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ORTHOPEDIC MANAGEMENT OF FRACTURES (M KACENA AND L GERSTENFELD, SECTION
EDITORS)
The Use of Platelet-Rich Plasma (PRP) for the Managementof Non-union Fractures
Christian Andersen1& Nicholas M. Wragg2,3
& Maryam Shariatzadeh2& Samantha Louise Wilson2
Accepted: 4 December 2020 /Published online: 4 January 2021# The Author(s) 2020
AbstractPurpose of Review The treatment of non-union fractures represents a significant challenge for orthopaedic surgeons. In recentyears, biologic agents have been investigated and utilised to support and improve bone healing. Among these agents, platelet-richplasma (PRP) is an emerging strategy that is gaining popularity. The aim of this review is to evaluate the current literatureregarding the application and clinical effectiveness of PRP injections, specifically for the treatment of non-union fractures.Recent Findings The majority of published studies reported that PRP accelerated fracture healing; however, this evidence waspredominantly level IV. The lack of randomised, clinical trials (level I–II evidence) is currently hampering the successful clinicaltranslation of PRP as a therapy for non-union fractures. This is despite the positive reports regarding its potential to heal non-union fractures, when used in isolation or in combination with other forms of treatment.Summary Future recommendations to facilitate clinical translation and acceptance of PRP as a therapy include the need toinvestigate the effects of administering higher volumes of PRP (i.e. 5–20 mL) along with the requirement for more prolonged(> 11 months) randomised clinical trials.
Keywords Bone healing . Fracture . Non-union . Platelet-rich plasma (PRP)
Introduction
The US Food and Drug Administration (FDA) defines a longbone non-union as a fracture that has failed to heal within thefirst 9 months following injury and has shown no signs ofhealing for at least 3 consecutive months [1]. However, there
is currently no standardised system to define a non-union, sofractures can also be classified as a non-union outside of theseparameters (Table 1). The diagnosis of non-union is depen-dent upon a number of factors including the location of injury,since healing times vary depending upon the type and locationof the bone; and weight-bearing bones, such as the femur andtibia, often require the longest healing times to achieve union[2]. A fracture can also be classified by a clinician as a ‘non-union’ when he/she believes the fracture has little or no po-tential to heal [3]. Specific examples of this arise when there isa persistent gap at the fracture site several months followingthe initial injury, and/or in instances whereby the patient suf-fers from persistent pain at the fracture site long after the initialpain of the break has occurred [4].
Impaired healing occurs in 10–15% of fracture patients,which ultimately can lead to a non-union [5]. Characteristicsof an impaired healing process include persistent pain, poorbridging of the fracture site by callus formation and a persis-tent radiolucent line at the fracture which can be visualised viaX-ray [6]. Risk factors associated with non-union include in-creasing age and alcohol consumption, smoking and deficien-cies in vitamin D, calcium or protein [4].
This article is part of the Topical Collection on Orthopedic Managementof Fractures
* Samantha Louise Wilsons.wilson2@lboro.ac.uk
1 National Centre for Sport and Exercise Medicine, School of Sport,Exercise and Health Sciences, Loughborough University, EpinalWay, Loughborough, Leicestershire LE11 3TU, UK
2 Centre for Biological Engineering, Wolfson School of Mechanical,Electrical and Manufacturing Engineering, LoughboroughUniversity, Epinal Way, Loughborough, Leicestershire LE11 3TU,UK
3 School of Pharmacy and Bioengineering, Guy Hilton ResearchCentre, Thornburrow Drive, Hartshill, Keele University,Stoke-on-Trent, Staffordshire ST4 7QB, UK
Current Osteoporosis Reports (2021) 19:1–14https://doi.org/10.1007/s11914-020-00643-x
Non-union fractures provide a socioeconomic burden thatputs pressure on already strained healthcare systems [6]. In theUK, the average cost of long bone non-union treatment is£29,204 per patient; in Canada, 67–97% of the total costs oftibia fractures were specifically related to non-unions in 2014[7]. Within European healthcare systems, this range narrowedto 82.8–93.3% in the same year [7]. Non-unions are a signif-icant source of morbidity and have a serious impact on patientquality of life (QoL). This is because delayed healing requiresadditional hospitalisation and the requirement for extensive,often uncomfortable surgical treatments which take, on aver-age, a further 4–8 months to recover from (assuming no fur-ther issues arise during treatment and rehabilitation) [7]. Thecurrent ‘gold standard’ for treatment of non-union fractures isthe use of autologous cancellous bone grafts [8]. Bone fromanother part of the body is transplanted to the non-union sitewhere it can act as a scaffold on which new bone can grow.Bone grafts provide the non-union site with a fresh source ofbone cells to help ‘jump start’ the healing process [4].However, researchers are currently exploring alternative ther-apies and treatment options, largely due to the limited supplyand donor site morbidity associatedwith autologous grafts [8].One potential alternative, which is gaining popularity in theliterature, is the use of platelet-rich plasma (PRP).
The aim of this review is to use the current literature toevaluate the effectiveness of PRP in accelerating the healingof non-union fractures. This can be used to inform as towhether PRP may eventually have the potential to become aprimary treatment perceptive option.
Methods
As a part of the systematic literature search, the followinginclusion criteria were utilised: clinical reports of any levelof evidence, published in the last 20 years (2000–2020) usingPRP for the treatment of fractures, with a specific focus onnon-unions. Keyword strings of (((‘platelet rich plasma’ OR
‘PRP’))) AND ((‘bone fracture’ OR ‘non-union fracture’ OR‘delayed healing’)) AND (‘human’ OR ‘clinical’) were usedto identify relevant English language articles using the elec-tronic database, PubMed. Scopus, Google Scholar andSpringer were also utilised to search for additional resources.
Results
Using the search terms described returned 38 articles that wereeligible for inclusion. The removal of duplicate records result-ed in 29 records being screened for relevance (Fig. 1). Thetitles and abstracts were screened, and 7 articles were removedsince they were unrelated and/or review articles, book chap-ters or conference proceedings. Four articles were removedsince they referred to soft tissues. Eighteen studies were in-cluded in a qualitative synthesis. Due to the diversity of pro-tocols implemented and the significant variation in outcomemeasures that were reported, it is extremely difficult to directlyquantitatively compare the studies. Thus, a narrative critiquewas deemed to be most appropriate to review and present therelevant literature. The search revealed that the vast majorityof literature has reported benefits of PRP in accelerating boneregeneration. The optimum dose of PRP for treating non-unions is currently undetermined, and the lack ofstandardisation regarding the preparation and delivery ofPRP is retarding clinical translation. Therefore, this reviewalso aims to provide recommendations for successful clinicaltranslation, uptake and acceptance.
PRP and Its Role in Regeneration
The use of PRP in tissue regeneration is a rapidly evolvingarea for both clinicians and researchers and is being employedin various fields, including osteoarthritis [9], rotator cuff repair[10, 11] and bone regeneration [12]. This is because autolo-gous platelet concentrations offer an easy, cost-effectivemeth-od to obtain the high concentrations of specific growth factors
Table 1 Classification of non-union fractures adapted from Panagiotis et al. 2005 [5]
Classification Description/pathology
Hypertrophic (hypervascular,viable, vital)
Inadequate immobilisation, yet adequate blood supply. In radiographs, callus formation is decreased with anelephant-foot or horseshoe configuration observed.
