Cell and Tissue Research (2018) 373:337–350

https://doi.org/10.1007/s00441-017-2778-6

REVIEW

Native tissue-based strategies for meniscus repair and regeneration

Zengzeng Zhang 1,2,3,4 & Weimin Guo 1,2,3 & Shuang Gao 5 & Mingxue Chen 1,2,3 & Xu Li 6 & Xueliang Zhang 1,2,3,7 &
Xiaoguang Jing 1,2,3,4 & Mingjie Wang 1,2,3 & Yu Zhang 1,2,3 & Shi Shen 1,2,3,8 & Zehao Wang 1,2,3 &
Baichuan Sun 1,2,3,4 & Ying Chai 4 & Chengfu Zhou 4 & Shuyun Liu 1,2,3 & Quanyi Guo 1,2,3

Received: 12 July 2017 / Accepted: 19 December 2017 / Published online: 3 February 2018
# Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
Meniscus injuries appear to be becoming increasingly common and pose a challenge for orthopedic surgeons. However, there is
no curative approach for dealing with defects in the inner meniscus region due to its avascular nature. Numerous strategies have
been applied to regenerate and repair meniscus defects and native tissue-based strategies have received much attention. Native
tissue usually has good biocompatibility, excellent mechanical properties and a suitable microenvironment for cellular growth,
adhesion, redifferentiation, extracellular matrix deposition and remodeling. Classically, native tissue-based strategies for menis-
cus repair and regeneration are divided into autogenous and heterogeneous tissue transplantation. Autogenous tissue transplan-
tation is performed more widely than heterogeneous tissue transplantation because there is no immunological rejection and the
success rates are higher. This review first discusses the native meniscus structure and function and then focuses on the use of the
autogenous tissue for meniscus repair and regeneration. Finally, it summarizes the advantages and disadvantages of heteroge-
neous tissue transplantation. We hope that this review provides some suggestions for the future design of meniscus repair and
regeneration strategies.

Keywords Native tissue . Meniscus . Tissue repair and regeneration . Autogenous tissue transplantation . Heterogeneous tissue
transplantation

Zengzeng Zhang and Weimin Guo contributed equally to this work.

* Chengfu Zhou Xueliang Zhang

hyd27zcf@163.com Xueliangzhang301@126.com
* Shuyun Liu Xiaoguang Jing
clear_ann@163.com 1490286555@qq.com
* Quanyi Guo
Mingjie Wang
doctorguo_301@163.com
waikejie@163.com
Zengzeng Zhang
Yu Zhang
Zzz04_26@163.com
526936415@qq.com
Weimin Guo Shi Shen
603580442@qq.com 583493289@qq.com
Shuang Gao Zehao Wang
591685142@qq.com 18210588395@163.com

