.g., scaffoldless approaches, self-assembly). A large number of different
chemical (e.g., TGF-b1, C-ABC) and mechanical stimuli (e.g., direct compression, hydrostatic pressure)
have also been investigated, both in terms of encouraging functional tissue formation, as well as in
differentiating stem cells. Even though the problems accompanying meniscus tissue engineering
research are considerable, we are undoubtedly in the dawn of a new era, whereby recent advances in
biology, engineering, and medicine are leading to the successful treatment of meniscal lesions.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction a meniscus transplant dates back to 1989 [3]. These studies are
landmarks in understanding the anatomical and functional utility
Six decades ago, the discovery that removing the meniscus from of the knee meniscus, and have since resulted in numerous inves-
the knee jointdthen commonly seen as the sole technique for tigations into different treatment approaches.
treating sports-related injuriesdresulted in the deterioration of The current prevailing trend in repairing meniscus-related
articular cartilage and the gradual development of arthritis, radi- lesions is to maintain the tissue intact whenever possible [4e6].
cally changed the approach for treating meniscus-related problems However, the inability of surgeons to restore the tissuedboth
[1]. In 1982, partial meniscectomy was suggested as an alternative anatomically and functionallydin cases of complex or total trau-
to complete meniscectomy [2], while the first published account of matic lesions continues to present challenges. The simultaneous
inability to delay the progressive development of osteoarthritis
presents a similar motivation to search for new therapeutic avenues.
This review will cover current knowledge regarding anatomical
* Corresponding author. Department of Biomedical Engineering, University of
and biochemical characteristics of the knee meniscus, and discuss
California, Davis, 451 Health Sciences Drive, Davis, CA 95616, USA. Tel.: þ1 530 754
6645; fax: þ1 530 754 5739. the tissue’s biomechanical and functional properties. The review
E-mail address: [email protected] (K.A. Athanasiou). will also address the causal pathologies precipitating the need for
0142-9612/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.biomaterials.2011.06.037
7412 E.A. Makris et al. / Biomaterials 32 (2011) 7411e7431
meniscus treatment, and the effectiveness of current tissue repair menisci have distinctly different dimensions: lateral menisci are
methods, among different age groups. Finally, current therapeutic approximately 32.4e35.7 mm in length and 26.6e29.3 mm wide,
developments in repairing the meniscus will be discussed, focusing while medial menisci are 40.5e45.5 mm long and 27 mm wide
especially on the field of tissue engineering. Within this topic, [10,11]. Though both menisci are roughly wedge-shaped and semi-
special emphasis will be placed on advances in scaffolds and lunar, lateral menisci display greater variety in size, shape, thick-
scaffold-free approaches to regenerate meniscal tissue. Finally, ness, and mobility than medial menisci [12,13]. Lateral menisci also
perspectives for the future of meniscus repair will be given. cover a larger portion of the tibial plateau (75e93% laterally) in
comparison to medial menisci (51e74% medially) [13].
Vascularization in this tissue is of high relevance. From prenatal
2. Structure and function of the knee meniscus
development until shortly after birth, the meniscus is fully vascu-
larized. Afterward, however, vascularization appears to subside. At
2.1. Meniscus anatomy
10 years of age, vascularization is present in around 10e30% of the
meniscus, and at maturity the meniscus contains blood vessels and
The knee joint contains the meniscus structure, comprised of both
nerves only in the peripheral 10e25% of the tissue [13]. Subse-
a medial and a lateral component situated between the corre-
quently, two distinct regions of the meniscus can be distinguished:
sponding femoral condyle and tibial plateau (Fig. 1) [7]. Each is
the outer, vascular/neural region (red-red zone), and the inner,
a glossy-white, complex tissue comprised of cells, specialized
completely avascular/aneural region (white-white zone). These
extracellular matrix (ECM) molecules, and region-specific innerva-
two areas are separated by the red-white region, which presents
tion and vascularization. Both menisci are critical components of
attributes from both the red-red and white-white regions (Fig. 3).
a healthy knee joint [7e12]. The main stabilizing ligaments are the
Critically, the healing capacity of each area is directly related to
medial collateral ligament, the transverse ligament, the meniscofe-
blood circulation, leaving the white region susceptible to perma-
moral ligaments, and attachments at the anterior and posterior horns
nent post-traumatic and degenerative lesions [14].
(Fig. 2) [8]. The meniscofemoral ligaments, also known as the
Humphrey and Wrisberg ligaments, connect the posterior horn of the
lateral meniscus to a location near the insertion site of the posterior 2.2. Biochemical content
cruciate ligament on the medial femoral condyle. Though only 46% of
people have both of these ligaments, 100% of people have at least one Regarding composition by wet weight, the meniscus is highly
of them [8]. The meniscus surface appears smooth upon both gross hydrated (72% water), with the remaining 28% comprised of organic
inspection and microscopically [9]. Human medial and lateral matter, mostly ECM and cells [15]. In general, collagens make up the
Fig. 1. Anatomy of the knee joint: anterior view. The knee meniscus is situated between the femur and the tibia. Crossing the meniscus are various ligaments, which aid in
stabilizing the knee joint.
E.A. Makris et al. / Biomaterials 32 (2011) 7411e7431 7413
Fig. 2. Anatomy of the meniscus: superior view of the tibial plateau. This view of the tibial plateau highlights the ligaments of Humphrey and Wrisberg, which attach the meniscus
to the femur. The menisci are attached to each other via the transverse ligament. The horn attachments connect the tibial plateau to the meniscus.
majority (75%) of this organic matter, followed by GAGs (17%), DNA less than 1%. In the white-white zone, collagen makes up 70% of the
(2%), adhesion glycoproteins (<1%), and elastin (<1%) [15,16]. The tissue by dry weight, of which 60% is collagen type II and 40% is
above proportions might vary depending on age, injuries, and other collagen type I [19]. Aside from collagen, another fibrillar compo-
pathological conditions [17,18]. nent is elastin: a combination of mature and immature elastin
Although collagen is the main fibrillar component of the fibers has been found in very low concentrations (<0.6%) in the
meniscus, different collagen types exist in varying quantities in adult meniscus. Elastin’s exact biochemical and functional impor-
each region of the tissue. In the red-red zone, collagen type I is tance in the meniscus has yet to be determined [9,18,20].
predominant, at approximately 80% composition by dry weight, Proteoglycans are heavily glycosylated molecules that constitute
with other collagen variants (type II, III, IV, VI, and XVIII) present at a major component of the meniscus ECM [21]. These molecules are
Fig. 3. Regional variations in vascularization and cell populations of the meniscus. Left: though fully vascularized at birth, the blood vessels in the meniscus recede during maturity.
In adulthood, the red-red region contains the overwhelming majority of blood vessels. Right: cells in the outer, vascularized section of the meniscus (red-red region) are spindle-
shaped, display cell processes, and are more fibroblast-like in appearance, while cells in the middle section (white-red region) and inner section (white-white region) are more
chondrocyte-like, though they are phenotypically distinct from chondrocytes. Cells in the superficial layer of the meniscus are small and round.
comprised of a core protein which is decorated with glycosami- compress the menisci. The wedge shape of the meniscus and its
noglycans (GAGs). The main types of GAGs found in normal human horn attachments serve to convert the vertical compressive forces
meniscal tissue are chondoitin-6-sulfate (60%), dermatan sulfate to horizontal hoop stresses (Fig. 4). At the same time, shear forces
(20e30%), chondroitin-4-sulfate (10e20%), and keratin sulfate are developed between the collagen fibers within the meniscus
(15%) [15]. Aggrecan is the major large proteoglycan of the while the meniscus is deformed radially [17,32,36].
meniscus while biglycan and decorin are the main small proteo- The biomechanical properties of the knee meniscus are appro-
glycans [22]. Regional variation of these molecules has also been priately tuned to withstand the forces exerted on the tissue. Many
observed, with the inner two-thirds containing a relatively higher studies have helped to quantify the properties of the tissue both in
proportion of proteoglycans than the outer one-third [22]. Their humans and in animal models (Tables 1 and 2). According to these
main function is to enable the meniscus to absorb water, whose studies, the meniscus resists axial compression with an aggregate
confinement supports the tissue under compression [22,23]. modulus of 100e150 kPa [37]. The tensile modulus of the tissue
Adhesion glycoproteins are also indispensible components of the varies between the circumferential and radial directions; it is
meniscus matrix, as they serve as a link between ECM components approximately 100e300 MPa circumferentially and 10-fold lower
and cells. The main adhesion glycoproteins present in the human than this radially [38]. Finally, the shear modulus of the meniscus is
meniscus are fibronectin, thrombospondin, and collagen VI [18,24]. approximately 120 kPa [38].
The contact forces on the meniscus within the human knee joint
2.3. Meniscus cells have been mapped. It has been calculated that the intact menisci
occupy approximately 60% of the contact area between the articular
During early development, all meniscus cells present the same cartilage of the femoral condyles and the tibial plateau, while they
cellular morphologydin terms of both size and shapedwith no transmit >50% of the total axial load applied in the joint [6,39,40].
regional variations. However, later in development, morphologi- However, these percentages are highly dependent on degree of
cally and phenotypically distinct cells appear, which also vary in knee flexion and tissue health. For every 30 of knee flexion, the
terms of number and topographic localization (Fig. 3) [25]. Gha- contact surface between the two knee bones decreases by 4% [41].
dially et al. [9] suggested categorization of meniscus cells according When the knee is in 90 of flexion the applied axial load in the joint
to their shape and the presence or absence of territorial matrix. is 85% greater than when it is in 0 of flexion [40]. In full knee
Under this classification method, chondrocytes, fibroblasts, or flexion, the lateral meniscus transmits 100% of the load in the
intermediate cells exhibiting characteristics of both were identified. lateral knee compartment, whereas the medial meniscus takes on
Today, the characterization of meniscus cells appears somewhat approximately 50% of the medial load [36].
controversial in the literature, with a number of different terms Conversely, of notable interest are the changes in contact area
being used (i.e., fibrocytes, fibroblasts, meniscus cells, fibrochon- and contact force following partial or total meniscectomy. Paletta
drocytes, and chondrocytes) [25]. Regardless of the varying termi- et al. [42] investigated the biomechanical effects of total removal of
nology used, it is apparent that outer zone cells have an oval, the lateral meniscus in 10 cadaveric knees and reported a 50%
fusiform shape and are similar in appearance and behavior to decrease in total contact area, resulting in a 235e335% increase in
fibroblasts. Thus, they may be described as fibroblast-like cells. peak local contact load. In a similar study, Kurosawa et al. [43]
These cells also display long cell extensions, which facilitate noted that following total meniscectomy the tibiofemoral contact
communication with other cells and the extracellular matrix. The area decreased by approximately 50%, therefore leading to an
matrix surrounding these cells is mainly comprised of type I overall increase in contact forces by 2e3 times. Correspondingly,
collagen, with small percentages of glycoproteins and collagen partial (16e34%) meniscectomy has been shown to lead to a >350%
types III and V present [26,27]. In contrast, cells in the inner portion increase in contact forces on the articular cartilage [44].
of the tissue appear more round and are embedded in an ECM
comprised largely of type II collagen intermingled with a smaller 3. Meniscus pathophysiology
but significant amount of type I collagen and a higher concentration
of GAGs than in the outer region. This relative abundance of In the United States, meniscal lesions represent the most
collagen type II and aggrecan in the inner region is more reminis- common intra-articular knee injury, and are the most frequent
cent of hyaline articular cartilage. Therefore, cells in this region are cause of surgical procedures performed by orthopedic surgeons
classified as fibrochondrocytes or chondrocyte-like cells [27,28]. A [45,46]. The mean annual incidence of meniscal lesions has been
third cell population has also been recognized in the superficial reported to be 66 per 100,000 inhabitants, 61 of which result in
zone of the meniscus. These cells possess a flattened, fusiform meniscectomy [47,48]. Men are more prone to such injuries than
morphology and are absent of cell extensions. It has been suggested women, with a male to female incidence ratio between 2.5:1 and
that these cells are possibly specific progenitor cells with thera- 4:1, and overall incidence peaking at 20e29 years of age for both
peutic and regenerative capabilities [29]. In summary, cell pheno- sexes [47,49,50]. Meniscal lesions are most commonly found in the
type and ECM composition render the outer portion of the right knee [47] and occur in all age groups, with the main etio-
meniscus akin to fibrocartilage, while the inner portion possesses logical and pathophysiological factors varying and being highly
similar, but not identical, traits to articular cartilage. dependent upon the patient’s age [46,51].
2.4. Biomechanical and functional properties 3.1. Meniscus tears in young people
The meniscus withstands many different forces such as shear, In young patients, sports-related (football, basketball, soccer,
tension, and compression. It also plays a crucial role in load- baseball, and skiing in particular) injuries are the most common
bearing, load transmission, shock absorption, as well as lubrica- cause of meniscal lesions, accounting for more than 1/3 of all cases
tion and nutrition of articular cartilage [16,30e33]. These multiple [47,49]. The underlying mechanism of these injuries usually
and complex functions require a specialized form. Since the tissue involves cutting or twisting movements, hyperextension, or actions
is wedge-shaped, it proves highly adept at stabilizing the curved of great force [12]. Meniscal tearing during these sports is accom-
femoral condyle during articulation with the flat tibial plateau panied by anterior cruciate ligament (ACL) tearing in >80% of cases
[17,34,35]. During everyday activity, axial tibiofemoral forces [52e58]. Most patients report an acute onset of sharp pain
Fig. 4. How force is transduced upon and throughout the knee meniscus. Free body diagram of the forces acting on the knee meniscus during loading (for simplicity, only the lateral
meniscus is shown). During everyday activity, the menisci are compressed by the downward force of the femur. Since the meniscus is a wedge, the femoral force is enacted at an
angle, and thus a vertical component exists which is countered by the upward force of the tibia. Additionally, a horizontal component of the femoral force exists, which is exerted
radially outward on each meniscus. This horizontal force is in turn countered by the anchoring force of the attachments at the posterior and anterior horns of the meniscus.
Additionally, as this compression occurs, circumferential stress is created along the meniscus. Therefore, the menisci function by converting compressive loads to circumferential
tensile loads. At the same time, shear forces are developed between the collagen fibers within the meniscus while the meniscus is deformed radially.
following a twisting injury with the knee flexed and the foot
planted on the ground [59,60]. Meniscal tears resulting from Table 2
vehicle accidents are also associated with increased incidences of Tensile properties of the knee meniscus.
meniscus lesions in this particular age group [47].
Study Animal Direction Location Stiffness
Classification of meniscal injuries occurs depending on location, type (SD; MPa)
thickness, and resulting stability [6,12,61]. Thus, tears in the
Fithian Human Circumferential Lateral meniscus:
peripheral vascularized portion are denoted as red-red tears, in the et al. [38] Anterior 159.1 47.4
middle third portion as red-white or white-white tears, and in the Central 228.8 51.4
inner avascular portion as white-white tears. According to the Posterior 294.1 90.4
Medial meniscus:
Anterior 159.6 26.2
Central 228.8 51.4
Table 1 Posterior 294.1 90.4
Compressive properties of the knee meniscus.
Tissakht Human Circumferential Lateral meniscus:
Study Species Location Aggregate Permeability et al. [280] Anterior 124.58 39.51
modulus (SD; 1015 Central 91.37 23.04
(SD; MPa) m4 N1 s1) Posterior 143.73 38.91
Medial meniscus:
Sweigart Human Medial superior:
Anterior 106.21 77.95
et al. [37] Anterior 0.15 0.03 1.84 0.64
Central 77.95 25.09
Central 0.10 0.03 1.54 0.71
Posterior 82.36 22.23
Posterior 0.11 0.02 2.74 2.49
Radial Lateral meniscus:
Medial inferior:
Anterior 48.47 25.67
Anterior 0.16 0.05 1.71 0.48
Central 45.86 24.20
Central 0.11 0.04 1.54 0.49
Posterior 0.09 0.03 1.32 0.61
Medial meniscus:
Bovine Medial superior:
Anterior 48.31 24.35
Anterior 0.21 0.06 6.22 2.55
Central 46.20 27.56
Central 0.14 0.05 5.73 6.19
Posterior 0.11 0.04 4.73 2.56
Medial inferior: Lechner Human Circumferential Medial meniscus:
Anterior 0.16 0.06 5.79 4.31 et al. [281] Anterior 141.2 56.7
Central 0.11 0.03 5.65 4.13 Central 116.4 47.5
Posterior 0.13 0.06 5.40 5.36 Posterior 108.4 42.9
depth of the tear, injuries are observed as partial or full thickness, of
Follow-up arthroscopy (18 mos)

which full thickness injuries can be further categorized as stable or
unstable. Another means of classifying meniscal injuries is based on
Histology þ biomechanical
þ clinical exam (51 mos)

Second look arthroscopy
tear pattern [6,62]. This way, one can distinguish between different
Arthrogram þ follow-up
Follow-up arthroscopy
types of meniscal tearsdthe most important being vertical/longi-
Clinical examination
MRI þ clinical exam
tudinal (including bucket handle), flat/oblique, radial/transverse,
up arthroscopy þ
and horizontal/complex (including degenerative) [63]. The above
arthroscopy
Evaluation
categorization is highly relevant when deciding upon the most
Histology
Histology
Histology
Histology
Histology
Histology
Histology
Histology
appropriate and effective therapy. Studies have shown that there is
testing
also a significant difference in tear pattern between stable knees
and those with concurrent ACL lesions [64e66].
71 (21 Incomplete
Diagnosing meniscal malfunction is greatly dependent upon
Cases completely
both the experience and insight of a physician. A detailed patient
25 (38 Partial
100 (71 mos)

Almost 100
60 (4 mos),
history, a thorough physical exam, and modern imaging techniques
healed (%)
healing)
healing)
can help guide the process toward reaching diagnostic consensus.
Starting from the patient’s history, an accurate description of the
100
100
100
100
64
40
75
69
75
0
0
injury’s acquisition can set the ground for suspected meniscal
tearing. Patient complaints concerning pain, swelling, or ‘locking’,
Porous polymer implant in partial

Vascular access channels þ suture
and diagnostic characteristics during physical examination (joint
Exogenous fibrin clot þ suture

Exogenous fibrin clot þ suture
Photoactive laser technique

effusion, joint line tenderness), should be taken under serious
Suture coated VEGF/PDLLA

Neodymium laser þ suture
Current research findings on meniscus repair techniques (alternatives to meniscectomy) for the avascular zone. ACLT: Anterior cruciate ligament transection.
Rasping without suturing

Transfer of pedunculated
thickness access channel

Free synovium allograft
consideration [12,67]. The main tests, which will need to be con-
Trephination þ suture
Arthroscopy þ suture
ducted each time a patient’s knee presents with any of the above
Fibrin clot þ suture

findings, are joint line palpation, the flexion McMurray test, the
Apley’s grind test, and the Thessaly test [68e70]. Imaging modali-
synovial flap
Technique
ties that need to be applied when diagnosing such injuries are X-ray
Suture
Suture
and MRI [12].
3.1.1. Peripheral meniscal tears Longitudinal, radial, flap,
Longitudinal, horizontal,
Numerous techniques have been described and applied horizontal split, bucket
regarding surgical meniscus repair in the peripheral (vascular)
zone. Though such techniques undergo continuous development,
handle, complex
radial, complex
surgical treatment approaches can be classified under four main
Longitudinal
Longitudinal
Radial split
categories: inside-out, outside-in, and all-inside arthroscopic
Type of
lesions
techniques; and open repair [5,6,71]. These techniques have been

extensively described in the literature, along with their accompa-
e
e
e
e
e
e
e
e
nying complications and appropriate rehabilitation programs, and
Concurrent
will therefore not be largely discussed in the present review.

