Article

The Early Effects of Sustained Platelet-Derived Growth Factor Administration on the Functional and Structural Properties of Repaired Intrasynovial Flexor Tendons: An In Vivo Biomechanic Study at 3 Weeks in Canines

Department of Biomedical Engineering, Washington University in St. Louis, San Luis, Missouri, United States
The Journal Of Hand Surgery (Impact Factor: 1.67). 04/2007; 32(3):373-9. DOI: 10.1016/j.jhsa.2006.12.009
Source: PubMed

ABSTRACT

A bioactive fibrin-based delivery system was used to provide sustained administration of platelet-derived growth factor (PDGF-BB) in a clinically relevant model of intrasynovial flexor tendon repair. We hypothesized that PDGF-BB administered in this manner would improve the sutured tendon's functional and structural properties 3 weeks after repair.
A delivery system consisting of 30 microL of fibrin matrix, peptide, heparin, and 100 ng of PDGF-BB was incorporated into the repair sites of randomly selected medial or lateral forepaw flexor digitorum profundus tendons of 8 adult mongrel dogs. The remaining forepaw flexor digitorum profundus tendons were repaired without the growth-factor and fibrin-based delivery system and served as controls. The surgically treated forelimbs were treated with controlled passive motion rehabilitation. The animals were killed at 3 weeks, at which time the tendons were tested for range of motion with a motion analysis system and for tensile properties with a materials testing machine.
Proximal interphalangeal joint and distal interphalangeal joint rotation values were significantly higher for the PDGF-BB-treated tendons compared with the repair-alone tendons. Excursion values were also significantly higher in the PDGF-BB-treated tendons. There were no significant differences in tensile properties when comparing PDGF-BB-treated with repair-alone tendons.
The functional properties of repaired intrasynovial flexor tendons were significantly improved with the sustained administration of PDGF-BB. The failure to achieve improvements in ultimate load, stiffness, and strain in the experimental group may have been due to suboptimal PDGF-BB dosage or suboptimal release kinetics.

Full-text

Available from: Stavros Thomopoulos, Aug 13, 2014
The Early Effects of Sustained Platelet-Derived
Growth Factor Administration on the
Functional and Structural Properties of
Repaired Intrasynovial Flexor Tendons:
An In Vivo Biomechanic Study at
3 Weeks in Canines
Richard H. Gelberman, MD, Stavros Thomopoulos, PhD,
Shelly E. Sakiyama-Elbert, PhD, Rosalina Das, MS,
Matthew J. Silva, PhD
From the Departments of Orthopaedic Surgery and Biomedical Engineering, Barnes-Jewish Hospital at
Washington University, St. Louis, MO.
Purpose: A bioactive fibrin-based delivery system was used to provide sustained administra-
tion of platelet-derived growth factor (PDGF-BB) in a clinically relevant model of intrasyno-
vial flexor tendon repair. We hypothesized that PDGF-BB administered in this manner would
improve the sutured tendon’s functional and structural properties 3 weeks after repair.
Methods: A delivery system consisting of 30
L of fibrin matrix, peptide, heparin, and 100 ng
of PDGF-BB was incorporated into the repair sites of randomly selected medial or lateral
forepaw flexor digitorum profundus tendons of 8 adult mongrel dogs. The remaining forepaw
flexor digitorum profundus tendons were repaired without the growth-factor and fibrin-based
delivery system and served as controls. The surgically treated forelimbs were treated with
controlled passive motion rehabilitation. The animals were killed at 3 weeks, at which time
the tendons were tested for range of motion with a motion analysis system and for tensile
properties with a materials testing machine.
Results: Proximal interphalangeal joint and distal interphalangeal joint rotation values were
significantly higher for the PDGF-BB–treated tendons compared with the repair-alone ten-
dons. Excursion values were also significantly higher in the PDGF-BB–treated tendons. There
were no significant differences in tensile properties when comparing PDGF-BB–treated with
repair-alone tendons.
Conclusions: The functional properties of repaired intrasynovial flexor tendons were signif-
icantly improved with the sustained administration of PDGF-BB. The failure to achieve
improvements in ultimate load, stiffness, and strain in the experimental group may have been
due to suboptimal PDGF-BB dosage or suboptimal release kinetics. (J Hand Surg 2007;32A:
373–379. Copyright © 2007 by the American Society for Surgery of the Hand.)
