Biological Approaches for Cartilage Repair
Alberto Gobbi, MD
Lyndon Bathan, MD
ABSTRACT: The social impact of bone and cartilage
pathologies entails high costs in terms of therapeutic
treatments and loss of income. As a result, the current
research trend includes preventive interventions and
therapeutic solutions that can lead to an enhancement
of tissue regeneration and the reduction of degenera-
tive mechanisms.
Many options have been made available to address
problems regarding cartilage damage, each with its
own advantages and disadvantages. Several stud-
ies are currently in progress to clarify some of the
questions that remain unanswered about the long-
term durability of these procedures and the possible
modifications that can be made to achieve better re-
sults.
Biotechnology is progressing at a rapid pace that al-
lows the introductions of several products for clinical
application; however, randomized, prospective studies
for these innovations should be conducted to validate
the safety and efficacy of cartilage regeneration.
[J Knee Surg. 2009;22:36-44.]
Introduction
According to a study conducted by the World Health
Organization, musculoskeletal injuries are the most
common cause of severe long-term pain and disability,
affecting millions of people worldwide.59 Accordingly,
The authors are from the Orthopaedic Arthroscopic Surgery Interna-
tional Bioresearch Foundation, Milan, Italy.
Correspondence: Alberto Gobbi, MD, Orthopaedic Arthroscopic
Surgery International Bioresearch Foundation, Via Amadeo 24, 20133
Milano, Italy.
36
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2000 to 2010 has been called the “decade of bone and
joints” to launch global awareness and promote further
research in the prevention, diagnosis, and treatment of
joint injuries.
The social impact of bone and cartilage pathologies
entails high costs through therapeutic treatments and
loss of income. In the United States, osteoarthritis medi-
cines cost $5.31 billion in 2007,4 and musculoskeletal
conditions including osteoarthritis cost nearly $128 bil-
lion per year in direct medical expenses (ie, total joint
replacement procedures and loss of income and produc-
tion in 2003).5
For these reasons, the trend of the research is now
going toward preventive interventions and therapeu-
tic solutions that can lead to an enhancement of tissue
regeneration and the reduction of degenerative mecha-
nisms.
Cartilage Treatment
Hyaline cartilage combines a smooth surface and the
ability to withstand an extreme amount of pressure. It is
extremely important to reconstruct a perfect surface that
will withstand heavy loads. Unfortunately, articular carti-
lage lesions, with their inherent limited healing potential,
remain a challenging problem for orthopedic surgeons.
In the past few decades, surgeons often replaced the ar-
ticular surface with expensive and sophisticated implants
when articular lesions become full-blown osteoarthritis.
However, recent studies have used new orthobiological
techniques in cartilage lesions with increasing frequency
and effectiveness as a way to regenerate tissue homeo-
stasis and delay the progression of osteoarthritis. Growth
factors and mesenchymal stem cells have been used suc-
cessfully in many medical fields, such as maxillofacial,
cosmetic, spine, orthopedic, and general wound healing
applications.
January 2009 / Vol 22 No 1

Conservative treatment and
preventive biologic solution
Nonsurgical treatment of cartilage lesions, including
diet, intra-articular injections, and rehabilitation were rele-
gated to pain control and activity modifications. Recent stud-
ies on pulsed electromagnetic fields and platelet-rich plasma
injections have shown that these methods have the capacity
to help heal cartilage tissue and delay osteoarthritis.
A recent study by Focht et al19 analyzed 316 adults
with obesity who underwent an arthritis, diet, and activity
promotion trial. This 18-month single-blind, randomized
controlled trial, compared the effects of exercise alone,
dietary weight loss alone, a combination of exercise plus
dietary weight loss, and a healthy lifestyle control inter-
vention. The study concluded that exercise and dietary
weight loss, compared with the healthy lifestyle control
intervention, resulted in improved mobility-related self-
efficacy and pain reduction.19
In an animal study, Ciombor et al13 showed that pulsed
electromagnetic fields preserved the morphology of ar-
ticular cartilage and retarded the development of osteo-
arthritic lesions in Hartley guinea pigs compared with a
control group. The study concluded that pulsed electro-
magnetic fields were disease modifying in this population.
