Biologic and Tissue Engineering Strategies for Tendon Repair
Biologic and Tissue Engineering Strategies for Tendon Repair
Ian R. Sigal 0 1
Daniel A. Grande 0 1
David M. Dines 0 1
Joshua Dines 0 1
Mark Drakos 0 1
Daniel A. Grande 0 1
0 Hospital for Special Surgery , 523 East 72nd Street, New York, NY 10021 , USA
1 Orthopedic Research Laboratory, The Feinstein Institute for Medical Research , 350 Community Drive, Manhasset, NY 11030 , USA
This review summarizes recent developments in biologic treatments-including growth factors, platelet-rich plasma (PRP), stem cells, and cell-seeded scaffolds-for tendon repair. Growth and differentiation faction-5 (GDF-5), insulin-related growth factor-1 (IGF-1), and basic fibroblast growth factor (bFGF) all improved extracellular matrix (ECM) production and tensile strength of treated tendons; however, no clinical trials were done on GDF-5. Platelet-derived growth factor-BB (PDGF-BB) improved proliferation and ECM production, but did not consistently improve mechanical properties. The literature was mixed on the efficacy of PRP for the treatment of chronic and acute tendinopathies. However, PRP did cause any complications, and its benefits may be enhanced once an ideal, standardized composition is developed. Therefore, PRP may be a valid treatment, especially once nonsurgical management options have failed. Mesenchymal stem cells (MSCs) significantly and substantially improved the quality of tendon repairs and demonstrated the ability to regenerate an enthesis. Adipose-derived stem cells (ADSCs) have similar effects and are easier to harvest. The periosteum may also regenerate the tendon-bone attachment. Tenocytes, meanwhile, may be ideal for midsubstance tendon repairs. Cell-seeded scaffolds-especially ECMderived scaffolds-were demonstrated to improve ECM production, enhancing the healing abilities of tenocytes or stem cells while providing early mechanical support to healing tendons. Each of these treatments demonstrated enhanced healing compared to common surgical techniques; moreover, patient outcomes may be enhanced by combining these treatments.
Tendon; Biologics; Growth factors; Platelet-rich plasma; Stem cells; Scaffolds
Tendinopathy is among the most common injuries in
athletes and the general population, affecting over 50 % of
runners and up to 80 % of runners. Chronic, nonhealing
tendon injuries frequently require surgical treatment, yet
despite recent advancements in orthopedic surgery, many
common tendon repair techniques yield less than optimal
results [1–3]. Healed tendons tend to form scar tissue
with different mechanical properties than healthy tendon
tissue. This may be due to the variance in collagen types
within the scar tissue compared with healthy tendon.
Collagen type I (Col-I) predominates in health tissue,
whereas collagen type III (Col-III) is more abundant after
tendon repair, resulting in elastic, loosely organized
fibrils [4–6]. These healed tendons, therefore, are more
prone to reinjury. Moreover, many common techniques
to repair tendon tears at the tendon–bone interface, such
as the use of suture anchors, cannot regenerate the
enthesis. The tendon and bone are thus only held together
primarily by sutures, resulting in a high incidence of
rerupture after tendon reattachment surgeries [7, 8].
Therefore, alternative surgical procedures may be
required to ensure proper tendon healing.
Biologic augmentation is a promising strategy to
enhance tendon repair and regeneration. Biologics refers to
cell-based products and therapies that can promote
cellular regeneration and differentiation. These materials may
limit the formation of scar tissue with undesirable
mechanical properties and, potentially, can aid in the
regeneration of the tendon–bone interface. This article will
focus on three developments in biologics with implications
in tendon healing: growth factor application, platelet-rich
plasma (PRP), and stem cell therapy.
PRP is blood plasma isolated via centrifuges and with
platelet concentrations substantially higher than whole
blood . Platelets, when activated, secrete growth factors
s u c h a s p l a t e l e t - d e r i v e d g r o w t h f a c t o r ( P D G F ) ,
transforming growth factor beta (TGF-β), and fibroblast
growth factor (FGF), which may promote healing, shorten
the duration of recovery from surgery, and impede the
formation of scar tissue . Moreover, as PRP is derived
from a patient’s own blood, its use is associated with few
complications . For this reason, PRP administration
has become an increasingly popular treatment for tendon
injuries. Growth factors and mitogens such as those found
in PRP can also be coated on scaffolds or sutures or
applied directly to an injury site.
Stem cells can differentiate to replace damaged cells
and tissues and have been thoroughly investigated as
augments for tendon repair surgery. Stem cell therapies are
particularly promising to promote the regeneration of the
enthesis , thereby providing a more durable tendon–
bone connection than suture anchors. Mesenchymal stem
cells (MSCs) are the cell type most commonly
investigated to promote tendon repair, although stem cells from a
variety of sources have been considered. Stem cells often
are delivered to an injury site through a scaffold or
injection. A scaffold fills a defect or gap in a tendon, taking on
much of the tendon’s mechanical load until the tissue
heals and the scaffolds degrades . These scaffolds
may also mimic the environment of uninjured tendon,
guiding the differentiation of seeded cells .
Growth and differentiation factor 5 (GDF-5, also known as
bone morphogenic protein-14) has been well studied in animal
models for its role in tendon repair. In vitro studies have
shown that GDF-5 may upregulate the expression of
aggrecan, collagen types I and III (Col-I, Col-III), scleraxis,
tenomodulin, and metalloproteinase 9 (MMP-9, an enzyme
which promotes tenocyte infiltration) in mouse and rat
tenocytes (Table 1) [14, 15]. Furthermore, GDF-5
augmentation increased proliferation and ECM production of tenocytes
 and rat adipose-derived stem cells at a concentration of
100 ng/kg . GDF-5 supplementation of human MSCs did
not affect cell proliferation, but did increase total collagen
synthesis, scleraxis and tenascin-C expression, and Col-I/III
ratios at 100 ng/kg .
