Page 1 of 6

Diagnosis & Treatment

Review
Cartilage regeneration revisited: entering of new one-step
procedures for chondral cartilage repair

Abstract
Introduction
This article reviews the evolution of
cartilage regeneration therapeutic
approaches from two-step cell-based
autologous chondrocyte implantation procedures to current one-step
cell-free scaffold-assisted cartilage
repair approaches for chondral cartilage repair. In particular, our research
is focused on clinical data about
commercially available cell-free
implants used in regenerative medicine approaches for the treatment of
chondral cartilage defects.
Discussion
Chondral cartilage lesions do
not heal spontaneously and may
progress to severe osteoarthritis. For
cartilage repair, a variety of surgical
techniques have been established
over the years. Further research led
to the development of current new
one-step cell-free scaffold-assisted
cartilage repair approaches based on
the experience with scaffold materials in previous two-step autologous chondrocyte implantation
procedures. Commercially available
scaffold-based products for one-step
chondral cartilage repair have been
recently tested in first case series and
showed promising clinical outcome
in the short-term follow-up; however,
medium- and long-term comparative
studies are necessary to evaluate
the regenerative potential of this

* Corresponding author
Email: christian.kaps@transtissue.com
1 TransTissue

Technologies GmbH, Berlin,

Germany
2 Tissue Engineering Laboratory, Department
of Rheumatology and Immunology, Charit
Campus Mitte, Charit Universittsmedizin
Berlin, Berlin, Germany
3 Department of Orthopaedics and Trauma
Surgery, Martin-Luther-Krankenhaus Berlin,
Berlin, Germany

new one-step cartilage repair procedure and to demonstrate its superiority over or adequacy to traditional
approaches.
Conclusion
This critical review summarises
the development from two-step
cell-based autologous chondrocyte
implantation procedures to new onestep cell-free cartilage repair and
discusses the first clinical outcome
of commercially available cell-free
implants. This new approach, based
on the principle of cell ingrowths
and guidance towards tissue repair,
showed promising first clinical
results and is considered as an effective and safe treatment option for
chondral cartilage repair.

Introduction
Damaged cartilage has a limited
self-healing capacity. Focal cartilage
lesions of the knee occur frequently,
are mostly located on the femoral
condyle and display a major health
problem because they may progress
to severe osteoarthritis, when
untreated. Predisposing factors for
the development of cartilage defects
are traumas, inflammatory conditions and biomechanics alterations of
the knee1.
In cartilage repair, a variety of
surgical techniques have been established, including bone-marrow
stimulation (e.g. abrasion, drilling
and microfracturing), osteochondral
autograft transfer and autologous
chondrocyte implantation (ACI) with
or without the use of scaffold materials2,3. Treatment options have to
be chosen individually, depending
on the defect size, depth and location of the cartilage lesion. Surgical
treatment options for small defects
include bone-marrow stimulation
techniques as well as osteochondral

autograft transplantation4,5. Especially, for the treatment of large

full-thickness chondral articular
defects and as second-line cartilage treatment option, two-step ACI
approaches based on the implantation of in vitro cultured autologous
chondrocytes have been developed.
The implantation of autologous
chondrocytes within the prepared
defect area improves the formation of
hyaline-like, biomechanical resistant
and durable repair tissue in contrast
to the outcomes after microfracture
procedure, leading to a fibrocartilaginous defect filled with material
properties that are inferior to hyaline
cartilage6.
Further research led to the development of one-step cell-free scaffoldassisted regenerative approaches for
in situ cartilage repair. This innovative procedure combines the wellknown microfracture technique with
the benefits and long-term experience of biomaterials used in earlier
ACI procedures.
This critical review shows the
evolution of different generations
for two-step ACI procedures up to
the development of the current new
one-step scaffold-assisted regenerative procedures and reports on
the clinical applications of scaffoldbased products for chondral cartilage repair. In particular, our research
is focused on published clinical data
for commercially available cell-free
implants used for one-step cell-free
scaffold-assisted cartilage repair.

Discussion
The authors have referenced
some of their own studies in this
review. These referenced studies
have been conducted in accordance
with the Declaration of Helsinki
(1964) and the protocols of these

Licensee OA Publishing London 2013. Creative Commons Attribution Licence (CC-BY)

FOR CITATION PURPOSES: Freymann U, Petersen W, Kaps C. Cartilage regeneration revisited: entering of new one-step
procedures for chondral cartilage repair. OA Orthopaedics 2013 Jun 05;1(1):6.

