Review Article
Injectable Natural Biomaterials for Cartilage Tissue Engineering
Li W and Yu X*
1Department of Orthopaedic Surgery, Shanghai Jiaotong University, China
*Corresponding author: Xiaowei Yu, Department of Orthopaedic Surgery, Shanghai Sixth people's hospital, Shanghai Jiaotong University, China
Published: 06 Sep, 2016
Cite this article as: Liu W, Yu X. Injectable Natural Biomaterials for Cartilage Tissue Engineering. Clin Surg. 2016; 1: 1103.
Abstract
Background: Osteoarthritis (OA) has been a common disease among the elderly people but there are no existing solutions clinically efficient for OA. Therefore, tissue engineering has developed in the field of cartilage regeneration. As we all know, tissue engineering has three basic elements: cell, scaffold and growth factor. Injectable scaffolds which can form a gel with original liquid form at the site of defect through a syringe are an emerging scaffold for cartilage engineering. Scaffold can be composed of many materials such as natural materials, synthetic materials, composite materials as well as hybrid materials. Here we mainly discuss the natural materials for cartilage regeneration.
Keywords: Cartilage Tissue; Osteoarthritis; Injectable scaffold
Background
A novel and promising treatment has been proposed for improving cartilage regeneration in
cartilage tissue engineering [1-3]. Extracellular matrix (ECM) could not only provide physical cues
for chondrocytes but also biological cues which can direct cellular behavior. Also, the chondrocytes
are encapsulated within the ECM, balancing the information inside and outside the chondrocytes [4]. Therefore, providing a good circumstance for cartilage is the most important thing for cartilage engineering up to now [5 and 6]. Chondrocytes live in a three dimensional (3D) extracellular matrix (ECM) microenvironment where the basic components such as glycosaminoglycans (GAGs) and collagen type II can be secreted. The content of GAGs and collagen II plays an important role in the physiological and mechanical strength of the implanted scaffold-cell constructs. The glycosaminoglycans (GAGs) (glycosaminoglycans) resemble chondroitin sulfate (CS), heparin sulphate (HS) and usually form proteoglycans by attaching to ECM proteins [2,3,7].
A suitable cartilage tissue engineering (CTTE) scaffold used to repair cartilage defects needs the
following properties. First of all, the scaffold should be easy to handle, as well as keeping stable and
reproducible under physiological conditions; secondly, it needs to be completely biocompatible and
cytocompatible and as well as could help for tissue remodeling; thirdly, the defect sites can be easily
filled, and the scaffolds must have excellent integration property which means it can strongly adhere
and integrate well with the surrounding host cartilage tissue; finally it is supposed to better imitate
cartilaginous ECM properties and promote chondrogenic potential of cells [8].
The significance of tissue engineering cartilage
Cartilage is highly specialized, and is composed of chondrocytes embedded in an extracellular
matrix which mainly consists of collagen, proteoglycans, and water. Cartilage has no internal vascular
network unlike bone with great regenerative potential, thus cartilage’s innate ability is limited for
repair and regeneration. Therefore, cartilage injury always leads to scar formation, resulting in
structure and function losing permanently. Injury of the joint surface can not heal spontaneously
and always develop to degenerative joint disease. Suspending chondrocytes in a three-dimensional
matrix, which is similar to their natural environment, could make the cells maintain the native
phenotype and produce their extracellular components [9].
Articular cartilage damage mechanism
Trauma, the change of joint biomechanical properties and long-term immobilization are the mechanism of articular cartilage damage. The first two mechanisms are related to the destruction of collagen fiber structure, while as prolonged immobility causing the degeneration of cartilage injury is considered to be due to the effect of the pressure pump cartilage loss that leads to joint soft tissue contractures, synovial infiltration or adhesions with cartilage. In consequence, articular surface pressure increased which prevents the mesenchymal cells in the synovial fluid from permeation. Nutritional deficiencies or cartilage damage or synovial fluid fibrinogen interaction could suppress the effect of chemokine factors
and mitogenic factor.
