Connective Tissue Research

ISSN: 0300-8207 (Print) 1607-8438 (Online) Journal homepage: http://www.tandfonline.com/loi/icts20

Biologic and Mechanical Aspects of Tendon

Fibrosis after Injury and Repair

Jack G. Graham, Mark L. Wang, Michael Rivlin & Pedro K. Beredjiklian

To cite this article: Jack G. Graham, Mark L. Wang, Michael Rivlin & Pedro K. Beredjiklian (2018):
Biologic and Mechanical Aspects of Tendon Fibrosis after Injury and Repair, Connective Tissue
Research, DOI: 10.1080/03008207.2018.1512979

To link to this article: https://doi.org/10.1080/03008207.2018.1512979

Accepted author version posted online: 20

Aug 2018.

Submit your article to this journal

Article views: 1

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=icts20
 1

Publisher: Taylor & Francis

Journal: Connective Tissue Research

DOI: 10.1080/03008207.2018.1512979
Biologic and Mechanical Aspects of Tendon Fibrosis after Injury and

Repair

t
ip
1. Jack G. Graham, BS1

cr
2. Mark L. Wang, MD, PhD1,2

us
3. Michael Rivlin, MD1,2,

4. Pedro K. Beredjiklian, MD1,2,*

an
1
Department of Orthopaedic Surgery, Sidney Kimmel Medical School, Thomas Jefferson
M

University; 2Hand Surgery Division, The Rothman Institute, at Thomas Jefferson University,

Philadelphia, PA, USA

ed
pt

*Corresponding Author:

Pedro K. Beredjiklian, Professor, Department of Orthopaedic Surgery

ce

Sidney Kimmel Medical College, Thomas Jefferson University

Chief, Division of Hand Surgery, The Rothman Institute

Ac

Pedro.Beredjiklian@rothmaninstitute.com

925 Chestnut Street, Philadelphia, PA 19107-1216, USA

Running head: Biologic Aspects of Tendon Fibrosis

Ac
ce
pt
ed
M
an
us
cr
ip
2

t
 3

Biologic and Mechanical Aspects of Tendon Fibrosis after Injury and Repair

Tendon injuries of the hand that require surgical repair often heal with excess scarring
and adhesions to adjacent tissues. This can compromise the natural gliding mechanics
of the flexor tendons in particular, which operate within a fibro-osseous tunnel system
similar to a set of pulleys. Even combining the finest suture repair techniques with
optimal hand therapy protocols cannot ensure predictable restoration of hand function
in these cases. To date, the majority of research regarding tendon injuries has revolved

t
around the mechanical aspects of the surgical repair (i.e. suture techniques) and

ip
postoperative rehabilitation. The central principles of treatment gleaned from this
literature include using a combination of core and epitendinous sutures during repair

cr
and initiating motion early on in hand therapy to improve tensile strength and limit
adhesion formation. However, it is likely that the best clinical solution will utilize

us
optimal biological modulation of the healing response in addition to these core
strategies and, recently, the research in this area has expanded considerably. While
an
there are no proven additive biological agents that can be used in clinical practice
currently, in this review, we analyze the recent literature surrounding cytokine
modulation, gene and cell-based therapies, and tissue engineering, which may
M
ultimately lead to improved clinical outcomes following tendon injury in the future.

Keywords: tendon injury; fibrosis; scarring; regeneration

ed

Introduction
pt

Whereas healing involves a process of controlled scar tissue formation, fibrosis can be
ce

defined as formation of excessive scar formation which hinders the structure and function of

the affected tissue. Fibrosis can occur in most tissues and organs. Cirrhosis in the liver, cystic
Ac

fibrosis in the lungs, arthrofibrosis in musculoskeletal joints, Crohn’s disease in the

gastrointestinal tract, and myelofibrosis in the spinal cord are examples of fibrosis or scarring

that is detrimental to organ function and health. While there have been attempts at

modulating or controlling fibrosis, no treatment solutions exist currently, and as such this

process remains a largely unsolved problem in current medical practice.

Restoration of function following tendon injuries demands the reestablishment not

 4

only of the continuity of the tendon fibers but of the gliding mechanism between the tendon

and its adjacent anatomic structures such as bones, joints, paratenon, and tendon sheaths

among others. This is especially the case in the more severe crush or degloving injuries

where injury to the adjacent tissues generates a more conducive environment for the

development of fibrosis (Figure 1A). Injury to the adjacent muscle, skeletal structures, and

soft tissue envelope creates further fibrosis around the injured tendon. Tendons can be

t
ip
classified as avascular or sheathed if they have a distinct direct blood supply (e.g. the flexor

tendons of the hand and foot) or vascular or unsheathed if the blood supply enters the blood

cr
parenchyma at multiple points along the tendon parenchyma (e.g. the patellar and rotator cuff

us
tendons). In a manner similar to many other tissues, tendons heal by scar tissue deposition at

the site of injury. While the initial formation of scar between tendon ends provides physical
an
continuity at the site of disruption, proliferation of the scar between the tendon and adjacent

tissues is undesirable because these attachments impede normal tendon gliding and function.
M

Adhesion formation results in loss of motion, contracture formation and functional disability
ed

(Figure 1B) (1).

The majority of the research in the area of tendon injury and repair has focused on
pt

mechanical aspects: for example, the development of improved suture repair techniques and

the enhancement of postoperative rehabilitation protocols allowing early motion (2-5). Out of
ce

the large body of literature in this area, certain important principles of flexor tendon repairs
Ac

have been established. Several of these principles are as follows: 1) Core sutures in

combination with a peripheral epitendinous suture provide the most strength at the repair site

(6); 2) Stress (motion) at the repair site will lead to an increase of the collagen deposited at

the site of injury and will aid in the organization of the collagen deposited, resulting in a

stronger repair (7,8); and 3) The strength of the repair is proportional to the number of sutures

and the caliber of the suture crossing the repair site (9-12).
 5

In addition to the large body of literature regarding the method of tendon repair, a

considerable amount of attention has also been given to the development of postoperative

rehabilitation protocols. The goals of postoperative rehabilitation techniques include

preventing the development of peritendinous adhesions and joint contractures, protecting the

integrity of the tendon repair, and improving the tensile strength of the repaired tendon (13).

These improved surgical methods and rehabilitation schemes have led to better clinical

t
ip
results. Nonetheless, post-surgical scarring and adhesion formation still remain a

disappointingly frequent complication (Figure 1B). Even with the best technical repairs and

cr
the optimal therapy protocols, functional restoration is not reliably achieved and results are

us
highly unpredictable (14). It is likely that the true clinical solution will encompass not only

the finest suture repair techniques and the best postoperative rehabilitation protocols, but also
an
the optimal biological modulation of the healing response.

