PT
Classroom - The latest research of ACL
reconstruction and repair with an emphasis on the bridge-enhanced
ACL repair (BEAR)
׀ by Billie Weber,
SPT
The latest research of ACL reconstruction and repair with an
emphasis on the bridge-enhanced ACL repair (BEAR)
The
anterior cruciate ligament (ACL) is an important stabilizer
of the knee joint (1,2,3,4). It is an intracapsular
structure that runs from the medial wall of the lateral
femoral condyle to the anterior intercondylar area of the
tibial plateau (3). The main function of the ACL is to act
as a rotary guide in the screw home mechanism and to limit
anterior translation and internal rotation of the tibia on
the femur (2,3).
Each year, more than 200,000 ACL injuries occur in the
United States (Figure 2) (5). Oftentimes, these injuries
arise during high velocity movements, like cutting,
pivoting, or landing a jump (3). They can occur at any age,
but they tend to occur more frequently in young, active
adults (2,3). Furthermore, women are 35 times more likely
than men to sustain an ACL injury (6), especially if
participating in sports that involve cutting and pivoting
(1). ACL injuries can be treated conservatively with
physical therapy, but 65% of the time, ACL ruptures are
treated surgically.5 Surgical reconstruction involves
removing the torn portions of the ACL and replacing it with
a patellar or hamstring tendon graft. The graft is most
often an autograft, but it could also be an allograft (2).
While ACL reconstruction improves the overall stability of
the knee, it does not prevent the development of
post-traumatic osteoarthritis (2,4,6). One study found that
post-traumatic osteoarthritis occurred as high as 78% of the
time 14 years after injury (7).
Therefore, researchers are searching for a different
approach to prevent post-traumatic osteoarthritis in
surgically reconstructed knees. The latest research focuses
on a bio-enhanced repair that involves the use of scaffolds,
cell seeding, and growth factors to augment ACL primary
suture repairs and reconstructions (4,9).
Scaffolds are bio-engineered tissues that serve to initiate
and promote healing of the ACL. In a suture repair,
scaffolds help to form a bridge between the torn ends of the
ACL to allow for ligament regrowth and repair (4,8,9).
Scaffolds have also been used to enhance reconstructions by
placing it around the graft. Typically, scaffolds are
designed to contain what is normally found in the
extracellular matrix of the ligament. Therefore bio-active
scaffolds are often seeded with cells and injected with
platelets to release a variety of growth factors that are
necessary for repair (8).
Cell seeding is another type of bio-enhanced repair
technology that is being investigated (4,9). This technology
involves supplementing the repair with exogenous cells, like
fibroblasts or bone marrow stomal cells (BMSC), to enable
faster and better healing of the ACL (4,9). One in vitro
study showed that 10 times more collagen was produced when
fibroblasts were added to a collagen scaffold. Another study
compared ACL reconstructions with a non-seeded silk scaffold
and a BMSC-seeded silk scaffold in a sheep model. The
results from this study showed that the BMSC-seeded silk
scaffold reconstructions had better healing as measured by
histological evidence (9). Similar studies have found
comparable results as evidenced by histological analysis,
biomechanical evidence, and higher load-to-failure rates
(4).
Growth factors are also being investigated for use in
bio-enhanced ACL repairs. In vitro studies of epidermal
growth factor (EGF), fibroblast growth factor (FGF),
insulin-like growth factor (IGF), platelet-derived growth
factor (PDGF), and transforming growth factor (TGF) increase
collagen synthesis and cell proliferation (4,8,10). Several
studies have shown the benefits of growth factors in vitro.
However, growth factors face challenges in vivo. Typically
endogenous growth factors are released by host cells in the
human body over time; whereas exogenous growth factors are
supplemented in a one-time dose. In addition, exogenous
growth factors have been found to be cleared from the joint
within a few hours (4,10). Thus researchers have been trying
to find a better way to incorporate growth factors into the
repair process.
