vol. 2 • no.

3 SPORTS HEALTH

[ Primary Care ]

Platelet-Rich Plasma: Where Are We

Now and Where Are We Going?
Brian J. Cole, MD, MBA,*§ Shane T. Seroyer, MD,* Giuseppe Filardo, MD,†
Sarvottam Bajaj, BE,* and Lisa A. Fortier, DVM, PhD‡

Context: Platelet-rich plasma (PRP) may affect soft tissue healing via growth factors released after platelet degranulation.
Because of this potential benefit, clinicians have begun to inject PRP for the treatment of tendon, ligament, muscle, and car-
tilage injuries and early osteoarthritis.
Evidence Acquisition: A PubMed search was performed for studies relating to PRP, growth factors, and soft tissue injuries
from 1990 to 2010. Relevant references from these studies were also retrieved.
Results: Soft tissue injury is a major source of disability that may often be complicated by prolonged and incomplete
recovery. Numerous growth factors may potentiate the healing and regeneration of tendons and ligaments. The potential
benefits of biologically enhanced healing processes have led to a recent interest in the use of PRP in orthopaedic sports
medicine. There has been widespread anecdotal use of PRP for muscle strains, tendinopathy, and ligament injuries and as
a surgical adjuvant to rotator cuff repair, anterior cruciate ligament reconstruction, and meniscal or labral repairs. Although
the fascination with this emerging technology has led to a dramatic increase in its use, scientific data supporting this use
are still in their infancy.
Conclusions: The literature is replete with studies on the basic science of growth factors and their relation to the main-
tenance, proliferation, and regeneration of various tissues and tissue-derived cells. Despite the promising results of several
animal studies, well-controlled human studies are lacking.
Keywords: platelet-rich plasma; tendinopathy; ligament injuries; muscle strain injuries; early osteoarthritis

S
oft tissue injury is a major source of disability and health autologous GFs.2 Generation of PRP involves centrifugation of
care expense, resulting in more than 1 million office autologous blood to separate and extract the plasma and buffy
visits per year in the United States.4 In addition to health coat portion of the blood, which contain high concentrations
care expense, the societal cost of these injuries includes lost job of platelets. PRP has established use in the fields of dentistry,
wages and production. In competitive or professional athletes, dermatology, plastic and maxillofacial surgery, acute trauma,
this vocational loss may have extreme consequences. Soft tissue cosmetic surgery, and veterinary medicine.12,28,36,38,53 The
healing in vivo is often a slow, complicated, and incomplete rationale for the widespread use of PRP in the healing process
process.28 Our understanding of the contribution of growth of such varied tissue types resides in the fact that platelets
factors (GFs) to the regulation of normal tissue structure and represent an easily accessible reservoir of critical GFs and other
development, as well as tissue’s response to injury, continues signaling molecules, including leukocyte-derived catabolic
to evolve at a rapid rate. Coupled with this advancing scientific cytokines and fibrinogen, which may govern and regulate the
knowledge is the fascination with the potential impact of tissue-healing process.8,41,44 This milieu of bioactive molecules
GF application on the healing of injured tissue. The ability contributes to a well-orchestrated tissue-healing response to
to modulate or augment the healing process and expedite injury, which proceeds sequentially through the inflammatory,
recovery times is a subject of vigorous scientific investigation. reparative, and remodeling phases of wound healing.62
Platelet-rich plasma (PRP) is a simple, efficient, and minimally The purpose of this review is to establish a foundation of
invasive method of obtaining a natural concentration of knowledge related to the definition of PRP and to analyze the

From *Rush University, Chicago, Illinois, †Rizzoli Orthopaedic Institute, Bologna, Italy, and ‡Cornell University, Ithaca, New York
§
Address correspondence to Brian J. Cole, Rush University, 1611 West Harrison, Suite 300, Chicago, IL 60612 (e-mail: [email protected]).
No potential conflict of interest declared.
DOI: 10.1177/1941738110366385
© 2010 The Author(s)

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 Cole et al May • June 2010

Table 1. Growth factors present in platelet-rich plasma.

