Orthopaedic Advances

Biologic Adjuvants for the

Management of Osteochondral
Lesions of the Talus

MaCalus V. Hogan, MD, MBA
Justin J. Hicks, MD
Monique C. Chambers, MD,
MSL
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Abstract
Surgical techniques for the management of recalcitrant osteochondral
lesions of the talus have improved; however, the poor healing potential
of cartilage may impede long-term outcomes. Repair (microfracture)
or replacement (osteochondral transplants) is the standard of care.

Reparative strategies lead to production of fibrocartilage, which,

John G. Kennedy, MD, FRCS
compared with the native type II articular cartilage, has decreased
mechanical and wear properties. The success of osteochondral
transplants may be hindered by poor integration between grafts and
host that results in peripheral cell death and cyst formation. These
challenges have led to the investigation of biologic adjuvants to
augment treatment. In vitro and in vivo models have demonstrated
promise for cartilage regeneration by decreasing inflammatory
damage and increasing the amount of type II articular cartilage.
Further research is needed to investigate optimal formulations and
time points of administration. In addition, clinical trials are needed to
investigate the long-term effects of augmentation.

O steochondral lesions of the

From the University of Pittsburgh
School of Medicine (Dr. Hogan,
Dr. Hicks, and Dr. Chambers), and the
Hospital for Special Surgery, New
York, NY (Dr. Kennedy).
J Am Acad Orthop Surg 2019;27:
e105-e111
DOI: 10.5435/JAAOS-D-16-00840
Copyright 2018 by the American
Academy of Orthopaedic Surgeons.
talus (OLT) pose clinical and
surgical challenges to orthopaedic
surgeons. Approximately two million
ankle sprains occur in the United
States annually, with up to 50% of
patients sustaining concurrent carti-
lage injury.1,2 Furthermore, ankle
fractures are associated with a high
risk (up to 73%) for cartilage in-
jury.1 Chondrocytes are the primary
cell type in cartilage and have little
capacity for self-renewal because of
limited vascularity, making OLT
management challenging.
The optimal treatment modality for
an OLT is unclear. Loveday et al,3
in a Cochrane review, concluded
that there is insufficient evidence
from current trials to determine which
treatment strategies are best for
managing OLT in adults. Nonsurgical
management involves nonsteroidal
anti-inflammatory medication and
limiting physical activity. The success
rates of nonsurgical treatment, in
minimally symptomatic patients, have
been reported to be 86%, compared
with 49% in moderately symptomatic
patients based on acute symptoms
and not long-term cartilage healing.4
Surgical management is indicated in
symptomatic patients and possibly in
patients with sizeable defects whose
condition does not improve under
conservative management.
Surgical management of OLT cur-
rently focuses either on reparative
cell-based therapies such as micro-
fracture or on replacement strategies
such as autologous chondrocyte
implantation, matrix-induced autol-
ogous chondrocyte implantation,
or osteochondral autologous trans-
plantations. Cell-based therapy in-
volves local recruitment or delivery of

February 1, 2019, Vol 27, No 3 e105

Copyright ª the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
Biologic Adjuvants for the Management of Osteochondral Lesions of the Talus

