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Allogeneic chondrocyte implantation: What is stopping it from being a standard of care?

Authors:

Abstract

Allogenic chondrocyte implantation refers to harvesting of donor chondrocytes, growing them in culture plates with growth factors and implanting them with/without biocompatible scaffolds into cartilage defects. Despite its huge potential, it suffers several drawbacks with respect to source, biomaterial, preservation, cell-culture conditions as well as clinical utility. Through this letter, we attempt to provide an account of these limitations that are stopping it from being a standard of care.
Journal of Arthroscopic Surgery and Sports Medicine • Article in Press | PB Journal of Arthroscopic Surgery and Sports Medicine • Article in Press | 1
Review Article
Allogeneic chondrocyte implantation: What is stopping it
from being a standard of care?
Sufyan Ibrahim1, Himanshu Yashavanthi Nagesh1, Vivek Pandey1
1Department of Orthopaedics, Kasturba Medical College, Manipal Academy of Higher Education, Udupi, Karnataka, India.
PROBLEM STATEMENT
Hyaline articular cartilage is composed of nests of chondrons dispersed in highly-organized, dense
extracellular matrix of collagen (Type II), proteoglycans (aggrecan), and glycosaminoglycans
(hyaluronan).[1] It is a unique tissue lining the joint surface - strong enough to allow weight-
bearing yet smooth enough to allow for frictionless motion. Being an avascular, aneural, and
alymphatic structure, and lacking a stem cell niche of its own, it has poor intrinsic capacity
for spontaneous healing. us, defects here either as a result of trauma in young (particularly
in sportsperson) or age-related attrition, tend not to heal, which in the long-term leads to
osteoarthritis, a debilitating illness aecting millions worldwide.[2]
TECHNIQUES CURRENTLY IN PLACE
Realizing the need for early intervention to prevent the chain of deterioration, scientists over
the years have advocated a myriad of techniques to repair the cartilage defects. While giving
the defect site access to bone marrow stem cells using procedures such as Pridie drilling and
microfracture techniques have been cheap and easy to perform, they have failed to mirror the
articular cartilage biochemically and biomechanically owing to brocartilage invasion, which
does not favor long term clinical outcomes.[3] Restorative techniques such as mosaicplasty or
osteochondral autogras have managed to overcome the said disadvantages but come with the
liability of donor site morbidity and increased risk of gra failure due to failed integration of the
autogra with the surrounding tissue.[4] With the emerging pandemic of cellular therapy in the
past two decades, autologous chondrocyte transplantation has been increasingly considered but
the process suers from major drawbacks, including the need of two surgeries – one to harvest
ABSTRACT
Allogenic chondrocyte implantation refers to harvesting of donor chondrocytes, growing them in culture plates
with growth factors and implanting them with/without biocompatible scaolds into cartilage defects. Despite
its huge potential, it suers several drawbacks with respect to source, biomaterial, preservation, cell-culture
conditions as well as clinical utility. rough this letter, we attempt to provide an account of these limitations that
are stopping it from being a standard of care.
Keywords: Allogenic chondrocyte, Implantation, Scaolds, Cartilage defect, Osteoarthritis
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©2021 Published by Scientific Scholar on behalf of Journal of Arthroscopic Surgery and Sports Medicine
www.jassm.org
Journal of Arthroscopic Surgery and
Sports Medicine Article in Press
*Corresponding author:
Dr. Vivek Pandey
Associate Professor and
Unit Head, Department of
Orthopaedics, Kasturba
Medical College, Manipal
Academy of Higher Education,
Udupi,
Karnataka, India.
vivek.pandey@manipal.edu
Received: 02 March 2021
Accepted: 13 March 2021
EPub Ahead of Print: 14 August 2021
Published:
DOI
10.25259/JASSM_8_2021
Quick Response Code:
Ibrahim, et al.: Allogeneic chondrocyte implantation
Journal of Arthroscopic Surgery and Sports Medicine • Article in Press | 2 Journal of Arthroscopic Surgery and Sports Medicine • Article in Press | 3
cells from the patient and one for surgical implantation of
the cultured cells; and insucient chondrocyte number to ll
larger sized defects.[5] Against this background, chondrocytes
from allogeneic sources have been explored as an alternative
for cartilage regeneration.