Key words: Flexor tendon repair, platelet derived growth factor, sustained delivery.
C
linical and experimental studies have shown
that the risk of failure after intrasynovial ten-
don transection is greatest in the first 3 weeks
after repair. The factors that most often lead to a loss
of function are the formation of adhesions within the
digital sheath and the development of repair-site
elongation and rupture. Growth factors, synthesized
naturally or administered therapeutically, have been
shown to be powerful regulators of biologic func-
tion.
1– 4
Manipulation of the growth factor environ-
ment has been an important strategy for improving
the properties of repaired tendon and ligament, with
platelet-derived growth factor (PDGF-BB), basic fi-
broblast growth factor, and transforming growth fac-
The Journal of Hand Surgery 373
Page 1
tor beta showing the greatest promise. Platelet-de-
rived growth factor, in particular, has been shown to
stimulate fibroblast proliferation and matrix and hya-
luronan biosynthesis,
2,5–24
leading to an improved
repair response. In the context of flexor tendon re-
pair, increased matrix synthesis may lead to im-
proved structural properties (eg, strength), and in-
creased hyaluronan may lead to improved functional
properties (eg, range of motion).
The local serum and tissue concentration of growth
factors, administered by bolus injection, has been
shown to fluctuate substantially. Cytokines delivered
in this manner appear to be removed rapidly from the
repair site by denaturation and by clearance from the
circulation.
25
Recent studies
26,28
have shown that
binding a cytokine to a biocompatible matrix can
prolong its elimination half-life, extending its phar-
macokinetic effects. Sustained delivery at the site of
repaired tendon may be especially beneficial, be-
cause the fibroblasts that mount the healing response
do not infiltrate the wound site until 2 to 3 days after
injury. The ideal delivery system has a biodegradable
matrix with a high surface-to-volume ratio. A novel
delivery system was developed recently that provides
for sustained administration by immobilizing high-
affinity heparin-binding growth factors, protecting
them from degradation during the early period after
delivery.
26
The delivery system, designed to mimic
the extracellular matrix, allows for the release of
growth factors from a 3-dimensional fibrin matrix in
an active, cell-mediated manner— one that responds
to the cellular activity associated with repair. The
delivery system is made up of a number of compo-
nents (fibrin, heparin, an engineered peptide) that are
recognized by fibroblasts as natural extracellular ma-
trix components. Because the delivery system is rec-
ognized by fibroblasts as extracellular matrix, it has
many advantages over polymer- or synthetic-based
delivery systems (eg, polymer scaffold degradation
often leads to a local acidic environment).
Our hypothesis was that the growth factor PDGF-
BB, administered in a sustained manner, would sig-
nificantly enhance the structural and functional prop-
erties of repaired intrasynovial flexor tendons after 3
weeks in a clinically applicable animal model.
Materials and Methods
Sixteen tendons from the right forelimbs of 8 adult
mongrel dogs (body mass range, 20–30 kg) were
transected and immediately repaired. For the surgical
procedure, the animals were anesthetized with an
initial intravenous dose of thiopental sodium (0.5
mL/kg) supplemented by intermittent injections of
atropine (0.5 mL) and acepromazine (0.2 mL). They
were intubated and were maintained on 1% halothane
anesthesia. The forelimbs were shaved, washed with
povidone-iodine, and exsanguinated, and the proce-
dure was performed under tourniquet control. The
sheaths of the second and fifth digits in the region
between the annular pulleys proximal and distal to
the proximal interphalangeal (PIP) joint were ex-
posed through midlateral incisions. The sheaths were
entered, and the flexor digitorum profundus tendons
were cut transversely. Transversely oriented defects
were created in the free ends of both tendon stumps
with a scalpel (Fig. 1). The tendons were repaired
with an 8-strand core-suture technique consisting of
2 orthogonally placed 4-strand repairs performed
with use of a continuous loop.