The tendon healing biologic response has been characterized into three sequential
M

phases: the inflammatory, the fibroblastic, and the remodeling phases (15-21). Immediately
ed

after injury, the coagulation cascade is initiated whereby platelet aggregation and fibrin clot

promote hemostasis (22). Platelet aggregation leads to the release of chemotactic factors
pt

including transforming growth factor β (TGF-β) and platelet derived growth factor (PDGF)

(22). The release of these factors first promotes migration of neutrophils from the extrinsic
ce

(blood supply) and intrinsic (tendon sheath, paratendon, adjacent anatomic structures)
Ac

sources to the injury site (15). These cells phagocytize necrotic tissue and clot and remove

any bacteria that may be present. Next, macrophages and lymphocytes are chemoattracted to

the injury site by TGF, PDGF, fibroblast growth factor (FGF) and epidermal growth factor

(EGF) (21). These cells help to maintain cytokine levels, promote angiogenesis, and release

factors that attract fibroblasts to the injury site. During the fibroblastic phase, fibroblasts

proliferate about the injury site and synthesize collagen and other components of the
 6

extracellular matrix (15,16,18). Finally, during the remodeling phase, newly produced

collagen fibers become organized longitudinally along the axis of the tendon. Fibroblasts are

the main structural cells in fibrotic healing reactions and the key cells responsible for

collagen deposition and the formation of scar (15,16,18).

Historically, the biologic modulation of tendon repair after injury has been attempted

on two fronts. The first method was to place a physical and mechanical barrier between the

t
ip
healing tendon and the surrounding tissues (23-26). The rationale of this approach is to

diminish the amount of adhesions around the repaired tendon by limiting contact between the

cr
tendon and its sheath – the tendon would be allowed to heal to itself but not to the sheath and

us
surrounding tissues. The various barrier materials that have been tried include silicone (23)

and chondroitin sulfate-coated polyhydroxyethyl methacrylate membranes (24) among many

an
others (25,26). These materials were selected based on gliding and anti-inflammatory

properties. In spite of the many different materials studied for this purpose, none are in
M

routine clinical use at this time due to lack of clinical efficacy and size constraints, especially
ed

in the flexor tendon sheath.

In a similar approach, many authors have attempted to use chemical modulation to

pt

diminish the amount of scar formation after repair. The chemical agents that have been used

in these efforts include local corticosteroids (27), hyaluronic acid (28), and 5–fluorouracil
ce

(29) among many others. These methodologies unite around the common theme of reducing
Ac

inflammation, which is strongly related to the development of adhesion. When using

corticosteroids and hyaluronic acid, the goal is to diminish inflammation by inhibiting

lymphocyte migration, proliferation and chemotaxis, as well as macrophage motility (27,28).

Similarly, 5–fluorouracil, an antimetabolite, suppresses scar formation by inhibiting

contraction of collagen lattice and proliferation of inflammatory cells (29).

 7

In the last several decades, our understanding of the molecular biology of soft tissues’

growth and repair has expanded dramatically. We have some knowledge regarding how genes

are regulated; how these genes are expressed and proteins are synthesized; and how these

proteins effect macroscopic and biomechanical changes in tissues. It is probable that the next

advance in the treatment of tendon injuries will result from the application of this basic science

knowledge. It is likely that the clinical solution will encompass not only the finest suture repair

t
ip
techniques and the best postoperative rehabilitation protocols, but also the optimal biological

modulation of the healing response.

cr
us
Molecular Mechanism of Tendon Fibrosis

Animal-based studies on tendon injury and analysis of the human-derived tendon

an
samples identify a few key processes and mediators that regulate the formation of fibrotic

scar tissue in injured tendons. Specifically, researchers identify three phases of tendon
M

healing: (i) inflammatory, (ii) fibroblastic, and (iii) remodeling (Figure 2) (17-21). During the
ed

inflammatory phase, a group of cells that includes neutrophils, monocytes, and macrophages

migrate into the injury sites. At this stage, the strength of the repair site depends primarily on
pt

surgical sutures, and the fibrin clot (13). During the inflammatory stage, a number of growth

factors are produced by the inflammatory cells. These factors activate fibroblastic cells that
ce

upregulate production of elements of the extracellular matrix (ECM). The ECM components,
Ac

including fibrillar collagens, assemble into randomly organized deposits. During the

remodeling stage, these deposits reorganize longitudinally. Despite this reorganization,

however, the repaired tendon does not regain full mechanical strength (12).

A prolonged exposure of fibroblastic cells to the inflammatory signals, may lead to

the excessive production of the ECM components and formation of fibrotic tissue in a form

of tendon scars and adhesions (10). Studies demonstrated that cells contributing to the
 8

production of scar tissue in tendon are from extrinsic and intrinsic sources (30,31). The

extrinsic cells are fibroblasts that invade from outside of the tendon, while intrinsic cells are

resident tenocytes.

Regardless of the source, the fibroblastic cells are activated by a group of growth

factors that include tissue growth factor β1 (TGF- β1), connective tissue growth factor

(CTGF), fibroblast growth factor (FGF) insulin-like growth factor 1 (IGF-1), vascular

t
ip
endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and bone

morphogenetic protein (BMP) (32). Numerous studies demonstrated that among these factors

cr
TGF- β1, CTGF, and BMP2, BMP4, BMP7 play a significant role in promoting fibrotic

us
healing of the tendon (33).
an
Cytokines and Growth Factors

Cytokines are secreted proteins that orchestrate cellular responses at a molecular

M

level and are of critical significance in the repair of soft tissues (Table 1). TGF-β is a
ed

cytokine that has received a significant amount of attention in this area (34-36).

Intrinsic tenocytes and extrinsic tendon sheath fibroblasts are known to produce TGF-
pt

β1, and this production is activated in a tendon wound environment. Furthermore, it has

been shown that TGF-β1 receptor production is upregulated during tendon injury (35).
ce

Farhat and colleagues assessed the effects of TGF-β1 using an in vitro collagen gel
Ac

model of flexor tendon healing (36). Their reverse transcription polymerase chain

reaction (RT-PCR) gene expression analysis demonstrated that TGF-β1is associated

with greater expression of genes tending toward the synthesis of extracellular matrix

synthesis versus matrix remodeling. This potentially predisposes the tendon to adhesion

formation (37). It was suggested that perioperative modulation of TGF-β1 levels (for

example, with neutralizing antibodies to TGF-β1) may help limit flexor tendon
 9

adhesion and excessive scar formation following repair; while, interestingly,

neutralizing TGF-β1 and TGF-β2 simultaneously eliminated this effect (38).

Connective tissue growth factor (CTGF), also referred to as CCN2, is a protein in the 36-

38 kilodalton range that is highly expressed in healthy flexor tendons and may contribute to

maintaining overall flexor tendon health (39,40). In addition, CTFG mediates TGF-β1 signals,

and in early tendon healing, both are upregulated (40-42). CTGF has also been shown to

t
ip
stimulate tendon stem/progenitor cells in rat patellar tendons, leading to enhanced healing after

cr
transection (43).