Cell sources
The basic principle of cartilage tissue engineering involves
isolation of cells that may be expanded in vitro and then either
encapsulated in a three-dimensional matrix for proliferation or mixed
with in situ gelling systems and subsequently implanted/injected
into the site of injury. Different sources of cells have been explored
for cartilage tissue engineering which includes primary autologous/
heterologous chondrocytes, fibroblasts, stems cells (mesenchymal
stem cells and embryonic stem cells. For tissue engineering, articular
cartilage have limited ability to regenerate in vivo which we have to
expand the chondrocytes prior to use, often causing dedifferentiation
of cells. The materials we choose to use must have the capacity to
preserve the cell phenotype, up regulating the expression of collagen
type II, aggrecan, the transcription factor Sox 9, and at the same time
down regulating the expression of collagen type I.
How to choose an injectable scaffold
Currently, a lot of materials have been used as an injectable
scaffold clinically to repair cartilage defects, including natural
materials, synthetic materials, composite materials and hybrid
materials and this review mainly focuses on the latest developments of
natural materials. Physical and chemical properties of materials such
as swelling ratio, mechanical properties and the ability to integrate
with the surrounding tissue is of vital importance for cartilage defects
repair. Followings are the recent researches of natural materials and
their respective introductions.
Natural Materials
Natural polymers derived from biological macromolecules and could be used to fabricate scaffolds for cartilage defect repair. Natural polymers should possess inherent biocompatibility and bioactivity as well except for providing a suitable 3-D environment for encapsulated and/or infiltrating cells. Natural polymers in common us include HA, collagen [10,11], alginate[12,13], chitosan [14-16], heparin, fibrin [17 and 18], cellulose [17] and so on.
HA
HA, also called hyaluronan, is a glycosaminoglycan existed widely
in many tissues. HA plays a significant role in cell proliferation and
migration as one of the main components of the extracellular matrix.
Direct transplantation of mesenchymal stem cells into the knee joints: Sato et al. [18]. Set up a model of spontaneous osteoarthritis in the Hartley strain guinea pigs knee joints of, aiming to prove if intra-articular transplantation of MSCs in hyaluronic acid (HA) has the favorable result. After five weeks partial cartilage repair was observed in the HA-MSC group but not in control groups. In the HA-MSC group, after examination the cells showcased the ability of proliferation, differentiation and migration of labeled MSCs. In addition, in the OA cartilage, they observed strongly positive immumohistochemical staining for type II collagen of both native chondrocytes as well as transplanted MSCs. These findings approved intra-articular injection’s validity in of HA-MSC hybrid in the application for OA.
Modulation of MSCs chondrogenesis in a tunable HA hydrogel: Wei Seong Toh et al. [19] used covalent cross-linking in vivo by adding peroxidase and hydrogen peroxide (H2O2) to form an injectable and biodegradable hydrogel system made up of hyaluronic acid-tyramine (HA-Tyr) conjugate. These observations suggest that cellular density could be modulated by the changeable 3-D microenvironment of the HA-Tyr hydrogels during chondrogenesis. It also has a surprising effect on spatial organization of cells and matrix biosynthesis [19].
Collagen
Collagen accounting for about 25% to 35% of the whole-body
protein content is the main component of the extracellular matrix
in many kinds of connective tissues. Whereas and Meanwhile, the
fibroblasts are the main cells producing collagen.
In this research, Pulkkinen HJ et al. [20] isolated bovine
chondrocytes (6×106) which were seeded into rhCII gels (rhCIIcell)
and subsequently injected subcutaneously into the back of nude
mice. The results demonstrated that extracellular matrix stained
heavily with toluidine blue and had strongly positive collagen type
II immunohistochemical staining. No evidence showed vascular
invasion or mineralization. These observations demonstrated
that rhCII-gel had good ability to promote cell proliferation and
mechanical strength for the formation of cartilage neotissue. RhCII
material might be available in repairing cartilage defects.
Alginate
An anionic polysaccharide alginic acid, known as alginate as well,
is distributed extensively in the cell walls of brown algae, which could
form a viscous gum by combining with water [21]. What’s more, it
also can be considered as a material for micro-encapsulation [22].
