Emerging Ideas: Engineering the Periosteum: Revitalizing Allografts by Mimicking Autograft Healing
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
To fulfill the need for large volumes, devitalized allografts are used to treat massive bone defects despite a 60%, 10-year postimplantation fracture rate. Allograft healing is inferior to autografts where the periosteum orchestrates remodeling.
By augmenting allografts with a tissue engineered periosteum consisting of tunable and degradable, poly(ethylene glycol) (PEG) hydrogels for mesenchymal stem cell (MSC) transplantation, the functions critical for periosteum-mediated healing will be identified and emulated.
Method of Study
PEG hydrogels will be designed to emulate periosteum-mediated autograft healing to revitalize allografts. We will exploit murine femoral defect models for these approaches. Critical-sized, 5-mm segmental defects will be created and filled with decellularized allograft controls or live autograft controls. Alternatively, defects will be treated with our experimental approaches: decellularized allografts coated with MSCs transplanted via degradable PEG hydrogels to mimic progenitor cell densities and persistence during autograft healing. Healing will be evaluated for 9 weeks using microcomputed tomography, mechanical testing, and histologic analysis. If promising, MSC densities, hydrogel compositions, and genetic methods will be used to isolate critical aspects of engineered periosteum that modulate healing. Finally, hydrogel biochemical characteristics will be altered to initiate MSC and/or host-material interactions to further promote remodeling of allografts.
This approach represents a novel tissue engineering strategy whereby degradable, synthetic hydrogels will be exploited to emulate the periosteum. The microenvironment, which will mediate MSC transplantation, will use tunable PEG hydrogels for isolation of critical allograft revitalization factors. In addition, hydrogels will be modified with biochemical cues to further augment allografts to reduce or eliminate revision surgeries associated with allograft failures.
- Benoit DS, Anseth KS. The effect on osteoblast function of colocalized RGD and PHSRN epitopes on PEG surfaces. Biomaterials. 2005;26:5209–5220. CrossRef
- Benoit DS, Anseth KS. Heparin functionalized PEG gels that modulate protein adsorption for hMSC adhesion and differentiation. Acta Biomater. 2005;1:461–470. CrossRef
- Benoit DS, Collins SD, Anseth KS. Multifunctional hydrogels that promote osteogenic hMSC differentiation through stimulation and sequestering of BMP2. Adv Funct Mater. 2007;17:2085–2093. CrossRef
- Benoit DS, Durney AR, Anseth KS. Manipulations in hydrogel degradation behavior enhance osteoblast function and mineralized tissue formation. Tissue Eng. 2006;12:1663–1673. CrossRef
- Benoit DS, Durney AR, Anseth KS. The effect of heparin-functionalized PEG hydrogels on three-dimensional human mesenchymal stem cell osteogenic differentiation. Biomaterials. 2007;28:66–77. CrossRef
- Benoit DS, Nuttelman CR, Collins SD, Anseth KS. Synthesis and characterization of a fluvastatin-releasing hydrogel delivery system to modulate hMSC differentiation and function for bone regeneration. Biomaterials. 2006;27:6102–6110. CrossRef
- Benoit DS, Schwartz MP, Durney AR, Anseth KS. Small functional groups for controlled differentiation of hydrogel-encapsulated human mesenchymal stem cells. Nat Mater. 2008;7:816–823. CrossRef
- Breitbart EA, Meade S, Azad V, Yeh S, Al-Zube L, Lee YS, Benevenia J, Arinzeh TL, Lin SS. Mesenchymal stem cells accelerate bone allograft incorporation in the presence of diabetes mellitus. J Orthop Res. 2010;28:942–949.
- Bukata SV, Puzas JE. Orthopedic uses of teriparatide. Curr Osteoporos Rep. 2010;8:28–33. CrossRef
- Cornejo A, Sahar DE, Stephenson SM, Chang S, Nguyen S, Guda T, Wenke JC, Vazquez A, Michalek JE, Sharma R, Krishnegowda NK, Wang HT. Effect of adipose tissue-derived osteogenic and endothelial cells on bone allograft osteogenesis and vascularization in critical-sized calvarial defects. Tissue Eng Part A. 2012;18:1552–1561. CrossRef
- DeForest CA, Polizzotti BD, Anseth KS. Sequential click reactions for synthesizing and patterning three-dimensional cell microenvironments. Nat Mater. 2009;8:659–664. CrossRef
- Derner R, Anderson AC. The bone morphogenic protein. Clin Podiatr Med Surg. 2005;22:607–618, vii. CrossRef
- Dhillon RS, Schwarz EM. Teriparatide therapy as an adjuvant for tissue engineering and integration of biomaterials. J Mater Res. 2011;4:1117–1131.