Table 1 ment of osteochondral defects of the

talus.10-12
Growth Factors and Their Known Function
Concerns with current treatment
Growth Factor Function modalities have led to recent studies
TGF-b1 Increased ECM synthesis. investigating the role of biologic
adjuncts in augmenting cartilage
Decreased catabolic signaling (IL-1 and MMP).
healing and the management of os-
Increased fibroblast proliferation and collagen synthesis.
teochondral lesions.
PDGF Increased proteoglycan synthesis. Increased production
of collagen.
VEGF Promotes new vessel growth.
BMP-7 (OP-1) Stimulates ECM synthesis.
Growth Factors and
Suppresses MMP and IL induced cartilage damage.
Platelet-rich Plasma
Not affected by age or presence of OA.
Growth factors are proteins that
IGF-1 Increased cell growth. stimulate the growth and develop-
Increased collagen synthesis of fibroblast. ment of tissue. Platelet-rich plasma
bFGF Increased production of collagen and angiogenesis. (PRP) is composed of a patient’s own
CTGF Increased cartilage regeneration and angiogenesis. concentrated platelets, which con-
tain over 1,500 growth factors
bFGF = basic fibroblast growth factor, BMP = bone morphogenetic protein, ECM = extracellular
matrix, FGF = fibroblast growth factor, IGF-1 = insulin growth factor 1, IL = interleukin, MMP = matrix located within the a-granules.13
metalloproteinase, OA = osteoarthritis, OP = osteogenic protein, PDGF = platelet-derived growth These growth factors have several
factor, TGF-b1 = transforming growth factor-b1, VEGF = vascular endothelial growth factor
functions including both cartilage
growth and extracellular matrix
synthesis, which in turn may have
cells with chondrocyte properties, Minced juvenile articular cartilage the potential to augment cartilage
whereas transplantation involves is a novel option for large or refrac- healing and repair (Table 1). It is
transferring cartilage explants or cells tory osteochondral lesions. This important to note that the compo-
to the defect site. Although midterm option entails the use of allograft sition of growth factors in PRP varies
studies report improved outcomes for cartilage harvested from donors less from person to person and even
these treatments, many patients still than 13-year old.10 It has been used between repeated preparations
experience persistent pain.5 This may since 2007 mostly in the knee within the same individual.14 Other
be due to biologic shortcomings and has been shown to contain up patient-specific factors and differences
inherent with each approach. Cell- to 10 times the cellular density of in commercial system preparation
based reparative therapies have pro- adult chondrocytes with improved methods can lead to variations in PRP
teoglycan depletion and chondrocyte ability to retain articular cartilage composition and can make interpre-
death at 1-year follow-up, and the fi- phenotype, theoretically leading tation of the literature challenging.14
brocartilage that is generated pos- to decreased production of fi- PRP is not only composed of con-
sesses inferior mechanical and biologic brocartilage.10 Early results from centrated platelets but also contains
properties compared with the native case reports and case series demon- leukocytes and reticulocytes. One
hyaline articular cartilage.6-8 With strate good-to-excellent clinical out- cannot ignore these ancillary factors
replacement strategies, concerns exist comes; however, more robust and because they can affect the function
regarding poor graft integration, cell long-term clinical studies are needed of PRP. For instance, high concen-
death, graft degeneration, and cyst to evaluate the efficacy of juvenile trations of leukocytes are associ-
formation.9 articular cartilage for the manage- ated with catabolic cytokines and

Dr. Hogan or an immediate family member is a member of a speakers’ bureau or has made paid presentations on behalf of Miller Review
Course; has received research or institutional support from Amniox Medical; and serves as a board member, owner, officer, or committee
member of the J. Robert Gladden Society, Nth Dimensions Education Solutions, the Orthopaedic Research Society. Dr. Kennedy or an
immediate family member serves as a paid consultant to and has received research or institutional support from Arteriocyte and serves as a
board member, owner, officer, or committee member of the American Orthopaedic Foot and Ankle Society, the Arthroscopy Association of
North America, the European Society for Sports Traumatology, Knee Surgery, and Arthroscopy, the Ankle and Foot Associates, and the
International Society for Cartilage Repair of the Ankle. Neither of the following authors nor any immediate family member has received
anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of
this article: Dr. Hicks and Dr. Chambers.

e106 Journal of the American Academy of Orthopaedic Surgeons

Copyright ª the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
 MaCalus V. Hogan, MD, MBA, et al

Table 2
HA and PRP OLT Adjunct Outcomes
Biologic Study Patient Average
Study Adjunct Description Type Number Average Defect Size Follow-up Outcomes

Guney et al17 PRP Mfx alone; Mfx 1 Case 35 ,20 mm diameter 16.2 mo (range, PRP as an adjunct improved
PRP series 12-24 mo) outcomes scores
compared with Mfx alone.
Doral et al18 HA Mfx 1 HAinjection* RCT 57 ,20 mm diameter 2 yr post op Both groups had increased
Mfx alone outcome scores.
— *3 weekly HA — — — — Injection group outcome
injections starting at scores were inceased
3 wk postop compared with Mfx alone.
Gormeli et al19 HA or PRP Mfx 1 HA RCT 27 PRP: 1.28 (range, 15.3 mo (range, Both PRP and HA improved
0.52-1.4) 11-25) clinical outcomes.
— Mfx 1 PRP — — HA: 1.24 (range, — Single-dose PRP yielded
0.48-1.46) better results than
multidose HA.
— — — — Control: 1.18 (range, — —
0.46-1.38)
Shang et al20 HA Mfx alone vs Mfx 1 RCT 35 1.4 cm2 (SD 0.4 cm2) 10.5 6 1.2 mo MRI outcomes demonstrated
HA injections (3 a higher thickness index
injections over 14 d) (0.8 6 0.1 versus 0.7 6
0.1) and lower T2 index
(1.2 6 0.1 versus 1.4 6
0.1) in the injection
group compared with the
noninjection group
(P , 0.01).
— — — — — — AOFAS and VAS scores both
yielded higher level of
improvement in the
injection group (P , 0.05).

