Keywords
articular cartilage - osteoarthritis - platelet-rich plasma - PRP
The articular cartilage in the setting of a diseased articular environment has very
poor regenerative capacity. Thus, clinical and laboratory research aimed at biological
approaches to repair cartilage injury using growth factors provides promise for the
treatment of disabling articular cartilage disease. Growth factors are naturally occurring
substances—often proteins or steroid hormones—that are capable of stimulating cellular
differentiation, growth or proliferation while serving an important role in regulating
various cellular processes. Numerous growth factors have quantitative and temporal
effects on articular cartilage growth including transforming growth factor-β1 (TGF-β1),
bone morphogenetic protein-2 and -7, insulin growth factor-1, fibroblast growth factor-2
and -18 (FGF-2, FGF-18), vascular endothelial growth factor (VEGF), epidermal growth
factor (EGF), and platelet-derived growth factor (PDGF). Many of these factors are
found stored in the α-granules of platelets, including VEGF, TGF-β, EGF, FGF, and
PDGF. Independently, these factors serve to promote local angiogenesis, modulate inflammation,
inhibit catabolic enzymes and cytokines, recruit local stem cells and fibroblasts
to sites of damage or injury, and induce healthy nearby cells to manufacture greater
numbers of growth factors.[1] In combination, these proanabolic and anticatabolic effects attempt to return injured
or diseased articular cartilage to its preinjury state. Platelet-rich plasma (PRP)
is a sample of plasma with a supraphysiological concentration of platelets manufactured
to harness and unleash these anabolic effects on injured or diseased cartilage in
an effort to augment cartilage regeneration. Platelets and their associated cytokines
and growth factors comprise the workhorse of the biological mixture, although the
plasma contains valuable biological molecules also involved in injury repair.[2]
Basic Science behind Platelet-Rich Plasma
Basic Science behind Platelet-Rich Plasma
Osteoarthritis is a chronic degenerative joint disease in which the catabolic activity
that becomes favored within chondrocytes leads to eventual articular cartilage wear.[2] Cartilage has an extremely limited ability for self-repair given its avascularity[3]; thus, the traditional inflammatory repair process does not contribute to the healing
response in the setting of cartilage injury as it has no means to travel to the locally
affected tissue. The rationale for the use of PRP is that the supraphysiological release
of platelet-derived factors at the direct site of cartilage injury or disease can
stimulate the natural healing cascade and tissue regeneration.[4] Platelet activation leads to a release of the aforementioned growth factors and
hundreds of others from its α-granules to promote cartilage matrix synthesis, increase
cell growth, migration, and phenotype changes, and facilitate protein transcription
within chondrocytes.[5]
[6] The chemoattractants stored in platelets draw proteins, such as fibrinogen and fibrin,
the latter of which acts as an initial scaffold for stem cells to migrate and differentiate.
Generally, basic science evidence has demonstrated the ability of PRP to increase
mesenchymal stem cell and chondrocyte proliferation, deposit type II collagen and
proteoglycan.[7]
[8] This in theory may accelerate the formation of cartilage repair tissue.
The abundance of platelets in PRP increases the concentrations of relevant substances
locally leading to a sustained effect on articular cartilage. The transcription of
many degradative cytokines including interleukin-1β, tumor necrosis factor-α, and
interleukin-6 are under the upstream control of nuclear factor KB (NF-KB), and the
α-granule contents in platelets inhibit this catabolic pathway on the downstream end
and prevent the otherwise detrimental effects on articular cartilage changes in the
process of osteoarthritis.[9]
[10]
[11] Activated PRP increases in vitro levels of hepatocyte growth factor, which enhances
cellular IkBα expression and subsequently disrupts the NF-KB transactivating activity.
It does so via NF-KB-p65 subunit cytosolic retention and nucleocytoplasmic shunting,
thus decreasing its downstream proinflammatory effects.[12] PRP additionally has antinociceptive and anti-inflammatory properties, which result
from the ability of PRP to decrease synoviocyte matrix metalloproteinase-13 expression
as shown in cartilage explant studies, which would otherwise have a primary role in
cartilage matrix degradation while undergoing osteoarthritic changes. The same research
demonstrated significantly increased hyaluronan synthase-2 expression in PRP-treated
samples, which is an enzyme known to produce large hyaluronic acid (HA) isoforms and
thus contribute to the cartilage construct ([Fig. 1]).[11] Of final note, PRP decreases the expression of cyclooxygenase-2 and chemokine-receptor
CXCR4 target genes which may regulate local inflammation when used in the setting
of articular cartilage injury.[12]
Fig. 1 The PRP activation pathway. EGF, epidermal growth factor; HGF, hepatocyte growth
factor; IL, interleukin; MMP, matrix metalloproteinase; PRP, platelet-rich plasma;
TGF, transforming growth factor; TNF, tumor necrosis factor; VEGF, vascular endothelial
growth factor.