Minority
Majority
Majority
Majority
Majority
A substantial amount of research has focused on the efficacy and

ACLT
reliability of these repair techniques for achieving anatomical and

e
e
e
e
e
e
e
e
functional restoration of the meniscus. In general, there is an ever-
time(s) (months)
increasing amount of literature supporting current meniscus repair

techniques for treating tears in the vascular zone. Functionally
0.5, 1
Follow-up
successful outcomes in young individuals with stable knees are

6
41
2, 5
1, 5
1
3, 6
1, 2
21
36
1, 3
12
18
4, 71
18, 51
fairly frequent, with success rates varying from 63% to 91%
[45,57,72e76]. However, more long-term follow-up studies need to
be conducted so as to robustly confirm such evidence, and exclude
Mean age
the possibility of long-term degenerative deteriorations of the

(years)
articular cartilage and meniscus.

23
24
20
28
20
16
e
e
e
e
e
e
e
e
3.1.2. Avascular zone meniscal tears

No. of
cases
12
153
15
30
14
24
48
25
10
21
18
71
44
91
Tears in the avascular zone of the meniscus are generally more

complex and broad, and are often associated with a poor prognosis
Type of study
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
following repair. Improving the healing process in this type of

injury is an ongoing challenge for clinicians and researchers.
Clinical
Clinical
Clinical
Clinical
Clinical
Clinical
Several different therapeutic approaches have been brought

forward, with a variety of reported results (Table 3). The most
notable of these new approaches are: the use of parameniscal
Arnockzy and Warren [14]
van Trommel et al. [137]
Papachristou et al. [286]
synovial tissue, trephination of the peripheral meniscus rim with

Jitsuiki and Ikuta [283]
Vangesness et al.[282]
Arnockzy et al. [189]
suture of the meniscus tear, creation of vascular access channels,

Petersen et al. [288]
Henning et al. [138]
Rubman et al. [52]
Tienen et al. [285]

Zhang et al. [132]
Noyes et al. [289]
and use of mesenchymal stem cells or growth factors [77,78].

Uchio et al. [131]
Pollo et al. [287]

Cisa et al. [284]
Despite these results, none of the above techniques has been

a recipient of general acceptance and application. Therefore, the
main strategy for treating such tears is partial meniscectomy, with
Author
Table 3
its related long-term degenerative implications for articular carti-