Growth differentiation factors (GDFs) are another group of signaling proteins within the

us
TGF-β super family (14). Compared to controls, GDF-5 knockout mice exhibit delayed Achilles

tendon healing after tenotomy and repair (44). These tendons also demonstrate less structural and
an
mechanical strength up to five weeks status post repair. In a similar study assessing tendon
M
composition in GDF-6 knockout mice, significant changes in tendon phenotype were noted in

male rats, while no differences were demonstrated in females (45). This family of signaling
ed

proteins warrants further study within the context of tendon healing.

Another cytokine that has generated interest in this area is basic fibroblast growth factor
pt

(b-FGF) (46). This cytokine is a 146 aminoacid polypeptide grouped in the heparin-binding

growth factor family. The principal effects of b-FGF, which has been isolated in normal canine
ce

and rabbit synovial flexor tendons, include induction of angiogenesis and fibroblast chemotaxis
Ac

and proliferation (47). In addition, b-FGF mRNA was found to be upregulated in tenocytes and

tendon sheath fibroblasts following synovial tendon wounding in a rabbit model (47). These

findings suggest that b-FGF may play an important role in the repair of synovial tendons.

Thomopoulos and colleagues provided a sustained delivery of b-FGF to repaired canine flexor

digitorum profundus tendons following their transection (48). Sterile fibrin matrices were loaded

with two different doses of b-FGF using a heparin-binding technique, and these matrices were
 10

implanted on healing tendons. The tendons receiving this biological intervention ultimately

demonstrated increased vascularity, cellularity, and adhesion formation three weeks later when

compared to control tendons receiving only operative repair. The authors advised that application

of growth factors must be performed cautiously as the potential for increased biological activity

leading to adhesion and decreased range of motion is a valid concern.

In healthy tendons, Insulin-like growth factor (IGF) is constitutively expressed by

t
ip
tenocytes, and subsequently up-regulated following tendon injury (49,50). Previous in vitro

studies have demonstrated that both IGF-I and IGF-II stimulate essential macromolecules to

cr
increase extracellular matrix synthesis, such as type I collagen and proteoglycan (50,51), as well

us
as increase fibroblast mitogenesis and proliferation at the epi- and endo-tendon levels (49,50,52).

In a rabbit Achilles tendon injury model, a single application of platelet-rich plasma (PRP) in a
an
ruptured tendon alters the expression of IGF-I in the early phase of healing in an animal wound

model. IGF-I was localized in the epitenon and endotenon, with an overexpression in the
M

epitenon in subjects treated with PRP group, which exhibited more rapid healing (52).
ed

Vascular endothelial growth (VEGF) stimulates increased epithelization, collagen

synthesis, and angiogenesis to local injured tissues, ultimately promoting dermal wound healing
pt

and mediating scar tissue generation (50,53). Previously, Boyer et al. demonstrated elevated

VEGF gene expression at one-week status post flexor tendon repair, and a return to baseline
ce

VEGF mRNA levels at Week 2 (54). Researchers have postulated that elevated VEGF
Ac

production at the flexor tendon repair site coincides with the neovascularization phase of the

tendon healing process (50,54,55).

PDGF is associated with initial tissue repair at the injury site and promoting wound

healing. In vitro studies have demonstrated that PDGF increases cellular proliferation and

collagen synthesis in canine flexor tendon-derived cells (50,56). Furthermore, in an in vivo

canine flexor tendon injury repair model, PDGF released from a fibrin matrix delivery system
 11

stimulated increased cellular proliferation and collagen remodeling (57). Delivery of PDGF

resulted in an increase in cell density, cell proliferation, and type I collagen mRNA expression

(57). Researchers postulated that the sustained delivery of growth factors by means of such a

delivery system could potentially accelerate flexor tendon healing and repair under clinical

conditions (57).

Interleukins are a group of cytokines that play a role in the body’s inflammatory response.

t
ip
Interleukin-10 (IL-10) in particular exhibits anti-inflammatory effects against its pro-

inflammatory counterparts (IL-6 and IL-8) and has been shown to suppress the migration of

cr
monocytes, neutrophils, and macrophages by way of secreted chemokine signals (58,59). Liechty

us
and colleagues found that IL-10 was associated with decreased formation of scar and fibrosis in

murine models of fetal wound repair (60). Additionally, overexpression of IL-10 in a murine
an
tendon model showed improved biomechanical properties versus control, although the trend did

not reach statistical significance (61).

M

Linderman et al. studied flexor digitorum profundus tendons in a canine model and
ed

utilized a novel, porous suture as a sustained delivery mechanism of CTGF (62). The growth

factor was introduced via the suture into transected tendons during repair and demonstrated
pt

positive effects. Based on histology and gene expression analysis, deleterious inflammation and

adhesions associated with other delivery systems were absent two weeks after the experimental
ce

repair (62).
Ac

Also utilizing a murine tendon model to investigate inhibition of TGF-β1, Wong and

colleagues reported favorable in vivo and in vitro effects of high-dose, hypertonic Mannose 6-

phosphate (M6P) solution (63). At two months post-op, in vivo results showed a 47% decrease in

tendon adhesions without any compromised tendon strength or predisposition to rupture when

compared to contralateral controls. The in vitro data demonstrated a “lag phase” of reduced cell

migration and proliferation for four to five days depending on the fibroblast samples’ exposure
 12

time to the M6P solution. These findings paralleled the decreased adhesion production noted in

the in vivo portion of the study (63).

Unfortunately, while the manipulation of cytokine concentration levels at the

injury/repair site is an attractive notion, it is unlikely that this approach will represent a

panacea for this difficult clinical problem. First, the interactions between these various

cytokines are extremely complex and beyond our current level of understanding. For

t
ip
instance, changing the concentration level of one cytokine is likely to have significant

repercussions on other cytokine systems (1). Second, it is likely that these cytokines, like

cr
most other biologic systems, have a built-in level of redundancy – it seems unlikely that

us
suppression of only one pro-inflammatory protein will decrease the degree of scarring at one

particular site (33). Third, it is likely that the effect of these cytokines is dependent on
an
specific concentrations of these proteins at the site of injury (34). Fourth, it is likely that the

role of each cytokine is extremely dependent on timing, being only effective in a narrow
M

window in the process (60).

ed
pt

Gene Therapy
ce

Gene therapy may provide such a biological delivery system. Gene therapy involves
Ac

the introduction of these genetic materials into cells and can be achieved using viral or non-

viral techniques. Gene therapy provides the ability to insert the genetic material of any

specific cytokine into the injury site. Moreover, with the use of various inducers, the timing

of the expression and concentration of the genetic material can be controlled (60). Several

researchers have reported successful transfer of genetic material into tendons using viral

vectors. Nakamura et al. were able to transfect cells from an injured patellar ligament with
 13

the PDGF-B gene using liposomes in a rat model (64). The authors found enhanced

expression of PDGF-B up to four weeks after transfection, leading to an initial promotion of

angiogenesis and subsequent enhanced collagen deposition in the wound. Genetic

modification of tenocytes with exogenous PDGF gene has been demonstrated to promote

increased collagen gene expression (65). Researchers concluded that exogenous PDGF genes

can be effectively transferred into tenocytes and the transfer of the PDGF gene may offer a

t
ip
novel way of effectively promoting healing of intrasynovial flexor tendons (65).

