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Review article: Biomedical intelligence

Vol. 146 No. 3334 (2016)

Learn, simplify and implement: developmental re-engineering strategies for cartilage repair

  • Paola Occhetta
  • Chiara Stüdle
  • Andrea Barbero
  • Ivan Martin
DOI
https://doi.org/10.4414/smw.2016.14346
Cite this as:
Swiss Med Wkly. 2016;146:w14346
Published
14.08.2016

Summary

The limited self-healing capacity of cartilage in adult individuals, and its tendency to deteriorate once structurally damaged, makes the search for therapeutic strategies following cartilage-related traumas relevant and urgent. To date, autologous cell-based therapies represent the most advanced treatments, but their clinical success is still hampered by the long-term tendency to form fibrous as opposed to hyaline cartilage tissue. Would the efficiency and robustness of therapies be enhanced if cartilage regeneration approaches were based on the attempt to recapitulate processes occurring during cartilage development (“developmental engineering”)? And from this perspective, shouldn’t cartilage repair strategies be inspired by development, but adapted to be effective in a context (an injured joint in an adult individual) that is different from the embryo (“developmental re-engineering”)? Here, starting from mesenchymal stem/stromal cells (MSCs) as an adult cell source possibly resembling features of the embryonic mesenchyme, we propose a developmental re-engineering roadmap based on the following three steps: (i) learn from embryonic cartilage development which are the key pathways involved in MSC differentiation towards stable cartilage, (ii) simplify the complex developmental events by approximation to essential molecular pathways, possibly by using in vitro high-throughput models and, finally, (iii) implement the outcomes at the site of the injury by establishing an appropriate interface between the delivered signals and the recipient environment (e.g., by controlling inflammation and angiogenesis). The proposed re-design of developmental machinery by establishing artificial developmental events may offer a chance for regeneration to those tissues, like cartilage, with limited capacity to recover from injuries.

References

  1. Tonge D, Pearson M, Jones S. The hallmarks of osteoarthritis and the potential to develop personalised disease-modifying pharmacological therapeutics. Osteoarthritis Cartilage. 2014;22(5):609–21.
  2. Minas T. A primer in cartilage repair. J Bone Joint Surg Br, British Volume, 2012. 94(11 Suppl A):141–6.
  3. Johnstone B, Alini M, Cucchiarini M, Dodge GR, Eglin D, Guilak F, et al. Tissue engineering for articular cartilage repair – the state of the art. Eur Cell Mater. 2013;25(248):e67.
  4. Dewan AK, Gibson MA, Elisseeff JH, Trice ME. Evolution of autologous chondrocyte repair and comparison to other cartilage repair techniques. Biomed Res Int. 2014. Epub 2014 Aug 18. doi: 10.1155/2014/272481.
  5. Niemeyer P, Pestka JM, Kreuz PC, Salzmann GM, Köstler W, Südkamp NP, et al. Standardized cartilage biopsies from the intercondylar notch for autologous chondrocyte implantation (ACI). Knee Surg Sports Traumatol Arthrosc. 2010;18(8):1122–7.
  6. Barbero A, Grogan S, Schäfer D, Heberer M, Mainil-Varlet P, Martin I. Age related changes in human articular chondrocyte yield, proliferation and post-expansion chondrogenic capacity. Osteoarthritis Cartilage. 2004;12(6):476–84.
  7. Pelttari K, Pippenger B, Mumme M, Feliciano S, Scotti C, Mainil-Varlet P, et al. Adult human neural crest–derived cells for articular cartilage repair. Sci Transl Med. 2014;6(251):251ra119-251ra119.
  8. Dowthwaite GP, Bishop JC, Redman SN, Khan IM, Rooney P, Evans DJ, et al. The surface of articular cartilage contains a progenitor cell population. J Cell Sci. 2004;117(6):889–97.
  9. Williams R, Khan IM, Richardson K, Nelson L, McCarthy HE, Analbelsi T, et al. Identification and clonal characterisation of a progenitor cell sub-population in normal human articular cartilage. PloS one. 2010;5(10):e13246.
