title: Degradable hydrogels for spatiotemporal control of mesenchymal stem cells localized at decellularized bone allografts.
abstract: The transplantation of cells, such as mesenchymal stem cells (MSCs), has numerous applications in the field of regenerative medicine. For cell transplantation strategies to be successful therapeutically, cellular localization and persistence must be controlled to maximize cell-mediated contributions to healing. Herein, we demonstrate that hydrolytic degradation of poly(ethylene glycol) (PEG) hydrogels can be used to spatiotemporally control encapsulated MSC localization to decellularized bone allografts, both in vitro and in vivo. By altering the number of hydrolytically degradable lactide repeat units within PEG-d,l-lactide-methacrylate macromers, a series of hydrogels was synthesized that degraded over ∼1, 2 and 3weeks. MSCs were encapsulated within these hydrogels formed around decellularized bone allografts, and non-invasive, longitudinal fluorescence imaging was used to track cell persistence both in vitro and in vivo. Spatiotemporal localization of MSCs to the exterior of bone allograft surfaces was similar to in vitro hydrogel degradation kinetics despite hydrogel mesh sizes being ∼2-3 orders of magnitude smaller than MSC size throughout the degradation process. Thus, localized, cell-mediated degradation and MSC migration from the hydrogels are suspected, particularly as ∼10% of the total transplanted MSC population was shown to persist in close proximity (within ∼650μm) to grafts 7weeks after complete hydrogel degradation. This work demonstrates the therapeutic utility of PEG-based hydrogels for controlling spatiotemporal cell transplantation for a myriad of regenerative medicine strategies.
authors.affiliation: University of Rochester, Department of Biomedical Engineering, University of Rochester, 207 Robert B. Goergen Hall, Box 270168, Rochester, NY 14627-0168, USA; University of Rochester, Department of Orthopaedics and Center for Musculoskeletal Research, University of Rochester Medical Center, 207 Robert B. Goergen Hall, Box 270168, Rochester, NY 14627-0168, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hoffman
authors.affiliation: University of Rochester, Department of Biomedical Engineering, University of Rochester, 207 Robert B. Goergen Hall, Box 270168, Rochester, NY 14627-0168, USA.
authors.forename: Amy H
authors.initials: AH
authors.lastname: Van Hove
authors.affiliation: University of Rochester, Department of Biomedical Engineering, University of Rochester, 207 Robert B. Goergen Hall, Box 270168, Rochester, NY 14627-0168, USA; University of Rochester, Department of Orthopaedics and Center for Musculoskeletal Research, University of Rochester Medical Center, 207 Robert B. Goergen Hall, Box 270168, Rochester, NY 14627-0168, USA; University of Rochester, Department of Chemical Engineering, University of Rochester, 207 Robert B. Goergen Hall, Box 270168, Rochester, NY 14627-0168, USA. Electronic address: benoit@bme.rochester.edu.
authors.forename: Danielle S W
authors.initials: DS
authors.lastname: Benoit
mesh_terms: D020341:Absorbable Implants; D064591:Allografts; D000818:Animals; D001672:Biocompatible Materials / Q000138:chemical synthesis; D016025:Bone Transplantation / Q000295:instrumentation* / Q000379:methods; D002474:Cell-Free System / Q000737:chemistry; D019544:Equipment Failure Analysis; D005264:Femoral Fractures / Q000473:pathology / Q000628:therapy*; D020100:Hydrogels / Q000737:chemistry*; D008422:Materials Testing; D045164:Mesenchymal Stem Cell Transplantation / Q000295:instrumentation* / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011474:Prosthesis Design; D062211:Spatio-Temporal Analysis; D023822:Tissue Engineering / Q000295:instrumentation / Q000379:methods; D054457:Tissue Scaffolds; D016896:Treatment Outcome
chemical_list: D001672:Biocompatible Materials; D020100:Hydrogels
keywords: Bone allografts; Cell transplantation; Hydrogels; Mesenchymal stem cells; Tissue engineering
references.citation: Chem Pharm Bull (Tokyo). 1979 Nov;27(11):2781-6
references.pmid: 527146
references.citation: Biomaterials. 2013 Dec;34(38):9969-79
references.pmid: 24060418
references.citation: Biomaterials. 2005 Jul;26(20):4273-9
references.pmid: 15683651
references.citation: J Am Coll Cardiol. 2004 Aug 4;44(3):654-60
references.pmid: 15358036
references.citation: Acta Biomater. 2011 Mar;7(3):959-66
references.pmid: 21056127
references.citation: J Bone Miner Res. 2005 Dec;20(12):2124-37
references.pmid: 16294266
references.citation: Biomaterials. 2010 Oct;31(30):7836-45
references.pmid: 20667588
references.citation: Am J Physiol Heart Circ Physiol. 2004 Jul;287(1):H302-10