In an avian in vivo flexor tendon injury model, Tang et al. demonstrated that b-FGF gene

cr
transfer to digital flexor tendons significantly increases healing strength during the critical

us
tendon-healing period without increased adhesion formation (66). However, the application of

growth factors in tendon models is nuanced, and the use of b-FGF in particular has had mixed
an
results. More recently, Goomer et al. demonstrated high-efficiency in vivo gene transfer using

nonviral techniques (67). Using a novel method of gene transfection, this group introduced a
M

marker gene into a canine model for intrasynovial flexor tendon injury during surgical repair
ed

using liposomes and found near perfect rates of gene transfer. Furthermore, Richetti et al.

demonstrated successful gene transfer of interleukin 10 (IL-10) into adult murine patellar tendon
pt

using a lentiviral vector. Injured mouse patellar tendons treated with the vector demonstrated

improved mechanical properties relative to controls. The treated tendons demonstrated an

ce

increased capacity to withstand stress testing (60).

Ac

Using a chicken flexor digitorum profundus tendon model, Zhou et al. formed

nanoparticle/TGF-β1 microRNA plasmid complexes to prevent the expression of the TGF-β1

gene (68). Western blot assays determined a significant decrease in TGF-β1 expression and

Collagen I and III synthesis. Tendons were assessed for adhesions under microscopy and given

an “adhesion score” - the experimental group scored significantly lower versus controls.
 14

However, treatment with plasmids significantly sacrificed strength of the repair, which could

potentially predispose the tendon to rupture (68).

Similarly, TGF-β1 and various components of its signaling pathways (Smad3, CTGF)

were individually targeted for suppression by antisense oligonucleotides (ASOs) in a recent study

by Loiselle and colleagues (69). The flexor digitorum longus in 8-week-old male mice was

transected and repaired using sutures. On post-operative days 2, 6, and 12, 300 μg of each

t
ip
specific ASO was injected into designated experimental tendons. The range of motion (ROM) of

the metatarsophalangeal (MTP) joint and tendon biomechanics were tested intermittently. At

cr
three weeks post-op, both the Smad3 ASO-treated and CTGF ASO-treated tendons demonstrated

us
increased tendon gliding as a function of MTP ROM when compared to controls. Additionally,

the Smad3 ASO-treated tendons exhibited significantly improved strength in this early window.
an
Equally as impactful was the finding that none of the experimental tendons lost strength or MTP

range of motion versus controls, and continued research in this area is needed to determine if
M

these are worthwhile targets for therapeutic gene therapy (69).

ed

One important concern with the gene therapy approach involves the substantial regulatory

hurdles that must be overcome to translate any progress in the laboratory into clinical trials and
pt

applications. The Food and Drug Administration (FDA) in the United States is charged with

regulating this process. Even though a faster process of clinical trial approval has been passed
ce

into legislation, most of these expedited approvals will be reserved for serious illnesses.
Ac

Burdensome regulatory processes will still have to be met, which may hinder the application of

these technologies in the clinical setting. Gene therapy, at least in the arena of tendon healing,

may have an investigative rather than a direct therapeutic role.

 15

Cell-based Therapies and Tissue Engineering

The use of gene therapy and cytokine regulation may be inadequate if the cells

in the area are cannot be manipulated to reduce fibrosis. This presents another line of

research: introducing cells with those powers to the region of repaired tendon.

Specifically, mesenchymal stem cells present an attractive option. Bone marrow

stromal cell (BMSC) therapies in ex vivo canine tendon models have demonstrated

t
ip
significant effects. Zhao et al. used a collagen gel patch seeded with BMSCs as a

delivery mechanism to repaired flexor digitorum profundus tendons and noted

cr
improved strength and stiffness in the experimental group compared to control (70).

us
Another study using similar techniques added GDF-5 to BMSC-seeded gel patches and

reported greater maximum strength one month post-operatively in the tendons receiving
an
this treatment combination (71). Interestingly, tendons treated with BMSCs or GDF-5

alone did not exhibit improved strength versus control. The same group performed a
M

comparable study adding platelet-rich plasma (PRP) to the BMSC treatment (72).
ed

Biomechnical testing determined that up to one month after the repair, the group

receiving BMSC-seeded collagen enhanced with PRP had significantly greater

pt

maximum breaking strength than control or the BMSC-only group (72).

Another canine model study assessed the impact of autologous adipose-derived

ce

mesenchymal stromal cells (ASCs) within the healing tendon environment delivered via a cell
Ac

sheet (73). One week after tendon repair and treatment, ASCs were noted to promote anti-

inflammatory effects via increased expression levels of M2 macrophages (73). More research

utilizing ASCs in tendon repair is needed.

The field of tissue engineering aims to modify or replace damaged or non-functional

tissue with substitutes developed using the principles of engineering and biology (74). As such,

the design of the engineered tissues should mimic the anatomic properties and constraints of each
 16

individual tendon. For example, recreating the normal anatomy would be critical in the flexor

tendons in the hand, where the tendons travel in a constrained environment in the tendon sheath

(Figure 3). In the ideal tissue engineered tendon, the surrounding sheath could also be generated,

providing the necessary mechanical properties inherent in the annular and cruciate pulleys. In the

case of flexor tendon injury, autologous tendon grafting is one classic treatment option, but has

the disadvantage of surgical site morbidity (75). Additionally, the number of potential autologous

t
ip
tendon grafts is finite. The ultimate goal is to create a bioengineered tendon construct that is able

to reproduce the natural flexor tendon’s ability to transmit tensile loads while natural gliding

cr
mechanics are maintained (75). Research efforts to design tissue-engineered tendons are ongoing.

us
This design process begins with either a bio-compatible synthetic scaffold or a biological

scaffold using mammalian tissues (human, porcine, bovine, or equine) (76). In general, these
an
scaffolds are chosen to maintain basic structural stability long enough for the seeding or coaxing

cells to incorporate into the construct and deposit extracellular matrix (75,76). Specifically, these
M

materials are selected for biocompatibility, degradation properties, porosity, cell adhesion
ed

profiles, and mechanical properties. Types of synthetic scaffolds using polymers that have been

investigated include: polyclycolic acid (PGA) sheets (77), devices using woven poly-L-lactide
pt

(78), bioabsorbable polyacetic acid patches (79), and nanofiber poly(lactic-co-glycolic acid)

(PLGA) (80,81). Theoretically, biological scaffolds have a decreased risk of host rejection.
ce

Types of biological scaffolds include: decellularized cadaveric flexor tendon (82-84),

Ac

decellularized equine FDS tendon (85,86), core-shell collagen-glycosaminoglycan composites

(87), porcine small-intestinal mucosa (88), and human umbilical veins (89).

