Restricted accessResearch articleFirst published online 2014-01
Influence of the Molecular Weight of Poly(Lactide-Co-Glycolide) on the In Vivo Cartilage Repair by a Construct of Poly(Lactide-Co-Glycolide)/Fibrin Gel/Mesenchymal Stem Cells/Transforming Growth Factor-β1
The poly(lactide-co-glycolide) (PLGA, LA/GA 75/25) sponges with different weight average molecular weights (Mw 52, 122, and 177 kDa) were fabricated and were used to build the constructs of PLGA/fibrin gel/mesenchymal stem cells (MSCs)/transforming growth factor-β1 (TGF-β1). The PLGA 177 with the highest Mw (177 kDa) had the fastest degradation rate at the initial stage, whereas the PLGA 122 had the moderate degradation rate and smallest mass loss. After implantation in rabbit knees for 12 weeks, the full-thickness defects (both cartilage and subchondral bone were destroyed with a diameter and depth of 4 mm) repaired by the PLGA 122 group had formed a hyaline cartilage-like tissue with abundant glycosaminoglycans on the top layer and subchondral bone on the bottom layer. The group also achieved the best macroscopic (11.3±0.8) and histological scoring (Wakitani, 0.5±0.6). To unveil the mechanism of the cartilage repair outcome and the PLGA degradation behaviors, the chondrogenesis-related genes, inflammatory cytokines, and matrix metalloproteinase (MMP) activity were analyzed by quantitative reverse transcription–polymerase chain reaction at week 1, 3, and 6 postsurgery. At each time point, the regenerated tissues by the PLGA 122 group had the highest mRNA expression of SOX9 and collagen type II, but the smallest mRNA expression of interleukin-1β and tumor necrosis factor α, and MMP-13 and MMP-3. In summary, as a scaffolding matrix, the PLGA with different Mw shows a huge difference in cartilage regeneration in vivo. The one with a moderate Mw (122 kDa) causes the weakest inflammatory response and results in the best cartilage regeneration.
Get full access to this article
View all access options for this article.
References
1.
DucheyneP., MauckR.L., and SmithD.H.Biomaterials in the repair of sports injuries. Nat Mater, 11, 652, 2012.
2.
HuX.H., ZhuY., and GaoC.Y.Hydrogels for cartilage regeneration. Prog Chem, 21, 2164, 2009.
3.
ZhaoH.G., MaL., GongY.H., GaoC.Y., and ShenJ.C.A polylactide/fibrin gel composite scaffold for cartilage tissue engineering: fabrication and an in vitro evaluation. J Mater Sci Mater Med, 20, 135, 2009.
4.
GongY.H., GaoC.Y., HeL.J., ZhouQ.L., MaZ.W., and ShenJ.C.Hydrogel-filled polylactide porous scaffolds for cartilage tissue engineering. Tissue Eng, 12, 1011, 2006.
5.
WangW., LiD., WangM.C., LiY.L., and GaoC.Y.A hybrid scaffold of poly(lactide-co-glycolide) sponge filled with fibrin gel for cartilage tissue engineering. Chin J Polym Sci, 29, 233, 2011.
6.
WangW., LiB., LiY., JiangY., OuyangH., and GaoC.In vivo restoration of full-thickness cartilage defects by poly(lactide-co-glycolide) sponges filled with fibrin gel, bone marrow mesenchymal stem cells and DNA complexes. Biomaterials, 31, 5953, 2010.
7.
WangW., LiB., YangJ.Z., XinL., LiY.L., YinH.P., QiY.Y., JiangY.Z., OuyangH.W., and GaoC.Y.The restoration of full-thickness cartilage defects with BMSCs and TGF-beta 1 loaded PLGA/fibrin gel constructs. Biomaterials, 31, 8964, 2010.
8.
EglinD., MortisenD., and AliniM.Degradation of synthetic polymeric scaffolds for bone and cartilage tissue repairs. Soft Matter, 5, 938, 2009.
9.
BabasolaI.O., BiancoJ., and AmsdenB.G.In vivo degradation and tissue response to poly(5-ethylene ketal epsilon-caprolactone-co-D,L-lactide). Biomacromolecules, 13, 2211, 2012.
10.
GogolewskiS., JovanovicM., PerrenS.M., DillonJ.G., and HughesM.K.Tissue response and in vivo degradation of selected polyhydroxyacids: polylactides (PLA), poly(3-hydroxybutyrate) (PHB), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHB/VA). J Biomed Mater Res, 27, 1135, 1993.
11.
CutrightD.E., PerezB., BeasleyJ.D.3rd, LarsonW.J., and PoseyW.R.Degradation rates of polymers and copolymers of polylactic and polyglycolic acids. Oral Surg Oral Med Oral Pathol, 37, 142, 1974.
12.
