Review Emerging technologies: What is the future of cartilage restoration?

Transcription

Trauma & Orthopaedics
Page 1 of 9
Review
Abstract
JM Ryan, DC Flanigan*
Introduction
Injury to articular cartilage injury
is a common and challenging diagnosis, often resulting in substantial
morbidity for patients. A treatment
strategy typically includes simple
debridement, microfracture, osteochondral autograft or allograft transplantation or cell-based therapy such
as autologous chondrocyte implantation. We review cell-based cartilage
repair technologies currently in the
early phases of clinical application
and highlight the promise and limitations in this rapidly advancing area of
musculoskeletal medicine.
Conclusion
Cartilage restoration is a field that is
currently growing at a fast pace. We
reviewed new cartilage restoration
technologies; many of these have
shown promise but have relatively
limited long-term outcome data to
guide clinicians. Future research will
help improve our understanding,
and more effective techniques can
become available.
Introduction
Despite substantial progress on basic
science and clinical fronts over the
last few decades, articular cartilage
injury remains an enormous challenge for musculoskeletal physicians.
The diagnosis is unfortunately quite
common–in a review of over 25,000
knee a rthroscopies performed over a
* Corresponding author:
Email: [email protected]
Cartilage Restoration Program, OSU Sports
Medicine, Sports Health and Performance
Institute, Department of Orthopaedics, The
Ohio State University, Columbus, OH
15-year period, the incidence of chondral lesions was noted to be 60%1.
Chondral injuries often cause substantial morbidity for patients, including
significant time lost from work and
sport2. Furthermore, while the natural
history of the various types of chondral
lesions is not yet fully understood3, a
long-term concern is development of
progressive degenerative joint disease.
The disease burden for both patients
and physicians is large, and given the
complexity of the issues involved,
treatment dilemmas often exist.
Algorithms for operative treatment
of symptomatic chondral lesions
vary, but guidelines for choosing between currently available treatments
have been offered4,5. These include
evaluation and treatment of any
associated joint pathologies including systemic disorders, limb malalignment, meniscal deficiency and
ligamentous instability. A thorough
assessment of the size, thickness and
location of the chondral lesion is also
required. Based on lesion and patient
characteristics, a treatment strategy
is chosen. In current practice, this
typically includes one of the following options: simple debridement, microfracture, osteochondral autograft
or allograft transplantation or cellbased therapy such as autologous
chondrocyte implantation (ACI).
Each of these strategies has relative merits and limitations, but no
currently available technique meets
all requirements for an ‘ideal’ treatment option. As described by Gomoll
and Farr, an ideal cartilage repair
technique would be (1) cost-efficient,
(2) easily available or of-the-shelf,
(3) implantable through a singlestage, minimally invasive technique,
(4) produce physiologically stratified,
fully
integrated
(basilar
and
marginal) hyaline repair tissue and
(5) allow for quick return to activity6.
While current options–with varying
degrees of efficacy–may ameliorate
symptoms, the broader goal of restoring a durable, smooth, hyaline tissue
that effectively transmits shear and
compressive loads from the cartilage
to the bone remains elusive7. A recapitulation of the multilayered nature
of hyaline cartilage, including the normal bone–cartilage interface, appears
to be fundamental to this endeavor7.
The goal of this critical review is
to provide an overview of cell-based
cartilage repair technologies currently in the early phases of clinical
application and highlight the promise and limitations in this rapidly
advancing area of musculoskeletal
medicine.