  10. Choi WH, Kim HR, Lee SJ, Jeong N, Park SR, Choi BH, et al. Fetal Cartilage-derived Cells have Stem Cell Properties and are a Highly Potent Cell Source for Cartilage Regeneration. Cell Transplant. 2016;25(3):449–61.
  11. Darwiche S, Scaletta C, Raffoul W, Pioletti DP, Applegate LA. Epiphyseal chondroprogenitors provide a stable cell source for cartilage cell therapy. Cell Med. 2012;4(1):23–32.
  12. Khan WS, Johnson DS, Hardingham TE. The potential of stem cells in the treatment of knee cartilage defects. Knee. 2010;17(6):369–74.
  13. Weiss ML, Troyer DL. Stem cells in the umbilical cord. Stem Cell Rev. 2006;2(2):155–62.
  14. Malgieri A, Kantzari E, Patrizi MP, Gambardella S. Bone marrow and umbilical cord blood human mesenchymal stem cells: state of the art. Int J Clin Exp Med. 2010;3(4):248–69.
  15. Cheng A, Hardingham TE, Kimber SJ. Generating cartilage repair from pluripotent stem cells. Tissue Eng Part B Rev. 2013;20(4):257–66.
  16. Diekman BO, Christoforou N, Willard VP, Sun H, Sanchez-Adams J, Leong KW, et al. Cartilage tissue engineering using differentiated and purified induced pluripotent stem cells. Proc Natl Acad Sci. 2012;109(47):19172–7.
  17. Kronenberg HM. Developmental regulation of the growth plate. Nature. 2003;423(6937):332–6.
  18. Mariani E, Facchini A. Clinical applications and biosafety of human adult mesenchymal stem cells. Curr Pharm Des. 2012;18(13):1821–45.
  19. Jorgensen C, Noël D. Mesenchymal stem cells in osteoarticular diseases. Regen Med. 2011;6(6s):44–51.
  20. Gupta PK, Das AK, Chullikana A, Majumdar AS. Mesenchymal stem cells for cartilage repair in osteoarthritis. Stem Cell Res Ther. 2012;3(4):25.
  21. Bornes TD, Adesida AB, Jomha NM. Mesenchymal stem cells in the treatment of traumatic articular cartilage defects: a comprehensive review. Arthritis Res Ther. 2014;16(5):432.
  22. Baugé C, Boumédiene K. Use of adult stem cells for cartilage tissue engineering: current status and future developments. Stem Cells Int. 2015;2015:438026.
  23. Kon E, Roffi A, Filardo G, Tesei G, Marcacci M. Scaffold-based cartilage treatments: with or without cells? A systematic review of preclinical and clinical evidence. Arthroscopy. 2015;31(4):767–75.
  24. Shimomura K, Moriguchi Y, Murawski CD, Yoshikawa H, Nakamura N. Osteochondral tissue engineering with biphasic scaffold: current strategies and techniques. Tissue Eng Part B Rev. 2014;20(5):468–76.
  25. Somoza RA, Welter JF, Correa D, Caplan AI. Chondrogenic differentiation of mesenchymal stem cells: challenges and unfulfilled expectations. Tissue Eng Part B Rev. 2014;20(6):596–608.
  26. Lv F-J, Tuan RS, Cheung K, Leung VY. Concise review: the surface markers and identity of human mesenchymal stem cells. Stem Cells. 2014;32(6):1408–19.
  27. Jones E, Schäfer R. Where is the common ground between bone marrow mesenchymal stem/stromal cells from different donors and species? Stem Cell Res Ther. 2015;6(1):1–8.
  28. Pelttari K, Winter A, Steck E, Goetzke K, Hennig T, Ochs BG, et al. Premature induction of hypertrophy during in vitro chondrogenesis of human mesenchymal stem cells correlates with calcification and vascular invasion after ectopic transplantation in SCID mice. Arthritis Rheum. 2006;54(10):3254–66.