Atrophic (avascular, non-viable,avital)
Poorly vascularised non-union, resulting in poor potential for forming bone cells and, therefore, delayed healing.There is little callus formation around the fibrous tissue–filled fracture gap.
Oligotrophic The body can initiate a healing response but is unable to complete the fracture formed between the two ends of thebone.
Septic A bacterial infection impedes the healing process. Typical bacterial strains that inflict non-union sites includecoagulase negative Staphylococcus spp. and Propionibacterium spp.
Pseudoarthrosis Persistent motion at fracture site causes formation of false joint (joint that develops at the site of a fracture), oftenproducing synovial fluid.
2 Curr Osteoporos Rep (2021) 19:1–14
including platelet-derived growth factor (PDGF), vascular en-dothelial growth factor (VEGF), transforming growth factor(TGF beta 1 and 2) and insulin-like growth factor (IGF-1)which are required for tissue healing and regeneration [9]. Ahealthy individual has a baseline platelet count between 1.5and 4.5 × 105/μL [12]; to be deemed as therapeutically bene-ficial, a platelet concentration of 4–5 times that of baselineshould be present. The preparation of PRP varies slightly inpublished literature. However, in general, blood is drawn intoa tubewhich is often treated with an anticoagulant [13]. This isfollowed by centrifugation and activation of the platelets via achemical agent [13]. Frequently used activators include calci-um chloride [13–19] and bovine [17, 20] or autologous throm-bin [15, 21, 22]. Thrombin forms a gel-like substance, fromwhich the PRP can be extracted and directly applied to thepatient intravenously [14, 17, 23].
Within platelets are granules, which contain numerousgrowth factors and cytokines that are important in the earlystages of bone repair [12]. On activation, following clotting,these platelets release these growth factors, which play a crit-ical role in the production of proteins required for regenerativeprocesses, such as cellular proliferation, matrix formation, os-teoid production and collagen synthesis [12].
Current Use of PRP in Non-union Fractures
Clinical trials have investigated the effect of PRP on non-union healing alone [14, 21, 24, 25] and in combination withother forms of treatment such as the use of mesenchymal stemcells (MSCs) [26, 27], internal fixation and/or nailing [16, 19,23, 28–30]. When using PRP in isolation to treat a non-union,the therapeutic benefit is divided; in some instances, PRP hasbeen deemed successful in achieving bony union at the frac-ture site [24, 25, 31] within 11 months of initial injury orsurgery [17]. In addition, PRP has been shown to enhancethe healing of non-unions when used in conjunction with otherforms of treatment such as the ‘gold standard’ autologousbone graft [32, 33], as well as MSCs [27, 34] and internalfixation [16, 28, 29]. Despite the majority of literaturereporting the success of PRP in accelerating healing, it hasbeen found to have less of an effect when compared to otherforms of treatment, most importantly the use of bone morpho-genetic proteins (BMPs), such as rhBMP-7 [35]. This is mostlikely due to the low concentration of growth factors whichcan be extracted with PRP in comparison to BMPs [36].
Among the literature concerning the use of PRP specifical-ly for the treatment of non-union fractures, there is currently a
Screenin
gIn
clu
de
dE
lig
ibility
Identification
Records excluded after
screening title and journal
abstract (n = 7)
- Unrelated
- Review articles, book
chapters, conference
abstracts/papers
Full-text articles
excluded, with reasons (n
= 4)
- not long-bone specific
- did not include PRP
Records identified through
database searching
(n = 38)
Records after duplicates removed
(n =29)
Records screened
(n = 29)
Full-text articles
assessed for eligibility
(n =22)
Studies included in
qualitative synthesis
(n = 18 )
Studies included in
quantitative synthesis
(meta-analysis)
(n = 0)
Fig. 1 Prisma flowchart of studyselection criteria
Curr Osteoporos Rep (2021) 19:1–14 3
lack of prospective randomised clinical trials (RCTs) and,therefore, a minimal amount of literature with level I–III evi-dence. Instead, studies are predominantly in the form of caseseries or preliminary studies (level IV evidence) [14–19, 22,24–27, 29, 31]. The advantage of case series is that they arerelatively easy to conduct whilst requiring less time and finan-cial resources in comparison to RCTs, cohort or case-controlstudies. However, the limitations include a lack of controlsubjects, which leaves the interpretation of results open tobias. Not only are the majority of published PRP studies caseseries, but the studies are also predominantly pre-clinical(Fig. 2). Fortunately, the most recent literature [14, 15, 22,31], summarised by Roffi et al. [37], demonstrated that studiesare moving towards a more clinical direction, which is vital forsuccessful translation of any therapy.
PRP Preparation and Administration
Despite PRP being widely used for several musculoskeletalpathologies [9–11], there is currently a lack of standardisationwith regard to the how PRP is prepared and delivered fortreatment of non-union fractures. In general, the PRP prepa-ration process involves the processes of collection, centrifuga-tion to separate out the platelets, extraction of platelet-richplasma from the red blood cells and platelet poor plasmaand activation using an anticoagulant agent (although this isnot always the case) followed by administration to the injurysite (Fig. 3).
During preparation, the process of centrifugation isutilised for concentrating platelets in all literature.However, the rates of centrifugation differ between stud-ies, ranging from 3200 up to 5200 rpm [15, 19, 21, 30],which leads to different relative forces depending on rotorlength, while other studies do not state the rate [7, 35].Furthermore, centrifugation can potentially lead to thefragmentation of the platelets and the early release ofgrowth factors which will ult imately reduce the
bioactivity of the PRP [15]. Thus, activation of the PRPcould be influenced by the relative centrifugal forces be-tween studies causing unwanted variation. Therefore, it isrecommended that future studies consider ultrafiltration,which potentially offers a more standardised process forPRP extraction [17].
Activation of PRP via the use of chemical anticoagulantagents is also a key component of the preparation process.Throughout the literature, this activator varies, with throm-bin, calcium chloride and calcium gluconate being themost common. Thrombin is often combined with calciumchloride (CaCl2) [19, 20] or calcium gluconate [15, 21] inan attempt to further increase activation of the platelets. Insome literature, details regarding activator use are absent[31], with some studies using none at all [24]. Differentreagents have differing half-lives [38], which also has animpact on the duration of the anticoagulant to clear thesystem. This in turn will have an impact on PRP activationand, therefore, have an impact on the rate of bone regen-eration and PRP efficacy. Furthermore, anticoagulant use,particularly those with prolonged half-lives, may limit thesuitability of PRP as a therapy for some patient groupsincluding those with anaemia and renal diseases [39].When analysing PRP delivery methods, it was noted thatthe volume of PRP delivered varies significantly betweenstudies, with the dose of a single injection varying from2.5 ml [14] up to 20 ml [24]. The total dose is usually givento a patient as a single dose [21, 24], but may also bedivided into multiple injections over consecutive weeks[14, 25] (Table 2). This will likely cause differing levelsof efficacy between methods of application as injecting asingle dose in comparison to the same dose being dividedover several weeks will impact upon the rate of bone re-generation. Dividing a set dose over a period of severalweeks will likely delay the intended effect of the injection,slowing the rate of non-union healing. Conversely, the ap-plication of multiple equivalent doses of PRP over a
Fig. 2 The current proportions ofpre-clinical and clinical studiesinvestigating the use of PRP forthe treatment of bone defects from2005 to 2016, reproduced fromRoffi et al. (2017) [37] withpermission from copyright owner(the authors)
4 Curr Osteoporos Rep (2021) 19:1–14
prolonged period may increase healing rates, although it isimpossible to say for certain since rate of healing is patientspecific and RCTs would need to be performed to clarifythis.