Mingxue Chen
chenmingxueplagh@hotmail.com Baichuan Sun
sunbaicuan@163.com
Xu Li
lixu0610@126.com Extended author information available on the last page of the article
338
Introduction
Scholars once believed that the meniscus was a non-functional
tissue in the refined body (Scotti et al. 2013). With medical
developments and in-depth research, medical workers have
accepted that the knee meniscus plays a vital role in the me-
chanical distribution, stability and homeostasis of the
tibiofemoral joint (Makris et al. 2011). Clinical knee injuries,
the largest proportion of which are those to the meniscus, are
quite common and complicated. Animal trials and clinical
studies have revealed that a meniscus injury without interven-
tion and meniscectomy increases the risk of osteoarthritis and
accelerates degeneration of the knee joint (Edd et al. 2015;
Papalia et al. 2011; Pengas et al. 2012). Therefore, to address
the key clinical issues concerning the suffering of patients and
delaying the time of arthroplasty, the replacement of
meniscectomy with meniscus transplantation is increasingly
being used to treat meniscus injuries. Considering the close
relationship between osteoarthritis and meniscus integrity, nu-
merous materials have been transplanted to replace an injured
meniscus or to accelerate its repair and regeneration (Lee et al.
2014; Merriam et al. 2015; Sarem et al. 2013; Zur et al. 2011).
Hydrogel-based scaffolds have been widely applied to menis-
cus repair and regeneration because they can deliver seed cells
and biochemical stimuli and easily restore the normal shape of
meniscus defects. However, their unsatisfactory biomechani-
cal capacity has restricted the therapeutic use of these scaf-
folds (Koh et al. 2017; Simson et al. 2013; Wu et al. 2015;
Yuan et al. 2017). Degradable natural polymers, such as bac-
terial cellulose, the collagen meniscus implant and the multi-
layered silk scaffold, represent a class of materials used for
meniscus implants (Bodin et al. 2007; Bulgheroni et al. 2010;
Mandal et al. 2011). However, their natural conformation is
significantly different from that of the meniscus. Their good
mechanical properties include high porosity and interconnec-
tivity. However, their long-term effects have not been con-
firmed due to the lack of a detailed description of their char-
acteristics. The use of non-degradable synthetic materials is
one of the mainstream directions for meniscus substitution
research (Elsner et al. 2010; Vrancken et al. 2012).
Nevertheless, the inherent shortcoming of this material is its
lack of biocompatibility and bioactivity. Moreover, the mate-
rial is vulnerable to shear force in the long-term mechanical
environment of the knee, possibly because the internal struc-
ture of the synthetic materials is not comparable with menis-
cus collagen orientation. Therefore, native tissue-based strat-
egies for meniscus repair and regeneration are of utmost im-
portance. The first meniscus transplantation was reported as
early as 1984 (Arnoczky et al. 1990). Soon after, the clinical
application of meniscus transplantation was introduced into
the literature (Keene et al. 1987). After many years of explo-
ration on meniscus injury, treatments using native tissue have
proven better than meniscus resection (Abrams et al. 2013).
Cell Tissue Res (2018) 373:337–350
Native tissue simulates the natural structure and composition
of the replaced tissue. Its high degree of geometric fidelity and
similar extracellular matrix (ECM) components provide a
space and environment for chondrocyte growth and its bio-
compatibility and degradability ensure cellular activities and
promote special matrix deposition in the meniscus. It also
regulates the interactions between bioactive factors and cells
to improve cell adhesion and differentiation. Furthermore, na-
tive tissue can be fabricated into specially designed shapes,
meeting personalized needs in meniscus transplantation.
Currently, multiple tissue engineering fields have applied na-
tive tissue to accelerate the functional tissue repair process.
Accordingly, the use of biomaterials in meniscus tissue engi-
neering and native tissue in regenerative medicine will contin-
ue to develop. Thus, native tissue-based strategies for tissue
repair and regeneration are rapidly emerging.
The purpose of this paper is to summarize native tissue-
based strategies for meniscus repair and regeneration and to
find available proposals or potential treatments of meniscus
defects, as well as to discuss future trends.
Meniscus structure and function
The biochemical content of the meniscus is mostly composed
of the ECM and cells (Makris et al. 2011; McDevitt and
Webber 1990; Sweigart and Athanasiou 2001). The ECM in-
cludes fibrillar components, proteoglycans and adhesion gly-
coproteins. Among them, the fibrous structure of the meniscus
can be refined to four layers (Fig. 1). The irregularly shaped
superficial fibers are woven into the reticular matrix by retic-
ular fibers. The lamellar surface layer is partly composed of an
irregular arrangement of collagen fibers. The middle layer is
composed of radially aligned collagen fiber bundles and cir-
cumferential fibers (Villegas and Donahue 2010). The large
and thick C-shaped bending fibers help resist tension and
transfer the knee joint load for the meniscus. The main fiber
of the outer region and medial region are collagen I and col-
lagen II, respectively (Cheung 1987). Collagen I, accounting
for no less than 90%, is a fibrillar component of the meniscus
and functions to improve meniscus tensile stress. Radially
scattered fibers (e.g., the “rope”), which strengthen the menis-
cus, prevent longitudinal tears caused by excessive pressure.
Regional variation in these molecules has been observed.
For example, the inner two-thirds contain a relatively higher
proportion of proteoglycans than the outer one-third (Scott
et al. 1997) and play a role in liquid absorption, acting as a
molecular sponge when the internal structure of the meniscus
is compressed (Adams and Muir 1981). Only the peripheral
part of the meniscus contains blood vessels and nerves, ac-
counting for 10–25% of the entire structure (Clark and Ogden
1983). However, they provide the central nervous system with
information regarding joint position and contribute to a reflex
Cell Tissue Res (2018) 373:337–350 339

Fig. 1 Schematic of the meniscus

fibers. a The irregularly shaped
superficial fibers. b The lamellar
surface layer. The middle layer is
composed of c (large and thick C-
shaped bending fibers) and d
(radially aligned collagen fiber
bundles)