27
After the suture had
been inserted into one tendon stump, a PDGF-BB–
containing fibrin matrix was incorporated into the
repair site of either the medial or lateral forepaw flexor
digitorum profundus tendon (Figs. 2, 3). The remaining
medial or lateral flexor digitorum profundus tendon
was repaired without the fibrin matrix and served as
Figure 1. A transversely oriented pocket was created in both
tendon stumps with a scalpel.
Figure 2. The fibrin matrix.
374 The Journal of Hand Surgery / Vol. 32A No. 3 March 2007
Page 2
a control. Groups (suture repair, suture repair
PDGF-BB) were assigned randomly to either the
medial or lateral tendon in each dog. The sheaths
were not repaired, and the skin was closed with a
running suture of 4-0 nylon.
The fibrin-based delivery system includes a bido-
main peptide with a factor XIIIa substrate derived
from
2
-plasmin inhibitor at the N-terminus, and a
C-terminal heparin-binding domain
26,28
(Fig. 4).
The
bidomain peptide is covalently crosslinked to a fibrin
matrix during coagulation by the transglutaminase
activity of factor XIIIa. The peptide immobilizes
heparin electrostatically to the matrix, which in turn
immobilizes heparin-binding growth factor (eg,
PDGF-BB), preventing its diffusion from the matrix.
Fibrin matrices (matrix volume, 30
L) were made
with the following final component concentrations:
100 ng of PDGF-BB (R&D Systems, 220-BB-010),
7.5 mg/mL of fibrinogen concentration (Sigma,
F-4883) (preparation as previously described
26
), 6.9
mmol/L of CaCl
2
, 12.5 units/mL of thrombin, pep
-
tide
26
0.53 mmol/L with sequence dLNQEQVSPK(
A)
FAKLAARLYRKA-NH
2
(where dL denotes dansyl
leucine), and 110
mol/L of heparin (Sigma,
H-9399) in tris-buffered saline (TBS) (137 mmol/L
of NaCl, 2.7 mmol/L of KCl, 33 mmol/L tris; pH,
7.4). Matrices were implanted between the cut ten-
don ends as described earlier and evaluated at 21
days.
After surgery, the right forelimbs were immobi-
lized with fiberglass shoulder spica casts with the
elbows flexed 90° and the wrists flexed 70°. The
distal ends of the casts were removable to allow for
controlled passive mobilization during two 5-minute
rehabilitation sessions performed 5 days a week start-
ing on the first postoperative day. At the time of
death, the right (repaired) and left (control) forelimbs
were disarticulated at the elbow and were stored at
4°C until range-of-motion testing.
The second and fifth digits from the untreated
(left) and repaired (right) forelimbs were disarticu-
lated at the metacarpophalangeal joint, and the flexor
digitorum profundus tendons were transected proxi-
mally at the musculotendinous junction. The ranges
of motion of both the untreated (uninjured control)
and the repaired digits with fibrin matrix were as-
sessed within 48 hours post mortem with a motion-
analysis system (PC-Reflex; Qualisys, Glastonbury,
CT).
29
Tests were conducted at room temperature
(23°C). Two cameras with infrared light sources
were placed 1 m from the region of interest with their
axes 60° apart. The system was calibrated with a
3-dimensional frame with 6 reflective markers at
known coordinate locations. A circle of reflective
tape (diameter, 2.5 mm) was glued to the flexor
tendon proximal to the A2 pulley with cyanoacrylate
glue. Two pairs of reflective hemispheric markers
(diameter, 4 mm) were pinned to the middle and
distal phalanges of each digit. The middle phalanx
was clamped in a vertical orientation, and the coor-
dinates of the markers were sampled first with the
digit in a flexed position and then in an extended
position as previously described.
29
Flexion was pro
-
duced by suspending a 1.5 N weight from the prox-
Figure 3. Completion of the core suture with the fibrin matrix
within the repair site.
fibrin peptide heparin growth
factor
G
Delivery System
Figure 4. The fibrin-based delivery system is designed to
administer PDGF-BB in a manner that is tailored specifically
to the temporal progression of tissue regeneration. A bido-
main peptide was used with a factor XIIIa substrate from
2
plasmin inhibitor at the N-terminus of the peptide to allow
covalent crosslinking to fibrin during polymerization. The
peptide C-terminus contained a heparin-binding domain
similar to that from antithrombin III. This domain allowed the
noncovalent immobilization of heparin to the fibrin matrix.
