Orthopedic applications of stem cells

ORTHOPEDIC
APPLICATIONS
OF STEM CELLS
BY:
Mohamed Samir El-Asaly
PT, CKTP
Under the supervision of:
Prof. Dr. Mokhtar El-Zawahry
Prof. Dr. Hanan El-baz

Outlines
 STEM CELLS IN BONE HEALING
 STEM CELL IN NON-UNION FRACTURES
 STEM CELLS IN AVASCULAR NECROSIS
 STEM CELLS AS FILLERS OF BONY VOIDS
 STEM CELLS IN CARTILAGE REPAIR & ARTHRITIS
 STEM CELLS IN TENDON REPAIR
 STEM CELLS IN LIGAMENT REPAIR
 STEM CELLS IN MENISCUS REPAIR
 STEM CELLS IN INTERVERTEBRAL DISC DEGENERATION
 CONCLUSION

Orthopedics
 The branch of medicine
that deals with the
prevention and
correction of injuries or
disorders of the
skeletal system and
associated muscles,
joints, and ligaments.

Stem Cells in Bone
Healing
We have to understand how a normal bone heal :
 Depending on the seriousness of the break, the
patient’s age and other factors.
 Normal bone can heal themselves in six weeks to three
months.

Stem Cells in Bone
Healing
1.Stem cells turn into cartilage
forming cells, creating soft scaffold
to bridge the break
2.Bone building cells called
osteoblasts lay down minerals to
change to bone.
3.New bone fills in the break,
becoming stiffer and stronger with
time

Stem Cells in Bone
Healing
MSCs are able to be differentiated
in osteoblasts under the influence
of growth factors:
 BMPs: Bone morphogenetic
proteins
 PDGF: Platelet-derived growth
factor
 Transforming growth factor
beta
 IGF: Insulin-like growth factor
 Fibroblast growth factor
 PTH: parathyroid hormone

STEM CELL IN NON-UNION
FRACTURES

Non-union fracture
 Non-union is a
serious complication of a
fracture and may occur when
the fracture moves too much,
has a poor blood supply or
gets infected.
 Patients who smoke have a
higher incidence of non-union.
 The normal process of bone
healing is interrupted.

Non-union fracture
 In some cases a pseudo-
joint (pseudarthrosis)
develops between the
two fragments
with cartilage formation
and a joint cavity.
 More commonly the
tissue between the un-
united fragments is scar
tissue.

Non-union fracture
 Since the process of bone healing is quite
variable, a non-union may go on to heal without
intervention in a very few cases.
 In general, if a non-union is still evident at 6
months post injury it will remain unhealed
without specific treatment, usually orthopedic
surgery.
 A non-union which does go on to heal is called a
delayed union.

Signs and symptoms
 A history of a broken bone is usually apparent.
 The patient complains of persistent pain at the
fracture site and may also notice abnormal
movement or clicking at the level of the
fracture.
 An x-ray plate of the fractured bone shows a
persistent radiolucent line at the fracture.
 Callus formation may be evident but callus does
not bridge across the fracture. If there is doubt
about the interpretation of the x-ray, stress x-
rays, tomograms or CT scan may be used for
confirmation.

Pathophysiology
The reasons for non-union are
 Avascular necrosis (the blood supply was
interrupted by the fracture)
 The two ends are not apposed (that is, they are
not next to each other)
 Infection (particularly osteomyelitis)
 The fracture is not fixed (that is, the two ends
are still mobile)
 Soft-tissue imposition (there is muscle or
ligament covering the broken ends and
preventing them from touching each other)

NON-UNION
FRACTURES
Hypertrophic
non-union
Atrophic
non-union

Hypertrophic non-union
 Callus is formed, but
the bone fractures
have not joined. This
can be due to
inadequate fixation
of the fracture, and
treated with rigid
immobilization.

Atrophic non-union
 No callus is formed. This is often due
to impaired bony healing, for example
due to vascular causes (e.g. impaired
blood supply to the bone fragments)
or metabolic causes
(e.g. diabetes or smoking).
 Failure of initial union, for example
the bone fragments are separated
by soft tissue may also lead to
atrophic non-union.