When compared with saline injections, 10 μg
GDF-5injections downregulated proinflammatory genes, improved
collagen organization, and promoted aggrecan, MMP-9, and
fibromodulin expression in mouse Achilles tenotomy suture
repairs . GDF-5-coated sutures (at dosages of 24, 55, 556,
and 1.0 μg/cm) also increased stiffness, tensile strength, and
cross-sectional area in lacerated rat Achilles tendons [18, 19].
GDF-5-coated sutures at 55 ng/cm improved collagen
organization and maximal load of severed rabbit flexor tendons after
3 weeks (11.6 ± 3.5 N vs. 8.6 ± 3.0 for controls without
GDF5), although these values were not significant after 6 weeks
. GDF-5 gene therapy using an adenovirus vector was also
shown to promote healing, lessening visible gapping and
improving tensile strength by 70 % compared with sham virus
controls in a rat Achilles model .
Although GDF-5 provides substantial healing benefits,
other GDFs may also be effective. Aspenberg et al. found
that the delivery of 10 μg GDF-5 or 1 μg GDF-6 (also
known as bone morphogenic protein-13) via Col-I sponges
enhanced tensile strength compared with controls
receiving unseeded sponges in a rat model of Achilles repair
, and ectopically implanted GDF-5, GDF-6, and
GDF-7 (also known as bone morphogenic protein-12) at
concentrations between 5 and 25 μg were all found to
induce neotendon formation in rats .
GDF-7 may have implications in stem cell preparations.
GDF-7 at 10 ng/mL stimulated the expression of scleraxis
and tenomodulin in vitro in rat MSCs. When Col-I scaffolds
seeded with these GDF-7-primed MSCs were implated in
half-width defects of rat calcaneal tendons in vivo, the
experimental tendons demonstrated enhanced matrix and cell
organization compared with untreated MSCs . Seeherman
et al. found that Col-I sponges treated with rhGDF-7 (also
known as BMP-12) more than doubled load-to-failure in an
ovine model of rotator cuff repair when compared with
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controls receiving untreated sponges . The injection of
2.5 μg of GDF-6 (BMP-13) or 7 also increased tendon
cellularity, thickness, and the rate of repair in a rat Achilles
transection model . Pending further research, this may be a
promising treatment for tendon damage.
GDF-5, 6, and 7 have been investigated as augments
for tendon repair due to their tenogenic specificity. Other
growth factors in the bone morphogenic protein (BMP)
family have osteogenic effects and are thus unsuitable
for midsubstance tendon regeneration, although these
growth factors may have applications for enthesis repair.
Bone morphogenic protein-2 (BMP-2) at 100, 500, and
1000 ng/mL and BMP-7 at 100, 500, 1000, and
2000 ng/mL enhanced Col-I production in cultured
tenocytes, and BMP-7 increased cell activity in a
dosedependant manner . RhBMP-2 injections (at a dosage
of 15 μg) appeared to promote the growth of enthesis-like
tissue and enhanced ultimate failure load in a rabbit model
of flexor tendon reattachment surgery . BMP-2’s
ability to induce bone formation may also enhance traditional
surgical techniques. Kim et al. found that fibrin gel
supplemented with BMP-2 at 10 μg/mL induced bone
formation in suture anchor holes during patellar tendon
reattachment surgery in a rabbit model. Consequently, the
anchor connections were stronger, resulting in higher
load-to-failure compared with suture holes treated with
BMP-2-seeded Col-1 gel or untreated controls . Not
all such studies have been promising; Thomopoulos et al.
found that BMP-2 delivery (at dosages 0.344 and
0.688 μg/L) via collagen sponges or calcium phosphate
matrix, as an augment for canine flexor tendon
reattachment, did not reduce the formation of fibrous scar tissue,
increase ultimate failure load, or promote enthesis
regeneration . The authors noted BMP-2 concentrations at
the injury site would have been low due to the slow
release kinetics from the collagen and calcium phosphate.
Thus, although the treatment could have promoted healing
long-term, it was ineffective during the 7-day critical
window immediately post-surgery .
TGF-ß1 has also been investigated as an augment for
tendon repair, but the results have not been as promising. In vitro
TFG-ß1 supplementation at 1, 10, and 100 ng/mL was found
to increase Col-II expression in cultured rat tendon stem cells
 and Col.V and XII expression in mouse tenocytes .
Although scleraxis was upregulated, Col-I was not .
Klauss et al. found that augmentation of cultured rabbit
endotenon-derived cells with 2 ng/mL TGF-ß decreased
Col1 expression and increased the production of Col-III .
Injection of 10 or 100 ng TGF-ß1 did, however, increase
failure loads and procollagen I and III expression in a rat Achilles
defect model . Analogous treatments with 5 ng TGF-ß1
injections also improved tangent modulus and failure loads in
rabbit patellar tendon resections .
Although basic science studies for these growth factors
have been promising, there is a dearth of clinical data.
Human trials would be needed to validate whether GDF-5,
6, and 7 augmentation may be valuable clinical options for
midsubstance repair and whether BMP-2 may enhance
Insulin-Like Growth Factor
Insulin-like growth factor (IGF-1) may also have implications
for tendon regeneration. IGF-1 augmentation of equine tendon
progenitor cells cultured in monolayer at 100 ng/mL increased
proliferation rate, GAG synthesis , and Col-I and Col-III
expression , and equine flexor tendon explants cultured in
250 ng IGF-1/mL increased DNA content by 31 %, GAG
content by 29 %, and collagen synthesis by 72 % .