  29. Gaut C, Sugaya K. Critical review on the physical and mechanical factors involved in tissue engineering of cartilage. Regen Med. 2015;10(5):665–79.
  30. Tonnarelli B, Centola M, Barbero A, Zeller R, Martin I. Re-engineering development to instruct tissue regeneration. Curr Top Dev Biol. 2014;108(4):319–38.
  31. Lenas P, Moos M Jr, Luyten FP. Developmental engineering: a new paradigm for the design and manufacturing of cell-based products. Part I: from three-dimensional cell growth to biomimetics of in vivo development. Tissue Eng Part B Rev. 2009;15(4):381–94.
  32. Bianco P, Cao X, Frenette PS, Mao JJ, Robey PG, Simmons PJ, et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med. 2013;19(1):35–42.
  33. Occhetta P, Centola M, Tonnarelli B, Redaelli A, Martin I, Rasponi M. High-throughput microfluidic platform for 3D cultures of mesenchymal stem cells, towards engineering developmental processes. Sci Rep. 2015;5:10288.
  34. Kim J-Y, Fluri DA, Marchan R, Boonen K, Mohanty S, Singh P, et al. 3D spherical microtissues and microfluidic technology for multi-tissue experiments and analysis. J Biotechnol. 2015;205:24–35.
  35. Occhetta P, Glass N, Otte E, Rasponi M, Cooper-White JJ. Stoichiometric control of live cell mixing to enable fluidically-encoded co-culture models in perfused microbioreactor arrays. Integr Biol (Camb). 2016;8(2):194–204.
  36. Occhetta P, Malloggi C, Gazaneo A, Redaelli A, Candiani G, Rasponi M. High-throughput microfluidic platform for adherent single cells non-viral gene delivery. RSC Adv. 2015;5(7):5087–95.
  37. Gobaa S, Hoehnel S, Roccio M, Negro A, Kobel S, Lutolf MP. Artificial niche microarrays for probing single stem cell fate in high throughput. Nat Methods. 2011;8(11):949–55.
  38. Klumpers DD, Mooney DJ, Smit TH. From skeletal development to tissue engineering: lessons from the micromass assay. Tissue Eng Part B Rev. 2015;21(5):427–37.
  39. Futrega K, Palmer JS, Kinney M, Lott WB, Ungrin MD, Zandstra PW, et al. The microwell-mesh: A novel device and protocol for the high throughput manufacturing of cartilage microtissues. Biomaterials. 2015;62:1–12.
  40. Decker RS, Koyama E, Pacifici M. Genesis and morphogenesis of limb synovial joints and articular cartilage. Matrix Biol. 2014;39:5–10.
  41. Decker RS, Koyama E, Pacifici M. Articular Cartilage: Structural and Developmental Intricacies and Questions. Curr Osteoporos Rep. 2015;13(6):407–14.
  42. Iwamoto M, Ohta Y, Larmour C, Enomoto-Iwamoto M. Toward regeneration of articular cartilage. Birth Defects Res C Embryo Today. 2013;99(3):192–202.
  43. Hartmann C, Tabin CJ. Wnt-14 plays a pivotal role in inducing synovial joint formation in the developing appendicular skeleton. Cell. 2001;104(3):341–51.
  44. Guo X, Day TF, Jiang X, Garrett-Beal L, Topol L, Yang Y. Wnt/β-catenin signaling is sufficient and necessary for synovial joint formation. Genes Dev. 2004;18(19):2404–17.
  45. Später D, Hill TP, O’Sullivan RJ, Gruber M, Conner DA, Hartmann C. Wnt9a signaling is required for joint integrity and regulation of Ihh during chondrogenesis. Development. 2006;133(15):3039–49.
  46. Koyama E, Young B, Nagayama M, Shibukawa Y, Enomoto-Iwamoto M, Iwamoto M, et al. Conditional Kif3a ablation causes abnormal hedgehog signaling topography, growth plate dysfunction, and excessive bone and cartilage formation during mouse skeletogenesis. Development. 2007;134(11):2159–69.
