BIOMECHANICS AND HEALING RESPONSE OF

THE MENISCUS
SUMITO KAWAMURA, MD, KRISTIN LOTITO, BS, and SCOTT A. RODEO, MD

The menisci are important in many aspects of knee function, including load bearing, shock absorption, joint
stabilization, joint lubrication, and proprioception. Total and partial meniscectomy significantly increase the load
per unit area in the tibiofemoral joint and result in early osteoarthritis. Meniscus repair has generally been limited
to the peripheral vascular area of the meniscus, but efforts have been made to promote the healing of tears in the
avascular inner area. Recent studies have demonstrated the potential for cytokines to increase extracellular matrix
synthesis by meniscal cells, suggesting the ability to improve meniscus healing. Meniscus allograft transplantation
represents one of the few available treatment options after total meniscectomy. Novel strategies for meniscal
repair using gene therapy techniques and engineered tissue are exciting options for the future. This review will
discuss these basic aspects of the meniscus, focusing on meniscus biomechanics, the healing response of meniscal
cells after injury and allograft transplantation, and future directions for meniscal repair and regeneration.
KEY WORDS: biomechanics, fibrochondrocyte, cytokines, meniscal allograft, tissue engineering
2003 Elsevier Inc. All rights reserved.

The menisci are fibrocartilaginous tissues composed primarily of an interlacing network of collagen fibers interposed with meniscal cells and extracellular matrix. The
menisci are an integral component of the knee joint, as
meniscus injury disrupts normal knee mechanics, resulting in progressive articular cartilage degeneration. TM Arthroscopic treatment of meniscal injuries has become one
of the most common orthopaedic surgical procedures in
the United States. s One of the limitations in the treatment
of meniscal injuries is their limited blood supply. Because
the inner two-thirds of the meniscus is avascular, this area
does not typically mount a healing response. 4 A number of
studies have evaluated methods to increase the blood
supply to this avascular region. More recent studies have
been directed toward applications of molecular biology to
promote meniscal repair and regeneration. The ability to
design novel treatment strategies depends on a thorough
understanding of meniscal anatomy, biology, and biomechanics.

MENISCALSTRUCTURE
The meniscus is a C-shape fibrocartilaginous tissue. The
peripheral border of each meniscus is thick and attached
to the capsule of the joint, while the inner border tapers to
a thin free edge. 4 The anterior and posterior horns of both
menisci directly attach to bone. The medial meniscus is
firmly attached to peripheral joint capsule and less mobile

From the Laboratory for Soft Tissue Research and the Sports Medicine
and Shoulder Service, Hospital for Special Surgery, New York, NY.
Address reprint requests to Scott A. Rodeo, The Hospital for Special
Surgery, 535 East 70th Street, New York, NY 10021.
2003 Elsevier Inc. All rights reserved.
1060-1872/03/1102-0001 $30.00/0
doi:l 0.1053/otsm.2003.35899
68

than the lateral meniscus. The lateral meniscus covers a

larger percentage of the articular surface than the medial
meniscus. The peripheral portion of the lateral meniscus
has a loose attachment to the joint capsule. 4,s The two
meniscofemoral ligaments (the ligaments of Humphrey
and Wrisberg) run from the posterior attachment of the
lateral meniscus to the medial femoral condyle, adjacent to
the posterior cruciate ligament. 4
There are two cell types in the meniscus: fibroblastic
cells on the meniscus surface and ovoid cells in the deeper
layer. This latter cell has been called a "fibrochondrocyte"
because, while it can synthesize a fibrous matrix, it has the
rounded appearance of a chondrocyte. 6 These cells are
responsible for synthesizing and maintaining the extracellular matrix. The extracellular matrix contains water (70%
total weight), type I, II, III, V, and VI collagen (60-70% of
the dry weight, with type I collagen predominant), and
proteoglycan (1-2% of dry weight). 4,7 Proteoglycans are
composed of polypeptides to which one or more specialized polysaccharides, called glycosaminoglycans (GAGs),
are covalently attached. The meniscus has a unique collagen structure orientation that is related to its function and
consists of three different layers that can be distinguished
microscopically. 4,s The superficial layer consists of a thin
layer of fine fibrils. Just below the superficial layer is a
layer of irregulary-aligned collagen bundles. The middle
layer consists of larger, circumferentially oriented fibers,
anchored by a small number of radially oriented fibers
(Fig 1). The principal GAG is chondroitin sulfate (40%),
with lesser amounts of dermatan sulfate and keratan sulfate. 7 GAGs function to bind water molecules and thus
provide the compressive properties of the tissue. 7 Several
adhesion molecules, including type-VI collagen, fibronectin, and thrombospondin, facilitate cell-matrix interactions. 7

