Mol Neurobiol
DOI 10.1007/s12035-015-9251-x
Platelet-Rich Plasma Promotes Axon Regeneration,
Wound Healing, and Pain Reduction: Fact or Fiction
Damien P. Kuffler 1
Received: 27 May 2015
# Springer Science+Business Media New York 2015
Abstract Platelet-rich plasma (PRP) has been tested in vitro,
in animal models, and clinically for its efficacy in enhancing
the rate of wound healing, reducing pain associated with inju-
ries, and promoting axon regeneration. Although extensive
data indicate that PRP-released factors induce these effects,
the claims are often weakened because many studies were
not rigorous or controlled, the data were limited, and other
studies yielded contrary results. Critical to assessing whether
PRP is effective are the large number of variables in these
studies, including the method of PRP preparation, which in-
fluences the composition of PRP; type of application; type of
wounds; target tissues; and diverse animal models and clinical
studies. All these variables raise the question of whether one
can anticipate consistent influences and raise the possibility
that most of the results are correct under the circumstances
where PRP was tested. This review examines evidence on
the potential influences of PRP and whether PRP-released
factors could induce the reported influences and concludes
that the preponderance of evidence suggests that PRP has
the capacity to induce all the claimed influences, although this
position cannot be definitively argued. Well-defined and rig-
orously controlled studies of the potential influences of PRP
are required in which PRP is isolated and applied using con-
sistent techniques, protocols, and models. Finally, it is con-
cluded that, because of the purported benefits of PRP admin-
istration and the lack of adverse events, further animal and
clinical studies should be performed to explore the potential
influences of PRP.
* Damien P. Kuffler
dkuffler@hotmail.com
1
Institute of Neurobiology, University of Puerto Rico, Medical
Sciences Campus, 201 Blvd. Del Valle, San Juan 00901, Puerto Rico
Keywords Platelet-rich plasma . Wounds . Healing .
Neurotrophic factors
General Introduction
There are extensive published studies examining the potential
influences of platelet-rich plasma (PRP) on the rate and extent
of wound healing and pain levels. An EndNote search of
PubMed for PRP and wound healing listed more than 600
publications involving in vitro and in vivo, animal model
and clinical studies and case reports. The publications were
controlled and uncontrolled, claiming that PRP did or did not
promote faster and more complete healing of tendons, chronic
wounds, epithelial lesions, ligamentous injuries, cartilage in-
juries, injured muscle, and bone; reduces pain; and promotes
axon regeneration. The positive results were attributed to
platelet and mesenchymal cell-released factors and plasma-
borne factors. Among the published literature reviews, some
involved comparative studies of much of the published data,
while others analyzed data selected from studies based on
whether the studies were considered rigorous, randomized,
well controlled, or of a sufficient sample size. Although these
studies were comprehensive, their results were often conflict-
ing, claiming that PRP induces significant influences, may
induce some improvements, or induced no improvements.
Similarly, there was no consistency in the outcomes of studies
for the influence of PRP on orthopedic bone and soft tissue
injuries although the evidence suggested a small trend favor-
ing the effectiveness of PRP [1–5]. However, in another set of
experiments, it was found that PRP had significant beneficial
effects on improving the rate of wound healing and fat graft
survival rates and in enhancing bone graft regeneration [6, 7].
The application of PRP with Biop-Oss onto bone defects re-
sulted in an increase in granulation, but only when associated

with Bio-Oss [3]. Finally, the influences of PRP on cells
in vitro were examined to see whether its influences are indic-
ative of those required for wound healing in vivo [3].
Introduction
PRP Contents
The complex cocktail of factors that can be harvested from
PRP is referred to as platelet-derived wound healing factors
(PDWHF) [8, 9]. Among these are several isotypes of platelet-
derived growth factors (PDGF), ADP, ATP, calcium, seroto-
nin, platelet factor 4, fibronectin, B-thromboglobulin, von
Willebrand factor (vWF), fibrinogen, coagulation factors V
and XIII, transforming growth factor-beta (TGF-beta), vascu-
lar endothelial growth factor (VEGF), epidermal growth fac-
tor (EGF), basic fibroblast growth factor (β-FGF), fibroblast
growth factor-2 (FGF-2), platelet factor 4 (PF4), ciliary neu-
rotrophic factor (CNTF), insulin-like growth factor-1 (IGF-1),
and platelet-derived angiogenesis factor (PDAF) [9, 10].
Diverse studies have shown that these factors are involved
in many of the steps required for promoting tissue/wound
repair, reducing pain, and promoting axon regeneration.
Although they are clearly involved in these functions, the
question remains as to whether when they are released from
PRP they serve these same functions.
Wounds
Wounds types are generally referred to as soft and hard tissue
damage, with soft tissue damage being of the epithelium, der-
mis, vasculature, muscle, and nerves, while hard tissue is con-
sidered to be bone. Wound healing involves the recruitment of
cells to the wound site that help eliminate detritus, such as
macrophages, mesenchymal stem cells, and other cells that
become integrated into the healing wound, such as fibroblasts,
while other cells, such as platelets and mesenchymal stem
cells, secrete factors that promote the wound healing process.
Wounds are associated with two types of pain, neurologic
and neuropathic. Neurologic is pain caused by damage or
disease, while neuropathic is pain associated with damage-
induced changes in nociceptive neurons, which are not elim-
inated when the wound becomes healed [11].
Wound Healing
Physiological Mechanism of Action of PRP in Wound
Healing The physiological method by which mammals pro-
mote wound healing and axon regeneration following trauma
is for a wound site or peripheral nerve gap to become filled
with a 3-dimensional polymerized fibrin clot containing plas-
ma, which is rich in wound healing factors, platelets, mesen-
chymal stem cells, and fibroblasts. Over the course of days
Mol Neurobiol
following the clot formation, the platelets and mesenchymal
stem cells within a wound release their complex cocktail of
wound healing, neurotrophic and other factors, which has
evolved to promote wound healing and neurological recovery.
Some of these factors recruit the invasion of cells required
to assist in promoting wound repair, while others act local-
ly and directly on cells within the wound site and on axons
and Schwann cells to allow them to actively participate in
the wound healing and axon regeneration-promoting
process.
The functions played by most PRP-released factors in the
cascade of wound healing and axon regeneration-promoting
events have been well elucidated in various papers and re-
views by others. Similarly, many reviews have addressed the
question of whether PRP is effective in inducing wound
healing and have come to the relatively consistent conclusions
that the evidence is mixed and that further studies are required
to make a definitive decision one way or the other. However,
what is still needed is an examination of whether the exoge-
nous application of PRP to wound sites can serve all the
claims of the wound healing functions of PRP. While this
review draws a similar conclusion to others before it, it places
significantly stronger emphasis on the observed positive in-
fluences by stressing that the negative observations most like-
ly result from the preparation of PRP that is not appropriate to
achieve positive results under the tested conditions. This per-
spective is based predominantly on data from in vitro studies
in which the actions of PRP and its released factors are ob-
served to induce cellular and genetic changes that are part of
the fundamental wound healing and axon regeneration-
promoting processes.
Numerous methods are available for separating PRP from
whole blood. However, when considering the potential actions
of PRP, great caution is required because the composition of
PRP can vary greatly due to variables in the preparation pro-
cess [12]. Therefore, when examining the reported influences
of PRP, it is essential to question whether the results differ so
greatly because the PRP is not working or that the PRP is not
working because its composition does not allow it to serve the
functions it has the potential to exert.
Blood extracts have been tested for wound healing since
the beginning of the twentieth century and have been com-
mercially available in Europe since the 1980s. The products
are known interchangeably as fibrin glues and fibrin adhesives
and can be distinguished on the basis of whether they are
industrially manufactured from large plasma pools or prepared
from single donations by blood-bank hospitals or point-of-
care centers. Fibrin sealants contain concentrated fibrinogen
and thrombin as their main active proteins and are usually
formulated in the presence of calcium chloride, which speeds
up fibrin polymerization. Platelet-rich plasma differs due to
the presence of concentrated platelets and mesenchymal stem
cells, which can contribute additional wound healing factors.
Mol Neurobiol
Wound Prevalence and Economics The prevalence rate for
chronic nonhealing wounds in the USA is 2 % of the general
population. The mean cost per wound to heal relative to health
care costs is $3927, with jeopardized skin flaps and grafts
being the most expensive at $9358, with a conservative asso-
ciated cost estimate caring for treating these wounds exceed-
ing $50 billion per year. Despite the fact that the prevalence
rate of chronic wounds is similar to that of heart failure, unlike
heart failure, little is known regarding the outcome of these
patients or the comparative effectiveness of the treatments
they receive.