  47. Brunet LJ, McMahon JA, McMahon AP, Harland RM. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science. 1998;280(5368):1455–7.
  48. Ray A, Singh PNP, Sohaskey ML, Harland RM, Bandyopadhyay A. Precise spatial restriction of BMP signaling is essential for articular cartilage differentiation. Development. 2015;142(6):1169–79.
  49. Soeda T, Deng JM, de Crombrugghe B, Behringer RR, Nakamura T, Akiyama H. Sox9-expressing precursors are the cellular origin of the cruciate ligament of the knee joint and the limb tendons. Genesis. 2010;48(11):635–44.
  50. Zhang Q, Cigan AD, Marrero L, Lopreore C, Liu S, Ge D, et al. Expression of doublecortin reveals articular chondrocyte lineage in mouse embryonic limbs. Genesis. 2011;49(2):75–82.
  51. Koyama E, ShibukawaY, Nagayama M, Sugito H, Young B, Yuasa T, et al. A distinct cohort of progenitor cells participates in synovial joint and articular cartilage formation during mouse limb skeletogenesis. Dev Biol. 2008;316(1):62–73.
  52. Hyde G, DoverS, Aszodi A, Wallis GA, Boot-Handford RP. Lineage tracing using matrilin-1 gene expression reveals that articular chondrocytes exist as the joint interzone forms. Dev Biol. 2007;304(2):825–33.
  53. Oldershaw RA, Baxter MA, LoweET, Bates N, Grady LM, Soncin F, et al. Directed differentiation of human embryonic stem cells toward chondrocytes. Nat Biotechnol. 2010;28(11):1187–94.
  54. Craft AM, Ahmed N, Rockel JS, Baht GS, Alman BA, Kandel RA, et al. Specification of chondrocytes and cartilage tissues from embryonic stem cells. Development. 2013;140(12):2597–610.
  55. Wu L, Bluguermann C, Kyupelyan L, Latour B, Gonzalez S, Shah S, et al. Human developmental chondrogenesis as a basis for engineering chondrocytes from pluripotent stem cells. Stem Cell Rep. 2013;1(6):575–89.
  56. Craft AM, Rockel JS, Nartiss Y, Kandel RA, Alman BA, Keller GM. Generation of articular chondrocytes from human pluripotent stem cells. Nat Biotechnol. 2015;33(6):638–45.
  57. Cleary MA, Osch GJ, Brama PA, Hellingman CA, Narcisi R. FGF, TGFβ and Wnt crosstalk: embryonic to in vitro cartilage development from mesenchymal stem cells. J Tissue Eng Regen Med. 2015;9(4):332–42.
  58. Pignatti E, Zeller R, Zuniga A. To BMP or not to BMP during vertebrate limb bud development. Semin Cell Dev Biol. 2014;32:119–27.
  59. Bénazet J-D, Pignatti E, Nugent A, Unal E, Laurent F, Zeller R. Smad4 is required to induce digit ray primordia and to initiate the aggregation and differentiation of chondrogenic progenitors in mouse limb buds. Development. 2012;139(22):4250–60.
  60. Karamboulas K, Dranse HJ, Underhill TM. Regulation of BMP-dependent chondrogenesis in early limb mesenchyme by TGFβ signals. J Cell Sci. 2010;123(12):2068–76.
  61. Liao J, Hu N, Zhou N, Lin L, Zhao C, Yi S. et al., Sox9 potentiates BMP2-induced chondrogenic differentiation and inhibits BMP2-induced osteogenic differentiation. PloS one. 2014;9(2):e89025.
  62. Centola M, Tonnarelli B, Schären S, Glaser N, Barbero A, Martin I. Priming 3D cultures of human mesenchymal stromal cells toward cartilage formation via developmental pathways. Stem Cells Dev. 2013;22(21):2849–58.