AOFAS = American Orthopaedic Foot and Ankle Society, HA = hyaluronic acid, Mfx = microfracture, PRP = platelet-rich plasma, RCT = randomized controlled trial,
VAS = visual analog score

proinflammatory signaling, which
can be detrimental to tissue healing,
compared with leukocyte-poor PRP,
which in vitro exhibits anabolic ef-
fects promoting chondrogenesis.15
As such, PRP may act as an adjunct
to cartilage repair by decreasing
inflammatory mediators, increasing
collagen and proteoglycan synthesis
and degradation, as well as recruiting
mesenchymal stem cells (MSCs),
which in turn undergo chondrogenesis
and synthesize type II collagen.
A preclinical animal model in rab-
bits demonstrated that osteochondral
defects treated with PRP demon-
strated improved histological scoring
with increased hyaline-like cartilage
and improved integration of the os-
teochondral graft at the cartilage
interface.16 Clinical studies assessing
the efficacy of PRP as an adjunct to
microfracture of OLT are promising,
reporting improved outcomes com-
pared with surgical repair alone
(Table 2). However, long-term, level
I randomized control trials are
needed. The optimal combination of
platelets, leukocytes, and eryth-
rocytes among other components of
PRP currently is unknown. A maxi-
mal efficacious platelet concentra-
tion may also be present. Therefore,
it is critical that future studies
properly characterize and report
PRP contents used, to optimize PRP
as an adjunct to OLT surgery and
accurately interpret findings.
Hyaluronic Acid
Hyaluronic acid (HA) is a glycos-
aminoglycan located within synovial
fluid. In water, HA forms a viscous
gel-like substance with nociceptive
blocking properties that may play a
role in osteoarthritis treatment.
In vitro, HA has been found to pro-
mote cartilage regeneration through
increased chondrocyte proliferation
and synthesis of proteoglycans while
also preventing cartilage degradation
and the production of deleterious
proinflammatory cytokines and matrix
metalloproteinases.21 The chon-
droprotective and regenerative ef-
fects of HA have been validated in
animal models. Strauss et al22 demon-
strated that HA supplementation
through three weekly intra-articular
injections enhanced filling of the
defects grossly and histologically in
rabbits after microfracture surgery.
Kaplan et al23 created 10- · 10-mm
partial-thickness articular cartilage

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Biologic Adjuvants for the Management of Osteochondral Lesions of the Talus

Figure 1 lesions in the medial condyle of

sheep followed by two HA in-
jections 7 days apart. Lesions were
evaluated at 12 weeks demon-
strating that early administration
of HA is chondroprotective.
Three recent studies comparing
OLT treatment using microfracture
surgery alone with microfracture
surgery supplemented with HA
demonstrate improved outcomes in
the HA group (Table 2). Compar-
ing a single-dose PRP injection
with a multidose HA injection regi-
men as adjunct to microfracture
surgery in OLT, the authors found
Magnetic resonance imaging (MRI) of the osteochondral lesion of the talus that both PRP and HA improved
(OLT). A, Coronal T2 showing medial talar dome OLT with surrounding marrow outcomes; however, PRP was rec-
edema. B, Sagittal T1 image showing medial central dome OLT with findings
ommended over HA because a single
consistent with unstable fragment.
injection yielded superior outcomes
(Table 2). Given the in vitro evidence
of chondroprotection and increased
Figure 2 cartilage regeneration as well as
improved outcomes scores clinically,
HA seems to be a viable adjunct to
OLT repair. Further studies are
needed to make more robust treat-
ment recommendations regarding
HA injections alone or even in
combination with PRP to supple-
ment cartilage regeneration.