The Impact of PRP Activation on Bone Regeneration
The majority of published studies currently fail to report keyaspects such as platelet concentrations, leukocyte componentsand activation modalities [37]. This is despite Chen et al. dem-onstrated how a medium concentration of PRP (2.65 ± 0.2 ×109/mL) induces oestrogenic differentiation of bone marrowstem cells (BMSCs/BM-MSCs), improving fracture healing,whereas a high concentrations of PRP (8.21 ± 0.4 × 109/mL)can inhibit osteogenic differentiation and delay callus remod-elling [40]. Labibzadeh et al. reported that leukocyte-rich PRPinduced higher proliferation of BMSCs [27], while other lit-eratures have found activation modality to influence the mol-ecules released by the PRP [41]. This highlights that differingconcentrations and ultimately levels of activation will affectthe efficacy of the therapy.
The Use of PRP in Isolation to Treat Non-unionFractures
Once PRP has been prepared, treated with an anticoagulant andactivated, it is often then applied alone as a form of treatment.Only one study reported PRP to be unsuccessful in achievingunion when used in isolation [14]. The study comprised 20 pa-tients, 12 of which were diagnosed with a non-union fracture.These subjects were treated weekly for 6months [14]. No patientachieved union up to 10 months following treatment. Therefore,the authors concluded that PRP was ineffective in treating non-unions [14]. However, the administration of the PRP was a lim-itation of the study. A total of 2.5 mL of PRP activated bycalcium chloride was injected each week for 3 weeks. A2.5 mL dose of PRP is relatively small in comparison to otherstudies; however, it is impossible to determine how the harvestblood and/or delivery volume used in any study compares to thenumber of platelets and/or leukocytes isolated, since this value is
very rarely stated in published studies (Table 2). Furthermore, thesize of non-union is widely varying when comparing patientswithin study groups and separate studies to each other.Moreover, the size/volume of the non-union is not always pre-scribed in published studies. PRP has been a reported successwith a dose of at least 5 mL per injection [28, 30], often appliedon at least three separate occasions [25, 31] In addition to this, thePRP was activated using calcium chloride. In the majority ofpublished literature where PRP has successfully induced union,bovine/autologous thrombin was utilised in the activation pro-cess [15, 17–19, 21, 22, 28], thus implying that activation usingcalcium chloride alone and the lower dose of PRP could poten-tially be key factors in the unsuccessful union of these patients’fractures.
Despite its common use, bovine thrombin as an activator hasbeen questioned in clinical application, since disease transmis-sion, possible carcinogenesis, availability and cost are all issuesrelated to bovine thrombin [20]. Furthermore, Malhotra claimedthat sufficient thrombin is produced via local trauma when thefracture site is infiltrated with a needle [24]. To test this hypoth-esis, a high volume of 20 mL of PRP was injected on one occa-sion without thrombin and with a high concentration of platelets(approximately 5 times normal values) [24]. Eighty-seven per-cent of patients achieved union at the end of the 4-month follow-up period. All of which had an average time of 9.1 months be-tween the injury and the PRP injection [24].
In 2008, Bielecki et al. concluded that PRP is a sufficientmethod to achieve union as long as the treatment occurs ≤11 months following initial surgery [17]. In Malhotra et al.’sstudy, the 13% of patients who had previously not achievedunion were treated with PRP over 12 months following initialdiagnosis. However, following the conclusions of Bielecki et al.,due to the delay in PRP treatment from diagnosis, the fracturegap most likely became too large for the PRP to have a regener-ative effect. Limitations that were acknowledged in the studywere that it was not a RCT and only involved non-unions whichhad more than 90% contact between the fracture fragments.Therefore, findings from this study may not be applicable tomore severe non-unions. A more recent study by Tawfik et al.had similar inclusion criteria (more than 90% contact between
Fig. 3 A generalised overview of the PRP process
Curr Osteoporos Rep (2021) 19:1–14 5
Table2
Platelet-richplasmaforthetreatm
entand
managem
ento
fnon-unionfractures:comparisonof
studies
Author/study
Size
andtype
ofnon-union
Treatment
Harvestvolume
Plateletseparation/centrifugatio
nprotocol
PRPextractionbloodcount
Bieleckietal.
2008
[17]
Establisheddelayedunionand
non-unionfractures(n=32):
Delayed
uniongroup(n=12):tib
ia(n=9),fibula(n=3).
Non-union
group(n=20):tib
ia(n=11),fibula(n=1),
humorous(n=3),radius(n=2).
Percutaneousinjectionof
autologous
platelet-leukocyte-richgel
(PLRG),interventio
n>12
monthsfollo
winginjury.
ForPR
P:108mlo
fautologous
basilic
vein
with
12mL
anticoagulant
(sodium
citrate).
Centrifugation×1@
3200
rpm
12min.
Preoperativ
eplateletcount
<130×10
9/L
tomeetinclusion
criteria.
Meanplateletcountw
as241±64
×10
9/L
andmean
leukocytecountw
as7.6±2.57
×10
9/L
inblood.
Plateletcountswereincreasedby
720%
andleukocytecounts
wereincreasedby
760%
onaverage.
Calorietal.
2008
[35]
Persistent
atrophiclong
bone
non-unions
(n=120)
including
tibia(n=15),femur
(n=10),
humerus
(n=15),ulnar(n
=12)
andradius
(n=8)
inrhBMP-7
group.
Tibia(n=19),femur
(n=8),
humerus
(n=16),ulnar(n
=8),
radius
(n=9)
inPR
P-treated
group.
Com
parisonof
rhBMP-7mixed
with
abio-reabsorbablecarrier
(3.5
mgEptoterminalfa,+
1g
collagen,Osigraft,reconstituted
with
2–3mLphysiological
solutio
n(n=60),comparedto
PRP(n=60).
54-or
108-mLwholebloodinacid
acid-citrate-dextrose;2
0mL
PRPextractedin
total.
Centrifugation2×14
min
(no
rpm/×ginform
ationprovided)
Novalues
provided.
Centeno
etal.