  63. Narcisi R, Cleary MA, Brama PA, Hoogduijn MJ, Tüysüz N, ten Berge D, et al. Long-term expansion, enhanced chondrogenic potential, and suppression of endochondral ossification of adult human MSCs via WNT signaling modulation. Stem Cell Rep. 2015;4(3):459–72.
  64. Leijten J, Emons J, Sticht C, Van Gool S, Decker E, Uitterlinden A, et al. Gremlin 1, Frizzled‐related protein, and Dkk‐1 are key regulators of human articular cartilage homeostasis. Arthritis Rheum. 2012;64(10):3302–12.
  65. Martin I, Muraglia A, Campanile G, Cancedda R, Quarto R. Fibroblast Growth Factor-2 Supports ex Vivo Expansion and Maintenance of Osteogenic Precursors from Human Bone Marrow 1. Endocrinology. 1997;138(10):4456–62.
  66. Correa D, Somoza R, LinP, Greenberg S, Rom E, Duesler L, et al. Sequential exposure to fibroblast growth factors (FGF) 2, 9 and 18 enhances hMSC chondrogenic differentiation. Osteoarthritis Cartilage. 2015;23(3):443–53.
  67. Kronenberg HM. Developmental regulation of the growth plate. Nature. 2003;423(6937):332–6.
  68. Mueller MB, Tuan RS. Functional characterization of hypertrophy in chondrogenesis of human mesenchymal stem cells. Arthritis Rheum. 2008;58(5):1377–88.
  69. Fischer J, Aulmann A, Dexheimer V, Grossner T, Richter W. Intermittent PTHrP (1–34) exposure augments chondrogenesis and reduces hypertrophy of mesenchymal stromal cells. Stem Cells Dev. 2014;23(20):2513–23.
  70. Weiss S, Hennig T, Bock R, Steck E, Richter W. Impact of growth factors and PTHrP on early and late chondrogenic differentiation of human mesenchymal stem cells. J Cell Physiol. 2010;223(1):84–93.
  71. Bian L, Zhai DY, Zhang EC, Mauck RL, Burdick JA. Dynamic compressive loading enhances cartilage matrix synthesis and distribution and suppresses hypertrophy in hMSC-laden hyaluronic acid hydrogels. Tissue Eng Part A. 2011;18(7-8):715–24.
  72. O’Conor CJ, Case N, Guilak F. Mechanical regulation of chondrogenesis. Stem Cell Res Ther. 2013;4(4):1.
  73. Marsano A, Conficconi C, Lemme M, Occhetta P, Gaudiello E, Votta E, et al. Beating heart on a chip: a novel microfluidic platform to generate functional 3D cardiac microtissues. Lab Chip. 2016;16(3):599–610.
  74. Li T, Longobardi L, Myers TJ, Temple JD, Chandler RL, Ozkan H, et al, Joint TGF-β type II receptor-expressing cells: ontogeny and characterization as joint progenitors. Stem Cells Dev. 2012;22(9):1342–59.
  75. Kozhemyakina E, ZhangM, Ionescu A, Ayturk UM, Ono N, Kobayashi A, et al. Identification of a Prg4-Expressing Articular Cartilage Progenitor Cell Population in Mice. Arthritis Rheumatol. 2015;67(5):1261–73.
  76. Iwamoto M, Ohta Y, Larmour C, Enomoto-Iwamoto M. Toward regeneration of articular cartilage. Birth Defects Res C Embryo Today. 2013;99(3):192–202.
  77. Stoddart MJ, Bara J, Alini M. Cells and secretome – towards endogenous cell re-activation for cartilage repair. Adv Drug Deliv Rev. 2015;84:135–45.
  78. Kristjánsson B, Honsawek S. Current perspectives in mesenchymal stem cell therapies for osteoarthritis. Stem Cells Int. 2014. Epub 2014 Dec 8. doi: 10.1155/2014/194318..
  79. Park MS, Kim YH, Jung Y, Kim SH, Park JC, Yoon DS, et al. In situ recruitment of human bone marrow-derived mesenchymal stem cells using chemokines for articular cartilage regeneration. Cell Transplant. 2015;24(6):1067–83.