Discussion
Restoration techniques based on
chondrocyte transplantation
ACI
ACI (Sanofi Bioservices, Cambridge,
MA) was the first technique developed to treat chondral defects with
chondrocyte transplantation. ACI
was pioneered in Sweden in the mid1980s and was the subject of a landmark clinical report by Peterson and
Brittberg in 19948. The technology
received FDA approval for use in the
United States in 19956. The concept
involves a two-stage procedure in
which a small sample of healthy, articular cartilage is biopsied and undergoes enzymatic digestion followed
by cultivation and expansion of chondrocytes in a laboratory setting over
a several week period. The resulting
cell culture is treated with trypsin
and placed in liquid suspension
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: JM Ryan, DC Flanigan. Emerging technologies: What is the future of cartilage restoration? Hard
Tissue 2013 Feb 26;2(2):12
Competing interests: none declared. Conflict of interests: declared in the article.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Emerging technologies: What is the future of
cartilage restoration?
Page 2 of 9
Review
Emerging cartilage restoration
technologies–two-stage
techniques
Matrix-induced ACI (MACI)
MACI (Sanofi Bioservices) is a second-generation ACI technique that
involves the use of a porcine-derived
type I/III collagen carrier matrix.
Like ACI, the technique requires a
two-stage surgical procedure, with
initial harvest of a cartilage sample,
followed by expansion in culture for
several weeks14. The cells are then
seeded on the collagen matrix and
cultured for an additional 3 days. The
collagen patch can then be implanted with either an arthroscopic or
open technique. Additionally, it can
be secured in place with fibrin glue,
rather than suture as in the original
ACI technique. Although it is available in Europe6, MACI is not yet FDA
approved in the United States and is
currently undergoing a phase 3 multicentre clinical trial in Europe15. A
number of case series have reported
initial results with MACI16–19, and
three recent studies have been published with MACI versus osteochondral autograft20, ACI with collagen
membrane21 and microfracture22. In
all three studies, MACI showed improved clinical results over the alternative restorative techniques.
Hyalograft C
Hyalograft C (Fidia Advanced Biopolymers Laboratories, Padova,
Italy) is a tissue engineered scaffold
(Figure 1), whose main component
– HYAFF11 – is an esterified derivative of hyaluronic acid (HA)23. HA is
a prominent component of normal
cartilage matrix. A cartilage sample
is obtained from an initial arthroscopy, and the chondrocytes are harvested and seeded onto the HA scaffold. This scaffold is comprised of a
network of 20-micron thick fibres.
It is believed that the scaffold promotes matrix production and limits
dedifferentiation of cells expressing
the chondrocyte phenotype4. The
graft can be implanted arthroscopically with application of gentle pressure to allow fit into the lesion bed23.
The scaffold is designed to take
advantage of the natural adhesive
properties of the complex sugars in
the matrix and allows for implantation without adjunctive fixation
(Figure 2)6. A number of case series
evaluating hyalograft C have been
conducted, including most recently
a seven-year follow study of 62 patients, which showed maintenance of
statistically improved International
Knee Documentation Committee
(IKDC) scores and reported an 11%
failure rate24.
BioSeed C
BioSeed C (BioTissue Technologies GmbH, Freiburg, Germany) is
a synthetic scaffold in clinical use
in Europe since 2001 (Figure 3).
The polymer scaffold contains fibrin, polylactic/polyglycolic acid
[polyglactin, Vicryl (Ethicon GmbH,
Norderstedt, Germany]) and polydioxanone. Autologous chondrocytes
are harvested and embedded in
the fibrin and cultured. At a second
stage, the graft material is fitted into
the chondral defect and secured at
each corner with resorbable sutures
via an anchor-knot technique25. The
fixation technique is felt to work
well even for partially uncontained
defects. Four-year follow-up data on
a cohort of 52 patients with BioSeed
C implants showed improved Lysholm, Knee Injury and Osteoarthritis Outcome Score (KOOS), and IKDC
scores and magnetic resonance imaging (MRI) documentation of moderate to complete defect fill in 43 of
44 patients25.