arc that stimulates protective or postural muscular reflexes considered in regenerative medicine and tissue engineer-
(O'Connor 1984; O'Connor and McConnaughey 1978). ing. Here, we review how native tissues naturally have a
The inner one-third is referred to as the white–white zone compound structure and similar mechanical properties and
(without vessels and nerves). However, upon mechanical retain almost all ECM functionality.
stimulation, the polycellular solid matrix in the white–
white zone becomes deformed and the liquid flows into
the gap (inter-tissue) so that cells can obtain nutrition
Table 1 ECM and cellular components of the meniscus
from the synovial and interstitial fluid. However, clinical-
ly, this structural feature presents obvious defects. For ECM Fibrillar Collagen: Superficial layer: Inner
example, once the fibrocartilage in the white–white zone compo- component irregular reticular re-
is damaged, it has very little capacity for spontaneous nents fibers gion:
Lamellar surface 60%
healing due to its intrinsically limited blood supply layer: partly colla-
(Arnoczky and Warren 1982). The different components irregular fibers gen II,
(from the outside in) of the meniscus are listed in Table 1. Middle Large and 40%
Clinically, when the calf is in semi-flexion and the layer thick colla-
C-sha- gen I
outside booth is in knee flexion, the femur quickly rotates Outer
ped
externally and, under this rotation pressure, the medial bend- re-
meniscus is vulnerable to acute tears (Englund et al. ing gion:
2012; Rongen et al. 2014). Based on mechanical analyses, ring >90%
fibers colla-
axial compression stress from the upper body is partly gen I,
converted into half-moon ring stress through the menis- Radially
types
arrang-
cus, resulting in shear force; the other part is transformed ed,
II, III,
into radial deformation of the collagen fibers (Donahue IV, VI,
scatter-
VIII
et al. 2015). During knee flexion, the joint reactive force ed fiber
and X
through the meniscus increases from 50 to 90% (Walker bun-
dles
and Erkman 1975). The complexity of the mechanical
Elastin
environment complicates the microstructure of the menis-
Proteoglycans Chondroitin-6-sulfate,
cus. A variety of fiber and ECM components of the me-
chondroitin-4-sulfate, dermatan sulfate,
niscus adapt to this change to transfer the knee joint load, keratin sulfate and hyaluronic acid
resist tension, prevent longitudinal tears in the meniscus Adhesion Fibronectin and trombospondin
and protect the knee. In summary, the meniscus maintains glycopro-
the stability and homeostasis of the femoral condyle and teins
tibial plateau and meniscus tears are the combined effects Cellular Outer one-third: fibroblast-like cells; superficial region:
compo- fusiform cells; inner two-thirds: chondrocyte-like cells.
of these forces. The mechanical properties are the most nents
important features of materials and are the first to be
340
Autogenic tissue transplantation
Tendon
The major constituents of the tendon ECM are type I collagen,
type III collagen and several proteoglycans (Hogan et al.
2011). Type I collagen makes up approximately 80–90% of
the dry mass of the tendon (Kannus 2000). The parallel fibrils
of collagen I increase tensile strength. Proteoglycans contrib-
ute to matrix assembly, fibril arrangement and the viscoelastic
response to crushing stress (Karousou et al. 2008). A compar-
ative analysis of the internal ultrastructure and related me-
chanical properties of the meniscus and tendon revealed that
the collagen type and content in a tendon graft is analogous to
the peripheral third of the native meniscus and that the natural
tendon’s tensile modulus (123.28 ± 35.05 MPa) (Deng et al.
2014) is similar to the circumferential tensile modulus of the
medial meniscus in humans (93.2–159.6 MPa) (Fithian et al.
1990) (i.e., a tendon graft not only mimics the constituents and
structure but also emulates resisting tension). Compared to
other native tissues, autogenous tendon tissue, as a surrenal
for an injured meniscus, has attractive features. For example,
tendon stem cells residing in the tendon can differentiate into
cartilage (Bi et al. 2007). As early as 1992, Kohn et al. (1992)
selected a partial patellofemoral tendon as a substitute after
total medial meniscectomy. Histological and macroscopic
analyses demonstrated that the graft was regenerated as the
tendon meniscus and delayed knee degeneration in sheep.
With the aims of reducing surgical trauma and simplifying
the operating procedure, donor tissue next to the transplant
site, such as the semicircular tendon, patellar ligament and
quadriceps tendon, was generally selected. Goble et al.
(1999a) used the quadriceps tendon for meniscal reconstruc-
tion. However, the desired effect was not achieved. Johnson
and Feagin (2000) performed a semitendinosus tendon trans-
plant (four cases) and a patellar tendon transplant (one patient)
after meniscal resection, which were also unsuccessful. The
follow-up results revealed that the five patients accepted or
would accept joint replacement. Goble speculated that the
cells in the autologous transplant tendon were unlike the var-
ious types of cells in the meniscus, which may have caused the
clinical trial to fail. Thus, by adding an interferential factor to
the cells, the meniscal defect repair was overturned. Several
lines of evidence have confirmed that mesenchymal stem cells
(MSCs) promote meniscus repair and regeneration
(Moriguchi et al. 2013; Shen et al. 2014). Ozeki et al. (2015)
pretreated the Achilles tendon with exogenous synovial-
derived MSCs (SMSCs) and repaired a partial meniscus de-
fect in a rat model. Macroscopic and histological analyses on
articular cartilage at the medial tibial plateau have proven that
an Achilles tendon graft with SMSCs protects the articular
cartilage and prevents cartilage degeneration. Based on the
role of bone morphogenetic protein 7 (BMP-7) in skeletal
Cell Tissue Res (2018) 373:337–350
growth (Macias et al. 1997) and its therapeutic effect on joint
cartilage injury (Acosta et al. 2006; Chubinskaya et al. 2007;
Cook et al. 2003), BMP-7 was used to enhance ECM deposi-
