Biological Approaches for Cartilage Repair

Alberto Gobbi, MD
Lyndon Bathan, MD

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ABSTRACT: The social impact of bone and cartilage 2000 to 2010 has been called the “decade of bone and
pathologies entails high costs in terms of therapeutic joints” to launch global awareness and promote further
treatments and loss of income. As a result, the current research in the prevention, diagnosis, and treatment of
research trend includes preventive interventions and joint injuries.
therapeutic solutions that can lead to an enhancement The social impact of bone and cartilage pathologies
of tissue regeneration and the reduction of degenera- entails high costs through therapeutic treatments and
tive mechanisms. loss of income. In the United States, osteoarthritis medi-
cines cost $5.31 billion in 2007,4 and musculoskeletal
Many options have been made available to address conditions including osteoarthritis cost nearly $128 bil-
problems regarding cartilage damage, each with its lion per year in direct medical expenses (ie, total joint
own advantages and disadvantages. Several stud- replacement procedures and loss of income and produc-
ies are currently in progress to clarify some of the tion in 2003).5
questions that remain unanswered about the long- For these reasons, the trend of the research is now
term durability of these procedures and the possible going toward preventive interventions and therapeu-
modifications that can be made to achieve better re- tic solutions that can lead to an enhancement of tissue
sults. regeneration and the reduction of degenerative mecha-
nisms.
Biotechnology is progressing at a rapid pace that al-
lows the introductions of several products for clinical Cartilage Treatment
application; however, randomized, prospective studies
for these innovations should be conducted to validate Hyaline cartilage combines a smooth surface and the
the safety and efficacy of cartilage regeneration. ability to withstand an extreme amount of pressure. It is
extremely important to reconstruct a perfect surface that
[J Knee Surg. 2009;22:36-44.] will withstand heavy loads. Unfortunately, articular carti-
lage lesions, with their inherent limited healing potential,
Introduction remain a challenging problem for orthopedic surgeons.
In the past few decades, surgeons often replaced the ar-
According to a study conducted by the World Health ticular surface with expensive and sophisticated implants
Organization, musculoskeletal injuries are the most when articular lesions become full-blown osteoarthritis.
common cause of severe long-term pain and disability, However, recent studies have used new orthobiological
affecting millions of people worldwide.59 Accordingly, techniques in cartilage lesions with increasing frequency
and effectiveness as a way to regenerate tissue homeo-
stasis and delay the progression of osteoarthritis. Growth
The authors are from the Orthopaedic Arthroscopic Surgery Interna- factors and mesenchymal stem cells have been used suc-
tional Bioresearch Foundation, Milan, Italy.
cessfully in many medical fields, such as maxillofacial,
Correspondence: Alberto Gobbi, MD, Orthopaedic Arthroscopic
Surgery International Bioresearch Foundation, Via Amadeo 24, 20133 cosmetic, spine, orthopedic, and general wound healing
Milano, Italy. applications.

36 January 2009 / Vol 22 No 1

 Biological Approaches for Cartilage Repair

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
1
controlled trial, compared the effects of exercise alone,
dietary weight loss alone, a combination of exercise plus Figure 1. I-One (IGEA).
dietary weight loss, and a healthy lifestyle control inter-
vention. The study concluded that exercise and dietary