IGF-1 treatments repeatedly enhanced ECM synthesis
in vivo as well. IGF-1 injections (at a dosage of 1 mg) to
the patellar tendon enhanced collagen fractional synthesis
rate by 25 and 100 % respectively in healthy human patients
when compared with saline-treated control tendons [39, 40].
In animal models, enhanced ECM production was associated
with improved mechanical properties of healed tendons.
Lyras et al. found that rabbit patellar tendon defects treated
with IGF-1 and TGF-ß1 in combination delivered via a
fibrin sealant saw significant increases in stiffness and
ultimate failure load . Witte et al. (2011) administered four
to five 25 or 50 μg intralesional IGF-1 injections to
racehorses suffering from superficial digital flexor tendonitis
(SDFT). IGF-1 augmentation reduced echolucency in 23 of
26 subjects, although only 62 % were able to return to
racing . Dahlgren et al. found that horses receiving ten
2 μg rhIGF-1 injections over 10 days saw significant
reductions in the size of collagenase-induced lesions, although
there were no significant differences GAG content, Col-I
and III ratios, or tendon strength between IGF-1-treated
and control tendons .
IGF-1 has also been studied in conjugation with stem cell
treatments. Tendon stem cells treated with IGF-1 maintained
multipotency for up to 28 days and increased decorin and
scleraxis expression . Schnabel et al. treated horses with
SDFT using mesenchymal stem cells (MSCs) cultured with or
without IGF-1. Although both treatments improved
histological scores relative to PBS-treated controls, there were no
significant differences between the MSCs and IGF-1 + MSC
treatments . Thus, IGF-1 does not seem to enhance the
reparative effect of stem cell treatments in vivo. Alternative
growth factors may have a synergistic effect with MSCs and
other stem cell treatments; this is a fertile area for future study.
Growth hormone (GH) has also been considered for the
treatment of tendinopathies. GH increases IGF-1
expression; acromegalic patients (who produce excess GH), for
example, display a 2.9-fold increase in IGF-1 expression
relative to GH-deficient patients. Musculotendinous
collagen expression was elevated 1.7-fold in these patients,
which the authors attribute to this excess IGF-1 production
. Doessing et al. demonstrated that subcutaneous GH
injections (at dosages between 33.3 and 50 μg/kg/day for
14 days) increased tendon Col-1 expression in healthy
human patients 3.9-fold . Furthermore, GH has been
demonstrated to aid in bone growth and healing .
Andersson et al. hypothesized that intramuscular GH
injections at a dosage of 2 mg/kg for 10 days could stimulate the
repair of transected rat Achilles tendons; however, it was
found that GH treatments neither increased the strength of
repaired tendons nor augmented the healing process .
In summary, IGF-1 promotes tendon regeneration by
increasing Col-I production, resulting in increased stiffness
and failure loads. GH increases IGF-1 production, although
it is unclear if it has applications in tendon regeneration due to
a lack of evidence. Further research should determine whether
GH has synergistic effects with IGF-1, or whether IGF-1 alone
is a superior treatment.
Fibroblast Growth Factor
Basic fibroblast growth factor (FGF) (bFGF or FGF-2)
has also been proposed as a treatment for tendon damage.
In vitro tests have shown that bFGF delivered via fibrin
matrices at dosages between 0.125 and 1.25 μg/mL
induced a 2-fold increase in canine tenocyte proliferation
, and administration of bFGF (5 ng/mL), PDGF
(50 ng/mL), and IGF-1 (100 ng/mL) to cultured synovial
sheath, epitenon, and endotenon cells harvested from
rabbit digital flexor digitorum profundus tendon increased
proliferation by up to 588 % . FGF-2 augmentation
at 100 ng/mL of equine tendon progenitor cells cultured
in monolayer significantly increased ECM and Col-III
synthesis . However, decreases in Col-I and III
expression were observed in canine tenocytes, perhaps
hindering repair .
In vivo studies have also been promising. In a rat model of
Achilles repair, electrospun PLLA scaffolds with bFGF
nanoparticles (releasing 2900 pg of bFGF) increased Col-1
expression 2-fold relative to controls implated with empty scaffolds
. Three studies demonstrated that serial bFGF injections
(three 1200 ng/kg injections administered over 1 week) also
improved the biomechanical properties of repaired rabbit
SDFTs [51–53]. In one study, adhesions were only present in
30 % of experimental tendons as opposed to 85 % of
salineinjected controls after 28 days . Experimental tendons in all
three studies more closely resembled healthy tendon tissue, and
experimental rabbits were more physically active than controls.
Moreover, maximal stress, yield stress, stiffness, ultimate strain,
and yield strain were significantly improved relative to controls
[51–53]. Gel-coated nylon sutures soaked in a 400 μg/mL bFGF
solution and used to treat severed rabbit flexor digitorum
fibularis tendons (FDFTs) increased epitenon proliferation and
epitenocyte infiltration and enhanced ultimate failure load by
more than 33 % at 3 weeks, suggesting that bFGF may
specifically promote early healing . In accord with this result, Ide
et al. found that rat supraspinatus tendon ruptures repaired with
bFGF-treated fibrin sealant (100 mg/kg) had significantly higher
tendon-to-bone insertion maturity scores (15.8 ± 0.8 vs.
10.6 ± 0.5 out of 32) and mechanical strength (6.6 ± 2.0 N vs.