NeoCart
After initial arthroscopic cartilage
biopsy, the NeoCart technique (Histogenics, Waltham, MA) requires
seeding of autologous chondrocytes
in a bovine-derived three-dimensional type I collagen honeycomb
matrix (Figure 4). The chondrocyteembedded matrix is then cultured
in a bioreactor, which creates an
environment of variable hydrostatic
pressure and low oxygen tension,
to simulate intra-articular conditions26. The resulting tissue has
been shown to contain glycosaminoglycan and a favourable ratio of
Tissue 2013 Feb 26;2(2):12
for
implantation at a second-stage
surgery. The cellular
implantation
requires an open surgery in which the
chondral lesion is carefully prepared
and a periosteal (or collagen) patch
is sutured in place over the lesion to
create a watertight seal. The cellular
suspension is then delivered into the
lesion bed below the patch8. By implanting expanded chondrocytes into
the lesion, the goal is to ultimately fill
the defect with a mature hyaline-like
cartilage, with wear and load transmission properties more closely approximating native cartilage4.
Since its introduction, ACI has
gained widespread acceptance as a
viable cartilage repair strategy. In addition, generally favourable clinical
results have been reported in numerous studies4,8–12, and ACI remains a
valuable tool for many cartilage restoration surgeons. However, there
are limitations to the technique.
These include the overall cost of the
procedure, the two-stage surgical
technique, lengthy and intensive rehab and complications attendant to
an extensive surgical procedure4,13.
This has limited the widespread use
of ACI.
To address some of these potential
problems and limitations with the
original ACI method, numerous variations on the original concept have
been developed in the past decade. As
tissue engineering capabilities have
become increasingly sophisticated,
much interest has focused on developing scaffolds (Table 1) that accommodate autologous chondrocytes and
promote their growth in a supportive three-dimensional environment,
thereby creating an implantable tissue with properties more closely
matched to hyaline cartilage.
Page 3 of 9
Review
Table 1 Characteristics of selected scaffolds used in emerging cartilage restoration techniques
Scaffold type
NeoCart (Histiogenics Corporation,
Waltham, MA)
Protein based (bovine-type I
collagen)
No
• Phase II studies complete No
• Ongoing phase III study
Harvested chondrocytes
grown into collagen and
secured via bioadhesive
CaReS-1S (ArthroKinetics, Esslingen,
Germany)
Protein based (rat-tail type I
collagen)
No
• Animal trials
Yes
• Case study of 15 humans
• No comparative human
Shown in animal studies to
trials to date
have equivalent repair tissue
compared to cellular technique
Hyalograft C (Fidia
Advanced Biopolymers, Abano Terme,
Italy)
Carbohydrate based
(HYAFF 11-esterified derivative of hyaluronate)
No
• Improved patient outcomes in clinical studies
• Multiple comparative
studies with MFx showing improved results at
5 years
No
• Phase II multicentre
study showed significant
improvements
• Two phase III trials comparing mosaicplasty and
MFx on-going in Europe,
Asia and Middle East
No
• Phase II clinical trials
show improved WOMAC
scores for pain, stiffness
and function
• Phase III randomized
multicentre study comparing with MFx alone
is complete but data not
published to date
Yes
• Phase III trials comparing
with ACI alone showed
improved outcome
scores and comparable
outcome levels
• Caution in that ACI-only
group had larger defect
and longer follow-up
No
Cartipatch (Tissue
Bank of France)
Carbohydrate based
(Agarose-alginate)
No
BST-CarGel (Biosyntech, Quebec,
Canada)
Combined scaffold (polysaccharide chitosan and an
aqueous glycerol phosphate
buffer)
Yes
Bioseed C (BioTissue
Technologies GmbH)
Combined scaffold (fibrin
glue combined with a
copolymer of PGA, PLA and
PDS)
No
Trials
Cell free?
Combined with autologous
articular chondrocytes
Advantage over ACI is less
invasive procedure
Autologous chondrocytes implanted into the 3D scaffold.