PamulaE., and MenaszekE.In vitro and in vivo degradation of poly(L: -lactide-co-glycolide) films and scaffolds. J Mater Sci Mater Med, 19, 2063, 2008.
13.
LuL., PeterS.J., LymanM.D., LaiH.L., LeiteS.M., TamadaJ.A., UyamaS., VacantiJ.P., LangerR., and MikosA.G.In vitro and in vivo degradation of porous poly(DL-lactic-co-glycolic acid) foams. Biomaterials, 21, 1837, 2000.
14.
WuX.S., and WangN.Synthesis, characterization, biodegradation, and drug delivery application of biodegradable lactic/glycolic acid polymers. Part II: biodegradation. J Biomater Sci Polym Ed, 12, 21, 2001.
15.
DingA.G., and SchwendemanS.P.Determination of water-soluble acid distribution in poly(lactide-co-glycolide). J Pharm Sci, 93, 322, 2004.
16.
TaylorM.S., DanielsA.U., AndrianoK.P., and HellerJ.Six bioabsorbable polymers: in vitro acute toxicity of accumulated degradation products. J Appl Biomater, 5, 151, 1994.
17.
YoonS.J., KimS.H., HaH.J., KoY.K., SoJ.W., KimM.S., Il YangY., KhangG., RheeJ.M., and LeeH.B.Reduction of inflammatory reaction of poly(D,L-lactic-Co-glycolic acid) using demineralized bone particles. Tissue Eng Pt A, 14, 539, 2008.
18.
SpenlehauerG., VertM., BenoitJ.P., and BoddaertA.In vitro and In vivo degradation of poly(D,L lactide/glycolide) type microspheres made by solvent evaporation method. Biomaterials, 10, 557, 1989.
19.
MiyamotoS., TakaokaK., OkadaT., YoshikawaH., HashimotoJ., SuzukiS., and OnoK.Evaluation of polylactic acid homopolymers as carriers for bone morphogenetic protein. Clin Orthop Relat Res, 278, 274, 1992.
20.
LiS.M., GarreauH., and VertM.Structure property relationships in the case of the degradation of massive poly(alpha-hydroxy acids) in aqueous-media .2. degradation of lactide-glycolide copolymers—Pla37.5ga25 and Pla75ga25. J Mater Sci Mater Med, 1, 131, 1990.
21.
ZhouQ.L., GongY.H., and GaoC.Y.Microstructure and mechanical properties of poly(L-lactide) scaffolds fabricated by gelatin particle leaching method. J Appl Polym Sci, 98, 1373, 2005.
22.
BensaidW., TriffittJ.T., BlanchatC., OudinaK., SedelL., and PetiteH.A biodegradable fibrin scaffold for mesenchymal stem cell transplantation. Biomaterials, 24, 2497, 2003.
23.
ScioreP., BoykiwR., and HartD.A.Semiquantitative reverse transcription-polymerase chain reaction analysis of mRNA for growth factors and growth factor receptors from normal and healing rabbit medial collateral ligament tissue. J Orthopaed Res, 16, 429, 1998.
24.
WakitaniS., GotoT., PinedaS.J., YoungR.G., MansourJ.M., CaplanA.I., and GoldbergV.M.Mesenchymal cell-based repair of large, full-thickness defects of articular-cartilage. J Bone Joint Surg Am Vol 76A, 579, 1994.
25.
WangW., LiB., and GaoC.Y.Modulating the differentiation of BMSCs by surface properties of biomaterials. Prog Chem, 23, 2160, 2011.
26.
RodriguesM.T., GomesM.E., and ReisR.L.Current strategies for osteochondral regeneration: from stem cells to pre-clinical approaches. Curr Opin Biotech, 22, 726, 2011.
27.
RichardsonS.M., HoylandJ.A., MobasheriR., CsakiC., ShakibaeiM., and MobasheriA.Mesenchymal stem cells in regenerative medicine: opportunities and challenges for articular cartilage and intervertebral disc tissue engineering. J Cell Physiol, 222, 23, 2010.
28.
SungH.J., MeredithC., JohnsonC., and GalisZ.S.The effect of scaffold degradation rate on three-dimensional cell growth and angiogenesis. Biomaterials, 25, 5735, 2004.
29.
SeyednejadH., GawlittaD., KuiperR.V., de BruinA., van NostrumC.F., VermondenT., DhertW.J., and HenninkW.E.In vivo biocompatibility and biodegradation of 3D-printed porous scaffolds based on a hydroxyl-functionalized poly(epsilon-caprolactone). Biomaterials, 33, 4309, 2012.
30.
PattersonJ., SiewR., HerringS.W., LinA.S.P., GuldbergR., and StaytonP.S.Hyaluronic acid hydrogels with controlled degradation properties for oriented bone regeneration. Biomaterials, 31, 6772, 2010.
31.