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weight loss, compared with the healthy lifestyle control plasma treatment prior to surgery prevented the necessity
intervention, resulted in improved mobility-related self- to undergo the surgical procedure.38 In addition, platelet-
efficacy and pain reduction.19 rich plasma combined with proper nutrition, including
In an animal study, Ciombor et al13 showed that pulsed control of body mass index, exercise, and lifestyle, can
electromagnetic fields preserved the morphology of ar- act as a preventive agent in chronic and degenerative
ticular cartilage and retarded the development of osteo- musculoskeletal disease.
arthritic lesions in Hartley guinea pigs compared with a
control group. The study concluded that pulsed electro- Surgical Treatment
magnetic fields were disease modifying in this population.
This supported a previous in vitro study of human chon- Traditional palliative or reparative treatment tech-
drocytes that showed increased cell proliferation with ex- niques have demonstrated variable results. Lavage and
posure to pulsed electromagnetic fields.16 The study noted chondroplasty can provide symptomatic pain relief with
that electric and electromagnetic fields increased gene ex- no actual hyaline tissue formation. However, these tech-
pression and synthesis of growth factors, and that this may niques remove superficial cartilage layers that include
amplify field effects through autocrine and paracrine sig- collagen fibers responsible for the tensile strength, which
naling. Electric and electromagnetic fields may produce creates a functionally inferior cartilage tissue.
a sustained regulation of growth factors that enhance, but Bone marrow stimulation techniques, such as sub-
do not disorganize, endochondral bone formation.1 chondral plate drilling or microfracture, have been re-
Similarly, Massari et al35 summarized the results of ported to stimulate production of hyaline-like tissue with
the translational research of the Cartilage Repair and variable properties and durability, compared with normal
Electromagnetic Stimulation study group on the use of cartilage. However, many cases showed that these tech-
specific pulsed electromagnetic fields (I-ONE; IGEA, niques tend to produce fibrocartilaginous tissue that will
Carpi, Italy) (Figure 1) to control local joint inflamma- degenerate with time.23,24,32,53,54
tion and, ultimately, to have a chondroprotection effect on Kreuz et al,32 in a systematic review of 28 microfrac-
articular cartilage. The study showed that of patients who ture studies, noted that most authors have reported a de-
underwent chondral coblation at 3-year follow-up, the cline in functional scores at medium term. However, at the
number of patients who completely recovered was higher last follow-up, patients still showed significant improve-
in the group treated with I-ONE therapy compared with ment from their preoperative scores.
the control group. Clinical results show how I-ONE thera- Kon et al31 recently compared microfracture with second-
py is an effective chondroprotective treatment for patients generation autologous chondrocyte implantation and showed
immediately after arthroscopic surgery without any nega- that at 5-year follow-up, sports activity of the microfracture
tive side effects and exerts a short-term effect in reducing group significantly decreased from the 2-year follow-up.
functional recovery time. Microfracture is commonly used as first-line treatment
However, platelet-rich plasma preparations have because it is easy and does not require special instruments
been used with effective results both in surgical and out- or implants. However, recent reports have shown that in a
patient procedures in the treatment of muscoloskeletal group of patients treated with autologous chondrocyte im-
problems.29,52 Some studies suggested that platelet-rich plantation, the worse results (failure and reoperation) oc-

www.JournalofKneeSurgery.com 37
THE JOURNAL OF KNEE SURGERY

2
Figure 2. Open second-generation autologous chondrocyte 3
implantation. Figure 3. Arthroscopic second-generation autologous chon-
drocyte implantation.

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curred in patients previously treated with microfracture,
compared with patients treated with autologous chondro-
cyte implantation as first-line surgery.32 cytotoxic. It should offer a temporary support to cells to
Osteochondral autologous transplantation and mosa- promote replacement of a newly synthesized matrix and
icplasty can restore normal cartilage tissue, but the ap- possibly induce proliferation of the transplanted cells. The
plication is restricted to small defects and there are some matrix should also be permeable to nutrients and provide
concerns about donor-site morbidity.28 firm adhesion to the surrounding cartilage wound edges
First introduced by Peterson,10 autologous chondro- to promote integration. In addition, the scaffold must be
cyte implantation has been proven capable of restoring reproducible and readily available, as well as versatile for
hyaline cartilage tissue. Recent studies41,46,47 suggested repair and resurfacing.12,25,42,55
the durability of this treatment, especially at long-term After a systematic review of the available literature
follow-up, primarily due to its ability to produce hyaline- about different scaffolds in the market, which includes
like cartilage that is mechanically and functionally stable. porcine collagen I and III (ie, membrane-seeded autolo-
Autologous chondrocyte implantation also allows inte- gous chondrocyte implantation [Genzyme Europe BV,
gration with the adjacent articular surface. However, this Naarden, The Netherlands]), three-dimensional bovine
method requires 2 surgical procedures and showed local collagen (NeoCart; Histogenics, Waltham, Mass), and
morbidity for periosteal harvest.11 polyactic acid and polyglycolic acid fleece (Bioseed,
The complexity of the Peterson periosteal technique Bangkok, Thailand), we concluded that a hyaluronan-
and the possible complication of periosteal patch hyper- based scaffold may be optimal for chondrocyte prolifera-
trophy prompted surgeons to seek alternative techniques tion.30
to enhance cell delivery and outcome. Among several other proteins, hyaluronan is a natu-
At present, the most promising technique is tissue en- rally occurring and highly conserved glycosaminoglycan
gineering, in which cells are combined with scaffolds to widely distributed in the body. It has proven to be an ideal
preform a tissue; in general, the concept involves cultured molecule for tissue engineering strategies in cartilage
autogenous chondrocytes integrated in biodegradable and repair because of its impressive multifunctional activ-
biocompatible scaffolds. After the chondrocytes are culti- ity through its structural and biological role. The three-
vated and seeded on the scaffold, they must reacquire and dimensional nonwoven scaffold, HYAFF (Fidia Farma-
maintain their chondrogenic phenotype to synthesize an ceutici, Padova, Italy), supports the in vitro growth of
extracellular matrix containing type II collagen, glycos- highly viable chondrocytes and promotes the expression
aminoglycans, and proteoglycans, all of which are neces- of the original chondrogenic phenotype.12 Chondrocytes
sary to produce hyaline cartilage. that were previously expanded on plastic and seeded into
the scaffold produce a characteristic extracellular matrix
Second-Generation Autologous rich in proteoglycans and express typical markers of hya-
Chondrocyte Implantation line cartilage, such as collagen II and aggrecan.25 When
implanted in full-thickness defects of the femoral condyle
The ideal scaffold should be biocompatible, biode- in rabbits, chondrocytes regenerated a cartilage-like tis-
gradable, not trigger any inflammatory response, and not sue.26,55