Plasma-rich protein (PRP) contains a multitude of growth
factors and has been used to successfully treat bony and
soft tissue conditions in animal studies and clinical trials
(10,11). Researchers have also attempted to stimulate the
healing of ACL and ACL grafts with PRP and have observed
varying results (4, 11). A systematic review concluded that
the use of PRP in ACL reconstructions is slightly beneficial
on graft maturation but has little to no effects on the
healing of the graft-bone interface. The study went on to
state that more research was necessary to determine the
efficacy of PRP in the use of ACL healing. The mixed results
seen in a variety of PRP and ACL repair studies could be due
to the large concentration of fibrinolysis found within
synovial joints. Fibrinolysis is an enzyme that degrades
fibrin, a protein that is necessary for blood clot
formation. With decreased blood clot formation, fewer growth
factors will be secreted by the platelets participating in
the clot and less growth will occur. However, when PRP is
combined with collagen, a copolymer is formed that is not as
susceptible to the fibrinolysis. Thus the copolymer could be
beneficial in bio-enhanced repairs.
Therefore, it has been proposed that fibrin-based PRP could
be combined with a collagen scaffold to create a suitable
environment for ligament healing. This proposal has led to
the creation of Bridge-Enhanced ACL Repair (BEAR), which
stimulates the ACL to repair itself. The BEAR involves
suturing a collagen scaffold to the torn ends of the ACL to
form a bridge. Once in place, platelets are injected into
the scaffold and a clot is formed. Slowly the torn ends of
the ACL grow into the scaffold and reform the ligament (4).
A few large animal studies have demonstrated improved ACL
histology and biomechanical properties in both
reconstruction and repairs with the bio-enhanced repair
technique (4). One study demonstrated that the bio-enhanced
ACL repairs had comparable strength to ACL reconstructions
at 3, 6, and 12 months post-operatively in large animals
(10). Moreover, two different studies in pigs observed
similar results between the ACL primary repair supplemented
with collagen-platelet composite bridge and the ACL
reconstruction (4). Furthermore, one of those studies,
Murray and Fleming 2013 saw significantly reduced
post-traumatic osteoarthritis in the bio-enhanced repair and
BEAR groups in comparison to the non-treatment and
reconstruction groups (Figure 2) (8).
Figure 2. Distal ends
of a pig femur in four different experimental groups: ACL
transection (ACLT), ACL reconstruction using patellar tendon
autograft (ACLR), bridge-enhanced repair with a scaffold and
autologous blood (BE-Repair), and bridge-enhanced ACL
reconstruction with scaffold and autologous blood (BE-ACLR).
Post-traumatic osteoarthritis can be observed at black
arrows (8).
While the mechanism of the BEAR
that is responsible for preventing the post-traumatic
osteoarthritis is unknown, it is thought to be due to the
anti-inflammatory effect of platelets (4,10). Platelets
release cytokines and growth factors that increase the
number of chondrocytes and enhance matrix production while
it minimizes the concentration of pro-inflammatory molecules
(4,8). Furthermore, it has been found that platelets
decrease the overall number of cytokines within the
cartilage and synovium, prevent the production of excess
synovial fluid, and promote the production of proteoglycans
and type II collagen. Therefore, the platelets may act to
protect the chondrocytes and slow the development of
post-traumatic osteoarthritis. It has also been proposed
that preservation of the torn ends of the ACL may allow for
the conservation of proprioception. Thus, in situations that
place excessive stress on the knee, the hamstrings may be
elicited to contract and dynamically protect the knee (4).
This could prevent further injury to the knee joint.
Although still in development, the
BEAR technique has had encouraging pre-clinical results
(4,8,10). In 2014, the first-in-human study to test the BEAR
procedure was approved by the FDA. In February 2015, the
first BEAR was performed on a human with MRI evidence of a
relatively normal ACL at 12 months post-operative (12). A
small, pre-clinical trial is ongoing with 10 individuals
participating in the BEAR experimental group. Thus far, all
patients in the BEAR experimental group have healing ACL
tissue and are on the same timeline as those repaired with
an ACL reconstruction (13). A larger, second pre-clinical
trial is currently accepting participants.