OVERVIEW OF ALLOGENEIC CHONDROCYTE
IMPLANTATION
In allogeneic chondrocyte implantation, chondrocytes are
harvested from cadaveric articular cartilage, and implanted
with/without biocompatible scaolds into cartilage defects,
aer growing them in culture plates with growth factors and
serial passage through monolayer cultures. Resemblance
of the neocartilage to hyaline cartilage, lack of ethical
concerns for harvesting chondrocytes, lack of the need for
double surgery, reduced patient morbidity, availability of
a large chondrocyte depot are the possible reasons why the
technique ought to be the “next big thing.[6,7] Despite the
huge potential, limitations exist with respect to culture and
clinical domains, and we attempt to provide an account of
the same [Tabl e 1], with potential solutions to tackle them.
Various important studies[5-18] conducted to highlight the
Tab l e1: Challenges during allogenic chondrocyte implantation and potential ways to mitigate.
Steps Existing Standards Hurdles Potential Solutions
Source of Chondrocytes Adult cadaveric articular
cartilage.
Lesser eciency in matrix synthesis
compared to juvenile sources.
Post-amputation limbs, Infant
syndactyly surgical waste, Nasal
chondrocytes.
Laboratory Culture Ex-vivo expansion of
chondrocytes by serial
passage through monolayer
cultures in a biocompatible
scaold and in the presence
of chondrogenic growth
factors.
Dedierentiation and terminal
dierentiation of chondrocytes.
3D culture techniques-Pellet culture,
Alginate encapsulation, suspension
culture.
Need for an ideal biomaterial
scaold.
Collagen, hyaluronic acid, brin.
Need for an ideal growth factor
Ecient growth factor delivery
system.
Non-serum based growth factors: IGF-1,
TGF-beta, PRP, SOX-9, and GDF-5
Chip based delivery systems for
sustained chondrogenesis.
Preservation Cryopreservation of
harvested articular cartilage.
Challenging to cryopreserve tissue
systems–dicult to maintain
matrix-cell relationship.
Isolated chondrocyte preservation,
Vitrication, Cartilage bio-banking.
Clinical Trials Preliminary stages based on
promising results in animal
studies.
Variations based on age, gender, size
of lesion, site of lesion need to be
studied.
Extrapolation of existing data from
autologous chondrocyte implantation
technique-based clinical trials.
Consent and Patient
Acceptance
Skepticism pertaining to
autologous/cadaveric based
tissue/organ donation as well
implantation.
Cultural, religious/racial, nancial
constraints.
Address individual concerns, generate
awareness among the population.
Surgical Implantation Implantation of harvested
chondrocytes under
Periosteal patch.
Periosteal hypertrophy, harvest site
pain.
Usage of brin glue for chondrocyte
suspension, Search for the ideal scaold
continues.
Collagen membrane. Inammatory reaction,
delamination, failed integration.
Biomaterial based scaold. Immunological reaction,
mechanical stability of the scaold,
failed integration.
Implantation Hurdles Primarily used to ll articular
cartilage defects>3-5cm in
diameter, especially in young
individuals with refractory
symptoms and continued
progression of cartilage
degeneration.
Ideal number of chondrocytes to be
transplanted.
Articial intelligence based neural
networks.
Immune rejection of transplanted
chondrocytes–steroids inhibiting
wound repair.
Alternate immune
suppressants–azathioprine,
cyclosporine, MMF.
Transmission of occult donor
diseases–infectious, genetic.
Screening assays, standardization
protocols, immunotherapeutic
protection.
Post-Operative Generic rehabilitation
protocols until full weight
bearing.
Post-operative complications and
recipient joint morbidity.
Supplementation with pre-transplant
rehabilitation protocols.
Ibrahim, et al.: Allogeneic chondrocyte implantation
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scope and utility of allogenic chondrocyte implantation have
been briey discussed in [Table 2].
LIMITATIONS AND POSSIBLE WAYS TO
CIRCUMVENT THE CHALLENGES
Source of chondrocytes
It is seen that chondrocytes from adult sources are less
ecient in synthesizing the matrix in vitro and subsequently
face diculty initiating repair in vivo, compared to juvenile
sources.[19] Apart from the ethical concerns associated,
juvenile sources may not be able to keep up with the demand-
supply discrepancy.