lage [79,80]. The lack of acceptance and clinical application of the
above methods is mainly due to a deficiency in long-term follow-up 4. Cell sources for tissue engineering the knee meniscus
studies and replication of results, which could confirm these find-
ings in a greater number of clinical cases. In future studies, evalu- 4.1. Autologous cells
ation of articular cartilage in a long-term follow-up is of special
importance. In addition to this, investigation of the biomechanical One of the leading questions in tissue engineering is whether
properties of healed meniscus in experimental and clinical studies the engineered tissue should be an exact replica of the native tissue,
is essential. or whether it should merely carry out its main functions. Several
researchers argue that the development of a biomimetic replica of
3.2. Meniscal tears in older people and children the native meniscus necessitates the use of a biodegradable scaffold
seeded with native cells that will produce the same fibrocartilagi-
In general, meniscal lesions occur frequently in middle-aged and nous ECM [99e101]. However, this approach exhibits several
elderly patients. Tears encountered in patients belonging to this age limitations. Two surgical interventions would be required of
group usually result from long-term degeneration. Such meniscal a patient: a biopsy to obtain autologous meniscal cells, and a second
lesions lead to joint swelling, joint line pain, and mechanical procedure to implant the tissue-engineered meniscus. Moreover,
blocking [81,82]. The reported prevalence of meniscal lesions in tissue scarcity and current techniques yield only a limited number
patients with clinical and radiographic findings of osteoarthritis is of isolated cells, of which only cells from the inner part of the
68e90% [83e85]. This high correlation creates a series of diagnostic meniscus produce sufficient matrix GAGs [102,103]. To tackle these
problems, mainly concerning the identification of the main issues, research has moved to the fairly simple expansion of
pathology in a symptomatic knee. Therefore, on some occasions, autologous meniscal cells in monolayer culture. However, mono-
symptoms that may be due to a pathological cause (such as oste- layer expansion of meniscus cells leads to significant down-
oarthritis) may be attributed by the physician to the presence of regulation of ECM gene expression [104]. Similarly, some
a meniscal tear in MRI, while on other occasions, symptoms which approaches have included the use of autologous chondrocytes for
may result from trauma (such as a meniscal tear) may be attributed meniscal tissue engineering, as they have proven to produce more
to osteoarthritis. This has obvious repercussions on the choice of GAGs and collagen II compared to meniscal cells after expansion,
proper therapy. For example, treatment of meniscal tears with although they too undergo differentiation [99,105,106].
partial meniscectomy is rather unlikely to reduce symptoms caused Though the development of functional tissue-engineered
by osteoarthritis. meniscus constructs has advanced, important problems still
Regarding the successful application of meniscus repairs in persist. The limited ability of cell isolation for large-scale constructs
older people, less promising findings have been reported as is a notable example. Furthermore, the dedifferentiation of cells
compared to patients in younger age groups [72,81]. The main after expansion, as well as the possibility of autologous cells already
reason behind such unfavorable results is the degenerative etiology being in either a degenerated state, or in an age-related disease
surrounding meniscal tears in such patient groups, as well as the state, deem their utility in tissue engineering questionable [107].
declining vascularization of the aging meniscus. Barrett et al. [81] For these reasons, a wide variety of cell sources may be considered
reported only a small percentage (6%) of repairable meniscal tears for meniscus tissue engineering.
in this special aged patient group. In general, the current preferred
intervention for the majority of surgeons is meniscectomy, either 4.2. Allogeneic and xenogeneic cell sources
partial or total, depending on the degree of meniscal damage.
An increased incidence in meniscal tearing has recently been The realization of the fact that the isolation of a sufficient
observed in skeletally immature children [86,87]. The main caus- number of healthy, undifferentiated meniscal cells extracted from
ative factor behind this increased incidence is the growing partic- an injured meniscus ranges from difficult to impossible, and the
ipation of children in highly demanding athletic activities. need for alternative cell sources, has led many researchers to use
Simultaneously, the expansion in health services focused on child allogeneic cells for meniscus tissue engineering [25]. The first trials
pathology, and the extensive use of highly specialized imaging in this direction have been largely based on the positive healing
techniques such as MRI, have aided in contributing to these outcomes of allogeneic articular, auricular, and costal chondrocytes
diagnoses. in lesions in the avascular zone of the meniscus, in a large animal
Meniscal lesions in children are different than those in adult model study [108]. In another study, both autologous and alloge-
patients. In children, the vast majority of cases (>71%) are isolated neic chondrocytes were seeded in a degradable scaffold and
meniscal lesions [88e90]. The main mechanism of meniscal tearing implanted in 17 pigs to repair previously inflicted bucket-handle
in children is sports-related twisting of the knee. In a small meniscal tears [109]. After 12 weeks, the authors found that both
percentage of these cases, a common predisposing factor is allogeneic and autologous-based scaffolds were capable of
a discoid meniscus [91]. Diagnosis is dependent upon the presence promoting healing when compared to the control group. The fact
of a complete medical history for the patient and a clinical exam- that no statistically significant therapeutic outcome was found
ination. If a meniscal tear is suspected following clinical examina- between the two cell-based implants is of importance, as it
tion, the application of an imaging technique should be pursued. suggests that the use of allogeneic cells is feasible [109].
Nonetheless, the sensitivity and specificity of MRI for diagnosing In terms of the use of xenogeneic cells in tissue engineering,
meniscal lesions in children is considerably less than that for adults increasing amounts of research seem to strongly encourage their
[92,93]. use [110e112]. In a study by Ramallal et al. [110], the investigators
Meniscus pathology in children has received fairly limited created cartilage defects in the femoral condyle of 30 rabbits and
attention in the literature with regards to repair techniques. Most of subsequently tried to repair the injury by suturing a periosteal flap
the studies in this field deal with patient groups comprised mostly to the articular cartilage, while also infusing cultured pig chon-
of adults, with children representing a small portion of cases and drocytes into the defect void. After 24 weeks, the authors reported
with fairly short follow-ups [94e98]. In general, most of these the appearance of articular cartilage neotissue, which integrated
studies report that the overall success rate for meniscal repair in with the native tissue, and an overall lack of measurable immune
children appears analogous to that observed in adults, especially for response. In another study, researchers used four different types of
cases of isolated tears [96e98]. cells: allogeneic chondrocytes, MSCs, fibroblasts, and human
umbilical cord blood (hUCB) stem cells, and embedded them in PLA administration of growth factors such as VEGF, which activates
scaffolds to repair cartilage defects in a rabbit model [111]. these MSC functions [128,129].
Although they found better results when using allogeneic MSCs, Another strategy is the local administration of autologous MSCs
they reported no immune response when using xenogeneic hUCB to replenish the population of local cells which has been dimin-
stem cells, motivating further investigations in this area. The results ished due to trauma, degeneration, tissue defects, or compromised
from these studies point toward the possibility of using xenogeneic vascularity. Currently, many surgeons use this method to transplant
cell sources in meniscus tissue engineering, which is further sup- bone marrow-derived stem cells (BMSCs) for bone healing appli-
ported by unpublished data from our lab based on both in vitro and cations due to its high value and low risk and cost [130]. This
in vivo studies. strategy has been the center of much interest as a therapeutic
approach for rehabilitating meniscal lesions. Some of the main
4.3. Human embryonic stem cells techniques utilized with this approach include the creation of
vascular access channels and vascular tunnels by trephination or
Lately, an increasing interest in the use of stem cells for regen- rasping in the vascular region of the meniscus. This allows the
erating destroyed or degenerative tissue (such as articular cartilage, influx of blooddand subsequently MSCsdinto the damaged avas-
meniscus, intervertebral disc, TMJ disc, and heart muscle) has been cular area [77,78,131,132]. Other techniques use vascularized
shown [113e117]. Stem cells can play an important role in rectifying synovial flaps or fibrin clots, based on the same rationale
meniscal damage through their ability to differentiate and regen- [133e138]. Results of these techniques appear to conflict in the
erate tissue, and through their ability to produce cytokines and existing literature.
growth factors [118]. Human embryonic stem cells (hESCs) have The transplantation of expanded or modified autologous MSCs
proven to be an emerging cell source for fibrocartilage tissue is another approach in MSC-based tissue engineering. The first
engineering [117]. Some of the main characteristics which make attempt of this took place in 2005, when Izuta et al. [139] used
this cell source ideal for tissue engineering are pluripotency and autologous BMSCs from green fluorescent protein transgenic rats;
unlimited proliferative capacity [119,120]. Attempts toward tissue these were isolated, expanded in monolayer culture, and then
engineering the meniscus using this cell source are still in early transplanted into meniscal defects inflicted in the avascular zone.
phases. A main step in this direction was made by Hoben et al. After 8 weeks follow-up, the investigators found that MSCs could
[121], who investigated hESCs’ differentiation potential into survive and proliferate in the meniscal tears while also developing
fibrochondrocyte-like cells, and characterized the resulting differ- an extensive extracellular matrix, aiding the healing process in the
entiated cells. In this study, hESCs were cultured with growth avascular meniscus [139]. Similarly, investigators in another study
factors (TGF-b3, BMP-2, BMP-4, BMP-6, PDGF-BB, sonic hedgehog reported that autologous BMSCs injected into meniscal wounds of
protein), and/or primary cells (chondrocyte or fibrochondrocytes) eight canines improved healing [140]. In the same light, studies
for 3 weeks. Following this time, their ability to produce GAGs and have proven the use of MSCs seeded onto scaffolds for meniscus
collagen types I, III, and VI was assayed, along with the presence of tissue engineering as a rather effective one [141,142]. Another study
certain surface markers (CD105, CD44, SSEA, PDGFRa). Following showed that undifferentiated MSCs, as opposed to precultured
comparison of these treatments, results showed that the combi- cells, display a more potent healing response [143]. Here, the
nation of TGF-b3 with BMP-4 yielded embryoid bodies positive for investigators studied the therapeutic value of autologous MSCs in
collagen type I, II, and VI with 6.7- and 4.8-fold increases in GAG meniscal tissue lesions in a rabbit model by comparing their action
and collagen, respectively. Also, co-culture with fibrochondrocytes to that of platelet-rich plasma and autologous BMSCs. More
led to 9.8-fold increases in collagen II production. Results from this specifically, they created circular meniscal punch defects (2 mm),
study point to the suitability of hESCs for meniscal tissue engi- and either left the resulting gap intact, or covered it with hyalur-
neering and highlight at least 3 effective strategies to create hESC- onanecollagen composite matrices using one or none of the above
derived fibrocartilage [121]. cell categories. Of notable importance is that some of the stem cell
matrices were precultured in chondrogenic medium for 14 days
4.4. Adult stem cells prior to transplantation. Twelve weeks after transplant the
researchers concluded that the non-precultured autologous MSCs
While the usage of hESCs in meniscal tissue engineering led to integrated meniscus-like repair tissue, while the precultured
remains at a preliminary stage, many studies have focused on MSCs led only to partial integration [143].
using mesenchymal stem cells (MSCs) as a potential cell source. Undoubtedly, the expansion of MSCs in vitro has significant
MSCs are multipotent progenitor cells of stromal origin whose advantages and disadvantages. The primary advantage of expan-
main source is adult bone marrow, although they may be isolated sion is an increase in cell number. Disadvantages include possible
from other tissues in both adults and fetuses [122e125]. The large cell infection during culture, as well as decreased capacity for
scientific interest surrounding these cells is due to two main proliferation prior to implantation [144e146]. Finally, another
abilities. First, MSCs have been observed to differentiate into many danger not extensively reported on in the literature is the devel-
terminally differentiated cells which synthesize mesenchymal opment of tumor-like abnormalities following implantation of
tissue (i.e., cartilage, bone, ligaments, muscle, fat, dermal, and precultured autologous MSCs with mutations or epigenetic changes
other connective tissue), and can therefore be used to engineer [130]. This appears to be a relatively unexplored topic, showing the
mesenchymal-derived tissue [126]. Second, MSCs secrete a large need for more studies.
variety of immunoregulatory molecules, and contribute to the Finally, another strategy utilizing MSCs is ex vivo tissue differ-
healing process of injured tissue by providing paracrine trophic entiation/generation, with subsequent transplantation of this
mediators [118]. tissue. Research using this approach is currently being conducted in
Different strategies for using autologous connective tissue the authors’ lab to generate fibrocartilaginous tissues, including
progenitors in MSC-based tissue engineering have been described meniscus tissue. The main challenges in this field coincide with the
in the literature. An approach that has been investigated by many main challenges of tissue engineering in general: development of
researchers is in situ activation of the migration, proliferation, and functional tissue mirroring the composition of native tissue, which
differentiation of local MSCs. This can be achieved by the trans- will satisfactorily integrate with the host, and which will allow
plantation of an acellular scaffold [127] or by the local long-term preservation of cell viability and meniscus function.
5. Scaffolds for tissue engineering the knee meniscus is essential, since loading of the meniscus in vivo is highly non-
uniform [38,39]. It has been demonstrated that fibers in PCL
Scaffolds for tissue engineering the meniscus may be catego- scaffolds may be preferentially aligned by the use of a rotating
rized into four broad classes: synthetic polymers, hydrogels, ECM collection platform during electrospinning [161]. When evaluated
components, or tissue-derived materials. Synthetic polymers are mechanically, these scaffolds exhibited a 33-fold change in tensile
materials that do not exist in the body, at least not in polymer form. moduli if tested in the direction parallel versus perpendicular to
Hydrogels are hydrophilic colloids capable of holding large fiber alignment [161]. Aligned scaffolds can also subsequently
amounts of water, and may be derived from natural or synthetic promote cell and ECM orientation [162e165]. It has been found that
sources. ECM component scaffolds are comprised of whole mate- aligned PCL scaffolds seeded with meniscus cells and cultured over
rials formed primarily from a component macromolecule of natural 10 weeks display a 7-fold greater increase in tensile modulus in the
matrix, such as collagen or hyaluronan. Finally, tissue-derived direction of alignment than corresponding non-aligned scaffolds
materials include decellularized ECM and other significant [162]. Importantly, collagen per DNA was not statistically different
components or byproducts of living tissue such as small intestinal between aligned and non-aligned scaffolds, suggesting differential
submucosa. Importantly however, these four categorizations are organization of the existing ECM [162], although some studies have
not mutually exclusive, and rather serve as a broad guide to also reported that scaffold alignment serves to increase matrix
appreciate significant differences in properties among scaffolds. deposition [166,167]. Regardless of the underlying mechanism,
Hybrids and composites between these materials also exist. Since scaffold orientation appears to have a beneficial effect.
cell-seeded polymers consistently outperform acellular scaffolds in Recent work has also demonstrated that scaffolds may be
terms of regenerative capacity [101,147,148], this section will physically woven to further increase their compressive, tensile, and
primarily focus on studies examining the capabilities of scaffolds shear properties and to introduce scaffold anisotropy [168,169]. In
incorporating cells. this strategy, a custom-built weaving loom was used to produce
The ideal meniscus construct will excel in three criteria: anisotropic PGA or PCL scaffolds with mechanical characteristics
mechanics, bioactivity, and logistics (Table 4). Since heterogeneous generally on the same order of magnitude as native articular
loading of the meniscus occurs everyday in vivo, appropriate cartilage [168,169]. These woven scaffolds may be combined with
mechanical properties, tissue anisotropy, geometry [149], and hydrogels to make composites capable of supporting seeded
lubrication are requirements of the mechanics criterion. Any articular chondrocytes or adipose-derived stem cells [168,169].
implanted meniscus construct will also need to display sufficient Although these studies focused on engineering articular cartilage,
bioactivity. This means maintenance of cell phenotype, induction of they would also be highly relevant for recapitulating the mechan-
ECM synthesis, lack of immunogenicity, and capacity for host tissue ical properties and anisotropy of the knee meniscus.
integration. Finally, the logistics of a successful construct must not Other recent advances focus on making synthetic polymers
be unwieldy: supply, processability, sterilization, and eventual more biomimetic and bioactive. One group of investigators recently
surgical implantation must all be practical. reported the fabrication of a peptide scaffold sensitive to matrix
metalloproteinase-2 (MMP-2) degradation [170]. Although this
5.1. Synthetic polymer scaffolds scaffold has not yet been applied to meniscus tissue engineering, it
may greatly aid in coupling cell-mediated matrix remodeling to
Synthetic polymers, such as polyurethane (PU), poly- scaffold degradation. Since native components of the ECM are
caprolactone (PCL), polylactic acid (PLA), polyglycolic acid (PGA), nanoscale molecules, nanofibrous scaffolds may also help to coax
and polylactic co-glycolic acid (PLGA), hold several advantages, cells to behave as they do in native matrix. One study comparing
including fabrication under a variety of methods, near-limitless PLLA nanofiber and microfiber scaffolds reported increased
supply, and the potential to achieve appropriate pore size, fiber production of sulfated GAGs, cartilage link protein, collagen II, and
size, mechanical properties, and scaffold geometry. These advan- aggrecan by bovine chondrocytes seeded in the nanofiber scaffolds
tages are countered by a central weaknessdminimal intrinsic [171]. Some synthetic polymers may also inherently provide a more
biomimetic and bioactive properties. By contrast, the mechanical biomimetic environment than hydrogels for meniscus cells. A
properties of some more highly bioactive scaffolds, such as small comparison of meniscus cells cultured in PGA or agarose scaffolds
intestinal submucosa, are considerably less than that of some over 7 weeks reported 2- to 6-fold higher cell numbers, 2- to 4-fold
synthetic polymers [158e160]. The lack of inherent biological higher GAG production, and 3-fold greater collagen production in
support among synthetic scaffolds has motivated the exploration the PGA scaffolds [172]. The authors concluded that cell prolifera-
and use of many synthetic scaffolds as acellular meniscus pros- tion and ECM synthesis may be reduced when meniscus cells are
theses, which provide some biomechanical functionality, as well as forced to assume a round morphology in highly hydrophobic
modest tissue regeneration, when implanted [150e157]. agarose, since meniscus cells display a morphology and phenotype
Tissue engineering has spurred recent advances in synthetic that is representative of elongated fibroblasts as well as chon-
polymer scaffolds that emphasize and build upon the advantages drocytes [173,174]. This conclusion is corroborated by other studies
stated above. Methods for generating mechanical anisotropy within of fibroblast functionality in gels, where proliferation diminished as
synthetic cartilage scaffolds are one example. This characteristic cell spreading was restrained [175,176].
Table 4
Leading biomaterials strategies for meniscus tissue engineering rated on three primary criteria. Categories were qualitatively rated from 1e4 stars in mechanics (mechanical
properties, geometry, anisotropy, lubrication), bioactivity (cell phenotype, ECM synthesis, immunogenicity, potential for host tissue integration), and logistics (supply, material
processability and sterilization, ease of surgical implantation).
Rated criterion Synthetic Hydrogel ECM component scaffolds Tissue-derived scaffolds Scaffold-free
scaffolds scaffolds (e.g., collagen, GAG) (e.g., SIS, decellularized matrix) (e.g., self-assembly)
Mechanics *** * *** ** ***
Bioactivity * ** ** **** ****
Logistics **** **** *** * **
Despite the recent advances described above, the main disad- the complex geometry of the meniscus. One method combines the
vantage of synthetic polymer scaffolds still lies in facilitation of the imaging capabilities of computed tomography or MRI with robotic
development of a functionally robust matrix prior to scaffold printing to automate creation of a geometrically accurate model of
degradation in vivo. Future research in this direction is needed. the meniscus [177,198]. Alginate scaffolds seeded with bovine
Integration of synthetic polymer tissue constructs with neigh- meniscus cells in high density (50 million/mL) in this manner dis-