Treatment
 Surgical treatment includes removal of all scar
tissue from between the fracture fragments,
immobilization of the fracture with metal
plates, rods and/or pins and bone graft.

Treatment
 In simple cases healing may be
evident within 3 months. Gavriil
Ilizarov revolutionized the treatment
of recalcitrant non-unions
demonstrating that the affected area
of the bone could be removed, the
fresh ends "docked" and the
remaining bone lengthened using an
external fixator device.
 The time course of healing after such
treatment is longer than normal bone
healing. Usually there are signs
of union within 3 months, but the
treatment may continue for many
months beyond that.

Treatment
 One possible treatment for non-
unions is a bone simulator.
Tentative evidence supports
better healing with the use of
an ultrasound system in long
bones that have no healing
after three months.
 Evidence however, does not
show that ultrasound decreases
rates of non-union.

Treatment
 Bone grafting is rather
considered as the gold
standard procedure for
non-unions.
 However, the autogenous
bone grafting technique
tends to produce donor
site morbidity and use of
allograft has the tendency
to produce immunological
reaction.

Prognosis
 The prognosis of non-union if treated
depends on many factors including the
age and general health of the patient, the
time since the original injury, the number
of previous surgeries, smoking history,
the patient's ability to cooperate with the
treatment.
 In the region of 80% of non-unions heal
after the first operation. The success rate
with subsequent surgeries is less.

Stem cell therapy for
non-union fractures
Mesincimal Stem Cells can
be used to:
1. Non-Union Fractures.
2. Enhance bone regeneration
and union in critical bone
defects
3. Improve bone quality in
Osteogenesis imperfecta
Osteogenesis imperfecta (OI), also
known as brittle bone disease, is a
group of genetic disorders that mainly
affect the bones. It results in bones
that break easily. The severity may be
mild to severe

non-union fractures
 MSCs have been shown to be the source of
endochondral bone formation.
 The method of application of MSCs, which are
usually harvested from the iliac crest, is usually
by percutaneous injections to the non-union
site.
 Percutaneous injection of MSCs has shown to
promote union in non-unions by Connolly et al.
(1991), Garg et al. (1993), Kettunen et al.
(2002), Hernigou et al. (2005) and Goel et al.
(2005)

non-union fractures
 The application by these investigators
has been on non-union of long bones
especially tibia and also for diagnosed
cases of pseudo-arthrosis.
 Fernandez et al. (2013) studied the
effects of autologous bone marrow
mononuclear cells combined with
allogenic bone graft for repair of pseudo-
arthrosis of long bones.

non-union fractures
 Bone marrow mononuclear cells (BM-MNCs)
comprise of progenitor and stem cells with pro-
angiogenic and pro-osteogenic properties.
 They concluded that, “Combination of
autologous BM-MNCs and allogenic bone graft
could constitute an easy, safe, inexpensive and
efficacious attempt to treat long-bone
pseudoarthrosis and non-union by reproducing
the beneficial properties of autologous bone
grafting while restricting its disadvantages”.
 Thus, stem cells are helpful in promoting union
in cases of non-unions when they are used alone
or in combination.

STEM CELLS IN
AVASCULAR NECROSIS

Avascular necrosis
 Avascular necrosis (AVN), also called
osteonecrosis, aseptic necrosis, or
ischemic bone necrosis, is a condition
that occurs when there is loss
of blood to the bone.
 Because bone is living tissue that
requires blood, an interruption to the
blood supply causes bone to die. If
not stopped, this process eventually
causes the bone to collapse.

Avascular necrosis
Avascular necrosis most commonly
occurs in the hip. Other common
sites are the shoulder, knees,
shoulder, and ankles.