As a potential solution, infant cartilage tissue obtained
from polydactyly/syndactyly surgical wastes can act as
substitutes.[20] In addition, nasal chondrocytes, harvested
from cadaveric sources or post-septoplasty/submucosal
resection specimens can be considered since they have been
shown to have a faster in vitro proliferation rate compared to
articular cartilage, thus needing less cell seeding densities.[21]
e depot can also be increased using chondrocytes from
post-amputation limbs.[20]
Need for cryopreservation
Despite having adequate number of chondrocytes for
transplantation, developing an eective preservation
strategies is a must since we cannot be waiting for a source
every time a patient needs an articular defect repair. Tissue
preservation systems have been well established compared
to isolated chondrocyte preservation but remain more
challenging nevertheless since there is a need to not only
store the cells and the matrix but also maintain the intricate
relationship between them.[22] Vitrication of cells, which
allows transition into a glass-like amorphous state, without
passing through the intermediate crystalline stage is all set to
be a forerunner in the eld of chondrocyte bio-banking.[22]
Culture conditions
While having an allogeneic source reduces the number of
times chondrocytes need to be expanded to increase their
number, its need cannot be completely negated. During
in vitro serial monolayer expansion, chondrocytes tend to be
replaced by complex cartilage phenotype containing Type I
collagen and low-level proteoglycan synthesis which would
lead to transplant failure either due to dedierentiation into
brocartilage or terminal dierentiation into hypertrophic
cartilage.[23] 3D culture techniques using pellet culture,
alginate encapsulation, suspension culture help overcome
this by promoting redierentiation at every stage and
allowing for higher cell seeding densities.[24]
While transplanting chondrons (chondrocytes with
pericellular matrix) would reduce the numbers available for
transplantation considerably, chondrocytes when transplanted
alone would fail to integrate with the surrounding tissues.[1,25]
is necessitates the use of a natural/synthetic biomaterial
scaold for chondrocyte culture and transplantation. An
ideal scaold is an elusive nd considering that it has to be
biodegradable and non-toxic, geometrically appropriate
with the correct pore-size and morphology to allow for
nutrient and by-products diusion and provide an ideal
micro-environment for chondrocyte growth while hosting
dierential matrix component distribution. A variety of
pro-chondrogenic natural and synthetic scaolds including
collagen, agarose, brin, hyaluronic acid, poly-L-Lactic acid
have been considered but the search continues.[26,27]
Enhancing chondrogenesis in vitro is done using growth
factors. Serum-based growth factors not only have limited
availability and increasing variability worldwide but also are
known to reduce in vitro chondrogenesis.[19,28] Non serum-
based factors (IGF-1, TGF-beta, PRP, SOX-9) could be used
but eective ways to deliver these short-lived factors for
sustained chondrogenesis in vivo, and their quality control
still remains an issue.[29,30] Micro and nanochips containing
these growth factors could be embedded in the scaolds at
graded concentrations which would help mimic the natural
structure of articular cartilage.[31]
Clinical hurdles
Implantation of the cultured cells under a periosteal cover is
not only technically challenging but may also lead to periosteal
hypertrophy with consequent pain, in addition to harvest site
pain thus reducing the quality of life.[32] Collagen scaolds
alleviate this problem but would lead to inammatory
reaction and gra failure, delamination or failed integration,
necessitating repeat surgery, reiterating the need for an eective
synthetic scaold.[33] e scaold, in addition to being near
perfect as a laboratory material, has to be immunogenically
non-reactive and mechanically compatible.
Although articular cartilage is pauci-immunogenic, studies
in rabbit model show immunogenic anti-gra rejection
response to the implanted chondrocytes, slowly destroying
the regenerated cartilage, unlike autologous chondrocytes.[34]
Use of corticosteroids in the patient to overcome this would
interfere with the subsequent repair process. Alternative
immunosuppressants such as cyclosporine, mycophenolate
mofetil, or azathioprine could be tried but need
substantiation.
e ideal number of chondrocytes needed to be transferred
to ll defects of varying size is beyond human intelligence
but articial intelligence-based approach using deep neural
networks could be path-breaking in this regard.[35]
Ibrahim, et al.: Allogeneic chondrocyte implantation
Journal of Arthroscopic Surgery and Sports Medicine • Article in Press | 4 Journal of Arthroscopic Surgery and Sports Medicine • Article in Press | 5
Article Aims Outcomes
Boopalan etal.[6] Compare ACT with allogenic chondrocyte
transplantation in the treatment of
experimentally created articular cartilage defects
in rabbit knee joints.
Allogenic chondrocyte transplantation seems to be
as eective as ACT in cartilage regeneration, with the
added advantages of increased cell availability and
reduced morbidity of a single surgery.