tion (Mainil-Varlet et al. 2013) by upregulating the expression
of hyaluronan receptors, hyaluronic acid synthase-2 (Nishida
et al. 2000) and aggrecan (Flechtenmacher et al. 1996) in
chondrocytes. Moreover, previous reports have revealed that
BMP-7 enhances tendon regeneration into meniscus-like tis-
sue at the defect site (Ozeki et al. 2013). Therefore, BMP-7
has been extensively explored in the field of meniscus
regeneration.
Recently, Li and his group attempted to use semitendinosus
tendon as an autograft to repair meniscus defects in a rabbit
model (Li et al. 2017). The reconstruction group regenerated a
new meniscus and there were no significant differences be-
tween the native and regenerated meniscus at 24 weeks in
terms of the elastic modulus and hardness. Moreover, the car-
tilage protection was significantly better in the reconstruction
group compared with the untreated group. Semitendinosus
tendon autografts are also promising in meniscus reconstruc-
tion. A very recent innovative study demonstrated that
kartogenin (KGN) can induce tendon stem cells (TSCs) to
convert directly into chondrocytes in vitro and in vivo (He
Huang and Zhao 2017). The prospects of using tendon to
repair meniscus defects seem to be improving, although more
experiments need to be performed.
Synovial tissue
The loose connective tissue-synovial membrane is divided
into two layers, namely, the cell layer (inner cavity) and the
vascular layer (subintima), in which the rich blood vessels and
a large number of differentiated cells repair the tearing menis-
cus. The subintima contains synovial parallel elastic fibers and
collagen fibers to prevent the formation of folds in the syno-
vial membrane and to provide mechanical strength. Therefore,
Ghadially and Veth used a synovial pedicle flap to repair an
avascular meniscus injury and achieved satisfactory results in
animal models (Ghadially et al. 1986; Veth et al. 1983).
However, one question that has always confused researchers
is whether augmented healing is due to the autologous syno-
vial tissue transplantation itself or from the increased blood
supply from the synovial flap. To address this question,
Jitsuiki et al. (1994) used interpositional free synovial auto-
grafts with a common horizontal suture to repair an artificial
longitudinal tear. The efficiency of autologous synovial tissue
transplantation for augmented meniscal healing has been re-
ported. Shirakura et al. (1997) observed the number of blood
vessels and the extending distance by light microscopy and
microangiography and verified the synovial membrane poten-
tiality as a graft to repair an injured meniscus rather than blood
vessels. However, unlike the tendon, the mechanical strength
of synovial tissue is not sufficient to protect the tibiofemoral
Cell Tissue Res (2018) 373:337–350
articular surface or decentralized concentrated stress. In syno-
vial tissue, synovium-derived stem cells (SDSCs) play a role in
meniscus repair and regeneration (Yu et al. 2015). Synovial
cells have a multi-directional differentiation ability and their
chondrogenic capacity has been confirmed (Horie et al. 2012;
Koga et al. 2007). During the repair process, synovial cells first
penetrate into the meniscus tear at the white–white zone
(Heatley 1980). Next, exudative synovial cells form fibrous
tissue that may turn into fibrous cartilage under local stress
(Heatley 1980). A previous study reported that, 3 weeks after
transplant surgery, 62% of synovial grafts were repaired with
fibrous tissue; 6 and 12 weeks after transplant surgery,
fibrocartilage tissue repaired more than 65% of tears (Sekiya
1992). This, in turn, demonstrates the authenticity of the
abovementioned repair process. To further explore how to im-
prove the effects of synovial graft repair and shorten the time to
regenerate mature meniscus tissue, Okamura et al. (1996) com-
pared the peak time that basic fibroblast growth factor (bFGF)
and synovial grafts repair a meniscal lesion and found the ap-
pearance of chondrocyte-like cells earlier in the bFGF group,
indicating that bFGF accelerates the repair process.
Infrapatellar fat pad
With respect to function, the infrapatellar fat pad (IPFP) is
adipose synovium tissue, which plays a role in the two
abovementioned organizations. The synovial tissue described
above is effective at repairing meniscal lesions. However,
whether the patellar fat pad is also effective remains unclear.
To address this question, Milachowski et al. (1990) used the
patellar fat pad as an implant but the graft did not achieve the
desired effect. Kohn et al. (1997) used the fat pad as a substi-
tute for the meniscus in a sheep model and concluded that the
fat pad is not suitable as a substitute for meniscus
transplantation. In summary, the IPFP is not strong enough
to divert the knee load, to separate the tibial plateau from the
femoral trochlear, to absorb shock, or to protect the articular
cartilage. Thus, Oda et al. (2015) performed relevant experi-
ments to improve the mechanical strength of the IPFP and
concluded that the IPFP can accelerate collagen scaffolds to
heal defects in the meniscus, which the author believes is due
to MSCs derived from the IPFP migrating toward the collagen
scaffold and differentiating into chondrocytes. A heuristic ex-
periment revealed that MSCs from the IPFP have more carti-
lage differentiation potential than skin adipose tissue
(Mochizuki et al. 2006). Based on this result, the IPFP should
be considered for use in various fields and could be widely
used in medical science research.
Perichondrium
Perichondrium derived from mesenchymal tissue has multi-
directional differentiation potential and can be transformed
341
into fibrocartilage by stimulation of the knee environment
and biological stress. Previous experiments have confirmed
that hyaline cartilage defects can be treated with a perichon-
drium graft, which offers a mechanical modulus to resist shear
stress (Engkvist and Ohlsén 2009; Woo et al. 1987).
Autologous perichondral tissue after transplantation also has
this advantage. Bruns et al. (1998, 2000) used autologous
costal perichondrium transplantation to displace the meniscus
in a sheep model and the graft formed a high-imitation menis-