2011
[26]
Stable,chronicnon-unionfractures
(n=6)
includingdistalhumerus
(n=1),sacralb
ase(n=1),1st
metatarsal(n=1),ischial
tuberosity
(n=1),tibia(n=1),
tibiaandfibula(n=1).
PRPcombinedwith
MSC
s,average
timeof
interventio
n8.75
months
post-fracture(range
4–18
months)
200mLof
heparinisedIV
venous
bloodwas
used
toharvest
plateletlysate(PL).MSC
isolated
using10
mLof
marrow
bloodfrom
rightp
osterior
iliac
spine(PSIS),and
10mLfrom
theleftPS
IS
Centrifugation@
200×
g(notim
e)~30.25×10
6±34.01MSC
sinjected
into
each
patient.
NoPL
countsprovided.
Chiangetal.
2007
[20]
Low
erextrem
itylong
bone
atrophic
non-unionfractures(n=12)of
tibia(n=8)
andfemur
(n=4),
both
septicandaseptic
patients
treated.
Bonegraftenrichedwith
autologous
plateletgel(APG
).APG
sprayed
onto
thebone
grafttoform
anAPG
/graftcomplex
which
was
cut/m
oulded
tobridge
thebony
defect.
Patientswith
smalld
efects(n=6)
cancellous
bone
autograftswere
harvestedfrom
theanterior
orposterioriliac
crest,dependent
upon
availability.
Forlarger
defects(n=6),the
graftconsisted
ofcancellous
autograftw
ithallograft(3patients)or
Osteoset
(3patients).45–55
mL
autologous
intravenousblood
used
toharvestp
latelets
Centrifugation@
3650
rpm,
follo
wed
by60
rpm
and
3000
rpm
(nospecifictim
ings
provided).
Novalues
provided.
Duram
azetal.
2018
[19]
PRPgroup:
long
bone
diaphysis
non-unions
(n=14);femur
(n=8),tibia(n=6)
Allpatientshadbeen
previously
treatedwith
intram
edullary
nailing
priorto
treatm
entw
ithpercutaneous
PRPinjectioninto
55mLvenous
blood.
Centrifugation×3@
3650
rpm,
follo
wed
by60
rpm
and
3000
rpm
(nospecifictim
ings
provided).
Novalues
provided.
6 Curr Osteoporos Rep (2021) 19:1–14
Tab
le2
(contin
ued)
Control
group:
femur
(n=7)
and
tibia(n=8).
thenon-unionsiteunder
fluoroscopicguidance
(n=14)
vs.control:exchange
intram
edullary
nailing
(EIN
,n=15).
Galasso
etal.
2008
[16]
Atrophicdiaphyseallong
bone
non-unions
(n=22)of
tibia
(n=11),femur
(n=8)
and
humerus
(n=3).
Intram
edullary
nailing
andPRPgel
placed
inpseudoarthrosisrim
during
surgery.
50mLautologous
blood,6mL
PRPextracted.
‘Centrifugation’
(novalues/rates).
Preoperativ
eplateletcount
<100,000cells/m
Lto
meet
inclusioncriteria.
Ghaffarpasand
etal.2016
[30]
Longbone
non-unionfracture
(n=75):femur
(n=35),tib
ia(n=26),humerus
(n=11)and
ulna
(n=3).
Control:salineplacebo(n
=38)vs.
PRPcombinedwith
autologous
iliac
crestb
onegraftin
gand
intram
edullary
nailing
(fem
oral
factors)or
open
reductionand
internalfixatio
nusingsteelplates
andscrewsfor(hum
eral
fractures)(n=37).
54mLvenous
bloodfrom
right
cubitalv
ein,~5–6mLPRP
extracted
Centrifugation×1:
3200
rpm
15min
Preoperativ
ehaem
oglobin
(mg/dL
)13.5±1.8(PRP),
13.1±2.3(control);
Preoperativ
eplateletcount
(×10
6/μL):2.1±0.6(PRP),
2.2±0.8(control);PRPplatelet
count(×10
6/μL)9.3±2.6
Golos
etal.
2014
[31]
Delayed
unionof
long
bones
(n=132)
including:
humerus
(n=28),forearm
(n=4),fem
ur(n=9)
andtib
ia(n=33).
PRPinjectiontothefractureclefton
average4.05
monthsfollo
wing
diagnosisofdelayedunion(range
2–5.8months)with
open
reductionandplatefixatio
n.
50mLwholeblood(3–4
mLPRP)
or150mLwholeblood(7.8
mL
PRP)
dependentu
ponfracture
locatio
nandcleftsize.
Noinform
ation.
Novalues
provided.
Jiangetal.
2016
[25]
Tibianon-unionwith
breakage
oftheplate(n=1).
Autologousplateletlysate(A
PL)
percutaneous
injection
~9monthsfollo
wingfracture
diagnosis,6monthspost-failed
internalfixatio
nsurgery.
40mLperipheralvein
blood,
~20
mLPRPextracted.
Centrifugation200×
g20
min
@RT;followed
byovernight
cryopreservatio
n@
−80
°C,
resuscitatio
nat37
°Cand
repeated
free
thaw
s(‘morethan
twice’);follo
wed
by1.700×
gfor
6min.
Novalues
provided.
Labibzadeh
etal.2016
[27]
Asepticnon-union(n=7)
offemur
(n=4),tibia(n=1),fibula
(n=1),tibiaandfibula(n=1).
PRP(plateletlysates,P
L)combined
with
bone
marrow–derived
mesenchym
alstem
cells
(BM-M
SCs)MSCs(20–50
millioncells
perinjection).
Durationof
non-unionranging
from
8monthsto
11years.
Umbilicalcord
blood.BM
aspiratio
n:100–150mLfrom
iliac
crest
Centrifugation2000×g2min
or1000×g15
min
at20
°C;
follo
wed
by3000×g10
min
@10
°C;o
vernight
freezing
@−70
°Cfollo
wed
bythaw
ingat
37°C
andheatinactiv
ationat
56°C
for30
min.F
inally,900×g
30min.
Novalues.
Mahadik
etal.
2018
[29]
Longbone
non-union(n=30):
femur
(n=17),tib
ia(n=5),
humerus
(n=5),radiusandulna
(n=3).
PRPandinternalfixatio
n(open
reductionandinternalfixatio
n,screwingor
nailing
dependanton
type
offracture
follo
winginitial
failedtreatm
entu
sing
conservativ
e/surgerydependent
upon
fracture
type).
Novalues.
Noinform
ation.
Novalues.
Malhotraetal.
2015
[24]
Establishedlong
bone
non-union
(n=94):tib
ia(n=35),femur
(n=30),humerus
(n=11),
PRPintravenousinjection;
~9.1monthsbetweeninjury
and
100mLautologous
bloodfrom
cubitalv
ein.
‘Seriesofcentrifugatio
n’(nofurther
inform
ationprovided).
>2millionplatelets/μL.
Curr Osteoporos Rep (2021) 19:1–14 7
Tab
le2
(contin
ued) radius
(n=4),ulna(n=12),
radius
andulna
(n=2).