Current Applications of PR
Blood is a rich source of biomaterials that is used for a variety
of clinical applications. Fibrin-based biomaterials are essential
for their hemostatic and sealing properties and as gels within
which to hold materials, such as bone chips for the promotion
of bone repair, and from which various factors can be released.
Platelets, platelet lysate, and mesenchymal stem cells are
abundant sources of complex cocktails of factors that have
the great potential for inducing both soft and hard tissue re-
pairs, pain reduction, and axon regeneration. PRP is increas-
ingly being used for a variety of clinical applications including
orthopedic surgery, maxillofacial surgery, plastic surgery,
healing related to sports medicine, reducing pain associated
with sports injuries, recalcitrant wounds (ulcers), burns, peri-
odontal and oral surgery, stimulation of bony tissue regenera-
tion in dentistry, and for promoting regeneration of peripheral
nerves following nerve trauma. Once PRP is placed in a
wound site, the platelets and mesenchymal stem cells release
their contents over a period of several days allowing them to
act precisely where they are required [13].
The Use of PRP
Following trauma, activated platelets, mesenchymal cells, and
fibrin fill the wound injury site, and through a cascade of
events, the fibrin polymerizes forming a platelet plug within
the wound site. In addition to its important role in hemostasis,
platelets contain a host of growth factors and biologically
active substances that enhance tissue repair mechanisms, by
means of chemotaxis, inducing cell proliferation, angiogene-
sis, tissue remodeling, and extracellular matrix and collagen
deposition.
Because of its physiological role in wound healing, it has
become increasingly popular to apply autologous PRP as part
of routine treatment, especially in sports medicine for sprains
and tendon injuries. In spite of mixed evidence about its effi-
cacy, the annual estimated use of PRP in the USA alone will
rise to $126 million by 2016. Because of the uncertainty about
the effectiveness of PRP in promoting wound healing and
reducing pain, and the high cost of its application, it is
essential to examine the data related to the outcomes of its
use to determine whether the claims are correct.
This review examines the published literature and dis-
cusses the evidence showing that PRP does or does not im-
prove tissue healing, first in animal models and then clinically.
Each section is followed by an examination of evidence from
in vitro studies asking whether or not PRP induced changes in
cells that are physiologically related to the phenomena of
wound healing, followed by a discussion of various methods
by which the influences of PRP can be enhanced. The prepon-
derance of evidence suggests that PRP induces wound healing
in many tissues and models. However, it is still not possible a
priori to know which data are correct, and therefore, we will
only know what PRP is capable of doing once further studies
are performed with irrefutable data.
Primary Applications/Uses of PRP
Musculoskeletal Healing
Animal: No Improvement
Several studies have shown that the application of PRP to
injured tendons of rats does not induce healing [14]. In another
study, filling conduits bridging nerve gaps induced equal axon
regeneration to fibrin glue, but not more regeneration than a
length of autologous sensory nerve [15].
Animal: Improvement
The poor vascularity of tendons is a major factor in their
limited healing capacity. Following induced tendon injury in
rabbits, the application of PRP results in improved alignment
of new collagen fibers, as well as an improved and increased
rate of tendon healing and strength, apparently due to the
induction of enhanced neovascularization [16, 17] and in part
via the increased expression of IGF-1 [18].
The application of PRP to injured sheep tendon results in
complete healing of the tendon gap without apparent fibrosis
or increase in tendon thickness [19] and results in healing of
chondral cartilage fractures in sheep [20], healing of superfi-
cial digital flexor tendon lesions in horses [21], and healing of
cartilage holes in horse hooves [22] and ligaments in pigs [2].
Working with a rabbit model, a novel compact platelet-rich
fibrin scaffold (CPFS) produced only from blood and calcium
gluconate increased the extent and speed of resectioned patel-
lar tendon healing, indicated by increased load failure and
stiffness [23]. Another important finding is that multiple
PRP treatments result in better tendon healing than a single
treatment [21].
Injecting PRP into mouse cardiac muscle following perma-
nent myocardial ischemia or 45 min of ligation-ischemia/

ischemia-reperfusion ischemia results in a 38 and 28 % greater
ventricular muscle function relative to sham-treated muscle
ventricular function, respectively [24]. For surgically injured
longissimus dorsi muscle in rats, the application of PRP im-
proves muscular regeneration, increases neovascularization,
causes a slight reduction of fibrosis compared to control mus-
cles, and results in long-term enhanced muscle vascularization
[25] and in the development of less muscle scar tissue than is
seen in control muscles [24, 25].
The recovery of full muscle contraction force by muscles
injured by a single in vivo rapid lengthening contraction is
faster if the muscle is injected with PRP [26]. Finally, the
application of PRP improves overall skeletal muscle healing
after muscle contusion injury [27].
The external application of PRP to the site at which the
nerve stumps of a transected nerve are anastomosed enhances
the degree of axon regeneration and neurological recovery
across a 1-cm-long nerve gap compared to the influence of
nerve stumps sutured together [28, 29]. In rats, combining
PRP with dissociated Schwann cells within a conduit induced
enhanced axon regeneration, but not greater than sensory
nerve grafts [30].
Clinical: No Improvement
Several large randomized control studies found that the clini-
cal application of PRP induces no improvement in healing of
the anterior cruciate ligament (ACL) reconstruction with
bone-patellar tendon-bone allograft [31], rotator cuff [32],
and hamstring tendons [33]. The injection of PRP was also
not found to induce any improvement in patients with lateral
epicondylitis, a common musculoskeletal disorder for which
an effective treatment strategy remains unknown [34].
However, the authors of this study raised concerns about
whether the lack of influence may have resulted from the
method used to prepare the PRP [32].
Clinical: Improvement
A relatively large number of clinical studies show that for
patients with patellar and elbow tendinosis, Achilles tendon
injuries, rotator cuff repairs, and ACL tears, PRP induces a
twofold increase in the elimination of the tendon defects, a
twofold reduction in the time required to achieve complete
homogeneous recovery, lower tendon retear rates, and a re-
duction in pain, even for patients whose tendinopathy was
resistant to other therapies [35–42].
Increasing the Influence of PRP
Animal Models Although PRP has been shown to increase
tendon tensile strength, in rabbits, its influence can be in-
creased by 67 % when it is combined with adipose-derived
Mol Neurobiol
stem cells [43]. Clinically, PRP combined with autologous
bone graft improves tendon healing while simultaneously re-
ducing pain due to sternal dehiscence after coronary artery
bypass grafting surgery [44]. Combining PRP with FGF or
VEGF, a potent mitogen and stimulator of vascular growth
[45], and in the presence of a lowered concentration of TGF-
beta1, 2, or 3, but increased levels of type 1 collagen, results in
improved tendon healing [46].
In Vitro Platelet-rich plasma stimulates cell proliferation, en-
hances matrix gene expression [11], and increases total colla-
gen synthesis seen at 7 and 14 days and glycosaminoglycan
(GAG) synthesis at day 14 [47]. The addition of thrombin to
PRP also increases its influences [48].
Muscle recovery following trauma requires the regenera-
tion of muscles from existing myoblasts. Muscle healing can
be significantly enhanced by supplementing muscle with
muscle-derived progenitor cells (hMDPCs). However, it is
first critical to expand these cells in vitro to have a sufficient
number to induce good muscle recovery. Extensive expansion
of hMDPCs can be achieved by the addition of PRP to cul-
tured hMDPCs [49]. Antibody neutralization of PDGF in such
cultures significantly blocks the mitogenic/proliferative ef-
fects of PRP on the hMDPCs indicating that platelet-
released PDGF is in great part responsible for inducing the
cell proliferation [49].
Although evidence from in vivo studies is not consistent in
finding that PRP induces tissue healing, the data from in vitro
studies indicate that platelet-released factors clearly and con-
sistently, in a dose-dependent manner, stimulate the increase
in the rate of differentiation of tendon stem cells into activated
tenocytes and the proliferation of osteocytes, myocytes, and
tenocytes. Since PRP also increases the rate of collagen pro-
duction, all combined, these findings indicate that PRP in-
duces the cellular activities associated with tendon healing
[50].
Mechanisms of PRP Action on Tendon Healing
Tendon healing induced by PRP has been proposed to result
from the actions of PRP- and platelet membrane-released
TGF-beta1 [51]. The application of mesenchymal stem cells
to tendons, which differentiate into tenocytes and endothelial
cells, promotes tendon healing [43]. Normally PRP contains
mesenchymal stem cells. Therefore, the cases where PRP is
not effective in inducing tendon healing may result from the
separated PRP not containing a sufficient concentration of
mesenchymal stem cells. PRP may also lead to tendon healing
by inducing the overexpression of IGF-1 activity predomi-
nantly in tenocytes [52] and by its up- and then downregulat-
ing the expression of TGF-beta1 [53].