cus based on histological analysis. These results confirm the
ability of perichondral tissue to regenerate into meniscal fi-
brous cartilage in the microenvironment of the knee joint and,
under compound stress, the orientation of the neo-
perichondrial meniscus collagen fibers are re-allocated and
adjusted.
Heterogenous tissue transplantation
Allogeneic meniscus
The three-dimensional spatial structure and biochemical con-
tent of the allograft meniscus is very close to the organ being
replaced at the molecular level. Theoretically, the allogeneic
meniscus is the ideal transplant to replace a damaged menis-
cus in situ. The meniscus, whose cells are buried in a dense
matrix and indirectly contact immune effector cells, belongs to
a dense connective organization. It is an immune-
advantageous organ due to immune shielding. The success
of fresh allogeneic meniscus transplantation has fully demon-
strated this advantage (Verdonk et al. 1994). However, recent
studies have shown that cells on the meniscus express Class-I
and Class-II human leucocyte antigen antigens, demonstrating
potent immunogenicity (Cao et al. 1997; Khoury et al. 1994;
Wada et al. 1998). Serving as a heterogenous tissue implant,
an allogeneic meniscus must be handled appropriately to de-
crease its potential immunogenicity before transplantation.
Three different processes, namely, cryopreservation, deep-
freezing and lyophilization, are the most often used in the
clinic. Wirth et al. (2002) found that the long-term results of
cryopreserved meniscus transplants were more similar to the
normal knee joint compared to lyophilized meniscal trans-
plants. Hence, it is clear that a cryopreserved graft will destroy
the original structure but reduce the antigen-antibody response
to a certain degree, which is of more practical significance.
However, the four methods of meniscus allogeneic transplan-
tation (MAT) described above cause a distinct challenge (i.e.,
whether donor cells can survive in the transplant). Several
researchers believe that donor cells can survive in the allograft
(Verdonk 1997), which positively reflects the graft success,
durability and mechanical integrity (Rodeo 2001; Siegel and
Roberts 1993). To demonstrate this relationship, histopatho-
logical observation of the rabbit meniscus revealed that
342
fibroblasts differentiate into chondrocytes at 8–12 weeks after
transplantation, which is helpful for meniscus repair and re-
generation (Shibuya 1999). Another study reported that donor
cells in an allogeneic meniscus disappeared rapidly after the
graft and were soon replaced by host MSCs (Jackson et al.
1993). Therefore, we cannot rule out the possibility that cells
in the graft may die rapidly and be replaced with host cells that
are gradually transformed into fibrocartilage. To date, whether
in clinical or scientific research, allogeneic meniscus
transplantation is a relatively mature technology to repair
meniscal injuries. Milachowski et al. (1988) were the first to
perform homologous meniscus transplantation; they demon-
strated that meniscus transplantation is a viable treatment op-
tion for men with a missing meniscus to reduce pain, increase
the range of joint activity and improve joint function
(Hommen et al. 2007; van der Wal et al. 2009). However,
some studies have shown that it does not achieve the desired
effects, nor does it prevent the degeneration of articular carti-
lage after prolonged observation (Milachowski et al. 1994;
Rijk et al. 2002). According to a semi-quantitative analysis
of the effects of MAT, the overall subjective knee condition
improved from 3.5 to 6.9, with an average satisfaction rate of
8.8. The overall success rate at the last follow-up was 88%
over 7 years in at least 22 menisci (Saltzman et al. 2012).
Whether MAT maintains the long-term protective effects on
the joint surface remains a hot topic. Allogeneic meniscus
transplantation has a significant advantage for repairing a se-
verely injured or absent meniscus but will require more in-
depth developments.
Xenogeneic meniscus
Unlike an allogeneic meniscus to reduce antigenicity, a xeno-
geneic meniscus must be decellularized for recellularization
after transplantation, which ultimately forms an acellular tis-
sue matrix (ACTM). Chemical treatments remove soluble
proteins and the cellular components of native tissue and in-
soluble matrix components that maintain the morphological,
histological and ultrastructural features are retained (i.e., col-
lagen, elastin and non-collagen glycoproteins). For example,
Gao et al. (2016) immersed a meniscus in 1% (w/w) sodium
dodecyl sulfate solution for decellularization. In the case of
dry weight, the comparison of an acellular meniscus with a
normal meniscus revealed that the amount of glycosaminogly-
cans accounting for the original meniscus was 0.503, the hy-
droxyproline content was increased relative to the natural me-
niscus and the DNA content of the decellularized meniscus
decreased by 92.2%. There were no statistically significant
differences in tension between the acellular meniscus and nor-
mal meniscus but the compression modulus of decellularized
menisci had discordant tension properties to intact ones (i.e.,
the acellularized meniscus retained the geometrical structure
of the original material and reduced knee stress, while
Cell Tissue Res (2018) 373:337–350
minimizing the immunogenicity to a greater extent). A hetero-
geneous allogeneic meniscus solves the clinical problem of a
limited source of human menisci. A subcutaneously implanted
porcine decellularized meniscus in galactosidase knockout
mice demonstrated good cell attachment ability, immune com-
patibility and infiltration adhesion (Stapleton et al. 2011).
Chinese scholars compared a rabbit knee meniscus allograft
(porcine meniscus as a donor) to allogeneic meniscus trans-
plantation and found that the meniscus and articular cartilage
were good and viable after xenogeneic meniscus transplanta-
tion in the short term (Huang et al. 2009; Jiang et al. 2012).
However, after 24 weeks, the graft was partially absorbed, the
articular cartilage began to degrade and the collagen was ab-