Platelet-Rich Plasma in the Treatment of Articular Cartilage Injury
Platelet-Rich Plasma in the Treatment of Articular Cartilage Injury
Preclinical animal studies on PRP have appraised its utility in both in vivo and in
vitro repair of focal cartilage lesions and osteoarthritis therapy.[5] Many of the early clinical human studies have reported on PRP use in the treatment
of osteoarthritis, with specific focus on the ability of PRP to achieve patient-reported
improvements in pain and symptoms during the treatment of such articular cartilage
pathology ([Table 1]).
Table 1
Clinical outcome studies of isolated platelet-rich plasma use in cartilage disease
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References
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Study design
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Methods
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PRP platelet count
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Results
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Conclusions
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Patel et al[13]
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Randomized controlled trial
Level of evidence: 1
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Group A: 52 OA knees, single PRP injection
Group B: 50 OA knees, two PRP injections at 3 wks apart
Group C: 46 OA knees, single saline injection (control)
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WBC-filtered
Leukocyte quality: poor
PLT count 300% of whole blood values
|
All WOMAC parameters improved significantly in Group A, B within 2–3 wks lasting to
6 mo follow-up but slight worsening at the final week
Ahlback grade 1 knees better than grade 2
22.2% of Group A with mild complications (nausea, dizziness); 44% of Group B with
mild complications
|
Both groups treated with PRP
had significantly superior results compared to control
Results declined after 6 mo
Single dose as effective as two injections
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Filardo et al[14]
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Prospective cohort study
Level of evidence: 4
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90 patients (114 OA knees)
All treated with three total intra-articular PRP injections (q3 wks)
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PLT count 600% of whole blood values
Leukocyte quality: N/S
|
Outcomes all improved at 24-mo follow-up compared with baseline
Outcomes all worsened with respect to 12-mo follow-up
Better results for younger patients, lower degrees of cartilage degeneration
Median duration clinical improvement: 9 mo
|
Treatment with PRP injections reduces pain, improves knee function, improves quality
of life in short- term
Less durable results in the long-term
|
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Kon et al[15]
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Prospective cohort study
Level of evidence: 4
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100 patients (115 OA knees)
All treated with three total intra-articular PRP injections (q3 wks)
|
PLT count 600% of whole blood values
Leukocyte quality: N/S
|
All clinical scores significantly improved from baseline to 6–12 mo follow-up
(IKDC, EQ VAS)
Results declined from 6- to 12-mo follow-up
|
PRP is safe, reduces pain, and improves knee function and quality of life
Superior results in younger patients, lower articular degeneration
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Sampson et al[16]
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Prospective cohort study
Level of evidence: 4
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14 patients with knee OA
All treated with three total intra-articular PRP injections (∼q4 wks)
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PLT count not reported
Leukocyte quality: rich
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No adverse events
Significant improvements in outcomes at 1-y follow-up (KOOS, VAS)
62% with favorable outcome at 1-y follow-up
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Positive trends for PRP use
Good safety profile for PRP use
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Filardo et al[17]
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Prospective cohort study, with control group
Level of evidence: 2
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109 total patients with knee OA
55 treated with HA
54 treated with PRP
Treated with a cycle of 3 weekly injections
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WBC present
Leukocyte quality: rich
PLT count 500% of whole blood value
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No major complications
Higher postinjective pain reaction in PRP > HA
Significant improvement in outcomes at 2-, 6-, and 12-mo follow-up
No significant difference in scores between HA and PRP groups
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PRP injections offer significant clinical improvement up to 1-y follow-up
PRP is not better than HA for middle-aged patients with moderate OA
More promising results in low-grade degenerative OA
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Spakova et al[18]
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Prospective cohort study, with control group
Level of evidence: 2
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120 patients with knee OA (grades 1–3)
60 treated with HA
60 treated with PRP