3.2 ± 0.6 N) than tendons repaired with untreated fibrin sealant
after 2 weeks, although there were no significant differences
between the two groups at 4 or 6 weeks . Alternative growth
factor delivery systems, such as scaffolds, may enhance or
prolong bFGF’s healing potential. Zhao et al. found that
bFGFseeded electrospun, randomly aligned PGLA scaffolds (at a
dosage of 20 μg/mL), significantly improved collagen organization
at all time points (22.6 ± 0.7 gray-scale units at 2 weeks,
32.7 ± 0.8 at 4 weeks, and 45.4 ± 1.2 at 8 weeks vs.
20.5 ± 0.9, 31.4 ± 0.7, and 43.8 ± 1.0 for scaffolds without
bFGF), ultimate failure load at 4 and 8 weeks (21.4 ± 1.3 N
and 32.7 ± 1.0 N for the PGLA + bFGF vs. 20.7 ± 1.6 N and
28.4 ± 1.2 N for PGLA), ultimate stress at 8 weeks (1.82 ± 0.03
vs. 1.62 ± 0.03 MPa), and stiffness at 8 weeks (14.9 vs. 13.7 N/
mm) in a rat model of rotator cuff repair , and administration
of a fibrin sealant with bFGF (100 μg/kg) in conjugation with
acellular dermal grafts significantly improved tendon maturity
scores (24.3 ± 1.0 vs. 20.6 ± 2.6 out of 28 at 6 weeks, 26.7 ± 0.8
vs. 25.2 ± 0.5 at 12 weeks) and ultimate failure loads
(10.2 ± 3.1 N vs. 7.2 ± 2.2 N at 6 weeks, 15.9 ± 1.6 N vs.
13.2 ± 2.0 N at 12 weeks) relative to the graft + fibrin group
in a rat model of rotator cuff repair .
Although bFGF has been shown to promote healing,
Thomopoulos et al. found it to be harmful. FGF-2 (500 or
1000 ng) delivery via fibrin matrices in a canine model of
operative flexor tendon repair not only increased cell proliferation,
but also promoted inflammation, adhesion formation,
neovascularization, and scar formation relative to controls only receiving
operative repair. Tendons treated with 1000 ng bFGF had a
mean Col-I/Col-III ratio of 3.4, whereas the operative repair
group had a mean Col-1/Col-III ratio of 4.3 . Zhao et al.
 demonstrated that bFGF delivered at high doses via fibrin
matrices can enhance tendon repair in a rat model; the findings
of Thomopoulos et al. may indicate that bFGF has adverse
effects that are more pronounced in a canine model.
Gene therapy has also been used to upregulate bFGF
expression. In vitro adenovirus-mediated bFGF gene transfer
increased expression of bFGF, Col-I, and Col-III in cultured
rat tenocytes . Tang et al. injected the severed ends of
surgically repaired chicken FDFTs in vivo with an adenovirus
vector to express bFGF. Ultimate strength of experimental
tendons was significantly higher than controls receiving a
sham virus or suture repair at 2 and 4 weeks. At 8 weeks,
the ultimate strength of adenovirus + bFGF tendons was
84.8 ± 22.0 N, whereas the strength of repair-only tendons
was 56.7 ± 17.6 N .
Not all gene therapy treatments were effective. Kraus et al.
treated severed rat Achilles tendons with MSCs that had been
induced to express bFGF via a lentivirus vector. The treatment
was only marginally effective; it did not enhance failure load
or stiffness, and no significant histological differences were
seen between the bFGF, the sham virus, or untreated control
groups after 4 weeks . This indicates that direct injection
of virus vectors, rather than indirect application via treated
MSCs, is a more effective application of gene therapy.
Platelet-Derived Growth Factor
In vitro tests have shown that platelet-derived growth
factorBB (PDGF-BB) may augment tendon repair [62–66]. PDGF
(100 ng/mL) increased Col-I expression by 60 % and
decreased Col-III production by 51 % in equine SDFT explants
, and PDGF (0.125, 0.25, and 1.25 μg/mL) delivered via
fibrin matrices induced an approximately 2-fold increase in
proliferation and significantly increased Col-I production of
cultured canine tenocytes at dosages of 0.125 and 1.25 μg/mL
. Cultured rat tenocytes treated with 15 μg of plasmid
containing PDGF-BB cDNA underwent a 125 % increase in
Col-I expression .
These benefits have been reflected in vivo; in three studies,
rhPDGF augmentation (100, 500, and 40 ng respectively) of
canine flexor tendon repair using a fibrin-heparin delivery
system promoted joint flexibility and rotation (19° ± 10° for
proximal interphalangeal joints receiving repair + PDGF vs. 8° ± 4°
for joints receiving repair only) , tendon gliding ,
fibroblast proliferation [65, 66], DNA content (20 % increase at
7 days), and Col-I expression at 7 days . However, these
treatments did not significantly affect the tensile properties of
treated tendons and may not affect risk of reinjury [64–66]. The
use of rhPDGF-BB demonstrated modest benefits in a rat model.
In a rat model of Achilles tendinopathy, rhPDGF injections
significantly increased maximal strength of augmented tendons
compared with those treated with saline or PRP. The 3-μg dose
increased maximal load to 24.5 ± 4.3 N after 7 days, whereas
maximal load of saline-injected controls was 12.5 ± 2.9 N. After
21 days, maximal load for tendons receiving 10 μg PDGF-BB
was 30.1 ± 5.5 N compared to 15.7 ± 4.4 N for controls . In
an ovine model of rotator cuff repair, bovine collagen matrix
scaffolds seeded with rhPDGF at dosages of 75 and 150 μg
s i g n i f i c a n t l y i m p r o v e d u l t i m a t e f a i l u r e l o a d s
(1490.5 ± 224.5 N and 1486.6 ± 229.0 N respectively vs.