The heparin can in turn bind heparin-binding growth factors,
such as PDGF-BB, and prevent them from diffusing out of the
fibrin matrix. The release of growth factor from the matrix
occurs via 3 mechanisms: (1) dissociation of growth factor
from matrix-bound heparin and subsequent diffusion of free
heparin-binding growth factor, (2) proteolytic degradation of
the fibrin matrix, or (3) enzymatic degradation of heparin.
Gelberman et al / Effects of Sustained PDGF Delivery on Tendon Healing 375
Page 3
imal stump of the flexor tendon and a 0.15-N coun-
terweight from the extensor tendon. For extension,
the 1.5 N weight was suspended from the extensor
tendon and the 0.15 N weight from the flexor tendon.
Based on differences between the flexed and ex-
tended positions, we computed rotations of the PIP
joint and the distal interphalangeal joint (DIP) and
the linear displacement of the flexor tendon.
The flexor tendons (with attached distal phalanges)
were then isolated from the repaired digits and tested
to failure in tension with a servohydraulic materials
testing system (Instron 8500R; Instron, Canton, MA)
as described.
29
Each distal phalanx was held rigidly
in a custom fixture, and the proximal tendon stump
was held in a soft-tissue clamp such that the tendon–
bone specimen was in approximately neutral align-
ment. A pair of reflective markers spaced 15 mm
apart were attached to the tendon, one on each side of
the repair site. The distal phalanx was then displaced
vertically to apply a 1-N preload. Five precondition-
ing cycles were applied in load control (triangle
waveform, 1–5 N, 0.25 Hz). The specimens were
then displaced by using a linear ramp at 0.375 mm/s
until failure. Synchronized force and marker data
were collected at 60 Hz. From the marker positions we
computed repair-site elongation per length (strain, mm/
mm), where the unit length was the initial vertical
distance between the markers. We determined peak
(ultimate) force, repair-site stiffness (slope of the
force– elongation curve), repair-site rigidity (slope of
the force–strain curve), and repair-site strain at 20 N
force.
Our experiment was designed based on a sample
size of n 8 being adequate for detecting a between-
group difference in ultimate force of greater than or
equal to 20% at a significance level of 0.05 and power
of 0.8. Repaired tendons treated with PDGF-BB versus
repair-only tendons were compared with paired t tests.
Results
The PIP and DIP joint rotations were significantly
higher in the PDGF-BB–treated tendons compared
with the repair-alone tendons (19° 10° vs
at the PIP joint (p .016); 24° 11° vs 14° at
the DIP joint (p .029) (Fig. 5). Total arc of motion
(ie, PIP DIP) was significantly higher in the
PDGF-BB–treated tendons compared with the repair-
alone tendons (42° 20° vs 21° 7°, p .019)
(Fig. 6). Excursion values were also significantly
higher in the PDGF-BB–treated tendons (5 2mm
vs 2.8 0.8 mm, p .010) (Fig. 7). These measures
were not significantly different when comparing
PDGF-BB–treated tendons with uninjured controls.
There were no significant differences in tensile prop-
erties between PDGF-BB–treated and repair–alone
tendons (p .05 for each comparison) (Table 1).
Discussion
Recent experimental studies have indicated that both
repair-site deformation and a loss of gliding proper-
ties occur regularly in the early stages after tendon
suture.
30 –32
Despite the use of multistrand suture
methods and early controlled motion, a rupture rate
of 13% and a repair-site elongation (gap) rate of 48%
have been reported.
31
These rates of failure are sim
-
ilar to those reported in clinical studies
30,33,34
in
PIP Range
of Motion
DIP Range
of Motion
21 days
0
5
10
15
20
25
30
35
40
45
Range of motion (degrees)
23.5 ± 11.3
13.6 ± 8.8
18.7 ± 10.0
7.8 ± 3.6
24.9 ± 18.6
21.5 ± 10.8
*
*
Uninjured
Suture repair
Suture repair
+ PDGF-BB
Figure 5. The PIP and DIP joint ranges of motion were
significantly higher in the PDGF-BB group compared with
repair alone (*p .05).