PRP induces changes in gene expression of type I, II, and
III collagen and the expressions of decorin and scleraxis,
Mol Neurobiol
which are necessary for GAG synthesis and required by
tenocytes for their synthesis of the tendon matrix [47, 54].
PRP also induces a significant increase in cellular metabolic
activity, reduces the rate of apoptosis, and stimulates collagen
production [55], all of which are normally associated with
tendon healing. Since poor tendon vascularization is consid-
ered a significant factor for tendon’s limited healing potential,
the tendon healing caused by PRP may be due to PRP induc-
ing tendon vascularization by the release of VEGF, by
follistatin expression, and by reducing the expression of phos-
phorylated Smad2/3 [27].
Bone Healing
Animals: No Improvement
In dogs, the application of PRP applied to surgically created
mandibular bone wound sites induces no statistically signifi-
cant histological wound improvements [56]. Similarly, al-
though histomorphologically bone deficits show a remarkable
increase in new bone following a double PRP application vs. a
single application in rabbits, statistical analyses reveal no sig-
nificant difference [57]. In similar studies on rabbit bone
healing, PRP was not observed to induce an increase in the
overall observed rate or extent of healing [58, 59]. In another
study, PRP was observed to hinder bone deposition while
enhancing the type III to type I collagen ratio and enhancing
the chemotaxis of CD34+ progenitor cells, similar to a
thrombogenic effect [60].
Animal: Improvement
In a rabbit model of an implant-associated spinal wound, PRP
treatment results in a significant increase in mineralized tis-
sues and better bone healing by postoperative weeks 2 and 3
[61]. In dogs, the application of PRP to class II furcation
defects results in the enhancement in the amount of new ce-
mentum and induces more and faster bone mineralization [62,
63]. In mini-pigs, PRP significantly increases new bone for-
mation within bone defects compared to bone treated with
autologous cancellous graft alone [5, 64, 65]. For rabbits,
the application of PRP into a bone defect induces a greater
amount of bone consolidation, cortical bone thickness, and
bone density than is induced by bone aspirate [66], while
degradable bioactive borate glass plus PRP induces more ex-
tensive bone growth than the glass alone [67]. The application
of PRP to surgically injured sheep sternum induces the forma-
tion of trabecular bone tissue and the formation of hematopoi-
etic medullary tissue, while controls show only extensive car-
tilaginous tissue [68]. The application of PRP to induced
mouse bone injury sites induces angiogenesis and the correct
functioning of osteoblasts, increases the amount of mobilized
cells for the repairing process, speeds up bone growth, and
increases the deposition of bone matrix deposition relative to
control animals [69]. PRP together with xenogenic bone min-
eral was beneficial in the treatment of intrabony defects [70].
Combining platelet-rich fibrin with PRP increases the influ-
ence of PRP alone [71]. PRP combined with fat grafts leads to
improved healing and fat maintenance [72]. The first step in
bone healing is forming a blood clot at injured bones and the
placement of a PRP clot within a dental defect can induce
bone healing. However, the extent of healing depends on the
composition of the PRP [73, 74]. Combining PRP with Bio-
Oss(R) particles enhances the rate of bone healing [75]. The
application of platelet-rich fibrin (PRF) to a bone injury may
increase the number of marrow cells. However, PRF together
with xenogenic bone substitutes does not significantly im-
prove bony regeneration [76]. The use of PRP for embedded
bone marrow stromal cells (BMSCs) prior to placing the mix-
ture on full-thickness bone defects in rabbits leads to enhanced
bone healing compared to that seen for the bone chips alone
[77]. It is not clear whether this is due to the direct action of
PRP-released factors or the better maintenance of the bone
chips where they were required to act. Thus, there is increas-
ing use of PRP, but predominantly together with other mate-
rials to induce bone healing [65, 78–80]. PRP has been tested
for its influence on intrabony defects when combined with
other regenerative procedures such as open flap debridement
(OFD) and with a covering membrane for guided tissue re-
generation (GTR). However, there is limited evidence regard-
ing their influences [81].
Clinical: No Improvement
In a two randomized, but small, controlled, parallel group
clinical trial, PRP did not induce a statistically significant in-
crease in pelvic crest bone growth [82, 83].
Clinical: Improvement
PRP has been extensively applied following surgery on a jaw
related to dental implants and found to induce significantly
increased bone regeneration providing periodontal support
for dental implants [39, 84–87]. Similarly, following surgery
requiring bone resection, the application of PRP leads to 80 %
of patients showing complete wound healing [88, 89], often
with greater than 70 % increases in bone formation compared
to bone wounds treated with a blood clot [90]. Although PRP
applied to tooth extraction sockets induces an increase in the
rate of alveolar bone regeneration [91, 92], the differences
disappeared over time postapplication [93, 94]. For patients
with maxillary atrophy, the addition of PRP to the grafting
material Bio-Oss significantly reduces the time required to
achieve bone healing compared to that induced by Bio-Oss
alone [95]. Part of this influence is on bone regeneration [96],
the induction of osteoblast proliferation, and its antimicrobial

effects [88] (see more in a later section). PRP also shortens the
suffering of postoperative pain by up to 3 days [97].
In Vitro
PRP induces higher assay values for osteopontin, osteocalcin,
and mineralization than are seen in control cultures of human
adipose stem cells, which means that PRP stimulates osteo-
blastic differentiation of hADSCs at their early and final mat-
uration stage [98]. In vitro, PRP promotes osteogenic differ-
entiation of muscle satellite cells [99] and adipose-derived
stem cells [100].
Increasing the Influence of PRP
The influence of applied PRP in inducing bone growth is
significantly enhanced when it is combined with
hyaluronic acid (HA) dressing [101], and hydroxyapatite,
a crystalline phase of calcium phosphate found naturally
in bone minerals, coral, and osteoconductive material
[102]. Combining the application to PRP with mesenchy-
mal stem cells increases rabbit bone formation and min-
eralization and improves bone mechanical properties and
rabbit mandibular gap healing by 20–34 % while reduc-
ing healing time by 6 days (20–35 %) [103]. Similarly,
PRP enriched with leukocytes increases the rate and ex-
tent of wound healing [104].
Mechanisms of Action
Bone healing involves a number of different components,
such as the stimulation of DNA replication, proliferation
of mesenchymal stem cells, and chemotaxis of osteo-
blasts, fibroblasts, leukocytes, monocytes, neutrophils,
a n d pe r i o do n t a l a n d al v e o l a r b o ne c e l l s [ 1 0 5 ] .
Clinically, PDGF in combination with other growth fac-
tors enhances periodontal tissue repair [105]. Since plate-
lets within PRP release PDGF and growth factors, it is
reasonable to expect that the application of PRP should
induce bone healing. Similarly, since in vitro PRP in-
duces a considerable proliferation of osteoblasts, which
are required for bone healing, in vivo PRP should induce
bone healing [25]. In rabbits, the application of PRP
promotes bone repair by interacting with type III colla-
gen to maintain high levels of collagen, which is required
for bone healing. TGF-β1 is also crucial in bone forma-
tion by stimulating osteoblast deposition on the collagen
matrix of bone, enhancing the chemotaxis and
mitogenesis functions of osteoblast precursors [99,
106]. TGF-β1 also plays a role in upregulating the syn-
thesis of VEGF, thereby favoring angiogenesis and re-
cruitment of inflammatory cells [107].
Mol Neurobiol
Corneal Epithelial Healing
Animal: No Improvement
No data has been reported here.
Animal: Improvement
In a well-controlled study on rabbits, following creation of an
epithelial defect, the injection of PRP under the conjunctiva
improves the rate and extent of corneal epithelial wound
healing [108]. PRP is also useful for attaching corneal flaps
in rabbits while promoting good corneal healing [109].
Clinical: No Improvement
No data has been reported here.
Clinical: Improvement
For years, plasma drops containing a host of growth factors
have been used clinically to promote healing of a variety of
persistent ophthalmic epithelial wounds and ocular surface
diseases and to reduce pain due to corneal injury [110].
However, more recently, PRP lysate, with its greater content
of growth factors, is being increasingly used [111].
PRP is also effective in treating persistent corneal epithelial
defect [112], when applied to the cornea postherpetic corneal
ulcers and ulcers due to trauma or exposure to caustic sub-
stances, and completely restores the lost epithelium [113]. A
similar influence is observed for PRP administered by
subconjunctival infiltration [114].