- Dwek JR. The periosteum: what is it, where is it, and what mimics it in its absence? Skeletal Radiol. 2010;39:319–323. CrossRef
- Ehrhart N, Kraft S, Conover D, Rosier RN, Schwarz EM. Quantification of massive allograft healing with dynamic contrast enhanced-MRI and cone beam-CT: a pilot study. Clin Orthop Relat Res. 2008;466:1897–1904. CrossRef
- Ellender G, Feik SA, Carach BJ. Periosteal structure and development in a rat caudal vertebra. J Anat. 1988;158:173–187.
- Ham AW. A histological study of the early phases of bone repair. J Bone Joint Surg Am. 1930;12:827–844.
- Han SK, Yoon TH, Lee DG, Lee MA, Kim WK. Potential of human bone marrow stromal cells to accelerate wound healing in vitro. Ann Plast Surg. 2005;55:414–419. CrossRef
- Hohmann EL, Elde RP, Rysavy JA, Einzig S, Gebhard RL. Innervation of periosteum and bone by sympathetic vasoactive intestinal peptide-containing nerve fibers. Science. 1986;232:868–871. CrossRef
- Hutmacher DW, Sittinger M. Periosteal cells in bone tissue engineering. Tissue Eng. 2003;9(suppl 1):S45–64. CrossRef
- Ito H, Koefoed M, Tiyapatanaputi P, Gromov K, Goater JJ, Carmouche J, Zhang X, Rubery PT, Rabinowitz J, Samulski RJ, Nakamura T, Soballe K, O’Keefe RJ, Boyce BF, Schwarz EM. Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy. Nat Med. 2005;11:291–297. CrossRef
- Murphy WL, Peters MC, Kohn DH, Mooney DJ. Sustained release of vascular endothelial growth factor from mineralized poly(lactide-co-glycolide) scaffolds for tissue engineering. Biomaterials. 2000;21:2521–2527. CrossRef
- Nuttelman CR, Benoit DS, Tripodi MC, Anseth KS. The effect of ethylene glycol methacrylate phosphate in PEG hydrogels on mineralization and viability of encapsulated hMSCs. Biomaterials. 2006;27:1377–1386. CrossRef
- Nuttelman CR, Tripodi MC, Anseth KS. Dexamethasone-functionalized gels induce osteogenic differentiation of encapsulated hMSCs. J Biomed Mater Res Part A. 2006;76:183–195. CrossRef
- O’Driscoll SW, Saris DB, Ito Y, Fitzimmons JS. The chondrogenic potential of periosteum decreases with age. J Orthop Res. 2001;19:95–103. CrossRef
- Petrie Aronin CE, Shin SJ, Naden KB, Rios PD Jr, Sefcik LS, Zawodny SR, Bagayoko ND, Cui Q, Khan Y, Botchwey EA. The enhancement of bone allograft incorporation by the local delivery of the sphingosine 1-phosphate receptor targeted drug FTY720. Biomaterials. 2010;31:6417–6424. CrossRef
- Pluhar GE, Manley PA, Heiner JP, Vanderby R Jr, Seeherman HJ, Markel MD. The effect of recombinant human bone morphogenetic protein-2 on femoral reconstruction with an intercalary allograft in a dog model. J Orthop Res. 2001;19:308–317. CrossRef
- Polizzotti BD, Fairbanks BD, Anseth KS. Three-dimensional biochemical patterning of click-based composite hydrogels via thiolene photopolymerization. Biomacromolecules. 2008;9:1084–1087. CrossRef
- Reynolds DG, Takahata M, Lerner AL, O’Keefe RJ, Schwarz EM, Awad HA. Teriparatide therapy enhances devitalized femoral allograft osseointegration and biomechanics in a murine model. Bone. 2011;48:562–570. CrossRef
- Rice MA, Anseth KS. Controlling cartilaginous matrix evolution in hydrogels with degradation triggered by exogenous addition of an enzyme. Tissue Eng. 2007;13:683–691. CrossRef
- Rice MA, Sanchez-Adams J, Anseth KS. Exogenously triggered, enzymatic degradation of photopolymerized hydrogels with polycaprolactone subunits: experimental observation and modeling of mass loss behavior. Biomacromolecules. 2006;7:1968–1975. CrossRef
- Santoni BG, Ehrhart N, Betancourt-Benitez R, Beck CA, Schwarz EM. Quantifying massive allograft healing of the canine femur in vivo and ex vivo: a pilot study. Clin Orthop Relat Res. 2012;470:2478–2487. CrossRef
- Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med. 2004;10:55–63. CrossRef
- Schonmeyr B, Clavin N, Avraham T, Longo V, Mehrara BJ. Synthesis of a tissue-engineered periosteum with acellular dermal matrix and cultured mesenchymal stem cells. Tissue Eng Pt A. 2009;15:1833–1841. CrossRef
- Sineva GS, Pospelov VA. Inhibition of GSK3beta enhances both adhesive and signalling activities of beta-catenin in mouse embryonic stem cells. Biol Cell. 2010;102:549–560. CrossRef
- Squier CA, Ghoneim S, Kremenak CR. Ultrastructure of the periosteum from membrane bone. J Anat. 1990;171:233–239.