After combined with calcium, alginate can gain an effect on various
types of medical products such as skin wound dressings to promote
healing [23], having better outcomes than conventional ones.
Some researchers made preparations of calcium alginate
microcapsules, which was made up with by human subchondral
cortico spongious progenitor cells to and the chondrogenic
differentiation potential was analyzed by RT-PCR. When
encapsulated in calcium alginate microcapsule stimulated with TGF–
β3, these cells can differentiated into chondrocytes. In the course of
culture, the mechanical stability and permeability of calcium capsules
were analyzed and found to be suitable for stable cell immobilization.
Therefore, from the cell biology perspective, Ca-alginate is
extremely suitable for regenerative medicine of cartilage defects
combined with progenitor cells [24].
Moreover, alginates are anionic linear polysaccharides with 1,
4-linked b-d-mannuronate (M) and 1, 4-linked a-L-guluronate (G)
residues, forming ionic hydrogels in the presence of divalent ions
(calcium ions) Biji Balakrishnan et al. [25] believe that alginatebased
hydrogels have been shown to have better properties than
poly (ethylene glycol)-based scaffolds by detecting the expression of
collagen type II and aggrecan and GAG deposition [26] and also can
induce re-differentiation of chondrocytes, which are de-differentiated
into fibroblast phenotype in monolayer cultures and this is of great
importance [27]. Nevertheless, unmodified alginate hydrogels are
non-biodegradable [28] and can cause foreign body cell reactions and
immunological responses [29 and 30]. Furthermore, there are no special
interactions between alginates and cells and only by incorporating
cell-adhesive peptides [31], gelatin [32], collagen type I and betatricalcium
phosphate [33] can this hydrogel have cell-adhesive
properties.
This kind of scaffolds can also act as a cellular matrix, promotinghealing by attracting cells from the surrounding native tissue towards
the matrix and can function within the matrix towards regeneration of new tissue [25].
Chitosan
Chitosan has biocompatiblity and biodegradability, which
as a result has been extensively applied as an injectable scaffold in
reparing cartilage defect. In Hao T’s [34] research, chondrocytes
were incorporated into chitosan hydrogel scaffold, aiming to obtain
tissue-engineered cartilage and repair sheep’s articular cartilage
defects. Chitosan owns specific interactions with many growth
factors. Tissue-engineered cartilage scaffolds were fabricated by
mixing sheep chondrocytes within a chitosan hydrogel in vitro,
from which the chondrocytes survived and maintained their ability
to secrete matrix. In vivo, within 24 weeks, sheep’s cartilage defects
were completely repaired. Besides, the chitosan-based hydrogel could
also support matrix accumulation of chondrocytes In conclusion,
this study demonstrates the success of a new approach in its ability
to reconstruct a kind of chitosan-based scaffold to repair articular
cartilage defects and it may be clinically significant in the future. [34]
In addition, there does another chitosan-beta glycerophosphatehydroxyethyl
cellulose (CH-GP-HEC) scaffold own biocompatible,
biodegradable and cytocompatible properties that could make
a transition from sol to gel at 37oC. similar to the physiological
temperature. In Naderi-Meshkin H’s. study, incorporated human
mesenchymal stem cells (hMSCs) chondrogenic differentiation
capacity of the was also ensured after inducted with TGF-β3. During
the 28-day investigation, MSCs showed excellent survival and
proliferative rates within CH-GP-HEC hydrogel which indicate the
material’s good cytocompatibility [35].
Firin
Fibrin, a component of blood clots, can actually a fabricate a kind
of protein-based scaffold which could support a variety of human
tissues. Therefore, it also has a wide application in repairing cartilage
defects due to its biodegradability and biocompatibility.
Fibrin gel, a natural biomaterial, shows excellent biocompatibility,
promoting cell attachment and migration, and can be degraded in a
controllable way has many advantages better than synthetic materials
as a tissue-engineered scaffold. Additionally, fibrin gel imitates
the natural blood-clotting process and can have the ability to selfassembles
into a polymer network, with already existing reports for
fibrin gel to repair the damaged cardiac and cartilage tissues in situ.