The application of PRP lysate eye drops to patients suffer-
ing from persistent epithelial defects (PEDs) induces signifi-
cantly higher healing rates of the corneal epithelia than treat-
ments with autologous serum, which contains fewer platelet-
released growth factors, most notably EGF [112]. Similarly,
topical application of autologous PRP to the eyes following
grade V chemical injury promotes rapid reepithelialization of
the ocular surface [115].
The application of PRP lysate combined with a
mucoadhesive gel to promote adhesion of factors within the
lysate to corneal ulcers further enhances cell growth leading to
corneal healing and induces a twofold reduction in the time
required to achieve complete epithelialization and visual acu-
ity compared with control patients [116–119]. In addition,
PRP lysate is a highly effective therapeutic agent for the treat-
ment of a broad etiopathological spectrum of corneal persis-
tent epithelial defects [119]. The subconjunctival application
of PRP to the eyes of patients who had ocular chemical burns
showed a significant reduction in corneal and conjunctival
epithelialization times, sick leave duration, and healing time
and a significant reduction in time of scarring [114].
Mol Neurobiol
Corneal lesions cause significant pain and visual impair-
ment, and in many cases, they are unresponsive to conven-
tional treatments. In addition to inducing corneal healing, the
application of PRP reduces corneal pain [120].
In Vitro
In vitro, the application of human PRP to human corneal ep-
ithelial cells induces a significant increase in their proliferation
and, in animals, a reduction in epithelial hyperplasia and haze
formation on the cornea [121], with rate of proliferation and
other influences increasing with the concentrations of PRP
factors [122]. PRP lysate added to cultured rabbit corneal
epithelial cells or fibroblasts induced significantly enhances
the proliferative activity of epithelial cells [123]. When com-
bined with chitosan to increase mucoadhesion, the efficacy of
the formulation was stable in spite of storage up to 2 weeks
[123]. The effect induced by the platelet lysate plus chitosan
formulation is faster than PRP combined with a polyacrylic
acid formulation, yet complete in vitro wound repair was
achieved within 48 h [123].
Mechanisms of Action
The influences of PRP in promoting healing of persistent cor-
neal epithelial defects are primarily attributed to the actions of
platelet-released TGF-beta2, which is required for normal col-
lagen homeostasis [112], including VEGF [122, 124] and fi-
bronectin [125]. These factors contribute to inducing a steady
invasion of fibroblasts, quicker epithelial regeneration, and
less inflammation. They also induce more rapid proliferation
and migration of keratocytes and conjunctival fibroblasts,
which are required for corneal healing [116, 126]. These fac-
tors prevent and inhibit TGF-beta1-induced myofibroblast dif-
ferentiation [108], thus reducing scarring and stimulating cor-
nea surface wound healing [126]. Thus, PRP can both reduce
scarring and stimulate ocular surface wound healing.
Wound Healing
Animal: No Improvement
For nude mice, PRP combined with fat grafts does not en-
hance free fat graft survival [127]. For cutaneous lesions on
New Zealand white rabbits, treatment of wounds with PRP or
mesenchymal stem cells (MSCs) induced equal
reepithelialization of cutaneous lesions, and the healing was
not enhanced when the two were combined [128].
Animal: Improvement
For mice, PRP induces improved skin flap retention, in part by
inducing improved angiogenesis and healing of the flap check
[129]. For rats, the application of PRP induces 61 % of the
flaps to survive vs. 36 % for those treated with platelet-poor
plasma and 28 % of controls [130, 131], and the results are
similar for rabbits [132]. For horses, PRP induces more rapid
epithelial differentiation and increased collagen presence, and
the dense collagen bundles are oriented parallel to each other
and to the overlying epithelium, contrary to what is seen for
control tissue, all of which is required for wound healing [133,
134]. The application of PRP under a skin flap in rats leads to
reducing the area of necrotic tissue and increasing the number
of arterioles within the skin flaps [135] and improved flap
adhesion [135, 136], and PRP application 2 days prior to flap
elevation further improves flap survival [130]. Thrombin ap-
plied alone increases flap necrosis [135]. PRP also induces a
significant increase in the amount of the free fat grafts surviv-
ing in rabbits, with little desorption taking place for at least
120 days, causing an increase in the number of viable adipo-
cytes, increasing the number of blood vessels, increasing tis-
sue granulation, while decreasing the size of necrotic tissue
areas and fibrosis [137]. PRP also induces a faster rate of
wound healing in an animal model of diabetic wounds
[138], and the application of PRP causes the grafts to become
and remain pink, soft, supple, and easily compressible, all
signs of tissue healing [139]. The application of PRP to cuta-
neous lesions of diabetic mice induces greater wound
reepithelialization than standard wound care [128]. Finally,
the application of PRP accelerates the onset of airway healing
while increasing blood flow and anastomosis stress-strain re-
sistance 30 days postsurgery by promoting an earlier release
of platelet-derived growth factors that stimulate
transanastomotic angiogenesis [140].
Clinical: No Improvement
Complicated diabetic patients show impaired and delayed
wound healing, and their wounds do not respond to PRP with
healing. In diabetic wounds, the expression of matrix metal-
loproteinase (MMP)-2 and MMP-9, which play important
roles in extracellular matrix regulation and wound healing, is
present in higher concentrations when PRP is applied to the
wounds than in its absence [138]. Thus, it appears that PRP
regulation of MMP concentration within the wound site may
underlie the failure of PRP to promote diabetic wound healing
[138].
Clinical: Improvement
The application of PRP to fresh nondiabetic wounds following
finger tissue loss prevents continued tissue loss and leads to
wound healing [141]. The application of PRP both under and
on top of skin grafts applied to skin ulcers results in the sta-
bility of the grafts at the wound, thus not requiring the use of
staples or sutures, and leads to ulcer healing without their

recurrence [142]. PRP applied to necrotic bone induces bone
angiogenesis, which in turn promotes new bone formation
[143]. For patients who underwent amputation surgery
followed by the application of PRP to the wound site, 96 %
of the wounds healed completely and had no postoperative
wound infections, while for control patients, the healing rate
was of 59 %, which was accompanied by severe infection of
the stump, which prompted follow-up proximal amputations
in 41 % of the patients [144].
PRP can be used to assist in the anastomosis of different
portions of separated tissues. When PRP is applied to the site
of pig tracheal anastomosis sites, the PRP accelerates the onset
of airway healing while resulting in increased blood flow and
increased anastomosis stress-strain resistance 30 days
postsurgery by promoting an earlier release of platelet-
derived growth factors that stimulate transanastomotic angio-
genesis [140].
In Vitro
In vitro, PRP increased the activity of human fibroblasts, mac-
rophages, and endothelial cells, which may in part explain
how PRP induces dermal regeneration and wound healing
[145].
Increasing the Influence of PRP
The beneficial influences of the application of PRP to wounds
can be improved. Thus, multiple PRP applications to recalci-
trant diabetic, pressure, or venous ulcer, dehisced, surgical, or
traumatic wounds, and wounds of other etiologies result in
wound healing of approximately 90 % of wounds. They also
result in ca. 50 % reduction in wound area and a 64 % reduc-
tion in wound volume [146]. In another study, multiple PRP
applications to chronic nonhealing wounds result in 97 % of
the wounds showing a 51 % reduction in wound volume and a
40 % decrease in wound area, despite most of the patients
being in depressed physiological conditions, indicated by their
having low albumin, hematocrit, and/or hemoglobin levels,
conditions which normally significantly slow wound healing
[147]. Although the addition of PRP to cultured human fibro-
blasts, macrophages, and endothelial cells induces the activity
of all these cells, their activity is increased when PRP is added
to the culture medium simultaneously with manuka honey
[145].
Mechanism of Action
PRP enhances greater skin flap retention and healing by in-
ducing angiogenesis by its release of VEGF [129] and by
inducing the increased expression of messenger RNA
(mRNA) for VEGF, PDGF, and TGF-beta3 and increased
neovascularization and reepithelialization of the flaps [131,
Mol Neurobiol
135]. In similar studies on rats, PRP also induces skin flap
retention by inducing a significant reduction in inflammatory
cells, which is far greater than when platelet-poor plasma is
applied or when the flaps are not treated [131]. Clinically, PRP
improves wound healing by causing the retention of fat grafts
and by promoting enhanced reepithelialization [148].
PRP also induces tissue healing by releasing EGF, which
acts as a potent mitogen for keratinocytes and endothelial
cells, accelerating their migration into acute wounds, thus re-
storing and triggering epithelialization [149]. This is nicely
demonstrated by experiments in which, although PRP pro-
motes endothelial cell proliferation, once EGF has been re-
moved from PRP supernatant using antibodies, endothelial
cell proliferation ceases [149].
