Repairing tendons with silk proteins
Date:
May 3, 2022
Source:
Terasaki Institute for Biomedical Innovation
Summary:
Researchers have developed a silk composite for significantly
improved tendon regeneration and repair.
FULL STORY ==========================================================================
Just mentioning a ruptured Achilles tendon would make anyone wince. Tendon injuries are well known for their lengthy, difficult and often incomplete healing processes. Sudden or repetitive motion, experienced by athletes
and factory workers, for example, increases the risk of tears or ruptures
in the tendons; thirty percent of all people will have a tendon injury,
with the risk being highest in women. What's more, those who suffer from
these injuries are more prone to further injuries at the site or never
recover fully.
========================================================================== Tendons are bands of fibrous connective tissue that attach muscles
to bones.
They are soft tissues connected to stiff bones; this creates a
complex interface with a very specific structure. Following injury,
this structure is disrupted, and the connective tissue changes from a
linear to a kinked formation. Excess scarring can also occur, changing
the tendon's mechanical properties and its ability to bear loads.
During the body's natural healing processes, tendon and other cells
are recruited to reconstruct the tendon's original matrix of aligned
connective tissue fibers. But this reconstruction can take weeks to months
and the resultant tendon is often imperfect. This results in weakness,
chronic pain and decreased quality of life.
Possible treatments for tendon injuries include tendon tissue grafts from patients or donors, but these pose risks such as infections, transplant rejection or necrosis. Synthetic transplants have been attempted, but mechanical, biocompatibility and biodegradation issues have hampered
these efforts.
Another approach is to use mesenchymal stem cells (MSCs), specialized
cells that play a pivotal role in tissue regeneration. At the wound site,
they can differentiate into various cells types and produce signaling
molecules which regulate immune response, cellular migration, and new
blood vessel formation; this enables tissue regeneration.
However, treatment methods using systemic infusion, direct injection or
genetic modification of MSCs present their own difficulties: infusion
lacks targeting specificity to the injury site, direct injection requires prohibitively high cell numbers, and genetic modification is inefficient
and produces cells that are difficult to isolate.
==========================================================================
Yet another approach has been to construct biomaterial frameworks,
or scaffolds, on which to introduce MSCs and growth factors in order
to generate new tendon tissue. A collaborative team from the Terasaki
Institute for Biomedical Innovation (TIBI) has utilized this approach
to develop a method which has yielded significant improvements in MSC
tendon regeneration.
The team first turned to silk fibroin, a silk protein produced by
the Bombyx mori silkworm. In addition to its use in beautiful silk
fabrics, silk fibroin is used in optical and electrical devices, and in
several biomedical applications, from suture materials to bioengineered ligaments, bone and even corneal tissue. Because of its superior strength, durability, biocompatibility and bio-degradative qualities, silk fibroin
is ideal for use in scaffolds for tendons.
In order to improve the scaffold's ability for tissue regeneration, the
team next paired silk fibroin with GelMA, a gelatin-based, water-retaining
gel, due to GelMA's biocompatibility, controllable degradation, stiffness
and ability to promote cell attachment and growth.
"The synergistic effects of GelMA's capacity for supporting regenerative
tissue formation and the structural advantages of silk fibroin make
our composite material well suited for tendon repair," said HanJun Kim,
Ph.D., D.V.M, TIBI's team leader on the project.
They prepared mixtures with varying ratios of silk fibroin and GelMA
(SG) and fabricated them into thin nanofiber sheets. They then tested
the sheets for fiber structure and stretchiness and chose an optimum formulation with the best mechanical properties. They also observed
that the silk fibroin imparted an increased porosity to the material;
this enhances tendon repair.
==========================================================================
The optimized SG sheets were seeded with MSCs and subjected to various
tests to measure MSC compatibility and differentiation, growth factor production, and genetic activity triggering matrix formation.
The MSCs on the SG sheets showed an increase in cell viability
and proliferation over those on silk fibroin sheets without GelMA
(SF). Genetic analysis showed that relevant gene activity in SG MSCs
was significantly increased, in contrast to those on SF sheets, which
was decreased.
Staining tests revealed that the MSCs on the SG sheets showed a more
than 80% attachment rate and had an elongated shape characteristic of
cells attached to a surface, as opposed to a 60% attachment rate, with spherically-shaped cells observed on SF and GelMA only surfaces.
Further tests on a growth factor secreted by MSCs seeded onto nanofiber
sheets showed that the growth factors produced by the MSCs on the SG
sheets were best able to repair injured tendon tissue cultivated in a
culture dish.
Experiments were also conducted on live rats with injured Achilles
tendons.
MSC-seeded nanofiber sheets were implanted onto the injury site and the
SG sheets promoted the most accelerated healing, with reduced injury
sites and the formation of well-aligned, densely packed tendon fibers
and remodeled muscle components.
"Tissue remodeling for tendon repair is especially difficult to achieve,"
said Ali Khademhosseini, Ph.D., TIBI's Director and CEO. "The work done
here significantly advances that achievement." Authors are: Yumeng Xue,
HanJun Kim, Junmin Lee, Yaowen Liu, Tyler Hoffman, Yi Chen, Xingwu Zhou,
Wujin Sun, Shiming Zhang, Hyun-Jong Cho, JiYong Lee, WonHyoung Ryu,
Chang Moon Lee, Samad Ahadian, Mehmet R. Dokmeci, Bo Lei, KangJu Lee,
and Ali Khademhosseini.
This work was supported by the National Institutes of Health (EB021857, EB022403 and R01EB021857).
========================================================================== Story Source: Materials provided by Terasaki_Institute_for_Biomedical_Innovation. Note: Content may be edited
for style and length.
========================================================================== Journal Reference:
1. Yumeng Xue, Han‐Jun Kim, Junmin Lee, Yaowen Liu, Tyler
Hoffman, Yi
Chen, Xingwu Zhou, Wujin Sun, Shiming Zhang, Hyun‐Jong Cho,
JiYong Lee, Heemin Kang, WonHyoung Ryu, Chang‐Moon Lee, Samad
Ahadian, Mehmet R. Dokmeci, Bo Lei, KangJu Lee, Ali Khademhosseini.
Co‐Electrospun Silk Fibroin and Gelatin Methacryloyl Sheet
Seeded with Mesenchymal Stem Cells for Tendon Regeneration. Small,
2022; 2107714 DOI: 10.1002/smll.202107714 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/05/220503091508.htm
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