Stem Cells

Embryonic Derived
Mesenchymal Cells
Embryonic-derived mesenchymal
cells (EMCs) are pluripotent stem
cells with the ability to differentiate
into all three primary germ layers:
endoderm (eg, lining of the gastroin-
testinal tract and lungs), mesoderm
(eg, muscle, bone, cartilage, blood),
and ectoderm (eg, nervous tissue).24
This pluripotency and unlimited self-
renewal distinguishes EMCs from
adult stem cells, which have limited
Osteochondral lesion of the talus (OLT) repair with iliac-crest bone marrow differentiating ability and are con-
aspirate concentrate (BMAC). A, OLT during initial insertion of BMAC, B, sidered multipotent. The utilization
insertion of prepared BMAC injection. C, OLT with BMAC in place after of EMCs for cartilage repair is in its
microfracture and débridement. D, OLT following final placement of BMAC and infancy. Currently, very few studies
Tisseell.
have been conducted to evaluate the

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 MaCalus V. Hogan, MD, MBA, et al

Table 3
Stem Cell Adjunct Outcomes
Average
Study Biologic Adjunct Description Average Defect Size Follow-up Outcomes

Kennday et al29 cBMA 1 OATs Case series. 72 patients 11.12 mm (range, 6-20 mm) 28.02 mo (range, Increased AOFAS score from 52.67
anterior to posterior 12-64 mo) to 86.19 and SF-12 from 59.40 to
88.63
— 10.74 mm (range, 7-20 mm) — Return to sports = 13 wk (range,
medial to lateral 11-20 wk)
Buda et al30 cBMA 1 scaffold Prospective. 64 (5.27 6 68 cm2) 54 mo Increased AOFAS score from 65.2
(collagen powder or patients with OLT (613.9) to 91.1 (68.7 at 24 mo
HA) (peak)
— — — Gradual decline and settled at 80.7
(614.1) at 72 mo
Kim et al31 MSC Retrospective. 65 108.7 (634.6 mm2) 21.8 mo (64.3) Mean VAS and AOFAS scores
patients. Mfx vs Mfx 1 improved in both groups.
MSC injection.
— — — Tegner activity scale improved in
the Mfx 1 MSC group (3.5 6 0.7
to 3.8 6 0.7)
— — — Large lesions (.109 mm2) and
existence of subchondral cysts
predicted unsatisfactory results
for the Mfx-only group
Gianni et al32 cBMA 1 scaffolded Case series. 49 patients 2.24 6 1.23 cm2 48 6 6.1 mo AOFAS score improved from 63.73
with OLT 6 14.13 to 82.19 6 17.04
— — — T2-mapping showed regenerated
tissue with T2 values of 35-45 ms,
similar to hyaline cartilage

AOFAS = American Orthopaedic Foot and Ankle Society, cBMA = concentrated bone marrow aspirate, HA = hyaluronic acid, Mfx = Microfracture, MSC = mesenchymal
stem cell, OATs = osteochondral autologous transplantation, OLT = osteochondral lesions of the talus, SF = short form, VAS = visual analog scale

ability of EMCs to repair os-
teochondral defects. EMC have been
induced in vitro to form MSCs
including chondrocytes.25,26 Pilichi
et al24 demonstrated that delivery of
EMCs into osteochondral defects in
sheep femoral condyles improved
cartilage regeneration for up to
24 months. Cheng et al27 used EMCs
encapsulated in a fibrin gel and im-
planted these cells into patellar
groove osteochondral defects. The
authors observed improved histo-
logic scoring and upregulation of
chondrogenic genes in groups
receiving EMCs. Although promis-
ing, the use of EMC-derived chon-
drocytes for the clinical management
of cartilage defects is far off. Further
research is needed to characterize
their potential to repair damaged
cartilage. In addition, the use of
EMCs raises ethical concerns because
they are derived from the early-stage
preimplantation embryo. Further-
more, their ability to self-renew and
multilineage properties raise concern
regarding tumorigenicity.
Bone Marrow-derived Stem
Cells and Bone Marrow
Aspirate Concentrate
MSCs are adult stem cells that can be
found in bone marrow and other tis-
sues. These stem cells are multipotent
with the ability to differentiate along
connective tissue cell lineages,
including chondrocytes, osteoblasts,
and myocytes. MSCs are thought to
be responsible for physiologic growth,
wound healing, and replenishing cells
lost during daily cell turnover and
have been shown to be effective for
managing musculoskeletal tissue
injury. Bone marrow stem cells are the
most commonly used source of cells
for cartilage regeneration. They are an
optimal option for cartilage regener-
ation because they are widely avail-
able and can be accessed easily during
surgery from the patient’s iliac crest
among other locations. Derived from
adult tissue, MSCs also avoid the
ethical concerns associated with
EMCs. Concentrated bone marrow
aspirate (cBMA) is a source of MSCs
and is a potential biologic adjunct to
OLT treatment modalities. In addi-
tion to MSCs, cBMA also contains
platelets that contain growth factors
within the platelet a-granules, anal-
ogous to PRP (Table 1). These
growth factors may potentially aug-
ment the regenerative and reparative
capacity of MSCs. Another major
advantage of cBMA is that it can be
obtained and prepared during the
index procedure.
Evidence supporting bone marrow
aspirate as an adjunct to cartilage
repair has been demonstrated in