boring host tissue also remains an issue to tackle. Finally, fine- played a high geometrical fidelity to the target shape, high cell
tuning of synthetic polymers, so as to promote joint lubrication viability, and some properties similar to native tissue (50% of
and to prevent tissue wear and tear at boneecartilage interfaces, aggregate modulus, 33% of GAG content, but 2% of hydroxyproline
also represent avenues for further research. content), though tensile properties were not examined [198].
However, tissue grown in this manner was highly heterogeneous,
5.2. Hydrogel scaffolds possibly due to limited transport in the fairly large construct.
Subsequent work demonstrated the use of a magnetic stir bar
Hydrogels have also been investigated for use as meniscus “mixing bioreactor” to produce constructs with a larger degree of
scaffolds. Hydrogels can be synthetic materials such as poly N- homogeneity, higher equilibrium and tensile moduli, and greater
isopropyl acrylamide (PNIPAAm), or natural materials such as ECM deposition, although detrimental effects were observed at
alginate. The physical properties of hydrogels are largely influenced higher stirring intensities [199]. This work underscores the neces-
by their water content, which is often >90%. Hydrogels are also sity of, and opportunities and challenges associated with, bringing
versatiledthey may be crosslinked through various methods together diverse tools (imaging modalities, processing methods,
[177e179], reversibly gelled [180], and patterned with cells bioreactors) to successfully tissue engineer the knee meniscus.
[181e184] and growth factors [185,186]. Many hydrogels can also Hydrogels represent a versatile class of tissue engineering
be synthesized from readily available reagents. However, hydrogels scaffolds, but their mechanical properties (especially in tension)
may hamper meniscus cell phenotype by preventing encapsulated and bioactivity (especially in promoting meniscus cell phenotype
cells from assuming their characteristic spread fibroblastic and ECM synthesis) need to be improved. Cell-adhesive hydrogels
morphology [172,173,175]. Additionally, the mechanical properties have been created, and these may help with cell spreading and
of hydrogel scaffolds are not as easily manipulated as in synthetic phenotype issues [176]. Other research has been directed toward
polymers. Finally, hydrogels such as polyvinyl alcohol (PVA) ECM molecule hydrogels, yielding studies on elastin-like poly-
[187,188] and fibrin [189,190] have been investigated as acellular peptide [200,201] and collagen-mimetic peptide [202,203] hydro-
meniscus materials, but these will not be focused on in this review. gels. Further research into these approaches may combine the
Much research has focused on utilizing the versatile chemistry of bioactivity of ECM molecules with the versatility of hydrogel
hydrogels to create more biomimetic structures. The chemical scaffolds.
functionalization of hydrogels is one strategy that has been pursued
to create a more native microenvironment for cells. Hybrid hydrogels 5.3. ECM component scaffolds
(chitosanealginateehyaluronan) have been conjugated with the
adhesive arginineeglycineeaspartic acid (RGD) polypeptide and ECM component scaffolds are materials formed primarily from
cultured with articular chondrocytes over 1e2 weeks to show higher a macromolecule abundant in native matrix. Examples include
collagen and GAG content over unconjugated controls [191]. collagen meniscus implants or hyaluronan scaffolds. Combinations
Hydrogels have also been functionalized to undergo proteolytic of these molecules may also be used (i.e., collageneGAG scaffolds or
degradation by MMPs [192e194]. Both of these approaches are scaffolds containing multiple types of collagen). Collagen scaffolds
highly relevant to meniscus tissue engineering, but further work is in particular are amenable to several fabrication and processing
needed to explore these scaffolds in conjunction with meniscus cells. methods, including nanofiber electrospinning, anisotropic deposi-
Hydrogel co-cultures may also be created by spatial patterning of tion, and crosslinking. Because of these methods, ECM scaffolds
different cell types [182e184], using insoluble adhesion molecules or may possess strength comparable to synthetic scaffolds. As far as
sequential photopolymerization. Fibroblasts have been co-cultured bioactivity, ECM scaffolds would logically constitute a natural
with BMSCs in this manner [183], although the diverse meniscus environment for seeded cells. Yet, although these scaffolds are
cell subpopulations have not. This method is one way in which the made of natural matrix, they may not completely recapitulate the
regional cellular variation of the meniscus may be replicated. cell microenvironment (i.e., the collagen VI pericellular matrix,
Another principal advantage of hydrogels is their ability to collagen IX crosslinks, etc.). In addition, some other scaffold
reversibly gel in response to environmental factors such as materials such as silk have also been shown to more robustly
temperature, pH, electric field, ultrasound, or salt concentration promote matrix deposition compared to collagen scaffolds
[180]. This has allowed for the development of “smart” biomaterials [204,205]. Yet, in general, ECM component scaffolds are more
whose design allows for responses according to the environment, intrinsically biomimetic than synthetic and hydrogel materials.
which is favorable for tissue engineering because injectable scaf- Since meniscus cells normally rest in a dense network of
folds that solidify in the body can be produced. Building on this collagen and GAG molecules, scaffolds made from these compo-
concept, Chen et al. [195] have produced temperature-sensitive nents would logically provide a natural environment for the
chitosanehyaluronaneNIPAAm hybrid gels which maintain regeneration of meniscus tissue. Interestingly, not all ECM mole-
meniscus cell viability, encourage native matrix synthesis, and cules are equally effective. An early study showed that
reversibly solidify in response to temperature. Though an injectable GAGecollagen II matrices promoted more meniscus cell prolifera-
knee meniscus hydrogel is minimally invasive and enticing, a major tion, more GAG deposition, and less contraction versus
limiting factor lies in the scaffold’s insufficient mechanical prop- GAGecollagen I matrices [206]. Other researchers have shown that
erties after solidification. This deficiency may potentially be aggrecan surfaces are more effective in encouraging meniscus cell
modulated through increased hydrogel crosslinking, but some ECM deposition than collagen I surfaces [104]. HYAFF-11 is another
crosslinking methods have been shown to affect cytotoxicity and ECM component scaffold, made by modifying the glucoronic acid
cellular metabolism [196,197]. groups in hyaluronan. A study comparing meniscus cells seeded in
Other tissue engineers have taken advantage of various methods HYAFF-11 and collagen scaffolds (types I, II, and III) found no
to create cell-seeded hydrogel scaffolds that accurately represent differences in GAG and collagen I synthesis [207]. Thus, a variety of
results have been observed when comparing the efficacy of similar to that of using ECM components: they constitute a natural
different ECM component scaffolds. More research into these ECM environment for cell seeding, migration, and ECM deposition.
component scaffolds and combinations of these scaffolds is needed. Though geometric fidelity and bioactivity of these scaffolds can be
Scaffolds, and especially ECM component scaffolds, can exert high, they must be procured from natural tissue, and thus supply is
a strong effect on seeded cells through the microenvironment they problematic. In addition, some decellularization and processing
provide. A recent investigation developed a hybrid scaffold con- protocols compromise the mechanical integrity of these tissues.
sisting of chitosan, hyaluronan, chondroitin-6-sulfate, collagen I, Several investigations have demonstrated the comparatively
and collagen II molecules [208]. Rat meniscus cells passaged in high bioactivity of processed whole tissue scaffolds. A study of
monolayer underwent conventional dedifferentiation, but those passaged and seeded canine chondrocytes in SIS and PLGA scaf-
subsequently cultured in these hybrid scaffolds underwent partial folds, implanted in athymic mice, reported that sulfated GAG and
redifferentiation over 1 week. Results from RT-PCR demonstrated hydroxyproline content was higher in the SIS scaffolds, although
the upregulation of collagen I, collagen II, and aggrecan, although collagen II was present only in PLGA scaffolds [158]. SIS has also
not to the levels seen prior to passage [208]. Although these results demonstrated superiority to other tissue-derived meniscus scaf-
are exciting in that they show scaffolds may induce rediffer- folds. In a fairly recent study, three dermis isolates (human, fetal
entiation of previously dedifferentiated meniscus cells, further bovine, and crosslinked porcine) were compared against two small
studies are needed to characterize the matrix deposited in these intestine isolates (porcine and crosslinked porcine) in a rat model
systems, especially over longer culture periods. [215]. Canine meniscal cells, synoviocytes, tendon fibroblasts, and
From a clinical perspective, ECM scaffolds have received perhaps bone marrow progenitor cells were seeded in co-culture in all five
the most attention of all scaffold categories, due to the use of scaffolds, and porcine small intestine (principally the non-
collagen meniscus implants. The collagen meniscus implant is crosslinked scaffolds) displayed the greatest capacity for encour-
a surgical mesh composed of bovine collagen type I, crosslinked aging retention, infiltration, and viability of these cells [215].
with aldehydes, and molded in the shape of the lateral or medial Though processed whole tissues such as SIS display significant
menisci [209]. A multi-center clinical trial of collagen meniscus bioactivity and have been seen to induce some tissue regeneration,
implants showed greater tissue restoration 1 year after operation the resulting tissue mechanics may be insufficient, which subse-
compared to partial meniscectomy; and activity levels also rose in quently compromises knee function. An early work studied
chronic sufferers of meniscal problems 7 years after implantation unseeded porcine SIS implanted in surgically created canine medial
[210]. Smaller non-randomized trials report positive patient meniscus defects [216]. After 12 weeks, improved lameness scores,
outcomes over longer periods, with losses in pain and higher activity less articular cartilage erosion, and some tissue growth and reten-
levels documented [211,212]. Despite these results, significant tion were observed over controls [216]. Similar results have also
scientific and clinical drawbacks associated with the collagen been reported in a longer-term study with SIS specimens assessed
meniscus implant exist. The implant is not an option for patients after up to 12 months of implantation, although the study also
who have undergone total meniscectomy. In addition, once reported samples with biomechanics inferior to contralateral
implanted, scaffold degradation and shrinkage as well as shape meniscectomy [217]. A contrasting study reported meniscal regen-
incongruency remain significant issues [213,214]. The technical eration but increased articular cartilage degeneration (compared to
difficulty of suturing the implant also limits its use [213,214]. Finally, contralateral controls) in the knee joints of goats implanted with
this acellular scaffold’s primary mode of healing is thought to be unseeded porcine SIS [218]. The fact that tissue growth seems
through host cell migration and subsequent synthesis of meniscus apparent in these studies, but inferior biomechanics and/or cartilage
matrix, yet results in sheep have indicated more developed healing degeneration are observed simultaneously, highlights the possibility
if collagen meniscus implants are seeded with autologous fibro- that this regenerated tissue is mechanically insufficient.
chondrocytes [101]. In this work, seeded constructs were signifi- Other research centers on the considerable difficulty of creating
cantly larger than unseeded constructs or resection controls after 3 tissue-derived scaffolds with appropriate pore sizes. Studies of
weeks of implantation. In addition, histology showed greater ECM native menisci have deemed pore sizes of 100e150 mm as appro-
deposition and lower cellularity in seeded constructs, suggesting priate for meniscus cells [219], yet cell infiltration can be highly
accelerated matrix remodeling [101]. This lends credit to cell-based variant through the depths of both whole processed tissue (SIS,
tissue engineering. Lastly, as of this writing, the FDA approval dermis, etc.) [215] and decellularized meniscus [220], likely due to
granted to the collagen meniscus implant in 2008 has been rescin- the dense matrix present even after processing. However, other
ded, and the device has been removed from clinical use. recent work has achieved progress by increasing decellularized
In general, ECM component scaffolds display a mix of desirable ovine menisci porosity (to a value of 80% in the outer meniscus) as
traits between mechanics, bioactivity, and logistics. This category well as connected pore volume, although residual DNA content was
may hold the most promise amongst scaffold-based approaches for still significant and compressive properties trended lower [221].
meniscus tissue engineering. However, the technology and use of Though decellularized tissue scaffolds are promising, several
these materials is still relatively new, and the efficient incorpora- studies have reported decreased mechanical properties (especially
tion and development of suitable replacement tissue within ECM compressive properties) due to the treatment protocols used for
scaffolds in vivo and in vitro remains a topic for more investigation. decellularizing tissue. Losses in GAG content are similarly reported.
The introduction of appropriate lubrication, and the modulation of A variety of alternate treatment methods have been investigated.
ECM component scaffold degradation kinetics, also present One recent study demonstrated no reaction to MHC1 and MHC2,
opportunities for further research in functional tissue engineering. and preservation of, or even increases in, compressive stiffness
after ovine menisci were treated with a self-developed enzymatic
5.4. Tissue-derived scaffolds solution [222]. Further, ovine meniscus cells were successfully
cultured within these scaffolds over 4 weeks. Despite these positive
Tissue-derived materials comprise the final category of scaf- findings, a 3-fold GAG loss and non-uniform cell distributions were
folding currently being investigated for engineering the knee observed within the re-seeded scaffolds [222]. Decellularization of
meniscus. Tissue-derived materials include processed whole tissue human meniscus has also been performed [223]. This investigation
such as small intestinal submucosa (SIS), decellularized tissue or revealed that collagen structure within the meniscus was intact,
ECM (dECM), and silk. The hypothesis of using such materials is and mechanical properties were comparable to native tissue, after
a 2-week treatment with 2% sodium dodecyl sulfate (SDS) [223]. stimuli (mechanical or chemical/biochemical), and supporting
However, the use of SDS is associated with many detrimental side scaffolds (Fig. 5). Although the use of these three elements in
effects. Other work has shown that it is possible to remove the vast combination comprises the classical approach to engineering
majority of cellular DNA as well as the primary xenogeneic epitope replacement tissue, in recent years cell self-assembly has begun to
galactose-a-1,3-galactose, though significant GAG loss is also gain recognition and support in generation of functional cartilage,
observed with this procedure [224]. fibrocartilage, vasculature, and retina [226e231], (Fig. 6). In carti-
Despite their advantages, tissue-derived meniscus scaffolds lage and fibrocartilage, the self-assembly approach supersedes the
suffer from several drawbacks. Uniform cell infiltration and pres- need for scaffolds by seeding cells in very high density, possibly
ervation of mechanics and chief ECM components such as GAGs are promoting cellecell adhesion, cellematrix adhesion, and cellecell
two areas for future research. Additionally, biological and signaling; and encouraging cells to rapidly develop and integrate
mechanical performance after recellularization and in vivo into a matrix with quantifiable mechanical properties
implantation represent areas for further exploration. Some work [226,232,233]. Characterization of this process in articular chon-
has been done in this regard with devitalized rat menisci re-seeded drocytes shows high expression of N-cadherin during cell coales-
with BMSCs [220,225]. Constructs displayed cell migration and cence, followed by collagen VI pericellular matrix synthesis, and
increases in compressive stiffness over 4 weeks, but collagen and finally collagen II and GAG ECM synthesis [233].
GAG content was not assayed [220]. More work in this area needs to Obviating the need for a support scaffold conveys key tissue
be pursued. By bringing together some of the approaches reviewed engineering advantages. First, the natural synthesis of and adher-
above, it may be possible to resolve these problems. However, the ence to cartilage ECM as it develops bestows the most bioactive
bottlenecks of supply, sterilization, and standardization of tissue- microenvironment of any approach. Second, the all-biologic
derived scaffolds still need to be addressed for a large-scale tissue construct greatly increases likelihood of integration with host
engineering solution to be obtained. tissue. Third, since no material is completely biocompatible in
every use, the lack of a scaffold diminishes further contributions to
6. Scaffoldless self-assembly of tissue an immune response. Fourth, removal of any degradation products
minimizes potential toxicity and allows for greater cell viability.
The paradigm of tissue engineering has traditionally been Fifth, stress-shielding effects exerted by scaffolds are mitigated.
defined as the combination of replacement cells, cell-signaling More robust and homogeneous mechanical stimulation is possible
Fig. 5. The classical, scaffold-based approach for meniscus tissue engineering. Generation of a functional meniscus requires several key considerations. Characterization of the
meniscus is essential for establishing design parameters. Following this, judicious choice of cell type(s), scaffold material(s), and exogenous stimuli must be made. Implantation
in vivo may be substituted for, or performed subsequent to, bioreactor culture. Using these tools, tissue engineering aims to regenerate or replace the meniscus.
Fig. 6. The strategy of tissue self-assembly for meniscus tissue engineering. This approach utilizes a hydrogel mold to form completely biologic tissue constructs. Selection of cells is
of paramount importance. Following isolation from allogeneic or xenogeneic sources, articular chondrocytes (ACs) and meniscus cells (MCs) are expanded to achieve the high
numbers needed for robust tissue engineering. Mesenchymal stem cells, but also potentially embryonic stem cells, are a promising alternative cell source for subsequent differ-
entiation into meniscus cells. Cells are then seeded in high density in a non-adherent biomaterial mold, secreting ECM that coalesces into a continuous tissue over several days.
Exogenous stimuli are added during culture to increase the synthetic activity and functional properties of neotissue, which is eventually implanted in vivo.
during tissue development, which is particularly pertinent for articular cartilage has been shown to withstand hydrostatic pres-
engineering the knee meniscus. Sixth, since self-assembled tissue sures of up to 10 MPa and respond positively by increasing aggregate
has a continuous ECM, it may be more fully able to remodel itself in modulus (96%), Young’s modulus (92%), collagen per wet weight
response to catabolic exogenous agents such as chondroitinase ABC (51%) and GAG per wet weight (52%) [235]. A somewhat similar study
(C-ABC). of scaffold-free porcine chondrocyte constructs demonstrated
Indeed, self-assembled constructs have been shown to beneficial responses to direct compression stimulation at strain
respond well to treatment with exogenous agents [234e236]. A amplitudes of 5e20% [229]. Following this loading, 200e300%
meniscus tissue engineering study using bovine meniscus cells increases in construct stiffness and a 250% increase in Young’s
and articular chondrocytes found that treatment with TGF-b1 modulus was measured [229]. Since the knee meniscus is also loaded
and C-ABC led to a 196% increase in collagen per wet weight, in cyclic direct compression in vivo [43,239] these results are
a 136% increase in compressive instantaneous modulus, a 68% promising for tissue engineering of the meniscus using scaffold-free
increase in compressive relaxation modulus, a 600% increase in self-assembly.
circumferential tensile modulus, and a 500% increase in radial It is important to note that while this method is scaffold-free, it
tensile modulus [232]. Circumferential and radial tensile moduli is not devoid of the utilization of biomaterials. Agarose hydrogel
were also significantly different, mirroring prior results indi- plays an important role in the self-assembly process as a hydro-
cating anisotropic collagen fiber alignment in scaffoldless phobic negative mold used to prevent cellesubstrate adhesion
meniscus constructs [232,237]. It is thought that confinement during tissue coalescence. Interestingly, it has also been shown that
in circular agarose molds during self-assembly may allow for the compliance and surface roughness of this mold can alter the
the development of circumferential contractile forces on coa- biomechanical properties (strength, stiffness) and even biochem-
lescing neotissue, thus aiding in the development of tissue ical content (cellularity, collagen I/II, GAG) of self-assembled
anisotropy [237]. constructs [240]. It is possible that still other hydrogels and
Mechanical stimulation of scaffold-free and self-assembled tissue biomaterials may function to significantly modulate the quality of
has also shown promising results [229,232,238]. Self-assembled tissue formed from scaffold-free self-assembly.
7. Biochemical stimuli in meniscus tissue engineering of matrix proteins [102,103,232]. Since the ECM largely confers the
mechanical properties which underlie the primary functions of the
A large variety of biochemical stimuli have been applied in knee meniscus, this is particularly salient. An early study demon-
meniscus tissue engineering investigations. Growth factors are the strated increased proteoglycan synthesis of meniscus cells in
most prominent biochemical stimuli for tissue engineering the monolayer, explant, and scaffold culture when treated with TGF-b1
knee meniscus (Table 5). Overall, for meniscus cell proliferation, b- [103]. Increased cell proliferation was also observed, in only the
FGF in particular has been seen to elicit a strong response monolayer cultures [103]. Additionally, in scaffold and monolayer
