Purpose of Review
The purpose of this review is to discuss the recent advances in gene therapy as a treatment for bone regeneration. While most fractures heal spontaneously, patients who present with fracture nonunion suffer from prolonged pain, disability, and often require additional operations to regain musculoskeletal function.
In the last few years, BMP gene delivery by means of electroporation and sonoporation resulted in repair of nonunion bone defects in mice, rats, and minipigs. Ex vivo transfection of porcine mesenchymal stem cells (MSCs) resulted in bone regeneration following implantation in vertebral defects of minipigs. Sustained release of VEGF gene from a collagen-hydroxyapatite scaffold to the mandible of a human patient was shown to be safe and osteoinductive.
In conclusion, gene therapy methods for bone regeneration are systematically becoming more efficient and show proof-of-concept in clinically relevant animal models. Yet, on the pathway to clinical use, more investigation is needed to determine the safety aspects of the various techniques in terms of biodistribution, toxicity, and tumorigenicity.
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Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance
de Vries F, Klop C, van Staa T, Cooper C, Harvey N, editors. The epidemiology of mortality after fragility fracture in England and Wales. Osteoporos Int. 2016: Springer London Ltd 236 Grays Inn RD, 6th floor, London WC1X 8HL, England.
Bonafede M, Espindle D, Bower AG. The direct and indirect costs of long bone fractures in a working age US population. J Med Econ. 2013;16(1):169–78.
Starr AJ. Fracture repair: successful advances, persistent problems, and the psychological burden of trauma. J Bone Joint Surg Am. 2008;90(Suppl 1):132–7.
Zura R, Xiong Z, Einhorn T, Watson JT, Ostrum RF, Prayson MJ, et al. Epidemiology of fracture nonunion in 18 human bones. JAMA Surg. 2016;151(11):e162775.
Giannoudis PV, Jones E, Einhorn TA. Fracture healing and bone repair. Injury. 2011;42(6):549–50.
Tay WH, de Steiger R, Richardson M, Gruen R, Balogh ZJ. Health outcomes of delayed union and nonunion of femoral and tibial shaft fractures. Injury. 2014;45(10):1653–8.
Giannoudis PV, Einhorn TA, Marsh D. Fracture healing: the diamond concept. Injury. 2007;38(Suppl 4):S3–6.
Bhargava R, Sankhla S, Gupta A, Changani R, Gagal K. Percutaneous autologus bone marrow injection in the treatment of delayed or nonunion. Indian J Orthop. 2007;41(1):67–71.
Giordano A, Galderisi U, Marino IR. From the laboratory bench to the patient's bedside: an update on clinical trials with mesenchymal stem cells. J Cell Physiol. 2007;211(1):27–35.
Sheyn D, Ben-David S, Shapiro G, De Mel S, Bez M, Ornelas L, et al. Human induced pluripotent stem cells differentiate into functional mesenchymal stem cells and repair bone defects. Stem Cells Transl Med. 2016;5(11):1447–60.
Sheyn D, Shapiro G, Tawackoli W, Jun DS, Koh Y, Kang KB, et al. PTH induces systemically administered mesenchymal stem cells to migrate to and regenerate spine injuries. Mol Ther. 2016;24(2):318–30.
Emara KM, Diab RA, Emara AK. Recent biological trends in management of fracture non-union. World J Orthop. 2015;6(8):623–8.
Bose S, Roy M, Bandyopadhyay A. Recent advances in bone tissue engineering scaffolds. Trends Biotechnol. 2012;30(10):546–54.
Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J. 2011;11(6):471–91.
Kimelman-Bleich N, Pelled G, Zilberman Y, Kallai I, Mizrahi O, Tawackoli W, et al. Targeted gene-and-host progenitor cell therapy for nonunion bone fracture repair. Mol Ther. 2011;19(1):53–9.
• Shapiro G, Kallai I, Sheyn D, Tawackoli W, Koh YD, Bae H, et al. Ultrasound-mediated transgene expression in endogenous stem cells recruited to bone injury sites. Polym Adv Technol. 2014;25(5):525–31. Mesenchymal stem cells recruited to a bone defect using a collagen scaffold were successfully transfected using naked DNA sonoporation.