>90%
contactb
etweenfracture
fragmentswith
suitableopen
reductionandinternalfixatio
n(n=71)or
stablereductionwith
plaster(n=23)im
mobilisatio
n.
PRPinterventio
n(range
7–24
months).
Mariconda
etal.2008
[15]
Longbone
aseptic
atrophic
non-union(n=20)locatedin
the
diaphysealtract(tib
ian=12,
humerus
n=6),forearm
(n=2)
comparedto
historicalcontrol
group(n=20)with
fracturesto
thetib
ia(n=12),humerus
(n=6)
andforearm
(n=2).
Externalfixationusingunilateral
externalfixatorsupportedin
compression
oflong
bone
non-unionsupplementedwith
plateletgel(PG
)comparedto
historicalcontrols
Average
duratio
nof
non-union
311±79
days
vs.333
±88
days
incontrolg
roup)
75mLvenous
bloodyielded
~14
mLPRP
Centrifugation×2:
1200×gfor
25min,followed
by1800×g
10min
Countsperformed
on5patients,
resulting
in~1,075,020
platelets/mL.
Meanplateletcountconcentratio
n4.1tim
esgreaterthan
the
baselin
eplateletcount.
Sanchezetal.
2009
[13]
Asepticnon-union(n=16):
diaphyseal(4
humerus,4
femur,
4tib
ia,n
=12),supracondylar
(n=4).
Surgicalfixatio
nwith
PRP
combinedwith
iliac
crest
autograft~
21monthsfollo
wing
priorsurgicaltreatm
ent(n=13);
PRPalone(n=3).
65mLperipheralvenous
blood.
Centrifugation×1:
640×
g8min.
Novalues.
Sayetal.2013
[14]
Tibia/fibulaaseptic
delayedunion
(n=8)
andnon-union(12)
follo
wingprevious
surgery
PRPmeantreatm
entp
ost-injury
~6–8monthsfollo
wingfracture
surgery.
30mLperipheralbloodfrom
antecubitalregion
Centrifugation×1:1800
rpm8min
PlateletcountP
RP/mLincreased
by400%
comparedto
thrombocytecount(no
values)
Tarallo
etal.
2012
[22]
Non-traum
aticulna
non-union
between1and5cm
PRPcombinedwith
iliac
crest
autograftand
compression
plate,
meantreatm
ent
post-injury=11.5
months
(n=10).Nocontrol.
450mLvenous
bloodcollected.
Centrifugation×2:
180×
g20
min
follo
wed
by580×
g15
min.
Novalues
Taw
fiketal.
2017
[21]
Nonhypertoniclong
bone
non-unions
with
90%
contact
betweenfracture
fragments
PRPalone,meandeliv
ery8months
post-injury.(n=20)Nocontrol.
5patientsreceived
additio
nal
injectionfollo
wing6weeks.
450mLwholebloodcollected,
~10%
used
forPR
PCentrifugation×2:
750×
g7min
follo
wed
by5300×g10
min.
Leukocytes0.15
±0.02
×10
3/μL.
Platelet(w
holeblood)
251±39
×10
3/μL.
Platelets(PRP)
989±265=10
3/μL.
Zhaoetal.
2017
[28]
Atrophicnon-unionof
femoralshaftControl
(conventionalinternal
fixatio
nsurgerywith
autologous/allo
geneicor
artificial
bone
graftn
=46)vs.P
RPand
conventio
nalsurgery
(n=46)
30mLcollected
from
elbowvein.
Centrifugation×2:
200×
g10
min
Novalues.
Author/study
Activation/useof
anticoagulant
Deliverymethod/volume
Outcomemeasure
Com
parison/benefito
fPRP
Typeof
study
Bieleckietal.
2008
[17]
12mLsodium
citratein
108mL
autologous
bloodused
asanticoagulant
forisolationof
PLRG.
Singlepercutaneous
injectionof
15mL
PLRG(12mLPL
RPwith
3mL
thrombinsolutio
n)directly
tositeof
delayed/non-unionunderfluoroscopic
guidance
Patientsfollo
wed
regularlyusing
clinicalexam
ination,
roentgenograms,dual-energyX-ray
absorptio
n(D
EXA)andfunctio
nal
Inthedelayeduniongroup,theaverage
hospitalstayperpatient
was
1.9days.
Union
was
observed
inallcases.T
heaveragetim
eto
unionwas
9.3weeks
Caseseries
8 Curr Osteoporos Rep (2021) 19:1–14
Tab
le2
(contin
ued)
12mLPLRPmixed
with
3ml
1600
U/m
Lbovine
thrombinina10%
calcium
chloride
(CaC
l 2)solutio
n.
evaluations
atdays
3and3,5,8,12,
18and24
weeks
(range
5–12
weeks)afterPLRG
injection.
Inthenon-uniongroup,theaverage
hospitalstaywas
1.8days
perpatient.
Union
was
observed
in13
of20
cases.
The
averagetim
eto
unionwas
10.3
weeks
(range
8–18
weeks)after
PLRGinjection
Calorietal.
2008
[35]
Acid-citrate-dextrose
asan
anticoagulant
(0.163
mLper1mLof
blood)
used
asan
anticoagulant.
Localadministrationduring
revision
surgery.1×
vialrhBMP-7used
in58/60patientsinrhBMP-7group,and
×2vialsinremaining
twopatients(no
volumes
provided).
20mLPRPor
slightly
less
deliv
ered
topatientsassigned
toPRPgroup.
Fracture
healingviaclinicaland
radiologicalevaluatio
n(X
-ray
and
CTscanning
where
required)
performed
pre-treatm
ent,follo
wed
upatintervalsof
1,3,6,9and
12+months.
Functio
nalo
utcomes
evaluatedin
term
sof
presence
orabsenceof
pain
assessed
used
amodifiedVAS.
Rateof
unionin
PRPgroup(68.3%
)significantly
lower
comparedto
rhBMP-7group(86.7%
)Pain-freemovem
entw
asreported
byall
of35
patientswith
upperextrem
ityfracturestreatedwith
rhBMP-7atthe
9-month
prim
aryendpoint,compared
to30
outo
f33
patientstreatedwith
PRPwho
hadasatisfactoryfunctio
nal
outcom
e.The
percentage
ofreported
pain
with
and
with
outw
eightbearing
inpatientswith
lower
extrem
ityfracturestreatedwith
either
rhBMP-7
orPRPwas
comparable.Alower
medianclinical
andradiographichealingtim
ewas
observed
intherhBMP-7group
(3.5
monthsvs.4
monthsand
8monthsvs.9
months,respectiv
ely)
Prospectiv
eRCT
Centeno
etal.
2011
[26]
Heparin
used
asanticoagulant
for
isolationof
PL(novalues);1000
I.U.
heparin/mLused
forisolatio
nof
MSC
sfrom
marrowblood.
Percutaneous
injectionof
autologous
bone
marrow–derived
MSC
sand
plateletlysatedeliv
ered
to‘several
locatio
ns’atthefracture
siteunder
fluoroscopicguidance
Fracture
healingviaradiographic
evaluatio
n(high-resolutio
nX-ray
and/or
CTim
aging)
@1,3and
6+months
Adequatehealingandreturn
tofunctio
nal
recovery
seen
in66.7%
(4/6)of
patients
Caseseries
Chiangetal.