[241e244]. One group studied the ability of nine growth factors studies comparing TGF-b1, IGF-1, b-FGF, and PDGF-AB, only TGF-b1
(EGF, b-FGF, TGF-a, PDGF-AB, a-FGF, TGF-b1, PDGF-AA, IGF-I, and stimulated significant simultaneous production of both collagens
NGF) to stimulate proliferation of meniscus cells in monolayer over and GAGs over controls [244,249]. TGF-b1 has also been seen to
4 days [241]. Of these nine, b-FGF, PDGF-AB, EGF, and TGF- upregulate the expression and secretion of lubricin, or superficial
a encouraged proliferation, with b-FGF inducing the greatest effect zone protein (SZP) [250]. This protein is thought to provide
[241]. These four growth factors also promoted increased collagen essential function to cartilage by aiding in lubrication. By contrast,
synthesis of meniscus cells [241]. Another study compared mono- the same study found that interleukin-1b decreased SZP protein
layer proliferation of meniscus cells from the different tissue content and gene expression [250]. Finally, TGF-b has also inter-
regions (inner/middle/outer) [245]. An up to 3-fold increase in DNA estingly been shown to inhibit meniscus cell proliferation [241].
synthesis was demonstrated when PDGF-AB, HGF, and BMP-2 were This highlights the proliferation/production interplay in which
applied to these cultured cells, while IGF-1 had no such effect [245]. meniscus cells are preferentially driven to one function or the other.
Interestingly, cells from different regions responded differently, One potentially important function of growth factors may be to
with BMP-2 having a slightly stronger effect on cells from the modulate matrix contraction. Both fibroblasts [251] and articular
middle zone, and HGF exerting a slightly stronger effect on cells chondrocytes [252] exert local contractile forces on their
from the inner zone [245]. The effects upon monolayer meniscus surrounding matrices. Contiguous tissue constructs may actually
cell migration were also examined. PDGF-AB and HGF stimulated benefit from controlled contraction, because ECM compaction and
migration in cells from all three zones of the meniscus, while EGF, alignment can lead to anisotropy and greater mechanical proper-
IGF-1, IL-1, and BMP-2 promoted cell migration only in specific ties. In fact, inhibition of fibroblast-mediated contraction has been
zones of the meniscus (outer and inner, middle and inner, outer and shown to disrupt development of tendon mechanical properties
middle, and only middle, respectively) [245]. [253]. Too much contraction, however, can render constructs of
Aside from proliferation and migration, another chief function of incorrect geometry [237]. However, the use of controlled contrac-
growth factors in meniscus tissue engineering is to stimulate tion as a biophysical means of modulating cartilage development is
matrix synthesis. The TGF-b family, regarded as one of the most relatively scarce in the literature. Both TGF-b1 and PDGF have been
important for cartilage tissue engineering [246e248], has repeat- documented as growth factors involved in encouraging matrix
edly demonstrated the ability to heighten meniscus cell synthesis contraction by meniscus cells, fibroblasts, and articular chon-
drocytes [232,254e256]. FGF-2 and IGF-1 can also induce articular
Table 5 chondrocyte-mediated contraction of collagen II/GAG gel scaffolds
Influence of selected growth factors administered to meniscus cells. [257]. The continued exploration of this topic may lead to inter-
Growth Effects Culture conditions
esting advances in the field.
Factor Phenotype maintenance or cell differentiation to fibrochon-
TGF-b1 [Y Proliferation Monolayer [103,241,242] drocytes is another vital application of growth factors in meniscus
[[ Collagen synthesis Monolayer [249]; scaffold [242,244]; tissue engineering. Relatively little work has been done in this area.
explant [290]; scaffoldless [232] However, it has been found that meniscus cell phenotype may be
[[ GAG/proteoglycan Monolayer [103,249];
salvaged by exposure to FGF-2 during monolayer expansion [258].
scaffold [103,244,291];
explant [103,290]; scaffoldless [232]
Subsequent 3-D pellet culture of FGF-2 exposed meniscus cells
[ SZP secretion Monolayer [250]; explants [250] revealed a 200-fold higher expression of collagen II and GAG than
[ Contraction Scaffold [255] controls [258]. Fibrochondrogenic differentiation of human
b-FGF [[[ Proliferation Monolayer [241e243]; scaffold [244] embryonic stem cells has also been performed [121]. CDMP-1 has
[ Collagen synthesis Monolayer [241,243]; scaffold [244] also been explored in a PGA scaffold modality to enhance fibro-
[ GAG/proteoglycan Monolayer [243,249]; explants [290] chondrogenesis of dermal fibroblasts [259], and has been demon-
PDGF-AB [[ Proliferation Monolayer [241,245]; strated to increase proteoglycan content and collagen II gene
scaffold [292]; explant [292] expression [260]. Lastly, exposure to TGF-b1 has also been sug-
[ Collagen synthesis Monolayer [241]; scaffold [242] gested to push meniscus fibrochondrocytes toward a more chon-
[ GAG/proteoglycan Monolayer [249]; explant [290]
drocytic phenotype [102]. Since meniscus fibrocartilage is a tissue
[ Contraction Scaffold [254]
[[ Migration Monolayer [245]; with varying regions, either similar to or distinct from the hyaline
scaffold [292]; explant [292] articular cartilage produced by chondrocytes, this is a relevant
result for prospective tissue engineers. These varying results
IGF-I [ Proliferation Monolayer [103,242];
scaffold [244] demonstrate considerable potential in, and promise for, further
[Y Collagen synthesis Monolayer [249]; scaffold [242] investigations of fibrochondrogenic differentiation of cells.
[ GAG/proteoglycan Explant [290] Chondroitinase ABC (C-ABC) is another biochemical stimuli that
[ Migration Monolayer [245]
has been employed in cartilage tissue engineering. This enzyme
EGF [ Proliferation Monolayer [241] cleaves chondroitin and dermatan sulfate from proteoglycan chains
[ Collagen synthesis Monolayer [241] while leaving collagen fibers unaffected [261,262]. It has been
[ Migration Monolayer [245]
suggested that a dynamic balance between the swelling pressure
HGF [[ Proliferation Monolayer [245]; scaffold [292]; caused by proteoglycans and the restraining strength of the
explant [292] collagen network exists [263]. Subsequently, it has been hypothe-
[[ Migration Monolayer [245]; scaffold [292];
explant [292]
sized that enzymatic depletion of cartilage GAG content (which is
afterward recovered by cellular synthesis) may facilitate increased
collagen network alignment and density, leading to heightened Direct compression stimulation of the meniscus has also been
tissue tensile properties [232,264e266]. Indeed, serum-free C-ABC pursued, although insufficient loading or excessive loading can be
treatment of tissue-engineered articular cartilage (in both self- detrimental. For example, static and dynamic loading regimens
assembled and agarose scaffold forms) has resulted in increased over 24 h using direct compression at 0.1 MPa and 0.08e0.16 MPa,
tensile properties versus untreated controls, as well as recovery of respectively, have been shown to decrease mRNA levels of type I
GAG content and compressive stiffness after 2e4 weeks of culture collagen, type II collagen, and decorin [273]. Furthermore, under
post-treatment [264e266]. The repeated beneficial results of C-ABC the same regimens, mRNA for ECM-degrading matrix
on tissue-engineered articular cartilage motivate its use for tissue metalloproteinase-1 (MMP-1) and collagenase were both upregu-
engineering meniscus fibrocartilage. Along these lines, self- lated [273]. Similarly, dynamic compression of porcine meniscus
assembled meniscus constructs (composed of meniscus cells and explants (24 h, 0.1 MPa, 0.5 Hz) has been demonstrated to upre-
articular chondrocytes) treated with C-ABC have been seen to gulate production of nitric oxide, a potent signaling molecule
display approximate 2- to 3-fold increases in tensile modulus over implicated in arthritis and meniscus degeneration [274]. Thus, the
untreated controls and GAG recovery after 3 weeks of culture post- use of incorrect loading regimen parameters can lead to matrix and
treatment [232]. However, more studies using C-ABC for meniscus tissue degradation.
tissue engineering, especially in conjunction with other stimuli, are By contrast, certain other loading regimens have shown bene-
necessary. ficial effects. Physiological loads on the meniscus in vivo may
Biochemical stimulus selection is not clear-cut, and the study of exceed 1000 N [39], and it is believed this compressive loading
multiple agents (especially growth factors) in conjunction necessi- helps facilitate nutrientewaste exchange in the otherwise
tates additional investigations. Culture conditions play a non-trivial transport-limited and avascular meniscus. For example, it has been
role in modulating cell responses to biochemical stimulus adminis- shown that tensile loading of meniscus cells can suppress the
tration, whether the treated tissue is arranged in monolayer, scaffold, production of inflammatory factors [275]. Further, dynamic
explant, or self-assembled form. The presence of serum in the media compression (2% oscillatory strain, 1 Hz, 1 min on/1 min off duty
of a study is also a critical variable [245,267]. Futures studies may cycle, 4 h per day for 4 days) of meniscus explants has been
focus on unconventional growth factors, such as the serum-derived reported to increase aggrecan expression compared to statically
phospholipid agent lysophosphatidic acid (LPA). LPA is naturally compressed samples [276]. A longer duration loading regimen
present in mammalian sera at concentrations ranging from 1 to 5 mM (0.1 MPa, 0.5 Hz, for 24 h) has also been shown to increase protein
[268], and has been studied extensively as an anti-apoptotic factor. (68%) and proteoglycan (58%) synthesis in meniscal explants [277].
Other potent agents may be derived from platelet-rich plasma, which Dynamic compression has also yielded other positive results in
has been shown to increase matrix deposition and proliferation of anatomically shaped alginate scaffolds containing bovine meniscus
meniscus cells cultured in monolayer [269]. Finally, although fibro- cells [278]. The investigated loading regimen (7e15% strain, 1 Hz,
cartilage is a particularly important soft tissue, research into its 1 h on/1 hr off duty cycle, 3 h per day, 3 days per week for 6 weeks)
generation with biochemical stimuli is nascent, and thus future work applied to meniscus constructs yielded increases in compressive
along these lines may produce significant medical advances. Much equilibrium modulus and GAG content after 2 weeks, and decreases
remains to be studied concerning biochemical stimuli used in tissue in these values but increases in collagen content after 6 weeks
engineering the knee meniscus. [278]. These results under different loading regimens highlight the
varied biosynthetic responses that may occur following mechanical
8. Mechanical stimulation for meniscus tissue engineering stimulus, and encourage the pursuit of additional research.
Of all of the factors being integrated to achieve successful
Meniscus cells may respond positively to mechanical stimuli by engineering of the knee meniscus, mechanical stimulation is
enhancing the fibrocartilage ECM, or negatively by secreting perhaps the one with the highest ambiguity and largest opportu-
matrix-degrading or inflammatory factors. The mechanical prop- nity for improvement. Interestingly, while shear is generally
erties of the matrix can be enhanced through three general thought of as detrimental to the chondrocyte phenotype, oscilla-
mechanisms: deposition, alignment, or compaction. To achieve tory fluid flow has been shown to upregulate calcium signaling and
these results, there are several possible methods of stimulating GAG production of meniscus cells in parallel plate flow chambers
meniscus tissue. These include high and low shear, fluid perfusion, [279]. The use of shear and other forces to generate fibrocartilage
hydrostatic pressure, direct compression, and even ultrasound. may yield benefits for meniscus tissue engineering in the future.
However, most current efforts are centered on hydrostatic pressure Due to the large amount of variable parameters (method, time of
and direct compression stimulation. application, magnitude, duration, and frequency of stimulation) the
Explant and engineered tissue can demonstrate varied remod- optimal and most dramatic combination of effects for mechanical
eling responses to hydrostatic pressure. For instance, leporine stimuli likely remains undiscovered.
meniscal explants subjected to cyclic hydrostatic pressure at 1 MPa,
0.5 Hz, for 1 min on/14 min off over 4 h, have been shown to 9. Conclusions and future directions
upregulate inflammatory factors and matrix degradation proteins
[270]. In contrast, leporine meniscus cells seeded in PLLA constructs This review has provided an account of current concepts in
and stimulated with hydrostatic pressure at 10 MPa statically for meniscus pathology and repair, as well as meniscus tissue engi-
1 h every 3 days exhibited beneficial responses [271]. In these neering. Undoubtedly, the need for effective therapies based on
constructs, collagen and GAG content, as well as compressive tissue engineering approaches is exceedingly high. The driving
properties, were all significantly higher than control or dynamic factors for this are high incidences of meniscal lesions amongst
hydrostatic pressure regimens run at 0.1 or 1 Hz [271]. Further- several age groups in the general population and significant defi-
more, when combined with TGF-b1, hydrostatic pressure stimula- ciencies associated with current repair techniques. Secondary to
tion of leporine meniscal cell-seeded PLLA constructs displayed these factors are degenerative changes in articular cartilage, which
additive increases in collagen and GAG deposition as well as lead to osteoarthritis and generate considerable socioeconomic
a synergistic increase in compressive properties [272]. These results costs for healthcare systems worldwide. Tissue engineering aims to
demonstrate the various responses meniscus cells may mount in ameliorate these problems by establishing new meniscus repair
response to hydrostatic pressure. techniques that, for example, can yield constructs that restore
mechanical function by integrating with or replacing the patient’s problem may be emerging from the collaborative efforts of
tissue. Apart from its potential clinical benefit, a tissue-engineered biomedical engineers, clinicians, and industry leaders.
meniscus can also be of great use in the study of developmental,
regenerative, and degenerative processes in the knee. Conflicts of interest
Despite considerable diversity amongst current strategies for
tissue engineering the meniscus, several important design princi- The authors have no conflicts of interest to disclose.
ples are emerging. In general, these principles relate to a biomi-
metic approach to generating replacement meniscus tissue by
Acknowledgements
recapitulating biological, structural, and functional features of the
native meniscus. First, cells in replacement tissue must possess
The authors would like to acknowledge support from the
a similar phenotype to those found in native meniscus. This dictates
following grant: NIH R01 AR047839.
the presence of both fibroblast-like and chondrocyte-like cells. In
cases of total meniscus replacement, this may also include vascu-
larization in the outer periphery. Second, the biochemical content References
in the meniscus (i.e., collagen, GAGs) should closely mirror the
[1] Fairbank TJ. Knee joint changes after meniscectomy. J Bone Joint Surg Br
regional variation displayed natively. This design principle will 1948;30B:664e70.
follow naturally from the use of cells with appropriate phenotypes. [2] Gillquist J, Hamberg P, Lysholm J. Endoscopic partial and total meniscectomy.
Third, functional anisotropy must be manifest in an engineered A comparative study with a short term follow up. Acta Orthop Scand 1982;
53:975e9.
meniscus. Functional anisotropy of mechanical properties may in [3] Milachowski KA, Weismeier K, Wirth CJ. Homologous meniscus trans-
turn be recapitulated from the presence of appropriate ECM plantation. Experimental and clinical results. Int Orthop 1989;13:1e11.
content. Taken together, these principles of tissue engineering [4] Turman KA, Diduch DR. Meniscal repair: indications and techniques. J Knee
Surg 2008;21:154e62.
using biomimicry may guide tissue engineers to generating a fully [5] DeHaven KE. Meniscus repair. Am J Sports Med 1999;27:242e50.
functional meniscus. [6] Noyes FR, Barber-Westin SD. Repair of complex and avascular meniscal tears
To achieve these goals, several strategies have been proposed, and meniscal transplantation. J Bone Joint Surg Am 2010;92:1012e29.
[7] Kohn D, Moreno B. Meniscus insertion anatomy as a basis for meniscus
with mixed results. Several cell sources have been studied for replacement: a morphological cadaveric study. Arthroscopy 1995;11:96e103.
meniscus engineering, including autologous, allogeneic, xenoge- [8] Kusayama T, Harner CD, Carlin GJ, Xerogeanes JW, Smith BA. Anatomical and
neic, and stem cells. Yet, amongst these, no specific cell source has biomechanical characteristics of human meniscofemoral ligaments. Knee
Surg Sports Traumatol Arthrosc 1994;2:234e7.
been established, although stem cells are particularly promising.
[9] Ghadially FN, Thomas I, Yong N, Lalonde JM. Ultrastructure of rabbit semi-
Whilst the various categories of biomaterial scaffolds offer different lunar cartilages. J Anat 1978;125:499e517.
advantages, no approach currently addresses all three fundamental [10] McDermott ID, Sharifi F, Bull AM, Gupte CM, Thomas RW, Amis AA. An
requirements of a successful meniscus tissue replacement (satis- anatomical study of meniscal allograft sizing. Knee Surg Sports Traumatol
Arthrosc 2004;12:130e5.
factory mechanics, bioactivity, and logistics). In this field, a scaf- [11] Shaffer B, Kennedy S, Klimkiewicz J, Yao L. Preoperative sizing of meniscal
foldless self-assembly process utilizing a biomaterial mold is allografts in meniscus transplantation. Am J Sports Med 2000;28:524e33.
another potentially effective strategy for meniscus tissue engi- [12] Greis PE, Bardana DD, Holmstrom MC, Burks RT. Meniscal injury: I. Basic
science and evaluation. J Am Acad Orthop Surg 2002;10:168e76.
neering that largely fulfills some of the above criteria. However, and [13] Clark CR, Ogden JA. Development of the menisci of the human knee joint.
perhaps more importantly, it lacks complications associated with Morphological changes and their potential role in childhood meniscal injury.
scaffolds such as integration, degradation, biocompatibility, and J Bone Joint Surg Am 1983;65:538e47.
[14] Arnoczky SP, Warren RF. Microvasculature of the human meniscus. Am J
stress shielding. In addition to these approaches, the use of syner- Sports Med 1982;10:90e5.
gistic biochemical and biomechanical stimuli are fundamental to [15] Herwig J, Egner E, Buddecke E. Chemical changes of human knee joint
the creation of functional tissue. Thus, based on these advantages, menisci in various stages of degeneration. Ann Rheum Dis 1984;43:635e40.
[16] Proctor CS, Schmidt MB, Whipple RR, Kelly MA, Mow VC. Material properties
the self-assembly process may provide sufficient flexibility to lead
of the normal medial bovine meniscus. J Orthop Res 1989;7:771e82.
to functional tissue-engineered meniscus constructs. [17] Sweigart MA, Athanasiou KA. Toward tissue engineering of the knee
Even though the existing studies in meniscus tissue engineering meniscus. Tissue Eng 2001;7:111e29.
[18] McDevitt CA, Webber RJ. The ultrastructure and biochemistry of meniscal
show promising results, research needs to progress further. At the
cartilage. Clin Orthop Relat Res 1992;252:8e18.
basic level, more long-term scaffold and scaffoldless studies aimed [19] Cheung HS. Distribution of type I, II, III and V in the pepsin solubilized
at improving mechanical properties and matching them to tissue collagens in bovine menisci. Connect Tissue Res 1987;16:343e56.
need to be undertaken. Especially vital is the avoidance of scaffold [20] Ghosh P, Taylor TK. The knee joint meniscus. A fibrocartilage of some
distinction. Clin Orthop Relat Res 1987;224:52e63.
degradation before mechanically competent tissue can be formed. [21] Yanagishita M. Function of proteoglycans in the extracellular matrix. Acta
In line with this, seeded cells must be encouraged to maintain their Pathol Jpn 1993;43:283e93.
phenotype and synthetic capacity in a scaffold. Additionally, the [22] Scott PG, Nakano T, Dodd CM. Isolation and characterization of small
proteoglycans from different zones of the porcine knee meniscus. Biochim
reproducibility of engineered tissue needs to be established. Going Biophys Acta 1997;1336:254e62.
a step further, experimental (animal) studies and well-designed [23] Adams ME, Muir H. The glycosaminoglycans of canine menisci. Biochem J
prospective, randomized, and controlled clinical trials with long- 1981;197:385e9.
[24] Miller RR, McDevitt CA. Thrombospondin in ligament, meniscus and inter-
term quantitative outcome measurement are key to in vivo evalu- vertebral disc. Biochim Biophys Acta 1991;1115:85e8.
ation of research in this field. The outlining of indications and [25] Nakata K, Shino K, Hamada M, Mae T, Miyama T, Shinjo H, et al. Human
contraindications, the selection of suitable patients for tissue repair meniscus cell: characterization of the primary culture and use for tissue
engineering. Clin Orthop Relat Res 2001;391:S208e18.
with engineered meniscus, and the establishment of specialized [26] Mcdevitt CA, Mukherjee S, Kambic H, Parker R. Emerging concepts of the cell
surgical techniques are therefore necessary. Moreover, the devel- biology of the meniscus. Curr Opin Orthop 2002;13:345e50.
opment of non-invasive assessment procedures for generated [27] Melrose J, Smith S, Cake M, Read R, Whitelock J. Comparative spatial and
temporal localisation of perlecan, aggrecan and type I, II and IV collagen in
tissue, both pre-implantation and post-implantation, is required.
the ovine meniscus: an ageing study. Histochem Cell Biol 2005;124:225e35.
Directions for future research should also be guided by minimiza- [28] Hellio Le Graverand MP, Ou Y, Schield-Yee T, Barclay L, Hart D, Natsume T,
tion of healthcare costs. These essential goals will be pivotal to the et al. The cells of the rabbit meniscus: their arrangement, interrelationship,
potential widespread clinical application of tissue-engineered morphological variations and cytoarchitecture. J Anat 2001;198:525e35.
[29] Van der Bracht H, Verdonk R, Verbruggen G, Elewaut D, Verdonk P. Cell-
meniscus. Although the challenge is vast, recent scientific based meniscus tissue engineering. In: Ashammakhi N, Reis R, Chiellini E,
advances suggest that a solution to this as-of-yet intractable editors. Topics in tissue engineering, vol. 3; 2007.
[30] Cameron HU, Macnab I. The structure of the meniscus of the human knee [63] Terzidis IP, Christodoulou A, Ploumis A, Givissis P, Natsis K, Koimtzis M.
joint. Clin Orthop Relat Res 1972;89:215e9. Meniscal tear characteristics in young athletes with a stable knee: arthro-
[31] Newman AP, Anderson DR, Daniels AU, Dales MC. Mechanics of the healed scopic evaluation. Am J Sports Med 2006;34:1170e5.