This supported a previous in vitro study of human chon-
drocytes that showed increased cell proliferation with ex-
posure to pulsed electromagnetic fields.16 The study noted
that electric and electromagnetic fields increased gene ex-
pression and synthesis of growth factors, and that this may
amplify field effects through autocrine and paracrine sig-
naling. Electric and electromagnetic fields may produce
a sustained regulation of growth factors that enhance, but
do not disorganize, endochondral bone formation.1
Similarly, Massari et al35 summarized the results of
the translational research of the Cartilage Repair and
Electromagnetic Stimulation study group on the use of
specific pulsed electromagnetic fields (I-ONE; IGEA,
Carpi, Italy) (Figure 1) to control local joint inflamma-
tion and, ultimately, to have a chondroprotection effect on
articular cartilage. The study showed that of patients who
underwent chondral coblation at 3-year follow-up, the
number of patients who completely recovered was higher
in the group treated with I-ONE therapy compared with
the control group. Clinical results show how I-ONE thera-
py is an effective chondroprotective treatment for patients
immediately after arthroscopic surgery without any nega-
tive side effects and exerts a short-term effect in reducing
functional recovery time.
However, platelet-rich plasma preparations have
been used with effective results both in surgical and out-
patient procedures in the treatment of muscoloskeletal
problems.29,52 Some studies suggested that platelet-rich
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Biological Approaches for Cartilage Repair
1
Figure 1. I-One (IGEA).
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plasma treatment prior to surgery prevented the necessity
to undergo the surgical procedure.38 In addition, platelet-
rich plasma combined with proper nutrition, including
control of body mass index, exercise, and lifestyle, can
act as a preventive agent in chronic and degenerative
musculoskeletal disease.
Surgical Treatment
Traditional palliative or reparative treatment tech-
niques have demonstrated variable results. Lavage and
chondroplasty can provide symptomatic pain relief with
no actual hyaline tissue formation. However, these tech-
niques remove superficial cartilage layers that include
collagen fibers responsible for the tensile strength, which
creates a functionally inferior cartilage tissue.
Bone marrow stimulation techniques, such as sub-
chondral plate drilling or microfracture, have been re-
ported to stimulate production of hyaline-like tissue with
variable properties and durability, compared with normal
cartilage. However, many cases showed that these tech-
niques tend to produce fibrocartilaginous tissue that will
degenerate with time.23,24,32,53,54
Kreuz et al,32 in a systematic review of 28 microfrac-
ture studies, noted that most authors have reported a de-
cline in functional scores at medium term. However, at the
last follow-up, patients still showed significant improve-
ment from their preoperative scores.
Kon et al31 recently compared microfracture with second-
generation autologous chondrocyte implantation and showed
that at 5-year follow-up, sports activity of the microfracture
group significantly decreased from the 2-year follow-up.
Microfracture is commonly used as first-line treatment
because it is easy and does not require special instruments
or implants. However, recent reports have shown that in a
group of patients treated with autologous chondrocyte im-
plantation, the worse results (failure and reoperation) oc-
37
THE JOURNAL OF KNEE SURGERY
2
Figure 2. Open second-generation autologous chondrocyte
implantation.
curred in patients previously treated with microfracture,
compared with patients treated with autologous chondro-
cyte implantation as first-line surgery.32
Osteochondral autologous transplantation and mosa-
icplasty can restore normal cartilage tissue, but the ap-
plication is restricted to small defects and there are some
concerns about donor-site morbidity.28
First introduced by Peterson,10 autologous chondro-
cyte implantation has been proven capable of restoring
hyaline cartilage tissue. Recent studies41,46,47 suggested
the durability of this treatment, especially at long-term
follow-up, primarily due to its ability to produce hyaline-
like cartilage that is mechanically and functionally stable.
Autologous chondrocyte implantation also allows inte-
gration with the adjacent articular surface. However, this
method requires 2 surgical procedures and showed local
morbidity for periosteal harvest.11
The complexity of the Peterson periosteal technique
and the possible complication of periosteal patch hyper-
trophy prompted surgeons to seek alternative techniques
to enhance cell delivery and outcome.
At present, the most promising technique is tissue en-
gineering, in which cells are combined with scaffolds to
preform a tissue; in general, the concept involves cultured
autogenous chondrocytes integrated in biodegradable and
biocompatible scaffolds. After the chondrocytes are culti-
vated and seeded on the scaffold, they must reacquire and
maintain their chondrogenic phenotype to synthesize an
extracellular matrix containing type II collagen, glycos-
aminoglycans, and proteoglycans, all of which are neces-
sary to produce hyaline cartilage.