Moreover, we could also use fibrin gel as a cell carrier to reduce the
loss of cells due to the forces during cell delivery processes so as to
guarantee certain number cells to enhance the cell viability and tissue
regeneration. [36].
In repairing cartilage defect, there appears evidence showing that
fibrin is not as chondro-permissive as other well developed hydrogels
[37], with bone marrow mesenchymal stem cells(BMSCs) and adipose
derived stem cells(ADSCs) showing a diminished chondrogenic
potential when encapsulated in fibrin [38-40]. Therefore, we need
to further functionalize this versatile injectable hydrogel system to
optimize for cartilage repair therapies. Articular cartilage extracellular
matrix (ECM)-derived materials have been previously used to
fabricate cartilage grafts with promising results [41-44]. Moreover,
ECM particles have also been used to functionalize other biomaterials
in order to enhance chondrogenesis [45-47].
Cellulose
Xu Y et al, [17] reported they developed a new method using
adipose tissue-derived stromal cells (ADSCs) incorporated into
hydroxypropylmethyl cellulose (HPMC) for fabricating injectable
tissue-engineered cartilage in vivo. HPMC, a cellulose derivative
polymer, is a methylcellulose modified with propylene glycol ether
groups attached to the an hydroglucose of the cellulose [47 and 48]. HPMC
has excellent solubility and can transit from liquid of low viscosity at
23oC to a solid gel at 37oC. Therefore, ADSCs isolated from rabbit
subcutaneous fat that is and cultured in chondrogenic differentiation
medium with TGF-β1 and basic fibroblast growth factor (bFGF)
are encapsulated in the HPMC hydrogel. After cultured for a short
time, the neocartilage began to secrete cartilage-like components like
collagen II as well as GAGs, proved by Masson’s trichrome staining,
picrosirius red staining and AB-PAS staining. We are not sure if the
differentiated chondrocytes maintained their phenotype, although
ther examinations like histological, immunohistochemistry and RTPCR
guaranteed that after induction, the ADSCs differentiated into
chondrocytes. The induced ADSCs were mixed with 15% HPMC, and
then injected into the dorsal subcutaneous tissue of nude mice and
after cultured for 8 weeks. Neocartilage can be observed at the site
of injection. Therefore, induced ADSCs-formed chondrocytes mixed
with HPMC has been proved to offer a feasible solution for cartilage
tissue engineering.
Summary
Natural biomaterials great potential for cartilage tissue
engineering as we already mentioned in the beginning. On one hand,
cartilage cells or MSCs of any kind need a 3-D microenvironment to
form into a complete cartilage tissue. It’s just the reason why we use
scaffolds. Not like osteogenic cells, chondroblasts need an agent that
can fully incorporate them like hydrogel. On the other hand, natural
material-related scaffold can promote the integration between
the scaffold and the native cartilage tissue to achieve s mechanical
stability.
The existing techniques like microfracture, mosaicplasty,
autologous chondrocyte transplantation, and osteochondral allograft
transplantation to treat cartilage defects have solved some problems of
patients, but cartilage produced by these methods are often composed
of collagen type I, while this kind of collagen is mainly present in scar
tissue, as well as tendons, ligaments, the endomysium of myofibrils,
the dermis and so on. Thus it is inferior to hyaline cartilage both
chemically and mechanically [48].
Compared with conventional methods in tissue engineering,
the injectable scaffolds have the advantages of minimal invasiveness
and targeted delivery at the preferred site. It also relieves the pain
of the patients and is easy for operation. Moreover, it can fill the
defects with irregular shape when the hydrogel form from sol to gel
in situ. In my opinion, for cartilage tissue engineering, the natural
materials should be used to repair cartilage defects because they have
the similar components of native cartilage and good biocapability
and cytocapability and it can be easier for the natural materials to
integrate with the surrounding tissue. Moreover, natural materials
could help secrete more extracellular matrix such as collagen II and
GAGs. However, the mechanical strength of natural materials is a
big issue. The tissue-engineered construct should be able to maintain
physiologic loads within the joints over a long term. To solve this kind
of problem, many researchers combined natural materials such as HA with synthetic materials such as PEG. The hybrid material could
not only enhance cell proliferation and differentiation but also could
enhance the mechanical strength of cartilage. Therefore, I believe the
best materials for cartilage tissue engineering in the future should be
a combination of these two kinds of materials, not just one of them.
