Repair of bone defects using synthetic mimetics of collagenous extracellular matrices
Open accessAbstract
We have engineered synthetic poly(ethylene glycol) (PEG)-based hydrogels as cell-ingrowth matrices for in situ bone regeneration. These networks contain a combination of pendant oligopeptide ligands for cell adhesion (RGDSP) and substrates for matrix metalloproteinase (MMP) as linkers between PEG chains. Primary human fibroblasts were shown to migrate within these matrices by integrin- and MMP-dependent mechanisms. Gels used to deliver recombinant human bone morphogenetic protein-2 (rhBMP-2) to the site of critical- sized defects in rat crania were completely infiltrated by cells and were remodeled into bony tissue within five weeks. Bone regeneration was dependent on the proteolytic sensitivity of the matrices and their architecture. The cell-mediated proteolytic invasiveness of the gels and entrapment of rhBMP-2 resulted in efficient and highly localized bone regeneration.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Synthetic hydrogels can be functionalized with biologically active moieties that permit the growth and spread of cells; concentration and spacing of these cues can be changed independently.
“Synthetic hydrogels can be functionalized with biologically active moieties that permit the growth and spread of cells146–151; concentration and spacing of these cues can be changed independently152–155.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [151]
Cites
How Matrix Metalloproteinases Regulate Cell Behavior
Sternlicht, M. D., & Werb, Z. (2001) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.17.1.463 · Cited by 3,959 · see citing works
Novel Regulators of Bone Formation: Molecular Clones and Activities
Wozney, J. M., Rosen, V., Celeste, A. J., Mitsock, L. M., Whitters, M. J., Kriz, R., Hewick, R. M., & Wang, E. A. (1988) · Science · doi:10.1126/science.3201241 · Cited by 3,874 · see citing works
Tissue Engineering--Current Challenges and Expanding Opportunities
Griffith, L. G., & Naughton, G. K. (2002) · Science · doi:10.1126/science.1069210 · Cited by 2,348 · see citing works
The Molecular and Cellular Biology of Wound Repair
Clark, R. A. F., & Henson, P. M. (1988) · Springer eBooks · doi:10.1007/978-1-4615-1795-5 · Cited by 1,524 · see citing works
Matrix metalloproteinases: effectors of development and normal physiologyPreprint
Vu, T. H., & Werb, Z. (2000) · Genes & Development · doi:10.1101/gad.815400 · Cited by 1,236 · see citing works
Osteogenic Protein-1 (Bone Morphogenetic Protein-7) in the Treatment of Tibial Nonunions
Friedlaender, G. E., Perry, C. R., Cole, J. D., Cook, S. D., Cierný, G., Muschler, G. F., Zych, G. A., Calhoun, J. H., LaForte, A. J., & Yin, S. (2001) · Journal of Bone and Joint Surgery · doi:10.2106/00004623-200100002-00010 · Cited by 956 · see citing works
Quantification of connectivity in cancellous bone, with special emphasis on 3-D reconstructions
Odgaard, A., & Gundersen, H. J. G. (1993) · Bone · doi:10.1016/8756-3282(93)90245-6 · Cited by 695 · see citing works
The molecular and cellular biology of wound repair
Naylor, I. L. (1996) · British Journal of Plastic Surgery · doi:10.1016/s0007-1226(96)90047-8 · Cited by 668 · see citing works
Bone Morphogenetic Protein and Bone Morphogenetic Protein Gene Family in Bone Formation and Repair
Wozney, J. M., & Rosen, V. (1998) · Clinical Orthopaedics and Related Research · doi:10.1097/00003086-199801000-00006 · Cited by 617 · see citing works
Stabilization of proteins encapsulated in injectable poly (lactide- co-glycolide)
Zhu, G., Mallery, S. R., & Schwendeman, S. P. (2000) · Nature Biotechnology · doi:10.1038/71916 · Cited by 610 · see citing works
Ruppert, R., Hoffmann, E., & Sebald, W. (1996) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1996.0295n.x · Cited by 562 · see citing works