Second-Generation Autologous
Chondrocyte Implantation
The ideal scaffold should be biocompatible, biode-
gradable, not trigger any inflammatory response, and not
38
3
Figure 3. Arthroscopic second-generation autologous chon-
drocyte implantation.
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cytotoxic. It should offer a temporary support to cells to
promote replacement of a newly synthesized matrix and
possibly induce proliferation of the transplanted cells. The
matrix should also be permeable to nutrients and provide
firm adhesion to the surrounding cartilage wound edges
to promote integration. In addition, the scaffold must be
reproducible and readily available, as well as versatile for
repair and resurfacing.12,25,42,55
After a systematic review of the available literature
about different scaffolds in the market, which includes
porcine collagen I and III (ie, membrane-seeded autolo-
gous chondrocyte implantation [Genzyme Europe BV,
Naarden, The Netherlands]), three-dimensional bovine
collagen (NeoCart; Histogenics, Waltham, Mass), and
polyactic acid and polyglycolic acid fleece (Bioseed,
Bangkok, Thailand), we concluded that a hyaluronan-
based scaffold may be optimal for chondrocyte prolifera-
tion.30
Among several other proteins, hyaluronan is a natu-
rally occurring and highly conserved glycosaminoglycan
widely distributed in the body. It has proven to be an ideal
molecule for tissue engineering strategies in cartilage
repair because of its impressive multifunctional activ-
ity through its structural and biological role. The three-
dimensional nonwoven scaffold, HYAFF (Fidia Farma-
ceutici, Padova, Italy), supports the in vitro growth of
highly viable chondrocytes and promotes the expression
of the original chondrogenic phenotype.12 Chondrocytes
that were previously expanded on plastic and seeded into
the scaffold produce a characteristic extracellular matrix
rich in proteoglycans and express typical markers of hya-
line cartilage, such as collagen II and aggrecan.25 When
implanted in full-thickness defects of the femoral condyle
in rabbits, chondrocytes regenerated a cartilage-like tis-
sue.26,55
January 2009 / Vol 22 No 1

The main indications for second-generation cartilage
transplantation are symptomatic focal, full-thickness car-
tilage lesions (ie, International Cartilage Repair Society
grades III to IV) in the absence of significant arthritis in
physiologically young patients (between ages 15 and 50).
Additional factors to consider include the patient’s moti-
vation and willingness to comply with the postimplanta-
tion rehabilitation regimen. Defect sizes (range, 2-12 cm2)
have been shown to be favorable to regeneration. Osteo-
chondritis dissecans is not a contraindication for cartilage
transplantation as long as the bone loss is not .8 mm.47
Adverse events of second-generation autologous
chondrocyte implantation are apparently lower than first
generation, as reported by Mandelbaum.33
Several reports from controlled trials in patients un-
dergoing surgery with the use of these hyaluronic acid
scaffolds have been presented.21,22,34,42 However, the larg-
est collection of data using the hyaluronic acid scaffold in
clinical practice is represented by a multicenter observa-
tional study conducted in Italian Orthopedic Centers since
2001.21,22,34
Autologous chondrocyte implantation can be per-
formed through the conventional arthrotomy approach.
However, recent advances in scaffold technology has
enabled surgeons to perform this technique arthroscopi-
cally (Figures 2 and 3).34 Some technical limitations pre-
vail, including treatment of patellar lesions and posterior
portions of femoral condyles or the tibial plateau. These
limits are common to all arthroscopic techniques and
could partly be resolved with the development of new ar-
throscopic tools.
In a prospective, nonrandomized study22 on patello-
femoral lesions treated with second-generation autolo-
gous chondrocyte implantation, we analyzed a group of
patients at the 5-year follow-up, using International Knee
Documentation Committee (IKDC) subjective and objec-
tive scores, the EuroQoL pain scale, and Tegner scores.
The authors noted significant improvement from preop-
erative scores to the final follow-up. Objective preopera-
tive data improved from 8 of 34 (23.5%) patients classi-
fied as IKDC A or B scores to 31 of 34 (91.2%) classified
IKDC A or B scores at the 5-year follow-up. Mean subjec-
tive scores improved from 46.09 points preoperatively to
70.39 points 5 years postoperatively, and Tegner scores
improved from 2.56 to 4.68. EuroQol visual analog scale
scores improved from 54.81 to 78.24.