Despite the BEAR being a
relatively new technique, the results of animal studies and
the current pre-clinical trial data are promising. At this
time, the BEAR is comparable to having an ACL reconstruction
without some of the common issues that arise with using an
autograft. However, It will take several years to determine
if the BEAR is truly as effective as the ACL reconstruction
and whether or not it is capable of preventing the
development of post-traumatic osteoarthritis. That being
said, if the BEAR is successful, it could shape the future
of the ACL reconstruction and become the dominant form of
treatment for ACL ruptures within the next five years.
Last revised: Ocotber 18, 2016
by Billie Weber, SPT
References
1.) Anderson MJ, Browning WM, Urband CE, et al. A systematic
summary of systematic reviews on the topic of the anterior
cruciate ligament. Orthop J Sports Med.
2016;4(3):2325967116634074. doi:10.1177/2325967116634074.
2.) Monk P, Davies L, Hopewell S, et al. Surgical versus
conservative interventions for treating anterior cruciate
ligament injuries. Cochrane Database Sys Rev.
2016:4(CD011166). doi: 10.1002/14651858.CD011166.pub2.
3.) Neumann D. Knee. In: Neumann D. Kinesiology of the
musculoskeletal system: foundations for rehabilitation. 2nd
ed. St. Louis, MO: Mosby; 2010
4.) Proffen BL, Perrone GS, Roberts G, et al.
Bridge-enhanced ACL repair: a review of the science and the
pathway through FDA investigational device approval. Ann
Biomed Eng. 2015;43(3):805-818.
doi:10.1007/s10439-015-1257-z.
5.) Spindler KP, Wright RW. Clinical practice: anterior
cruciate ligament tear. N Engl J Med. 2008;359(20):135-42.
doi: 10.1056/NEJMcp0804745.
6.) Friel, N, Chu, C. The role of ACL injury in the
development of posttraumatic knee osteoarthritis. Clin
Sports Med. 2013;32(1): 1-12.
7.) Von Porat A, Roos EM, Roos H. High prevalence of
osteoarthritis 14 years after an anterior cruciate ligament
tear in male soccer players: a study of radiographic and
patient relevant outcomes. Ann Rheum Dis. 2004;63:269–273.
doi: 10.1136/ard.2003008136.
8.) Murray MM, Fleming BC. Use of a bioactive scaffold to
stimulate ACL healing also minimizes post-traumatic
osteoarthritis after surgery. Am J Sports Med.
2013;41(8):1762-1770. doi:10.1177/0363546513483446.
9.) Teuschl A, Heimel P, Nuernberger S, van Griensven M,
Redl H, Nau T. A novel silk fiber-based scaffold for
regeneration of the anterior cruciate ligament: histological
results from a study in sheep. Am J Sports Med. 2016;44(6):
1547-1557. doi: 10.1177/0363546516631954.
10.) Proffen BL, Sieker JT, Murray M. Bio-enhanced repair of
the anterior cruciate ligament. Arthroscopy.
2015;31(5):990-997. doi:10.1016/j.arthro.2014.11.016.
11.) Kopka M, Bradley J. The use of biologic agents in
athletes with knee injuries. The Journal of Knee Surgery.
2016;29(5): 379-386. doi: 10.1055/s-0036-1584194.
12.) Murray M. Q+A: what you need to know about the
bridge-enhanced ACL repair. Boston Children’s Hospital Web
site.
http://notes.childrenshospital.org/qa-what-you-need-to-know-about-bridge-enhanced-acl-repair/.
Published March 2016. Accessed August 19, 2016.
13.) Martha Murray, MD. Boston Children’s Hospital Web site.
http://www.childrenshospital.org/researchers/martha-murray.
Accessed August 19, 2016.
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The
anterior cruciate ligament (ACL) is an important stabilizer
of the knee joint (1,2,3,4). It is an intracapsular
structure that runs from the medial wall of the lateral
femoral condyle to the anterior intercondylar area of the
tibial plateau (3). The main function of the ACL is to act
as a rotary guide in the screw home mechanism and to limit
anterior translation and internal rotation of the tibia on
the femur (2,3).