Competing interests: none declared. Conflict of Interests: declared in the article.

All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.

U Freymann1,2, W Petersen3, C Kaps1,2*

Page 2 of 6

Review

studies have been approved by the

relevant ethics committees related
to the institution in which they were
performed. All human subjects,
in these referenced studies, gave
informed consent to participate in
these studies.
Generations of two-step ACI
procedures
The classic first generation ACI
is based on the implantation of a
suspension of cultured chondrocytes underneath a sealed periosteal
cover in a two-step procedure7. Since
Brittberg et al. introduced this technique in 1987, more than 15,000
patients have been treated with ACI
worldwide8. The first step includes
arthroscopic cartilage biopsy harvest
from a minor weight-bearing area of
the injured knee followed by in vitro
cell expansion under good manufacturing practice (GMP) conditions
to a defined cell number (Figure 1).
The second operation includes
arthrotomy, preparation of the defect,
periosteal harvest, suturing the periosteum over the defect, application
of fibrin glue sealant and the injection of the cell suspension underneath the periosteal flap (Figure 2).
Autologous chondrocytes in a cell
suspension are offered by different
manufacturers (Carticel, Genzyme,
USA;
ChondroCelect,
Tigenix,
Belgium; Novocart, B. Braun-Tetec,
Germany). First-generation ACI has

inherent disadvantages, including

periosteal complications such as
periost hypertrophy, periosteal graft
detachment and delamination as well
as loss of cells into the joint cavity911
leading to a revision surgery rate of
up to 25% to 40%12,13.
Second-generation ACI uses a
collagen membrane rather than a
periosteal flap to cover the cartilage defect before cell injection.
The use of a bi-layer type-I/typeIII collagen membrane (ChondroGideTM,
Geistlich,
Switzerland)
reduces the length and number of
incisions, surgical morbidity and the
risk of hypertrophy compared with
periosteal flap suturing12. The use
of first and second-generation ACI is
limited and may be difficult in knee
defect locations lacking a stable and
intact cartilage rim as known from
post-traumatic and/or focal degenerative cartilage defects.
Further development of tissue
engineering/regenerative medicine
led to the third-generation of ACI to
overcome these limitations. Thereby,
three-dimensional scaffolds are
seeded with in vitro cultured chondrocytes and subsequently implanted
into the lesion area to generate new
functional cartilage repair tissue.
After debridement of the defect, the
cartilage graft is cut to the defect
size and implanted without the use
of a periosteal or collagen cover flap
(Figure 3). The use of three-dimensional scaffolds ensures a homogeneous cell distribution and avoids

the risk of chondrocyte leakage from

the liquid cell suspension. The easy
handling of the tissue-engineered
graft has surgical advantages and
allows for a minimally invasive and
faster surgical procedure by avoiding
additional periost harvest and defect
covering14,15.
Many biomaterials have been
tested for scaffold-based chondrocyte implantation. Therein, various
hydrogels were used as three-dimensional cell carriers for autologous
chondrocytes. Among these geltype scaffolds, a three-dimensional
type-I collagen gel (CaReSTM, Arthro
Kinetics, Germany) is clinically
used, where isolated chondrocytes
are immediately cultivated in the
collagen gel without expansion in
monolayer culture 16. Other hydrogelbased technologies use either a
mixture of autologous chondrocytes
with a hydrogel composed of agarose
and alginate (Cartipatch; Tissue Bank
of France, France), which involves the
injection of a cell suspensionfibrin
mixture into the cartilage defect
(Chondron; Sewon Cellontech Co.
Ltd., Korea), or use autologous chondrocytes cultured on an atelocollagen
gel for cartilage repair16.
Other technologies using scaffolds based on collagen, hyaluronan
and resorbable polymers have been
shown to be clinically efficient for the
repair of cartilage defects16: collagen
membranes
(ACI-maix/MACI,
Matricel, Germany) and hyaluronanbased scaffolds (Hyalograft CTM;

Licensee OA Publishing London 2013. Creative Commons Attribution Licence (CC-BY)

FOR CITATION PURPOSES: Freymann U, Petersen W, Kaps C. Cartilage regeneration revisited: entering of new one-step
procedures for chondral cartilage repair. OA Orthopaedics 2013 Jun 05;1(1):6.

Competing interests: none declared. Conflict of Interests: declared in the article.

All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.

Figure 1: Cartilage biopsy harvest

and in vitro cell expansion in monolayer cultures.