0
10
20
30
40
50
60
70
DIP+PIP Range
of Motion
21 days
Range of motion (degrees)
46.3 ± 19.4
Uninjured
Suture repair
Suture repair
+ PDGF-BB
42.2 ± 19.6
21.4 ± 6.8
*
Figure 6. Total arc of motion (ie, PIP DIP) was significantly
higher in the PDGF-BB group compared with repair alone
(*p .05).
376 The Journal of Hand Surgery / Vol. 32A No. 3 March 2007
Page 4
which controlled passive- and active-motion rehabil-
itation was used. Repair-site gap formation greater
than 3 mm adversely affects the structural and func-
tional properties of the repair site.
31
Reasons for the
delayed repair response include the relative paucity
of tendon fibroblasts and the extensive avascular area
in the region in which injuries frequently occur (zone
2). Improving the properties of repair with biologic
interventions by the effective administration of
growth factors appears to be the most promising
approach leading to improvement in the early healing
period.
In the current study, a fibrin-based delivery system
was used to deliver PDGF-BB in an effort to improve
tendon gliding and strength after repair. Previous
studies in our laboratory have shown that this method
of delivery provides for prolonged PDGF-BB release
in vitro (Thomopoulos S et al, presented at the 52nd
Annual Meeting of the Orthopaedic Research Soci-
ety, 2006). These prior studies also showed that the
fibrin gel is retained at the injury site for at least 10
days after repair.
Other studies have shown that PDGF-BB stimu-
lates hyaluronan biosynthesis in animal fibroblasts in
vivo and human fibroblasts in vitro.
16,17,19 –24,35
Hya
-
luronan, a glycosaminoglycan, is normally found on
the surface of intrasynovial tendons and serves as a
lubricant. It plays a structural and regulatory role in
connective tissue and synovial fluid and has been
shown to have a beneficial effect on intrasynovial
tendon repair by binding to hyaluronan-binding pro-
tein on the cell surface of fibroblasts.
36 –38
Its appli
-
cation has resulted in a restoration of the gliding
surface of repaired intrasynovial tendons
36,37
and a
decrease in the peripheral inflammatory response
in vivo.
18
In one recent study,
19
PDGF-BB stimu
-
lated normal human mesothelial cells to synthesize
hyaluronan, which when extruded from cells, formed
hyaluronan-containing pericellular matrices or coats.
In the current in vivo study, the sustained delivery of
PDGF-BB led to improved tendon gliding, possibly
through a stimulation of hyaluronic acid synthesis.
The tensile properties of the repaired tendons were
not improved significantly with sustained PDGF-BB
delivery in this study. The failure to achieve in-
creases in ultimate load, stiffness, and reductions in
strain in the experimental group may have been due
to a suboptimal dose of PDGF-BB or to suboptimal
release kinetics. The selection of dosage level was
essentially empirical, because there are no data avail-
able on which to base in vivo dose levels. Although
there are considerable in vitro dose response data, the
translation of those values to the in vivo model is not
easily accomplished. We selected a conservative
dose level to minimize the potential for adhesion
formation in this initial study. An improvement in
tensile properties might be seen as the dosage level is
optimized in our animal model.
Further, growth factor release from this delivery
system is related directly to the ratio of heparin to
growth factor.
26
Our selection of a ratio of 1:1000,
based on previous in vitro findings, may have led to
delivery that was either too fast or too slow to
achieve the most effective cellular response (Thomo-
poulos S et al, presented at the 52nd Annual Meeting
of the Orthopaedic Research Society, 2006). Our
previous report showed that manipulation of the he-
parin–to– growth factor ratio will lead to a slower or
Uninjured
Suture repair
Suture repair
+ PDGF-BB
21 days
0
1
2
3
4
5
6
7
Excursion (mm)
5.1 ± 1.9
2.8 ± 0.8
5.4 ± 1.4
*
Figure 7. Tendon excursion was significantly higher in the
PDGF-BB groups compared with repair alone (*p .05).
Table 1. Structural Properties Were Not Significantly Different When Comparing the PDGF-BB–Treated
Group to the Repair-Alone Group
Group Peak Force, N Stiffness, N/mm Rigidity, N/mm/mm Strain at 20 N/mm/mm
Suture repair 64 31 19 6 1079 520 0.03 0.01
Suture repair PDGF-BB 65 27 19 4 1189 427 0.03 0.01
Values are given as mean SD.