normally expressed. A heterogeneous meniscus cannot fully
match the structure of the recipient joint, which may result in
unclear long-term curative effects. Thus, it will be important
to address the permanent survival of a heterogenous meniscus
transplant to better explore meniscus acellular methods for
reducing a foreign body reaction and achieving long-term
protection of articular cartilage.
Small intestine submucosa
The small intestine submucosa (SIS) is a commercialized na-
tive tissue-derived ACTM developed by a company in the
United States. The ACTM is usually formed through a
decellularization procedure using physical and chemical
methods or their combination, which mostly retain the major
components and structures of the original organization and
remove the relevant antigen. SIS retains submucosal tissue
after removing the small intestine mucosa, serosa and tunicae
muscularis by physical methods, which retains a small amount
of cellular components in the matrix but also maintains solu-
ble substances (Allman et al. 2001). SIS can be rapidly de-
graded in vivo with antimicrobial activity (Sarikaya et al.
2002), good biocompatibility and biomechanical properties
(Grimes et al. 2005). It also contains collagen, amino polysac-
charides, glycoproteins and other ingredients; however, colla-
gen, particularly types I and III, accounts for approximately
40% of its dry weight, similar to the meniscal ECM of the
inner two-thirds region (Roeder et al. 1999). SIS also contains
a variety of growth factors (Nihsen et al. 2008), including
FGF-2, TGF-β and VEGF (Rosen et al. 2002). Many senior
scholars have applied it to zoopery and clinical applications
(Bradley et al. 2007; Cook et al. 2001; Fox et al. 2004). In
Cook’s utilization of a heterotopic allograft (Cook et al.
2006b), SIS transplantation induced regeneration of the recep-
tor’s own tissue into cartilage tissue and restored the meniscal
form. Long-term animal experiments in the field of injured
meniscus repair have also shown that SIS has good effects
(Cook et al. 2006a). To analyze the function of SIS in the
meniscus and progenitor cells (Tan 2009; Warnock et al.
2014; Zhao et al. 2007) and the relationship between their
Cell Tissue Res (2018) 373:337–350
interaction and meniscus regeneration, Tan et al. (2010) mixed
meniscus cells, synovial-derived stem cells and fibrinogen
into freeze-dried SIS and cultured the mixture in vitro. After
inoculation, attached cells were evaluated by electron micros-
copy and cell migration was tracked by fluorescence micros-
copy. During culture for 30 days, neonatal tissue invasion was
observed in SIS, indicating good biocompatibility between the
cells and scaffolds. Thus, it was concluded that SIS can be
used as a scaffold for meniscus tissue engineering.
Discussion
The goal of the implant is to mimic the composition and
structure of the meniscus. This article reviews native tissue-
based strategies for meniscus repair and regeneration. The
potential regeneration mechanism is summarized in Fig. 2.
Table 2 summarizes results of research in vivo concerning
native tissue for meniscus repair and regeneration. These
can be divided into two categories: autogenic tissue trans-
plantation and heterogenous tissue transplantation (native
tissue-derived ACTM), which is further divided into alloge-
neic tissue and xenogeneic tissue. The application of selected
autologous tissue transplantation methods has a positive ef-
fect on the replacement or repair of a damaged meniscus. In
general, the tendon and perichondrium function as a support-
er for cells, while the perichondrium, synovium and IPFP
provide a large number of stem cells as a cell source.
Moreover, these tissues contain a small number of growth
factors that have a certain effect on tissue regeneration and
repair. Compared to the perichondrium, the tendon has a fa-
miliar elastic modulus as the natural meniscus and provides a
well-defined structure for repairing cells to ensure their activ-
ity and function. Although the perichondrium contains a large
number of cartilage MSCs, it has disadvantages (i.e., its in-
sufficient mechanical strength). One of the main reasons why
it is no longer used is that its own access is highly limited.
The advantage of synovial tissue is that SDSCs have the
potential to differentiate into fibrocartilage and can be applied
to clinical tissue engineering regeneration. However, due to
mechanical defects, it can only be used for meniscus tear
repair and cannot repair or replace a full-cut meniscus. In
the same manner, the advantage of the patellar fat pad is that
it is located in abundant capillaries that contain a large num-
ber of pericytes, which help repair and regenerate the carti-
lage and meniscus but cannot serve as a single scaffold.
Therefore, the tendon best plays the role of a meniscal scaf-
fold. Therefore, the use of autologous tendon transplantation
in the clinic should be further explored to enhance its regen-
eration qualifications. The use of autogenic tissue transplan-
tation to replace a full-cut meniscus is limited. For example, it
is difficult to find autogenic tissue that matches the native
meniscus regarding both its shape and structure and the
343
function of the remaining tissues in the original site has little
effect after cutting the original tissue. In regenerative medi-
cine research, these native tissue materials are generally used
for tissue engineering in vivo. Although some natural tissue
materials cannot be used directly for regeneration, they are
still advantageous. In the near future, the identification of
growth factors and a mechanism that explains chondrogenic
differentiation will be researched (Centeno et al. 2008; Fan
et al. 2009). Combined with growth factor chemotaxis effect,
mechanical property of the materials and microenvironment
of knee joint, these materials will be very promising to repair
the medial area of the meniscus.
Heterogenous tissue transplantation for rescuing meniscal
lesions, whether in a trial or clinic, is more extensive. In clin-
ical applications, MAT can significantly ameliorate symptoms
of pain and protect the articular surface in the short term (Rijk