Operative Techniques in Sports Medicine, Vol 11, No 2 (April), 2003: pp 68-76

1
/

Superficial
cells

collagen fibers (Fig 2).8 There are significant regional variations in the circumferential tensile strength and stiffness,
with lower values in the posterior two-thirds of the medial
meniscus than in the anterior or the lateral meniscus. 11
These variations are probably because of differences in
collagen fiber ultrastructure, because the variations in material properties are not correlated with differences in
biochemical composition. 11-13 Tissackt and co-workers 13
measured the tensile modulus in both the radial and circumferential directions in the human meniscus. Their

Su~
zor

A
Femur

Fh = horizontal force
Fv=ve~icleforce
Deep
cells

Circumferential
collagen fibers
Fh

Fig 1. Collagen ultrastructure and cell types in the meniscus. The illustration demonstrates the collagen fiber orientation in the surface and deep zones. The radial tie fibers are
also shown. Superficial meniscal cells tend to be fibroblastic, while the deep cells have a rounded morphology.

Tibia

BIOMECHANICS AND FUNCTIONAL ROLES

OF MENISCUS
The menisci perform important functional roles within the
knee joint. These functions include load bearing, shock
absorption, joint stability, joint lubrication, and the proprioception.4 The biomechanical properties of the meniscus
depend on the anatomic characteristics and material properties of this tissue.

B = circumferential force
Fr = radial force
~
'
~

Posterior

LOAD BEARING
During loading the meniscus experiences tensile, compressive, and shear stress. The medial meniscus transmits
50% of the joint load in the medial compartment while the
lateral meniscus transmits 70% of the joint load in the
lateral compartment. 9 The menisci transmit 50% of the
load when the knee is in extension and 85 to 90% of the
joint load when the knee is in flexion.9 It has been shown
that resection of as little as 15 to 34% of the meniscus
increases contact pressure by more than 350%. 4,9 When
one-third of the inner meniscus is lost, contact stresses are
increased by 65%. 1 Such significantly increased compression stress across the joint causes articular cartilage damage and eventual degeneration. Thus, even partial meniscectomy can affect the ability of the meniscus to function
in load transmission across the knee. 1-3
When an axial load is applied to the knee joint the
meniscus is compressed, but because of its wedge-shaped
structure and firm anterior and posterior attachments to
the tibia, it is displaced away from the joint center, resulting in tensile stress (hoop stress) in the circumferential

BIOMECHANICSAND HEALING RESPONSEOF THE MENISCUS

FrFr

'~"

horn

Fig 2. (A, B) The intact meniscus converts axial forces into

radial strain. Because of its geometry and anatomic location
in the joint, the meniscus is subjected to compressive, tensile, and shear stresses (A). When a load is applied, the
meniscus is displaced away from the center, resulting in
tensile stress because of the anterior and posterior horn
tibial attachments (B).

