Extract
Articular cartilage is a hypocellular, avascular, alymphatic tissue with a
dense collagen and proteoglycan matrix that provides a low-friction and highly
durable wear-resistant
surface1 to both
shear and compressive stress.Normal maintenance of articular cartilage results from the balance between
anabolic and catabolic activity. Resident chondrocytes control the
extracellular matrix turnover—collagen and proteoglycans synthesis and
degradation—from the tidemark to the tangential zone of the cartilage.
However, little is known about the physiological processes regulating cellular
turnover and cartilage homeostasis, mainly because of the large number of
factors involved (mechanical load, cell density, matrix composition, growth
factors, cytokines, injury, and aging) and the complexity of their
interactions.
Articular cartilage is a hypocellular, avascular, alymphatic tissue with a
dense collagen and proteoglycan matrix that provides a low-friction and highly
durable wear-resistant
surface1 to both
shear and compressive stress.
Normal maintenance of articular cartilage results from the balance between
anabolic and catabolic activity. Resident chondrocytes control the
extracellular matrix turnover—collagen and proteoglycans synthesis and
degradation—from the tidemark to the tangential zone of the cartilage.
However, little is known about the physiological processes regulating cellular
turnover and cartilage homeostasis, mainly because of the large number of
factors involved (mechanical load, cell density, matrix composition, growth
factors, cytokines, injury, and aging) and the complexity of their
interactions.
Insufficient knowledge of the physiology and homeostasis of articular
cartilage greatly impairs the ability to stop or slow disease progression. It
is commonly accepted that articular cartilage is a tissue with little or no
regenerative potential and thus undergoes degradation over time.
The notion that it is impossible to prevent or reverse degeneration of
articular cartilage has been challenged recently by the growing body of
evidence in the literature based on basic-research findings concerning the
physiology and pathophysiology of articular cartilage, so that new strategies
for its maintenance and repair are
emerging2. In two
recent studies by Glasson et
al.3 and Stanton et
al.4, a knockout
mouse model of osteoarthritis, a degenerative disease that eventually leads to
destruction of articular cartilage, demonstrated how a single protein, ADAMTS
5, is the main aggrecanase responsible for cartilage degradation and the
principal mediator of the catabolic effects of pro-inflammatory cytokines,
such as interleukin-1 (IL-1). Their findings identify a rational target for
therapeutic intervention to limit cartilage degradation in osteoarthritis and
demonstrate that interference with a single pathway can dramatically alter the
natural history of joint disease.
Chondral injury rapidly results in local chondrocyte apoptosis, which
progresses with loss of the articular surface and leads to joint
deterioration. Acute direct trauma as well as surgical procedures involving
vascularized tissues, synovial tissues, and subchondral bone may elicit an
inflammatory response; also, repetitive or prolonged overloading of lesser
magnitude (shear load) may cause joint inflammation that initiates a series of
events detrimental to cartilage integrity.
In the articular environment, the activity of inflammatory cells and
pro-inflammatory cytokines can lead to degradation of the extracellular matrix
and loss of proteoglycans, which compromises the mechanical competence of the
cartilage. Once begun, cartilage loss accelerates through a combination of
mechanical and biological events; therefore, it is of the utmost importance to
prevent and limit the catabolic effect of inflammation of the articular
cartilage (Fig. 1).
Efforts to develop chondroprotective treatments should be aimed toward
limiting the damage of cartilage following injury (trauma or inflammation),
augmenting the reparative response, and finally preventing degeneration.
Therapy to prevent the negative effect of inflammation on articular cartilage
can be both systemic, with use of anti-inflammatory steroidal or nonsteroidal
drugs, and local (when the inflammation is limited to one or a few joints),
with use of intra-articular injection or physical stimulation.
The use of physical stimuli has been the subject of several studies aimed
at understanding the mechanism through which they are able to control
inflammation and stimulate articular cartilage anabolic activities. Pulsed
electromagnetic fields, which have been investigated for years by our group,
can be easily applied to single joints without systemic effect. Their use is
not indicated for the treatment of joint inflammation associated with systemic
diseases such as rheumatoid arthritis.