Sheyn D, Kimelman-Bleich N, Pelled G, Zilberman Y, Gazit D, Gazit Z. Ultrasound-based nonviral gene delivery induces bone formation in vivo. Gene Ther. 2008;15(4):257–66.
Shapiro G, Wong AW, Bez M, Yang F, Tam S, Even L, et al. Multiparameter evaluation of in vivo gene delivery using ultrasound-guided, microbubble-enhanced sonoporation. J Control Release. 2016;223:157–64.
•• Bez M, Sheyn D, Tawackoli W, Avalos P, Shapiro G, Giaconi JC, Da X, David SB, Gavrity J, Awad HA, Bae HW, Ley EJ, Kremen TJ, Gazit Z, Ferrara KW, Pelled G, Gazit D. In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs. Sci Transl Med. 2017;9(390). Endogenous mesenchymal stem cells recruited to a critical fracture were transfected to express BMP6 using microbubble-enhanced sonoporation, leading to fracture healing in minipigs.
Feichtinger GA, Hofmann AT, Slezak P, Schuetzenberger S, Kaipel M, Schwartz E, et al. Sonoporation increases therapeutic efficacy of inducible and constitutive BMP2/7 in vivo gene delivery. Hum Gene Ther Methods. 2014;25(1):57–71.
Wilson CG, Martin-Saavedra FM, Padilla F, Fabiilli ML, Zhang M, Baez AM, et al. Patterning expression of regenerative growth factors using high intensity focused ultrasound. Tissue Eng Part C Methods. 2014;20(10):769–79.
Qiao C, Zhang K, Jin H, Miao L, Shi C, Liu X, et al. Using poly(lactic-co-glycolic acid) microspheres to encapsulate plasmid of bone morphogenetic protein 2/polyethylenimine nanoparticles to promote bone formation in vitro and in vivo. Int J Nanomedicine. 2013;8:2985–95.
Kaur H, Uludag H, El-Bialy T. Effect of nonviral plasmid delivered basic fibroblast growth factor and low intensity pulsed ultrasound on mandibular condylar growth: a preliminary study. Biomed Res Int. 2014;2014:426710.
Fang J, Zhu YY, Smiley E, Bonadio J, Rouleau JP, Goldstein SA, et al. Stimulation of new bone formation by direct transfer of osteogenic plasmid genes. Proc Natl Acad Sci U S A. 1996;93(12):5753–8.
Bozo IY, Deev RV, Drobyshev AY, Isaev AA, Eremin II. World’s first clinical case of gene-activated bone substitute application. Case Rep Dent. 2016;2016:8648949.
Qiao C, Zhang K, Sun B, Liu J, Song J, Hu Y, et al. Sustained release poly (lactic-co-glycolic acid) microspheres of bone morphogenetic protein 2 plasmid/calcium phosphate to promote in vitro bone formation and in vivo ectopic osteogenesis. Am J Transl Res. 2015;7(12):2561–72.
• Elangovan S, D'Mello SR, Hong L, Ross RD, Allamargot C, Dawson DV, et al. The enhancement of bone regeneration by gene activated matrix encoding for platelet derived growth factor. Biomaterials. 2014;35(2):737–47. The delivery of polyethylenimine-platelet derived growth factor B to bone marrow stromal cells using a collagen scaffold favors cellular attachment and proliferation in vitro and in vivo osteogenesis in rat calvarial defects.
D’Mello S, Elangovan S, Salem AK. FGF2 gene activated matrices promote proliferation of bone marrow stromal cells. Arch Oral Biol. 2015;60(12):1742–9.
Yue J, Wu J, Liu D, Zhao X, Lu WW. BMP2 gene delivery to bone mesenchymal stem cell by chitosan-g-PEI nonviral vector. Nanoscale Res Lett. 2015;10:203.