69

study showed that the meniscus is much stronger and

stiffer in the circumferential direction than the radial direction, and the low radial shear strength is thought to be
at least partly responsible for the occurrence of longitudinal tears. 14,15

SHOCK ABSORPTION
The meniscus can be viewed as a biphasic medium comprising a fluid phase (the interstitial water) and a solid phase
(collagen, GAGs, and the other matrix proteins) 6 The
collagen network and GAGs form a porous-permeable
solid matrix. Interstitial fluid flow and solid matrix deformation during loading cause the meniscus to act as a
viscoelastic material. This viscoelasticity determines the
creep and stress relaxation behavior of the meniscus. Proctor and co-workers 12 found that the meniscus is one-tenth
as permeable as articular cartilage. Experimental studies
using bovine tissue have show that articular cartilage is
stiffer than meniscal tissue. 11,12 This combination of the
lower compressive stiffness and lower permeability suggest that the menisci play a role in shock absorption.

JOINT STABILITY
The superior concave and inferior flat surface of the meniscus conforms to the femoral and tibial condyles, and the
wedge shape of the meniscus contributes to its function in
joint stabilization (Fig 3). 17 Medial meniscectomy in the
anterior cruciate ligament (ACL) intact knee has little effect on anteroposterior motion; however, in the ACL-deficient knee medial meniscectomy results in an increase in
anterior tibial translation of up to 58% at 90 of flexion.17,18
Shoemaker and co-workers 19 demonstrated that the posterior horn of the medial meniscus resists an applied anterior tibial force in an ACL-deflcient knee. Allen and
co-workers 2 showed that the resultant force in the medial
meniscus of the ACL-deficient knee increased by 52% in
full extension and by 197% at 60 of flexion under a 134-N
load. Papageorgiou and co-workers 21 demonstrated that
the resultant force in an anterior cruciate ligament graft
increased following medial meniscectomy; this findings
supports the concept that medial meniscal transplantation
should be considered at the time of reconstruction of the
ACL in the medial meniscus-deficient knee. A cadaveric
biomechanical study demonstrated that knees with an
absent ACL and a deficient medial meniscus exhibited
greater varus-valgus laxity than did those with an absent
ACL but an intact medial meniscus. 22

Intact ACL

\ ~

us

Ruptured ACL

meniscus

Fig 3. The medial meniscus acts as a restraint to anterior

tibial translation in the ACL-deficient knee. (Reprinted from:
Levy IM, Torzilli PA, Warren RF: The effect of medial meniscectomy on anterior-posterior motion of the knee. J Bone
Joint Surg Am 64:887, 1982)

JOINT LUBRICATION
The menisci contribute significantly to joint conformity. It
has been suggested that such conformity promotes the
viscous hydrodynamic action required for fluid-film lubrication, and this function assists in the overall lubrication of
the articular surfaces of the knee joint. 4 Water may be
extruded into the joint space during compressive loading,
aiding in joint lubrication. 4,12The meniscus may also aid in
articular cartilage nutrition by helping to maintain a
synovial fluid film over the articular surface and by
compressing synovial fluid into articular cartilage. 11,23
However, the exact contribution of the meniscus to joint
lubrication has yet to be fully elucidated.
7'0

PROPRIOCEPTION
The menisci may provide proprioceptive feedback for joint
position sense. Neural elements are most abundant in the
outer portion of the meniscus, particularly type-I and
type-II nerve fibers. 24 The anterior and posterior horns of
the meniscus are innervated with mechanoreceptors that
may play a role in proprioceptive feedback during extremes of motion. 24,25These neural elements are thought to
be part of a proprioceptive reflex arc that may contribute
to the functional stability of the knee. 4,24,25