In joints, especially the knee, pulsed electromagnetic fields, unlike
drugs, have the ability to completely and homogeneously permeate the whole
articular cartilage and the underlying subchondral bone. Their use is aimed at
controlling inflammation, stimulating the anabolic activity of the
chondrocytes, and preventing cartilage degeneration, ultimately resulting in a
chondroprotective activity. The treatment should lead to improvement in the
overall articular function of the patient.
Present clinical use of pulsed electromagnetic fields as a chondroprotector
is based on preclinical and clinical research studies conducted by the CRES
(Cartilage Repair and Electrical Stimulation) study group over the past seven
years.
In Vitro
Pulsed Electromagnetic Fields Have an Adenosine A2A
Receptor Agonist Activity
Recent investigations into inflammation have revealed the physiological
role that adenosine receptors play in the control of inflammatory events.
Adenosine interacts with four cell-surface adenosine receptor subtypes
(A1, A2A, A2B, and A3), which are
coupled to different G-proteins and finally reduce nitric oxide production and
down-regulate the expression of pro-inflammatory cytokines. The A2A
receptor has the highest anti-inflammatory
activity5,6.
Adenosine levels are tightly regulated in cartilage since depletion leads to
increased glycosaminoglycan release and to production of matrix
metalloproteinase (MMP)-3, MMP-13, prostaglandins, and nitric
oxide7,8.
Drugs with A2A adenosine receptor agonist activity have been shown
to protect articular cartilage in animal models of induced
osteoarthritis9
(Fig. 2).
In 2002, Varani et al. observed a significant increase in binding of
adenosine to the adenosine receptor subtype A2A in human
neutrophils exposed to pulsed electromagnetic fields (p <
0.05)10.
Dose-response studies demonstrated that the effect was detectable after thirty
minutes of exposure and saturation of the receptors was achieved with a
magnetic field of 1.5 mT (Fig.
3). The effect of pulsed electromagnetic fields on adenosine
binding with the A2A adenosine receptor was later confirmed in
cultures of isolated fibroblast-like bovine synoviocytes and chondrocytes by
the same group11
(Fig. 4). Together, these
findings show that pulsed electromagnetic fields have an A2A
adenosine receptor agonist activity, thereby identifying the A2A
adenosine receptor as the pharmacological molecular target of therapeutic
intervention with pulsed electromagnetic fields in patients with inflammatory
joint diseases.
Pulsed Electromagnetic Fields Favor Chondrocyte Proliferation
In another study, human chondrocytes were isolated from articular cartilage
of donors and cultured. Exposure to pulsed electromagnetic fields increased
chondrocyte proliferation, as measured by
H3-thymidine
incorporation. The effect was observed when cultures were exposed to pulsed
electromagnetic fields for more than six hours; furthermore, proliferation was
significantly increased when 10% fetal calf serum was present in the culture
medium (p = 0.0392), and it was also increased in low-density cultures
compared with high-density
cultures12,13.
Ex Vivo
Pulsed Electromagnetic Fields Show Anabolic Activity in
Full-Thickness Cartilage Explants in a Dose-Response Manner
To test the sensitivity of chondrocytes in a microenvironment that more
closely mimics the in vivo conditions, full-thickness bovine articular
cartilage explants were exposed to pulsed electromagnetic fields in culture.
Under these experimental conditions, it is possible to challenge the explants
in the presence of both catabolic and anabolic
stimuli14.
Dose-response curves for proteoglycan synthesis in explants subjected to
pulsed electromagnetic fields were prepared.
Figure 5 shows the effect of
the duration of the exposure, the magnetic field peak value, and the pulse
frequency15. On the
basis of these findings, we selected 75 Hz and 1.5 mT as the magnetic field
parameters to be used in subsequent studies.
The effect of pulsed electromagnetic fields on cartilage explants was then
challenged against catabolic or anabolic stimuli. When the cartilage explants
were exposed to pulsed electromagnetic fields, proteoglycan synthesis
increased. When a pro-inflammatory cytokine (IL-1ß) was added to the
culture medium, proteoglycan synthesis decreased significantly compared with
control basal values; however, when the cultures were exposed to pulsed
electromagnetic fields, proteoglycan synthesis returned to basal values. These
data demonstrate that pulsed electromagnetic fields can reverse the catabolic
effect of IL-1ß on the cartilage
matrix16
(Fig. 6). Another study showed
that pulsed electromagnetic fields had a synergistic-summatory effect when an
anabolic cytokine, insulin growth factor-1 (IGF-1), was added to the culture
medium at high
concentrations17
(Fig. 7).