2004; Samitier et al. 2015). Medium- and long-term follow-up
results have also been affirmed (Saltzman et al. 2012). From
the cellular and molecular levels, newly formed chondrocytes
in an allogeneic meniscus will remold grafts. As the cellular
phenotype changes and the matrix becomes more transparent,
meniscus reconstruction will progress. In this manner, the
transplanted organization assimilation is achieved and the pro-
cess of tissue regeneration is completed. However, regenerat-
ed cells in a failed experiment were identified as fibroblasts,
fibrous chondrocytes and monocytes/synovial cells (Rodeo
et al. 2000), with fibroblasts accounting for more of the mix-
ture than fibrochondrocytes (Noyes 1995), which are not con-
ducive to matrix secretion and meniscus regeneration. It is
widely known that a repopulating cell phenotype, which is
guided by a well-defined structure (Stevens et al. 2004), ulti-
mately determines the biomechanical behavior of the graft;
therefore, an allogeneic meniscus is extremely suitable mate-
rial. However, the size deviation between the allograft and
graft can lead to knee load abnormalities (Rodeo 2001),
resulting in poor compliance with the femoral condyle and
failure of the implant. With the quick improvements and in-
depth studies of heterogenous meniscus fixation (Goble et al.
1999b), the graft can be fully matched to the recipient
tibiofemoral joint in the future. There is also a risk of an
immune response. However, at present, there is only one re-
port of immune rejection of a cryopreserved meniscus allo-
graft (Hamlet et al. 1997), which confirmed the feasibility of
this MAT. A xenogeneic meniscus and SIS form the ACTM.
As a novel biomaterial for repairing damaged tissue, the
ACTM is a cell-free natural tissue scaffold and reproduces
many functions of the ECM, which is immediately remodeled
and reshaped in accordance with heterogenous tissue after
implantation. It is not difficult to reason why the ACTM gen-
erally serves as a tissue engineering meniscus scaffold be-
cause of its low immunity, good biocompatibility, good cell
attachment ability and good regulatory function for migration.
Remnant elastic fibers and collagen fibers maintain the
344
Fig. 2 The possible mechanism of native tissue-based strategies for
meniscus regeneration can be outlined briefly as follows. After
transplantation of the native tissue graft, the surgical trauma induces a
local inflammatory reaction. This inflammatory reaction triggers synovial
hyperplasia around the graft and blood vessels grow into the graft from
the peripheral synovium. Stem cells from the synovial membrane or
elasticity and mechanical strength of the natural structure, which
can resist degradation to play a transitional effect between the
material and regenerated tissue. The ACTM has extensive devel-
opment and application values and thus is considered the most
promising meniscus replacement material and is favored by
many researchers (Wong and Griffiths 2014). It is commonly
used for in vitro tissue engineering applications and has opened
a new avenue for meniscus repair and reconstruction. With the
developments from tissue engineering research on a global scale,
the ACTM has attracted increasing attention in related fields and
has become a research hot spot. In heterogenous tissue transplan-
tations, disease transmission is the biggest concern, because HIV
and other pathogens can withstand many of the current technical
challenges (Nemzek et al. 1994). At present, the first step that we
can take is to perform strict donor screening and the second is to
choose the sterilization technology (e.g., chemical sterilization
and gamma irradiation). However, many problems remain to
be studied, such as the establishment of a rapid, unified and
efficient preparation method, reducing the immune effect and
the risk of animal-borne diseases (Samitier et al. 2015) and to
solve the dense structure of biological materials that are not con-
ducive to cell growth. These issues will become a focus of future
research.
It is very difficult to find native tissue-based strategies that
completely mimic the inherent morphology and microstruc-
ture of the meniscus. The development of three-dimensional
(3D) printing has provided a new avenue for meniscus repair
and regeneration. Shannon et al. used 3D printing combined
Cell Tissue Res (2018) 373:337–350
synovial fluid and from circulating blood also migrate into the graft.
The extracellular matrix (ECM) of the native graft degrades gradually
and the native cells in the graft are replaced by endogenous stem cells.
These stem cells proliferate, differentiate into fibrochondrocytes and
remodel the surrounding ECM, ultimately forming a neo-meniscus
with digital modeling to construct fiber-reinforced meniscus
hydrogels that mimic the native meniscus collagen alignment
(Bakarich et al. 2014). Similarly, Yang et al. fabricated a bio-
mimetic anisotropic reinforcement meniscus micro-structure
using electrically-assisted nanocomposite 3D printing (Yang
et al. 2017). Some scientists have also applied 3D printing
strategies to meniscus regeneration in vivo. Chang and his
group produced a 3D printing scaffold loaded with spatiotem-
porally delivered connective tissue growth factor and
transforming growth factor-β3 to regenerate sheep meniscus
defects by recruiting endogenous cells (Lee et al. 2014) and
Zheng et al. confirmed that a 3D-printed poly(e-caprolactone)
scaffold can enhance meniscus regeneration in a rabbit model
(Zhang et al. 2016, 2017). The combination of native tissue-
based strategies with 3D printing is a potential solution for
future meniscus repair and regeneration.
Conclusions
With increasing interest in the tissue engineering field, the
construction of a tissue engineered meniscus model is endless.
Although the best construction model has not yet been
established, the material used should be one of the foremost
considerations (compared to cells and growth factors), be-
cause it is a vital characteristic of functional organization.
The native tissue-based strategies for meniscus repair and re-
generation provide important insights into a high level of
Cell Tissue Res (2018) 373:337–350 345