meniscus in a canine model. Am J Sports Med 1989;17:164e75. [64] Schmitz MA, Rouse Jr LM, DeHaven KE. The management of meniscal tears in
[32] Zhu W, Chern KY, Mow VC. Anisotropic viscoelastic shear properties of the ACL-deficient knee. Clin Sports Med 1996;15:573e93.
bovine meniscus. Clin Orthop Relat Res 1994;306:34e45. [65] Smith 3rd JP, Barrett GR. Medial and lateral meniscal tear patterns in anterior
[33] Tissakht M, Ahmed AM, Chan KC. Calculated stress-shielding in the distal cruciate ligament-deficient knees. A prospective analysis of 575 tears. Am J
femur after total knee replacement corresponds to the reported location of Sports Med 2001;29:415e9.
bone loss. J Orthop Res 1996;14:778e85. [66] Duncan JB, Hunter R, Purnell M, Freeman J. Meniscal injuries associated with
[34] Hoshino A, Wallace WA. Impact-absorbing properties of the human knee. acute anterior cruciate ligament tears in alpine skiers. Am J Sports Med 1995;
J Bone Joint Surg Br 1987;69:807e11. 23:170e2.
[35] Radin EL, de Lamotte F, Maquet P. Role of the menisci in the distribution of [67] Weinstabl R, Muellner T, Vecsei V, Kainberger F, Kramer M. Economic
stress in the knee. Clin Orthop Relat Res 1984;185:290e4. considerations for the diagnosis and therapy of meniscal lesions: can
[36] Walker PS, Erkman MJ. The role of the menisci in force transmission across magnetic resonance imaging help reduce the expense? World J Surg 1997;
the knee. Clin Orthop Relat Res 1975;109:184e92. 21:363e8.
[37] Sweigart MA, Zhu CF, Burt DM, DeHoll PD, Agrawal CM, Clanton TO, et al. [68] Konan S, Rayan F, Haddad FS. Do physical diagnostic tests accurately detect
Intraspecies and interspecies comparison of the compressive properties of meniscal tears? Knee Surg Sports Traumatol Arthrosc 2009;17:806e11.
the medial meniscus. Ann Biomed Eng 2004;32:1569e79. [69] Karachalios T, Hantes M, Zibis AH, Zachos V, Karantanas AH, Malizos KN.
[38] Fithian DC, Kelly MA, Mow VC. Material properties and structureefunction Diagnostic accuracy of a new clinical test (the Thessaly test) for early
relationships in the menisci. Clin Orthop Relat Res 1990;252:19e31. detection of meniscal tears. J Bone Joint Surg Am 2005;87:955e62.
[39] Fukubayashi T, Kurosawa H. The contact area and pressure distribution [70] Howell GED. Clinical presentation of the knee. In: Bulstrode CJK,
pattern of the knee. A study of normal and osteoarthrotic knee joints. Acta Buckwalter J, Carr A, Marsh L, Fairbank J, Wilson-MacDonald J, Bouden G,
Orthop Scand 1980;51:871e9. editors. Oxford textbook of orthopedics and trauma, Vol. 2. New York:
[40] Ahmed AM, Burke DL. In-vitro measurement of static pressure distribution in Oxford University Press; 2002. p. 1108e13.
synovial joints e part I: tibial surface of the knee. J Biomech Eng 1983;105: [71] Starke C, Kopf S, Petersen W, Becker R. Meniscal repair. Arthroscopy 2009;
216e25. 25:1033e44.
[41] Walker PS, Hajek JV. The load-bearing area in the knee joint. J Biomech 1972; [72] Eggli S, Wegmuller H, Kosina J, Huckell C, Jakob RP. Long-term results of
5:581e9. arthroscopic meniscal repair. An analysis of isolated tears. Am J Sports Med
[42] Paletta Jr GA, Manning T, Snell E, Parker R, Bergfeld J. The effect of allograft 1995;23:715e20.
meniscal replacement on intraarticular contact area and pressures in the [73] Warren RF. Arthroscopic meniscus repair. Arthroscopy 1985;1:170e2.
human knee. A biomechanical study. Am J Sports Med 1997;25:692e8. [74] Hanks GA, Gause TM, Sebastianelli WJ, O’Donnell CS, Kalenak A. Repair of
[43] Kurosawa H, Fukubayashi T, Nakajima H. Load-bearing mode of the knee peripheral meniscal tears: open versus arthroscopic technique. Arthroscopy
joint: physical behavior of the knee joint with or without menisci. Clin 1991;7:72e7.
Orthop Relat Res 1980;149:283e90. [75] Miller Jr DB. Arthroscopic meniscus repair. Am J Sports Med 1988;16:315e20.
[44] Seedhom BB, Hargreaves DJ. Transmission of the load in the knee joint with [76] Barber FA, Coons DA, Ruiz-Suarez M. Meniscal repair with the RapidLoc
special reference to the role of the menisci part II: experimental results, meniscal repair device. Arthroscopy 2006;22:962e6.
discussion, and conclusions. Eng Med Biol 1979;8:220e8. [77] Arnoczky SP, Warren RF. The microvasculature of the meniscus and its
[45] Morgan CD, Wojtys EM, Casscells CD, Casscells SW. Arthroscopic meniscal response to injury. An experimental study in the dog. Am J Sports Med 1983;
repair evaluated by second-look arthroscopy. Am J Sports Med 1991;19: 11:131e41.
632e7. [78] Zhang ZN, Tu KY, Xu YK, Zhang WM, Liu ZT, Ou SH. Treatment of longitudinal
[46] Salata MJ, Gibbs AE, Sekiya JK. A systematic review of clinical outcomes in injuries in avascular area of meniscus in dogs by trephination. Arthroscopy
patients undergoing meniscectomy. Am J Sports Med 2010;38:1907e16. 1988;4:151e9.
[47] Baker BE, Peckham AC, Pupparo F, Sanborn JC. Review of meniscal injury and [79] Andersson-Molina H, Karlsson H, Rockborn P. Arthroscopic partial and total
associated sports. Am J Sports Med 1985;13:1e4. meniscectomy: a long-term follow-up study with matched controls.
[48] Hede A, Jensen DB, Blyme P, Sonne-Holm S. Epidemiology of meniscal lesions Arthroscopy 2002;18:183e9.
in the knee. 1,215 Open operations in Copenhagen 1982e84. Acta Orthop [80] Roos EM, Ostenberg A, Roos H, Ekdahl C, Lohmander LS. Long-term outcome
Scand 1990;61:435e7. of meniscectomy: symptoms, function, and performance tests in patients
[49] Steinbruck K Epidemiology of sports injuries e 25-year-analysis of sports with or without radiographic osteoarthritis compared to matched controls.
orthopedic-traumatologic ambulatory care. Sportverletz Sportschaden 1999; Osteoarthritis Cartilage 2001;9:316e24.
13:38e52. [81] Barrett GR, Field MH, Treacy SH, Ruff CG. Clinical results of meniscus repair in
[50] Steinbruck K Epidemiology of sports injuries. A 15 year analysis of sports patients 40 years and older. Arthroscopy 1998;14:824e9.
orthopedic ambulatory care. Sportverletz Sportschaden 1999;13:38e52. [82] Englund M, Guermazi A, Gale D, Hunter DJ, Aliabadi P, Clancy M, et al.
[51] Noble J, Hamblen DL. The pathology of the degenerate meniscus lesion. Incidental meniscal findings on knee MRI in middle-aged and elderly
J Bone Joint Surg Br 1975;57:180e6. persons. N Engl J Med 2008;359:1108e15.
[52] Rubman MH, Noyes FR, Barber-Westin SD. Arthroscopic repair of meniscal [83] Englund M, Niu J, Guermazi A, Roemer FW, Hunter DJ, Lynch JA, et al. Effect
tears that extend into the avascular zone. A review of 198 single and of meniscal damage on the development of frequent knee pain, aching, or
complex tears. Am J Sports Med 1998;26:87e95. stiffness. Arthritis Rheum 2007;56:4048e54.
[53] Kimura M, Shirakura K, Hasegawa A, Kobuna Y, Niijima M. Second look [84] Kornaat PR, Bloem JL, Ceulemans RY, Riyazi N, Rosendaal FR, Nelissen RG,
arthroscopy after meniscal repair. Factors affecting the healing rate. Clin et al. Osteoarthritis of the knee: association between clinical features and MR
Orthop Relat Res 1995;314:185e91. imaging findings. Radiology 2006;239:811e7.
[54] Horibe S, Shino K, Nakata K, Maeda A, Nakamura N, Matsumoto N. Second- [85] Bhattacharyya T, Gale D, Dewire P, Totterman S, Gale ME, McLaughlin S, et al.
look arthroscopy after meniscal repair. Review of 132 menisci repaired by an The clinical importance of meniscal tears demonstrated by magnetic reso-
arthroscopic inside-out technique. J Bone Joint Surg Br 1995;77:245e9. nance imaging in osteoarthritis of the knee. J Bone Joint Surg Am 2003;85-A:
[55] Kurosaka M, Yoshiya S, Kuroda R, Matsui N, Yamamoto T, Tanaka J. Repeat 4e9.
tears of repaired menisci after arthroscopic confirmation of healing. J Bone [86] DeHaven KE, Lintner DM. Athletic injuries: comparison by age, sport, and
Joint Surg Br 2002;84:34e7. gender. Am J Sports Med 1986;14:218e24.
[56] Beaufils P, Bastos R, Wakim E, Cho SH, Petit-Jouvet C Meniscal injury in the [87] Kocher MS, Micheli LJ. The pediatric knee: evaluation and treatment. Surgery
plastic reconstruction of the anterior cruciate ligament. Meniscal suture or of the knee. 3rd ed. New York: Churchill-Livingstone; 2001. p. 1356e97.
abstention. Rev Chir Orthop Reparatrice Appar Mot 1992;78:285e91. [88] Maffulli N, Chan KM, Bundoc RC, Cheng JC. Knee arthroscopy in Chinese
[57] Scott GA, Jolly BL, Henning CE. Combined posterior incision and arthroscopic children and adolescents: an eight-year prospective study. Arthroscopy
intra-articular repair of the meniscus. An examination of factors affecting 1997;13:18e23.
healing. J Bone Joint Surg Am 1986;68:847e61. [89] Angel KR, Hall DJ. The role of arthroscopy in children and adolescents.
[58] Stone RG, Frewin PR, Gonzales S. Long-term assessment of arthroscopic Arthroscopy 1989;5:192e6.
meniscus repair: a two- to six-year follow-up study. Arthroscopy 1990;6: [90] Robert M, Gouault E, Moulies D, Alain JL Meniscal lesions in the child athlete.
73e8. Acta Orthop Belg 1986;52:72e80.
[59] DeHaven KE, Collins HR. Diagnosis of internal derangements of the knee. The [91] Kramer DE, Micheli LJ. Meniscal tears and discoid meniscus in children:
role of arthroscopy. J Bone Joint Surg Am 1975;57:802e10. diagnosis and treatment. J Am Acad Orthop Surg 2009;17:698e707.
[60] Daniel D, Daniels E, Aronson D. The diagnosis of meniscus pathology. Clin [92] McDermott MJ, Bathgate B, Gillingham BL, Hennrikus WL. Correlation of MRI
Orthop Relat Res 1982;163:218e24. and arthroscopic diagnosis of knee pathology in children and adolescents.
[61] Noyes FR, Barber-Westin SD. Meniscus tears: diagnosis, repair techniques, J Pediatr Orthop 1998;18:675e8.
clinical outcomes. In: Noyes FR, Barber-Westin SD, editors. Noyes’ knee [93] Takeda Y, Ikata T, Yoshida S, Takai H, Kashiwaguchi S. MRI high-signal
disorders: surgery, rehabilitation, clinical outcomes. Philadelphia: Saunders; intensity in the menisci of asymptomatic children. J Bone Joint Surg Br
2009. p. 733e71. 1998;80:463e7.
[62] Rosas HG, De Smet AA. Magnetic resonance imaging of the meniscus. Top [94] Scott WN, Rubinstein M. Posterior stabilized knee arthroplasty. Six years’
Magn Reson Imaging 2009;20:151e73. experience. Clin Orthop Relat Res 1986;205:138e45.
[95] Cannon Jr WD, Vittori JM. The incidence of healing in arthroscopic meniscal [125] Zvaifler NJ, Marinova-Mutafchieva L, Adams G, Edwards CJ, Moss J, Burger JA,
repairs in anterior cruciate ligament-reconstructed knees versus stable et al. Mesenchymal precursor cells in the blood of normal individuals.
knees. Am J Sports Med 1992;20:176e81. Arthritis Res 2000;2:477e88.
[96] Anderson AF. Transepiphyseal replacement of the anterior cruciate ligament [126] Caplan AI. Adult mesenchymal stem cells for tissue engineering versus
in skeletally immature patients. A preliminary report. J Bone Joint Surg Am regenerative medicine. J Cell Physiol 2007;213:341e7.
2003;85-A:1255e63. [127] Nerurkar NL, Sen S, Baker BM, Elliott DM, Mauck RL. Dynamic culture
[97] Bloome DM, Blevins FT, Paletta Jr GA, Newcomer JK, Cashmore B, Turker R. enhances stem cell infiltration and modulates extracellular matrix production
Meniscal repair in very young children. Arthroscopy 2000;16:545e9. on aligned electrospun nanofibrous scaffolds. Acta Biomater 2011;7:485e91.
[98] Mintzer CM, Richmond JC, Taylor J. Meniscal repair in the young athlete. Am J [128] Kopf S, Birkenfeld F, Becker R, Petersen W, Starke C, Wruck CJ, et al. Local
Sports Med 1998;26:630e3. treatment of meniscal lesions with vascular endothelial growth factor. J Bone
[99] Marsano A, Vunjak-Novakovic G, Martin I. Towards tissue engineering of Joint Surg Am 2010;92:2682e91.
meniscus substitutes: selection of cell source and culture environment. Conf [129] Forriol F. Growth factors in cartilage and meniscus repair. Injury 2009;40:
Proc IEEE Eng Med Biol Soc 2006;1:3656e8. S12e6.
[100] Kon E, Chiari C, Marcacci M, Delcogliano M, Salter DM, Martin I, et al. Tissue [130] Muschler GF, Nakamoto C, Griffith LG. Engineering principles of clinical cell-
engineering for total meniscal substitution: animal study in sheep model. based tissue engineering. J Bone Joint Surg Am 2004;86-A:1541e58.
Tissue Eng Part A 2008;14:1067e80. [131] Uchio Y, Ochi M, Adachi N, Kawasaki K, Iwasa J. Results of rasping of meniscal
[101] Martinek V, Ueblacker P, Braun K, Nitschke S, Mannhardt R, Specht K, et al. tears with and without anterior cruciate ligament injury as evaluated by
Second generation of meniscus transplantation: in-vivo study with tissue- second-look arthroscopy. Arthroscopy 2003;19:463e9.
engineered meniscus replacement. Arch Orthop Trauma Surg 2006;126: [132] Zhang Z, Arnold JA, Williams T, McCann B. Repairs by trephination and
228e34. suturing of longitudinal injuries in the avascular area of the meniscus in
[102] Tanaka T, Fujii K, Kumagae Y. Comparison of biochemical characteristics of goats. Am J Sports Med 1995;23:35e41.
cultured fibrochondrocytes isolated from the inner and outer regions of [133] Gershuni DH, Skyhar MJ, Danzig LA, Camp J, Hargens AR, Akeson WH.
human meniscus. Knee Surg Sports Traumatol Arthrosc 1999;7:75e80. Experimental models to promote healing of tears in the avascular segment of
[103] Collier S, Ghosh P. Effects of transforming growth factor beta on proteo- canine knee menisci. J Bone Joint Surg Am 1989;71:1363e70.
glycan synthesis by cell and explant cultures derived from the knee joint [134] Yamazaki K, Tachibana Y. Vascularized synovial flap promoting regeneration
meniscus. Osteoarthritis Cartilage 1995;3:127e38. of the cryopreserved meniscal allograft: experimental study in rabbits.
[104] Gunja NJ, Athanasiou KA. Passage and reversal effects on gene expression of J Orthop Sci 2003;8:62e8.
bovine meniscal fibrochondrocytes. Arthritis Res Ther 2007;9:R93. [135] Kobuna Y, Shirakura K, Niijima M. Meniscal repair using a flap of synovium.
[105] Peretti GM, Caruso EM, Randolph MA, Zaleske DJ. Meniscal repair using An experimental study in the dog. Am J Knee Surg 1995;8:52e5.
engineered tissue. J Orthop Res 2001;19:278e85. [136] Sethi PM, Cooper A, Jokl P. Technical tips in orthopaedics: meniscal repair
[106] Peretti GM, Gill TJ, Xu JW, Randolph MA, Morse KR, Zaleske DJ. Cell-based with use of an in situ fibrin clot. Arthroscopy 2003;19:E44.
therapy for meniscal repair: a large animal study. Am J Sports Med 2004;32: [137] van Trommel MF, Simonian PT, Potter HG, Wickiewicz TL. Arthroscopic
146e58. meniscal repair with fibrin clot of complete radial tears of the lateral
[107] Darling EM, Athanasiou KA. Rapid phenotypic changes in passaged articular meniscus in the avascular zone. Arthroscopy 1998;14:360e5.
chondrocyte subpopulations. J Orthop Res 2005;23:425e32. [138] Henning CE, Lynch MA, Yearout KM, Vequist SW, Stallbaumer RJ, Decker KA.
[108] Weinand C, Peretti GM, Adams Jr SB, Randolph MA, Savvidis E, Gill TJ. Arthroscopic meniscal repair using an exogenous fibrin clot. Clin Orthop
Healing potential of transplanted allogeneic chondrocytes of three different Relat Res 1990;252:64e72.
sources in lesions of the avascular zone of the meniscus: a pilot study. Arch [139] Izuta Y, Ochi M, Adachi N, Deie M, Yamasaki T, Shinomiya R. Meniscal repair
Orthop Trauma Surg 2006;126:599e605. using bone marrow-derived mesenchymal stem cells: experimental study
[109] Weinand C, Peretti GM, Adams Jr SB, Bonassar LJ, Randolph MA, Gill TJ. An using green fluorescent protein transgenic rats. Knee 2005;12:217e23.
allogenic cell-based implant for meniscal lesions. Am J Sports Med 2006;34: [140] Abdel-Hamid M, Hussein MR, Ahmad AF, Elgezawi EM. Enhancement of the
1779e89. repair of meniscal wounds in the red-white zone (middle third) by the
[110] Ramallal M, Maneiro E, Lopez E, Fuentes-Boquete I, Lopez-Armada MJ, Fer- injection of bone marrow cells in canine animal model. Int J Exp Pathol 2005;
nandez-Sueiro JL, et al. Xeno-implantation of pig chondrocytes into rabbit to 86:117e23.
treat localized articular cartilage defects: an animal model. Wound Repair [141] Pabbruwe MB, Kafienah W, Tarlton JF, Mistry S, Fox DJ, Hollander AP. Repair
Regen 2004;12:337e45. of meniscal cartilage white zone tears using a stem cell/collagen-scaffold
[111] Yan H, Yu C. Repair of full-thickness cartilage defects with cells of different implant. Biomaterials 2010;31:2583e91.
origin in a rabbit model. Arthroscopy 2007;23:178e87. [142] Nerurkar NL, Han W, Mauck RL, Elliott DM. Homologous structure-function
[112] Revell CM, Athanasiou KA. Success rates and immunologic responses of relationships between native fibrocartilage and tissue-engineered from
autogenic, allogenic, and xenogenic treatments to repair articular cartilage MSC-seeded nanofibrous scaffolds. Biomaterials 2011;32:461e8.
defects. Tissue Eng Part B Rev 2009;15:1e15. [143] Zellner J, Mueller M, Berner A, Dienstknecht T, Kujat R, Nerlich M, et al. Role
[113] Pittenger MF, Martin BJ. Mesenchymal stem cells and their potential as of mesenchymal stem cells in tissue engineering of meniscus. J Biomed
cardiac therapeutics. Circ Res 2004;95:9e20. Mater Res A 2010;94:1150e61.
[114] Pelttari K, Steck E, Richter W. The use of mesenchymal stem cells for [144] Shi S, Gronthos S, Chen S, Reddi A, Counter CM, Robey PG, et al. Bone
chondrogenesis. Injury 2008;39:S58e65. formation by human postnatal bone marrow stromal stem cells is enhanced
[115] Angele P, Johnstone B, Kujat R, Zellner J, Nerlich M, Goldberg V, et al. Stem by telomerase expression. Nat Biotechnol 2002;20:587e91.
cell based tissue engineering for meniscus repair. J Biomed Mater Res A [145] Simonsen JL, Rosada C, Serakinci N, Justesen J, Stenderup K, Rattan SI, et al.
2008;85:445e55. Telomerase expression extends the proliferative life-span and maintains the
[116] Anderson DG, Risbud MV, Shapiro IM, Vaccaro AR, Albert TJ. Cell-based osteogenic potential of human bone marrow stromal cells. Nat Biotechnol
therapy for disc repair. Spine J 2005;5:297Se303S. 2002;20:592e6.
[117] Hoben GM, Koay EJ, Athanasiou KA. Fibrochondrogenesis in two embryonic [146] Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains.
stem cell lines: effects of differentiation timelines. Stem Cells 2008;26: Exp Cell Res 1961;25:585e621.
422e30. [147] Li WJ, Chiang H, Kuo TF, Lee HS, Jiang CC, Tuan RS. Evaluation of articular
[118] Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell cartilage repair using biodegradable nanofibrous scaffolds in a swine model:
Biochem 2006;98:1076e84. a pilot study. J Tissue Eng Regen Med 2009;3:1e10.
[119] Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, [148] Peretti GM, Campo-Ruiz V, Gonzalez S, Randolph MA, Wei Xu J, Morse KR,
Marshall VS, et al. Embryonic stem cell lines derived from human blasto- et al. Tissue-engineered cartilage integration to live and devitalized carti-
cysts. Science 1998;282:1145e7. lage: a study by reflectance mode confocal microscopy and standard
[120] Rao BM, Zandstra PW. Culture development for human embryonic stem cell histology. Connect Tissue Res 2006;47:190e9.
propagation: molecular aspects and challenges. Curr Opin Biotechnol 2005; [149] Haut Donahue TL, Hull ML, Rashid MM, Jacobs CR. The sensitivity of tibio-
16:568e76. femoral contact pressure to the size and shape of the lateral and medial
[121] Hoben GM, Willard VP, Athanasiou KA. Fibrochondrogenesis of hESCs: menisci. J Orthop Res 2004;22:807e14.
growth factor combinations and cocultures. Stem Cells Dev 2009;18: [150] Kobayashi M, Chang YS, Oka M. A two year in vivo study of polyvinyl
283e92. alcohol-hydrogel (PVA-H) artificial meniscus. Biomaterials 2005;26:3243e8.
[122] Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, Fisk NM. [151] Maher SA, Rodeo SA, Doty SB, Brophy R, Potter H, Foo LF, et al. Evaluation of
Identification of mesenchymal stem/progenitor cells in human first- a porous polyurethane scaffold in a partial meniscal defect ovine model.
trimester fetal blood, liver, and bone marrow. Blood 2001;98:2396e402. Arthroscopy 2010;26:1510e9.
[123] Igura K, Zhang X, Takahashi K, Mitsuru A, Yamaguchi S, Takashi TA. Isolation [152] Heijkants RG, van Calck RV, De Groot JH, Pennings AJ, Schouten AJ, van
and characterization of mesenchymal progenitor cells from chorionic villi of Tienen TG, et al. Design, synthesis and properties of a degradable poly-
human placenta. Cytotherapy 2004;6:543e53. urethane scaffold for meniscus regeneration. J Mater Sci Mater Med 2004;15:
[124] In’t Anker PS, Noort WA, Scherjon SA, Kleijburg-van der Keur C, 423e7.
Kruisselbrink AB, van Bezooijen RL, et al. Mesenchymal stem cells in human [153] Chen GQ, Wu Q. The application of polyhydroxyalkanoates as tissue engi-
second-trimester bone marrow, liver, lung, and spleen exhibit a similar neering materials. Biomaterials 2005;26:6565e78.
immunophenotype but a heterogeneous multilineage differentiation [154] Farng E, Sherman O. Meniscal repair devices: a clinical and biomechanical
potential. Haematologica 2003;88:845e52. literature review. Arthroscopy 2004;20:273e86.
[155] Klompmaker J, Jansen HW, Veth RP, de Groot JH, Nijenhuis AJ, Pennings AJ. [185] Ilkhanizadeh S, Teixeira AI, Hermanson O. Inkjet printing of macromolecules
Porous polymer implant for repair of meniscal lesions: a preliminary study in on hydrogels to steer neural stem cell differentiation. Biomaterials 2007;28:
dogs. Biomaterials 1991;12:810e6. 3936e43.
[156] Ramrattan NN, Heijkants RG, van Tienen TG, Schouten AJ, Veth RP, Buma P. [186] Jones CN, Tuleuova N, Lee JY, Ramanculov E, Reddi AH, Zern MA, et al.
Assessment of tissue ingrowth rates in polyurethane scaffolds for tissue Cultivating liver cells on printed arrays of hepatocyte growth factor.
engineering. Tissue Eng 2005;11:1212e23. Biomaterials 2009;30:3733e41.
[157] Chiari C, Koller U, Dorotka R, Eder C, Plasenzotti R, Lang S, et al. A tissue [187] Holloway JL, Lowman AM, Palmese GR. Mechanical evaluation of poly(vinyl
engineering approach to meniscus regeneration in a sheep model. Osteo- alcohol)-based fibrous composites as biomaterials for meniscal tissue
arthritis Cartilage 2006;14:1056e65. replacement. Acta Biomater 2010;6:4716e24.
[158] Beatty MW, Ojha AK, Cook JL, Alberts LR, Mahanna GK, Iwasaki LR, et al. [188] Kobayashi M. A study of polyvinyl alcohol-hydrogel (PVA-H) artificial
Small intestinal submucosa versus salt-extracted polyglycolic acid-poly-L- meniscus in vivo. Biomed Mater Eng 2004;14:505e15.
lactic acid: a comparison of neocartilage formed in two scaffold materials. [189] Arnoczky SP, Warren RF, Spivak JM. Meniscal repair using an exogenous
Tissue Eng 2002;8:955e68. fibrin clot. An experimental study in dogs. J Bone Joint Surg Am 1988;70:
[159] Liang R, Fisher M, Yang G, Hall C, Woo SL. Alpha 1,3-galactosyltransferase 1209e17.
knockout does not alter the properties of porcine extracellular matrix bio- [190] Hashimoto J, Kurosaka M, Yoshiya S, Hirohata K. Meniscal repair using fibrin
scaffolds. Acta Biomater 2011;7:1719e27. sealant and endothelial cell growth factor. An experimental study in dogs.
[160] Agrawal CM, Ray RB. Biodegradable polymeric scaffolds for musculoskeletal Am J Sports Med 1992;20:537e41.
tissue engineering. J Biomed Mater Res 2001;55:141e50. [191] Hsu SH, Whu SW, Hsieh SC, Tsai CL, Chen DC, Tan TS. Evaluation of chito-
[161] Li WJ, Mauck RL, Cooper JA, Yuan X, Tuan RS. Engineering controllable sanealginateehyaluronate complexes modified by an RGD-containing
anisotropy in electrospun biodegradable nanofibrous scaffolds for muscu- protein as tissue-engineering scaffolds for cartilage regeneration. Artif
loskeletal tissue engineering. J Biomech 2007;40:1686e93. Organs 2004;28:693e703.
