title: Multiscale mechanobiology of de novo bone generation, remodeling and adaptation of autograft in a common ovine femur model.
abstract: The link between mechanics and biology in the generation and the adaptation of bone has been studied for more than a century in the context of skeletal development and fracture healing. However, the interplay between mechanics and biology in de novo generation of bone in postnatal defects as well as healing of morcellized bone graft or massive cortical bone autografts is less well understood. To address this, here we integrate insights from our previously published studies describing the mechanobiology on both de novo bone generation and graft healing in a common ovine femoral defect model. Studying these effects in a common experimental model provides a unique opportunity to elucidate factors conducive to harnessing the regenerative power of the periosteum, and ultimately, to provide mechanistic insights into the multiscale mechanobiology of bone generation, remodeling and adaptation. Taken together, the studies indicate that, as long as adequate, directional transport of cells and molecules can be insured (e.g. with periosteum in situ or a delivery device), biological factors intrinsic to the periosteum suffice to bridge critical sized bone defects, even in the absence of a patent blood supply. Furthermore, mechanical stimuli are crucial for the success of periosteal bone generation and bone graft healing. Interestingly, areas of highest periosteal strain around defects correlate with greatest amounts albeit not greatest mineralization of newly generated bone. This may indicate a role for convection enhanced transport of cells and molecules in modulation of tissue generation by pluripotent cells that ingress into the defect center, away from the periosteum and toward the surface of the intramedullary nail that fills the medullary cavity. These insights bring us much closer to understanding the mechanobiological environment and stimuli that stimulate the proliferation and differentiation of periosteum-derived progenitor cells and ultimately drive the generation of new bone tissue. Furthermore, these insights provide a foundation to create virtual predictive computational models of bone mechanophysiology, to develop cell seeding protocols for scale up and manufacture of engineered tissues, to optimize surgical procedures, and to develop post-surgical therapies with the ultimate goal of achieving the best possible healing outcomes for treatment and/or reconstruction of postnatal bone defects.
authors: Department of Mechanical & Aerospace Engineering, Case Western Reserve University, Cleveland, OH 44106, United States. knothetate@case.edu
authors: Melissa L
authors: ML
authors: Knothe Tate
authors: Scott
authors: S
authors: Dolejs
authors: Sarah H
authors: SH
authors: McBride
authors: R
authors: R
authors: Matthew Miller
authors: Ulf R
authors: UR
authors: Knothe
references: Tissue Eng Part A. 2008 Sep;14(9):1561-72
references: 18774910
references: Clin Orthop Relat Res. 1998 Feb;(347):11-8
references: 9520870
references: J Surg Res. 1998 Jul 15;78(1):68-77
references: 9733621
references: J Biomech. 2003 Oct;36(10):1409-24
references: 14499290
references: J Orthop Res. 2010 Dec;28(12):1657-64
references: 20589937
references: World J Surg Oncol. 2005 Feb 03;3(1):7
references: 15691380
references: Nature. 1977 Sep 1;269(5623):80-2
references: 895891
references: Br J Plast Surg. 1988 Sep;41(5):528-32
references: 3179599
references: Anat Rec. 2001 Dec 1;264(4):348-57
references: 11745090
references: J Bone Joint Surg Am. 1997 Apr;79(4):542-50
references: 9111398
references: Tissue Eng Part A. 2008 Sep;14(9):1573-80
references: 18774911
references: J Exp Biol. 2000 Sep;203(Pt 18):2737-45
references: 10952874
references: J Hand Surg Am. 2002 Mar;27(2):307-15
references: 11901390
references: Arch Orthop Trauma Surg. 1994;114(1):18-24
references: 7696043
references: J Bone Miner Res. 1994 Aug;9(8):1143-52
references: 7976496
references: J Craniomaxillofac Surg. 2001 Aug;29(4):219-23
references: 11562091
references: Am J Phys Anthropol. 2004 Feb;123(2):156-71
references: 14730649
references: J Oral Maxillofac Surg. 1997 Nov;55(11):1265-8
references: 9371118
references: Biomaterials. 1999 Nov;20(21):2007-18
references: 10535812
references: Acta Chir Iugosl. 2005;52(2):101-5
references: 16237904
references: J Oral Maxillofac Surg. 2005 Apr;63(4):499-504
references: 15789322
references: Microsurgery. 1994;15(2):93-7
references: 8183118
references: Calcif Tissue Int. 1994 Oct;55(4):316-7; author reply 318
references: 7820784
references: Philos Trans A Math Phys Eng Sci. 2009 Sep 13;367(1902):3339-62
references: 19657003
references: Bone. 1998 Sep;23(3):307-10
references: 9737355
references: Plast Reconstr Surg. 1979 Sep;64(3):361-5
references: 382210
references: Injury. 2009 Nov;40 Suppl 4:S95-102
references: 19895960
references: Int J Biochem Cell Biol. 2008;40(12):2720-38
references: 18620888
references: Clin Orthop Relat Res. 1990 Oct;(259):223-32
references: 2208860
references: Plast Reconstr Surg. 1990 Apr;85(4):587-92
references: 2315398
references: Bone. 2004 Nov;35(5):1003-12
references: 15542024
references: Otolaryngol Head Neck Surg. 1985 Dec;93(6):731-5
references: 3937093
references: Biomaterials. 1991 Mar;12(2):101-10
references: 1652292
references: PLoS One. 2010 Sep 17;5(9):
references: 20862249
references: Scand J Plast Reconstr Surg. 1978;12(3):195-205
references: 368969
references: J Biomech. 2010 Oct 19;43(14):2728-37
references: 20673900
references: Bone. 2005 Feb;36(2):311-6
references: 15780957
references: Scand J Plast Reconstr Surg. 1978;12(3):207-14
references: 368970
references: J Bone Joint Surg Am. 2007 Feb;89(2):307-16
references: 17272445
references: Br Med J. 1919 Feb 1;1(3031):119-120.1
references: 20769348
references: Clin Orthop Relat Res. 1984 Oct;(189):300-7
references: 6478702
references: Microsurgery. 1994;15(2):87-92
references: 8183117
references: J Appl Physiol (1985). 2000 Jun;88(6):1943-8
references: 10846003