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Biologic Adjuvants for the Management of Osteochondral Lesions of the Talus
preclinical animal models (Figures 1
and 2). In an equine model, Fortier
et al28 compared microfracture alone
with microfracture with cBMA to
manage full-thickness cartilage de-
fects of the lateral trochlear ridge.
Histological and MRI analysis indi-
cated improved healing in the cBMA
group. Early studies suggest that
these findings have translated to
surgical repair of human OLTs.
Improved clinical outcome scores
and radiographic findings have been
demonstrated in several clinical
studies (Table 3). These findings may
be limited by defect size as Kim et al
found that large lesions (.109 mm2)
and subchondral cysts predicted
unsatisfactory outcomes. Additional
long-term randomized controlled
trials are needed. Reporting of defect
size and depth is critical to under-
standing the efficacy of bone marrow
stem cell as an adjunct to OLT repair
and will aid in the optimization of
this method.
Adipose-derived Stem Cells
Adipose tissue represents another
source of MSCs capable of differen-
tiating into chondrocytes. In vitro,
cartilage derived from adipose stem
cells has a high total collagen count
but lower levels of type II collagen. A
recent study by Kim et al33 compar-
ing marrow stimulation in OLT with
marrow stimulation augmented with
adipose stem cells demonstrated
improved clinical and MRI out-
comes scores in the adipose stem cell
group compared with marrow stim-
ulation alone. Although encourag-
ing, the self-renewal capacity of
adipose stem cells is not completely
understood, and further studies are
needed to optimize the chondrogenic
potential of these cells.
Synovial- and Periosteum-
derived Stem Cells
Synovial chondromatosis, a benign
tumor of the synovial membrane, led
e110
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researchers to investigate the carti-
lage regeneration potential of these
cells. In vitro, chondrocytes derived
from the synovial lineage retain
fibroblastic characteristics needed to
form hyaline cartilage. Studies com-
paring them with MSCs demonstrate
higher chondrocyte differentiation
potential.34 Application of synovial
stem cells to OLT surgery is far from
clinical application; however, their
potential for future use is intriguing.
Another novel source of stem cells is
periosteum-derived cells. Periosteum-
derived cells have the potential to
serve as chondroprogenitor cells and
are currently appreciated for their
dual lineage (bone and hyaline carti-
lage) potential. Further studies are
needed to characterize conditions to
induce cartilage growth.25
Summary
The optimal management of OLT is
still undefined. An international con-
sensus meeting on the treatment of
OLTs was recently held at the Uni-
versity of Pittsburgh (M.V.H.).35 The
results of this meeting as it pertains to
biologics were reported.36 Concerns
regarding the biologic shortcomings
of current reparative and replacement
strategies still remain. Biologic ad-
juncts using stem cells, growth fac-
tors, HA, scaffolds, or a combination
thereof are potential interventions
that may enhance the regeneration of
these defects. In vitro and preclinical
animal models support this hypothe-
sis, and early clinical studies of bio-
logic augmentation are promising.
Research exploring the efficacy of
these biologic treatment modalities is
underway and may improve the out-
comes of OLT treatment in the future.
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Evidence-based Medicine: Levels of
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Journal of the American Academy of Orthopaedic Surgeons
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References 1, 31, and 33 are level III
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