In another study, we compared second-generation
autologous chondrocyte implantation with microfracture
and found a higher improvement in the IKDC objective
and subjective scores in the group treated with second-
generation autologous chondrocyte implantation at the
5-year follow-up.31 Analyzing the resumption of sports
activity obtained with the Tegner score, we observed sim-
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Biological Approaches for Cartilage Repair
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4
Figure 4. ChondroCelect (TiGenix NV) scientific monogram.
Reprinted with permission from TiGenix NV.
ilar level in both groups at the 2-year follow-up, which
remained stable at the 5-year follow-up in the second-
generation autologous chondrocyte implantation group,
whereas return to sport activities worsened in the micro-
fracture group.31
Future Implications
Third-Generation Autologous Chondrocyte
Implantation
Promising results have been shown with autologous
chondrocyte implantation. Autologous chondrocyte im-
plantation is a technology that involves the implantation
of an expanded chondrocyte population derived from a
cartilage biopsy. These expansions result in the loss of
phenotypic traits, also called dedifferentiation.7 This pro-
duces chondrocytes with a decreased capacity to regener-
ate hyaline cartilage cells.
Characterized chondrocyte implantation is a new
generation of autologous chondrocyte implantation
procedures that uses ChondroCelect (TiGenix NV,
Haasrode, Belgium). ChondroCelect was developed to
limit the loss of phenotype and is an expanded popula-
tion of chondrocyte with a proven ability to produce
stable cartilage in vivo (Figure 4). The highly con-
trolled and consistent manufacturing process is based
on the expression of a marker profile to characterize
this cell population.
A recent prospective, randomized controlled trial that
compared characterized chondrocyte implantation ver-
39
THE JOURNAL OF KNEE SURGERY
sus microfracture as treatment for a single symptomatic
cartilage defect of the femoral condyle showed that char-
acterized chondrocyte implantation produced a superior
type of tissue regenerate.53 The primary aims of the trial
were to demonstrate superiority of characterized chondro-
cyte implantation over microfracture in overall quality of
structural regeneration of the articular tissue at 12 months
posttreatment using histomorphometry and the overall
histology assessment score. In addition, the study aimed
to demonstrate that clinical outcomes at 12 to 18 months
posttreatment were comparable in both treatment groups.
For the first time, it was proved that joint surface repair
and regeneration using cell technology produced a higher
quality regenerate than did intrinsic repair.53 Recently, the
authors released their 36-month results, which showed
that the ChondroCelect group continues improvement,
according to Knee Injury and Osteoarthritis Outcome
Scores; these results suggest characterized chondrocyte
implantation may lead to an improved long-term clinical
outcome (Saris DB, oral communication, May 2008).
Future clinical studies using combinations of char-
acterized chondrocyte implantation technology and hy-
aluronic acid could analyze whether the combination of
viable cells and scaffold can lead to a more stable and
long-lasting regenerated cartilage.
Mesenchymal Stem Cells Implantation: Toward
1-Step Surgery
Second-generation and third-generation autologous
chondrocyte implantation represents a modern and viable
technique for cartilage full-thickness chondral lesion re-
pair. However, these are 2-step procedures that include an
arthroscopic biopsy, cell cultivation, and subsequent im-
plantation. Aside from the risks associated with harvest-
site morbidity, 2 surgical procedures, and the total cost
of the operation, scaffold and chondrocytes cultivation is
still high.
Future directions in cartilage repair consider the pos-
sibility of 1-step surgery, including the use of stem cells
and growth factors. The use of autologous mesenchymal
stem cells and growth factors represent an improvement
on the currently available techniques, which avoids the
first surgery for cartilage biopsy and chondrocyte cultiva-
tion.