TGF-β is a potent regulator of extracellular matrix (ECM)
synthesis, enhances gene expression of fibronectin and colla-
gen, inhibits collagen breakdown, and inhibits various MMP
inhibitors. This leads to ECM reinforcement, fibroblast prolif-
eration, and the synthesis and accumulation of collagen, all of
which are essential for wound healing, as well as for fibril and
scar formation [150]. PRP also promotes wound healing by
increasing the amount of collagen matrix formation,
keratinocyte and dermal fibroblast, and macrophage prolifer-
ation and migration; by enhancing the expression of alpha-
smooth muscle actin protein and differentiation of dermal fi-
broblasts into myofibroblasts; and by promoting wound con-
traction [138, 145, 151]. Thus, through these mechanisms,
PRP can induce dermal regeneration and wound healing
[145]. The influence of PRP on cell activity is enhanced when
it is combined with manuka honey [145].
Antimicrobial Activity of PRP
Clinical bacterial infections play a major role in retarding or
preventing wound healing. Reducing and eliminating infec-
tions by systemic or local antibiotic administration leads to an
increase in the rate of onset and completion of the wound
healing process. PRP also has the potential of serving as an
antimicrobial agent.
Animal: No Improvement
No data has been reported here.
Animal: Improvement
For horses, the application of PRP exerts an antimicrobial
effect on infected cutaneous burn sites, while non-PRP treated
burns become infected [152]. For rabbits, the immediate ap-
plication of PRP to the site of an intentional spinal bone in-
fection results in reduced infections and better postoperative
bone healing [61], and PRP application significantly reduces
spinal bone infections when PRP is applied up to 3 weeks
Mol Neurobiol
following trauma-induced bacterial infection [61].
Simultaneously, the PRP induces a significant increase in min-
eralized tissue, leading to better bone healing by postoperative
weeks 2 and 3 [61]. However, the antimicrobial activity of
PRP is only to certain bacterial populations [61]. Therefore,
prior to applying PRP, it is advantageous to determine whether
the infection in a wound site is one against which PRP is
effective.
Clinical: No Improvement
In an in vivo study, the application of PRP to the surgical
wound sites following vein harvesting surgery for cardiac by-
pass surgery had no influence on infection rates compared to
control patients [153].
Clinical: Improvement
Clinically, PRP exerts an antimicrobial influence and inhibits
the growth of a large number of different bacteria, but not
others [154]. Following transmetatarsal amputation, PRP ap-
plication results in a significant reduction in bacterial colonies
and a significant reduction in infection rates [144].
In Vitro
The types of bacteria killed by PRP differ slightly between
different studies [155–157], and this antimicrobial activity is
influenced by how the fibrin sealant is prepared.
Cryoprecipitate-derived fibrin sealant inhibits the growth of
Escherichia coli but not Staphylococcus aureus or Bacillus
fragilis, whereas a pasteurized commercial fibrin sealant has
no effect [158]. The antimicrobial properties of PRP depend
on the concentration of thrombin [61] as well as how thrombin
is prepared [159]. However, the antimicrobial action of PRP
also involves human beta defensin-3 (HBD-3), which is re-
leased in bactericidal concentrations [156, 160], or to a func-
tionally active complement [161]. Platelet lysates also act with
synergistic effects with beta-lactam antibiotic (oxacillin) and
glycopeptide (vancomycin) but not with oxazolidinone
(linezolid) [162].
Pain Reduction
Animal: No Improvement
No data has been reported here.
Animal: Improvement
Following sciatic nerve sections, rats may be observed to self-
mutilate, eating their toes and foot, a behavior called autoto-
my. Moderate to severe autotomy is observed in 88 % of
animals with a transected sciatic nerve, while for animals
which had the end of the severed nerve inserted into an empty
collagen tube, autotomy was manifest in only 13 % of the
animals [163]. Autotomy is now interpreted as an indication
of the animal suffering pain [164, 165]. The reduction in neu-
ropathic pain has been attributed to a significant enhancement
in Schwann cell migration away from the proximal stump and
linear axon regeneration within the collagen nerve guide,
resulting in the absence of neuromas and other symptoms
associated with neuropathic pain [163].
Clinical: No Improvement
PRP application to surgical sites following toenail surgery
produces a slight increase in the acute inflammatory phase
of dermal wound healing, but no statistically significant re-
duction in recovery times or postoperative pain [166].
Injection of PRP to the site of lateral epicondylitis (LE) caus-
ing pain had no influence on the pain [167].
Clinically, the injection of PRP for the treatment of rotator
cuff tendinopathy was not found to induce any reduction in
pain by 1-year postsurgery [168]. PRP stimulates endogenous
HA production and decreased cartilage catabolism and shows
similar effects to HA in suppressing the inflammatory media-
tor concentration and expression of their genes in
synoviocytes and cartilage [169].
Clinical: Improvement
Following total knee arthroplasty, PRP application significant-
ly reduces postoperative pain while enhancing the short-term
clinical outcome [170]. For patients whose epicondylitis was
unresponsive to nonsurgical treatment (including steroid in-
jection) for >6 months, a single injection of PRP injection
significantly reduced their pain as well as elbow function,
which allowed the avoidance of surgery [171].
Although the injection of PRP following surgery for in-
grown hallux toenails does not statistical decrease in wound
recovery time, it does reduce postoperative pain [172, 173].
The injection of PRP to the site of chronic, recalcitrant
tendinosis (chronic lateral elbow epicondylitis) (tennis elbow)
[174, 175] and following shoulder arthroplasty [97] and the
application of PRP induce a significant reduction in pain com-
pared to the application of whole blood or corticosteroid in-
jection, even after a 2-year follow-up [176] while also induc-
ing healing [176]. PRP injections reduce pain associated with
osteoarthritis [177]. For patients suffering from pain associ-
ated with rotator cuff injury, PRP injections lead to a pro-
gressive reduction in pain and disability compared to dry
needling [178]. The application of PRP to the refreshed
end of peripheral nerves evoking neuropathic pain, includ-
ing excruciating pain, results in the reduction/elimination
of that pain [11, 179–181].

Increasing the Influence of PRP
In Vitro
No data has been reported here.
Mechanisms of Action
Platelets and neutrophils play important roles in the elim-
ination of neuropathic pain. Platelet-released IL-17 signif-
icantly increases the numbers of neutrophils that infiltrate
a wound site which leads to enhanced inflammation that
pushes the inflammatory response to complete resolution
[182]. This allows the wound healing process to precede
to completion, leading to the reestablishment of normal
nociceptive axon biophysical properties and the elimina-
tion of their hyperexcitability and, thus, neuropathic pain.
The importance of platelet-released IL-17 has been dem-
onstrated in mice with genetic impairment of IL-17 sig-
naling, in which neuropathic pain behavior is reduced as
well as ectopic neuronal activity [183]. Neuropathic pain
can also be reduced by antibody depletion of neutrophils,
although their elimination has no effect on the recovery of
neurological function and peripheral axon regeneration
[184]. Therefore, enhanced platelet infiltration, the admin-
istration of IL-17, and neutrophil elimination can lead to
the reduction of neuropathic pain.
Factors from Platelet-Rich Plasma
PRP is being increasingly injected into joints to promote
healing and reduce the pain associated with osteoarthritis
[177, 185, 186]) and by sports medicine clinicians to pro-
mote tendon, ligament, connective tissue, and other soft
tissue healing, to reduce neuropathic pain [171, 174, 177,
186–193] and to promote axon regeneration [194]. PRP
has also been applied to reduce neuropathic pain in case
where neuropathic pain is caused by arthroplasty and
transgluteal decompression of the pudendal nerve [195]
and to the surgical site following tonsillectomy [196].
However, despite the claims, a rigorous block-randomized,
double-blind clinical study found that PRP injections were
no more effective in reducing pain or improving activity
than placebo saline shots for the patients [190]. Another
paper recommends that, due to the lack of good evidence to
support the use of PRP, serious consideration should be
considered before PRP is used [197]. However, the conclu-
sion of that review may be questioned, because although it
may be true that platelet-released factors do not Bdirectly^
reduce pain, platelets may directly trigger the events that
lead to the elimination of neuropathic pain (this issue is
further discussed in a later section of this paper).
Mol Neurobiol
Angiogenesis
Animal: No Improvement
In rabbits, PRP was not found to promote new bone formation
or vascularization in vertebral spine fusion [198].