[162] Baker BM, Mauck RL. The effect of nanofiber alignment on the maturation of [192] Kim S, Healy KE. Synthesis and characterization of injectable poly(N-
engineered meniscus constructs. Biomaterials 2007;28:1967e77. isopropylacrylamide-co-acrylic acid) hydrogels with proteolytically degrad-
[163] Yang F, Murugan R, Wang S, Ramakrishna S. Electrospinning of nano/micro able crosslinks. Biomacromolecules 2003;4:1214e23.
scale poly(L-lactic acid) aligned fibers and their potential in neural tissue [193] Galler KM, Aulisa L, Regan KR, D’Souza RN, Hartgerink JD. Self-assembling
engineering. Biomaterials 2005;26:2603e10. multidomain peptide hydrogels: designed susceptibility to enzymatic
[164] Sarkar S, Lee GY, Wong JY, Desai TA. Development and characterization of cleavage allows enhanced cell migration and spreading. J Am Chem Soc
a porous micro-patterned scaffold for vascular tissue engineering applica- 2010;132:3217e23.
tions. Biomaterials 2006;27:4775e82. [194] Lutolf MP, Lauer-Fields JL, Schmoekel HG, Metters AT, Weber FE, Fields GB,
[165] Xie J, Li X, Lipner J, Manning CN, Schwartz AG, Thomopoulos S, et al. et al. Synthetic matrix metalloproteinase-sensitive hydrogels for the
“Aligned-to-random” nanofiber scaffolds for mimicking the structure of the conduction of tissue regeneration: engineering cell-invasion characteristics.
tendon-to-bone insertion site. Nanoscale 2010;2:923e6. Proc Natl Acad Sci U S A 2003;100:5413e8.
[166] Lee CH, Shin HJ, Cho IH, Kang YM, Kim IA, Park KD, et al. Nanofiber alignment [195] Chen JP, Cheng TH. Thermo-responsive chitosan-graft-poly(N-
and direction of mechanical strain affect the ECM production of human ACL isopropylacrylamide) injectable hydrogel for cultivation of chondrocytes
fibroblast. Biomaterials 2005;26:1261e70. and meniscus cells. Macromol Biosci 2006;6:1026e39.
[167] Teh TK, Toh SL, Goh JC. Aligned hybrid silk scaffold for enhanced differen- [196] Williams CG, Malik AN, Kim TK, Manson PN, Elisseeff JH. Variable cyto-
tiation of mesenchymal stem cells into ligament fibroblasts. Tissue Eng Part compatibility of six cell lines with photoinitiators used for polymerizing
C Methods; 2011. hydrogels and cell encapsulation. Biomaterials 2005;26:1211e8.
[168] Moutos FT, Freed LE, Guilak F. A biomimetic three-dimensional woven [197] Bryant SJ, Chowdhury TT, Lee DA, Bader DL, Anseth KS. Crosslinking density
composite scaffold for functional tissue engineering of cartilage. Nat Mater influences chondrocyte metabolism in dynamically loaded photocrosslinked
2007;6:162e7. poly(ethylene glycol) hydrogels. Ann Biomed Eng 2004;32:407e17.
[169] Moutos FT, Guilak F. Functional properties of cell-seeded three-dimension- [198] Ballyns JJ, Gleghorn JP, Niebrzydowski V, Rawlinson JJ, Potter HG, Maher SA,
ally woven poly(epsilon-caprolactone) scaffolds for cartilage tissue engi- et al. Image-guided tissue engineering of anatomically shaped implants via MRI
neering. Tissue Eng Part A 2010;16:1291e301. and micro-CT using injection molding. Tissue Eng Part A 2008;14:1195e202.
[170] Chau Y, Luo Y, Cheung AC, Nagai Y, Zhang S, Kobler JB, et al. Incorporation of [199] Ballyns JJ, Wright TM, Bonassar LJ. Effect of media mixing on ECM assembly
a matrix metalloproteinase-sensitive substrate into self-assembling peptides and mechanical properties of anatomically-shaped tissue-engineered
e a model for biofunctional scaffolds. Biomaterials 2008;29:1713e9. meniscus. Biomaterials 2010;31:6756e63.
[171] Li WJ, Jiang YJ, Tuan RS. Chondrocyte phenotype in engineered fibrous [200] McHale MK, Setton LA, Chilkoti A. Synthesis and in vitro evaluation of
matrix is regulated by fiber size. Tissue Eng 2006;12:1775e85. enzymatically crosslinked elastin-like polypeptide gels for cartilaginous
[172] Aufderheide AC, Athanasiou KA. Comparison of scaffolds and culture tissue repair. Tissue Eng 2005;11:1768e79.
conditions for tissue engineering of the knee meniscus. Tissue Eng 2005;11: [201] Betre H, Ong SR, Guilak F, Chilkoti A, Fermor B, Setton LA. Chondrocytic
1095e104. differentiation of human adipose-derived adult stem cells in elastin-like
[173] Sanchez-Adams J. The knee meniscus: a complex tissue of diverse cells. Cell polypeptide. Biomaterials 2006;27:91e9.
Mol Bioeng 2009;2:332e40. [202] Lee HJ, Lee JS, Chansakul T, Yu C, Elisseeff JH, Yu SM. Collagen mimetic
[174] Verdonk PC, Forsyth RG, Wang J, Almqvist KF, Verdonk R, Veys EM, et al. peptide-conjugated photopolymerizable PEG hydrogel. Biomaterials 2006;
Characterisation of human knee meniscus cell phenotype. Osteoarthritis 27:5268e76.
Cartilage 2005;13:548e60. [203] Lee HJ, Yu C, Chansakul T, Hwang NS, Varghese S, Yu SM, et al. Enhanced
[175] Thie M, Schlumberger W, Rauterberg J, Robenek H. Mechanical confinement chondrogenesis of mesenchymal stem cells in collagen mimetic peptide-
inhibits collagen synthesis in gel-cultured fibroblasts. Eur J Cell Biol 1989;48: mediated microenvironment. Tissue Eng Part A 2008;14:1843e51.
294e302. [204] Hofmann S, Knecht S, Langer R, Kaplan DL, Vunjak-Novakovic G, Merkle HP,
[176] Shin H, Nichol JW, Khademhosseini A. Cell-adhesive and mechanically et al. Cartilage-like tissue engineering using silk scaffolds and mesenchymal
tunable glucose-based biodegradable hydrogels. Acta Biomater 2011;7: stem cells. Tissue Eng 2006;12:2729e38.
106e14. [205] Meinel L, Hofmann S, Karageorgiou V, Zichner L, Langer R, Kaplan D, et al.
[177] Cohen DL, Malone E, Lipson H, Bonassar LJ. Direct freeform fabrication of Engineering cartilage-like tissue using human mesenchymal stem cells and
seeded hydrogels in arbitrary geometries. Tissue Eng 2006;12:1325e35. silk protein scaffolds. Biotechnol Bioeng 2004;88:379e91.
[178] Shu XZ, Liu Y, Luo Y, Roberts MC, Prestwich GD. Disulfide crosslinked hya- [206] Mueller SM, Shortkroff S, Schneider TO, Breinan HA, Yannas IV, Spector M.
luronan hydrogels. Biomacromolecules 2002;3:1304e11. Meniscus cells seeded in type I and type II collageneGAG matrices in vitro.
[179] Zheng Shu X, Liu Y, Palumbo FS, Luo Y, Prestwich GD. In situ crosslinkable Biomaterials 1999;20:701e9.
hyaluronan hydrogels for tissue engineering. Biomaterials 2004;25: [207] Chiari C, Koller U, Kapeller B, Dorotka R, Bindreiter U, Nehrer S. Different
1339e48. behavior of meniscal cells in collagen II/I, III and Hyaff-11 scaffolds in vitro.
[180] Soppimath KS, Aminabhavi TM, Dave AM, Kumbar SG, Rudzinski WE. Tissue Eng Part A 2008;14:1295e304.
Stimulus-responsive “smart” hydrogels as novel drug delivery systems. Drug [208] Tan GK, Dinnes DL, Butler LN, Cooper-White JJ. Interactions between
Dev Ind Pharm 2002;28:957e74. meniscal cells and a self assembled biomimetic surface composed of hya-
[181] Liu Tsang V, Chen AA, Cho LM, Jadin KD, Sah RL, DeLong S, et al. Fabrication of luronic acid, chitosan and meniscal extracellular matrix molecules. Bioma-
3D hepatic tissues by additive photopatterning of cellular hydrogels. FASEB J terials 2010;31:6104e18.
2007;21:790e801. [209] Stone KR, Steadman JR, Rodkey WG, Li ST. Regeneration of meniscal cartilage
[182] Richter C, Reinhardt M, Giselbrecht S, Leisen D, Trouillet V, Truckenmuller R, with use of a collagen scaffold. Analysis of preliminary data. J Bone Joint Surg
et al. Spatially controlled cell adhesion on three-dimensional substrates. Am 1997;79:1770e7.
Biomed Microdevices 2010;12:787e95. [210] Rodkey WG, DeHaven KE, Montgomery 3rd WH, Baker Jr CL, Beck Jr CL,
[183] Hammoudi TM, Lu H, Temenoff JS. Long-term spatially defined coculture Hormel SE, et al. Comparison of the collagen meniscus implant with partial
within three-dimensional photopatterned hydrogels. Tissue Eng Part C meniscectomy. A prospective randomized trial. J Bone Joint Surg Am 2008;
Methods 2010;16:1621e8. 90:1413e26.
[184] Tuleuova N, Lee JY, Lee J, Ramanculov E, Zern MA, Revzin A. Using growth [211] Bulgheroni P, Murena L, Ratti C, Bulgheroni E, Ronga M, Cherubino P. Follow-
factor arrays and micropatterned co-cultures to induce hepatic differentia- up of collagen meniscus implant patients: clinical, radiological, and magnetic
tion of embryonic stem cells. Biomaterials 2010;31:9221e31. resonance imaging results at 5 years. Knee 2010;17:224e9.
[212] Zaffagnini S, Marcheggiani Muccioli GM, Lopomo N, Bruni D, Giordano G, [241] Kasemkijwattana C, Menetrey J, Goto H, Niyibizi C, Fu FH, Huard J. The use of
Ravazzolo G, et al. Prospective long-term outcomes of the medial collagen growth factors, gene therapy and tissue engineering to improve meniscal
meniscus implant versus partial medial meniscectomy: a minimum 10-year healing. Mater Sci Eng C Mater Biol Appl 2000;13:19e28.
follow-up study. Am J Sports Med 2011;39:977e85. [242] Stewart K, Pabbruwe M, Dickinson S, Sims T, Hollander AP, Chaudhuri JB. The
[213] Schoenfeld AJ, Landis WJ, Kay DB. Tissue-engineered meniscal constructs. effect of growth factor treatment on meniscal chondrocyte proliferation and
Am J Orthop (Belle Mead NJ) 2007;36:614e20. differentiation on polyglycolic acid scaffolds. Tissue Eng 2007;13:271e80.
[214] Steadman JR, Rodkey WG. Tissue-engineered collagen meniscus implants: 5- [243] Tumia NS, Johnstone AJ. Platelet derived growth factor-AB enhances knee
to 6-year feasibility study results. Arthroscopy 2005;21:515e25. meniscal cell activity in vitro. Knee 2009;16:73e6.
[215] Cook JL, Fox DB, Kuroki K, Jayo M, De Deyne PG. In vitro and in vivo [244] Pangborn CA, Athanasiou KA. Growth factors and fibrochondrocytes in
comparison of five biomaterials used for orthopedic soft tissue augmenta- scaffolds. J Orthop Res 2005;23:1184e90.
tion. Am J Vet Res 2008;69:148e56. [245] Bhargava MM, Attia ET, Murrell GA, Dolan MM, Warren RF, Hannafin JA. The
[216] Cook JL, Tomlinson JL, Kreeger JM, Cook CR. Induction of meniscal regener- effect of cytokines on the proliferation and migration of bovine meniscal
ation in dogs using a novel biomaterial. Am J Sports Med 1999;27:658e65. cells. Am J Sports Med 1999;27:636e43.
[217] Cook JL, Fox DB, Malaviya P, Tomlinson JL, Kuroki K, Cook CR, et al. Long-term [246] Johnstone B, Hering TM, Caplan AI, Goldberg VM, Yoo JU. In vitro chondro-
outcome for large meniscal defects treated with small intestinal submucosa genesis of bone marrow-derived mesenchymal progenitor cells. Exp Cell Res
in a dog model. Am J Sports Med 2006;34:32e42. 1998;238:265e72.
[218] Bradley MP, Fadale PD, Hulstyn MJ, Muirhead WR, Lifrak JT. Porcine small [247] Mackay AM, Beck SC, Murphy JM, Barry FP, Chichester CO, Pittenger MF.
intestine submucosa for repair of goat meniscal defects. Orthopedics 2007; Chondrogenic differentiation of cultured human mesenchymal stem cells
30:650e6. from marrow. Tissue Eng 1998;4:415e28.
[219] Klompmaker J, Jansen HW, Veth RP, Nielsen HK, de Groot JH, Pennings AJ. [248] Yaeger PC, Masi TL, de Ortiz JL, Binette F, Tubo R, McPherson JM. Synergistic
Porous implants for knee joint meniscus reconstruction: a preliminary study action of transforming growth factor-beta and insulin-like growth factor-I
on the role of pore sizes in ingrowth and differentiation of fibrocartilage. Clin induces expression of type II collagen and aggrecan genes in adult human
Mater 1993;14:1e11. articular chondrocytes. Exp Cell Res 1997;237:318e25.
[220] Yamasaki T, Deie M, Shinomiya R, Izuta Y, Yasunaga Y, Yanada S, et al. [249] Pangborn CA, Athanasiou KA. Effects of growth factors on meniscal fibro-
Meniscal regeneration using tissue engineering with a scaffold derived from chondrocytes. Tissue Eng 2005;11:1141e8.
a rat meniscus and mesenchymal stromal cells derived from rat bone [250] Lee SY, Niikura T, Reddi AH. Superficial zone protein (lubricin) in the
marrow. J Biomed Mater Res A 2005;75:23e30. different tissue compartments of the knee joint: modulation by transforming
[221] Stabile KJ, Odom D, Smith TL, Northam C, Whitlock PW, Smith BP, et al. An growth factor beta 1 and interleukin-1 beta. Tissue Eng Part A 2008;14:
acellular, allograft-derived meniscus scaffold in an ovine model. Arthroscopy 1799e808.
2010;26:936e48. [251] Freyman TM, Yannas IV, Yokoo R, Gibson LJ. Fibroblast contraction of a col-
[222] Maier D, Braeun K, Steinhauser E, Ueblacker P, Oberst M, Kreuz PC, et al. In lageneGAG matrix. Biomaterials 2001;22:2883e91.
vitro analysis of an allogenic scaffold for tissue-engineered meniscus [252] Zaleskas JM, Kinner B, Freyman TM, Yannas IV, Gibson LJ, Spector M.
replacement. J Orthop Res 2007;25:1598e608. Contractile forces generated by articular chondrocytes in collagen-
[223] Sandmann GH, Eichhorn S, Vogt S, Adamczyk C, Aryee S, Hoberg M, et al. glycosaminoglycan matrices. Biomaterials 2004;25:1299e308.
Generation and characterization of a human acellular meniscus scaffold for [253] Kalson NS, Holmes DF, Kapacee Z, Otermin I, Lu Y, Ennos RA, et al. An
tissue engineering. J Biomed Mater Res A 2009;91:567e74. experimental model for studying the biomechanics of embryonic tendon:
[224] Stapleton TW, Ingram J, Katta J, Knight R, Korossis S, Fisher J, et al. Devel- evidence that the development of mechanical properties depends on the
opment and characterization of an acellular porcine medial meniscus for use actinomyosin machinery. Matrix Biol 2010;29:678e89.
in tissue engineering. Tissue Eng Part A 2008;14:505e18. [254] Rhee S, Grinnell F. P21-activated kinase 1: convergence point in PDGF- and
[225] Yamasaki T, Deie M, Shinomiya R, Yasunaga Y, Yanada S, Ochi M. Trans- LPA-stimulated collagen matrix contraction by human fibroblasts. J Cell Biol
plantation of meniscus regenerated by tissue engineering with a scaffold 2006;172:423e32.
derived from a rat meniscus and mesenchymal stromal cells derived from rat [255] Zaleskas JM, Kinner B, Freyman TM, Yannas IV, Gibson LJ, Spector M. Growth
bone marrow. Artif Organs 2008;32:519e24. factor regulation of smooth muscle actin expression and contraction of
[226] Hu JC, Athanasiou KA. A self-assembling process in articular cartilage tissue human articular chondrocytes and meniscal cells in a collageneGAG matrix.
engineering. Tissue Eng 2006;12:969e79. Exp Cell Res 2001;270:21e31.
[227] Hoben GM, Hu JC, James RA, Athanasiou KA. Self-assembly of fibrochon- [256] Bisson MA, Beckett KS, McGrouther DA, Grobbelaar AO, Mudera V. Trans-
drocytes and chondrocytes for tissue engineering of the knee meniscus. forming growth factor-beta1 stimulation enhances Dupuytren’s fibroblast
Tissue Eng 2007;13:939e46. contraction in response to uniaxial mechanical load within a 3-dimensional
[228] L’Heureux N, Dusserre N, Konig G, Victor B, Keire P, Wight TN, et al. Human collagen gel. J Hand Surg Am 2009;34:1102e10.
tissue-engineered blood vessels for adult arterial revascularization. Nat Med [257] Veilleux N, Spector M. Effects of FGF-2 and IGF-1 on adult canine articular
2006;12:361e5. chondrocytes in type II collagen-glycosaminoglycan scaffolds in vitro.
[229] Hoenig E, Winkler T, Goepfert C, Mielke G, Paetzold H, Schuettler D, et al. Osteoarthritis Cartilage 2005;13:278e86.
High amplitude direct compressive strain enhances mechanical properties of [258] Adesida AB, Grady LM, Khan WS, Hardingham TE. The matrix-forming
scaffold-free tissue-engineered cartilage. Tissue Eng Part A 2011;17: phenotype of cultured human meniscus cells is enhanced after culture
1401e11. with fibroblast growth factor 2 and is further stimulated by hypoxia.
[230] Proulx S, d’Arc Uwamaliya J, Carrier P, Deschambeault A, Audet C, Giasson CJ, Arthritis Res Ther 2006;8:R61.
et al. Reconstruction of a human cornea by the self-assembly approach of tissue [259] Zhao G, Yin S, Liu G, Cen L, Sun J, Zhou H, et al. In vitro engineering of
engineering using the three native cell types. Mol Vis 2010;16:2192e201. fibrocartilage using CDMP1 induced dermal fibroblasts and polyglycolide.
[231] Eiraku M, Takata N, Ishibashi H, Kawada M, Sakakura E, Okuda S, et al. Self- Biomaterials 2009;30:3241e50.
organizing optic-cup morphogenesis in three-dimensional culture. Nature [260] Le Maitre CL, Freemont AJ, Hoyland JA. Expression of cartilage-derived
2011;472:51e6. morphogenetic protein in human intervertebral discs and its effect on
[232] Huey DJ, Athanasiou KA. Maturational growth of self-assembled, functional matrix synthesis in degenerate human nucleus pulposus cells. Arthritis Res
menisci as a result of TGF-beta1 and enzymatic chondroitinase-ABC stimu- Ther 2009;11:R137.
lation. Biomaterials 2011;32:2052e8. [261] Yamagata T, Saito H, Habuchi O, Suzuki S. Purification and properties of
[233] Ofek G, Revell CM, Hu JC, Allison DD, Grande-Allen KJ, Athanasiou KA. Matrix bacterial chondroitinases and chondrosulfatases. J Biol Chem 1968;243:
development in self-assembly of articular cartilage. PLoS One 2008;3:e2795. 1523e35.
[234] Elder BD, Athanasiou KA. Systematic assessment of growth factor treatment [262] Lyyra T, Arokoski JP, Oksala N, Vihko A, Hyttinen M, Jurvelin JS, et al.
on biochemical and biomechanical properties of engineered articular carti- Experimental validation of arthroscopic cartilage stiffness measurement
lage constructs. Osteoarthritis Cartilage 2009;17:114e23. using enzymatically degraded cartilage samples. Phys Med Biol 1999;44:
[235] Elder BD, Athanasiou KA. Synergistic and additive effects of hydrostatic 525e35.
pressure and growth factors on tissue formation. PLoS One 2008;3:e2341. [263] Asanbaeva A, Masuda K, Thonar EJ, Klisch SM, Sah RL. Mechanisms of
[236] Kalpakci KN, Kim EJ, Athanasiou KA. Assessment of growth factor treatment cartilage growth: modulation of balance between proteoglycan and collagen
on fibrochondrocyte and chondrocyte co-cultures for TMJ fibrocartilage in vitro using chondroitinase ABC. Arthritis Rheum 2007;56:188e98.
engineering. Acta Biomater 2011;7:1710e8. [264] Natoli RM, Revell CM, Athanasiou KA. Chondroitinase ABC treatment results
[237] Aufderheide AC, Athanasiou KA. Assessment of a bovine co-culture, scaffold- in greater tensile properties of self-assembled tissue-engineered articular
free method for growing meniscus-shaped constructs. Tissue Eng 2007;13: cartilage. Tissue Eng Part A 2009;15:3119e28.
2195e205. [265] Natoli RM, Responte DJ, Lu BY, Athanasiou KA. Effects of multiple chon-
[238] Elder BD, Athanasiou KA. Effects of temporal hydrostatic pressure on tissue- droitinase ABC applications on tissue-engineered articular cartilage. J Orthop
engineered bovine articular cartilage constructs. Tissue Eng Part A 2009;15: Res 2009;27:949e56.
1151e8. [266] Bian L, Crivello KM, Ng KW, Xu D, Williams DY, Ateshian GA, et al. Influence
[239] Shrive NG, O’Connor JJ, Goodfellow JW. Load-bearing in the knee joint. Clin of temporary chondroitinase ABC-induced glycosaminoglycan suppression
Orthop Relat Res; 1978:279e87. on maturation of tissue-engineered cartilage. Tissue Eng Part A 2009;15:
[240] Gunja NJ, Huey DJ, James RA, Athanasiou KA. Effects of agarose mould 2065e72.
compliance and surface roughness on self-assembled meniscus-shaped [267] Buma P, Ramrattan NN, van Tienen TG, Veth RP. Tissue engineering of the
constructs. J Tissue Eng Regen Med 2009;3:521e30. meniscus. Biomaterials 2004;25:1523e32.
[268] Eichholtz T, Jalink K, Fahrenfort I, Moolenaar WH. The bioactive phospholipid [281] Lechner K, Hull ML, Howell SM. Is the circumferential tensile modulus within
lysophosphatidic acid is released from activated platelets. Biochem J 1993; a human medial meniscus affected by the test sample location and cross-
291:677e80. sectional area? J Orthop Res 2000;18:945e51.
[269] Ishida K, Kuroda R, Miwa M, Tabata Y, Hokugo A, Kawamoto T, et al. The [282] Vangsness Jr CT, Akl Y, Marshall GJ, Subin W, Smith CF. The effects of the
regenerative effects of platelet-rich plasma on meniscal cells in vitro and its neodymium laser on meniscal repair in the avascular zone of the meniscus.
in vivo application with biodegradable gelatin hydrogel. Tissue Eng 2007;13: Arthroscopy 1994;10:201e5.
1103e12. [283] Jitsuiki J, Ochi M, Ikuta Y. Meniscal repair enhanced by an interpositional free
[270] Natsu-Ume T, Majima T, Reno C, Shrive NG, Frank CB, Hart DA. Menisci of the synovial autograft: an experimental study in rabbits. Arthroscopy 1994;10:
rabbit knee require mechanical loading to maintain homeostasis: cyclic 659e66.
hydrostatic compression in vitro prevents derepression of catabolic genes. [284] Cisa J, Basora J, Madarnas P, Ghibely A, Navarro-Quilis A. Meniscal repair by
J Orthop Sci 2005;10:396e405. synovial flap transfer. Healing of the avascular zone in rabbits. Acta Orthop
[271] Gunja NJ, Athanasiou KA. Effects of hydrostatic pressure on leporine meniscus Scand 1995;66:38e40.
cell-seeded PLLA scaffolds. J Biomed Mater Res A 2010;92:896e905. [285] Tienen TG, Heijkants RG, Buma P, De Groot JH, Pennings AJ, Veth RP.
[272] Gunja NJ, Uthamanthil RK, Athanasiou KA. Effects of TGF-beta1 and hydrostatic A porous polymer scaffold for meniscal lesion repair e a study in dogs.
pressure on meniscus cell-seeded scaffolds. Biomaterials 2009;30:565e73. Biomaterials 2003;24:2541e8.
[273] Upton ML, Chen J, Guilak F, Setton LA. Differential effects of static and [286] Papachristou G, Efstathopoulos N, Plessas S, Levidiotis C, Chronopoulos E,
dynamic compression on meniscal cell gene expression. J Orthop Res 2003; Sourlas J. Isolated meniscal repair in the avascular area. Acta Orthop Belg
21:963e9. 2003;69:341e5.
[274] Fink C, Fermor B, Weinberg JB, Pisetsky DS, Misukonis MA, Guilak F. The [287] Pollo FE, Jackson RW, Kane RR, Chang HM, Zhang J, Dieterichs CP, et al.
effect of dynamic mechanical compression on nitric oxide production in the Sutureless avascular meniscal repair with a photoactive naphthalimide
meniscus. Osteoarthritis Cartilage 2001;9:481e7. compound: a preliminary animal study. Arthroscopy 2004;20:824e30.
[275] Ferretti M, Madhavan S, Deschner J, Rath-Deschner B, Wypasek E, Agarwal S. [288] Petersen W, Pufe T, Starke C, Fuchs T, Kopf S, Raschke M, et al. Locally applied
Dynamic biophysical strain modulates proinflammatory gene induction in angiogenic factors e a new therapeutic tool for meniscal repair. Ann Anat
meniscal fibrochondrocytes. Am J Physiol Cell Physiol 2006;290:C1610e5. 2005;187:509e19.
[276] Aufderheide AC, Athanasiou KA. A direct compression stimulator for articular [289] Noyes FR, Barber-Westin SD. Arthroscopic repair of meniscal tears extending
cartilage and meniscal explants. Ann Biomed Eng 2006;34:1463e74. into the avascular zone in patients younger than twenty years of age. Am J
[277] Shin SJ, Fermor B, Weinberg JB, Pisetsky DS, Guilak F. Regulation of matrix Sports Med 2002;30:589e600.
turnover in meniscal explants: role of mechanical stress, interleukin-1, and [290] Imler SM, Doshi AN, Levenston ME. Combined effects of growth factors and
nitric oxide. J Appl Physiol 2003;95:308e13. static mechanical compression on meniscus explant biosynthesis. Osteoar-
[278] Ballyns JJ, Bonassar LJ. Dynamic compressive loading of image-guided tissue- thritis Cartilage 2004;12:736e44.
engineered meniscal constructs. J Biomech 2011;44:509e16. [291] Gruber HE, Mauerhan D, Chow Y, Ingram JA, Norton HJ, Hanley Jr EN, et al.
[279] Eifler RL, Blough ER, Dehlin JM, Haut Donahue TL. Oscillatory fluid flow Three-dimensional culture of human meniscal cells: extracellular matrix and
regulates glycosaminoglycan production via an intracellular calcium proteoglycan production. BMC Biotechnol 2008;8:54.
pathway in meniscal cells. J Orthop Res 2006;24:375e84. [292] Bhargava MM, Hidaka C, Hannafin JA, Doty S, Warren RF. Effects of hepa-
[280] Tissakht M, Ahmed AM. Tensile stressestrain characteristics of the human tocyte growth factor and platelet-derived growth factor on the repair of
meniscal material. J Biomech 1995;28:411e22. meniscal defects in vitro. In Vitro Cell Dev Biol Anim 2005;41:305e10.