Who Gets Avascular Necrosis
and What Causes It?
 As many as 20,000 people develop AVN each
year. Most are between ages 20 and 50.
 For healthy people, the risk of AVN is small.
 Most cases are the result of an underlying
health problem or injury. Possible causes
include:
1.Dislocation or fracture of the thigh bone
(femur). This type of injury can affect the
blood supply to the bone, leading to trauma-
related avascular necrosis. AVN may develop in
20% or more of people who dislocate a hip.

and What Causes It?
2.Chronic corticosteroid use. Long-term use of
these inflammation-fighting drugs, either orally or
intravenously, is associated with 35% of all cases of
non-traumatic AVN. Although the reason for this is
not completely understood, doctors suspect these
drugs may interfere with the body's ability to break
down fatty substances. These substances collect in
the blood vessels -- making them narrower -- and
reduce the amount of blood to the bone.
3.Excessive alcohol use. Much like corticosteroids,
excessive alcohol may cause fatty substances to
build in the blood vessels and decrease the blood
supply to the bones.

and What Causes It?
4.Blood clots, inflammation, and damage to
the arteries. All of these can block blood flow
to the bones.
5.Other conditions associated with non-traumatic
AVN include:
 Gaucher’s disease, an inherited metabolic
disorder in which harmful quantities of a fatty
substance accumulate in the organs
 Sickle cell disease
 Pancreatitis, inflammation of the pancreas

and What Causes It?
 HIV infection
 Radiation therapy or chemotherapy
 Autoimmune diseases
 Decompression sickness, a condition
that occurs when the body is subjected
to a sudden reduction in surrounding
pressure, causing the formation of gas
bubbles in the blood.

Symptoms of Avascular
Necrosis
 In its early stages, AVN
typically cause no
symptoms; however, as
the disease progresses it
becomes painful.
 At first, you may
experience pain when you
put pressure on the
affected bone.
 Then, pain may become
more constant.

Symptoms of Avascular
Necrosis
 If the disease progresses and the
bone and surrounding joint collapse,
you may experience severe pain
that interferes with your ability to
use your joint.
 The time between the first
symptoms and collapse of the bone
may range from several months to
more than a year.

Treatment for Avascular
Necrosis
The best treatment will depend on a number of factors,
including:
1. Age
2. Stage of the disease
3. Location and amount of bone damage
4. Cause of AVN
 If the cause of your avascular necrosis is identified,
treatment will include efforts to manage the underlying
condition.
 For example, if AVN is caused by blood clots, your doctor
will prescribe medications to dissolve clots. If
inflammation of the arteries is responsible, your doctor
may prescribe anti-inflammatory medicines.

Treatment for
Avascular Necrosis
 If avascular necrosis is caught early, treatment may
involve taking medications to relieve pain or limiting the
use of the affected area.
 If your hip, knee, or ankle is affected, crutches may be
necessary to take weight off the damaged joint.
 The doctor may also recommend ROM exercises to
help keep the affected joint mobile.
 While these non-surgical treatments may slow the
progression of avascular necrosis, most people with
the condition eventually need surgery.

Treatment for
Avascular Necrosis
Surgical options include:
1.Bone grafts, which involve removing healthy
bone from one part of the body and using it to
replace the damaged bone.
2.Osteotomy, a procedure that involves cutting
the bone and changing its alignment to relieve
stress on the bone or joint.
3.Total joint replacement, which involves
removing the damaged joint and replacing it
with a synthetic joint.

Treatment for
Avascular Necrosis
4. Core decompression, a procedure that
involves removing part of the inside of the bone
to relieve pressure and allow new blood vessels
to form.
5.Vascularized bone graft, a procedure that
uses the patient's own tissue to rebuild diseased
or damaged hip joints; the surgeon first
removes the bone with the poor blood supply
from the hip and then replaces it with the blood-
vessel-rich bone from another site, such as the
fibula, the smaller bone located in the lower leg.

STEM CELLS IN
AVASCULAR NECROSIS
MSCs have been applied for the
re-growth of the dead area of
the femoral head.
A common method of
application has been by the
injection of bone marrow
concentrate (Figures 1 and 2).