Many authors have recognized that nucleated cells
found in bone marrow are a useful source of cells for res-
toration of damaged tissue.49,58 After mesenchymal stem
cells are cultured in the appropriate microenvironment,
they can differentiate from chondrocytes and form carti-
lage. The onset of chondrogenesis requires a chemically
defined serum-free medium supplemented with dexa-
methasone, ascorbic acid, and growth factors, such as
transforming growth factor-beta.57 Along with appropriate
40
scaffolds, these cells can be used to regenerate cartilage in
a variety of applications.49 In addition, the combination of
mesenchymal stem cells and platelet-rich plasma make it
possible to improve the healing response of cartilage le-
sions in a 1-step procedure.45 Some animal and laboratory
studies have shown the chondrogenic potential of mesen-
chymal stem cells, but only few clinical human studies
have been published that show these results.20,45,49,57,58,61
Wakitani et 57 used autologous cultures of expanded
bone marrow for repair of cartilage defects in osteoarthrit-
ic knees. The study examined 24 knees in 24 patients with
knee osteoarthritis who underwent a high tibial osteoto-
my.57 The patients were divided into a cell-transplanted
group and cell-free group.57 After 16 months of follow-up,
the study concluded that mesenchymal stem cells were
capable of regenerating a repair tissue for large chondral
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defects.57
Ochi et al45 observed that in a rat model, the injection
of cultured mesenchymal stem cells combined with bone
marrow stimulation can accelerate the regeneration of ar-
ticular cartilage; they noted that this cell therapy was a
less invasive treatment for cartilage injury. In their animal
study,61 they introduced a mesenchymal stem cell delivery
system with the help of an electromagnetic field, enhanc-
ing the proliferation of cartilage inside the chondral defect
after intra-articular injection and decreasing ectopic car-
tilage formation.
Fortier20 concluded in animal studies that development
of patient-side configuration techniques for intraoperative
stem cell isolation and purification for immediate grafting
have significant advantages in time savings and immedi-
ate application of an autogenous cell for cartilage repair.
Simplicity and low cost are 2 major advantages of
mesenchymal stem cell implantation. This technique
does not require cartilage harvesting, transportation to a
laboratory and subsequent cell cultivation, seeding on the
scaffold, and reimplantation; this 1-step procedure could
significantly reduce operating time and related costs.
Conservative Biological Approach to
Osteoarthritis: Platelet-Rich Plasma
Recently the idea of a “biological solution for biologi-
cal problems” has lead to the development of less invasive
procedures and accelerated treatments that usually reduce
morbidity while enhancing functional recovery.3 Platelet-
rich plasma, which was first introduced by Ferrari et al18
in 1987 in open heart surgery, is an interesting therapy.
Later, this therapy increased in popularity because of its
versatility, biocompatibility, and low costs, which has
stimulated its therapeutic use in many medical fields. Sci-
entific research and technology have provided new insight
to understand the biological potential of platelets in the
January 2009 / Vol 22 No 1

5
Figure 5. Centrigel (ReGenTHT Regen PRP Kit; ReGenLab
SA, Mollens, Switzerland).
wound-healing process.3,52 It is well known that platelets
have many functions beyond simple hemostasis platelets
contain many important bioactive proteins and growth
factors, such as platelet-derived growth factor, insulin-
like growth factor, transforming growth factor, epidermal
growth factor, fibroblast growth factor, and vascular endo-
thelial growth factor. These factors, if secreted, regulate
key processes involved in tissue repair, including cell pro-
liferation, chemotaxis, migration, cellular differentiation,
and extracellular matrix synthesis.6,39
The rationale for topical use of platelet-enriched prepa-
rations is to stimulate the natural healing cascade and tissue
regeneration by a supraphysiological release of platelet-
derived factors directly in the site of treatment. Several sys-
tems are available to prepare the platelet-rich plasma and the
platelet gel. Through these systems, a 2- to 6-fold enrichment
of platelet concentration is obtained to achieve comparable
growth factor enrichment (Figures 5 and 6). The amount of
growth factor available to the tissue healing depends on the
growth factors actually stored in platelets and the kinetics of
the adsorption of the platelet gel.17 In addition, evidence is
mounting to show that the crucial factors in the effectiveness
of this treatment are the number of platelets used (ie, >1.2
to 2.03109/mL in platelet-rich plasma) and the way in which
they are processed, as the growth factor content of the gel is
highly sensitive to these 2 variables.8,9,36,37
Recent studies2,15,29,40 have documented the effec-
tiveness of growth factors in chondrogenesis and in pre-
venting degeneration of the joints. In particular, Kon29
studied 30 patients with symptomatic degenerative dis-
ease of the knee joints treated with 3 platelet-rich plasma
intra-articular injections weekly. The 6-month follow-up
showed positive effects on function and symptoms with
an improvement of 85% in scores evaluated for pa-
tients with median age ,60 years, whereas in patients
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Biological Approaches for Cartilage Repair
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6
Figure 6. Harvest SmartPReP 2 APC60 Process Kit (Harvest
Technologies, Plymouth, Mass).