References
- Jin R, Moreira Teixeira LS, Dijkstra PJ, van Blitterswijk CA, Karperien M, Feijen J. Chondrogenesis in injectable enzymatically crosslinked heparin/ dextran hydrogels. Journal of controlled release: official journal of the Controlled Release Society. 2011; 152: 186-195.
- Jin R, Moreira Teixeira LS, Dijkstra PJ, Zhong Z, van Blitterswijk CA, Karperien M, et al. Enzymatically crosslinked dextran-tyramine hydrogels as injectable scaffolds for cartilage tissue engineering. Tissue engineering Part A. 2010; 16: 2429-2440.
- Moreira Teixeira LS, Bijl S, Pully VV, Otto C, Jin R, Feijen J, et al. Selfattaching and cell-attracting in-situ forming dextran-tyramine conjugates hydrogels for arthroscopic cartilage repair. Biomaterials. 2012; 33: 3164- 3174.
- Coburn JM, Gibson M, Monagle S, Patterson Z, Elisseeff JH. Bioinspired nanofibers support chondrogenesis for articular cartilage repair. Proceedings of the National Academy of Sciences of the United States of America. 2012; 109: 10012-10017.
- Yao X, Peng R, Ding J. Cell-material interactions revealed via material techniques of surface patterning. Advanced materials. 2013; 25: 5257-5286.
- Li Y, Rodrigues J, Tomas H. Injectable and biodegradable hydrogels: gelation, biodegradation and biomedical applications. Chemical Society reviews. 2012; 41: 2193-2221.
- Izumikawa T, Sato B, Kitagawa H. Chondroitin sulfate is indispensable for pluripotency and differentiation of mouse embryonic stem cells. Scientific reports. 2014; 4: 3701.
- Chen F, Yu S, Liu B, Ni Y, Yu C, Su Y, et al. An Injectable Enzymatically Crosslinked Carboxymethylated Pullulan/Chondroitin Sulfate Hydrogel for Cartilage Tissue Engineering. Scientific reports. 2016; 6: 20014.
- Peretti GM, Xu JW, Bonassar LJ, Kirchhoff CH, Yaremchuk MJ, Randolph MA. Review of injectable cartilage engineering using fibrin gel in mice and swine models. Tissue engineering. 2006; 12: 1151-1168.
- YLiu Y, Ramanath HS, Wang DA. Tendon tissue engineering using scaffold enhancing strategies. Trends in biotechnology. 2008; 26: 201-209.
- Capito RM, Spector M. Collagen scaffolds for nonviral IGF-1 gene delivery in articular cartilage tissue engineering. Gene therapy. 2007; 14: 721-732.
- Rowley JA, Madlambayan G, Mooney DJ. Alginate hydrogels as synthetic extracellular matrix materials. Biomaterials. 1999; 20: 45-53.
- Rouillard AD, Berglund CM, Lee JY, Polacheck WJ, Tsui Y, Bonassar LJ, et al. Methods for photocrosslinking alginate hydrogel scaffolds with
- Khor E, Lim LY. Implantable applications of chitin and chitosan. Biomaterials. 2003; 24: 2339-2349.
- Jiang T, Kumbar SG, Nair LS, Laurencin CT. Biologically active chitosan systems for tissue engineering and regenerative medicine. Current topics in medicinal chemistry. 2008; 8: 354-364.
- Cheng M, Cao W, Gao Y, Gong Y, Zhao N, Zhang X. Studies on nerve cell affinity of biodegradable modified chitosan films. Journal of biomaterials science Polymer edition. 2003; 14: 1155-1167.