2007
[20]
5–7mLcitrate-basedanticoagulant
used
asan
anticoagulant
forisolationof
platelets.PR
PandPP
Pactiv
ated
using
5000
Upurified
bovine
thrombinor
autologous
thrombinand5mLof
10%
CaC
l 2.
Singleinjection(n=6)
ortwoinjections
(n=6)
Fracture
healingviaradiologic
evaluatio
nandbone
mineraldensity
(BMD)@
3days
aftertreatm
ent,
follo
wed
upat1,2,3,6and
12months.
Functio
nalo
utcomes
measuredusing
theshort-form
36health
survey
(SF-36).
11/12patients(91.7%
)healed
onaverage
19.7
weeks
follo
wingsingletreatm
ent,
1/12
patientshealed
at21
weeks
follo
wingasecond
treatm
ent.
AllSF
-36subscores
improved,w
ithSignificantimprovem
entsrecorded
regardingphysicalfunctio
n,role
physical,bodily
pain,vitality,social
functio
ning
andmentalh
ealth
.
Prelim
inary
case
study
Duram
azetal.
2018
[19]
500Ubovine
thrombincombinedwith
10%
CaC
l 2.
Singlepercutaneous
injectionof
10mL
PRPplus
1mLthrombinand1mL
CaC
l2injected
into
thenon-unionsite
underfluoroscopicguidance.
Clin
icalassessment:Absence
ofpain/tenderness
atsiteevery
2weeks
usingVAS.
Fracture
healingviaradiological
evaluatio
nevery4weeks
(X-ray
andCTscanning
performed
onall
Meanhealingduratio
nwas
shorterin
PRPgroupcomparedto
controls
(16.71
d±2.4weeks
vs.
19.07±3.67
weeks),although
the
difference
was
notsignificant.
Retrospectiv
ecase
study,
with
control
group.
Curr Osteoporos Rep (2021) 19:1–14 9
Tab
le2
(contin
ued)
patients)foratleast2
4months,
meanfollo
w-up
34.97±8.78
months(PRPgroup)
and33.73±10.53months(control
group).
PRPtreatedpatientsachieved
92.8%
unionvs.80%
inthecontrolg
roup.
PostoperativeVASscores
werereduced
inboth
PRPandcontrolg
roups,
although
theresults
whencomparing
PRPto
controlswerenotsignificant.
Galasso
etal.
2008
[16]
Low
-molecular-w
eighth
eparin
used
asanticoagulant
(novalues).PR
Pactiv
ated
with
batroxobin
andCaC
l 2(novalues)to
obtain
agel
6mLPRPactiv
ated
with
batroxobinand
CaC
l 2(novalues)deliv
ered
asagelto
therim
ofthenon-unionsite.
Clin
icalassessment:absenceof
pain/tenderness
atsite.
Fracture
healingviaradiologic
evaluatio
nperformed
every45
days
until
unionachieved.F
inal
follo
w-upat13
months.
AdditionalCTscansperformed
ifrequired.
91%
(n=20)of
patientsachieved
bony
unionat13-m
onth
follo
w-up,average
timeto
union:
2.5weeks
with
noinfection,complications
orlim
bshortening
observed.
Caseseries
Ghaffarpasand
etal.2016
[30]
PRPactiv
ated
with
acid-citrate-dextrose
containing
gravitatio
nalp
latelet
separatio
nsystem
reagent(GPS®)
priorto
centrifugatio
nfollo
wed
by1g
cefazolin
andlow-m
olecular-w
eight
heparinfollo
wingtheoperation.
5mLPRPvs.5
mLsalin
e(placebo
group)
injected
into
theperiosteum
.Clin
icalassessment:absenceof
pain/tenderness
atsiteusingVAS.
SSracturehealingviaradiologic
evaluationevery45
days
for
270days
(9months).
Lim
blength
was
also
measuredand
comparedwith
postoperativelength
andincidenceof
infection;malunion
andnon-unionwerealso
recorded.
Healin
gratein
PRP-treated
patients
81.1%
(placebo
55.3%,p
=0.025)with
shorteradmission
(6.6±1.3vs.
7.7±1.4days;p
<0.001)
andhealing
duratio
n8.1±1.2vs.
8.5±10.7
months(p=0.003).N
ostatisticalsignificance
inpostoperative
infectionincidence.
Malunionwas
comparablebetween
groups
(10.8%
vs.15.8%
;p=0.136).
Lim
bshortening
lower
inPR
Pgroup
comparedto
control(p=0.030).
Postoperativepain
significantly
reducedinPR
Pgroupatday45
and90.
Randomised
doubled
blinded
placebo
controlled
clinicaltrial
Golos
etal.
2014
[31]
Noinform
ation.
PRPinjectionto
thefracture
cleftu
nder
radiographicguidance
×2.
Multip
ledosesdependentu
ponfracture
(predominantly
distaltib
ialand
forearm
shaftfracturepatients),i.e.3,
or4injections.
Radiologicevaluatio
nat6–8weeks
post-treatmentfollowed
bysubsequent
radiographsevery
6weeks
until
unionachieved.
Boneunionachieved
inin
81.8%
ofpatents(n=108),onaverage
3.5monthsfollo
wingadministration.
PRPmostsuccessfulinhealingof
forearm
fractures(92.8%
).Healin
grate82%
intib
ialfractures.
82.6%
infemoralfracturesand66.7%
inhumeralfractures.
Caseseries,
nocontrols
Jiangetal.
2016
[25]
PRPactiv
ated
with
1000
IUlow-m
olecular-w
eighth
eparin
sodium
follo
wed
by10
mg/mLdoxycycline,
ratio
1000:1
priorto
injection.
5mLAPL
injected
weeklydirectly
tofracture
siteunderfluoroscopic
guidance
×3
Fracture
healingviaradiologic
evaluationatmonthly
intervalsuntil
unionachieved
Improved
clinicaloutcom
eandcallo
usform
ationat4-
and6-month
post-injectio
n;good
bony
unionat
8months.
Casestudy
Labibzadeh
etal.2016
[27]
Noinform
ation.
3mLPLwith
BM-M
SCsim
plantedinto
non-unionsiteusingfluoroscopic
guidance.
Radiologicalevaluationat1,3,6and
12monthspost-implantatio
n.57%
(4/7)successfulbony
unionwith
PL+BM-M
SCs:@
2months(n=1),
6months(n=2)
and12
months
(n=1)
Caseseries
clinical
trial,no
controls
Mahadik
etal.
2018
[29]
Noinform
ation.
~10
mLinjected
around
fracture
sitein
theperiosteum
Clin
icalassessment:absenceof
pain/tenderness
atsite.V
ASand
radiologicalevaluatio
nat1,2and
Allfracturesshow
edradiological
evidence
with
in4months;65.25days
inclosed
fracturesand93.25days
in
Prospectiv
ecase
series,
nocontrols
10 Curr Osteoporos Rep (2021) 19:1–14
Tab
le2
(contin
ued)
3months,follo
wed
byevery
45days
for12
months.