  80. Zhang W, Chen J, Tao J, Jiang Y, Hu C, Huang L, et al. The use of type 1 collagen scaffold containing stromal cell-derived factor-1 to create a matrix environment conducive to partial-thickness cartilage defects repair. Biomaterials. 2013;34(3):713–23.
  81. Huang H, Zhang X, Hu X, Shao Z, Zhu J, Dai L, et al. A functional biphasic biomaterial homing mesenchymal stem cells for in vivo cartilage regeneration. Biomaterials. 2014;35(36):9608–19.
  82. Luo Z, Jiang L, Xu Y, Li H, Xu W, Wu S, et al. Mechano growth factor (MGF) and transforming growth factor (TGF)-β3 functionalized silk scaffolds enhance articular hyaline cartilage regeneration in rabbit model. Biomaterials. 2015;52:463–75.
  83. Bourgine PE, Scotti C, Pigeot S, Tchang LA, Todorov A, Martin I. Osteoinductivity of engineered cartilaginous templates devitalized by inducible apoptosis. Proc Natl Acad Sci. 2014;111(49):17426–31.
  84. Gawlitta D, Benders KE, Visser J, van der Sar AS, Kempen DH, Theyse LF, et al. Decellularized cartilage-derived matrix as substrate for endochondral bone regeneration. Tissue Eng Part A. 2014;21(3-4):694–703.
  85. Caldwell K, Wang J. Cell-based articular cartilage repair: the link between development and regeneration. Osteoarthritis Cartilage. 2015;23(3):351–62.
  86. Goldring MB. Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis. Ther Adv Musculoskelet Dis. 2012;4(4):269–85.
  87. Caron MM, Welting TJ, van Rhijn LW, Emans. Targeting Inflammatory Processes for Optimization of Cartilage Homeostasis and Repair Techniques. In: Emans P., Peterson L, editors. Developing Insights in Cartilage Repair. 1st ed. London: Springer-Verlag; 2014. p. 43–63.
  88. Godwin JW, Pinto AR, Rosenthal NA. Macrophages are required for adult salamander limb regeneration. Proc Natl Acad Sci U S A. 2013;110(23):9415–20.
  89. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496(7446):445–55.
  90. Sesia SB, Duhr R, Medeiros da Cunha C, Todorov A, Schaeren S, Padovan E, et al. Anti-Inflammatory/Tissue Repair Macrophages Enhance the Cartilage-Forming Capacity of Human Bone Marrow‐Derived Mesenchymal Stromal Cells. J Cell Physiol. 2015;230(6):1258–69.
  91. Hoemann CD, Chen G, Marchand C, Tran-Khanh N, Thibault M, Chevrier A, et al. Scaffold-guided subchondral bone repair implication of neutrophils and alternatively activated arginase-1+ macrophages. Am J Sports Med. 2010;38(9):1845–56.
  92. Suri S, Gill SE, de Camin SM, McWilliams DF, Wilson D, Walsh DA. Neurovascular invasion at the osteochondral junction and in osteophytes in osteoarthritis. Ann Rheum Dis. 2007;66(11):1423–8.
  93. Lafont JE, Talma S, Hopfgarten C, Murphy CL. Hypoxia promotes the differentiated human articular chondrocyte phenotype through SOX9-dependent and-independent pathways. J Biol Chem. 2008;283(8):4778–86.
  94. Lafont JE, Talma S, Murphy CL. Hypoxia-inducible factor 2α is essential for hypoxic induction of the human articular chondrocyte phenotype. Arthritis Rheum. 2007;56(10):3297–306.
  95. Gerber H-P, Vu TH, Ryan AM, Kowalski J, Werb Z, Ferrara N. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med. 1999;5(6):623–8.
  96. Kubo S, Cooper GM, Matsumoto T, Phillippi JA, Corsi KA, Usas A, et al. Blocking vascular endothelial growth factor with soluble Flt-1 improves the chondrogenic potential of mouse skeletal muscle–derived stem cells. Arthritis Rheum. 2009;60(1):155–65.