Foreign-body reactions to fracture fixation implants of biodegradable synthetic polymers
Böstman, O. M., Hirvensalo, E., Mäkinen, J. E., & Rokkanen, P. (1990) · Journal of Bone and Joint Surgery - British Volume · doi:10.1302/0301-620x.72b4.2199452 · Cited by 524 · see citing works
Hubbell, J. A. (1999) · Current Opinion in Biotechnology · doi:10.1016/s0958-1669(99)80021-4 · Cited by 474 · see citing works
Self-citationMatrix metalloproteinases and TIMPs
Woessner, J. F., & Nagase, H. (2000) · Medical Entomology and Zoology · Cited by 380 · see citing works
Polymer concepts in tissue engineering
Peter, S. J., Miller, M. J., Yasko, A. W., Yaszemski, M. J., & Mikos, A. G. (1998) · Journal of Biomedical Materials Research · doi:10.1002/(sici)1097-4636(199824)43:4 · Cited by 380 · see citing works
Protein delivery from materials formed by self-selective conjugate addition reactions
Elbert, D. L., Pratt, A. B., Lütolf, M. P., Halstenberg, S., & Hubbell, J. A. (2001) · Journal of Controlled Release · doi:10.1016/s0168-3659(01)00398-4 · Cited by 356 · see citing works
Self-citationSystematic Modulation of Michael-Type Reactivity of Thiols through the Use of Charged Amino Acids
Lütolf, M. P., Tirelli, N., Cerritelli, S., et al. (2001) · Bioconjugate Chemistry · doi:10.1021/bc015519e · Cited by 356 · see citing works
Delivering on the promise of bone morphogenetic proteins
Li, R. H., & Wozney, J. M. (2001) · Trends in biotechnology · doi:10.1016/s0167-7799(01)01665-1 · Cited by 340 · see citing works
Halstenberg, S., Panitch, A., Rizzi, S. C., Hall, H., & Hubbell, J. A. (2002) · Biomacromolecules · doi:10.1021/bm015629o · Cited by 315 · see citing works
Self-citationBone morphogenetic proteins: An update on basic biology and clinical relevance
Schmitt, J., Hwang, K., Winn, S. R., & Hollinger, J. O. (1999) · Journal of Orthopaedic Research® · doi:10.1002/jor.1100170217 · Cited by 312 · see citing works
What do BMPs do in mammals? Clues from the mouse short-ear mutation
Kingsley, D. M. (1994) · Trends in Genetics · doi:10.1016/0168-9525(94)90014-0 · Cited by 298 · see citing works
Cell migration through defined, synthetic extracellular matrix analogues
Gobin, A. S., & West, J. L. (2002) · The FASEB Journal · doi:10.1096/fj.01-0759fje · Cited by 257 · see citing works
A biodegradable polymer as a cytokine delivery system for inducing bone formation
Saito, N., Okada, T., Horiuchi, H., Murakami, N., Takahashi, J. A., Nawata, M., Ota, H., Nozaki, K., & Takaoka, K. (2001) · Nature Biotechnology · doi:10.1038/86715 · Cited by 254 · see citing works
Müller, R., Hildebrand, T., & Ruegsegger, P. (1994) · Physics in Medicine and Biology · doi:10.1088/0031-9155/39/1/009 · Cited by 248 · see citing works
Self-citationBone Formation with Use of rhBMP-2 (Recombinant Human Bone Morphogenetic Protein-2)*
Zegzula, H. D., Buck, D. C., Brekke, J. H., et al. (1997) · Journal of Bone and Joint Surgery · doi:10.2106/00004623-199712000-00003 · Cited by 241 · see citing works
Immune Responses to Allogeneic and Xenogeneic Implants of Collagen and Collagen Derivatives
Delustro, F. A., Dasch, J. R., Keefe, J., & Ellingsworth, L. R. (1990) · Clinical Orthopaedics and Related Research · doi:10.1097/00003086-199011000-00043 · Cited by 210 · see citing works
Photopolymerizable degradable polyanhydrides with osteocompatibility
Anseth, K. S., Shastri, V. P., & Langer, R. (1999) · Nature Biotechnology · doi:10.1038/6152 · Cited by 205 · see citing works
Micro-tomographic imaging for the nondestructive evaluation of trabecular bone architecture.
Müller, R., & Ruegsegger, P. (1997) · PubMed · Cited by 199 · see citing works
Self-citationKenley, R. A., Marden, L. J., Turek, T., et al. (1994) · Journal of Biomedical Materials Research · doi:10.1002/jbm.820281004 · Cited by 183 · see citing works
The human immune response to reconstituted bovine collagen.