KAWAMURAETAL

Meniscal Pathology
Intrinsic meniscal degeneration begins around 30 years of
age, progresses with age, occurs in both men and women,
and occurs in both active and inactive subjects. 26 Histologic analysis demonstrates mucinous degeneration, hypocellularity, and loss of normal collagen fiber organization. 27 The etiology of such changes is unknown, but may
reflect recurrent chronic microtrauma to the meniscus.
Studies in animals have demonstrated that following ACL
transection the menisci undergo alterations in their extracellular matrices, including an increase in water content. 7,28 An initial decrease in the concentration of GAGs
has also been observed following ACL transection. 2s However, in joints with chronic ACL insufficiency, the concentration of GAGs was found to increase substantially. 28 This
reflects a remarkable ability of meniscal fibrochondrocytes
to replenish the lost GAGs.
Degenerative meniscal tissue is believed to have a
poorer potential for healing4; thus, careful attention
should be paid to the appearance and consistency of the
meniscus at the time of surgery. Although preservation of
the meniscus may be more important in a knee with axial
malalignment, the rate of healing may be lower because of
concomitant degenerative changes. 29
The concept that the meniscus will regenerate following
its removal has long provided the rationale for total meniscectomy. 30 Animal studies have demonstrated that after
total meniscectomy there is regrowth of a structure that is
similar in shape and texture to the removed meniscus. 4,g
It is thought that bleeding from the perimeniscal vessels
results in an organized clot within the peripheral joint
space, s However, only the peripheral rim of the meniscus
regenerates. Although such regenerated tissues grossly
resembled normal peripheral mensical tissue, the material
properties and functional role of this regenerated meniscus is unknown.

IMPORTANCE OF BLOOD SUPPLY AND

MENISCUS HEALING RESPONSE
The menisci are relatively avascular structures with a limited peripheral blood supply that originates predominantly from the lateral and medial genicular arteries. 4
Branches from these vessels give rise to a perimeniscal
capillary plexus within the synovial and capsular tissues
of the knee joint. Anatomic studies have shown that the
degree of vascular penetration is 10 to 30% of the width of
the medial meniscus and 10 to 25% of the width of the
lateral meniscus, gl A small reflection of vascular synovial
tissue (synovial fringe) also extends over the peripheral
attachment of the medial and lateral menisci on both the
femoral and tibial articular surfaces. 31
Whereas the peripheral aspects of the menisci are vascular, the vast majority of the meniscus is avascular and
must therefore derive its nutrition through synovial fluid
diffusion. 4 A meniscal tear in the vascular periphery has
the potential to heal, while tears that occur in the avascular
zone of the meniscus do not heal. 32-34
Injury within the peripheral vascular zone of the meniscus results in formation of a fibrin clot at the tear site. This
clot acts as a scaffold for the reparative process. Vessels
BIOMECHANICS AND HEALING RESPONSE OF THE MENISCUS

from the perimeniscal capillary plexus and synovial fringe

proliferate through this fibrin scaffold, accompanied by
proliferation of undifferentiated mesenchymal cells. 32,35
Eventually, the lesion is filled with a fibrovascular scar
tissue that bonds the w o u n d edges together and appears
continuous with the adjacent normal meniscal fibrocartilage. 32,B5 However, the exact phenotype of the cells that
initiate and regulate the healing process is unknown. Like
other connective tissues, the lesion heals with scar tissue
that likely has inferior material properties. For example,
the tensile strength of the healed lesion did not reach the
strength of normal meniscus even by 12 to 16 weeks in one
animal study. 4 Furthermore, the long-term histologic and
biomechanical characteristics of the reparative tissue are
unknown.

INDICATIONS FOR MENISCAL REPAIR

The indications for meniscal repair have been well-defined. The important factors for consideration include the
location of the tear, the type of tear, the quality of tissue,
chronicity, the age of the patient, and the stability of the
knee. 5 The most important factor in determining repairability is the location of the tear, as tears in the vascular
periphery of the meniscus can mount a healing response. 5"32"36 The ideal tear is an acute, vertical, longitudinal tear in the peripheral one-third of the meniscus (socalled red-red tear) in a young patient who has a stable
knee or will have concomitant reconstruction of the ACL. 5
Because of the importance of the meniscus, repair can be
considered for tears that extend into the central, avascular
zone (red-white tear) of the meniscus in young patients.
Noyes and co-workers B7 reported the results of meniscal
repair in patients 19 years of age or younger who had
meniscal tears that extended into the central avascular
region. These authors reported that retention of the majority of meniscal tissue was accomplished in 67% of the
menisci. It appears that the rates of healing after repairs of
the lateral meniscus are better than those of the medial
meniscus, and thus, there are broader indications for repair of the lateral meniscus. B6
Several techniques are available for meniscal repair.
These include open, outside-in, 5 inside-out, 3B and all-inside 9-38 arthroscopic methods. Most repairable meniscal
tears can be repaired with any of these techniques. The
outside-in method is useful for suturing a meniscal replacement to the capsule, and for securing materials such
as a fibrin clot to a repair site 5 (Fig 4). A particular disadvantage is the difficulty of achieving perpendicular orientation of sutures for far posterior tears, adjacent to the site
of attachment of the posterior horn. 5 Use of the inside-out
technique or an all-inside implant is suggested for these
tears.5,37