Figure 2: Principle of autologous chondrocyte implantation (ACI): a harvested

periosteum flap (first-generation ACI) or collagen membrane (second-generation ACI) is sutured over the debrided cartilage defect and the cell suspension
is injected underneath.

Page 3 of 6

Figure 3: Surgical steps of third-generation scaffold-based ACI including the

transplantation of a chondrocyte-seeded scaffold into the debrided defect.

Figure 4: Principle of one-step scaffold-assisted cartilage repair including bonemarrow stimulation and additional implantation of the cell-free scaffold for a
tissue-guided cartilage repair.
Fidia Advanced Biopolymers, Italy)
have been used in combination with
autologous chondrocytes in clinical
practice since more than a decade16.
Other clinically used biomaterials
for cartilage repair are, for example,
three-dimensional collagen-chondroitin sulphate scaffolds with
embedded autologous chondrocytes (Novocart 3D, B. Braun-Tetec,
Germany) or cell-seeded type I
collagen scaffolds produced in a
bioreactor (NeoCart, Histogenics
Corporation, USA)16. Among resorbable polymer scaffolds, BioSeed-C
(BioTissue Technologies GmbH,
Germany), a two-component scaffold using a porous gel-like matrix
composed of fibrin and a textile polyglycolic acid-based felt-like scaffold,
is one of the most widely used cartilage grafts, which combines autologous chondrocytes with an initially
mechanically stable polymer scaffold, allowing stable, subchondral
and containment-independent fixation with resorbable nails or anchors
for the first time. These characteristics have led to the possibility to
treat degenerative defects also for
the first time, showing to be clinically efficient for cartilage repair of
those indications17.

Although the scaffold-based chondrocyte implantation is already a

clinically effective procedure for
cartilage repair, there still remain
some disadvantages. This method is
a two-step operation, which needs
the removal of a healthy cartilage
biopsy first and second, an implantation of the cultivated scaffold or
matrix seeded with chondrocytes.
The procedure may increase donorsite morbidity, the creation of a new
defect at an undamaged cartilage
zone has to be accepted and a potentially longer rehabilitation time must
be tolerated. Furthermore, the timeintensive cultivation period for the
autologous chondrocytes under GMP
conditions, requiring for example
up to 4 weeks, is cost-intensive,
may have a potential risk leading to
degeneration/de-differentiation of
the cells and can resultdepending
on the degree of sub-culturing and
de-differentiationin an efficiency
loss of cartilage regeneration18.
New one-step scaffold-assisted
regenerative procedures
To overcome these limitations, a new
concept for in situ cartilage repair,
based on the use of cell-free scaffolds for cell ingrowths and guidance
towards tissue repair, was devel-

oped. This procedure is an innovative

treatment combining the well-known
microfracture technique with the
benefits and long-term experience of
known biomaterials.
Behrens et al. first introduced this
new matrix-coupled microfracture
with a collagen matrix implant to
cover cartilage defects19. Thereby
microfracturing of the subchondral
bone for the recruitment of human
mesenchymal stem cells (MSCs) from
the bone marrow blood was combined
with a cell-free scaffold, which was
fixated with fibrin glue. By covering
the defect area, endogenous progenitor or stem cells that float into the
cartilage defect are kept in the scaffold/matrix and the resulting blood
clot is held in the defect zone. The
resorbable scaffold thereby builds up
a natural 3D environment, which optimises cell migration and ingrowths,
leads to a homogeneous cell arrangement and supports differentiation into
cartilaginous repair tissue (Figure 4).
This new cell-free one-step
approach has several advantages as
compared with previous cell-based
techniques. The scaffolds are offthe-shelf products, which are storable and available on demand, allow
for a single-stage surgical step with
reduced surgery time and avoid
donor-site morbidity and costs for
cell expansion.
However, at this time there is
limited clinical data available on the
outcome of the one-step scaffoldassisted regenerative procedures for
the repair of chondral knee defects.
Different commercially available
cell-free medical devices based on
collagen (Chondro-GideTM, Geistlich,
Switzerland; CaReS-1STM, Arthro
Kinetics, Germany; MeRG, Bioteck,
Italy), different hydrogels (BSTCargel, Piramal Healthcare, Canada;
GelrinCTM, Regentis Biomaterials,
Israel) and resorbable synthetic polymers (chondrotissue, BioTissue
AG, Switzerland) have been recently
tested for one-step chondral cartilage repair and showed first clinical
outcomes.

Licensee OA Publishing London 2013. Creative Commons Attribution Licence (CC-BY)

FOR CITATION PURPOSES: Freymann U, Petersen W, Kaps C. Cartilage regeneration revisited: entering of new one-step
procedures for chondral cartilage repair. OA Orthopaedics 2013 Jun 05;1(1):6.