STEM CELLS IN
AVASCULAR NECROSIS
 The studies by Hernigou et al. (2009),
Gangji et al. (2004) and Sen et al. (2012)
have shown promising results.
 Wang et al. (2012) reported debridement,
autogenous bone grafting and bone-marrow
mononuclear cells implantation as an effective
procedure in patients with small lesion, early-
stage AVN of the femoral head.
 The concept of introducing osteo-progenitor
cells into the area of dead bone seems logical
and the results speak for themselves.

STEM CELLS IN
AVASCULAR NECROSIS
 Limitation for the use of stem cells in this
condition is the stage of presentation as
once the collapse has started, the shape
of femoral head cannot be returned back
to normal by the stem cells.
 Overall, with proper patient selection the
stem cells do appear to be a promising
prospect for management of AVN of
femoral head.

STEM CELLS AS FILLERS
OF BONY VOIDS

Stem cells as fillers of
bony voids
 Generally, following a surgical
procedure there is a void left
behind in the bone. Such a
scenario is seen in cases of
benign bone tumors such as
simple bone cysts for which
curettage has been done and in
cases where there is a bone
defect.
 Although autogenous bone graft
may be used to fill up these
voids, use of stem cells in
conjugation with bone grafts
has been done by investigators.

bony voids
 Park et al. (2008) and
Zamzam et al. (2009) have
used stem cells for filling the
voids in simple bone cysts with
good results.
 However, Wright et al.
(2008) found the injections of
intra-lesional bone marrow
into simple bone cysts to be
inferior to intra-lesional methyl
prednisolone injections.

bony voids
 Marcacci et al. (2007)used autologous MSCs that
were expanded in vitro and seeded on hydroxyl-
appatite scaffolds for filling of diaphyseal bone
defects and reported good integration of the graft 7
years post-op without any secondary fractures.
 Jager et al. (2009) too concluded that the MSCs
may be a promising alternative to autogenous bone
grafts for volumetric bone defects.
 Thus, the studies conducted so far are supportive of
using the MSCs in bone marrow as a viable and
promising alternative to autogenous bone grafts.

STEM CELLS IN CARTILAGE
REPAIR & ARTHRITIS

CARTILAGE & ARTHRITIS
 Cartilage as a result of its
avascularity is notorious for
non-healing. Once damaged
the ability to repair itself is
very poor.
 Autologous cartilage
transplantation and
autologous chondrocyte
transplantation have been
used for large cartilaginous
defects with varying degrees
of success.

CARTILAGE & ARTHRITIS
 Abrasion
chondroplasty in which
drill holes are made into
the cartilage to allow for
the subchondral bone
marrow to come out and
layer the cartilage
defects have shown good
results.
 Such a procedure is
followed by formation of
fibro-cartilage at the
cartilage defect site.

REPAIR & ARTHRITIS
 The encouraging results of MSC-based
cartilage repair of full thickness cartilage
defects in rabbit models reported by
Shafiee et al. (2011) and Tay et al.
(2012) led to similar use in clinical
practices.
 Wakitani et al. (2007) reported a
series of three cases of repair of articular
cartilage defects in the patello-femoral
joint with autologous bone marrow MSCs.

REPAIR & ARTHRITIS
 They expanded the MSCs harvested
from iliac crest in vitro for 4 weeks
and then transplanted them to the
site of defect using collagen gel and
covered the defect with a periosteal
flap. They reported satisfactory
clinical and macroscopic results.
 The small sample size decreased
the impact of the study.

REPAIR & ARTHRITIS
 A cohort study was performed by
Nejadnik et al. (2010) on a total
of 36 patients. The patients
underwent autologous cartilage
transfer or MSCs implantation.
 At 24 months post-operatively, no
significant difference of functional
knee scores between the groups
was noted.

REPAIR & ARTHRITIS
 Buda et al. (2010) used MSCs for
treatment of osteochondral lesions of the
femur and talus.
 They reported satisfactory clinical results
and integration of cells in defects in both
types of osteochondral lesions.
 Thus, use of MSCs in cartilaginous lesions
has come to the clinical stages from
experimental stages and the results have
been encouraging.