- Stansbury LG, Lalliss SJ, Branstetter JG, Bagg MR, Holcomb JB. Amputation in U.S. military personnel in the current conflicts in Afghanistan and Iraq. J Orthop Trauma. 2008;22:43–46. CrossRef
- Stevens MM, George JH. Exploring and engineering the cell surface interface. Science. 2005;310:1135–1138. CrossRef
- Takahata M, Awad HA, O’Keefe RJ, Bukata SV, Schwarz EM. Endogenous tissue engineering: PTH therapy for skeletal repair. Cell Tissue Res. 2011;347:545–552. CrossRef
- Taylor JF. The periosteum and bone growth. In: Hall BK, ed. Bone, Vol. 6: Bone Growth - A. Boca Raton, FL: CRC Press; 1992:21–52.
- Tibbitt MW, Anseth KS. Hydrogels as extracellular matrix mimics for 3D cell culture. Biotechnol Bioeng. 2009;103:655–663. CrossRef
- Tseng AS, Engel FB, Keating MT. The GSK-3 inhibitor BIO promotes proliferation in mammalian cardiomyocytes. Chem Biol. 2006;13:957–963. CrossRef
- Weber LM, Cheung CY, Anseth KS. Multifunctional pancreatic islet encapsulation barriers achieved via multilayer PEG hydrogels. Cell Transplant. 2008;16:1049–1057. CrossRef
- Wheeler DL, Haynie JL, Berrey H, Scarborough M, Enneking W. Biomechanical evaluation of retrieved massive allografts: preliminary results. Biomed Sci Instrum. 2001;37:251–256.
- Xie C, Reynolds D, Awad H, Rubery PT, Pelled G, Gazit D, Guldberg RE, Schwarz EM, O’Keefe RJ, Zhang X. Structural bone allograft combined with genetically engineered mesenchymal stem cells as a novel platform for bone tissue engineering. Tissue Eng. 2007;13:435–445. CrossRef
- Yazici C, Takahata M, Reynolds DG, Xie C, Samulski RJ, Samulski J, Beecham EJ, Gertzman AA, Spilker M, Zhang X, O’Keefe RJ, Awad HA, Schwarz EM. Self-complementary AAV2.5-BMP2-coated femoral allografts mediated superior bone healing versus live autografts in mice with equivalent biomechanics to unfractured femur. Mol Ther. 2011;19:1416–1425. CrossRef
- Zhang X, Awad HA, O’Keefe RJ, Guldberg RE, Schwarz EM. A perspective: engineering periosteum for structural bone graft healing. Clin Orthop Relat Res. 2008;466:1777–1787. CrossRef
- Zhang X, Xie C, Lin AS, Ito H, Awad H, Lieberman JR, Rubery PT, Schwarz EM, O’Keefe RJ, Guldberg RE. Periosteal progenitor cell fate in segmental cortical bone graft transplantations: implications for functional tissue engineering. J Bone Miner Res. 2005;20:2124–2137. CrossRef
- Emerging Ideas: Engineering the Periosteum: Revitalizing Allografts by Mimicking Autograft Healing
Clinical Orthopaedics and Related Research®
Volume 471, Issue 3 , pp 721-726
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Industry Sectors
- Author Affiliations
- 1. Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA
- 2. Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- 3. Departments of Biomedical Engineering and Chemical Engineering, University of Rochester, 207 Robert B. Goergen Hall, Box 270168, Rochester, NY, 14627-0168, USA
- 4. Center for Musculoskeletal Research and Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY, USA