• Plonka AB, Khorsand B, Yu N, Sugai JV, Salem AK, Giannobile WV, et al. Effect of sustained PDGF nonviral gene delivery on repair of tooth-supporting bone defects. Gene Ther. 2017;24(1):31–9. Platelet-derived growth factor BB delivered on polyethylenimine to collagen scaffolds in periodontal defects resulted in a sustained inflammatory response and delayed bone healing in rodents.
Keeney M, Chung MT, Zielins ER, Paik KJ, McArdle A, Morrison SD, et al. Scaffold-mediated BMP-2 minicircle DNA delivery accelerated bone repair in a mouse critical-size calvarial defect model. J Biomed Mater Res A. 2016;104(8):2099–107.
D'Mello SR, Elangovan S, Hong L, Ross RD, Sumner DR, Salem AK. A pilot study evaluating combinatorial and simultaneous delivery of polyethylenimine-plasmid DNA complexes encoding for VEGF and PDGF for bone regeneration in calvarial bone defects. Curr Pharm Biotechnol. 2015;16(7):655–60.
Jin H, Zhang K, Qiao C, Yuan A, Li D, Zhao L, et al. Efficiently engineered cell sheet using a complex of polyethylenimine–alginate nanocomposites plus bone morphogenetic protein 2 gene to promote new bone formation. Int J Nanomedicine. 2014;9:2179.
Ginn SL, Alexander IE, Edelstein ML, Abedi MR, Wixon J. Gene therapy clinical trials worldwide to 2012—an update. J Gene Med. 2013;15(2):65–77.
Gafni Y, Pelled G, Zilberman Y, Turgeman G, Apparailly F, Yotvat H, et al. Gene therapy platform for bone regeneration using an exogenously regulated, AAV-2-based gene expression system. Mol Ther. 2004;9(4):587–95.
Ben Arav A, Pelled G, Zilberman Y, Kimelman-Bleich N, Gazit Z, Schwarz EM, et al. Adeno-associated virus-coated allografts: a novel approach for cranioplasty. J Tissue Eng Regen Med. 2012;6(10):e43–50.
Yazici C, Takahata M, Reynolds DG, Xie C, Samulski RJ, Samulski J, et al. 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(8):1416–25.
Li W, Wei H, Xia C, Zhu X, Hou G, Xu F, et al. Gene gun transferring-bone morphogenetic protein 2 (BMP-2) gene enhanced bone fracture healing in rabbits. Int J Clin Exp Med. 2015;8(11):19982–93.
Liu F, Porter RM, Wells J, Glatt V, Pilapil C, Evans CH. Evaluation of BMP-2 gene-activated muscle grafts for cranial defect repair. J Orthop Res. 2012;30(7):1095–102.
Betz OB, Betz VM, Schroder C, Penzkofer R, Gottlinger M, Mayer-Wagner S, et al. Repair of large segmental bone defects: BMP-2 gene activated muscle grafts vs. autologous bone grafting. BMC Biotechnol. 2013;13:65.
• Liu F, Ferreira E, Porter RM, Glatt V, Schinhan M, Shen Z, et al. Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle. Eur Cell Mater. 2015;30:118–30; discussion 30–1. Sheep skeletal muscle transfected with a BMP2 encoding adenovirus resulted in well-organized new bone after being transplanted in calvarial defects of immunosuppressed rats.
• Tian K, Qi M, Wang L, Li Z, Xu J, Li Y, et al. Two-stage therapeutic utility of ectopically formed bone tissue in skeletal muscle induced by adeno-associated virus containing bone morphogenetic protein-4 gene. J Orthop Surg Res. 2015;10:86. Gene therapy-associated bone overgrowth may be overcome by first transfecting skeletal muscle with a BMP4 encoding adeno-associated virus, and then transplanting the ectopic bone into a murine calvarial defect.
Gazit D, Turgeman G, Kelley P, Wang E, Jalenak M, Zilberman Y, et al. Engineered pluripotent mesenchymal cells integrate and differentiate in regenerating bone: a novel cell-mediated gene therapy. J Gene Med. 1999;1(2):121–33.