Ellingsworth, L. R., Delustro, F. A., Brennan, J. E., et al. (1986) · The Journal of Immunology · doi:10.4049/jimmunol.136.3.877 · Cited by 173 · see citing works
Animal studies of application of rhBMP-2 in maxillofacial reconstruction
Boyne, P. J. (1996) · Bone · doi:10.1016/s8756-3282(96)00144-5 · Cited by 150 · see citing works
Matrix Metalloproteinases and TlMPs
Woessner, J. F., & Nagase, H. (2000) · doi:10.1093/oso/9780198502685.001.0001 · Cited by 148 · see citing works
West, J. L., & Hubbell, J. A. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.23.13188 · Cited by 124 · see citing works
Self-citationUludağ, H., Frieß, W., WILLIAMS, D., Porter, T. J., Timony, G., DʼAugusta, D., BLAKE, C., Palmer, R., BIRON, B., & Wozney, J. M. (1999) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1999.tb08519.x · Cited by 77 · see citing works
Weber, F. E., Eyrich, G., Grätz, K. W., et al. (2002) · International Journal of Oral and Maxillofacial Surgery · doi:10.1054/ijom.2001.0154 · Cited by 74 · see citing works
Self-citationMeikle, M. C., Papaioannou, S., Ratledge, T. J., Speight, P. M., Watt-Smith, S. R., Hill, P. A., & Reynolds, J. J. (1994) · Biomaterials · doi:10.1016/0142-9612(94)90017-5 · Cited by 71 · see citing works
Ertel, S. I., Kohn, J., Zimmerman, M. C., & Parsons, J. R. (1995) · Journal of Biomedical Materials Research · doi:10.1002/jbm.820291105 · Cited by 53 · see citing works
Polymeric Precipitants for the Crystallization of Macromolecules
Patel, S. A., Cudney, B., & McPherson, A. (1995) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1995.1260 · Cited by 50 · see citing works
Disulfide Bridge Conformers of Mature BMP Are Inhibitors for Heterotopic Ossification
Weber, F. E., Eyrich, G., Grätz, K. W., et al. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.5408 · Cited by 34 · see citing works
Self-citationCell-responsive synthetic biomaterials formed in situ
Pratt, A. B. (2001) · doi:10.7907/hfef-7f61 · Cited by 5 · see citing works
Jeong (2000) · doi:10.1002/(sici)1097-4636(200005)50:2
Flagged first, then by citations
Cited by
Sorted by citations
Lutolf, M. P., & Hubbell, J. A. (2005) · Nature Biotechnology · doi:10.1038/nbt1055 · Cited by 4,551 · see citing works
Self-citationExploring and Engineering the Cell Surface Interface
Stevens, M. M., & George, J. H. (2005) · Science · doi:10.1126/science.1106587 · Cited by 2,607 · see citing works
Cell-laden microengineered gelatin methacrylate hydrogels
Nichol, J. W., Koshy, S. T., Bae, H., Hwang, C. M., Yamanlar, S., & Khademhosseini, A. (2010) · Biomaterials · doi:10.1016/j.biomaterials.2010.03.064 · Cited by 2,377 · see citing works
Biomaterials: Where We Have Been and Where We Are Going
Ratner, B. D., & Bryant, S. J. (2004) · Annual Review of Biomedical Engineering · doi:10.1146/annurev.bioeng.6.040803.140027 · Cited by 1,507 · see citing works
Lutolf, M. P., Lauer-Fields, J. L., Schmoekel, H. G., Metters, A. T., Weber, F. E., Fields, G. B., & Hubbell, J. A. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0737381100 · Cited by 1,508 · see citing works
Self-citationThree-Dimensional Cell Culture Matrices: State of the Art
Lee, J., Cuddihy, M. J., & Kotov, N. A. (2008) · Tissue Engineering Part B: Reviews · doi:10.1089/teb.2007.0150 · Cited by 1,047 · see citing works
Extracellular matrix-based materials for regenerative medicine
Hussey, G. S., Dziki, J. L., & Badylak, S. F. (2018) · Nature Reviews Materials · doi:10.1038/s41578-018-0023-x · Cited by 844 · see citing works
Loessner, D., Stok, K. S., Lutolf, M. P., Hutmacher, D. W., Clements, J. A., & Rizzi, S. C. (2010) · Biomaterials · doi:10.1016/j.biomaterials.2010.07.064 · Cited by 602 · see citing works
Self-citationFedorovich, N. E., Alblas, J., de Wijn, J. R., Hennink, W. E., Verbout, A. J., & Dhert, W. J. A. (2007) · Tissue Engineering · doi:10.1089/ten.2006.0175 · Cited by 467 · see citing works