METHODS OF HEALING ENHANCEMENT

Several techniques have been developed that provide vascularity to the inner, avascular area of the meniscus. Experimental studies have shown that by connecting a lesion
in the avascular portion of the meniscus to the peripheral
blood supply via vascular channel, these lesions can heal

71

There is very little information available about the effect

of mechanical load and knee range of motion on meniscal
healing. One study using a dog model found that cast
immobilization of repaired meniscal lesions in the vascular zone of canine menisci resulted in a decrease in collagen formation after 10 weeks of immobilization compared
with nonimmobilized controls. 42 An experimental study in
rabbits found that immobilization of the normal meniscus
resulted in diminished matrix permeability and degenerative changes in the deep layers of the meniscus. 43 The
adverse effect of such immobilization was associated with
a significant reduction in blood flow compared with the
nonimmobilized joint. 44 In clinical situations, a period of
joint immobilization may be necessary for initial postoperative protection of articular tissues, but normal mobility
of the joint should be restored as soon as possible to
promote long-term joint homeostasis. Further studies are
required to determine the optimal type, magnitude, and
duration of loading for meniscal healing.
GROWTH

Fig 4, Illustration showing a fibrin clot placed at the site of

the tear using the outside-in technique, The fibrin clot may
promote meniscal healing.

through a normal process. 3s However, the creation of a

large vascular channel may disrupt the normal collagen
fiber architecture of the peripheral meniscus. Other methods to stimulate vascular ingrowth have been proposed,
including synovial abrasion, 33 use of vascular pedicle
grafts of synovium, 4 and meniscal rasping. 41 These procedures are intended to produce a vascular pannus, which
will migrate from the synovium into the tear site and
support a reparative response. Amoczky and co-workers 35
demonstrated that an exogenous fibrin clot placed in a
stable lesion in the avascular portion of the meniscus
could support a reparative response similar to that seen in
the vascular area. The clot is presumed to provide chemotactic and mitogenic stimuli for reparative cells and to act
as a scaffold for the reparative process. 35

FACTORS

Recent emphasis has been directed toward applications of

cell and molecular biology to promote meniscal healing
and regeneration. Numerous growth factors have been
identified as signaling molecules that control mitogenic
behavior and differentiation of cells. These growth factors
have been used on meniscal cells to test their effects on the
healing of tears or defects, as well as their effects on extracellular matrix synthesis in tissue and cell culture 6,45-53
(Table 1).
Cells from the peripheral part of the meniscus have an
increased ability to synthesize collagen in cell culture compared with cells derived from the inner part of the meniscus. 45 There are other differences in cellular physiology
between the cells in the inner and outer regions of the
meniscus, including the responsiveness to growth factors
and cytokines. Webber and co-workers 6 tested the effect of
fibroblastic growth factor (FGF) and human platelet lysate
(PL), both of which were found to stimulate proliferation
of meniscal cells. Transforming growth factor-/3 (TGF-/3)
increased proteoglycan synthesis of fibrochondrocytes
from all different regions of the meniscus in a dose-depen-

T A B L E 1. The Effect of Various Growth Factors on Meniscal Tissue

Type and Reference

In Vitro or In Vivo (animal)