Treated with a cycle of 3 weekly injections
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PLT count 450% of whole blood value
Leukocyte quality: rich
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No severe adverse events
Significantly higher WOMAC index and NRS scores in PRP group at 3- and 6-mo follow-up
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PRP is safe, effective in the initial stages of knee OA
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Gobbi et al[4]
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Prospective cohort study
Level of evidence: 4
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50 patients with knee OA
Treated with two injections, 1 mo apart
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PLT count 200% of whole blood
Leukocyte quality: rich
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All patients with significant outcome score (IKDC) at 6- and 12-mo follow-up
All patients returned to previous activities
No differences in improvements in patients with or without previous cartilage operation
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PRP is well-tolerated with encouraging clinical results
PRP had efficacy in patients with previous microfracture or cartilage shaving procedures
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Hart et al[19]
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Randomized, controlled trial
Level of evidence: 1
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100 patients with knee OA (grade II/III chondromalacia)
50 treated with PRP
50 treated with mesocaine (control)
Treated with six injections weekly, then 3 mo break, followed by three injections
every 3 mo for maintenance
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PLT count 200–250% of whole blood
Leukocyte quality: poor
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No adverse events
Significant improvement in all clinical outcome scores (Lysholm, Tegner, IKDC, Cincinnati)
Results improved at 12-mo follow-up
MRI evaluation of cartilage showed no significant regeneration
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PRP reduced pain significantly, improved quality of life for patients with low amounts
of cartilage degeneration
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Jang et al[20]
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Prospective cohort study
Level of evidence: 4
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65 patients with knee OA
Treated with a single injection
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PLT count not reported
Leukocyte quality: N/S
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Clinical improvement in mean VAS score at 6-mo follow-up, declined some at 1-y follow-up
Significant IKDC outcome score improvement
Relapsed pain at mean 8.8 mo follow-up
Significant negative correlation between patient age and VAS, IKDC
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PRP injection is useful in the treatment of early cartilage degeneration
Increasing age, developing degeneration, presence of patellofemoral degeneration all
decrease PRP efficacy
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|
Kon et al[21]
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Prospective cohort study, with control group
Level of evidence: 2
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150 patients with knee OA
50 treated with PRP
50 treated with LW HA (control)
50 treated with HW HA (control)
All treated with three total intra-articular injections (q2 wks)
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PLT count 600% of whole blood
Leukocyte quality: N/S
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At 2-mo follow-up, PRP and LW HA groups improved more than HW HA
At 6-mo follow-up, significantly better results in PRP group
PRP and LW HA treatments similar in patients > 50 y old, and in advanced OA
PRP > HA in younger patients with early OA, chondral lesions
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PRP was superior to control groups in reducing symptoms, pain
PRP had better results in more active, young patients with early OA
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Filardo et al[22]
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Prospective, comparison cohort study
Level of evidence: 4
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144 patients with knee OA
72 treated with PRGF (single-spinning)
72 treated with PRP (double-spinning)
All treated with three total intra-articular injections (q3 wks)
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PLT count not reported
Leukocyte quality: rich (single-spinning) vs. poor (double-spinning)
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Both groups improved significantly in terms of outcome scores over the course of 1-y
follow-up
Significantly more minor local adverse (swelling, pain) events in PRP group
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PRP injections produced more pain or swelling than PRGF
Significant clinical improvement, with best results in younger patients with low degree
of OA
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Abbreviations: HA, hyaluronic acid; HW, high weight; IKDC, International Knee Documentation
Committee; LW, low weight; N/S, not specified; OA, osteoarthritis; PRP, platelet-rich
plasma; q, every; VAS, visual analog scale; WOMAC, Western Ontario and McMaster Universities
Arthritis Index.