3D scaffold thought to improve stability and ease of
surgical handling
Scaffold is inserted in one
step to an area that has been
prepared using bone marrow
stimulation techniques
Harvested autologous chondrocytes are implanted onto
the 3D scaffold
Tissue 2013 Feb 26;2(2):12
Adjunct
with
MFx?
Product name
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Review
Table 1 (Continued)
BioCart II (ProChon
BioTech Ltd., Ness
Ziona, Israel)
Combined scaffold (polymerization of homologous
fibrinogen and recombinant
hyaluronan)
No
• Phase II clinical trial
versus MFx on-going in
United States and Israel
No
Cartilage biopsy with high
chondrogenic potential
placed in recombinant FGF-2
prior to seeding 3D scaffold
Applied via miniarthrotomy
and sealed with fibrin glue
Combined scaffold (bilayered collagen membrane)
type I to type II collagen. The tissue
is implanted into chondral defects
with a sutureless technique utilizing a collagen polymer (CT-3, Histogenics). A recently published
randomized trial compared microfracture to NeoCart at 2-year followup and demonstrated statistically
significant improvement in KOOS
pain and IKDC scores for the NeoCart group versus the microfracture
group26. NeoCart is currently undergoing a phase III trial27.
BioCart II
BioCart II (ProChon BioTech, Rehovot, Israel) is a two-stage autologous
chondrocyte technique that utilizes
autologous serum with additional
growth factors to expand the chondrocytes and seed them onto a fibrin/HA-based scaffold (Figure 5)28.
The scaffold has a three-dimensional
open pore design, which promotes
chondrocyte growth. A recent case
series reported on 31 patients at an
average of 17-month follow-up and
demonstrated significantly improved
IKDC scores as well as MRI T2-mapping values28.
Yes
• Outcome score improvement with adjunct to CCI
Can also • Positive clinical imbe used
provement and MRI
in charimprovement when used
acterized
as adjunct to MFx
chon- • No current studies to
drocyte
compare long-term
implanresults of ACI or versus
tation
MFx alone
CaReS
CaReS (Ars Arthro, Esslingen, Germany) utilizes a three-dimensional
hydrogel based on rat-tail–derived
type I collagen to promote growth of
harvested autologous chondrocytes.
The chondrocyte-gel mixture is cultured with autologous serum for 2
weeks and is then implanted into the
chondral defect and secured with
fibrin glue. The three-dimensional
framework is believed to decrease
the potential for chondrocyte dedifferentiation29. In addition, the hydrogel can be manufactured to meet
surgeon-requested size specifications, and due to its water content
it can be moulded intra-operatively
to conform to the unique shape of
each lesion. A multicentre case series reported on 116 patients treated
with CaReS with average follow-up
of 30 months and showed substantially improved IKDC, SF-36 and pain
scores29.
Cartipatch
Cartipatch (Tissue Bank of France,
Lyon, France) also uses a threedimensional hydrogel scaffold for
Both acelluar and cellular
techniques
Can be used in two-step
process as an adjunct to
injected chondrocytes or as a
one-step adjunct to microfracture in a technique known
as autologous matrix-induced
chondrogenesis
t reating chondral defects. In this case,
the hydrogel scaffold is comprised
of a novel agarose-alginate mixture.
The technique requires two stages,
with initial harvest of a cartilage
sample, culture of the chondrocytes
with autologous serum, suspension
of the cells in agarose-alginate and
a second surgery with implantation
of the chondrocyte-impregnated hydrogel into the defect via a miniarthrotomy30. The size of the hydrogel
plug can be manufactured to meet the
size r equirements of the defect being
treated. The hydrogel plug is manufactured to a predetermined diameter, and at implantation the lesion is
drilled to a depth of 4 mm and a diameter corresponding to the size of the
implant. The implant is then pressfit into the defect without adjunctive
fixation. A multicentre case series of
17 patients with 2-year outcome data
has been reported for Cartipatch30.
The series demonstrated significantly
improved IKDC scores over baseline.
