MSC-Hydrogel for cartilage repair

About Solution

Articular cartilage injury is still a signifcant challenge because of the poor intrinsic healing
potential of cartilage. Stem cell-based tissue engineering is a promising technique for cartilage
repair. As cartilage defects are usually irregular in clinical settings, scaffolds with moldability that
can fill any shape of cartilage defects and closely integrate with the host cartilage are desirable.
Tissue engineering scaffolds provide cells with adhesion growth, whose material composition
and microstructure characteristics have an effect on cell growth. Therefore, good tissue
engineering scaffolds need both biocompatibility and microstructure formation . Naturally sourced
injectable thermosensitive hydrogels can simultaneously encapsulate and release growth factors.
Meanwhile , they have the ability to recruit MSCs from surrounding tissues to migrate to
In this study, we constructed an injectable temperature-sensitive bioactive
agarose/gelatin/hyaluronic acid hydrogel scaffold modifed by Chondrocyte extracellular matrix
(ECM) particles for cartilage engineering. As a natural plant polysaccharide material, agarose is a
linear polymer, whose solution has good temperature sensitivity. It is generally soluble in water at
90℃. When the temperature drops to 40℃, a stable hydrogel structure can be formed. As a natural
hydrogel, agarose hydrogel has the advantages of non-toxic cells, low material cost, and simple
gelation method. In this study, the preparation of hydrogel with agarose not only made the whole
hydrogel have temperature-sensitive properties, but also enhanced the biomechanical strength of
the whole system to some extent. Gelatin is a product of alkaline or acidic hydrolysis of collage,
which is non-toxic, low in immunogenicity, and has good cell adhesion, biodegradability and
biocompatibility. The hydrogel scaffold prepared by gelatin in this study has many excellent
properties, which not only improves the compressive strength and cell adhesion ability of the
whole system, but also promotes the proliferation and differentiation of cells. HA is an anionic
linear high molecular weight polysaccharide, which is an important component of
glycosaminoglycan (GAG) in the cartilage matrix and can be used to make injectable hydrogels.
For that it can support cell proliferation and maintain cartilage phenotype formation, HA has
attracted wide attention of researchers, and has been widely used in artificial tissue, wound healing
and chondrocyte culture and so on. Previous studies have reported that HA binds to the cell
surface receptor CD44 and promotes cell expression of more chondrocyte markers such as SOX-9,
aggrecan and COL II. Obviously, HA plays an important role in the formation of cartilage matrix.
Therefore, it is an important component of the entire hydrogel system.
Cartilage ECM is a filling between cartilage cells and a scaffold for cartilage tissue. The
ECM particles retain the basic skeleton of natural cartilage tissue,which is a loose porous
structure composed of abundant proteoglycans and collagen fibers.They play an important role in
the aspects of the increase in chondrocytes, migration, signal transmission between cells and
mechanical response of tissue engineered cartilage. Specifically speaking, the role of ECM in
tissue engineered cartilage is mainly reflected in three aspects: First, ECM itself is a loose porous
structure similar to natural cartilage tissue, which can provide a microenvironment suitable for
normal stem cell survival, meanwhie, can promote Cell adhesion, proliferation and induction of
differentiation into the cartilage direction; Second, the addition of ECM particles can significantly
improve the biomechanical strength of the hydrogel-cell composite scaffold; third, the addition
of ECM particles makes the hydrogel-cell composite scaffold more in line with the 3D structure of
natural cartilage tissue. This is mainly reflected in the presence of cell growth factors such as

transforming progesterone β and insulin-like growth factor 1 in the cartilage matrix . Transforming
growth factor beta is abundant in articular cartilage and is a known growth factor that plays an
important role in the primary stage of chondrogenesis. It not only promotes the secretion of
cartilage matrix including type II collagen, but also induces Mesenchymal stem cells differentiate
into chondrocytes, playing an important role in the survival of cells grown in serum-free medium.
The hydrogel scaffold we prepared exhibited a good ultrastructure, which provided a 3D
microenvironment that supports cell adhesion and proliferation. Cell proliferation and DNA
content analysis indicated that the agarose/gelatin/hyaluronic acid/DBA hydrogel scaffold
promoted better rat bone mesenchymal MSCs (BMSCs) survival than the agarose/ gelatin/
hyaluronic acid groups. Meanwhile, the agarose/ gelatin/ hyaluronic acid /ECM hydrogel scaffold
increased matrix production and improved chondrogenic differentiation ability of CHs-BMSCs in
vitro. Furthermore, after implantation in vivo for four weeks, compared to those in control groups,
the regenerated tissue in the agarose/ gelatin/ hyaluronic acid/ECM hydrogel group exhibited
translucent and superior cartilage-like structures, as indicated by gross observation, histological
examination, and assessment of matrix staining. Overall, the functional composite scaffold of
agarose/ gelatin/ hyaluronic acid/DBA hydrogel is a promising option for repairing irregularly
shaped cartilage defects.



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