38 January 2009 / Vol 22 No 1

 Biological Approaches for Cartilage Repair

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

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scaffolds have been presented.21,22,34,42 However, the larg-
est collection of data using the hyaluronic acid scaffold in 4
clinical practice is represented by a multicenter observa- Figure 4. ChondroCelect (TiGenix NV) scientific monogram.
tional study conducted in Italian Orthopedic Centers since Reprinted with permission from TiGenix NV.
2001.21,22,34
Autologous chondrocyte implantation can be per-
formed through the conventional arthrotomy approach. ilar level in both groups at the 2-year follow-up, which
However, recent advances in scaffold technology has remained stable at the 5-year follow-up in the second-
enabled surgeons to perform this technique arthroscopi- generation autologous chondrocyte implantation group,
cally (Figures 2 and 3).34 Some technical limitations pre- whereas return to sport activities worsened in the micro-
vail, including treatment of patellar lesions and posterior fracture group.31
portions of femoral condyles or the tibial plateau. These
limits are common to all arthroscopic techniques and Future Implications
could partly be resolved with the development of new ar-
throscopic tools.
In a prospective, nonrandomized study22 on patello- Third-Generation Autologous Chondrocyte
femoral lesions treated with second-generation autolo- Implantation
gous chondrocyte implantation, we analyzed a group of Promising results have been shown with autologous
patients at the 5-year follow-up, using International Knee chondrocyte implantation. Autologous chondrocyte im-
Documentation Committee (IKDC) subjective and objec- plantation is a technology that involves the implantation
tive scores, the EuroQoL pain scale, and Tegner scores. of an expanded chondrocyte population derived from a
The authors noted significant improvement from preop- cartilage biopsy. These expansions result in the loss of
erative scores to the final follow-up. Objective preopera- phenotypic traits, also called dedifferentiation.7 This pro-
tive data improved from 8 of 34 (23.5%) patients classi- duces chondrocytes with a decreased capacity to regener-
fied as IKDC A or B scores to 31 of 34 (91.2%) classified ate hyaline cartilage cells.
IKDC A or B scores at the 5-year follow-up. Mean subjec- Characterized chondrocyte implantation is a new
tive scores improved from 46.09 points preoperatively to generation of autologous chondrocyte implantation
70.39 points 5 years postoperatively, and Tegner scores procedures that uses ChondroCelect (TiGenix NV,
improved from 2.56 to 4.68. EuroQol visual analog scale Haasrode, Belgium). ChondroCelect was developed to
scores improved from 54.81 to 78.24. limit the loss of phenotype and is an expanded popula-
In another study, we compared second-generation tion of chondrocyte with a proven ability to produce
autologous chondrocyte implantation with microfracture stable cartilage in vivo (Figure 4). The highly con-
and found a higher improvement in the IKDC objective trolled and consistent manufacturing process is based
and subjective scores in the group treated with second- on the expression of a marker profile to characterize
generation autologous chondrocyte implantation at the this cell population.
5-year follow-up.31 Analyzing the resumption of sports A recent prospective, randomized controlled trial that
activity obtained with the Tegner score, we observed sim- compared characterized chondrocyte implantation ver-