- Xu Y, Zhang J, Ma Y, Han Y, Min J, Liang Y, et al. The role of adiposederived stromal cells and hydroxypropylmethylcellulose in engineering cartilage tissue in vivo. Cytotechnology. 2014; 66: 779-790.
- Sato M, Uchida K, Nakajima H, Miyazaki T, Guerrero AR, Watanabe S, etal. Direct transplantation of mesenchymal stem cells into the knee joints of Hartley strain guinea pigs with spontaneous osteoarthritis. Arthritis research & therapy. 2012; 14: R31.
- Toh WS, Lim TC, Kurisawa M, Spector M. Modulation of mesenchymal stem cell chondrogenesis in a tunable hyaluronic acid hydrogel microenvironment. Biomaterials. 2012; 33: 3835-3845.
- Pulkkinen HJ, Tiitu V, Valonen P, Jurvelin JS, Lammi MJ, Kiviranta I. Engineering of cartilage in recombinant human type II collagen gel in nude mouse model in vivo. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2010; 18: 1077-1087.
- JLeid JG, Willson CJ, Shirtliff ME, Hassett DJ, Parsek MR, Jeffers AK. The exopolysaccharide alginate protects Pseudomonas aeruginosa biofilm bacteria from IFN-gamma-mediated macrophage killing. Journal of immunology. 2005; 175: 7512-7518.
- Aizpurua-Olaizola O, Navarro P, Vallejo A, Olivares M, Etxebarria N, Usobiaga A. Microencapsulation and storage stability of polyphenols from Vitis vinifera grape wastes. Food chemistry. 2016; 190: 614-621.
- Lansdown AB. Calcium: a potential central regulator in wound healing in the skin. Wound repair and regeneration: official publication of the Wound Healing Society [and] the European Tissue Repair Society. 2002; 10: 271-285.
- Endres M, Wenda N, Woehlecke H, Neumann K, Ringe J, Erggelet C, et al. Microencapsulation and chondrogenic differentiation of human mesenchymal progenitor cells from subchondral bone marrow in Caalginate for cell injection. Acta biomaterialia. 2010; 6: 436-444.
- Balakrishnan B, Joshi N, Jayakrishnan A, Banerjee R. Self-crosslinked oxidized alginate/gelatin hydrogel as injectable, adhesive biomimetic scaffolds for cartilage regeneration. Acta biomaterialia. 2014; 10: 3650- 3663.
- Grande DA, Halberstadt C, Naughton G, Schwartz R, Manji R. Evaluation of matrix scaffolds for tissue engineering of articular cartilage grafts. Journal of biomedical materials research. 1997; 34: 211-220.
- Adolphe M, Demignot S. [Versatility of differentiated functions of cultured joint chondrocytes. Eventual usefulness in treatment]. Bulletin de l'Academie nationale de medecine. 2000; 184: 593-600.
- Bouhadir KH, Lee KY, Alsberg E, Damm KL, Anderson KW, Mooney DJ. Degradation of partially oxidized alginate and its potential application for tissue engineering. Biotechnology progress. 2001; 17: 945-950.
- Mathe Z, Bucher P, Bosco D, Andres A, Fux C, Toso C, et al. Shortterm immunosuppression reduces fibrotic cellular infiltration around barium-M-alginate microbeads injected intraportally. Transplantation proceedings. 2004; 36: 1199-1200.
- Lansdown AB, Payne MJ. An evaluation of the local reaction and biodegradation of calcium sodium alginate (Kaltostat) following subcutaneous implantation in the rat. Journal of the Royal College of Surgeons of Edinburgh. 1994; 39: 284-288.
- Rowley JA, Mooney DJ. Alginate type and RGD density control myoblast phenotype. J Biomed Materi Res. 2002; 60: 217-223.
- Liu Y, Sakai S, Taya M. Impact of the composition of alginate and gelatin derivatives in bioconjugated hydrogels on the fabrication of cell sheets and spherical tissues with living cell sheaths. Acta biomaterialia. 2013; 9: 6616- 6623.
- Lawson MA, Barralet JE, Wang L, Shelton RM, Triffitt JT. Adhesion and growth of bone marrow stromal cells on modified alginate hydrogels. Tissue engineering. 2004; 10: 1480-1491.