Name Acronym Function

Platelet-derived PDGF Stimulates fibroblast production, chemotaxis, stimulates transforming growth factor–
growth factor β1, collagen production, upregulation of proteoglycan synthesis

Transforming growth TGF-β1 Modulates proliferation of fibroblasts, formation of extracellular matrix, cell viability;
factor–β1 increases production of collagen from fibroblasts, suppression interleukin
1–mediated effects on proteoglycan synthesis in cartilage

Basic fibroblastic bFGF Produces collagen; stimulates angiogenesis, proliferation of myoblasts

growth factor

Vascular endothelial VEGF Promotes angiogenesis

growth factor

Epidermal growth EGF Promotes cell differentiation, angiogenesis, proliferation of mesenchymal and epithelial cells
factor

PRP results in preclinical and clinical studies to determine if Although many GFs are associated with wound healing,
the cumulative scientific evidence suggests efficacy of PRP and PDGF and TGF-β1 appear to be 2 of the more integral
supports its use for the treatment of musculoskeletal injuries. A modulators.34 PDGF has activity in early wound healing (during
tremendous challenge to the interpretation and extrapolation the acid tide).19,33 In vitro studies have shown that at lower pH
of the available data lies in the variability of platelet and (5.0), platelet concentrate lysate has increased concentrations
leukocyte concentrations among the various methodologies of PDGF, with an increased capacity to stimulate fibroblast
used in preclinical and clinical studies. proliferation.33 TGF-β increases the production of collagen
from fibroblasts.33,61 Its release (in vitro) is enhanced by neutral
The Role of Platelets or alkaline pHs, which correspond to the later phases of
healing.33 Through modulation of interleukin-1 production by
Platelets are the first cell type to arrive at the site of tissue macrophages, PRP may inhibit excessive early inflammation
injury and are particularly active in the early inflammatory that could lead to dense scar tissue formation.66
phases of the healing process.62 They play a role in Insulinlike GF-I (IGF-I) has also been extensively studied for
homeostasis, through cell membrane adherence, aggregation, its ability to induce proliferation, differentiation, and hypertrophy
clot formation, and release of substances that promote of multiple cell lines. Separate analyses of GFs in PRP have
tissue repair and that influence the reactivity of blood shown significant increases in PDGF, VEGF, TGF-β1, and EGF,
vessels and blood cell types involved in angiogenesis and compared with their concentrations in whole blood.21,23,38,56,64
inflammation.8,44 Platelets mediate these effects through However, there are conflicting results with regard to IGF-I, where
degranulation, in which platelet-derived GF (PDGF), the majority of studies reported no increase in IGF-I in PRP,
transforming GF-β1 (TGF-β1), vascular endothelial GF (VEGF), compared with whole blood. There are also conflicting results
basic fibroblastic GF (bFGF), and epidermal GF (EGF) are regarding the correlation between the GF content and platelet
released from alpha granules (Table 1).21,23,38 Platelets also counts in PRP.21,23,38,49,64 The basis of these contradictions are not
store antibacterial and fungicidal proteins, metalloproteases, fully understood and may be related to variability in patient age,
coagulation factors, and membrane glycoproteins, which may health status, or platelet count. Alternatively, differences in GF
influence inflammation by inducing the synthesis of other content and platelet count may be due to the various methods of
integrins, interleukins, and chemokines.2 Dense granules in processing, handling, and storing of samples, in addition to the
platelets store and release ADP, ATP, calcium ions, histamine, type of assay performed. The diversity of PRP products should
serotonin, and dopamine, which are active in tissue be taken into account when interpreting and comparing results
modulation and regeneration.49 Platelet degranulation begins and methods for generating PRP.
within 10 minutes of exposure to clotting cascade factors
(such as thrombin) or, in their absence, contact to exposed
PRP in Orthopaedics
basement membrane. The majority of GF secretion occurs
within the first hour, although continued release occurs The allure of PRP use in soft tissue injuries resides in the
throughout the period of platelet viability (7 days).38 possible delivery of a physiologically natural balance/ratio of