Perrier-Groult etal.[7] To investigate tolerance of allogeneic HACs
by the human immune system, developing
a humanized mouse model implanted with
allogeneic cartilage constructs generated
invitro.
No sign of T-cell or macrophage inltration was seen in
the cartilaginous constructs and no signicant increase
in subpopulations of T lymphocytes and monocytes was
detected in peripheral blood and spleen.
Man etal.[8] To explore the eect of allogeneic
chondrocytes transplantation with the
CS‑DBM hybrid scaold via one-step
operation to repair the full-thickness cartilage
defect in rabbits.
e CS/DBM scaold was found to be an ideal
biomaterial for cartilage tissue engineering. Allogenic
chondrocytes delivered with the CS/DBM scaold could
eectively repair rabbit cartilage injury via one-step
operation.
Takizawa etal.[9] Investigate the regenerative eects of human
chondrocyte sheets and synoviocyte sheets
for articular cartilage regeneration in a
xenogeneic model using immune‐decient rats
to establish a human translational model.
Results indicate that layered chondrocyte sheet
transplantation contributes to articular cartilage
regeneration.
Tani etal.[10] To examine the ecacy of using
vitried‑thawed cryostored chondrocyte
sheets in treating full-thickness articular defects
induced in the knees of rabbits.
Signicantly better pain-alleviating eects and tissue
repair were achieved by using vitried–thawed
chondrocyte sheet transplantation compared with
no treatment(an osteochondral defect alone). No
signicant dierences were observed between the
transplantation of conventional fresh chondrocyte
sheets and vitried chondrocyte sheets.
Wu etal.[11] Explore the application of 3D micromass stem
cell culture for chondrocyte and osteoblast
induction prior to bioreactor-based cells-loaded
scaold culture for treatment behavior of
chondrocyte and osteoblast‑loaded β‑TCP
bioceramic scaolds for articular cartilage
defect treatment.
Chondrocyte/osteoblast-loaded β-TCP bioceramic
scaolds had several advantages for the treatment
of cartilage defects:(i) Good cartilage regeneration
ability;(ii) wide allogenic BMSCs availability;(iii) no
need additional surgery for patients;(iv) no donor site
defect formation in patients;(v) less possible blood
loss and infection. is work suggested micromass
stem cell culture and bioreactor-based cells-loaded
scaold culture can be applied to prepare chondrocyte/
osteoblast-loaded β-TCP bioceramic scaold.
Choi etal.[5] To evaluate the results of autologous
bone marrow cell stimulation and
allogenic chondrocyte implantation using
3‑dimensional gel‑type brin matrix in an
animal model.
Suggested that autologous bone marrow cells
stimulation and implantation of allogenic chondrocytes
are both useful methodologies for regenerating
hyaline-like cartilage in full-thickness cartilage defects
in animal model.
Lee etal.[12] To assess the occurrence of apoptotic
chondrocyte death in the areas of defect in
the articular cartilage following chondrocyte
transplantation in the knee of the rabbit.
During the remodeling stage aer chondrocyte
transplantation, there is a rapid and signicant decrease
in total cellularity along with a concomitant signicant
increase in apoptosis, especially in the supercial
layers. erefore, apoptosis may be one of the factors
responsible for the decrease in total cellularity of
transplanted chondrocytes during the remodelling stage
of chondrocyte transplantation.
Boopalan etal.[13] To study the eectiveness of invitro expanded
allogenic chondrocyte transplantation for
focal articular cartilage defects in rabbits.
Articular cartilage defects treated with allogenic
chondrocyte transplantation result in better repair
tissue formation with hyaline characteristics than those
in control knees.
Tab l e2: Important studies pertaining to allogenic chondrocyte implantation.
(Contd...)