Cell Source

Result

FGF6
HumanPLe
ECGF53
ECGFs2
PDGF-AB4a

In vitro
In vitro
Dog
Dog
In vitro
In vitro
Rabbit
In vitro
in vitro
In vitro
In vitro
In vitro
In vitro
In vitro
Rabbit

Rabbit
Rabbit
No
No
Ovine
Ovine
No
Human
Bovine
Bovine
Bovine
Bovine
Bovine
Bovine
No

Stimulate proliferation
Stimulate proliferation
Improve healing in cylindrical defect
Increase short-term healing in tears
Affect mitogenic response from outer one-third of meniscus
Increase proteoglycan synthesis
Increase rate of healing in a cylindrical defect
Increase proteoglycan synthesis
Stimulate cell migration, increased DNA synthesis
Stimulate cell migration, increased DNA synthesis
Some celt migration, increased DNA synthesis
Some cell migration
Some cell migration
Some cell migration
Stimulate collagen remodeling in peripheral zone

TGF-,B 47

Hyaluronic acidsl
TGF-/346
PDGF-AB49
HGF49
BMP-249
IGF-149
IL-149
EGF49
Hyaluronan 5o

FGF, fibroblast growth factor; Human PL, human platelet lysate; ECGF, endothelial cell growth factor; PDGF-AB: platelet derived growth factor-AB;
TGF-/3, transforming growth factor-/3; HGF, hepatocyte growth factor; BMP-2, bone morphogenetic protein-2; IGF-1, insulin like growth factor-I; IL-1,
interleukin-1; EGF, epidermal growth factor. (Sweigart M: Tissue engineering, 7:1 11-12, 2001)
72

KAWAMURA ET AL

dent manner. 7-46 Spindler and co-workers 4s demonstrated

that the cells in the inner, central region of the tissue
(where the healing capability is diminished) are much less
responsive to platelet-derived growth factor-AB (PDGFAB) than are the cells in the peripheral portion of the
tissue. On the other hand, Bhargava and co-workers 49
demonstrated that at optimal concentrations, PDGF-AB,
hepatocyte growth factor (HGF), and bone morphogenetic
protein-2 (BMP-2) are equally effective in stimulating
DNA synthesis in cells isolated from different zones of the
meniscus. BMP-2 and insulin-like growth factor-1 (IGF-1)
stimulated the migration of fibrochondrocytes from the
middle zone by 40 to 50%. This study also reported that
interleukin-1 (IL-1) and epidermal growth factor (EGF)
stimulated migration of meniscal cells. Other studies reported that hyaluronan 5 and hyaluronic acid 51 increased
healing in a cylindrical meniscal defect and stimulated
collagen remodeling in the peripheral zone. Endothelial
growth factor (ECGF) was reported to accelerate healing of
an allograft to the joint capsule. 52 Hashimoto and coworkers 53 tested the effect of ECGF on a cylindrical defect
in the canine meniscus and found that defects that contained both the fibrin sealant and ECGF had the best
healing.
The major challenge for growth factor application at this
time is delivery of the selected factor into the target tissue.
Because of rapid dilution and short half-lives, single doses
of growth factors may not provide adequate local concentrations to induce significant biological effects.54 Thus, it is
evident that a carrier vehicle, such as an absorbable material, will be required to localize the growth factor at the
repair site in a biologically relevant concentration. Alternatively, gene therapy techniques may be used to induce
local production of the desired protein.

MENISCAL REPLACEMENT
Although techniques of meniscal repair and partial meniscectomy have limited the cases of total meniscectomy,
there are still instances in which total resection of the
tissue is the only option. Because of the deleterious consequences of meniscal loss, replacement of the meniscus
through allograft transplantation or tissue-engineered meniscus is being explored.