Table 2 Summary of research

concerning native tissue for Tissue Model Follow- Results Reference
meniscus repair and regeneration up
in vivo
Autogenic Tendon Sheep 12 M Tissue remodeling had taken (Kohn et al.
tissue Human 4Y place but the failure stress and 1992)
transplanta- tensile modulus were lower (Goble et al.
Rat 8W
tion Only 2 of 9 tendon autografts 1999a)
Rat 12 W
looked like a meniscus; 6 were (Ozeki et al.
Rabbit 3M in position but looked like 2013)
tendons
(Ozeki et al.
Meniscus size was increased; 2015)
articular cartilage was
(He Huang
significantly better in the
and Zhao
tendon + MSC group
2017)
BMP-7 induced tendon cells into
fibrochondrocytes and altered
the collagen gene profile to
more closely resemble
meniscal tissue; meniscus size
was increased; articular
cartilage degradation was
delayed
KGN-treated tendon graft group
revealed normal meniscus like
structure and the collagen type
I and type II expression.
Synovial Rabbit 17 W Fibrous tissue healing in some (Veth et al.
tissue Dog 12 W areas 1983)
Rabbit 6W Eleven of 35 menisci with free (Shirakura
synovium healed and repaired et al. 1997)
Canine 12 W
with fibrous tissue (Heatley
Canine 16 W
Incisions in the central part of the 1980)
meniscus were repaired via (Sekiya 1992)
fibrous tissue stroma; fibrous
(Okamura
tissue transformed into
et al. 1996)
fibrocartilage
Fibrous reparation in 62% of 13
defects after 3 weeks; complete
fibrocartilaginous repair with
no signs of tissue retraction in
more than 65% of 17 defects
after 12 weeks
Chondrocyte-like cells appeared
earlier in the FGF group
Infrapatellar Human 12 M Neotissue was weak and not (Milachowski
fat pad Sheep 12 M identical to that of a normal et al. 1990)
meniscus; reduced in size (Kohn et al.
Rabbit 8W
Degenerative changes visible; 1997)
osteoarthritis was detected (Oda et al.
Surface area was maintained; 2015)
Ishida score and Ki67-positive
ratio were higher; expression of
matrix metalloproteinase was
lower; expression of IL-1 was
not increased
Perichondrium Sheep 12 M No significant differences in (Bruns et al.
newly grown perichondrial 2000)
menisci and natural menisci
346 Cell Tissue Res (2018) 373:337–350

Table 2 (continued)
Tissue Model Follow- Results Reference
up

Heterogenous Allogeneic Human 14Y Size of the lyophilized meniscus (Wirth et al.
tissue meniscus Rabbit 16 W was reduced; deep-frozen 2002)
transplanta- meniscus was more (Shibuya
Human 141 M
tion comparable to an intact 1999)
Human 13.8 Y meniscus
(Hommen
Human 7Y Fibroblasts observed at 4 weeks; et al. 2007)
immature chondrocytes
(van Der Wal
emerged at 12 weeks;
et al. 2009)
chondrocytes and extracellular
matrix were virtually normal at (Saltzman
16 weeks et al. 2012)
Knee pain and function improved;
Lysholm scores improved
90%; 55% of allografts failed
Eight medial and 10 lateral
allografts failed; overall
Lysholm scores significantly
improved from 36 ± 18
preoperatively to 61 ± 20 at
long-term follow-up
Average satisfaction and success
rate 88%; overall subjective
knee condition improved from
3.5 to 6.9
Xenogeneic Rabbit 24 W Regenerated tissue healed to the (Jiang et al.
meniscus synovium and slowed down 2012)
articular cartilage degeneration
SIS Dog 12 W Cross-sectional and surface area (Cook et al.
Goat 12 W of the replaced tissue was 2001)
greater than the controls at all (Bradley et al.
Dog 12 M
time points 2007)
Partial meniscal regeneration with (Cook et al.
meniscal-appearing connective 2006b)
tissue
Production of meniscus-like
replacement tissue, which was
superior to meniscectomy in
amount, type and integration of
new tissue; chondroprotection
and limb function

W week; M month; Y year

biocompatibility, plasticity, smaller rejection, more durable and Beijing Science and Technology Development Foundation
(Z161100005016059).
mechanical toleration, delay of the occurrence of osteoarthritis
and other goals. Eventually, with the continuing developments
Compliance with ethical standards
of new tissue regeneration, native tissue-based transplants will
become the self-meniscus in the full sense. This review high- Conflict of interest The authors declare that they have no conflict of
lights the various treatments of meniscus disease, as well as interest.
tissue and organ transplantation.

Funding This study was funded by the National Key Research and
Development Program of China (2017YFC1104102, 2017YFC1103404),
National Natural Science Foundation of China (81472092), High
Technology Research and Development Program of China
(2012AA020502,2015AA020303), National Key Research and
Development Program of China (2017YFC1104102, 2017YFC1103404)
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Affiliations

Zengzeng Zhang 1,2,3,4 & Weimin Guo 1,2,3 & Shuang Gao 5 & Mingxue Chen 1,2,3 & Xu Li 6 & Xueliang Zhang 1,2,3,7 &
Xiaoguang Jing 1,2,3,4 & Mingjie Wang 1,2,3 & Yu Zhang 1,2,3 & Shi Shen 1,2,3,8 & Zehao Wang 1,2,3 &
Baichuan Sun 1,2,3,4 & Ying Chai 4 & Chengfu Zhou 4 & Shuyun Liu 1,2,3 & Quanyi Guo 1,2,3

1 5
Institute of Orthopedics, Chinese PLA General Hospital, Center for Biomaterial and Tissue Engineering, Academy for
Beijing 100853, China Advanced Interdisciplinary Studies, Peking University,
2 Beijing 100871, China
Beijing Key Lab of Regenerative Medicine in Orthopedics,
6
Beijing 100853, China School of Medicine, Nankai University, Tianjin 300071, China
3 7
Key Lab of Musculoskeletal Trauma & War Injuries, PLA, Institute of Traditional Chinese Medicine, 46 Bingzhou West Street,
Beijing 100853, China Yingze District, Taiyuan, Shanxi Province 030012, China
4 8
First Affiliated Hospital of Jiamusi University, Jiamusi 154002, Department of Bone and Joint Surgery, Affiliated Hospital of
China Southwest Medical University, Sichuan Province, Luzhou 646000,
China
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