Overall, the ex vivo data demonstrate that pulsed electromagnetic fields
stimulate anabolic activities in full-thickness cartilage explants and
counteract the catabolic effect of the pro-inflammatory cytokine IL-1ß.
These results are consistent with the described A2A adenosine
receptor agonist activity of pulsed electromagnetic fields.
In Vivo
Effective Chondroprotection by Pulsed Electromagnetic Fields in an
Osteoarthritis Model
Because osteoarthritis with strict morphological, biochemical, and
immunohistochemical similarities to human osteoarthritis spontaneously
develops in the Dunkin Hartley guinea pig, this animal model is frequently
employed to study osteoarthritis and the activity of
disease-progression-modifying drugs. The capability of pulsed electromagnetic
fields to modify osteoarthritis progression was first reported by Ciombor et
al.18. They
demonstrated that pulsed electromagnetic fields could prevent cartilage
degeneration as measured with the Mankin histologic score, and their
immunohistochemical analysis showed that the expression of IL-1ß was
down-regulated while the expression of transforming growth factor-1 beta
(TGF-1ß) was up-regulated, in animals treated with pulsed electromagnetic
fields (Fig. 8). These results
indicate a chondroprotective effect of pulsed electromagnetic fields on
articular cartilage in vivo.
We investigated the effect of pulsed electromagnetic fields in Dunkin
Hartley guinea pigs. Animals of twelve or fifteen months of age were exposed
to pulsed electromagnetic fields for three or six months, respectively, to
determine if the effect of pulsed electromagnetic fields could be observed in
cartilage lesions of increasing severity. We evaluated the effect of pulsed
electromagnetic fields on both femoral and tibial cartilage joint surfaces.
The whole joint was sectioned, and the six most central slices (300 µm
thick) were microradiographed and then reduced to 5 µm for histologic
evaluation. The effect of pulsed electromagnetic fields was evident on all
joint surfaces and was greater in the medial tibial plateau, where the
degeneration begins. We observed higher Mankin scores, decreased cartilage
thickness, and increased fibrillation in control animals than in animals
treated with pulsed electromagnetic
fields19
(Fig. 9). These data confirmed
the results reported by Ciombor et
al.18.
Microradiographic investigation of these animals demonstrated that the
treatment prevented the subchondral bone from thickening
(Fig. 10). This effect was
particularly evident in the older animals, in which the thickness of the
tibial medial plateau averaged 263 ± 18 µm after treatment with
pulsed electromagnetic fields compared with 329 ± 82 µm in controls
(p < 0.05). This effect was also observed in the subchondral bone of the
femur20. These
findings were confirmed by bone density studies. Subchondral bone thickening
as arthritis progressed was explained by considering that cartilage
degeneration observed in control animals reduces its mechanical competence to
absorb the load applied to the joint, which is instead transferred to the
bone.
Overall, the results of these studies demonstrate that stimulation with
pulsed electromagnetic fields significantly slowed the progression of
osteoarthritic lesions in knee cartilage. Even in the presence of severe
osteoarthritic lesions, pulsed electromagnetic fields maintained a significant
capacity to reduce lesion progression in both the cartilage and the
subchondral bone.
Pulsed Electromagnetic Fields and Cartilage Healing: Autologous
Osteochondral Grafts in Sheep
The above-described experiments did not address the hypothesis that pulsed
electromagnetic fields might reverse already-established severe lesions with
associated exposure of subchondral bone. We have no rationale for
hypothesizing that pulsed electromagnetic fields can by themselves result in
healing of a cartilage defect. On the other hand, it is recognized that
factors in the microenvironment as well as in the joint space environment may
play a role in the success of techniques used for the repair of full-thickness
cartilage defects.
Use of autologous osteochondral grafts is a well-established technique for
the treatment of cartilage lesions; nevertheless, there are several conditions
that may jeopardize the success of the graft. Osteochondral grafts may undergo
central necrosis, subchondral cyst formation, or insufficient integration with
subchondral bone, which together cause mechanical instability of the graft and
poor cartilage nutrition, and ultimately may result in graft
failure21.