BASIC SCIENCE OF MENISCAL

TRANSPLANTATION
Meniscal transplantation presents a useful reconstructive
option for patients with loss of the meniscus because of
previous meniscectomy or an irreparable meniscus tear. 9,55
Laboratory studies have provided the impetus for the
clinical use of meniscal allografts, and subsequent clinical
and basic science investigations have further refined its
application. 6-55 As with any tissue, successful transplantation is dependent on several factors, including tissue preservation, the immunologic compatibility of the donor and
host, and the long-term biologic and biomechanical integrity of the transplant. 56
The basic biology of meniscus transplantation has been
studied in various animal models. 57-6 Fresh and cryopreBIOMECHANICS AND HEALING RESPONSE OF THE MENISCUS

served allografts contain viable cells at the time of transplantation, while fresh-frozen and lyophilized tissue are
acellular. 56 It is not known what proportion of the cells in
a fresh transplant survive after transplantation, and for
how long these cells survive in humans. Jackson and coworkers 58 used DNA probe analysis in a goat model and
found that all of the donor cells in a fresh meniscal transplant were rapidly replaced by host cells. Experimental
studies in goats have suggested that there are no important differences between cryopreserved and deep-frozen
grafts. 59,6 Lyophilized grafts have been found to undergo
shrinkage, and thus are not currently recommended. 55 The
tissue may be secondarily sterilized using gamma irradiation or ethylene oxide, but these processes may adversely
affect the material properties or induce synovitis. 55
Animal studies as well as human biopsy studies demonstrate incomplete cellular repopulation, with the central
core of the graft often remaining acellular. Animal studies
demonstrate active collagen remodeling by the cells that
repopulate the meniscus. 61 There are alterations in the
biochemical composition of the meniscus (ie, proportions
of water and proteoglycan) compared with the normal
meniscus after transplantation, which are likely to adversely affect the material properties of the tissue. 59
The process of cellular repopulation requires migration
of extrinsic cells into the dense meniscal matrix, resulting
in structural remodeling of the matrix. The biomechanical
effect of such structural remodeling was demonstrated by
Bylski-Austrow and co-workers 6a who studied meniscal
transplantation in a goat model and found that grafts with
the greatest degree of cellular repopulation were actually
the least effective in load distribution. The long-term ability of the cells that repopulate the allograft to synthesize
appropriate matrix proteins and maintain the extracellular
matrix is also unknown. The graft undergoes gradual,
incomplete revascularization, with new capillaries derived
from the capsular and synovial attachment?
Another important aspect of meniscus transplantation is
healing of the anterior and posterior horn attachment sites.
Rodeo and co-workers 63 found improved healing rates in
menisci transplanted with attached bone plugs, suggesting that healing of bone plugs in a bone tunnel is more
secure than healing of the meniscus to bone. This findings
supports cadaver models that have demonstrated superior
load transmission with meniscal horn bone plug fixation
compared with no bone plugs. 64,65 There is very little
information available on the healing of meniscus to bone,
and no studies have compared healing of bone plugs to
healing of meniscal tissue in a bone tunnel. Gao and
co-workers 66 reported that the tensile strength of a healed
meniscal attachment after detachment and repair to bone
in a rabbit model approached only 20% of the strength of
the normal meniscal horn attachment. It is likely that
secure fixation of the allograft is critical for initial healing,
remodeling of the allograft, and long-term function.
There is very little information available on the histologic characteristics of meniscus transplants in humans.
Rodeo and co-workers s6 used histologic techniques to examine biopsies of meniscus and synovium from patients
with both intact and failed meniscus transplants. This
analysis demonstrated findings consistent with gradual

73

TISSUE-ENGINEERED MENISCUS

n?[
Fig 5. Future techniques to enhance meniscal healing.

repopulation of the allograft with host cells. Although

frank immune rejection is rarely seen clinically, there is
histologic evidence of an immune response directed
against the graft. It has been demonstrated that both class
I and class II histocompatibility antigens are expressed on
the meniscal cells, even after freeze-thaw cycles. 56,67 The
presence of these histocompatibility antigens at the time of
transplantation indicates the potential for an immune response. Rodeo and co-workers ~6 found that the majority of
the specimens contained a small number of immune-reactive cells (B-lymphocytes or T-cytotoxic cells) in the meniscus or synovium, or both. The presence of these cells
suggests the possibility of a subtle immune reaction
against the transplant. Such an immune reaction may
modulate graft healing, incorporation, and graft revascularization. 56 Further studies are required to increase our
understanding of the process of cell migration into the
allograft tissue during cellular repopulation, the resultant
phenotype of the repopulating cells, and the effect of an
immune response on graft remodeling.