Gelberman et al / Effects of Sustained PDGF Delivery on Tendon Healing 377
Page 5
faster rate of PDGF-BB release than that used in the
current study. An improvement in tensile properties
may be seen as the heparin–to– growth factor ratio is
optimized.
Improvements in mechanical properties may also
be seen with the delivery of additional factors in
combination with PDGF-BB. Our approach is to first
evaluate the effect of the most promising factors
alone before moving on to the evaluation of growth
factors in combination. We chose PDGF-BB as the
most promising growth factor to initiate this group of
studies. Future studies will first test the effect of
basic fibroblast growth factor alone and then test the
effect of basic fibroblast growth factor in combina-
tion with PDGF-BB.
There are several limitations to this study. First,
although we propose that a stimulation of hyaluronan
biosynthesis was the likely mechanism for improved
functional properties in the PDGF-BB–treated group,
we have not established that this was the operative
mechanism in this model. Future studies will seek to
identify hyaluronic acid upregulation in PDGF-BB–
treated tendons compared with controls. Second, our
comparison groups, although the most clinically rel-
evant, did not include all possible controls. We com-
pared standard surgical repair without a biologic
enhancement with a treatment that included a fibrin
matrix, a delivery system, and a growth factor. We
did not investigate other possible combinations, such
as a fibrin matrix without a growth factor or delivery
system or bolus growth factor delivery. We plan
future studies to test all combinations of delivery
system components to determine if the measured
differences are due to the growth factor, the fibrin
matrix, or the nature of the delivery (ie, bolus vs
sustained). Finally, we examined only one repair
interval, 3 weeks from the time of tendon suture, in
this study. It is unclear if the improved biomechanic
properties would be maintained at later timepoints.
The 3-week interval was selected to determine if an
improved response could be achieved at a particu-
larly critical time point insofar as repair-site strength
and gliding are concerned. Because a previous in
vivo study in our laboratory showed increased cellu-
lar proliferation and significantly higher total DNA
and collagen cross-link levels in a PDGF-BB–treated
group at early points, we sought to correlate biome-
chanic findings at a similar interval (Thomopoulos S
et al, presented at the 52nd Annual Meeting of the
Orthopaedic Research Society, 2006). Further studies
will seek to establish if improved results can be
achieved at 3 weeks with refined release kinetics and
higher growth factor dosage levels.
In this study, we showed the potential for im-
proved functional outcomes after PDGF-BB sus-
tained delivery in a clinically relevant animal model.
Combined with previous findings of increased cellu-
lar proliferation and matrix remodeling, the potential
for accelerating the rate of flexor tendon healing by
manipulation of the growth factor environment is
promising. Future experiments will explore a variety
of dosage levels and delivery vehicle constructs in
vivo in an effort to further enhance the early stages of
intrasynovial flexor tendon repair.
Received for publication August 10, 2006; accepted in revised form
December 15, 2006.
Supported by grants from NIH-NIAMS (NIH RO1 5RO1AR033097)
and the Barnes-Jewish Hospital Foundation.
No benefits in any form have been received or will be received from
a commercial party related directly or indirectly to the subject of this
article.
Corresponding author: Richard H. Gelberman, MD, Department of
Orthopaedic Surgery, 660 S Euclid, Campus Box 8233, St. Louis, MO
63110; e-mail: gelbermanr@wustl.edu.
