Page 377 - Advances in Biomechanics and Tissue Regeneration

374 18. CARTILAGE REGENERATION AND TISSUE ENGINEERING

focus on four of the principal factors: those of the transforming growth factor-β superfamily (TGF-β), bone morpho-
genetic proteins subfamily (BMPs), fibroblast growth factors family (FGFs), and insulin-like growth factor
family (IGFs).
Of the five members of the TGF-β superfamily, TGF-β1, TGF-β2, and TGF-β3 stimulate proteoglycan and type II
collagen synthesis by chondrocytes and induce chondrogenic differentiation of MSCs in vitro [122, 123]; types 1
and 3 are the most effective in terms of synthesis of ECM markers [124].
Although in vivo studies have shown that TGF-β1 induces MSCs to differentiate chondrally, other studies found
that direct injection into joints triggered calcification [122, 125], suggesting that the use thereof must be regulated.
BMPs are members of the TGF-β superfamily that induce bone and cartilage formation. About 15 members have
been identified to date; BMP-2, BMP-4, BMP-6, BMP-7, and BMP-9 have been best studied in terms of chondrogenic
potential and effectively stimulated expression of chondrocyte-specific markers when added to isolated chondrocytes
or various MSCs [126, 127]. Also, scaffolds chemically loaded with BMP-2 or genetically modified MSCs of various
origins expressing BMP-2, BMP-4, BMP-6, and BMP-7 have proved useful for repair of osteochondral defects [126].
Microfracture triggers articular cartilage repair via the induction of fibrous cartilage. Some authors combined micro-
fracture with administration of BMP-2 or BMP-7, affording a more hyaline-like cartilage repair [126].
BMP-2, BMP-4, and BMP-6 enhance stem cell chondrogenesis because they induce expression of the TGF-β receptor
[128]. BMP-2 seems to be the most effective in this context [129]. However, a disadvantage is that higher levels of BMP
may trigger ectopic bone formation in vivo; the spectrum of the tissue regenerative dose is thus narrow [130].
Although TGF-β and the BMPs are the most important factors in terms of chondral differentiation, other factors
(such as FGFs and IGFs) can also be used. Of the FGFs, types 2 and 18 are interesting because of their MSC chondro-
genic potentials. FGF-18 exerts anabolic effects on cartilage, and FGF-2 participates in cartilage homeostasis [123]. Both
FGFs exhibited chondrogenic potential in vitro and in vivo, promoting matrix deposition and the expression of chon-
drogenic markers of stimulated MSCs when used either alone or in combination with other growth factors such as
TGF-β1 or BMP-2 [131–133].
IGF-1 is an essential mediator of cartilage homeostasis, stimulating proteoglycan synthesis and promoting chon-
drocyte survival and proliferation [134]. IGF-1 enhanced cartilage formation in vitro in tissue-engineered cartilage con-
structs and IGF-1-transfected MSC pellets [135] and also promoted cell-based repair of articular cartilage defects
in vivo [115, 136].
Recently, platelet-rich plasma (PRP) has been investigated as a chondrogenic inducer of various types of stem cells
[137]. PRP is an autologous platelet concentrate obtained from fresh blood via centrifugation and contains various
growth factors and bioactive proteins [138]. We recently used PRP in combination with biomaterials to enhance chon-
drogenic differentiation to an extent greater than that in the absence of PRP [114].
In summary, cartilage tissue engineering has been extensively researched, using various cell sources, scaffold mate-
rials, and growth factors. However, determining the optimal combination of these components, yielding optimal func-
tional, regenerated articular cartilage, requires further work.

Acknowledgments

Supported by projects from the Spanish Ministry of Economy and Competitiveness (project no. MAT2016-76039-C4-2-R) and from CIBER-BBN
Valorization program (JOINTCART project). CIBER-BBN is an initiative funded by the VI National R&D&I Plan 2008-2011, Iniciativa Ingenio
2010, and Consolider Program. CIBER Actions are financed by the Instituto de Salud Carlos III with assistance from the European Regional
Development Fund. The authors would like to acknowledge William V. Barber for the drawings and graphics support.

References
[1] M.H. Ross, W. Pawlina, Histology: A Text and Atlas, sixth ed., Lippincott Williams & Wilkins, Baltimore, 2011 (Chapter 7).
[2] A.L. Kierszenbaum, L.L. Tres, Histology and Cell Biology: An Introduction to Patology, third ed., Elsevier Saunders, Philadelphia, 2012
(Chapter 4).
[3] S. Chen, P. Fu, H. Wu, M. Pei, Meniscus, articular cartilage and nucleus pulposus: a comparative review of cartilage-like tissues in anatomy,
development and function, Cell Tissue Res. 370 (1) (2017) 53–70.
[4] R.A. Calandruccio, W. Gilmer, W. Scott, Proliferation, regeneration, and repair of articular cartilage of immature animals, J. Bone Joint Surg.
Am. 44 (3) (1962) 431–455.
[5] E. Muiños-López, M.E. Rendal-Vázquez, T. Hermida-Gómez, I. Fuentes-Boquete, S. Díaz-Prado, F.J. Blanco, Cryopreservation effect on pro-
liferative and chondrogenic potential of human chondrocytes isolated from superficial and deep cartilage, Open Orthop. J. 6 (2012) 150–159.
[6] E.B. Hunziker, K. Lippuner, N. Shintani, How best to preserve and reveal the structural intricacies of cartilaginous tissue, Matrix Biol. 39 (2014)
33–43.

II. MECHANOBIOLOGY AND TISSUE REGENERATION