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Biomaterials 32 (2011) 7411e7431

Contents lists available at ScienceDirect

The knee meniscus: Structureefunction, pathophysiology, current repair

depth of the tear, injuries are observed as partial or full thickness, of

Follow-up arthroscopy (18 mos)

þ clinical exam (51 mos)

100 (71 mos)

Porous polymer implant in partial

Exogenous ﬁbrin clot þ suture

Photoactive laser technique

Suture coated VEGF/PDLLA

Rasping without suturing

thickness access channel

Fibrin clot þ suture

3.1.1. Peripheral meniscal tears Longitudinal, radial, ﬂap,

techniques; and open repair [5,6,71]. These techniques have been

will therefore not be largely discussed in the present review.

A substantial amount of research has focused on the efﬁcacy and

reliability of these repair techniques for achieving anatomical and

increasing amount of literature supporting current meniscus repair

successful outcomes in young individuals with stable knees are

the possibility of long-term degenerative deteriorations of the

articular cartilage and meniscus.

3.1.2. Avascular zone meniscal tears

Tears in the avascular zone of the meniscus are generally more

following repair. Improving the healing process in this type of

Several different therapeutic approaches have been brought

van Trommel et al. [137]

Papachristou et al. [286]

synovial tissue, trephination of the peripheral meniscus rim with

suture of the meniscus tear, creation of vascular access channels,

Rubman et al. [52]

Tienen et al. [285]

Noyes et al. [289]

and use of mesenchymal stem cells or growth factors [77,78].

Pollo et al. [287]

Despite these results, none of the above techniques has been

its related long-term degenerative implications for articular carti-

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