Furthermore, a strong local inflammatory response following graft insertion
may lead to an excessive local increase in pro-inflammatory cytokines that can
severely damage the cartilage. Thus, early graft integration and
stabilization, inhibition of osteoclast activity, and local control of
inflammation are biological targets of paramount importance for the success of
an osteochondral graft. We hypothesized that the use of pulsed electromagnetic
fields immediately after insertion of an osteochondral graft could favor
healing of subchondral bone, control the local joint environment, and prevent
the negative effects of pro-inflammatory cytokines released in the synovial
fluid following the surgical procedure, all favoring cartilage healing.
Line-to-line osteochondral grafting was performed in the knees of sheep.
This technique has the advantage of limiting the trauma required for graft
insertion when a press-fit technique is used; however, immediate graft
stability is not guaranteed, and the graft may be exposed to the detrimental
effect of the synovial
fluid22,23.
In a short-term study, six animals were killed at the end of one month of
treatment with pulsed electromagnetic fields for six hours a day. In a
medium-term study, fourteen animals were treated for two months and then
allowed to roam free in the pasture for another four months before they were
killed. An external coil was positioned on the operatively treated knee of
each animal, but it was not energized in the control group. Histologic
examination and microradiographic analysis were performed on the osteochondral
grafts and the subchondral bone.
In the short-term study, the microradiographs demonstrated that more bone
had formed at the interface between the graft and the host tissue in the
animals treated with the pulsed electromagnetic fields; furthermore, areas of
bone resorption were present at the interface in the control animals.
Histologic examination demonstrated a fibrous tissue surrounding the grafts,
and, occasionally, histochemical analysis showed intense tartrate-resistant
acid phosphatase (TRAP), a marker of osteoclast activity, in the control
animals (Fig. 11). The
transplanted cartilage appeared healthy in both groups of animals.
The results in the medium-term study (at six months) showed complete
resorption of four grafts in the control group, while resorption was not
observed in the animals treated with the pulsed electromagnetic fields. Also,
cyst-like resorption areas were more frequent in the untreated grafts
(Fig. 12).
Histologic analysis of the cartilage grafts did not show any difference
between the two groups, although more fibrous tissue was present in the
control grafts. We did not observe integration between the transplanted and
the adjacent native cartilage. When the animals were killed, we recovered the
synovial fluid from knees and tested the cytokine concentration. The
concentrations of pro-inflammatory cytokines were lower (a 47% decrease in the
Il-1ß concentration and a 24% decrease in the TNF-a concentration)
and the TGF-ß1 concentration was higher (a 64% increase) in the knees
treated with the pulsed electromagnetic fields than they were in the knees of
the control animals.
These results show that treatment of osteochondral grafts with pulsed
electromagnetic fields favors, in the short term, osteogenetic activity and
early graft integration; in the medium term, this effect is associated with a
lower frequency of resorption areas, which may be the weak points where graft
failure begins. We have not observed an effect of pulsed electromagnetic
fields on integration of grafted cartilage with the surrounding bone.
Cartilage integration is, of course, a major issue, not yet solved, which
requires a more sophisticated approach, including the local control of
chondrocyte activity and its progression to matrix synthesis and integration.
Nevertheless, it is important to stress that the cytokine profile in the
synovial fluid of animals treated with pulsed electromagnetic fields was more
favorable for graft and cartilage survival than was the profile in the
controls.
The experimental results discussed above support the hypothesis that
exposure of articular cartilage to pulsed electromagnetic fields results in
chondroprotection: pulsed electromagnetic fields stimulate chondrocyte
anabolic activity, limit inflammation, and prevent cartilage degeneration.
Pulsed electromagnetic fields have been used to treat un-united fractures
for more than thirty years; nevertheless, to our knowledge, until now they
never have been applied to the joints of patients immediately after an
arthroscopic procedure.
The results of the preclinical studies reported above provide a rational
basis for the clinical use of pulsed electromagnetic fields to control
inflammation and its catabolic effect on articular cartilage. Thus, we
hypothesized that pulsed electromagnetic fields could be used in patients
after minimally invasive surgery, such as arthroscopy, to control the
inflammatory response, to enhance functional recovery, and ultimately to
protect cartilage.
On the basis of our research, we selected pulsed-electromagnetic-field
parameters with chondroprotective activity and developed a pulse generator
(I-ONE; Igea, Carpi, Modena, Italy) to be used in clinical studies
(Fig. 13).