- Hao T, Wen N, Cao JK, Wang HB, Lu SH, Liu T, et al. The support of matrix accumulation and the promotion of sheep articular cartilage defects repair in vivo by chitosan hydrogels. Osteoarthritis and cartilage/OARS, Osteoarthritis Research Society. 2010; 18: 257-265.
- Naderi-Meshkin H, Andreas K, Matin MM, Sittinger M, Bidkhori HR, Ahmadiankia N, et al. Chitosan-based injectable hydrogel as a promising in situ forming scaffold for cartilage tissue engineering. Cell biology international. 2014; 38: 72-84.
- Li Y, Meng H, Liu Y, Lee BP. Fibrin gel as an injectable biodegradable scaffold and cell carrier for tissue engineering. The Scientific World Journal. 2015; 2015: 685690.
- Thorpe SD, Buckley CT, Steward AJ, Kelly DJ. European Society of Biomechanics S.M. Perren Award 2012: the external mechanical environment can override the influence of local substrate in determining stem cell fate. J Biomechanics. 2012; 45: 2483-2492.
- Sheehy EJ, Mesallati T, Vinardell T, Kelly DJ. Engineering cartilage or endochondral bone: a comparison of different naturally derived hydrogels. Acta biomaterialia. 2015; 13: 245-253.
- Im GI, Shin YW, Lee KB. Do adipose tissue-derived mesenchymal stem cells have the same osteogenic and chondrogenic potential as bone marrow-derived cells? Osteoarthritis and cartilage/OARS, Osteoarthritis Research Society. 2005; 13: 845-853.
- Rowland CR, Lennon DP, Caplan AI, Guilak F. The effects of crosslinking of scaffolds engineered from cartilage ECM on the chondrogenic differentiation of MSCs. Biomaterials. 2013; 34: 5802-5812.
- Benders KE, van Weeren PR, Badylak SF, Saris DB, Dhert WJ, Malda J. Extracellular matrix scaffolds for cartilage and bone regeneration. Trends in biotechnology. 2013; 31: 169-176.
- Almeida HV, Liu Y, Cunniffe GM, Mulhall KJ, Matsiko A, Buckley CT, et al. Controlled release of transforming growth factor-beta3 from cartilageextra- cellular-matrix-derived scaffolds to promote chondrogenesis of human-joint-tissue-derived stem cells. Acta biomaterialia. 2014; 10: 4400- 4409.
- Almeida HV, Cunniffe GM, Vinardell T, Buckley CT, O'Brien FJ, Kelly DJ. Coupling Freshly Isolated CD44(+) Infrapatellar Fat Pad-Derived Stromal Cells with a TGF-beta3 Eluting Cartilage ECM-Derived Scaffold as a Single-Stage Strategy for Promoting Chondrogenesis. Advancedhealthcare materials. 2015; 4: 1043-1053.
- Visser J, Gawlitta D, Benders KE, Toma SM, Pouran B, van Weeren PR, et al. Endochondral bone formation in gelatin methacrylamide hydrogel with embedded cartilage-derived matrix particles. Biomaterials. 2015; 37: 174-182.
- Sutherland AJ, Detamore MS. Bioactive Microsphere-Based Scaffolds Containing Decellularized Cartilage. Macromolecular bioscience. 2015; 15: 979-989.
- Chang CH, Chen CC, Liao CH, Lin FH, Hsu YM, Fang HW. Human acellular cartilage matrix powders as a biological scaffold for cartilage tissue engineering with synovium-derived mesenchymal stem cells. J Biomed Materi Res Part A. 2014; 102: 2248-2257.
- PFatimi A, Tassin JF, Quillard S, Axelos MA, Weiss P. The rheological properties of silated hydroxypropylmethylcellulose tissue engineering matrices. Biomaterials. 2008; 29: 533-543.
- Jackson DW, Scheer MJ, Simon TM. Cartilage substitutes: overview of basic science and treatment options. J Am Acad Orthop Surg. 2001; 9: 37- 52.