Copyright © 2007 by the American Society for Surgery of the Hand
0363-5023/07/32A03-0012$32.00/0
doi:10.1016/j.jhsa.2006.12.009
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    • "In this manner, we can isolate the effect of each growth factor delivered to inform the next, potentially combinatorial, approach . Based on previous studies, we hypothesize that PDGF-BB would enhance flexor tendon repair [6] [7] [9] and ASC proliferation [52] [53] [54], with little effect on ASC differentiation. Other growth factors (such as the tenogenic bone morphogenetic protein 12 [24] [25] [55]) can also be examined. "
    [Show abstract] [Hide abstract] ABSTRACT: Outcomes after tendon repair are often unsatisfactory, despite improvements in surgical techniques and rehabilitation methods. Recent studies aimed at enhancing repair have targeted the paucicellular nature of tendon for enhancing repair; however, most approaches for delivering growth factors and cells have not been designed for dense connective tissues such as tendon. Therefore, we developed a scaffold capable of delivering growth factors and cells in a surgically manageable form for tendon repair. Platelet-derived growth factor BB (PDGF-BB), along with adipose-derived mesenchymal stem cells (ASCs), was incorporated into a heparin/fibrin-based delivery system (HBDS). This hydrogel was then layered with an electrospun nanofiber poly(lactic-co-glycolic acid) (PLGA) backbone. The HBDS allowed for the concurrent delivery of PDGF-BB and ASCs in a controlled manner, while the PLGA backbone provided structural integrity for surgical handling and tendon implantation. In vitro studies verified that the cells remained viable, and that sustained growth factor release was achieved. In vivo studies in a large animal tendon model verified that the approach was clinically relevant, and that the cells remained viable in the tendon repair environment. Only a mild immunoresponse was seen at dissection, histologically and at the mRNA level; fluorescently labeled ASCs and the scaffold were found at the repair site 9days post-operatively; and increased total DNA was observed in ASC-treated tendons. The novel layered scaffold has the potential for improving tendon healing due to its ability to deliver both cells and growth factors simultaneously in a surgically convenient manner.
    Full-text · Article · Feb 2013 · Acta biomaterialia
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    • "erimental outcomes remain substantially below normal in terms of digital range of motion and repair site strength. As healing tendons are at greatest risk for rupture in the first few weeks after surgical repair, recent treatment approaches have focused on accelerating the early repair process by manipulating the biologic environment of the repair. 11,14,19,33 Growth factors have been shown to be powerful regulators of biological function and their presence in tendons is highly regulated in both time and space. 19 It is hypothesized that controlled delivery of growth factors may enhance tendon fibroblast proliferation and extracellular matrix synthesis. An accelerated repair process c"
    [Show abstract] [Hide abstract] ABSTRACT: Flexor tendon injuries are often encountered clinically and typically require surgical repair. Return of function after repair is limited due to adhesion formation, which leads to reduced tendon gliding, and due to a lack of repair site strength, which leads to repair site gap formation or rupture. The application of the growth factors basic fibroblastic growth factor (bFGF) and platelet derived growth factor BB (PDGF-BB) has been shown to have the potential to enhance tendon healing. The objectives of this study were to examine: (1) the conditions over which delivery of bFGF can be controlled from a heparin-binding delivery system (HBDS) and (2) the effect of bFGF and PDGF-BB released from this system on tendon fibroblast proliferation and matrix gene expression in vitro over a 10-day interval. Delivery of bFGF was controlled using a HBDS. Fibrin matrices containing the HBDS retained bFGF better than did matrices lacking the delivery system over the 10-day period studied. Delivery of bFGF and PDGF-BB using the HBDS stimulated tendon fibroblast proliferation and promoted changes in the expression of matrix genes related to tendon gliding, strength, and remodeling. Both growth factors may be effective in enhancing tendon healing in vivo.
    Full-text · Article · Nov 2009 · Annals of Biomedical Engineering
  • [Show abstract] [Hide abstract] ABSTRACT: Basic science research on the biology, repair, and rehabilitation of intrasynovial flexor tendon injuries has led to major advances in the clinical management of these injuries. Clinically applicable animal models have been developed to test novel treatments prior to clinical use. Initial research efforts focused on improving the biomechanics of the suture repair and reducing adhesions during healing through passive motion rehabilitation. Recent trends for flexor tendon repair include biological and biomaterial approaches to improve healing. Treatment of the tendon surface with natural and synthetic materials has led to dramatic improvements in the gliding properties of the tendons, and hence the function of the digit. Development of biofactor delivery systems has allowed investigators to test the effects of growth factors for enhanced flexor tendon healing. Application of these new biomaterials to intrasynovial flexor tendon repair has the potential to improve both tendon function (by improving the gliding properties of the tendon) and tendon strength (by enhancing extracellular matrix synthesis).
    No preview · Article · Jan 2009
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