FUTURE TECHNIQUES FOR ENHANCEMENT

OF MENISCAL HEALING
Research is currently ongoing into methods to enhance
meniscus healing and to regenerate meniscus tissue (Fig
5). Recent studies have demonstrated the ability to transfect meniscal fibrochondrocytes with novel genes using
gene therapy techniques, suggesting that bioactive factors
could be delivered to meniscus by transferring growth
factor genes to meniscal cells, s-75 Tissue engineering techniques using absorbable polymer scaffolds seeded with
cells and growth factors are also being explored as a
means to heal meniscus lesions, as well as to potentially
regenerate meniscus t i s s u e . 54,69-78

74

Creating a tissue-engineered meniscus requires that specific biologic considerations such as cell type, matrix scaffold, bioreactor design, and environmental conditions be
addressed. Meniscal cells, fibroblasts, chondrocytes, and
mesenchymal stem cells have been proposed as potential
cell sources and have been grown (both in vivo and in
vitro) on various scaffolds including collagen-based scaffolds, 9-68 chondrocyte-seeded cartilaginous scaffolds, 7
biodegradable polymers, 71 and small intestine submucosa
(SIS). 72-74 Gastel and co-workers 72 showed that SIS grafts
are capable of supporting the complete healing of meniscal
defects in rabbits. Cook and co-workers 73 found that the
use of SIS grafts in dogs with large (>50%), completely
avascular meniscal defects resulted in superior clinical
function, greater and more representative replacement tissue, and increased cartilage protection when compared
with ungrafted controls. Although the mechanism of tissue regeneration using SIS grafts remains unclear, the
presence of collagen types I, III, IV, and VI, GAGs, fibroblast growth factor, and transforming growth factor in SIS
may contribute to structural, chemotactic, mitogenic, and
stimulatory effects on cells and matrix, r4

GENE THERAPY
Recent emphasis in meniscal research has been directed
toward applications of molecular biology to promote meniscal regeneration. Gene transfer has emerged as a new
approach for growth factor delivery. 76 Several investigators have demonstrated the ability to transfer specific
genes into meniscal chondrocytes using retroviral and
a d e n o v i r a l v e c t o r s . 54,75,77,78 Goto and co-workers 77 implanted an adenoviral suspension with a fibrin clot into
experimentally created canine and lapine meniscal lesions.
They demonstrated successful delivery with gene expression lasting the 3-week duration of the experiment. In the
same study Goto and co-workers 77 observed successful
transgene expression 6 weeks after transplantation of retrovirally transduced cells into meniscal defects.
The future ability of gene therapy to treat meniscal
injuries depends on precise identification of appropriate
growth factors and finding the most effective means for
gene delivery. Understanding the appropriate length of
time for gene expression and finding a means to control
levels of gene expression are important. 7s Future research
in gene therapy will also focus on methods to accelerate
meniscal allograft healing and enhance bioengineered meniscal tissue.

SUMMARY
The important role of the meniscus in normal knee function is well established. Efforts must be continued to find
better methods and techniques to manage meniscal injuries. These targets should include new techniques of repair
for meniscal tears, methods to enhance the cellular response for healing of meniscus tissue, and novel methods
to regenerate lost or damaged tissue. Meniscus transplantation has emerged as a useful treatment option for selected patients with meniscus deficiency. Further studies
KAWAMURA ET AL

are required to increase our understanding of the process

of cell migration into the meniscus, the resultant phenotype of these cells, and the effect of an immune response
on graft remodeling. This information will also be applicable to tissue-engineered meniscus replacements. Tissueengineered menisci will provide a valuable treatment option, but further investigations are required before this
will become a clinical reality.

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