As cellular proliferation increases within the scaffold, the strength of the tissue-

engineered tendon also increases. Maintaining a gliding surface while adding mechanical

strength in this way becomes a complicated balancing act (75).

 17

Shen and colleagues used a knitted silk-collagen scaffold integrated with stromal cell–

derived factor-1α (SDF-1α) that resulted in increased expression of collagens I and III and a

reduced inflammatory response during healing (90). Similarly, Sahoo and coinvestigators

used similar constructs with a layer of poly-lactic coglycolic acid (PLGA) fibers coated with

bFGF on the surface (91). Rabbit mesenchymal progenitor cells seeded onto the PLGA fibers

infiltrated into the knit silk portion of the scaffold. The addition of bFGF led to increased

t
ip
expression of collagen, fibronectin, and biglycan, mediators potentially beneficial to tendon

healing. Research and development of these models will continue to progress, and access to a

cr
rapidly available and reliable tissue-engineered tendon may eventually become a real clinical

us
option versus the theoretical one that it is today.
an
Conclusion

The ability to restore functional ability following treatment of tendon injuries has
M

been greatly improved due to the development of improved suture techniques and
ed

rehabilitation protocols. In spite of these improvements, the outcome of surgical repair is

often less than desirable due to scarring at the injury site. At present, there are no proven
pt

additive biological agents that can be reliably used in clinical practice to augment surgical

repair and diminish adhesion formation. Developments in our understanding of soft tissue
ce

healing at the cellular, molecular, and genetic levels are likely to give the treating surgeon an
Ac

ability to modulate the healing response to improve the strength of the repair while

simultaneously diminishing the degree of adhesion formation following injury and surgical

repair. Given the difficulties entailed in the cytokine approach (redundant mechanisms,

timing, delivery systems) and regulatory issues with the genetic therapy approach, it appears

that cell therapies (mesenchymal stem cells) in combination with bioengineered scaffolds

using a tissue engineering approach are likely to be the approaches that may yield clinically
 18

viable options in the near future.

Funding

The authors report no outside funding for this study.

Declaration of Interests

t
ip
The authors report no conflicts of interest.

cr
us
an
M
ed
pt
ce
Ac

References
 19

1. Beredjiklian PK. Biologic aspects of flexor tendon laceration and repair. J Bone Joint Surg

Am. 2003;85-A(3):539-550.

2. Dy CJ, Daluiski A. Update on Zone II Flexor Tendon Injuries. J Am Acad Orthop Surg.

2014;22(12):791-799.

3. Rawson S, Cartmell S, Wong J. Suture techniques for tendon repair; a comparative review.

Muscles Ligaments Tendons J. 2013;3(3):220-228.

t
ip
4. Wang JH, Guo Q, Li B. Tendon biomechanics and mechanobiology--a minireview of basic

concepts and recent advancements. J Hand Ther. 2012;25(2):133-140.

cr
5. Boyer MI1, Goldfarb CA, Gelberman RH. Recent progress in flexor tendon healing. The

us
modulation of tendon healing with rehabilitation variables. J Hand Ther. 2005;18(2):80-85.

6. Wieskötter B, Herbort M, Langer M, Raschke MJ, Wähnert D. The impact of different

an
peripheral suture techniques on the biomechanical stability in flexor tendon repair. Arch

Orthop Trauma Surg. 2018;138(1):139-145.

M

7. Heinemeier KM, Olesen JL, Haddad F, Schjerling P, Baldwin KM, Kjaer M. Effect of
ed

unloading followed by reloading on expression of collagen and related growth factors in rat

tendon and muscle. J Appl Physiol (1985). 2009;106(1):178-186.

pt

8. Frueh FS, Kunz VS, Gravestock IJ, Held L, Haefeli M, Giovanoli P, Calcagni M. Primary

flexor tendon repair in zones 1 and 2: early passive mobilization versus controlled active
ce

motion. J Hand Surg Am. 2014;39(7):1344-1350.

Ac

9. Winters SC, Gelberman RH, Woo SL, Chan SS, Grewal R, Seiler JG 3rd. The effects of

multiple-strand suture methods on the strength and excursion of repaired intrasynovial flexor

tendons: a biomechanical study in dogs. J Hand Surg Am. 1998;23(1):97-104.

10. Dinopoulos HT, Boyer MI, Burns ME, Gelberman RH, Silva MJ. The resistance of a

four- and eight-strand suture technique to gap formation during tensile testing: an
 20

experimental study of repaired canine flexor tendons after 10 days of in vivo healing. J Hand

Surg Am. 2000 May;25(3):489-498.

11. Barrie KA, Tomak SL, Cholewicki J, Wolfe SW. The role of multiple strands and locking

sutures on gap formation of flexor tendon repairs during cyclical loading. J Hand Surg Am.

2000;25(4):714-720.

12. Taras JS, Raphael JS, Marczyk SC, Bauerle WB. Evaluation of suture caliber in flexor

t
ip
tendon repair. J Hand Surg Am. 2001;26(6):1100-1104.

13. Starr HM, Snoddy M, Hammond KE, Seiler JG 3rd. Flexor tendon repair rehabilitation

cr
protocols: a systematic review. J Hand Surg Am. 2013;38(9):1712-7.e1-14.

us
14. Ansorge HL, Beredjiklian PK, Soslowsky LJ. CD44 deficiency improves healing tendon

mechanics and increases matrix and cytokine expression in a mouse patellar tendon injury
an
model. J Orthop Res. 2009;27(10):1386-1391.

15. Brink HE, Miller GJ, Beredjiklian PK, Nicoll SB. Serum-dependent effects on adult and
M

fetal tendon fibroblast migration and collagen expression.Wound Repair Regen.

ed

2006;14(2):179-186.

16. Gelberman RH, Steinberg D, Amiel D, Akeson W. Fibroblast chemotaxis after tendon
pt

repair. J Hand Surg Am. 1991;16(4):686-693.

17. Wong JK, Lui YH, Kapacee Z, Kadler KE, Ferguson MW, McGrouther DA. The cellular
ce

biology of flexor tendon adhesion formation: an old problem in a new paradigm. Am J

Ac

Pathol. 2009;175(5):1938-1951.

18. Wojciak B, Crossan JF. The accumulation of inflammatory cells in synovial sheath and

epitenon during adhesion formation in healing rat flexor tendons. Clin Exp Immunol.

1993;93(1):108-114.
 21

19. Branford OA, Mudera V, Brown RA, McGrouther DA, Grobbelaar AO. A novel

biomimetic material for engineering postsurgical adhesion using the injured digital flexor

tendon-synovial complex as an in vivo model. Plast Reconstr Surg. 2008;121(3):781-793.

20. Garner WL, McDonald JA, Koo M, Kuhn C 3rd, Weeks PM. Identification of the

collagen-producing cells in healing flexor tendons. Plast Reconstr Surg. 1989;83(5):875-879.