references.pmid: 15016633
references.citation: Eur Heart J. 2006 May;27(9):1114-22
references.pmid: 16510464
references.citation: Biomacromolecules. 2006 Jun;7(6):1968-75
references.pmid: 16768421
references.citation: Biomaterials. 2007 Jan;28(1):66-77
references.pmid: 16963119
references.citation: J Biomed Mater Res A. 2004 Mar 15;68(4):704-16
references.pmid: 14986325
references.citation: Adv Funct Mater. 2007;17(13):2085-2093
references.pmid: 18688288
references.citation: Circulation. 2004 Nov 23;110(21):3378-83
references.pmid: 15557385
references.citation: J Card Fail. 2009 Sep;15(7):629-36
references.pmid: 19700140
references.citation: J Biomed Mater Res A. 2014 Feb;102(2):400-12
references.pmid: 23686850
references.citation: Biomacromolecules. 2004 Jul-Aug;5(4):1280-7
references.pmid: 15244441
references.citation: Pharm Res. 2009 Mar;26(3):631-43
references.pmid: 19089601
references.citation: Biomaterials. 2013 Nov;34(35):8887-98
references.pmid: 23958029
references.citation: Tissue Eng. 2006 Jun;12(6):1663-73
references.pmid: 16846361
references.citation: Biomacromolecules. 2007 Oct;8(10):3000-7
references.pmid: 17883273
references.citation: Orthod Craniofac Res. 2005 Aug;8(3):150-61
references.pmid: 16022717
references.citation: Biomed Sci Instrum. 1999;35:33-8
references.pmid: 11143373
references.citation: Tissue Eng. 2003 Jun;9(3):431-9
references.pmid: 12857411
references.citation: FASEB J. 2011 May;25(5):1486-96
references.pmid: 21282205
references.citation: Arthritis Rheum. 2009 Apr;60(4):1006-19
references.pmid: 19333946
references.citation: Am J Cardiol. 2004 Jul 1;94(1):92-5
references.pmid: 15219514
references.citation: J Biomed Mater Res A. 2006 Jan;76(1):183-95
references.pmid: 16265650
references.citation: Matrix Biol. 2005 May;24(3):208-18
references.pmid: 15896949
references.citation: Regen Med. 2009 Jul;4(4):527-38
references.pmid: 19580402
references.citation: J Cell Physiol. 2007 Nov;213(2):341-7
references.pmid: 17620285
references.citation: J Biomed Mater Res A. 2007 May;81(2):259-68
references.pmid: 17335036
references.citation: Stem Cells. 2004;22(2):180-7
references.pmid: 14990857
references.citation: Biomaterials. 2006 Mar;27(8):1377-86
references.pmid: 16139351
references.citation: Nat Mater. 2008 Oct;7(10):816-23
references.pmid: 18724374
references.citation: Clin Orthop Relat Res. 2013 Mar;471(3):721-6
references.pmid: 23179118
references.citation: Stem Cells. 2009 Oct;27(10):2614-23
references.pmid: 19650040
references.citation: Nat Biotechnol. 2003 May;21(5):513-8
references.pmid: 12704396
references.citation: J Tissue Eng Regen Med. 2015 Nov;9(11):E13-26
references.pmid: 23554411
references.citation: J Orthop Res. 2004 Nov;22(6):1254-60
references.pmid: 15475206
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5413-8
references.pmid: 12686696
references.citation: J Biomed Mater Res A. 2003 Dec 15;67(4):1430-6
references.pmid: 14624532
references.citation: Biochem Biophys Res Commun. 1999 Jul 14;260(3):712-7
references.pmid: 10403831
references.citation: Biomacromolecules. 2010 May 10;11(5):1348-57
references.pmid: 20355705
references.citation: Biomaterials. 2009 Dec;30(35):6702-7
references.pmid: 19783300
references.citation: Hum Gene Ther. 1999 May 1;10(7):1163-73
references.pmid: 10340548
references.citation: J Histochem Cytochem. 2005 May;53(5):593-602
references.pmid: 15872052
references.citation: Biomaterials. 2007 Jul;28(21):3217-27
references.pmid: 17445882
references.citation: Stem Cells. 2006 Feb;24(2):454-61
references.pmid: 16099993
references.citation: Circulation. 2004 Mar 30;109(12):1543-9
references.pmid: 15023891
references.citation: Tissue Eng Part A. 2008 Jun;14(6):1025-36
references.pmid: 18476809
references.citation: Biomacromolecules. 2012 Nov 12;13(11):3841-9
references.pmid: 23020123
references.citation: Circulation. 2005 Sep 6;112(10):1451-61
references.pmid: 16129797
references.citation: Biomaterials. 2001 Nov;22(22):3045-51
references.pmid: 11575479
references.citation: J Vis Exp. 2013 Oct 29;(80):e50890
references.pmid: 24193366
references.citation: Osteoarthritis Cartilage. 2005 Aug;13(8):655-64
references.pmid: 15905106
references.citation: J Cell Biochem. 2006 Aug 1;98(5):1076-84
references.pmid: 16619257
references.citation: Adv Drug Deliv Rev. 2001 Dec 31;53(3):321-39
references.pmid: 11744175
references.citation: Biomaterials. 2006 Mar;27(8):1399-409
references.pmid: 16169074
references.citation: Tissue Eng Part B Rev. 2008 Jun;14(2):149-65
references.pmid: 18498217
references.citation: Nat Rev Clin Oncol. 2011 Sep 27;8(11):677-88
references.pmid: 21946842
references.citation: Tissue Eng. 2007 Mar;13(3):435-45
references.pmid: 17518596