CTscan
incorporated
ifX-ray
findings
wereinconclusive
oram
biguous.
open
fractures.VASscores
reduced
from
11patientswith
VAS>6(severe
pain)at1-monthpost-interventionto5
patientsat1month.A
t6months
post-intervention,only
7patientshad
mild
pain,23patientshadno
pain
(VAS=0).
Malhotraetal.
2015
[24]
Noneused.
15–20mLdose
injected
once
via
intravenouscannulaunder
fluoroscopyguidance
(w/o
anticoagulant).
Clin
icalassessment:absenceof
pain/tenderness
atsite.
Fracture
healingviaradiologic
evaluatio
n@
1,2,3and4months.
87%
(n=82)patientsachieved
unionat
4months,36%
(n=34)show
edtrabecular
bridging
viaX-ray,44%
(n=41)trabecular
bridging
at3months,13%
(n=12)failedunion.
Caseseries,
lack
ofcontrols
Mariconda
etal.2008
[15]
Citrate/citricacid/dextroseused
asanticoagulant.
Autologousthrombin(0.2
mL/m
Lof
PRP)combinedwith
calcium
gluconate(0.2–0.5
mL/m
LPP
P)used
toactiv
atePRP,followed
bycalcium
glutam
ate(0.2
mL/m
L)drop
bydrop
toform
thePG
priorto
injection.
Duringsurgery,PG
was
percutaneously
injected
intheinterfragm
entary
space
underfluoroscopicguidance.
Clin
icalassessment:absenceof
pain/tenderness
atsiteevery
2weeks.
FracturehealingviaX-ray
everymonth
The
studyfailedto
show
theclinical
usefulness
ofisolated
percutaneous
plateletgelsupplem
entatio
nin
long
bone
non-uniontreatedby
external
fixatio
n.The
healingrateof
non-unionwas
90%
(18/20)in
plateletgelcases
and85%
(17/20)in
controls,respectively
(p=0.633).T
hemeantim
euntil
radiographicconsolidationin
non-unionsupplementedwith
platelet
gel(147663
days)w
asnotdifferentto
theresultin
thecontrolg
roup
(153
661
days;p
=0.784).
Caseseries,
with
retrospec-
tive
(historical)
controls
Sanchezetal.
2009
[13]
PRPactiv
ated
with
3.8%
(wt/v
ol)sodium
citratepriorto
centrifugatio
nfollo
wed
by10%
(wt/v
ol)CaC
l 2priortomixing
with
bone
graft/adm
inistration.
PRPwith
bone
allograftb
iomaterial
injected
atexposedinjury
sitein
13patients(novalues),remaining
3patientswerepercutaneously
injected
with
6–8mLPRPaloneevery
2weeks
for6weeks
Clin
icalassessment:absenceof
pain/tenderness
atsite.
Fracture
healingviaX-ray
at2weeks
follo
wed
by~monthly
intervals
until
unionachieved.
CTscan
incorporated
ifno
improvem
entfollowing
10–16weeks.
Union
ratein
surgicalfixatio
nwith
PRP
combinedwith
surgery=84.6%,w
ithaverageuniontim
eof
4.9months.
Dualcentre
retrospec-
tivecase
series
Sayetal.2013
[14]
PRPactiv
ated
with
3.2%
CaC
l 2priorto
centrifugatio
n,plus
5.5%
CaC
l 2(50μL/m
L)priorto
administration
2.5mLPR
Pplus
CaC
l 2activ
ator
injected
into
fracture
lineunder
fluoroscopyguidance
3tim
esover
aweek
Clin
icalassessment.Fracturehealing
viaradiologicevaluatio
nat
~15
weeks
Delayed
unionpatients:unionin
60%;
non-unionpatients:PRPunsuccessful
inachievingunionwhenused
inisolationfollo
wing12-m
onth
follo
w-up
Prospectiv
ecase
series
Tarallo
etal.
2012
[22]
PRPactiv
ated
with
citrate/citric
acid/dextrose(novalues)priorto
centrifugatio
n,plus
autologous
thrombinandcalcium
gluconateprior
toadministration.
Injectionatexposedinjury
site(no
values).
Clin
icalassessment:absenceof
pain/tenderness
atsite.
Fracture
healingviaradiologic
evaluatio
nat~21
months(range
7–14
months).
VASanddisabilityassessmentfor
shoulder
andhand
(DASH
).
Union
achieved
in90%
caseswith
averageuniontim
eof
4.11
months.
MeanVASscore=1atrest,V
AS=2
during
activ
ity.D
ASH=17
Single-centre
prospective
study
Curr Osteoporos Rep (2021) 19:1–14 11
the fracture fragments) and dose of PRP (20 mL) and found verysimilar rates (85%) of union among patients [21] in comparisonto Malhotra et al. (87%).
PRP as a Hybrid Treatment
PRP can also be utilised in combination with other forms ofnon-union fracture treatment, including autografts, compres-sion plates and/or fixation devices [13, 15, 19, 27, 28, 30, 31].Some studies have investigated the effect of combining PRPwith an iliac crest autograft and concluded that the addition ofPRP has the potential to enhance healing [13, 22, 30]. However,in these studies, the authors could not attribute the healing of thefracture to the addition of PRP in isolation, due to the lack ofrandomised control groups. Therefore, no information could beprovided regarding the efficacy of one particular method. Thisis apparent in the case of Tarallo et al. where patients weretreated using a bone graft, dynamic compression plate andPRP [22]. Despite this, union was achieved in 90% of caseswith an average time to union of 4 months. Ghaffarpasand et al.conducted the only randomised double blinded placebo-controlled clinical trial investigating the effect of PRP on therate of healing of non-union fractures treated with an autolo-gous bone graft and internal fixation. Patients received either5 mL of PRP or 5 mL of saline (placebo) during surgery. Thehealing rate was significantly higher in the PRP group in com-parison to that in the control (81.1% vs. 55.3%, p = 0.025) [30].
Reports on the effectiveness of PRP and autograft fixation as anon-union fracture treatment are divided. Case series findingshave largely been positive in terms of improved rates of non-union healing [13, 17, 20, 26]. Though, the rate of healing cannotbe attributed to the use of PRP due to a lack of effective controls.However, in a unique case series byMariconda et al., the healingrate of union of patients treated with PRP and external fixation(90%) was compared to the healing rate of union of a historicalcontrol group (85%), with no significant clinical usefulness ofPRP being reported [15]. However, caution should be takenwhen interpreting this result, since the sample size was relativelysmall (n = 20), limiting the statistical power of the data. A recentrandomised, controlled clinical trial regarding the combined useof PRP and internal fixation [28] reported that the addition ofPRP to internal fixation significantly increased the rate of healing(94% vs. 78%, p< 0.05) whilst reducing healing time (91.6 ± 6.9vs. 115.2 ± 8.4 days, p < 0.05) in comparison to a control group[28]. The study had not only the primary measure of healing ratebut also secondary outcome measures assessed using a visualanalogue scale (VAS). The VASwas used to measure subjectivecharacteristics that cannot be directly measured such as painintensity, treatment costs and adverse reactions; all of which areimportant aspects in a method of treatment [28], particularlywhen considering clinical acceptance and translation. SincePRP elevated the healing rate, this shortened the treatment timewhilst reducing pain and costs.T
able
2(contin
ued)
Taw
fiketal.