910.4 ± 156.1 N for suture-only controls) . Dip-coated
PDGF-BB sutures (at dosages of 1.0 and 10.0 mg/mL)
significantly lowered cross-sectional area and increased ultimate
tensile strength (1.9 ± 0.5 and 2.1 ± 0.5 MPa respectively vs.
1.0 ± 0.2 MPa for controls) in a rat model of Achilles repair
. PDGF sutures did not significantly improve tendon
strength in an analogous study investigating ovine rotator cuff
repair using PDGF-coated sutures at concentrations ranging
from 0.1 to 3.33 mg/mL, but tendon stiffness and collagen
organization were enhanced at all concentrations, resulting in a
tendon–bone attachment more closely resembling an enthesis
structure (Fig. 1) .
Although PDGF-BB enhances proliferation and Col-I
expression, there is conflicting evidence that this treatment substantially
affect tendon tensile properties. Any adverse side effects of
PDGF-BB may have been more pronounced in the canine
model, resulting in substandard repair relative to PDGF treatments in
rat and ovine models. PDGF will need to be studies in a clinical
setting to determine whether it is suitable for humans.
Furthermore, PDGF dip-coated sutures promoted repair of
insertion-site injuries in rat and ovine models. Further research
should examine the role of PDGF in enthesis regeneration.
Platelets contain many growth factors and thus can promote
healing through similar mechanisms as growth factor
applications . However, the platelet concentration in PRP is
relatively low, only two to ten times more than that of whole
blood. For this reason, the growth factor concentrations
released from PRP are analogous to those of the body, reducing
the risk of complications. Dallaudiére et al.  treated 408
patients with intratendinous PRP injections. During the
32Fig. 1 Sheep enthesis 6 weeks post-operatively. Insertion point defects
were repaired with two suture anchors using rhPDGF-BB-coated sutures.
Tissue sections were stained with Safranin-O/Fast Green (×100
magnification). Distinct tendon (T), cartilage (C), and bone (B) layers
are evident in the sample, suggesting this treatment may promote
enthesis regeneration 
month trial, no clinical complications were reported,
demonstrating the safety of such procedures.
In vitro studies have shown PRP to be a promising
treatment. Beitzel et al. showed that PRP significantly increases
tenocyte viability when compared with an FBS-treated control
. Sadoghi et al. treated human tenocytes with PRP of
varying platelet concentrations (1-, 5-, and 10-fold). All PRP
treatments increased proliferation, DNA levels, and GAG
levels, although lower concentrations were more effective
. Jo et al. found that PRP significantly increased the
production of matrix, GAGs, and Col-1 and III in human
tenocytes in a dose-dependant manner .
PRP for Acute Tendinopathies
Animal studies have demonstrated the efficacy of PRP
treatments for the healing of acute tendon tears or ruptures. Lane
et al. treated damaged rabbit patellar tendons with PRP
injections. It w as found that the injections resu lted in
hypercellularity, an upregulation in Col-1 expression, and an
increase in cell proliferation rate . PRP treatments in
combination with low-level laser therapy could also enhance the
production of Col-1 in a rat model, whereas unaugmented laser
therapy had no significant benefits . PRP administration of
rat Achilles ruptures also enhanced Col-1 expression and
ultimate failure loads when compared with controls given saline or
platelet-poor plasma treatments [78, 79]. The PRP treatments
also increased Col-1 fiber density and inflammation .
In randomized human clinical studies, PRP injections were
found to significantly reduce pain [80–82], increase shoulder
rotation, and improve load-bearing capacity [80, 81] during
the first 3 to 6 months after rotator cuff surgery, suggesting
that PRP may aid early healing. Moreover, PRP was found to
significantly reduce retear rates in the long term . De
Almeida et al. similarly found that PRP significantly reduced
the size of the patellar tendon gap area after ACL
reconstruction, signifying a more complete repair . Sanchez et al.
found that augmentation of Achilles suture repair using
platelet-rich fibrin matrices also improved range of motion,
decreased tendon cross-sectional area, and shortened
recovery, allowing athletes to resume training .
Other studies did not find PRP to be effective. PRP did not
affect the biomechanical properties of Achilles repair in a rat
model , and PRP-treated flexor–tendon lesions in sheep
were found to have elevated Col-1II expression, poorly aligned
ECM, and extensive, pathological hypervascularization .
Beck et al. surgically repaired defects of the supraspinatus
tendon–bone interface using transosseus repair methods in a rat
model. The PRP group tendons were also augmented with
subsequent PRP injections. After 21 days, there were no significant
differences between the repair and PRP groups in failure load,
although the PRP group had a higher failure strain and the
standard repair group had higher stiffness. PRP collagen fibers were
more organized and thicker than in the control. Aside from slight
infiltration by hypertrophic chondrocytes during the first 7 days,
the PRP treatment did not have any negative effects but did not
aid or accelerate healing .
In a human clinical study, PRP augmentation of
Achilles rupture repair did not improve modulus or
tendon function (as measured using a heel-raise index) after
1 year . This may suggest that PRP is less effective at
healing more severe injuries.
To date, the results of PRP on acute tendon repair have
been conflicting at best. There are many confounding
variables within these clinical studies including the
mechanism PRP delivery, white blood cell concentration, and
even the daily fluctuations of growth factor and platelet
levels within a single individual. This variation may
significantly affect outcomes.
PRP for Chronic Tendinopathies
Outcomes following PRP treatments for chronic tendon
injuries and inflammation have also been mixed. Over eight
clinical human trials, the vast majority of patients suffering from
chronic, recalcitrant tendinosis saw significant and substantial
reductions in pain [88–95] and increases in joint function [72,
88, 90, 92–95] when treated with PRP without supplemental
procedures. These patients had experienced symptoms of
tendonosis for at least 3 months and had not responded to
nonsurgical interventions [88–90, 92–95]. Raymond Monto
treated 30 patients experiencing severe, persistent Achilles
tendinopathy with a single 4 mL injection of PRP . After
2 years, mean pain scores had improved dramatically. Nine of
ten patients who had been forced to leave their jobs due to
their injuries were able to return to work, and 18 of 22 treated
athletes were able to resume playing their sports. In a similar
study, 32 patients suffering from midsubstance Achilles
tendinosis were treated with a single PRP injection .