www.JournalofKneeSurgery.com 39
THE JOURNAL OF KNEE SURGERY

sus microfracture as treatment for a single symptomatic scaffolds, these cells can be used to regenerate cartilage in
cartilage defect of the femoral condyle showed that char- a variety of applications.49 In addition, the combination of
acterized chondrocyte implantation produced a superior mesenchymal stem cells and platelet-rich plasma make it
type of tissue regenerate.53 The primary aims of the trial possible to improve the healing response of cartilage le-
were to demonstrate superiority of characterized chondro- sions in a 1-step procedure.45 Some animal and laboratory
cyte implantation over microfracture in overall quality of studies have shown the chondrogenic potential of mesen-
structural regeneration of the articular tissue at 12 months chymal stem cells, but only few clinical human studies
posttreatment using histomorphometry and the overall have been published that show these results.20,45,49,57,58,61
histology assessment score. In addition, the study aimed Wakitani et 57 used autologous cultures of expanded
to demonstrate that clinical outcomes at 12 to 18 months bone marrow for repair of cartilage defects in osteoarthrit-
posttreatment were comparable in both treatment groups. ic knees. The study examined 24 knees in 24 patients with
For the first time, it was proved that joint surface repair knee osteoarthritis who underwent a high tibial osteoto-
and regeneration using cell technology produced a higher my.57 The patients were divided into a cell-transplanted
quality regenerate than did intrinsic repair.53 Recently, the group and cell-free group.57 After 16 months of follow-up,
authors released their 36-month results, which showed the study concluded that mesenchymal stem cells were
that the ChondroCelect group continues improvement, capable of regenerating a repair tissue for large chondral

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according to Knee Injury and Osteoarthritis Outcome defects.57
Scores; these results suggest characterized chondrocyte Ochi et al45 observed that in a rat model, the injection
implantation may lead to an improved long-term clinical of cultured mesenchymal stem cells combined with bone
outcome (Saris DB, oral communication, May 2008). marrow stimulation can accelerate the regeneration of ar-
Future clinical studies using combinations of char- ticular cartilage; they noted that this cell therapy was a
acterized chondrocyte implantation technology and hy- less invasive treatment for cartilage injury. In their animal
aluronic acid could analyze whether the combination of study,61 they introduced a mesenchymal stem cell delivery
viable cells and scaffold can lead to a more stable and system with the help of an electromagnetic field, enhanc-
long-lasting regenerated cartilage. ing the proliferation of cartilage inside the chondral defect
after intra-articular injection and decreasing ectopic car-
Mesenchymal Stem Cells Implantation: Toward tilage formation.
1-Step Surgery Fortier20 concluded in animal studies that development
Second-generation and third-generation autologous of patient-side configuration techniques for intraoperative
chondrocyte implantation represents a modern and viable stem cell isolation and purification for immediate grafting
technique for cartilage full-thickness chondral lesion re- have significant advantages in time savings and immedi-
pair. However, these are 2-step procedures that include an ate application of an autogenous cell for cartilage repair.
arthroscopic biopsy, cell cultivation, and subsequent im- Simplicity and low cost are 2 major advantages of
plantation. Aside from the risks associated with harvest- mesenchymal stem cell implantation. This technique
site morbidity, 2 surgical procedures, and the total cost does not require cartilage harvesting, transportation to a
of the operation, scaffold and chondrocytes cultivation is laboratory and subsequent cell cultivation, seeding on the
still high. scaffold, and reimplantation; this 1-step procedure could
Future directions in cartilage repair consider the pos- significantly reduce operating time and related costs.
sibility of 1-step surgery, including the use of stem cells
and growth factors. The use of autologous mesenchymal Conservative Biological Approach to
stem cells and growth factors represent an improvement Osteoarthritis: Platelet-Rich Plasma
on the currently available techniques, which avoids the
first surgery for cartilage biopsy and chondrocyte cultiva- Recently the idea of a “biological solution for biologi-
tion. cal problems” has lead to the development of less invasive
Many authors have recognized that nucleated cells procedures and accelerated treatments that usually reduce
found in bone marrow are a useful source of cells for res- morbidity while enhancing functional recovery.3 Platelet-
toration of damaged tissue.49,58 After mesenchymal stem rich plasma, which was first introduced by Ferrari et al18
cells are cultured in the appropriate microenvironment, in 1987 in open heart surgery, is an interesting therapy.
they can differentiate from chondrocytes and form carti- Later, this therapy increased in popularity because of its
lage. The onset of chondrogenesis requires a chemically versatility, biocompatibility, and low costs, which has
defined serum-free medium supplemented with dexa- stimulated its therapeutic use in many medical fields. Sci-
methasone, ascorbic acid, and growth factors, such as entific research and technology have provided new insight
transforming growth factor-beta.57 Along with appropriate to understand the biological potential of platelets in the