Martino, M. M., Tortelli, F., Mochizuki, M., Traub, S., Ben-David, D., Kuhn, G. A., Müller, R., Livne, E., Eming, S. A., & Hubbell, J. A. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002614 · Cited by 459 · see citing works
Self-citationTowards organoid culture without Matrigel
Kozlowski, M. T., Crook, C. J., & Ku, H. T. (2021) · Communications Biology · doi:10.1038/s42003-021-02910-8 · Cited by 409 · see citing works
Cellular and Molecular Dynamics in the Foreign Body Reaction
Luttikhuizen, D. T., Harmsen, M. C., & Luyn, M. J. A. V. (2006) · Tissue Engineering · doi:10.1089/ten.2006.12.1955 · Cited by 396 · see citing works
Monocytes and macrophages in tissue repair: Implications for immunoregenerative biomaterial design
Ogle, M. E., Segar, C. E., Sridhar, S., & Botchwey, E. A. (2016) · Experimental Biology and Medicine · doi:10.1177/1535370216650293 · Cited by 378 · see citing works
Design, printing, and engineering of regenerative biomaterials for personalized bone healthcare
Jia, Z., Xu, X., Zhu, D., & Zheng, Y. (2023) · Progress in Materials Science · doi:10.1016/j.pmatsci.2023.101072 · Cited by 176 · see citing works
Hydrogels for Musculoskeletal Tissue Engineering
Varghese, S., & Elisseeff, J. H. (2006) · Advances in Polymer Science · doi:10.1007/12_072 · Cited by 173 · see citing works
Bioengineering approaches to guide stem cell-based organogenesis
Gjorevski, N., Ranga, A., & Lutolf, M. P. (2014) · Development · doi:10.1242/dev.101048 · Cited by 137 · see citing works
Role of plasma fibronectin in the foreign body response to biomaterials
Keselowsky, B. G., Bridges, A. W., Burns, K. L., Tate, C. C., Babensee, J. E., LaPlaca, M. C., & García, A. J. (2007) · Biomaterials · doi:10.1016/j.biomaterials.2007.04.035 · Cited by 130 · see citing works
Peptide-Based Functional Biomaterials for Soft-Tissue Repair
Hosoyama, K., Lazurko, C., Muñoz, M., McTiernan, C. D., & Alarcon, E. I. (2019) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2019.00205 · Cited by 118 · see citing works
Hacker, M. C., Klouda, L., Ma, B. B., Kretlow, J. D., & Mikos, A. G. (2008) · Biomacromolecules · doi:10.1021/bm8000414 · Cited by 104 · see citing works
Sow, W. T., Wang, Y., Chen, L., Lai, Q., Chen, Q., Chen, L., Zhang, C., & Li, H. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202201886 · Cited by 18 · see citing works
- Authors
- Lutolf, M. P., Weber, F. E., Schmoekel, H. G., Schense, J. C., Kohler, T., Müller, R., & Hubbell, J. A.
- Affiliations
- University Hospital Zurich (CH)
- University of Bern (CH)
- Straumann (Switzerland) (CH)
- University of Zurich (CH)
- Corresponding author
- Hubbell, Jeffrey A.
- Venue
- Nature Biotechnology
- Published
- 2003-04-21
- Volume
- 21
- Issue
- 5
- Pages
- 513-518
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W1970525947
- Cited by
- 850
- References
- 41
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 15 · 2023: 25 · 2022: 12 · 2021: 26 · 2020: 39 · 2019: 36 · 2018: 25 · 2017: 29 · 2016: 38 · 2015: 44 · 2014: 60 · 2013: 35 · 2012: 60
- FWCI
- 28.85
- Type
- journal article
- Language
- en
- Open access
- green
- infoscience.epfl.ch
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › Bone Tissue Engineering Materials
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- bone regeneration, bone defects, synthetic hydrogels, polyethylene glycol, extracellular matrix mimics, matrix metalloproteinases, integrin-mediated adhesion, fibroblast migration, BMP-2, critical-size calvarial defect, proteolysis
- MeSH terms
- Animals, Bone Regeneration, Collagen, Extracellular Matrix, Skull Fractures, Infusion Pumps, Implantable, Transforming Growth Factor beta, Treatment Outcome, Bone Substitutes, Bone Morphogenetic Proteins, Prostheses and Implants, Coated Materials, Biocompatible, Tissue Engineering, Biomimetic Materials, Culture Techniques, Rats, Bone Morphogenetic Protein 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