A randomized double-blinded study of 78 total patients by Patel et al[13] demonstrated that PRP injections into the knee of patients with mild or moderate
osteoarthritis produced higher Western Ontario and McMaster Universities Arthritis
(WOMAC) subjective knee symptom scores when compared with a saline injection control
cohort. Filardo et al[14] prospectively evaluated 91 patients who received three PRP injections every 3 weeks
for degenerative osteoarthritic knee chondral lesions and reported a median duration
of improvement of 9 months. Outcome measures were still improved from baseline at
2 years but were not maintained at the same level as the 1-year level of improvement,
thus leading the authors to question the long-term efficacy of PRP. The research team
also determined that superior results were gathered from younger patients and those
with less cartilage degradation. Kon et al[15] prospectively followed 100 patients with degenerative chondral lesions and osteoarthritis
who received three PRP injections every 3 weeks, and similarly reported superior responses
to treatment in younger patients and a decrease in the improvement of outcomes at
1 year following injections when compared with the results at 6 months. Sampson et
al[16] prospectively followed 14 patients with knee osteoarthritis treated with three PRP
injections at 4-week intervals and reported significant improvements in pain and symptom
relief in the majority of patients at 12 months postinjection as per Knee Injury and
Osteoarthritis Outcome Score (KOOS) and Brittberg–Peterson visual analog scale (VAS)
scores.
Filardo et al[17] compared PRP to HA injections in the treatment of knee chondropathy or osteoarthritis
and reported a trend toward favorable outcomes in the PRP group at 1-year follow-up
for patients with low-grade articular degeneration, but no superiority to HA injections
in middle-aged patients with moderate signs of arthritis. By contrast, significantly
better results in WOMAC index and Numeric Rating Scale scores were recorded in patients
receiving three PRP injections as compared with HA injections for knee osteoarthritis
at 3- and 6-month follow-up, as per the findings of Spaková et al.[18]
Gobbi et al[4] treated 50 patients with knee osteoarthritis using two intra-articular injections
of autologous PRP and reported significant improvements in all outcome scoring scales
at both 6- and 12-month follow-up with 100% return to previous activities. These results
were irrespective of whether or not the patients had undergone previous operative
intervention for cartilage lesions (cartilage shaving and/or microfracture). Total
50 consecutive patients with grade II or III chondromalacia underwent 1 year of treatment
with nine PRP injections by Hart et al,[19] with the results demonstrating significant improvements in all measured outcome
scores. Magnetic resonance imaging determined that despite the reduced pain and improved
quality of life in these patients, there was no significant cartilage regeneration.
Jang et al[20] prospectively evaluated 65 patients suffering from osteoarthritis treated with intra-articular
PRP injection; their results showed statistically significant improvements in several
outcome scores, but pain relapsed at an average 8.8 months after the procedure. Increased
age and the presence of patellofemoral joint degeneration worsened the outcomes with
PRP in this study. Similarly, Kon et al[21] reported on 50 patients with degenerative cartilage lesions of the knee and severe
osteoarthritis who were treated with three autologous PRP intra-articular injections
and found that PRP had longer therapeutic efficacy than HA injections in comparable
demographic cohorts. As with many of the aforementioned clinical studies, superior
results were reported in younger and more active patients with a lower degree of cartilage
degeneration.
The variety of techniques for PRP production has also been compared in patients with
degenerative knee cartilage lesions and osteoarthritis. Filardo et al[22] compared 72 patients treated with three injections of PRP prepared with a single-spinning
procedure (plasma rich in growth factors [PRGF]) to an equal number of patients treated
in similar fashion with PRP prepared with a double-spinning approach. The authors
reported statistically significant improvements in subjective knee clinical outcome
scores at 2-, 6-, and 12-month follow-up, particularly in younger patients with a
lower degree of cartilage degeneration. There were no differences in the comparative
analysis of the two groups at these follow-up outcome time points, although a significantly
larger number of double-spinning PRP injections produced transient local pain and
swelling reactions.
While most clinical studies on PRP have evaluated its use in patients with chronic
degenerative cartilage disease, a single case report from Freitag et al[23] found good efficacy for a course of photoactivated PRP injections in a 38-year-old
patient with a traumatic focal chondral lesion of the knee from a basketball injury.
Another case reported by Sánchez et al[24] reported accelerated articular cartilage healing and excellent symptomatic improvement
in a patient with a nontraumatic knee cartilage avulsion injury treated by arthroscopic
reattachment supplemented with PRP injection.