In addition, biopsies of the lesion
were available in 13 patients–in eight
of these, hyaline-like tissue was found
at the site of the implantation.
Tissue 2013 Feb 26;2(2):12
Chondro-Gide
Page 5 of 9
Figure 1: Hyalograft C after having been templated for a chondral defect.
Reprinted with permission from Gobbi A, Kon E, Berruto M, Francisco R, Filardo
G, Marcacci M. Patellofemoral full-thickness chondral defects treated with
Hyalograft-C: A clinical, arthroscopic, and histologic review. Am J Sports Med.
2006 Nov;34(11):1763–73.
Emerging cartilage restoration
technologies–one-stage
techniques
Cartilage autograft implantation
system (CAIS)
CAIS (Depuy Mitek, Raynham, MA)
involves arthroscopic harvest of
healthy cartilage tissue, followed by
mechanical digestion of the cartilage
with a specialized instrument to create 1 to 2 mm chondral fragments.
The fragments are secured to a synthetic scaffold (comprised of a 35%
polycaprolactone, 65% polyglycolic
acid copolymer and polydioxanone
mesh) with fibrin glue. The scaffold is
trimmed to the desired size and shape
and implanted via a miniarthrotomy
into the defect, with the chondral
fragments facing the subchondral
bone and then secured with two or
more bioabsorbable staples31. Initial
results of a prospective randomized
trial of CAIS versus microfracture followed 29 patients at 2-year follow up.
The CAIS group showed statistically
improved outcome scores for IKDC
and KOOS but no difference in SF36 compared with the microfracture
group. MRI data revealed increased
number of intralesional osteophytes
in the microfracture group31. Clinical trials of CAIS are on-going in the
United States32 (no longer enrolling
patients) and Singapore (actively
enrolling)33.
DeNovo
DeNovo NT (Natural Tissue) Graft
(Zimmer, Inc., Warsaw, IN) consists
of allogenic cartilage tissue obtained
from juvenile human donor joints.
The graft is minced into small pieces
and implanted in a single stage into a
chondral lesion and secured with fibrin glue. Juvenile donor cartilage is
chosen based on the concept that juvenile chondrocytes have greater capacity for cell multiplication and anabolic
activity than adult chondrocytes34. The
juvenile minced cartilage graft is considered allograft tissue and is therefore not formally regulated by the FDA.
DeNovo NT is currently being studied
in several on-going postmarket trials35.
DeNovo ET (Engineered Tissue)
(ISTO, St. Louis, MO) like DeNovo
NT is derived from juvenile human
donor cartilage; however, the ET
product undergoes expansion in culture to produce a hyaline-like graft
that can be trimmed to size and implanted with fibrin glue6. DeNovo ET
is the subject of an on-going phase III
clinical trial36. Currently published
clinical outcome data for DeNovo NT
and ET are limited to case reports37.
Autologous matrix-induced
chondrogenesis (AMIC)
AMIC is a novel approach to cartilage
restoration that combines microfracture with a porcine-derived collagen type I/III patch (Chondro-Gide,
Geistlich Pharma AG, Wolhusen, Switzerland). In contrast to other techniques that have been discussed, no
allogenic or autologous chondrocytes
are implanted into the defect. In theory, the application of the collagen
patch overtop of the microfracture
bed can stabilize the clot and provide an enhanced three-dimensional
framework for cell growth and expansion. In addition, AMIC has the advantage of being a one-stage procedure.
The technique requires preparation
and microfracture of the chondral defect in a standard fashion. This is followed by fixation of a collagen patch
with suture or fibrin glue over top
Tissue 2013 Feb 26;2(2):12
Review
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Review
Technologies, Plymouth, MA), activated with an enzyme (Batroxobin,
Plateltex S.R.O., Bratislava, Slovakia)
to produce a sticky clot and implanted
into the chondral defect. The defect is
then covered with a collagen-type I/
III patch (Chondro-Gide). A case series of 15 patients treated with this
technique has been reported40. This
showed significantly improved VAS,
SF-36, KOOS, IKDC, Tegner, Marx and
Lysholm scores at 2-year follow-up.