21. Khan U, Edwards JC, McGrouther DA. Patterns of cellular activation after tendon injury.

t
ip
J Hand Surg Br. 1996;21(6):813-820.

22. Demidova-Rice TN, Hamblin MR, Herman IM. Acute and impaired wound healing:

cr
pathophysiology and current methods for drug delivery, part 1: normal and chronic wounds:

us
biology, causes, and approaches to care. Adv Skin Wound Care. 2012;25(7):304-314.

23. Austin RT, Walker F. Flexor tendon healing and adhesion formation after Sterispon
an
wrapping: a study in the rabbit. Injury. 1979;10(3):211-216.

24. Gudemez E, Eksioglu F, Korkusuz, P, Asan, E, Gursel, I, Hasirci V. Chondroitin sulfate-

M

coated polyhydroxyethyl methacrylate membrane prevents adhesion in full-thickness tendon

ed

tears of rabbits. J Hand Surg Am. 2002;27(2): 293-306.

25. Ferguson RE, Rinker B. The use of a hydrogel sealant on flexor tendon repairs to prevent
pt

adhesion formation. Ann Plast Surg. 2006;56(1):54-58.

26. Menderes A, Mola F, Tayfur V, Vayvada H, Barutçu A. Prevention of peritendinous

ce

adhesions following flexor tendon injury with seprafilm. Ann Plast Surg. 2004;53(6):560-4.
Ac

27. Kulick MI, Brazlow R, Smith S, Hentz VR. Injectable ibuprofen: preliminary evaluation

of its ability to decrease peritendinous adhesions. Ann Plast Surg. 1984;13(6): 459-467.

28. Salti NI, Tuel RJ, Mass DP. Effect of hyaluronic acid on rabbit profundus flexor tendon

healing in vitro. J Surg Res. 1993;55(4): 411-415.

29. Moran SL, Ryan CK, Orlando GS, Pratt CE, Michalko KB. Effects of 5-fluorouracil on

flexor tendon repair. J Hand Surg Am. 2000;25(2): 242-251.

 22

30. Potenza AD. Critical Evaluation of Flexor-Tendon Healing and Adhesion Formation

within Artificial Digital Sheaths. J Bone Joint Surg Am. 1963;45:1217-1233.

31. Matthews P, Richards H. The repair potential of digital flexor tendons. An experimental

study. J Bone Joint Surg Br. 1974;56-B(4):618-625.

32. Klass BR, Rolfe KJ, Grobbelaar AO. In vitro flexor tendon cell response to TGF-beta1: a

gene expression study. J Hand Surg Am. 2009;34(3):495-503.

t
ip
33. Morita W, Snelling SJ, Dakin SG, Carr AJ. Profibrotic mediators in tendon disease: a

systematic review. Arthritis Res Ther. 2016;18(1):269.

cr
34. Beredjiklian PK, Favata M, Cartmell JS, Flanagan CL, Crombleholme TM, Soslowsky

us
LJ. Regenerative versus reparative healing in tendon: a study of biomechanical and

histological properties in fetal sheep. Ann Biomed Eng. 2003;31(10):1143-1152.

an
35. Ngo, M, Pham H, Longaker MT, Chang, J. Differential expression of transforming

growth factor-beta receptors in a rabbit zone II flexor tendon wound healing model. Plast
M

Reconstr Surg. 2001;108(5): 1260-1267.

ed

36. Farhat YM, Al-Maliki AA, Chen T, Juneja SC, Schwarz EM, O'Keefe RJ, Awad HA.

Gene expression analysis of the pleiotropic effects of TGF-β1 in an in vitro model of flexor
pt

tendon healing. PLoS One. 2012;7(12):e51411.

37. Favata M, Beredjiklian PK, Zgonis MH, Beason DP, Crombleholme TM, Jawad AF,
ce

Soslowsky LJ. Regenerative properties of fetal sheep tendon are not adversely affected by
Ac

transplantation into an adult environment. J Orthop Res. 2006;24(11):2124-2132.

38. Chang J, Thunder R, Most D, Longaker MT, Lineaweaver WC. Studies in flexor tendon

wound healing: neutralizing antibody to TGF-beta1 increases postoperative range of motion.

Plast Reconstr Surg. 2000;105(1): 148-155.

 23

39. Lee CH, Shah B, Moioli EK, Mao JJ. CTGF directs fibroblast differentiation from human

mesenchymal stem/stromal cells and defines connective tissue healing in a rodent injury

model. J Clin Invest. 2010;120(9):3340-3349.

40. Chen CH, Cao Y, Wu YF, Bais AJ, Gao JS, Tang JB. Tendon healing in vivo: gene

expression and production of multiple growth factors in early tendon healing period. J Hand

Surg Am. 2008;33(10):1834-1842.

t
ip
41. Bonniaud P1 Martin G, Margetts PJ, Ask K, Robertson J, Gauldie J, Kolb M. Connective

tissue growth factor is crucial to inducing a profibrotic environment in "fibrosis-resistant"

cr
BALB/c mouse lungs. Am J Respir Cell Mol Biol. 2004;31(5):510-516.

us
42. Mori T, Kawara S, Shinozaki M, Hayashi N, Kakinuma T, Igarashi A, Takigawa M,

Nakanishi T, Takehara K. Role and interaction of connective tissue growth factor with
an
transforming growth factor-beta in persistent fibrosis: A mouse fibrosis model. J Cell

Physiol. 1999;181(1):153-159.
M

43. Tarafder S, Chen E, Jun Y, Kao K, Sim KH, Back J, Lee FY, Lee CH. Tendon
ed

stem/progenitor cells regulate inflammation in tendon healing via JNK and STAT3 signaling.

FASEB J. 2017;31(9):3991-3998.
pt

44. Chhabra A, Tsou D, Clark RT, Gaschen V, Hunziker EB, Mikic B. GDF-5 deficiency in

mice delays Achilles tendon healing. J Orthop Res. 2003;21(5):826-835.

ce

45. Mikic B, Rossmeier K, Bierwert L. Sexual dimorphism in the effect of GDF-6 deficiency
Ac

on murine tendon. J Orthop Res. 2009;27(12):1603-1611.

46. Duffy FJ Jr, Seiler JG, Gelberman RH, Hergrueter CA. Growth factors and canine flexor

tendon healing: initial studies in uninjured and repair models. J Hand Surg Am. 1995;20(4):

645-649.
 24

47. Chang J, Most D, Thunder R, Mehrara B, Longaker MT, Lineaweaver WC. Molecular

studies in flexor tendon wound healing: the role of basic fibroblast growth factor gene

expression. J Hand Surg Am. 1998;23(6): 1052-1058.