.60 years, the improvement shown was only 30%. Na-
kagawa et al40 demonstrated the efficacy of autologous
platelet-rich plasma in stimulating the proliferation and
collagen synthesis of human chondrocytes, suggesting
the use of this method in the treatment of cartilage de-
fects. Anitua et al2 showed that an intra-articular injec-
tion of platelet-rich plasma could induce an increase in
production of hyaluronic acid structure and promote
angiogenesis and cell proliferation. Cugat et al15 used
platelet-rich growth factors to treat chondral defect in
athletes and obtained good results. According to their
experiences with other connective tissue repair, they
showed that platelet-rich growth factors in physiological
concentration are effective for the recovery of connective
tissue. In addition, local treatment is safe and does not
alter the systemic concentrations of these proteins. They
also had good results using platelet-rich growth factors in
articular cartilage lesion treatment and presented the fol-
lowing positive results: platelet-rich growth factors can
increase total glycosaminoglycans collagen II synthesis
and can decrease degradation. In addition, platelet-rich
growth factors induce chondrogenesis of mesenchymal
stem cells and promote chondrocyte proliferation, dif-
ferentiation, and adhesion.7
41
THE JOURNAL OF KNEE SURGERY

Table
Rehabilitation Protocol
Phase
Phase 1: cartilage protection and
recovery of walk
Phase 2: cartilage transition and
recovery of running
Phase 3: cartilage maturation and
athletic recovery
Objective
Protect the transplant; decrease pain
and effusion; increase range of move-
ment; delay muscle atrophy
Return to a correct running pathway
Sustain high loads and impact activi-
ties; prepare athlete for a return to
competition with good recovery
of aerobic endurance; recovery of
sports-specific skills; stimulate carti-
Criteria to Progress
Full active knee extension; knee flexion
.120°; no swelling; no pain during weight
bearing; recovery of correct walk pattern;
adequate muscle recruitment (ie, quadriceps)
Running without pain or swelling at 8 km/h
for 15 feet; adequate recovery of coordination
and neuromuscular control; .80% recovery of
strength in the contralateral limb; .80% single-
leg hop test in the contralateral limb
Can ascend and descend stairs and, for ath-
letes, running without pain or effusion at 10
km/h for 15 feet and without a significant
increase of blood lactic acid concentration
above resting values; recovery of sports-

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Phase 4: cartilage turnover and
maintenance
lage tissue remodeling specific skills
Maintain a good quality of life and
good physical condition; avoid excess
body fat; prevent risk of reinjury;
return to team and competitions

In an experimental study done on animals, Wu et al60
showed the effectiveness of intra-articular injections of
platelet-rich plasma with chondrocytes grown in vivo that
resulted in the formation of new cartilage tissue.
Finally, as observed by Nishimoto et al,43 we believe
that simultaneous concentration of platelets and bone
marrow cells, acting as a sources of growth factors and
“working cells,” could play important roles in future re-
generative medicine.
Rehabilitation Program After
Cartilage Transplantation
The importance of rehabilitation after cartilage trans-
plantation cannot be overemphasized. These protocols are
an important part of the success of cartilage regeneration
studies in Italy. A standardized postoperative functional
rehabilitation protocol is adopted based on current knowl-
edge of the biology of graft healing and on functional cri-
teria and therapy goal progression.48,56 Patients will prog-
ress through 4 rehabilitation phases51:
l Phase 1: Protection of the transplant and the recovery
of normal gait.
l Phase 2: Recovery of a correct run.
l Phase 3: Recovery of sports-specific skills.
l Phase 4: Maintenance of the physical fitness attained
during rehabilitation and prevention of the risk of re-
injury.
Progression between phases is decided accord-
ing to the achievement of specific criteria (Table),
with particular care to avoid swelling and pain in the
joint.14,27,44,50
Conclusion
A biological approach to cartilage lesions is a new chal-
lenge. A number of viable options have been made available
over the years to address problems concerning cartilage dam-
age, and each technique has its advantages and disadvan-
tages. Numerous studies are currently in progress to clarify
some of the questions that still remain unanswered regarding
the long-term durability of these procedures and the possible
modifications that can still be done to achieve better results.
Biotechnology is progressing at a rapid pace, explor-
ing new horizons and allowing the introduction of numer-
ous products for clinical application. However, carefully
conducted randomized, prospective studies for each of
these innovations should be conducted to validate the
safety and efficacy of cartilage regeneration.
Acknowledgment
The authors thank Dr Lorenzo Boldrini from the Iso-
kinetic Rehabilitation Network, Milan, Italy, for his con-
tributions to the rehabilitation program and the platelet-
rich plasma sections of this article.
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