AlexisF.Factors affecting the degradation and drug-release mechanism of poly(lactic acid) and poly[(lactic acid)-co-(glycolic acid)]. Polym Int, 54, 36, 2005.
32.
HernandezA., SanchezE., SorianoI., ReyesR., DelgadoA., and EvoraC.Material-related effects of BMP-2 delivery systems on bone regeneration. Acta Biomater, 8, 781, 2012.
33.
ZengJ., ChenX., LiangQ., XuX., and JingX.Enzymatic degradation of poly(L-lactide) and poly(epsilon-caprolactone) electrospun fibers. Macromol Biosci, 4, 1118, 2004.
34.
BiW.M., DengJ.M., ZhangZ.P., BehringerR.R., and de CrombruggheB.Sox9 is required for cartilage formation. Nat Genet, 22, 85, 1999.
35.
AkiyamaH.Control of chondrogenesis by the transcription factor Sox9. Mod Rheumatol, 18, 213, 2008.
36.
BillinghurstR.C., DahlbergL., IonescuM., ReinerA., BourneR., RorabeckC., MitchellP., HamborJ., DiekmannO., TschescheH., ChenJ., VanWartH., and PooleA.R.Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage. J Clin Invest, 99, 1534, 1997.
37.
KammermannJ.R., KincaidS.A., RumphP.F., BairdD.K., and ViscoD.M.Tumor necrosis factor-alpha (TNF-alpha) in canine osteoarthritis: immunolocalization of TNF-alpha, stromelysin and TNF receptors in canine osteoarthritic cartilage. Osteoarthritis Cartilage, 4, 23, 1996.
38.
TakaishiH., KimuraT., DalalS., OkadaY., and D'ArmientoJ.Joint diseases and matrix metalloproteinases: a role for MMP-13. Curr Pharm Biotechnol, 9, 47, 2008.
39.
TetlowL.C., AdlamD.J., and WoolleyD.E.Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage—associations with degenerative changes. Arthritis Rheum, 44, 585, 2001.
40.
FranzS., RammeltS., ScharnweberD., and SimonJ.C.Immune responses to implants—a review of the implications for the design of immunomodulatory biomaterials. Biomaterials, 32, 6692, 2011.
41.
SitcheranR., CogswellP.C., and BaldwinA.S.NF-kappa B mediates inhibition of mesenchymal cell differentiation through a posttranscriptional gene silencing mechanism. Gene Dev, 17, 2368, 2003.
42.
BaugeC., LegendreF., LeclercqS., EfissaldeJ.M., PujolJ.P., GaleraP., and BoumedieneK.Interleukin-1 beta impairment of transforming growth factor beta 1 signaling by down-regulation of transforming growth factor beta receptor type II and up-regulation of smad7 in human articular Chondrocytes. Arthritis Rheum, 56, 3020, 2007.
43.
MurakamiS., LefebvreV., and de CrombruggheB.Potent inhibition of the master chondrogenic factor Sox9 gene by interleukin-1 and tumor necrosis factor-alpha. J Biol Chem, 275, 3687, 2000.
44.
BordenP., SolymarD., SucharczukA., LindmanB., CannonP., and HellerR.A.Cytokine control of interstitial collagenase and collagenase-3 gene expression in human chondrocytes. J Biol Chem, 271, 23577, 1996.
45.
AidaY., MaenoM., SuzukiN., NambaA., MotohashiM., MatsumotoM., and MakimuraM.The effect of IL-1 beta on the expression of inflammatory cytokines and their receptors in human chondrocytes. Life Sci, 79, 764, 2006.
46.
LiS.Hydrolytic degradation characteristics of aliphatic polyesters derived from lactic and glycolic acids. J Biomed Mater Res, 48, 342, 1999.
47.
XiaZ., and TriffittJ.T.A review on macrophage responses to biomaterials. Biomed Mater, 1, R1, 2006.
48.
GunatillakeP.A., and AdhikariR.Biodegradable synthetic polymers for tissue engineering. Eur Cell Mater, 5, 1, 2003.
49.
BrownB.N., RatnerB.D., GoodmanS.B., AmarS., and BadylakS.F.Macrophage polarization: an opportunity for improved outcomes in and regenerative medicine. Biomaterials, 33, 3792, 2012.
50.
CeonzoK., GaynorA., ShafferL., KojimaK., VacantiC.A., and StahlG.L.Polyglycolic acid-induced inflammation: role of hydrolysis and resulting complement activation. Tissue Eng, 12, 301, 2006.
51.
RotterN., UngF., RoyA.K., VacantiM., EaveyR.D., VacantiC.A., and BonassarL.J.Role for interleukin 1alpha in the inhibition of chondrogenesis in autologous implants using polyglycolic acid-polylactic acid scaffolds. Tissue Eng, 11, 192, 2005.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