40 January 2009 / Vol 22 No 1

 Biological Approaches for Cartilage Repair

5
Figure 5. Centrigel (ReGenTHT Regen PRP Kit; ReGenLab
SA, Mollens, Switzerland).

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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 6
key processes involved in tissue repair, including cell pro-
Figure 6. Harvest SmartPReP 2 APC60 Process Kit (Harvest
liferation, chemotaxis, migration, cellular differentiation,
Technologies, Plymouth, Mass).
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 .60 years, the improvement shown was only 30%. Na-
regeneration by a supraphysiological release of platelet- kagawa et al40 demonstrated the efficacy of autologous
derived factors directly in the site of treatment. Several sys- platelet-rich plasma in stimulating the proliferation and
tems are available to prepare the platelet-rich plasma and the collagen synthesis of human chondrocytes, suggesting
platelet gel. Through these systems, a 2- to 6-fold enrichment the use of this method in the treatment of cartilage de-
of platelet concentration is obtained to achieve comparable fects. Anitua et al2 showed that an intra-articular injec-
growth factor enrichment (Figures 5 and 6). The amount of tion of platelet-rich plasma could induce an increase in
growth factor available to the tissue healing depends on the production of hyaluronic acid structure and promote
growth factors actually stored in platelets and the kinetics of angiogenesis and cell proliferation. Cugat et al15 used
the adsorption of the platelet gel.17 In addition, evidence is platelet-rich growth factors to treat chondral defect in
mounting to show that the crucial factors in the effectiveness athletes and obtained good results. According to their
of this treatment are the number of platelets used (ie, >1.2 experiences with other connective tissue repair, they
to 2.03109/mL in platelet-rich plasma) and the way in which showed that platelet-rich growth factors in physiological
they are processed, as the growth factor content of the gel is concentration are effective for the recovery of connective
highly sensitive to these 2 variables.8,9,36,37 tissue. In addition, local treatment is safe and does not
Recent studies2,15,29,40 have documented the effec- alter the systemic concentrations of these proteins. They
tiveness of growth factors in chondrogenesis and in pre- also had good results using platelet-rich growth factors in
venting degeneration of the joints. In particular, Kon29 articular cartilage lesion treatment and presented the fol-
studied 30 patients with symptomatic degenerative dis- lowing positive results: platelet-rich growth factors can
ease of the knee joints treated with 3 platelet-rich plasma increase total glycosaminoglycans collagen II synthesis
intra-articular injections weekly. The 6-month follow-up and can decrease degradation. In addition, platelet-rich
showed positive effects on function and symptoms with growth factors induce chondrogenesis of mesenchymal
an improvement of 85% in scores evaluated for pa- stem cells and promote chondrocyte proliferation, dif-
tients with median age ,60 years, whereas in patients ferentiation, and adhesion.7

www.JournalofKneeSurgery.com 41
THE JOURNAL OF KNEE SURGERY

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

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lage tissue remodeling specific skills
Phase 4: cartilage turnover and Maintain a good quality of life and
maintenance 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 with particular care to avoid swelling and pain in the
showed the effectiveness of intra-articular injections of joint.14,27,44,50
platelet-rich plasma with chondrocytes grown in vivo that
resulted in the formation of new cartilage tissue. Conclusion
Finally, as observed by Nishimoto et al,43 we believe
that simultaneous concentration of platelets and bone A biological approach to cartilage lesions is a new chal-
marrow cells, acting as a sources of growth factors and lenge. A number of viable options have been made available
“working cells,” could play important roles in future re- over the years to address problems concerning cartilage dam-
generative medicine. age, and each technique has its advantages and disadvan-
tages. Numerous studies are currently in progress to clarify
Rehabilitation Program After some of the questions that still remain unanswered regarding
Cartilage Transplantation the long-term durability of these procedures and the possible
modifications that can still be done to achieve better results.
The importance of rehabilitation after cartilage trans- Biotechnology is progressing at a rapid pace, explor-
plantation cannot be overemphasized. These protocols are ing new horizons and allowing the introduction of numer-
an important part of the success of cartilage regeneration ous products for clinical application. However, carefully
studies in Italy. A standardized postoperative functional conducted randomized, prospective studies for each of
rehabilitation protocol is adopted based on current knowl- these innovations should be conducted to validate the
edge of the biology of graft healing and on functional cri- safety and efficacy of cartilage regeneration.
teria and therapy goal progression.48,56 Patients will prog-
ress through 4 rehabilitation phases51: Acknowledgment
l Phase 1: Protection of the transplant and the recovery
of normal gait. The authors thank Dr Lorenzo Boldrini from the Iso-
l Phase 2: Recovery of a correct run. kinetic Rehabilitation Network, Milan, Italy, for his con-
l Phase 3: Recovery of sports-specific skills. tributions to the rehabilitation program and the platelet-
l Phase 4: Maintenance of the physical fitness attained rich plasma sections of this article.
during rehabilitation and prevention of the risk of re-
injury. References
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42 January 2009 / Vol 22 No 1

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