48. Thomopoulos S, Kim HM, Das R, Silva MJ, Sakiyama-Elbert S, Amiel D, Gelberman

RH. The effects of exogenous basic fibroblast growth factor on intrasynovial flexor tendon

healing in a canine model. J Bone Joint Surg Am. 2010;92(13):2285-2293.

t
ip
49. Chen CH, Zhou YL, Wu YF, Cao Y, Gao JS, Tang JB. Effectiveness of microRNA in

Down-regulation of TGF-beta gene expression in digital flexor tendons of chickens: in vitro

cr
and in vivo study. J Hand Surg Am. 2009;34:1777-1784.

us
50. Branford OA, Klass BR, Grobbelaar AO, Rolfe KJ. The growth factors involved in flexor

tendon repair and adhesion formation. J Hand Surg Eur. Vol 2014;39:60-70.
an
51. Chetty A, Cao GJ, Nielsen HC. Insulin-like Growth Factor-I signaling mechanisms, type

I collagen and alpha smooth muscle actin in human fetal lung fibroblasts. Pediatr Res.
M

2006;60:389-394.
ed

52. Lyras DN, Kazakos K, Georgiadis G, Mazis G, Middleton R, Richards S, O'Connor D,

Agrogiannis G. Does a single application of PRP alter the expression of IGF-I in the early
pt

phase of tendon healing? J Foot Ankle Surg. 2011;50:276-282.

53. Wilgus TA, Ferreira AM, Oberyszyn TM, Bergdall VK, Dipietro LA. Regulation of scar
ce

formation by vascular endothelial growth factor. Lab Invest. 2008 Jun;88(6):579-590.

Ac

54. Boyer MI, Watson JT, Lou J, Manske PR, Gelberman RH, Cai SR. Quantitative variation

in vascular endothelial growth factor mRNA expression during early flexor tendon healing:

an investigation in a canine model. J Orthop Res. 2001;19:869-872.

55. Gelberman RH, Khabie V, Cahill CJ. The revascularization of healing flexor tendons in

the digital sheath. A vascular injection study in dogs. J Bone Joint Surg Am. 1991;73:868-

881.
 25

56. Thomopoulos S, Das R, Silva MJ, Sakiyama-Elbert S, Harwood FL, Zampiakis E, Kim

HM, Amiel D, Gelberman RH. Enhanced flexor tendon healing through controlled delivery

of PDGF-BB. J Orthop Res. 2009;27:1209-1215.

57. Thomopoulos S, Zaegel M, Das R, Harwood FL, Silva MJ, Amiel D, Sakiyama-Elbert S,

Gelberman RH. PDGF-BB released in tendon repair using a novel delivery system promotes

cell proliferation and collagen remodeling. J Orthop Res. 2007;25:1358-1368.

t
ip
58. Moore KW, O'Garra A, de Waal Malefyt R, Vieira P, Mosmann TR. Interleukin-10.

Annu Rev Immunol. 1993;11:165-190.

cr
59. Peranteau WH1, Zhang L, Muvarak N, Badillo AT, Radu A, Zoltick PW, Liechty KW.

us
IL-10 overexpression decreases inflammatory mediators and promotes regenerative healing

in an adult model of scar formation. J Invest Dermatol. 2008;128(7):1852-1860.

an
60. Liechty KW, Kim HB, Adzick NS, Crombleholme TM. Fetal wound repair results in scar

formation in interleukin-10-deficient mice in a syngeneic murine model of scarless fetal

M

wound repair. J Pediatr Surg. 2000;35(6):866-873.

ed

61. Ricchetti ET, Reddy SC, Ansorge HL, Zgonis MH, Van Kleunen JP, Liechty KW,

Soslowsky LJ, Beredjiklian PK. Effect of interleukin-10 overexpression on the properties of

pt

healing tendon in a murine patellar tendon model. J Hand Surg Am. 2008;33(10):1843-1852.

62. Linderman SW, Shen H, Yoneda S, Jayaram R, Tanes ML, Sakiyama-Elbert SE, Xia Y,
ce

Thomopoulos S, Gelberman RH. Effect of connective tissue growth factor delivered via
Ac

porous sutures on the proliferative stage of intrasynovial tendon repair. J Orthop Res. 2017.

doi: 10.1002/jor.23842. [Epub ahead of print]

63. Wong JK, Metcalfe AD, Wong R, Bush J, Platt C, Garcon A, Goldspink N, McGrouther

DA, Ferguson MW. Reduction of tendon adhesions following administration of Adaprev, a

hypertonic solution of mannose-6-phosphate: mechanism of action studies. PLoS One.

2014;9(11):e112672.
 26

64. Nakamura N, Shino K, Natsuume T, Horibe S, Matsumoto N, Kaneda Y, Ochi T. Early

biological effect of in vivo gene transfer of platelet-derived growth factor (PDGF)-B into

healing patellar ligament. Gene Ther. 1998;5(9): 1165-1170.

65. Wang XT, Liu PY, Tang JB. Tendon healing in vitro: genetic modification of tenocytes

with exogenous PDGF gene and promotion of collagen gene expression. J Hand Surg Am.

2004;29:884-890.

t
ip
66. Tang JB, Cao Y, Zhu B, Xin KQ, Wang XT, Liu PY. Adeno-associated virus-2-mediated

bFGF gene transfer to digital flexor tendons significantly increases healing strength. an in

cr
vivo study. J Bone Joint Surg Am. 2008;90:1078-1089.

us
67. Goomer RS, Maris TM, Gelberman R, Boyer M, Silva M, Amiel D. Nonviral in vivo

gene therapy for tissue engineering of articular cartilage and tendon repair. Clin Orthop Relat
an
Res. 2000;(379 Suppl):S189-200.

68. Zhou Y, Zhang L, Zhao W, Wu Y, Zhu C, Yang Y. Nanoparticle-mediated delivery of

M

TGF-β1 miRNA plasmid for preventing flexor tendon adhesion formation. Biomaterials.
ed

2013;34(33):8269-8278.

69. Loiselle AE, Yukata K, Geary MB, Kondabolu S, Shi S, Jonason JH, Awad HA, O'Keefe
pt

RJ. Development of antisense oligonucleotide (ASO) technology against Tgf-β signaling to

prevent scarring during flexor tendon repair. J Orthop Res. 2015;33(6):859-866.

ce

70. Zhao C, Chieh HF, Bakri K, Ikeda J, Sun YL, Moran SL, An KN, Amadio PC. The
Ac

effects of bone marrow stromal cell transplants on tendon healing in vitro. Med Eng Phys.

2009;31(10):1271-1275.

71. Hayashi M, Zhao C, An KN, Amadio PC. The effects of growth and differentiation factor

5 on bone marrow stromal cell transplants in an in vitro tendon healing model. J Hand Surg

Eur Vol. 2011;36(4):271-279.

 27

72. Morizaki Y, Zhao C, An KN, Amadio PC. The effects of platelet-rich plasma on bone

marrow stromal cell transplants for tendon healing in vitro. J Hand Surg Am.

2010;35(11):1833-1841.