Use of I-ONE After Arthroscopic Surgery
Microfractures
A prospective, randomized, double-blind study of thirty-four patients
undergoing arthroscopic chondroabrasion or microfracture treatment of chondral
lesions was conducted to assess tolerance to treatment with the I-ONE and the
effect of the I-ONE on functional
recovery24.
Patients were instructed to use the stimulator for six hours per day for
ninety days. The patients' acceptance of the treatment was high, and no
negative side effects were associated with the therapy. After the procedure,
the percentage of patients using nonsteroidal anti-inflammatory medications
was lower in the I-ONE-treatment group than in a control group (26% compared
with 75%, p < 0.05). The patients treated with the I-ONE had faster
functional recovery, and the average Knee Injury and Osteoarthritis Outcome
Score (KOOS) for the I-ONE-treated patients at forty-one days was the same as
that observed for the controls at ninety days
(Fig. 14).
Anterior Cruciate Ligament Reconstruction
A multicenter, prospective, randomized, double-blind study was conducted to
evaluate the effect of I-ONE treatment in sixty patients who had undergone
arthroscopic reconstruction of the anterior cruciate ligament with use of a
double-looped semitendinosus and gracilis tendon graft. After the tendons had
been prepared with use of the classic technique, they were introduced in the
previously prepared tibial and half femoral tunnels. The graft was fixed with
the femur at 90° of flexion and in the tibia with an interference screw at
30° of tibial flexion (Fig.
15). Patients were evaluated at one, two, and six months after
reconstruction. In the initial thirty days after the reconstruction, the
I-ONE-treatment group used less nonsteroidal anti-inflammatory drugs compared
with the control group (p < 0.05). After both two and six months of
follow-up, the patients in the I-ONE-treatment group had higher International
Knee Documentation Committee (IKDC) scores than the controls (p < 0.01).
Furthermore, objective evaluation by an orthopaedic surgeon showed a faster
resolution of joint swelling and an earlier recovery of a complete range of
motion in the I-ONE-treatment group than in the controls (p < 0.05).
Figure 16 shows that, in a
subgroup of patients who underwent reconstruction of the anterior cruciate
ligament and meniscectomy at the same time, the recovery of Short Form-36
scores was significantly faster among the I-ONE-treated patients (p <
0.05).
The two clinical studies reviewed here show that I-ONE treatment can be
effective after knee surgery. Although we could not measure the cytokine
levels in the synovial fluid of our patients, we hypothesize that an
anti-inflammatory effect was indirectly demonstrated by the decrease in the
use of non-steroidal anti-inflammatory drugs, by the lower prevalence of joint
swelling, and by the better range of motion of the treated patients compared
with the controls.
Finally, the long-term results of the first study showed that patients in
the treatment group were still doing better clinically at three years, thus
supporting the hypothesis that pulsed electromagnetic fields may preserve the
functional competence of cartilage.
Inflammation in a joint following surgery represents a potentially harmful
event for the articular cartilage, which ultimately may jeopardize the
positive effects expected from the surgery.
Our working hypothesis has been that the anti-inflammatory and anabolic
effects of pulsed electromagnetic fields demonstrated in preclinical studies
could be translated into useful treatment for patients who have undergone
arthroscopic surgery, allowing early effective control of inflammation,
protecting the articular cartilage from degeneration, and providing an earlier
return to daily activity.
The CRES study group has thus provided the scientific background and has
demonstrated the therapeutic value of pulsed electromagnetic fields for the
control of inflammatory processes and ultimately for cartilage protection. The
effect is limited to the area where the magnetic field is present, but the
entire knee joint can be treated.
The rationale for the use of I-ONE therapy lies in the following
observations: cartilage slowly degenerates during life and, every time that
articular cartilage is exposed to an injury, catabolic consequences are
triggered that may impair cartilage competence and integrity with different
levels of severity. Unlike bone function, cartilage function does not return
to its antecedent initial competence once the damaging event has resolved.
Cartilage will continue to degenerate. Thus, all means to limit the duration
and intensity of events that can damage the cartilage are of paramount
importance. The work that has been done in the last seven years has provided
the scientific background and allowed us to develop a rational basis for the
use of I-ONE therapy to protect articular cartilage; it has also demonstrated
that the treatment can be effective, is well accepted by the patients, and is
without side effects. ?
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