TENDONS
 Tendons, which are
primarily composed of
collagen, are one of the
less vascular structures
of the body and once
injured do not tend to
heal quickly. This
tendency of non-healing
produces a condition
called tendinosis.

STEM CELLS IN
TENDON REPAIR
 Scientists have been trying various ways
to improve tendon healing.
 Use of growth stimulating substances
such as platelet rich plasma has been
used for enhancing tendon healing.
 Experimental laboratory studies on
animal models using MSCs embedded on
various types of scaffolds have returned
some encouraging but in homogenous
results.

STEM CELLS IN
TENDON REPAIR
Chong et al. (2007) used
MSCs with fibrin sealant in a
rabbit Achilles tendon model.
In their study, no differences
between fibrin and fibrin with
MSC could be shown
histologically.

STEM CELLS IN
TENDON REPAIR
 Gulotta et al. (2011) succeeded in
enhancing tendon healing in rotator
cuff model, applying transfected
MSCs using the embryonic
transcription factor membrane type
1–matrix metalloproteinase and the
tendon transcription factor scleraxis.

STEM CELLS IN
TENDON REPAIR
 Recently, tendon-derived stem cells
(TDSCs) have been identified within tendon
tissues. TDSCs exhibit universal stem cell
characteristics, such as clonogenicity, a
high proliferative capacity, multi-
differentiation potential, non-
immunogenicity and immunosuppression
and hence may become a potent agent of
tendon repair once their clinical efficacy is
demonstrated in laboratory and clinical
settings.

STEM CELLS IN
TENDON REPAIR
Thus, the use of stem cells may
be a good option for use in
tendon injuries but the results
so far have been limited to
experimental studies only and
clinical evidences are still
awaited before one may
recommend their use.

ACL
 An ACL injury is the tearing of the
anterior cruciate (KROO-she-ate)
ligament (ACL) — one of the major
ligaments in your knee.
 ACL injuries most commonly occur during
sports that involve sudden stops,
jumping or changes in direction — such
as basketball, soccer, football, tennis,
downhill skiing, volleyball and
gymnastics.

Signs and symptoms of an
ACL injury
 A loud "pop" or a "popping" sensation in
the knee
 Severe pain and inability to continue
activity
 Swelling that begins within a few hours
 Loss of range of motion
 A feeling of instability or "giving way"
with weight bearing

CAUSES
 Suddenly slowing down and changing direction
(cutting)
 Pivoting with your foot firmly planted
 Landing from a jump incorrectly
 Stopping suddenly
 Receiving a direct blow to the knee or collision, such
as a football tackle
 When the ligament is damaged, there is usually a
partial or complete tear across the tissue. A mild
injury may overextend the ligament but leave it
intact.

Diagnosis
 X-rays. X-rays may be needed to rule out a
bone fracture. However, X-rays can't visualize
soft tissues, such as ligaments and tendons.
 Magnetic resonance imaging (MRI). An MRI
uses radio waves and a strong magnetic field to
create images of both hard and soft tissues in
your body. An MRI can show the extent of an
ACL injury and signs of damage to other tissues
in the knee.
 Ultrasound. Using sound waves to visualize
internal structures, ultrasound may be used to
check for injuries in the ligaments, tendons and
muscles of the knee.

Treatment
 Rehabilitation
 Surgery (ACL RECONSTRUCTION)

STEM CELLS IN ACL
LIGAMENT REPAIR
 Silva et al. (2012) conducted a
prospective randomized trial on 43
patients undergoing anterior cruciate
ligament (ACL) reconstruction.
 20 patients in an experimental group
received adult non-cultivated bone
marrow stem cells and 23 patients in the
control group did not receive stem cells.

STEM CELLS IN ACL
LIGAMENT REPAIR
 All patients underwent magnetic
resonance imaging of the knee at 3
months after surgery to evaluate the
signal-to-noise ratio of the interzone.
 They concluded that adult non-cultivated
bone marrow stem cells did not seem to
accelerate graft-to-bone healing in ACL
reconstruction, hence stem cells have
limited role in ACL reconstruction.