Animal: Improvement
Angiogenesis plays key roles in normal development, wound
healing, recovery from ischemic disease, and organ regenera-
tion, and appropriate physiological combinations and ratios of
various angiogenic factors are critical for long-term functional
blood vessel formation. Soluble mouse PRP extract, which
includes abundant angiopoetin-1 (Ang1) and other angiogenic
factors, stimulates endothelial cell growth, migration, and dif-
ferentiation in neonatal mouse retinal angiogenesis in vivo
[199]. In rabbits, PRP induces extensive angiogenesis during
the early phase of Achilles tendon healing [16]. Inhibition of
Ang1-Tie2 signaling suppresses PRP extract-induced angio-
genesis in vitro and angiogenic ability of the PRF matrix
in vivo [199].
The application of PRP prior to skin flap placement induces
a twofold increase in flap adhesion and survival vs. rats not
treated with PPP. This effect is due to PRP significantly re-
ducing the invasion of inflammatory cells and increasing
blood vessel density [131]. In addition, PRP treatment signif-
icantly increases the mRNA levels of VEGF and PDGF,
which are associated with increased angiogenesis [131, 200].
Following hind limb ischemia in mice, the application of
PRP induces enhanced blood perfusion, apparently by induc-
ing angiogenesis [201].
Contrary to the negative results of one study on rabbits
[198], PRP can induce angiogenesis and bone formation
[202, 203]. PRP induces angiogenesis both in vitro and
in vivo and may result from the activation of the ERK and
phosphatidylinositol-3-kinase-Akt pathways [10].
Clinical: No Improvement
No data has been reported here.
Clinical: Improvement
Both fresh PRP and freeze-dried PRP applied to a wound
induce wound angiogenesis [10, 199, 204]. Part of the influ-
ence of PRP is by inducing the invasion of inflammatory cells
and fibroblasts and stimulating collagen deposition [205].
This is accompanied by a marked increase in the expression
in the HaCaT keratinocyte cells of the cell cycle regulatory
proteins cyclin A and cyclin-dependent kinase (CDK) 4, and
an associated increase in the rates of cell proliferation, cell
migration, and epithelialization of HaCaT cells [117]. Thus,
Mol Neurobiol
in part, PRP promotes wound healing by significantly
accelerating the epithelialization process, probably
through the upregulation of the cell cycle regulatory
proteins cyclin A and CDK4 and the induction of an-
giogenesis [206].
In Vitro
In vitro, activated human platelets enriched for VEGF result in
significantly greater angiogenesis and osteogenesis around
bone defects and enhance new bone formation around acellu-
lar bone graft material indicating that PRP is critical in the
induction of rapid angiogenesis [207]. Soluble mouse PRP
extract, which includes abundant Ang1 and other angiogenic
factors, stimulates endothelial cell growth, migration, and dif-
ferentiation in cultured human dermal microvascular endothe-
lial cells [199].
Mechanism of Action
Following trauma, platelets are the primary driving force
behind the development of inflammation. Upon entering a
wound and contacting mature collagen, platelets become
activated, aggregate, and release factors that promote va-
sodilation, increased blood flow, and increased capillary
permeability. This increased permeability allows plasma
proteins to move from the blood into the wound site,
causing the initial phase of inflammation. Platelet-
released factors also promote angiogenesis [200, 208],
thus promoting increased blood flow to and oxygenation
of the wound site.
Tissue Augmentation/Transplant
Animal: No Improvement
No data has been reported here.
Animal: Improvement
Infiltrating isolated fat cells with PRP prior to transplantation
of the fat cells improves the survival and quality of fat grafts
than is seen for grafts in the absence of PRP in nude mice
[209], rats [139], and rabbits [137]. In rabbits, PRP results in
reduced inflammatory reactions, fewer oily cysts, and better
fat transplantation than transplants performed without PRP
[210].
Clinical: No Improvement
It has also been reported that the addition of PRP to fat tissue
prior to transplantation has no influence on fat survival [211].
Clinical: Improvement
Infiltrating isolated fat cells with PRP prior to transplantation
of the fat cells results in better fat graft survival than is seen in
the absence of PRP [212–214], as well as reduced inflamma-
tory reactions, fewer oily cysts, and better fat transplantation
than for transplants performed without PRP [210].
Axon Regeneration
Animal: No Improvement
Transected axons generally regenerate only several millime-
ters into an empty collagen tube bridging a nerve gap [28, 215,
216]. Bridging a 1-cm-long rat sciatic nerve gap with a tube
filled with PRP induces axons to regenerate no further than
through an empty nerve tube [28, 215–217].
Animal: Improvement
In similar experiments, PRP induced thicker axon myelination
[215], and in another, it induced thicker myelin, a faster rate of
axon regeneration, and longer axon regeneration [28,
218–221]. Thus, in small animal models, PRP can enhance
axon regeneration across nerve gaps, but the results are
inconsistent.
However, combining PRP within a vein conduit is an ef-
fective alternative adjuvant to autologous nerve grafts, al-
though further investigations are required to fully define the
role of PRP in nerve regeneration [222]. Similarly, combining
PRP with an autologous sensory nerve results in enhanced
axon regeneration across short (i.e., 1 cm long) nerve gaps
[223]. Further, it has been shown that the application of PRP
to a nerve anastomosis site enhances the extent of axon regen-
eration [29].
Clinical: Improvement
Peripheral Nervous System Following a simple peripheral
nerve transection, the central and distal nerve stumps retract
resulting in a nerve gap of about 3 mm in length. As part of the
physiological mechanism of peripheral nerve repair, the nerve
gap becomes filled with a blood clot composed of fibrin, plas-
ma, platelets, and mesenchymal stem cells, which induces the
axons to regenerate across the clot-filled gap and to the distal
nerve [224–226].
When nerve gaps are >3 mm in length, the PRP does not
polymerize within the gap because the PRP flows away before
it polymerizes and no structure forms between the nerve
stumps that can support axon outgrowth and constrain axon
regeneration to the region of the gap, and thus, axons do not
regenerate across the nerve gap. To induce axon regeneration
across nerve gaps >3 mm in length, the nerve gap must be

bridged with a material that both supports and promotes axon
regeneration.
Polymerized pure fibrin within conduit bridging nerve gaps
passively supports axon regeneration across gaps of up to
about 3 mm [29, 222, 227–230]. PRP within acellular nerve
grafts induce axon regeneration that is significantly greater
than through the nerve graft alone, but it is good only for nerve
gaps up to 1.5 cm in length [223]. Creation of a conduit of
PRP around the region of peripheral nerve anastomosis with
sutures induces more axon regeneration than without the PRP
membrane [29].
For fibrin to promote more axons to regenerate longer dis-
tances, the fibrin must bind to and interact with neurotrophic
factors such as nerve growth factor (NGF), brain-derived neu-
rotrophic factor (BDNF), GDNF, NT-3, and PDGF [224,
231–236]. These platelet- and mesenchymal stem cell-
released factors transform pure fibrin from a 3-dimensional
matrix that passively permits axon regeneration to one that
actively promotes axon regeneration [237]. Even if PRP is
applied to the exterior site of a rat sciatic nerve crush, signif-
icantly greater numbers of axons regenerate longer distances
[238]. Similar results are obtained with the application of PRP
to the site of a nerve transection and anastomosis of the guinea
pig facial nerve [221], rat facial nerve [28], rat sciatic nerve
[15, 215, 219, 238], and rat cavernosus nerve [220, 221].
Clinically bridging peripheral nerve gaps with a collagen
tube filled with autologous PRP induces axon regeneration
across nerve gaps up to 16 cm in length, despite nerves being
repaired up to 3.25 years postnerve trauma and in patients up
to 58 years of age [181, 239, 240]. Thus, PRP can induce axon
regeneration under conditions where the clinical Bgold stan-
dard,^ peripheral nerve grafts, is ineffective [181, 240].
However, filling collagen tubes with PRP induces axons to
regenerate across nerve gaps up to 20 cm in length, when
the nerve repair is performed up to 3 years posttrauma and
in a patient up to 58 years of age [241].
The injection of PRP to sites of peripheral neuropathies
associated with leprosy induces nerve regeneration and the
reestablishment of some sensitivity [242].
Central Nervous System PRP induces axon regeneration in-
to the CNS. In organ culture, peripheral axons regenerate into
spinal cord tissue which would not otherwise happen [243].
This influence is in part due to the actions of IGF-1 and VEGF
[243]. Thus, PRP may induce axon regeneration and neuro-
logical recovery following spinal cord trauma, as well as pro-
vide a therapeutic approach for CNS diseases, traumatic brain
injury, and autoimmune diseases and neurodegenerative dis-
orders such as Alzheimer’s disease, Parkinson’s disease, and
amyotrophic lateral sclerosis [244].