  97. Matsumoto T, Cooper GM, Gharaibeh B, Meszaros LB, Li G, Usas A, et al. Cartilage repair in a rat model of osteoarthritis through intraarticular transplantation of muscle-derived stem cells expressing bone morphogenetic protein 4 and soluble flt-1. Arthritis Rheum. 2009;60(5):1390–405.
  98. Centola M, Abbruzzese F, Scotti C, Barbero A, Vadala G, Denaro V, et al. Scaffold-based delivery of a clinically relevant anti-angiogenic drug promotes the formation of in vivo stable cartilage. Tissue Eng Part A. 2013;19(17-18):1960–71.
  99. Lee H-H, Chang C-C, Shieh M-J, Wang J-P, Chen Y-T, Young T-H, et al. Hypoxia enhances chondrogenesis and prevents terminal differentiation through PI3K/Akt/FoxO dependent anti-apoptotic effect. Scientific Rep. 2013. 3.
  100. Leijten J, Georgi N, Teixeira LM, van Blitterswijk CA, Post JN, Karperien M. Metabolic programming of mesenchymal stromal cells by oxygen tension directs chondrogenic cell fate. Proc Natl Acad Sci U S A. 2014;111(38):13954–9.
  101. Reed S, Wu B. Sustained growth factor delivery in tissue engineering applications. Ann Biomed Eng. 2014;42(7):1528–36.
  102. Belair DG, Le NN, Murphy WL. Design of growth factor sequestering biomaterials. Chem Commun (Camb). 2014;50(99):15651–68.
  103. Vulic K, Shoichet MS. Affinity-based drug delivery systems for tissue repair and regeneration. Biomacromolecules. 2014;15(11):3867–80.
  104. Grim JC, Marozas IA, Anseth KS. Thiol-ene and photo-cleavage chemistry for controlled presentation of biomolecules in hydrogels. J Control Release. 2015;219:95–106.
  105. Mosiewicz KA, Kolb L, van der Vlies AJ, Martino MM, Lienemann PS, Hubbell JA, et al. In situ cell manipulation through enzymatic hydrogel photopatterning. Nat Mater. 2013;12(11):1072–8.
  106. Moghadam MN, Kolesov V, Vogel A, Klok H-A, Pioletti DP. Controlled release from a mechanically-stimulated thermosensitive self-heating composite hydrogel. Biomaterials. 2014;35(1):450–5.
  107. Timko BP, Arruebo M, Shankarappa SA, McAlvin JB, Okonkwo OS, Mizrahi B, et al. Near-infrared–actuated devices for remotely controlled drug delivery. Proc Natl Acad Sci U S A. 2014;111(4):1349–54.
  108. Lee TT, García JR, Paez JI, Singh A, Phelps EA, Weis S, et al. Light-triggered in vivo activation of adhesive peptides regulates cell adhesion, inflammation and vascularization of biomaterials. Nat Mat. 2015;14(3):352–60.
  109. Bian L, Hou C, Tous E, Rai R, Mauck RL, Burdick JA. The influence of hyaluronic acid hydrogel crosslinking density and macromolecular diffusivity on human MSC chondrogenesis and hypertrophy. Biomaterials. 2013;34(2):413–21.
  110. Murphy CM, Matsiko A, Haugh MG, Gleeson JP, O’Brien FJ. Mesenchymal stem cell fate is regulated by the composition and mechanical properties of collagen–glycosaminoglycan scaffolds. J Mech Behav Biomed Mater. 2012;11:53–62.
  111. Marsano A, Medeiros da Cunha CM, Ghanaati S, Gueven S, Centola M, Tsaryk R, et al. Spontaneous in vivo chondrogenesis of bone barrow-derived mesenchymal progenitor cells by blocking vascular endothelial growth factor signaling. Stem Celle Transl Med. 2016 Jul 26. pii: sctm.2015-0321. [Epub ahead of print]

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