MENISCUS
 It's a piece of cartilage in your knee that
cushions and stabilizes the joint. It
protects the bones from wear and tear.
But all it takes is a good twist of the knee
to tear the meniscus.
 In some cases, a piece of the shredded
cartilage breaks loose and catches in the
knee joint, causing it to lock up.

STEM CELLS IN
MENISCUS REPAIR
STRATEGIES
Filling the tear with
a piece of meniscus
grown in a lab
Bathing damaged
menisci in an intra-
articular solution of
stem cells to aid
the healing process

STEM CELLS IN
MENISCUS REPAIR
Filling the tear with a piece of meniscus grown in a
lab
 MSCs are cultured in a chondrogenic medium to promote
differentiation into chondrocytes, and then ”seeded” onto
a scaffold and allowed some time to mature before
implantation into the meniscal defect.
 Results in menisci of rabbits that had hyaluronan/gelatin
composite scaffolds inserted into the meniscal defects on
each leg, one seeded with SCs, the other left empty.
 SCS seeded scaffolds produced a statistically significant
amount of new fibrocartilage relative to control.

STEM CELLS IN
MENISCUS REPAIR
Bathing damaged menisci in an intra-
articular solution of stem cells to aid
the healing process:
 Isolated and cultured MSCs from a
chronic knee pain patient, then inject
those stem cells into his knee 3 times
over 2 weeks.
 After 3 moth the patient showed
statistically significant increase in
meniscal volume on MRI, knee ROM and
improved knee function.

STEM CELLS IN
INTERVERTEBRAL
DISC DEGENERATION

INTERVERTEBRAL DISC
DEGENERATION
 Degenerative disc disease is not really a disease
but a term used to describe the normal changes
in your spinal discs as you age. Spinal discs are
soft, compressible discs that separate the
interlocking bones (vertebrae) that make up the
spine.
 The discs act as shock absorbers for the spine
allowing it to flex, bend, and twist. Degenerative
disc disease can take place throughout the
spine, but it most often occurs in the discs in
the lower back (lumbar region) and the neck
(cervical region).

INTERVERTEBRAL DISC
DEGENERATION
 It’s the leading cause of back pain and
associated morbidity.
 Due to the avascular nature of IVD, the
healing process is slow or absent, once
the degeneration starts either from
mechanical trauma, ageing or idiopathic
processes.
 Current conservative and invasive
treatment options are aimed to
symptomatic relief.

INTERVERTEBRAL DISC
DEGENERATION
 The surgical options
available for IVD
degeneration are spinal
fusion and/or discectomy
at the affected level.
 However, while these
options create short term
solutions, there are
frequent complications due
to alternations made to
the biomechanics of the
spine.

STEM CELLS IN INTERVERTEBRAL
DISC DEGENERATION
 Stop or even reverse
the degeneration of
cells within the IVD in
order to produce a
matrix with similar or
more advanced
properties when
compared to the
original.

STEM CELLS IN INTERVERTEBRAL
DISC DEGENERATION
 The current research has made
considerable progress with the use of
biodegradable materials to act as scaffold
for the MSCs in order to promote 3D
growth in animal models.
 The 3D scaffold are made of materials
such as hyaluronic acid and collagen that
provide the MSCs with the initial stability
and homogeneous distribution required
for growth in vivo.

CONCLUSION
 Stem cell therapy is as an attractive option for
the treatment of intractable diseases.
 Its use is based on sound biological principles.
 Many of these studies have shown good results
but at the same time many have shown failures.
 This might also be linked to the patient
selection, the type of cells used, the
concentration of cells used, the method of
application, duration of follow up and evaluation
tools among others.

CONCLUSION
 Many more long-term prospective randomized
human trials need to have good results before
one may actually recommend the use of these
cells.
 Establishing the safety profile of these is equally
important, for many of the iPS cells have been
shown to be teratogenic.
 Thus, one should tread with caution the path of
stem cell application but wherever a suitable
case is available a trial should be taken of this
treatment modality.

Orthopedic applications of stem cells

Orthopedic applications of stem cells

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