PRP has recently been studied as an augmentation device with various other cartilage
procedures for the purpose of osteochondral lesion treatment with early reports of
success ([Table 2]). Guney et al[25] evaluated treatment for osteochondral lesions of the talus by comparing arthroscopic
microfracture alone to that augmented with PRP injection on the 1st postoperative
day. The latter cohort of patients had significantly superior American Orthopaedic
Foot and Ankle Society (AOFAS) scores, Foot and Ankle Ability Measure (FAAM) overall
pain domain and 15-minute walking domain subgroup scores, and VAS pain scores in comparison
to isolated arthroscopic microfracture. Siclari et al[26] reported significant KOOS improvements in all subcategories after treatment of focal
knee chondral defects with a cell-free resorbable polyglycolic acid-hyaluronan implant
immersed with autologous PRP after bone marrow stimulation via subchondral drilling.
The improvement seen at 1 year postoperatively was still present at 2 years after
the surgery, with histological analysis of biopsy tissue showing potential regeneration
of hyaline-like cartilage. Recently, the senior author (B.J.C.) published a promising
technique using micronized allogeneic articular cartilage combined with PRP as a scaffold
and adjunct to traditional microfracture surgery (BioCartilage, Arthrex, Inc., Naples,
FL).[27]
Table 2
Clinical outcome studies of platelet-rich plasma use in combination with articular
cartilage surgery for cartilage injury
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References
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Study design
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Methods
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PRP platelet count
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Results
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Conclusions
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|
Guney et al[25]
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Case–control study
Level of evidence: 2
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Group A: 16 OA lesions of talus, arthroscopic microfx alone (control)
Group B: 19 OA lesions of the talus, arthroscopic microfx + PRP
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PLT mean count 5.4-folds ( ± 1.2) increase from whole blood
Leukocyte quality: N/S
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At average 16.2 mo follow-up, combined treatment arthroscopic microfx
+ PRP had significantly better functional score outcomes (AOFAS, FAAM overall pain,
FAAM 15-min walking domain, VAS pain)
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PRP as an adjunct to arthroscopic microfx for treating osteochondral lesions of talus
improves medium-term functional score status in patients compared with microfx alone
|
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Siclari et al[26]
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Case series
Level of evidence: 4
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52 patients with focal chondral defects of the knee treated with arthroscopic subchondral
drilling
+ PGA-HA implant immersed with autologous PRP
|
PRP not conditioned, mean concentration 832.1 × 103 PLT/µL
Leukocyte quality: N/S
|
At 1-, 2-y follow-up, significant improvement in all KOOS subcategories compared with
baseline and 3-mo follow-up
Maintained KOOS data between 1 and 2 y
Biopsy histological analysis showed hyaline-like to hyaline cartilage repair tissue
rich in chondrocyte morphology cells, type II collagen and PGs
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Patients with focal cartilage defects improve clinically with PGA-HA implant + PRP
after subchondral drilling, and may have greater potential for regeneration of hyaline-like
cartilage
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Abbreviations: AOFAS, American Orthopaedic Foot and Ankle Society scoring system;
FAAM, Foot and Ankle Ability Measure; KOOS, Knee Injury and Osteoarthritis Outcome
Score; microfx, microfracture; N/S, not specified; PRP, platelet rich plasma; PLT,
platelet; PGA-HA, cell-free resorbable polyglycolic acid-hyaluronan; PGs, proteoglycans;
VAS, visual analog scale for pain.
Future Roles for Platelet-Rich Plasma in Treating Cartilage Disease
Future Roles for Platelet-Rich Plasma in Treating Cartilage Disease
Cartilage damage can take place secondary to both acute and chronic processes. Acute
traumatic injury to articular cartilage can create focal chondral loss and potentially
lead to a more widespread osteoarticular problem. By contrast, chronic joint stress
over a prolonged period of time may lead to eventual widespread inflammatory chondral
degradation and osteoarthritis. Most studies evaluating PRP have evaluated its use
within the setting of uniform cartilage degeneration as seen in osteoarthritis. While
relatively devoid from the literature in human clinical studies, animal studies have
evaluated the proposed effect of PRP on focal osteochondral defects ([Fig. 2]). Sun et al[3] evaluated the treatment of large osteochondral defects created in the patellofemoral
groove of rabbit models with treatment arms consisting of PRP in a polylactic-glycolic
acid (PLGA), PLGA alone, or no treatment. The authors reported no significant differences
between the PRP and untreated groups in terms of macroscopic examination, microcomputed
tomography (larger amount of subchondral bone formation) and histological changes
of the newly formed bone and cartilage within the defect after 12 weeks. With the
knowledge of the efficacy of PRP in younger cohorts, future clinical evaluations of
the use of PRP with younger patients sustaining acute osteochondral defects would
be valuable.[23] Moreover, the utility of PRP in the treatment of cartilage degeneration and injury
in joints other than the knee is largely unreported and may become a worthwhile research
venue that is pursued.