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GFs and other cytokines containing anabolic and catabolic There is a lack of animal and clinical studies to demonstrate
functions in supraphysiologic concentrations directly into the site the potential of PRP in soft tissue repair. Application of PRP
of injury to potentially optimize the healing environment.3,15,41 for musculoskeletal injuries is relatively new, and accumulation
Maintaining a natural ratio of GFs may allow maintenance of of data to support Level 1 clinical studies will take time.
the body’s homeostatic environment and theoretically provide Individual functions of GFs tested in vitro may not accurately
an abundance of healing factors without disrupting their in represent their in vivo function, because the interrelations
vivo relationships. Equally appealing is its simplicity, low cost, among the numerous GFs may be such that they require the
availability, and absence of significant adverse consequences. symbiotic presence of other GFs to properly modulate their
The autologous nature of PRP eliminates the risk of immune effects.
rejection or disease transmission. Despite this nearly intuitive
and enormous potential, well-conducted randomized controlled
PRP for Tendinopathy
clinical trials are lacking (Table 2).
Several manufacturers have commercially available devices In tendinopathy, the essential pathology includes chronic
to produce PRP. The techniques used to generate the platelet microscopic tears occurring in hypovascular tendon tissue.
concentrate products differ in the amount of whole blood, These tears heal by scar formation rather than the normal
the use of anticoagulant (acid citrate dextrose), the time and vascular and inflammatory-driven tendon-healing pathways.14
speed of centrifugation, the final volume, and the number of Modulation of bioactive factors in the diseased tendon may
platelets in the platelet concentrate. In addition, the application increase the potential for tendon healing.43 Individual in vitro
can vary, depending on the use of either bicarbonate, to GFs in PRP have been shown to increase type I collagen
buffer the acidic nature of PRP derived with acid citrate synthesis and tenocyte proliferation, including TGF-β1, PDGF,
dextrose, or thrombin, to initiate the clotting cascade through VEGF, and EGF.29,34,61,67 When exposed to PRP, tendon matrix
degranulation of platelets.15,37 A theoretical advantage of PRP synthesis is enhanced in cultures of isolated tenocytes and in
gel administration may be the adhesive support that can ex vivo tendon explant cultures.16,38,56
confine the platelets and their GFs at the treatment site.3 Animal studies have suggested positive effects of PRP on
According to the American Red Cross, PRP is greater than tendon repair—namely, improved repair with abundant
or equal to 5.5 × 1010 platelets per 50 mL. This translates to a tendon callus and increased force to failure.5,63 Injection of PRP
two- to sevenfold increase in platelet concentration compared into areas of tendon injury in animal models enhances the
with that of whole blood. The normal human range of platelet contribution of circulation-derived cells to tendon healing in
concentration is 150 000 to 450 000 platelets per µL of whole the early phases of tendon healing.27
venous blood.18,40 Concentrations of platelets in PRP differ Some clinical evidence supports the translational application
widely, ranging from 2.5 to 8.0 times the concentration of of PRP in tendinopathy in Level 4 studies. In a cohort study
platelets found in whole blood.16 Reportedly, the clinical benefit conducted by Mishra and Pavelko,42 93% of the patients
of platelet concentrates occurs more predictably when this reported reduction in epicondylar pain at a 2 year follow-up
fourfold increase in platelet concentration is achieved,37 but after receiving a single PRP injection. Kon et al31 prospectively
substantial scientific evidence is lacking, and concentrates followed 20 patients with patellar tendinosis who presented
lower than this may prove to be clinically beneficial. with pain and dysfunction for an average of 20 months. Three
The importance of the leukocyte concentration in PRP PRP injections at 15-day intervals were delivered into the
is unclear. In an ex vivo study investigating the effects of diseased tendon. Statistically significant improvements in SF-36
PRP products on matrix synthesis in the flexor digitorum Health Survey, visual analogue scale, and sporting activity
superficialis tendon, leukocyte concentration was positively (using Tegner score) were realized at 6-month follow-up.
correlated with collagen type III transcription (indicative Most recently, a Level 1 randomized controlled trial suggested
of scar formation) and matrix metalloproteinases 3 and that PRP treatment for chronic Achilles tendinopathy did
13 (which degrade intact collagen fibers).38 Leukocyte not improve patient pain or activity, compared with a saline
concentration was also negatively correlated with indicators control.17 Unfortunately, the platelet or leukocyte counts in the
of matrix synthesis, including the ratio of COL1A1 to COL3A1, PRP treatment were not reported, nor was patient age, lesion
cartilage oligomeric matrix protein, and decorin.38 The clinical size, or chronicity of the condition.
importance of leukocytes in acute or chronic tendinopathy is The use of PRP as an adjuvant to surgical repair of
presently unknown, but leukocyte concentration should be rotator cuff and Achilles tendon tears has been tested.24,50,54
considered and reported in preclinical and clinical studies. Athletes undergoing Achilles tendon repair augmented with
Further investigation is still needed to determine the most PRP intraoperatively recovered range of motion earlier,
efficacious platelet concentration and appropriate additives had fewer wound complications, and resumed training
to produce the optimal PRP preparation. An important step activities earlier than did those treated with surgical repair
toward determining an optimal PRP preparation is adoption alone.54 Rotator cuff repairs augmented with PRP resulted in
of a standardized nomenclature for PRP products to accurately significant improvement over a 24-month period (based on
reflect platelet and leukocyte concentrations.18 visual analogue scale, UCLA, and Constant scores), as well

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Table 2. Outcomes of clinical trials using platelet-rich plasma (PRP).