Within 6 months, 25 patients were asymptomatic.
Despite marked improvements in tendon pain and function
after PRP treatment, its effects may not be as substantial as
previously suggested. In human clinical studies, de Vos et al.
found that PRP did not significantly affect ultrasonographic
tendon structure, neovascularization, or pain scores compared
with saline placebo controls [96, 97]. A 1-year follow-up
confirmed that PRP did not affect clinical outcomes or the
duration of injury recovery . Jo et al. demonstrated that PRP
did not diminish pain in patients after rotator cuff repair
surgery. Moreover, although the PRP group did experience a
lower retear rate than controls, this difference was not
statistically significant . Owens et al. found that MRI appearance
improved for only one of six damaged tendons treated with
PRP, suggesting they had not healed properly . However,
despite lack of apparent healing, pain and function scores rose
significantly. Raeissadat et al. also found that PRP was no
more effective as whole blood injections. Thirty patients
received 2 mL of whole blood, and 31 received PRP. Both
groups saw significant reductions in pain, but there were no
significant differences in the outcomes of either group .
Many patients whose symptoms were relieved by PRP
therapies may have seen improvements without treatment. In
a double-blinded, controlled, randomized study involving 230
patients, Mishra et al. demonstrated that PRP can reduce
symptoms of tennis elbow . The PRP group had a success
rate (defined as a 25 % reduction in pain) of 84 % over
24 weeks. However, controls treated with bupivacain (a local
anesthetic) had a success rate of 64 %. This difference was
significant, but it suggests that PRP only improved prognosis
by 20 %. Regardless, PRP-treated patients did experience
significantly larger reductions in pain than the control group,
indicating that, although the treatment is not as effective as
suggested in other studies, it is still beneficial for patients.
PRP has also been demonstrated to be effective in
conjugation with other techniques for the treatment of tendinosis
[100–102]. A treatment involving the application of
adiposederived MSCs (ADSCs) and PRP to alleviate digital flexor
tendonitis in horses was able to return 17 of 19 horses to their
previous levels of competition . Only two horses
experienced reinjuries. However, as PRP and ADSC treatments
were not evaluated separately, it is not clear which augments
had a larger impact on the healing process. In a human clinical
study, Finnoff et al. treated 31 patients suffering from
tendinosis with needle tenotomy supplemented with a PRP
injection . Eighty-four percent of patients regained
tendon function, and 86 % of patients experienced significant
reductions in pain. In a double-blinded, randomized,
controlled trial, Dragoo found that dry-needling (DN) treatments
are enhanced by supplementation with PRP . Every
patient treated with PRP saw improvements in their symptoms,
whereas three of 13 DN treatments failed. Moreover, patients
receiving PRP injections recovered more rapidly and had
significantly higher VISA (Victorian Institute of Sports
Assessment) scores for tendinopathy at 12 weeks.
PRP may be more effective than some traditional
techniques. Smith et al. demonstrated that PRP treatment had
better functional outcomes than electroshock wave therapy
(ESWT) . In a clinical trial, both procedures reduced pain
and improved VISA scores; however, VISA scores of
PRPtreated patients were significantly higher than those of ESWT
patients after 6 and 12 months, and 91 % of PRP patients were
satisfied with the results of their procedures, as opposed with
only 61 % of ESWT patients.
There is mixed evidence supporting the use of PRP for
chronic tendinopathies. Multiple animal studies and clinical
trials can reduce pain and increase tendon function when
traditional treatments have failed. However, several studies have
shown that PRP had no effect on patient outcomes [96–99].
These conflicting data may be caused by variations in PRP
composition, such as platelet and white blood cell
concentrations. Future research should strive to identify the ideal PRP
makeups to enhance tendon repair. Given the marked
improvements in pain and tendon function scores after PRP
treatment reported by some studies, PRP has the potential to be an
effective, cheap, and safe procedure if the ideal composition
can be identified.
Bone Marrow Stem Cells
The ability of mesenchymal stem cells (MSCs) to augment
tendon healing has been demonstrated in both animal and
human trials. Injections of MSCs into midsubstance Achilles
tendon ruptures increased ultimate failure load in a rat model
[103, 104]. Huang et al. found that failure load for the
normoxic MSC group was 2.7 N/mm2 at 4 weeks vs. 1.7 N/
mm2 for untreated controls. Culturing MSCs in a hypoxic
environment (1 % O2) significantly more than doubled failure
load (5.5 N/mm2) relative to normoxic MSCs . Okamoto
also found MSCs to be more effective than bone marrow cells
(BMCs). Ultimate failure loads following MSC treatment
were 3.8 N vs. 0.9 N for controls and 2.1 N for bone marrow
cell-treated tendons (p < 0.016) . Nourissat et al. 
removed the enthesis of the Achilles tendon in a rat model.
Two tunnels were made through the calcaneum, the detached
tendon was sutured to the bone, and the injury site was then
injected with either chondrocytes, MSCs, or saline. The MSC
and chondrocyte-treated tendons achieved significantly higher
failure loads after 45 days (84.6 ± 17.1 N and 80.3 ± 13.0 N
respectively) than the saline group (68.6 ± 15.1 N) and, in fact,
had higher failure loads than healthy, uninjured tendon
(74.4 ± 10.9 N). Moreover, the MSC group regenerated an
organized enthesis, showing that MSC treatments can result
in high quality repairs .