In conclusion, following nerve trauma, PRP induces en-
hanced axon regeneration and neurological recovery by (1)
binding to the fibrin within the nerve gap, thereby
Mol Neurobiol
transforming it from a passive supporter to an active promoter
of axon regeneration [231, 245]; (2) acting directly on the
transected axons to promote their regeneration [194]; (3) act-
ing on the Schwann cells of the central and distal portions of
the nerve to promote their proliferation and upregulating their
synthesis and release of neurotrophic and other factors that act
in concert with platelet-released factors on axons to promote
their enhanced axon regeneration [246–248]; and (4) mesen-
chymal stem cells differentiating into Schwann cells that re-
lease axon regeneration-promoting factors [249–252]. It is
likely that these are only some of the mechanisms by which
PRP induced axon regeneration and neurological recovery.
In Vitro
In rat brain cortex-spinal cord organ culture, PRP induces
axons from the cortex to regenerate into the spinal cord
through mechanisms associated with IGF-1 and VEGF, while
platelet-released TGF-beta1 inhibits axon growth [243].
Increasing the Influence of PRP
The outcome of management of diabetic foot ulceration is
poor and insufficient. The standard therapy includes manage-
ment such as debridement of the wound, revascularization
procedures, off-loading of the ulcer, antibacterial actions,
and supplementation of growth factors and cytokines, leading
to stimulation of granulation, epidermization, and angiogene-
sis [253]. Combining the application of PRP to such wounds
and adding hyperbaric oxygen therapy (HBOT) reduce the
time required to achieve wound healing, short-term morbidity,
and the risk of major amputations [253].
Mechanisms of Action
The significant differences between the observed influences of
PRP on axon regeneration between the clinical and animal
model experiments are best explained by the use of different
PRP separation techniques, which result in PRP with different
compositions, with the PRP applied clinically being better
optimized to enhance the extent of regeneration of human
axons, while the PRP used in the animal model experiments
is not being so optimized. However, it is reasonable to hypoth-
esize that using a better PRP isolation technique, similar out-
comes would be achieved both clinically and in animal
models. It must be noted that according to studies performed
by Biomet Inc., the company that manufactures the PRP sep-
aration device used in clinical studies and produces PRP with
a significantly different composition when used with blood
from different animal models, the PRP from animal models
that is most similar to that from human blood is that from the
horse. The next most similar PRP is that separated from dog
blood. These studies clearly indicate the importance of
Mol Neurobiol
assuring that the PRP to be studied is optimized to achieve a
high concentration of platelets with a high ratio of unactivated
vs. activated platelets and a high concentration of mesenchy-
mal stem cells and plasma factors
Mesenchymal Stem Cells
The application of mesenchymal cells to created mouse bone
injury sites induces angiogenesis and the correct functioning
of osteoblasts, increases the amount of mobilized cells for the
repairing process, speeds up the rate of growth, and increases
the deposition of bone matrix deposition relative to control
animals [69]. The application of mesenchymal cells to cuta-
neous lesions of diabetic mice induces greater wound
reepithelialization than standard wound care [128].
PRP induces enhanced axon regeneration due to mesen-
chymal stem cells within a nerve gap differentiating into pro-
liferating Schwann cells that synthesize and release axon
regeneration-promoting neurotrophic factor [254].
Mesenchymal stem cells applied to damaged peripheral
nerves promote and enhance axon regeneration and neurolog-
ical recovery [255, 256]. They act through a number of differ-
ent mechanisms, one of which is the induction of angiogenesis
[257]. Another is their release of MMPs that enzymatically
degrade the chondroitin sulfate proteoglycan (CSPG) that is
present in the ECM of denervated peripheral nerve Schwann
cells, which inhibits axon regeneration [258–260].
Mesenchymal stem cells also cause the downregulation of
CSPG synthesis in peripheral nerves, thus changing the
ECM from one that inhibits to one that promotes axon regen-
eration [261].
Mesenchymal stem cells also promote enhanced axon re-
generation by promoting Schwann cells within the central and
distal nerve stumps to migrate into the nerve gap where they
proliferate and release additional axon regeneration-
promoting factors [254, 262–271]. These and other mesen-
chymal stem cell-released factors simultaneously act directly
on axons to induce and promote their regeneration [28, 221].
Finally, mesenchymal stem cells also promote enhanced axon
regeneration by their release of neurotrophic factors, such as
CNTF, PDGF-alpha, LIF, beta-NGF, TGF-beta1, BDNF, and
β-FGF, but not NT-3 and NT-4 [272–277], and axon guidance
and neural cell adhesion molecules, such as ECM components
[273, 278] that act directly on axons to promote their regener-
ation. This can be demonstrated by applying mesenchymal
stem cells to the end of a transected nerve [221, 279] and their
addition to acellular nerves or into empty nerve conduits
bridging nerve gaps [280–282]. This promotes axons to re-
generate across nerve gaps and improves the restoration of
neurological function [283]. Part of this induction appears
due to 50 % of the stem cells differentiating into a Schwann
cell phenotype [281], cells that release axon regeneration-
promoting neurotrophic factors [282, 284].
Platelet-Released Factors
Like mesenchymal stem cells, platelets promote enhanced ax-
on regeneration by releasing a complex cocktail of neuro-
trophic and other factors referred to as PDWHF. Among
platelet-released factors that promote axon regeneration are
as follows: several isotypes of PDGF, ADP, ATP, calcium,
and seroto nin, pla te let factor 4 , fibron ectin, B -
thromboglobulin, vWF, fibrinogen, coagulation factors V
and XIII, TGF-beta [251], EGF [251], VEGF, β-FGF, FGF-
2, PF4, CNTF, IGF-1 [238], BDNF [285], and PDAF [251,
286, 287].
EGF is a family of proteins that includes neuregulins,
which when administered to nerve trauma sites promotes axon
regeneration [288–291], the development of larger diameter
axons, and enhanced neurological recovery [288]. EGF fur-
ther promotes axon regeneration and neurological recovery by
inducing Schwann cell proliferation [292, 293] and their re-
lease of neurotrophic factors that promote axon regeneration
[294], Schwann cell migration [292, 295], Schwann cell
myelination [293, 296], and angiogenesis [149].
PDGF is critical to promoting axon regeneration by regu-
lating neurotrophic factor release and cell proliferation and for
promoting angiogenesis. Although PDGF and its receptor are
present on Schwann cells in vitro and in vivo [248], upon
denervation, Schwann cells increase their expression of
PDGF receptors [248, 297, 298] and expression and release
of PDGF [297]. Thus, the administration of exogenous PDGF
to injured peripheral axons enhances the extent of their regen-
eration by direct action on the injured axons [297, 299], but
also by inducing Schwann cell proliferation, differentiation,
myelin formation, and triggering their upregulation of the syn-
thesis and release of neurotrophic factors [246], which act
directly on injured axons to promote them to regenerate
[247, 248]. This influence is increased when PDGF is admin-
istered simultaneously with IGF-1 [299].
IGF-1 is involved in neurogenesis, myelination, synapto-
genesis, dendritic branching, and neuroprotection, inducing
Schwann proliferation, differentiation, and myelination
[300–302]. IGF-1 also promotes Schwann cell synthesis and
release of axon regeneration-promoting neurotrophic factors
[246, 303, 304]. The infusion of IGF-1 onto injured peripheral
axons significantly increases the number of axons that regen-
erate, the distance they regenerate, their diameter, extent of
myelination, and the degree of neurological recovery [238].
As stated above, the simultaneous application of IGF-1 and
PDGF to transected axons induces more extensive axon re-
generation than is induced by either singly [299].
Angiogenesis is essential for axon regeneration and VEGF
that induces both angiogenesis and the extent of axon regen-
eration [200, 208, 305–309]. The simultaneous application to
injured axons of PRP and antibodies that neutralize the activ-
ity of VEGF reduces the regeneration-promoting influence of

PRP [243], thereby showing that VEGF is one of the factors
released by PRP that promotes axon regeneration.
Cyclic adenosine monophosphate (cAMP) promotes axon
regeneration by an intracellular signaling mechanism [310,
311]. In vitro, a cAMP analog promotes an increase in the
distance axons regenerate [312, 313]. In vivo, the elevation
of cAMP in axotomized neurons accelerates peripheral axon
outgrowth by increasing the levels of neuron-produced endog-
enous neurotrophic factors [314]. cAMP also induces axon
regeneration by inducing Schwann cell proliferation and their
release of neurotrophic factors [314] and the expression of
myelination-associated genes [247]. Simultaneously, cAMP
acts on the growth cones of regenerating axon allowing them
to ignore regeneration-inhibiting factors, such as MAG [315].