Pathology Epicondylar pain42

Patient number Group 1: bupivacaine, 5; Group 2: PRP, 15

Mean follow-up period (months) 25.6

Volume of injection 2-3 cc of PRP

Number of injections 1

Outcomes Mayo score*: initial, 50.3; 6 months, 86.3. Mean pain score*: initial, 80.3; 6 months,
15.07. *P = .0001.

Study level and comments Level 2, cohort study. Three-fifths of bupivacaine patients withdrew from study,
preventing analysis. PRP patients reported a 93% decrease in pain. Conclusion: PRP
reduced pain from elbow tendinosis and should be considered before surgery.

Pathology Rotator cuff50

Patient number 14

Mean follow-up period (months) 24

Volume of injection Not applicable

Number of injections 1 injection

Outcomes Visual analogue scale*: initial PRP, 5.64; 2-year PRP, 1.00 ± 0.58. UCLA*: initial PRP,
16.54 ± 5.46; 2-year PRP, 32.92 ± 1.19. Constant*: initial PRP, 54.62 ± 16.98; final
PRP, 85.23 ± 7.22. *P = .001.

Study level and comments Level 4, case series; 13 patients were seen at follow-up. Conclusion: PRP is safe and
effective for treatment of the rotator cuff and produces results that are consistent over
time.

Pathology Achilles tendon (plasma-rich growth factor)54

Patient number Group 1: plasma-rich growth factor, 6; Group 2: control, 6

Mean follow-up period (months) Group 1: 32; Group 2: 50

Volume of injection 4 cc of plasma-rich growth factor

Number of injections 1 injection after repair

Outcomes Time (weeks) of improvement: Return of ankle motion*: control, 11 ± 3; plasma-rich

growth factor, 7 ± 2. Return to running*: control, 18 ± 3; plasma-rich growth factor, 11
± 1. Return to training*: control, 21 ± 3; plasma-rich growth factor, 14 ± 0.8. *P < .05.

Study level and comments Level 3, case control. Conclusion: Plasma-rich growth factor may be a new option for
enhanced healing and functional recovery.

Pathology Achilles tendon17

Patient number Group 1: PRP, 27; Group 2: saline, 27

Mean follow-up period (months) 24

Volume of injection 4 cc of PRP

(continued)

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Table 2. (continued)

Number of injections 1 injection

Outcomes Composite pain and activity score, mean improvement from baseline: PRP, 21.7; saline,
20.5. Improvement between groups nonsignificant.

Study level and comments Level 1, randomized control trial. Conclusion: In treating Achilles tendinopathy, PRP,
when compared to saline, does not result in greater improvement in pain or activity.

Pathology Anterior cruciate ligament reconstruction57

Patient number 50

Mean follow-up period (months) 3

Volume of injection 3 cc of PRP

Number of injections 1 injection

Outcomes Magnetic resonance signal intensity: PRP demonstrated no differences within femoral
tunnels following anterior cruciate ligament reconstruction, compared to controls.

Study level and comments Level 3, cohort control. Conclusion: The use of PRP or thrombin does not appear to
accelerate tendon integration.

Pathology Jumper’s knee31

Patient number 20

Mean follow-up period (months) 6

Volume of injection 5 cc of PRP

Number of injections 3 Injections

Outcomes Functional improvement*: before therapy, 56.7; end of therapy, 82.0. Pain
improvement*: before therapy, 35.7; end of therapy, 63.8. *P < .05.

Study level and comments Level 4, case series. Conclusion: Short-term results show reduced pain and a return to
activity when PRP is used to treat jumper’s knee.

Pathology Lateral epicondylitis20

Patient number 28

Mean follow-up period (months) 9.5

Volume of injection 2 cc of PRP

Number of injections 1 Injection

Outcomes Average pain score: preinjection, 7.8; postinjection, 2.3. Average Nirschl stage:
preinjection, 6.5; postinjection, 2.0. No statistics performed.

Study level and comments Level 4, case series. Of 28 patients, 22 report complete pain relief even during
strenuous activity. Conclusion: Encouraging results to address lateral epicondylitis.