73. Shen H, Kormpakis I, Havlioglu N, Linderman SW, Sakiyama-Elbert SE, Erickson IE,

Zarembinski T, Silva MJ, Gelberman RH, Thomopoulos S. The effect of mesenchymal

stromal cell sheets on the inflammatory stage of flexor tendon healing. Stem Cell Res Ther.

t
ip
2016;7(1):144.

74. Langer R, Vacanti JP. Tissue engineering. Science. 1993;260(5110):920-926.

cr
75. Galvez MG, Crowe C, Farnebo S, Chang J. Tissue engineering in flexor tendon surgery:

us
current state and future advances. J Hand Surg Eur Vol. 2014;39(1):71-78.

76. Longo UG, Lamberti A, Petrillo S, Maffulli N, Denaro V. Scaffolds in tendon tissue
an
engineering. Stem Cells Int. 2012;2012:517165.

77. Yokoya S, Mochizuki Y, Nagata Y, Deie M, Ochi M. Tendon-bone insertion repair and
M

regeneration using polyglycolic acid sheet in the rabbit rotator cuff injury model. Am J Sports
ed

Med. 2008;36(7):1298-1309.

78. Derwin KA, Codsi MJ, Milks RA, Baker AR, McCarron JA, Iannotti JP. Rotator cuff
pt

repair augmentation in a canine model with use of a woven poly-L-lactide device. J Bone

Joint Surg Am. 2009;91(5):1159-1171.

ce

79. MacGillivray JD, Fealy S, Terry MA, Koh JL, Nixon AJ, Warren RF. Biomechanical
Ac

evaluation of a rotator cuff defect model augmented with a bioresorbable scaffold in goats. J

Shoulder Elbow Surg. 2006;15(5):639-644.

80. Manning CN, Schwartz AG, Liu W, Xie J, Havlioglu N, Sakiyama-Elbert SE, Silva MJ,

Xia Y, Gelberman RH, Thomopoulos S. Controlled delivery of mesenchymal stem cells and

growth factors using a nanofiber scaffold for tendon repair. Acta Biomater. 2013;9(6):6905-

6914.
 28

81. Vaquette C, Slimani S, Kahn CJ, Tran N, Rahouadj R, Wang X. A poly(lactic-co-glycolic

acid) knitted scaffold for tendon tissue engineering: an in vitro and in vivo study. J Biomater

Sci Polym Ed. 2010;21(13):1737-1760.

82. Pridgen BC, Woon CY, Kim M, Thorfinn J, Lindsey D, Pham H, Chang J. Flexor tendon

tissue engineering: acellularization of human flexor tendons with preservation of

biomechanical properties and biocompatibility. Tissue Eng Part C Methods. 2011;17(8):819-

t
ip
828.

83. Raghavan SS, Woon CY, Kraus A, Megerle K, Choi MS, Pridgen BC, Pham H, Chang J.

cr
Human flexor tendon tissue engineering: decellularization of human flexor tendons reduces

us
immunogenicity in vivo. Tissue Eng Part A. 2012;18(7-8):796-805.

84. Woon CY, Pridgen BC, Kraus A, Bari S, Pham H, Chang J. Optimization of human
an
tendon tissue engineering: peracetic acid oxidation for enhanced reseeding of acellularized

intrasynovial tendon. Plast Reconstr Surg. 2011;127(3):1107-1117.

M

85. Youngstrom DW, Barrett JG, Jose RR, Kaplan DL. Functional characterization of
ed

detergent-decellularized equine tendon extracellular matrix for tissue engineering

applications. PLoS One. 2013;8(5):e64151.

pt

86. Youngstrom DW1, Rajpar I, Kaplan DL, Barrett JG. A bioreactor system for in vitro

tendon differentiation and tendon tissue engineering. J Orthop Res. 2015;33(6):911-918.

ce

87. Caliari SR, Ramirez MA, Harley BA. The development of collagen-GAG scaffold-
Ac

membrane composites for tendon tissue engineering. Biomaterials. 2011;32(34):8990-8998.

88. Murphy KD, Mushkudiani IA, Kao D, Levesque AY, Hawkins HK, Gould LJ. Successful

incorporation of tissue-engineered porcine small-intestinal submucosa as substitute flexor

tendon graft is mediated by elevated TGF-beta1 expression in the rabbit. J Hand Surg Am.

2008;33(7):1168-1178.
 29

89. Abousleiman RI, Reyes Y, McFetridge P, Sikavitsas V. Tendon tissue engineering using

cell-seeded umbilical veins cultured in a mechanical stimulator. Tissue Eng Part A.

2009;15(4):787-795.

90. Shen W, Chen X, Chen J, Yin Z, Heng BC, Chen W, Ouyang HW. The effect of

incorporation of exogenous stromal cell-derived factor-1 alpha within a knitted silk-collagen

sponge scaffold on tendon regeneration. Biomaterials. 2010;31(28):7239-7249.

t
ip
91. Sahoo S, Toh SL, Goh JC. A bFGF-releasing silk/PLGA-based biohybrid scaffold for

ligament/tendon tissue engineering using mesenchymal progenitor cells. Biomaterials.

cr
2010;31(11):2990-2998.

us
an
M
ed
pt
ce
Ac
 30

Legends

Figure 1A. Severe degloving injury to the dorsal aspect of the hand with extensor tendon

injuries. The white arrow reveals complete devitalization of the soft tissue envelope

including the skin and subcutaneous tissues. The white asterisk shows intrinsic muscle injury

and a metacarpal fracture.

t
ip
cr
us
an
M
ed
pt
ce

Figure 1B. Fibrosis encasing all of the tendons three months post tendon repair. The white
Ac

arrows reveal adhesions between the extensor tendons, while the star reveals substantial

fibrosis in the dermis at the site of injury.

Ac
ce
pt
ed
M
an
us
cr
ip
31

t
 32

Figure 2. Key stages in the healing of tendon

t
ip
cr
us
an
Figure 3. Schematic of a flexor tendon apparatus (volar aspect) including the annular (A1-
M
A5) and cruciate (C1-C3) ligaments, which serve as pulleys within the fibro-osseous sheath.
ed
pt
ce

Table 1. Summary of growth factors and their effects

Ac
 33

Table 1: Summary of growth factors and their effects

B-FGF, VEGF, TGF-β Angiogenesis

PDGF, IGFI, IGFII, B-FGF Cell migration/division
TGF-β, IGFI ECM synthesis

t
BMP-12 Differentiation

ip
IL-1Ra, IL-10 Anti-inflammatory
IGFI, IGFII Proteoglycan synthesis

cr
Legend:

us
B-FGF = basic fibroblast growth factor; VEGF = vascular endothelial growth factor;

PDGF = platelet-derived growth factor; IGF = insulin-like growth factor;

an
TGF-β = transforming growth factor-β; BMP-12 = bone morphogenic protein-12;
M
IL-1Ra = interleukin-1 receptor antagonist; IL-10 = interleukin-10;

ECM = extracellular matrix

ed
pt
ce
Ac