Ibrahim, et al.: Allogeneic chondrocyte implantation
Journal of Arthroscopic Surgery and Sports Medicine • Article in Press | 4 Journal of Arthroscopic Surgery and Sports Medicine • Article in Press | 5
e implanted chondrocytes could serve as a new parenteral
means to transmit diseases – infectious diseases could be
screened for but occult congenital diseases, autoimmune
diseases, and malignancies could be manifested only in the
recipient post-transplant. Optimal screening assays and
standardization of transplant protocols are a must before the
procedure can kick in as a standard of care.[36]
Post-chondrocyte transplant, the patient needs to be put
on a safe, customized, optimal rehabilitation program,
ranging from progressive partial weight-bearing to
subsequent complete weight-bearing in order to obtain full
joint motion and function. Pre-transplant rehabilitation
protocols could also be put in considering the complex joint
biomechanics.[37]
e fact that the cells are obtained from allogeneic sources
gives immense scope for rejection of the procedure by
the patients and convincing the mass about the pros of
the procedure can be a challenge. e laboratory and
preservation-related costs may also prevent widespread use
of the technique, particularly in developing countries.[13-18]
CONCLUSION
Cartilage repair is an ever-evolving eld with huge scope
for improvement and exploration, allogeneic chondrocyte
implantation being just another cusp of it. ere is no
doubt about its immense potential but it probably suers
from the “middle child syndrome” – its precursors (surgical
techniques) have been relied upon by many due to their low
cost, its contemporaries (autologous transplants) have passed
through reliable clinical trials, and its potential successors
(stem cell therapy, gene editing, and bio-printing) are even
more enticing. Adequate large-scale studies to prove long-
term clinical ecacy of the technique, assessment of benet
versus risk in patients, age, gender, and lesion-size-based
variation in results need to be validated before accepting it as
a standard of care.
Declaration of patient consent
Patients consent not required as there are no patients in this
st u dy.
Tab l e2: (Continued).
Article Aims Outcomes
Toy od a etal.[14] Evaluate the ecacy of PD sheets as an
allogeneic alternative to standard chondrocyte
sheets was examined using an orthotopic
xenogeneic transplantation model.
Ecacy-associated genes that may contribute to hyaline
cartilage regeneration via PD sheet transplantation. e
identied characteristics could act as markers to predict
the invivo ecacy of using PD sheets.
Maehara etal.[15] Investigate the characteristics of PD sheets
fabricated from the chondrocytes of young
polydactyly donors.
PDs proliferated rapidly to establish a layered structure
with sucient extracellular matrix and formed sheets
that could be easily manipulated without tearing. PD
sheets exhibited characteristics thought to be important
to chondrocyte sheets as well as proliferative capacity
that may facilitate provision of a stable supply in the
future.
Guo etal.[16] To investigate the eect of allogeneic
chondrocytes‑calcium alginate gel composite
under the intervention of LIPUS for repairing
rabbit articular cartilage defects.
Allogeneic chondrocytes-calcium alginate gel composite
can eectively repair articular cartilage defect. e eect
of LIPUS optimized allogeneic chondrocytes-calcium
alginate gel composite is better.
Dhollander etal.[17] To evaluate the implantation of alginate
beads containing human mature allogenic
chondrocytes for the treatment of symptomatic
cartilage defects of the knee. MRI was used for
the morphological analysis of cartilage repair.
e correlation between clinical outcome and MRI
ndings was poor. Further validation of these scoring
systems is mandatory. e promising short-term clinical
outcome of the allogenic chondrocytes/alginate beads
implantation was not conrmed by the short-term MRI
ndings.
Lin etal.[18] Animal model to study the eects on a 4-week
healing process of chondral defects by the
implantation of allogenous chondrocyte‐
seeded HA/Col II microspheres that had
been cultured invitro for 7days prior to
implantation compared with unseeded HA/Col
II microspheres or an untreated wound.
More GAG staining appeared in the defect implanted
with chondrocyte‐seeded HA/Col II microspheres,
which demonstrated a higher level of hyaline cartilage
regeneration. Due to the short healing period assigned
to this study, the repaired cartilage showed limited
incorporation into the surrounding host cartilage and
some loose connection to the subchondral bone.
ACT: Autologous chondrocyte transplantation, CS/DBM: Chitosan hydrogel/demineralized bone matrix, LIPUS: Low intensive pulsed ultrasound,
PD: Polydactyly-derived chondrocyte
Ibrahim, et al.: Allogeneic chondrocyte implantation
Journal of Arthroscopic Surgery and Sports Medicine • Article in Press | 6 Journal of Arthroscopic Surgery and Sports Medicine • Article in Press | 7
Financial support and sponsorship
Nil.
Conicts of interest
ere are no conicts of interest.
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How to cite this article: Ibrahim S, Nagesh HY, Pandey V. Allogeneic
chondrocyte implantation: What is stopping it from being a standard of
care? J Arthrosc Surg Sports Med, doi: 10.25259/JASSM_8_2021
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