2017
[21]
~20
mLPR
Pactiv
ated
with
5mL
autologous
thrombincombinedwith
2mLcalcium
gluconatepriorto
administration
25–30mLPR
Pplus
activ
ator
(throm
bin/calcium
gluconate)
percutaneously
injected
Clin
icalassessment:absenceof
pain/tenderness
atsite.
Fracture
healingrateat6weeks
via
radiologicevaluatio
nfollo
wed
every
4weeks
until
union.
AdditionalCTscansperformed
at10–16weeks
ifsuboptim
aloutcom
esdetected.
85%
successful
unionam
ongpatients
receivingPR
Pat17
wks.75%
‘fair’
results
follo
wingsingleinjection
Single-centre
prospective
study
Zhaoetal.
2017
[28]
PRP(novalues)activ
ated
with
sodium
citrate(novalues
provided)priorto
centrifugatio
nplus
thrombinpriorto
administration(100
U/m
L)
5mLPRPplus
activ
ator
(throm
bin)
directly
injected
atexposedinjury
site
Clin
icalassessment:absenceof
pain/tenderness
atsite.
Fracture
healingrateat9monthsvia
radiologicevaluatio
n;VASat3,6,9
and12
months
PRPwith
internalfixatio
nsignificantly
increasedhealingrate(94%
vs.78%
comparedto
control).
Reduced
healingtim
e(91.6days
vs.
115.2days
incontrol).N
osignificant
difference
inVAS.
Randomised,
controlled
clinicaltrial
APG,autologous
platelet
gel;APL,
autologous
platelet
lysate;BM-M
SCs,bone
marrow–derived
mesenchym
alstem
cells;CaC
l 2,calcium
chloride;CT,
computerizedtomography;
DASH
,disability
assessmentforshoulderandhand;E
IN,exchangeintram
edullarynailing;M
SCs,mesenchym
alstem
cells;P
G,plateletgel;P
LRG,platelet-leukocyte-rich
gel;PRP,platelet-rich
plasma;PSIS,posterioriliac
spine;rhBMP-7,recom
binant
human
bone
morphogeneticprotein-7;
RT,
room
temperature;S
F-36,short-form
36health
survey;V
AS,visualanalogue
score
12 Curr Osteoporos Rep (2021) 19:1–14
Two case studies have been conducted investigating if thecombination of PRP and MSCs can facilitate healing of non-union fractures, both reporting success with the method [27,34]. Labibzadeh et al. stated that, when combined with MSCs,PRP is successful in patients who had previously failed toachieve union using the ‘gold standard’ iliac bone graft. Thishighlights how effective PRP could be in improving bone regen-eration in difficult cases of non-union [27]. However, Centenoet al. did reveal a limitation of the method, including the fact thatthe MSCs isolated from bone marrow aspirate obtained from theiliac crest required a second invasive surgical intervention. Thisincreased the potential risk of infection and causes further pain tothe patient [34]. Moving forward, double blinded, controlledtrials are still required to assess the clinical efficacy of thistreatment.
The Use of PRP vs. Alternative Treatments
In a well-documented, prospective RCT, it was suggested thatrhBMP-7 was a superior bone-stimulating agent compared toPRP. Rather than being injected into the site of the non-union,both PRP and rhBMP-7 were applied locally during revisionsurgery allowing both methods to be directly compared.Subjects (n= 120) in the PRP group had an average non-unionduration of 19.2 ± 2.86months [35]. As discussed above, Bieleckiet al. proposed that, for PRP to be a success, the treatment shouldbe made within 11 months of injury or initial surgery [17]. Thiswould suggest that, whilst the rate of union in the PRP group wassignificantly lower (68.3% PRP vs. 86.7% rhBMP-7), the find-ings of this study should be interpreted with caution. The authorsconcluded that administering PRP alone without a bone graftcould be deemed non-ideal in terms of exploiting PRP’s innatebone regeneration enhancement capabilities [35]. Since the study,PRP has demonstrated success alone in accelerating rate of union[7, 21, 29], with the majority of the literature investigating thepotential of PRP to enhance current treatment strategies [20, 28,30]. Thus, it is unlikely that PRP as a therapy will be used aloneon a large scale. However, PRP could potentially be applied as aminimally invasive method as a way of saving resources in med-ical care, with no significant difference being found between PRPand intramedullary nailing in achieving union [19]. Larger,randomised controlled studies under optimal treatment conditionsare needed to give more powerful and accurate results.
Conclusion
The consensus from the literature is that PRP is effective in accel-erating the healing of non-union fractures. The success it hasdemonstrated when used in isolation ranges in doses from 2.5 to20 mL, implying that it could potentially become a primary formof treatment.However, the non-unionwould have to be inherentlystable and PRP would ideally be administered within 11 months
of injury or initial surgery, although further investigation is neededto confirm this barrier. Moving forward, it is recommended thatRCTs should focus on the effect of injections of at least 5 mL ofPRP, since lower doses have not been reported as successful ininducing bone regeneration [14]. The study by Malhotra et al., amajor contribution to the research, suggested that the commonactivator bovine thrombin may not be a necessity [24] and thisshould be investigated further in future studies to determinewhether sufficient thrombin is produced via local trauma whenthe fracture site is infiltrated with a needle in order to activate theplatelets. Other major contributions include the work byGhaffarpasand et al. and Zhao et al., whereby they have demon-strated the success of PRP and internal fixation as a combinationtreatment [28, 30].However,moreRCTSareneeded to determineif PRP is a more effective bone-stimulating agent for augmentingunion in comparison to the likes ofMSCs and BMPs. Finally, themost effective method of PRP preparation (rate of centrifugation/ultrafiltration, activator, dose, etc.) and administration (single ormultiple injections) needs to be systematically investigated andstandardised in order for the therapy to develop further.
Compliance with Ethical Standards
Conflict of Interest The authors have no other relevant affiliations orfinancial involvement with any organisation or entity with a financialinterest in or financial conflict with the subject matter or materialsdiscussed in this manuscript.
Human and Animal Rights and Informed Consent This article does notcontain any studies with human or animal subjects performed by any ofthe authors.
Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing, adap-tation, distribution and reproduction in any medium or format, as long asyou give appropriate credit to the original author(s) and the source, pro-vide a link to the Creative Commons licence, and indicate if changes weremade. The images or other third party material in this article are includedin the article's Creative Commons licence, unless indicated otherwise in acredit line to the material. If material is not included in the article'sCreative Commons licence and your intended use is not permitted bystatutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of thislicence, visit http://creativecommons.org/licenses/by/4.0/.
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14 Curr Osteoporos Rep (2021) 19:1–14
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