Competing interests: none declared. Conflict of Interests: declared in the article.

All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.

Review

Page 4 of 6

One of these products is a bilayer

matrix of porcine type I and III
collagen with one compact and
one porous side (Chondro-GideTM,
Geistlich, Switzerland) to cover chondral cartilage defects after microfracturing. Clinical outcome was
recently shown in several case series,
including up to 38 patients with
a follow-up time of maximum 51
months. Therein, results of patients
showed a significant improvement
in clinical scores (International Knee
Documentation Comitee (IKDC),
Lysholm, Tegner, Visual Analog Scale
(VAS) pain score) and patient satisfaction with the treatment procedure,
whereas magnet resonance imaging
showed an incomplete and inhomogeneous repair tissue formation and
defect filling rates between 50% and
58.8%1,20,21. Recently, a controlled,
randomised trial was initiated,
comparing the use of ChondroGideTM in second-generation ACI
and in a one-step cell-free scaffoldassisted approach for the repair of
symptomatic knee cartilage defects.
Both techniques use the ChondroGideTM membrane in an arthrotomic
approach to cover the defects of 40
patients each22. So far no preliminary
or clinical results are available for
this randomised trial.
Another collagen-based product
for one-step scaffold-assisted cartilage repair is a round type I collagen
gel-matrix derived from rat tails for
deep chondral defects (CaReS-1STM,
Arthro Kinetics, Germany), which is
implanted into the debrided defect
in a press-fit manner. Clinical results
were shown in first case series for
up to 15 patients and with 2436
months follow-up23,24. After 24
months, magnetic resonance imaging
showed complete filling with a
mainly smooth surface, complete
integration, homogenous repair
tissue structure and nearly normal
signal intensity. Histological examination of one specimen at 42 months
after implantation revealed type
II collagen positive repair tissue23.

Functional, clinical and subjective assessment showed significant

improvement when compared with
the preoperative values24. First
analysis of preliminary results of an
ongoing multi-centre study including
37 patients with 324 months
follow-up showed identical or better
IKDC scores for the one-step cell-free
product when compared with those
of a multi-centre study with the twostep cell-based product CaReS 2S.
Another
collagen
product,
consisting of a microfibrillar equine
type I collagen membrane (MeRG,
Bioteck, Italy) was described in a
first case presentation. Therein, a
37-year-old man with a 3 cm2 cartilage lesion of the medial condyle was
treated with covered microfracture
and bone marrow concentrate for
arthroscopic knee cartilage repair25.
Magnetic resonance imaging results
at 12 months postoperatively showed
good defect filling with a tissue signal
similar to that of surrounding tissue.
In a follow-up of 24 months, the
patient remained asymptomatic.
As an alternative to collagen-based
matrix, different hydrogels are now
being clinically tested for one-step
scaffold-assisted cartilage repair. In
a mini-arthrotomic approach, these
gels are mixed with whole blood or
bone marrow released after microfracturing to fill the chondral cartilage
defect. In this group, a chitosan-glycerol phosphate/blood implant (BSTCargel, Piramal Healthcare, Canada)
was clinically tested. First clinical
results are available for a randomised,
comparative multi-centre clinical trial
evaluating BST-CarGel and microfracture at 12 months for cartilage
repair. Therein, BST-CarGel treatment achieved significantly better
results compared with microfracture
in defect filling and in the quality of
the repair tissue26.
Other commercially available
hydrogels are mixed compositions
of polyethylene glycol diacrylate
with fibrinogen (GelrinCTM, Regentis
Biomaterials, Israel). Thereby, a gel is