Human clinical trials investigating the repair of rotator cuff
tears using MSCs have also been promising [105, 106].
Hernigou et al. found that a bone marrow aspirate concentrate
(BMAC) injection, in conjugation with suture-anchor repair
surgery, significantly lowers the risk of retears of the
supraspupinatus tendon after surgery. Twenty-five of 45
control group patients experienced tendon retears within 10 years
of the repair procedure; in contrast, only 6 of 45 patients who
received BMAC injections experienced analogous reinjuries
. In fact, patients in the BMAC group who had received
fewer MSCs were significantly more likely to have a retear.
Ellera Gomes et al.  complemented the use of sutures
with injected bone marrow mononuclear cells (BMMCs) for
rotator cuff lesion repair in 14 patients. After 1 year, the
integrity of the tendon tissue in all patients remained
uncompromised, and mean UCLA shoulder rating scores
increased from 12 ± 3.0 to 31 ± 3.2.
Ozasa et al. found that bone marrow stem cell (BMSC) and
muscle-derived stem cell (MDSC) treatments promoted
tendon healing in excised canine Achilles, resulting in
regenerated tissues with similar mechanical properties . There
were no significant differences between the two groups in
mean failure strength or mean stiffness after 4 weeks.
However, MDSC administered in conjugation with a
100 ng/mL rhGDF-5 gel patch significantly enhanced mean
failure strength relative to the BMSC (p < 0.001) MDSC
(p < 0.001) and BMSC + GDF-5 tendon (p = 0.019). No
clinical studies have been conducted on MDSCs; this may
be a promising future direction for stem cell research. This
study also indicates that stem cells may have synergistic
effects with growth factors.
Adipose-Derived Stem Cells
ADSCs are an alternative to bone marrow-derived MSCs that
can be harvested using liposuction. ADSCs release growth
factors that may promote differentiation and
immunosuppressive factors that may reduce inflammation [108, 109].
Moreover, they require much less invasive procedures to
obtain than MSCs. Therefore, ADSCs may be a viable
alternative to MSCs. Using a rabbit model, Oh et al.  found that
the injection of cultured ADSCs into muscle adjacent to the
insertion site of torn subscapularis tendons in conjugation with
a standard suture anchor treatment resulted in a higher quality
repair than the suture anchor repair alone. The ADSC-treated
tendons had less fatty infiltration, stronger tendon–bone
connections, and higher load-to-failure values than the saline +
suture anchor repair tendons. Uysal et al. similarly found that
ADSC augmentation of rabbit Achilles repair significantly
improved tensile strength of the regenerated tissues .
Future studies directly comparing the effects of MSC and
ADSC administration will be necessary to determine whether
ADSCs are a viable replacement for MSCs.
Periosteal cells can differentiate into either chondrocytes
or osteocytes, and they may promote enthesis
regeneration. Chang et al. detached the infraspinatus tendon from
the greater tuberosity and sutured periosteal flaps from the
proximal tibia to the torn tendon in a rat model. Controls
received the same treatment without periosteum
augmentation. Extensive fibrocartilage and bone had formed at
the tendon–bone interface of the experimental group after
12 weeks, perhaps indicating the regeneration of an
enthesis. This was accompanied by significant increases
in failure load and attachment strength .
Karaoglu et al. compared periosteum and bone marrow
aspirate treatments in rabbit extensor digitorum repair. The
tendons of the periosteum group were wrapped in freshly
harvested periosteal tissue, and a BMAC group was given a
BMAC injection at the injury site. The control group
underwent analogous surgeries without the inclusion of
BMAC or periosteum. The periosteum and BMAC groups
had thinner, better-organized tendon tissue after 6 weeks.
Obvious bone ingrowth was present in both experimental
groups. After 12 weeks, a well-defined fibrocartilage zone
was only present in the BMAC group. Overall, it appeared
that periosteum had an early repair advantage .
Scaffolds have been shown to improve the mechanical
properties of repaired tendons [114–121], so several studies have
investigated artificial scaffolds and stem cell treatments in
conjugation. Kim et al., investigating the viability of seeded
stem cells, repaired full-thickness window defects of the
infraspinatus tendon of 50 rabbits with MSC-seeded or
unseeded open-cell PLA fiber scaffolds. After 6 weeks,
fluorescence microscopy showed an increase in cell density in the
seeded scaffolds, and the production of Col-I was significantly
higher in the seeded scaffolds .
Funakoshi et al. investigated the efficacy of a
fibrocyteseeded, chitosan-based hyaluronan hybrid polymer fiber
scaffold (CSS). A defect of the humeral insertion of the
infraspinatus tendon was repaired with either
fibroblastseeded or unseeded CSS scaffolds in a rabbit model. After
12 weeks, the regenerated tissue of the seeded CSS group
had a significantly higher tangent modulus and tensile
strength than the repairs involving unseeded scaffolds.
Moreover, Col-I production was only seen in the
fibroblastseeded scaffolds .
Yokoya et al. found that MSC-seeded
poly(lactide-coglycolide) (PGLA) fiber scaffold rotator cuff repairs had
significantly higher tensile strength (3.04 ± 0.54, 2.38 ± 0.63, and
1.58 ± 0.13 MPa for MSC, PGLA, and control groups,
respectively, at 16 weeks), failure loads (111.9 ± 9.43, 90.0 ± 11.3,
and 44.3 ± 3.67 N at 16 weeks), and maturity scores
(21.0 ± 0.82, 16.7 ± 2.05 and 10.2 ± 0.98 at 8 weeks) than
both the unseeded PGLA group and controls receiving no
scaffold in a rabbit model. Both the seeded and unseeded
scaffolds were comprised primarily of Col-III at 8 weeks; after
16 weeks, Col-I/Col-III ratios had improved in the
MSCPGLA tendons, but not in the PGLA-only group .