Fig. 2 (A) A blood draw is performed on the patient intraoperatively after the induction
of anesthesia. (B) The blood is spun down in a centrifuge to separate out the platelet-rich
plasma. (C) The platelet-rich plasma is placed at the microfracture site with a fibrin
glue sealant.
Aside from cartilage degeneration, the clinical use of PRP has been studied in numerous
clinical and preclinical reports to determine value in the following sports medicine
pathologies: Achilles tendon rupture, chronic tendinosis, chronic rotator cuff tendinopathy
or tearing, muscle injury, and meniscal repair.[28] Sadoghi et al[29] systematically reviewed the use of PRP in the treatment of Achilles tendon ruptures
in animal and human studies, and found that analysis of 14 total studies demonstrated
significant effects of PRP in the treatment of Achilles tendon ruptures likely secondary
to enhanced scar tissue maturation. Krogh et al[30] systematically reviewed and analyzed randomized controlled trials of injection therapies
for patients with lateral epicondylitis, and determined that PRP was statistically
superior to placebo, although most studies were at risk for bias using the Cochrane
risk of bias tool. Carter et al[31] analyzed 24 articles evaluating PRP use in advanced wound therapy and concluded
that PRP therapy in cutaneous wounds showed improved partial and complete wound healing
compared with wound care alone in a control group. Villela et al[32] reported similar conclusions in the treatment of diabetic ulcers with PRP. These
additional uses for PRP continue to be studied with higher levels of evidence, with
the hope that more definitive conclusions can be made either in favor of or against
routine use in the orthopedics.
While most of the cartilage-related research on the efficacy of PRP has been devoted
to its effect on chondrocytes thus far, recent studies have examined the effect of
both leukocyte-rich and leukocyte-poor PRP on synoviocytes. More than 80% of normal
human synovium is composed of synoviocytes that produce cytokines and matrix metalloproteinases
that can mediate cartilage metabolism. While no differences in clinical outcomes have
been observed till date between leukocyte-rich and leukocyte-poor derivatives, a recent
laboratory study by Braun et al[33] found that leukocyte-rich PRP and red blood cell concentrates both led to significantly
greater cell death and proinflammatory mediator production than leukocyte-poor PRP
or platelet-poor plasma. These findings led the authors to suggest that clinicians
consider using leukocyte-poor, red blood cell–free formulations of PRP when performing
intra-articular procedures. Further research and clinical correlation is required
in this area to determine whether clinical consequences may exist secondary to the
release of catabolic proteases that may perpetuate inflammation and potentially inhibit
tissue healing.
Conclusion
There are numerous basic science and clinical studies demonstrating the positive effects
that PRP has on cartilage degeneration or injury, with many of the aforementioned
in vivo studies exhibiting improvements in both symptoms and joint function. The improvement
in symptoms after intra-articular injection of PRP in knee osteoarthritis is short-term,
with many studies demonstrating declines in efficacy after 1 year. In addition, both
age and degree of cartilage degeneration have an inverse relationship with the effectiveness
of PRP. PRP as a treatment option for cartilage damage or injury is attractive given
the low rate of adverse events observed in numerous clinical studies, its simplicity
of quickly obtaining a sample of autogenous whole blood, and the absent risk of disease
transmission. PRP has been used as an adjunct to several cartilage-related procedures
including microfracture surgery and graft, scaffold and implant insertion.[7] Ultimately, however, recent systematic reviews on the topic conclude that there
is still a paucity of high-quality data providing sufficient evidence to support or
disprove the clinical utility of PRP in symptomatic osteoarthritis of the knee.[34] There is even less clinical evidence supporting its use in other joints or in the
treatment of focal osteochondral defects despite the basic science evidence in favor
of its use.[35] In addition, not all basic science and clinical studies on PRP have concluded it
has positive effects.[7] Further studies—particularly randomized, controlled trails—to evaluate the in vivo
effects of PRP on human cartilage are imperative to conclusively determine the proper
patient population and expected outcomes for the use of PRP in the setting of cartilage
damage and injury.