TGF-beta controls cell proliferation and differentiation as
well as other functions. Fibrinogen, which enters wound sites
following trauma, is a carrier of latent TGF-beta, which in-
duces fibroblast proliferation and the synthesis and accumu-
lation of collagen fibrils and scar formation [316]. In a rat
wound model, a reduction in TGF-beta is associated with
reduced scaring and better wound healing, which is attributed
to reduced collagen accumulation [317].
The administration of TGF-beta to neurons in vitro in-
creases neurite outgrowth [318, 319]. In vitro, TGF-beta in-
duces rat astrocytes to upregulate their synthesis of NGF
[320]. In vivo, TGF-beta administration to injured axons pro-
motes their regeneration by triggering Schwann cell prolifer-
ation, their differentiation, and their release of neurotrophic
factors [321, 322]. It may also act by upregulating the synthe-
sis and release of β-FGF in the anterior horn motor neurons of
the spinal cord during regeneration [279] and other neuro-
trophic factors. However, not all experiments with TGF-beta
have found that it induces enhanced axon regeneration [323].
Leukocytes
Another variable in harvesting PRP is the great differences in
the concentration of white blood cells (WBCs) and red blood
cells (RBCs). A high absolute WBC concentration in PRP
contributes to the increased production of inflammatory cyto-
kines, such as interleukin-1beta (IL-1beta) and tumor necrosis
factor-alpha (TNF-alpha), which increase inflammation and
pain and both delay and reduce PRP-induced tissue healing
[324, 325]. When the physiological ratio of platelets/WBC
cannot be maintained, there is no physiological capability of
counteracting the inflammatory effect. This results in inferior
tendon repair associated with scar tissue formation [325].
Therefore, leukocyte-poor PRP may be a better PRP compo-
sition for avoiding persistent inflammation stimulating supe-
rior healing without scar tissue formation [325]. However, the
inclusion of WBCs in PRP improves wound healing where
cells required for tissue regeneration are induced by cytokines
released from the transplanted cells [87]. These differences
Mol Neurobiol
must still be explained. The presence of leukocytes in PRP
may also be positive because of their immune and antibacte-
rial properties [324].
Cautions in Using PRP: PRP Composition
As has been pointed out, the influences of PRP application
vary greatly. These variations can be attributed to a number of
factors that include donor variability and health status, device
used to separate PRP [326–328], centrifuge acceleration rate,
speed, and duration, which will also influence platelet concen-
tration, ratio of unactivated to activated platelets, and which
plasma factors are present and their concentrations [329–331].
The concentrations of factors PDGF, TGF-beta, and VEGF in
PRP are positively correlated with platelet concentration of
PRP [332]. PRP preparation and delivery method also influ-
ences the number of mesenchymal stem cells and concentra-
tion of erythrocytes [329, 333, 334]. Even if the same method
is used to prepare the PRP, its influence still varies depending
on the delivery method, delivery duration, the number of times
it is applied, the time between multiple PRP applications, and
the type of thrombin used to activate the platelets [329, 335].
Still other variables that will affect the PRP are the animal
model, differences in animal species, differences in the injured
tissue on which it is tested, the type and cause of injury as well
as the injury age, and how the thrombin is prepared [12]. Since
each of these can influence the actions of PRP, a reliable com-
parative study requires that these variables be reduced to a
minimum.
In vitro, PRP obtained using three different separation tech-
niques from the human blood induced differing influences on
the proliferation rates of human bone, muscle, and tendon
cells [336, 337]. Varying the concentration of white blood
cells within PRP is one factor influencing cell proliferation
[336, 337]. Different separation techniques also result in great-
ly varying concentrations of platelet-derived growth factors
[329] and can vary greatly in the concentration of platelets
by four- to ninefold [338]. In addition, regardless of the sep-
aration method used, even blood from different individuals
has large variations in platelet and cell numbers and in the
levels of various growth factors [337]. These data suggest that
specific and different methods of separating PRP must be
considered depending on the cell type one wants to induce
to proliferate.
New methods of analyzing centrifugation forces on plate-
lets, RBCs, and WBCs and the use of discontinuous centrifu-
gation allow for the separation of PRP of varying composi-
tions, such as pure PRP without RBCs and white blood cells
[339]. Some methods can yield relatively consistent PRP com-
positions, such as a double centrifugation tubes allow the con-
sistent separation of dog PRP at about four times the base level
and WBCs at not more than twofold above base level [340].
Mol Neurobiol
Further studies are attempting to determine how to obtain a
constant PRP composition with the ideal concentration of
platelets and whether there are benefits to include or exclude
RBCs and WBCs [339]. Accomplishing this may require the
use of a double centrifugation approach, which allows a re-
duction in the WBC concentration [340]. The concentration of
platelets in PRP varies by four- to ninefold depending on the
separation system used [328, 336, 341]. However, more ex-
tensive studies are required to determine which composition
of PRP and various cell ratios are optimal for different types of
tissues [336, 342].
In a study on nude mice, PRP enriched with red blood cells
and applied to the auricle induced tissue augmentation and
greater tissue repair vs. normal PRP. This influence was in-
creased more when white blood cell-enriched PRP was com-
bined with β-FGF [343].
A PRP classification system has been proposed in
which three variables are compared: (1) the absolute num-
ber of platelets, (2) the manner in which platelet activa-
tion occurs, and (3) the presence or absence of white cells.
Using these variables, the content of PRP used in different
studies can be compared, and differences in experimental
results can be explained based on differences in the com-
position of PRP used [342]. However, it is still uncertain
whether such a system may provide an explanation of the
great variability in published results. Adding to the chal-
lenge of estimating the composition of PRP is the great
differences in PRP composition that is seen, even when
PRP is separated by the same devices from blood of dif-
ferent individuals.
The lack of standardized study protocols and platelet sep-
aration techniques, the many varied models (animal and clin-
ical), different types of tissues, and types of wounds on which
the influences of PRP were studied and their outcomes sug-
gest that certainty about whether PRP induces specific influ-
ences is not possible. This will require the application of PRP
of a consistent composition and in a consistent manner. Only
once this has been achieved can further studies be performed
to determine whether the influence of PRP can be improved
and made more reliable.
Thus, a number of papers, similar to this one, cannot
yet provide a definite conclusion as to the influences of
PRP. This review faces the same challenge as the others.
However, relative to other reviews, this one more strongly
considers that the results of the studies are all true, but
that the results differ almost because of the differences in
the PRP applied, its application protocol, and specific
model in which it is tested. For example, a clinical study
determined that PRP induced extensive axon regeneration,
while in two similar studies using rats, one found no in-
fluence and the other only a minor influence. It is con-
cluded that the results of all three studies are correct but
that the differences in the PRP used were so great that the
results were significantly different. If this is the case, it is
relatively meaningless to perform extensive meta-analyses
of published data when the data cannot be validly com-
pared. Therefore, it is more important to examine the data
from studies in which the technical approaches were more
similar than they were different.
Another variable in the potential influences of the applica-
tion of PRP is how the platelet area is activated, in the pres-
ence or absence of exogenous thrombin or calcium chloride to
induce fibrin formation, because each of these can affect the
character and potential efficacy of the final PRP product
[344]. In one study in which PRP was applied to clinical bone
injuries, both in the absence and presence of thrombin, bone
healing was the same, although the authors felt that there was a
tendency of the presence of thrombin to induce somewhat
better healing [345].
Conclusion
Studies with varying levels of evidence have demonstrated the
safety and beneficial effects of PRP in these applications, but
standardization of the methods of PRP preparation and appli-
cation protocols is necessary for further advancements.
Continued efforts to identify factors that influence the biolog-
ical response to PRP treatment may yield new formulations
tailored to suite each specific application. Recent reviews have
come to different conclusions with some indicating no signif-
icant or reliable evidence that PRP exerts positive effects on
wound healing [191, 346–350], while others conclude that
PRP is beneficial in healing injuries [190, 192, 351–356].
But most indicate that until there are clear results from rigor-
ously conducted controlled and double blinded clinical and
animal studies, caution should be used about the continued
clinical use of PRP until more evidence is available. This
review comes to a similar conclusion as most previous re-
views, but stresses that the abundance of evidence is extreme-
ly compelling that PRP is more efficacious than any other
techniques in promoting more rapid and extensive wound
healing and that most in vitro studies find that PRP-released
factors induce the cellular actions that are required to induced
wound healing.
The author concludes that the striking number of positive
results suggests that more and better controlled animal and
clinical studies are required in which more similar or identical
protocols are used that will make it possible to affirm or refute
claims of the efficacy of PRP in promoting enhanced wound
healing and pain reduction. Finally, due to the absence of
adverse events associated with the application of PRP, the
author recommends the continued application of PRP to pro-
mote wound healing, axon regeneration, and the reduction of
neuropathic pain.

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