Biological scaffolds may have advantages over absorbable
synthetic scaffolds, as they may better mimic the environment
of uninjured tendon, guiding the differentiation of seeded cells.
Fini et al. found that rat tenocytes seeded on decellularized
human dermis produced significantly more Col-I than
tenocytes cultured in polystyrene wells (p < 0.0001 at 3 days)
. These results indicate that biological, ECM-derived
scaffolds may promote the production of Col-1, leading to higher
quality repairs. However, one study found that biological and
artificial scaffolds could produce in comparable mechanical
properties. Pietschmann et al. treated midsubstance defects of
rat Achilles tendon with polyglycolic acid (PGA) fiber or
porous Col-I scaffolds seeded with either MSCs or tenocytes.
There were no significant differences in failure strength or
failure strength/cross section between the PGA and Col-I
scaffolds. MSC-seeded PGA and Col-I scaffolds were no more
effective than unseeded controls, potentially due to
MSCinduced ossification. However, the tenocyte-seeded scaffolds
had significantly higher failure strength/cross section than
either the MSC or empty scaffolds .
Little et al. investigated whether ligament-derived matrix
(LDM) could induce human ADSCs to express a ligamentous
or tendinous phenotype. Pulverized anterior cruciate ligament
harvested from porcine knee joints was mixed with rat tail
Col-1 to form the LDM gel scaffolds. Human ADSCs were
cultured on these scaffolds or on rat Col-I scaffolds without
porcine ligament. ADSCs seeded on the LDM scaffolds
demonstrated elevated GAG content and Col-I and Col-III
synthesis relative to the Col-I scaffold controls. The LDM also
increased cell proliferation, and the authors concluded that the
treatment had induced the ADSCs to express a tendinous or
ligmentous phenotype. Chainani et al. further highlighted
pot e n t i a l b e n e f i t s o f E C M s c a f f o l d s . E l e c t r o s p u n
polycaprolactone (PCL) scaffolds were coated with either
fibronectin (FN), phosphate-buffered saline (PBS), or
tendonderived ECM (TDM) and then seeded with ADSCs. Col-III
expression increased at day seven after culturing for all
coating types, and Col-1 expression began increasing after day 4.
However, Col-1 content was significantly elevated in the
TDM scaffolds after 28 days .
In summary, scaffolds augment the mechanical strength of
healing tendons and may guide the differentiation and ECM
production of stem cells, leading to repairs more closely
resembling natural tendon. ECM-derived scaffolds induce Col-I
expression and may therefore be more suitable than synthetic
scaffolds when administered in conjugation with tenocytes
and stem cells. There is little data regarding how scaffold
architecture (rather than composition) directs stem cell or
fibroblast phenotype; this should be addressed with further
research. Furthermore, clinical trials will be necessary to
determine if these treatments are effective in humans and identify
any adverse effects.
Biologics for tendon repair represent an attractive
augmentation to traditional surgical methods. However, tendon healing
and regeneration is an intrinsically complex process involving
numerous different growth factors. The process is a sequence
of healing phases in which different growth factors and cells
may be activated in disparate quantities. While research has
illuminated many of the biochemical reactions in healing, the
regenerative process of normal tendon remains elusive.
Growth factors have been shown to improve the quality of
tendon repairs. The efficacy of GDF-5, IGF-1, and bFGF has
been demonstrated in multiple studies, although clinical data
on GDF-5 treatments is necessary. PDGF-BB increased ECM
production but did not consistently improve tensile properties.
Evidence on the efficacy of PRP is mixed. However, there
is good basic science supporting its use, and numerous clinical
studies have found that PRP substantially reduces pain and
increases joint function for chronic and acute tendinopathies.
The standardization of PRP may enhance these effects.
Moreover, reactions to autologous PRP are very uncommon.
Therefore, the use of PRP may be warranted in patient
refractory to other conservative treatments.
Cell-seeded scaffolds result in much higher quality repairs
than unseeded controls or cells alone. The scaffolds increase
mechanical strength of regenerated tendon tissues and
promote the production of Col-I over Col-III. Tenocytes may be
especially effective for midsubstance repairs, although stem
cells would be required to regenerate a multilayered structure
such as the enthesis.
Enthesis regeneration is one of the greatest challenges in
the field of orthopedics today, but several growth factor and
stem cell augments have proven promising. BMP-2 [28, 29],
bFGF , and PDGF-BB [70, 71] all increased the strength
and enhanced the tensile properties of repairs at the tendon
insertion site, and BMP-2 and PDGF-BB administration
resulted in regeneration of an enthesis-like structure [28, 70].
MSC  and BMAC  administration for insertion-site
defects also resulted in multilayered, organized enthesis
structures, and periosteal cells were similarly effective due to their
ability to differentiate into osteocytes or chondrocytes.
Ultimately, as the regenerative puzzle is solved, it is likely
that a combination of approaches will provide more advanced
and successful outcomes. Stem cell research is particularly
promising in that stem cells may mediate repair and continue
to produce regenerative stimuli long after an initial application
of a growth factors via a more conventional approach. The
idea that stem cells may be small growth factor factories is
appealing and may ultimately allow the tissues to autoregulate
the appropriate chemical mileau at the various stages of
healing to ensure more normal repairs. More research,
particularly clinical research, that directly compares the efficacy of
different cell types, growth factors, and materials used as
augments is needed to reach that conclusion.
Acknowledgments The authors declare that they have no conflict of
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