inserted as a liquid to fill the cartilage

defect and is then converted into a
solid through exposure to ultra-violet
light. First short-time results of a pilot
clinical study including 15 patients
with focal cartilage defects showed
significantly higher levels of tissue
fill and reduced pain levels compared
with microfracture controls and an
improvement in patients knee function after 6 months27. A multi-centre
study is currently recruiting patients
to evaluate the safety and effectiveness of the hydrogel in the treatment
of articular cartilage lesions28.
Newer one-step scaffold-based
cartilage repair approaches favour
the use of stable textile polyglycolicacidhyaluronan implants (chondrotissue, BioTissue AG, Switzerland)
to cover the defect after microfracturing or bone marrow stimulation.
This scaffold incorporates biological
factors, such as hyaluronic acid, and
can be used in combination with for
example human serum or platelet rich
plasma, to recruit MSCs into the scaffold and guide them towards cartilage
repair. In contrast to other unstable
biomaterials, the textile scaffold
provides a mechanically stable formulation, which can be stably fixated into
the defect by suturing, trans-osseous
fixation, pin fixation or fibrin glue
and even allows for the implantation
into partly un-shouldered degenerative defects. First pilot studies have
shown that covering of microfractured cartilage defects with the chondrotissue cartilage implant is safe,
improves the patients situation and
leads to complete defect filling with
histologically confirmed hyaline-like
cartilaginous repair tissue formation in a follow-up period of up to 2
years2933. Preliminary clinical results
of a randomised, comparative multicenter clinical trial showed that the
chondrotissue treatment for cartilage repair significantly improves
the patients situation as assessed by
VAS, Knee Injury and Osteoarthritis
Outcome Score (KOOS) and IKDC
score, while there is no significant

Licensee OA Publishing London 2013. Creative Commons Attribution Licence (CC-BY)

FOR CITATION PURPOSES: Freymann U, Petersen W, Kaps C. Cartilage regeneration revisited: entering of new one-step
procedures for chondral cartilage repair. OA Orthopaedics 2013 Jun 05;1(1):6.

Competing interests: none declared. Conflict of Interests: declared in the article.

All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.

Review

Page 5 of 6

improvement after microfracture

treatment in patients with 1224
months follow-up34.

Conclusion
Regenerative medicine led to the
development of a variety of cartilage
repair treatment options. Cell-based
approaches include an initial invasive
biopsy harvest to obtain the cells and
in vitro proliferation and possibly
de-differentiation of the cells before
implantation. Newer one-step scaffold-based procedures for cartilage
repair have been recently developed
to simplify and further improve regenerative techniques. The new one-step
treatment option includes the attraction of MSCs to the site of the cartilage
defect and thereby overcomes the
necessity of in vitro proliferation and
differentiation of cells before transplantation. This one-step approach
also avoids donor-site morbidity,
reduces costs, surgical steps and
potentially patients rehabilitation
time. The use of biomaterials for the
treatment of chondral knee cartilage
defects is strongly increasing, since
the properties of the used polymers
are varied, allow for modification and
can be adapted to the surgical need.
Clinical applications are described
for different types of commercially
available cell-free implants, including
collagen variations, hydrogels and
synthetic textile. For the abovementioned products, first promising
clinical results showed a reduction in pain, a functional improvement of the knee and the formation
of hyaline-like repair tissue. By the
application of cell-free scaffolds for
defect covering after bone-marrow
stimulation, the newly formed tissue
was shown to be structured similar
to native cartilage tissue and to be
superior to the repair tissue formed
after microfracture alone.
Difficulties in comparing various
studies arise from the different
study populations, follow-up times,
evaluation systems, scaffold fixation
methods, surgical approaches and

postoperative rehabilitation procedures. However, evaluation of current

clinical outcome is based on first
case series with short- to mid-term
follow-up and preliminary results
of ongoing controlled, randomised
clinical studies. Thus, well-designed
mid- to long-term comparative
studies are needed to evaluate the
potential of these new regenerative
one-step cartilage repair approaches
and to show its superiority over or
adequacy to traditional two-step ACI
approaches.

Conflict of Interest
C.K. and U.F. are employees of TransTissue Technologies GmbH (TTT), a
subsidiary of BioTissue Technologies
GmbH. TTT developed the products
BioSeed-C and chondrotissue. C.K.
is a shareholder of BioTissue AG.

Abbreviations list
ACI, autologous chondrocyte implantation; GMP, good manufacturing
practice; MSC, mesenchymal stem
cells.

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Licensee OA Publishing London 2013. Creative Commons Attribution Licence (CC-BY)

FOR CITATION PURPOSES: Freymann U, Petersen W, Kaps C. Cartilage regeneration revisited: entering of new one-step
procedures for chondral cartilage repair. OA Orthopaedics 2013 Jun 05;1(1):6.

Competing interests: none declared. Conflict of Interests: declared in the article.

All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.

Review

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Licensee OA Publishing London 2013. Creative Commons Attribution Licence (CC-BY)

FOR CITATION PURPOSES: Freymann U, Petersen W, Kaps C. Cartilage regeneration revisited: entering of new one-step
procedures for chondral cartilage repair. OA Orthopaedics 2013 Jun 05;1(1):6.

Competing interests: none declared. Conflict of Interests: declared in the article.

All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.

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