Pathology Anterior cruciate ligament reconstruction47

Patient number N, 108; Group 1: control, 27; Group 2: PRP, 26; Group 3: bone plug, 28; Group 4: PRP +
bone plug, 27

(continued)

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 Cole et al May • June 2010

Table 2. (continued)

Mean follow-up period (months) 6

Volume of injection 6 cc of PRP

Number of injections 1 injection

Outcomes Mature graft magnetic resonance imaging signal in femoral tunnel at 6 months:
Group 1, 21 of 27 (78%); Group 2, 26 of 26 (100%)*; Group 3, 25 of 28 (89%);
Group 4, 25 of 27 (93%). *P = .036. International Knee Documentation Committee,
6 months postoperatively: all groups, > 89% reported excellent and good outcomes
(nonsignificant). Lysholm, 6 months postoperatively: all groups, > 90% reported
excellent and good outcomes (nonsignificant).

Study level and comments Level 2, quasirandomized controlled trial. Conclusion: PRP has enhanced effect on
graft maturation evaluated by magnetic resonance imaging intensity at 6 months. PRP
+ bone plug did not show a synergistic effect.

as no adverse effects related to the application during the PRP in the Treatment of Muscle
procedure.25,51 Strain Injuries
GFs, in particular IGF-I, hepatocyte GF (HGF), fibroblast GF-2,
PRP Use in Ligament Injuries and TGF-β1 may be key regulators of muscle regeneration
The use of PRP to augment the healing of ligamentous injuries and myogenisis.25,39 In a recent animal study, Hammond et al,
remains controversial yet promising. As in the in vitro and found that local delivery of PRP to a multiply loaded, eccentric
preclinical studies performed with tendons, GFs (PDGF, TGF- muscle injury model in animals decreased full recovery time
β1, and bFGF) are actively involved during the early stage from 21 days to 14 days. To date, the authors are unaware of
of medial collateral ligament and anterior cruciate ligament any human clinical studies investigating PRP for use in the
(ACL) healing.6,32,52,65 Application of PRP to ligaments in ex vivo treatment of muscle injuries.
culture has also been shown to improve matrix synthesis.56
In animal ACL transection models, platelet hydrogels improve PRP for Use in Cartilage Injuries
and Early Osteoarthritis
healing of central ACL partial-thickness defects, load to failure,
and stiffness, when compared with controls.45,58 Augmentation Articular cartilage is frequently exposed to multiple macro-
of ACL autograft reconstruction with PRP has been shown to or microtraumatic events that may lead to the loss of tissue
preserve the mechanical integrity of the graft during the first homeostasis, resulting in the accelerated loss of articular
12 months postoperatively.6,11,13,20,47,52 Although these studies cartilage and progressing to arthritis. The inherently poor
seem promising, note that conflicting data do exist showing no regenerative capacity of cartilage continues to make articular
effect of PRP on graft healing.46 cartilage disease a challenging problem for orthopaedic
Biological augmentation may play a role in graft integration, surgeons.9,10
potentially allowing for a quicker return to function without GFs play a crucial role in modulating the phenotypic
prematurely exposing the graft to increased forces. However, expression of chondrocytes. TGF-β affects cartilage
in a recent prospective clinical ACL study that analyzed regeneration through increased chondrocyte phenotype
osseous integration of hamstring autograft in the ACL tunnel expression and matrix synthesis, through chondrogenic
using magnetic resonance imaging evaluation, graft integration differentiation of mesenchymal stem cells, and through
was not accelerated at 3 months.57 suppression of interleukin-1-mediated decrease in
As with the ACL, animal studies investigating the effects proteoglycan synthesis.22,48 PDGF helps maintain the hyaline-
of GFs on medial collateral ligament healing have yielded like chondrogenic phenotype; it increases chondrocyte
conflicting results.60 Increased strength and improved proliferation; and it up-regulates proteoglycan synthesis.55
healing time has been reported after application of PDGF.7,26 IGF-I has been shown to stimulate proteoglycan synthesis and
Conversely, Spindler et al59,60 found that the addition of PDGF suppress proteoglycan catabolism.35,55 Other GFs, including
and TGF-β1 did not change the mechanical properties of bFGF and VEGF, have chondroinductive roles. These GFs are
healed medial collateral ligaments in rabbits. all present in the α-granules of platelets, with the possible

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exception of IGF-I,49 and they may be delivered intra-articularly 7. Batten ML, Hansen JC, Dahners LE. Influence of dosage and timing of
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