MRI data revealed complete fill of the
defect in 12 of 15 patients. Histologic
analysis of three biopsy specimens
revealed tissue with a mixture of hyaline and fibrocartilage.
Figure 2: Appearance of the patellar chondral defect immediately after
hyalograft C transplantation. Reprinted with permission from Gobbi A, Kon E,
Berruto M, Francisco R, Filardo G, Marcacci M. Patellofemoral full-thickness
chondral defects treated with Hyalograft-C: A clinical, arthroscopic, and
histologic review. Am J Sports Med. 2006 Nov;34(11):1763–73.
of the lesion38,39. The technique can
be performed through a standard or
miniarthrotomy. Several case series
are reported in the literature, the
most recent and largest report 2- to
3-year year follow-up data. Gille et
al.39 reported on 27 patients treated
with AMIC followed-up at an average
of 37 months. They found substantial
improvement across five different outcome scores (Meyer, Tegner, Lysholm,
ICRS and Cincinatti). Kusano et al.38
reported on 38 AMIC patients with an
average 28-month follow-up. Outcome
scores, including IKDC, Lysholm, Tegner and visual analogue scale (VAS),
were significantly improved. MRI data
were available on 16
patients, and
these were graded according to the
MOCART scale. Results were mixed,
with 10 having greater than 50% fill
and six having less than 50% fill of
the defect. Nearly all patients had increased signal at the repair site.
Bone marrow aspirate concentrate
(BMAC) with collagen patch
Similar to AMIC, the concept of treating damaged cartilage with BMAC involves a single-stage surgery without
implantation of autologous or allogenic chondrocytes. Instead of chondrocytes, m
arrow-derived mesenchymal
stem cells are aspirated from the patient’s iliac crest, centrifuged (BMAC
Harvest Smart PreP2 System, Harvest
Cartilage restoration is a vast field
currently experiencing rapid growth.
The scope of the clinical problem of
chondral injury is large, and there
is a clear need for new technologies
with wide availability, simple application and efficacious, lasting clinical
results. We have reviewed some of
the cartilage restoration technologies currently emerging in clinical
practice. While many of these technologies show significant promise, in
most cases, there is a paucity of highlevel, long-term outcome data to
guide clinicians. Future research will
clarify the picture greatly. However,
at this point, an ideal cartilage restoration technique is not yet available.
Conflict of interests
David C. Flanigan, MD, is a consultant
for Sanofi and Smith and Nephew.
Abbreviations list
ACI, autologous chondrocyte implantation; AMIC, autologous matrix-induced chondrogenesis; BMAC, bone
marrow aspirate concentrate; CAIS,
cartilage autograft implantation
system; HA, hyaluronic acid; IKDC,
International Knee Documentation
Committee; KOOS, Knee Injury and
Osteoarthritis Outcome Score; MRI,
magnetic resonance imaging; VAS,
visual analogue scale
Tissue 2013 Feb 26;2(2):12
Conclusion
Page 7 of 9
Figure 3: BioSeed C scaffold seeded with 2 × 106 autologous chondrocytes
(a). Vicryl sutures are then placed at every corner to serve as a pulley (b). The
sutures are then fixed transosseously using 1.7-mm k-wires in an inside-out
technique (c). The graft as a result fits smoothly into the defect (d). The graft
is now securely fixed via a press-fit technique (e). Reprinted with permission
from Erggelet C, Kreuz PC, Mrosek EH, Schagemann JC, Lahm A, Ducommun
PP, Ossendorf C. Autologous chondrocyte implantation versus ACI using
3D-bioresorbable graft for the treatment of large full-thickness cartilage lesions
of the knee. Arch Orthop Trauma Surg. 2010 Aug;130(8):957–64.
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