Turgeman G, Pittman DD, Muller R, Kurkalli BG, Zhou S, Pelled G, et al. Engineered human mesenchymal stem cells: a novel platform for skeletal cell mediated gene therapy. J Gene Med. 2001;3(3):240–51.
•• Pelled G, Sheyn D, Tawackoli W, Jun DS, Koh Y, Su S, et al. BMP6-engineered MSCs induce vertebral bone repair in a pig model: a pilot study. Stem Cells Int. 2016;2016:6530624. Locally implanted allogeneic BMP6 overexpressing mesenchymal stem cells increased bone formation in a porcine vertebral defect model.
Liu J, Chen W, Zhao Z, Xu HH. Reprogramming of mesenchymal stem cells derived from iPSCs seeded on biofunctionalized calcium phosphate scaffold for bone engineering. Biomaterials. 2013;34(32):7862–72.
Benjamin S, Sheyn D, Ben-David S, Oh A, Kallai I, Li N, et al. Oxygenated environment enhances both stem cell survival and osteogenic differentiation. Tissue Eng A. 2013;19(5–6):748–58.
Schwabe P, Greiner S, Ganzert R, Eberhart J, Dahn K, Stemberger A, et al. Effect of a novel nonviral gene delivery of BMP-2 on bone healing. ScientificWorldJournal. 2012;2012:560142.
Khorsand B, Nicholson N, Do AV, Femino JE, Martin JA, Petersen E, et al. Regeneration of bone using nanoplex delivery of FGF-2 and BMP-2 genes in diaphyseal long bone radial defects in a diabetic rabbit model. J Control Release. 2017;248:53–9.
Atluri K, Seabold D, Hong L, Elangovan S, Salem AK. Nanoplex-mediated codelivery of fibroblast growth factor and bone morphogenetic protein genes promotes osteogenesis in human adipocyte-derived mesenchymal stem cells. Mol Pharm. 2015;12(8):3032–42.
Lin Z, Rios HF, Park CH, Taut AD, Jin Q, Sugai JV, et al. LIM domain protein-3 (LMP3) cooperates with BMP7 to promote tissue regeneration by ligament progenitor cells. Gene Ther. 2013;20(1):1–6.
Shen Y, Qiao H, Fan Q, Zhang S, Tang T. Potentiated osteoinductivity via cotransfection with BMP-2 and VEGF genes in microencapsulated C2C12 cells. Biomed Res Int. 2015;2015:435253.
Seamon J, Wang X, Cui F, Keller T, Dighe AS, Balian G, et al. Adenoviral delivery of the VEGF and BMP-6 genes to rat mesenchymal stem cells potentiates osteogenesis. Bone Marrow Res. 2013;2013:737580.
Reichert JC, Schmalzl J, Prager P, Gilbert F, Quent VM, Steinert AF, et al. Synergistic effect of Indian hedgehog and bone morphogenetic protein-2 gene transfer to increase the osteogenic potential of human mesenchymal stem cells. Stem Cell Res Ther. 2013;4(5):105.
Ishihara A, Weisbrode SE, Bertone AL. Autologous implantation of BMP2-expressing dermal fibroblasts to improve bone mineral density and architecture in rabbit long bones. J Orthop Res. 2015;33(10):1455–65.
Xiang L, Liang C, Zhen-Yong K, Liang-Jun Y, Zhong-Liang D. BMP9-induced osteogenetic differentiation and bone formation of muscle-derived stem cells. J Biomed Biotechnol. 2012;2012:610952.
Dumanian ZP, Tollemar V, Ye J, Lu M, Zhu Y, Liao J, et al. Repair of critical sized cranial defects with BMP9-transduced calvarial cells delivered in a thermoresponsive scaffold. PLoS One. 2017;12(3):e0172327.
• Huang C, Tang M, Yehling E, Zhang X. Overexpressing sonic hedgehog peptide restores periosteal bone formation in a murine bone allograft transplantation model. Mol Ther. 2014;22(2):430–9. N-terminal sonic hedgehog gene transfected periostal-derived mesenchymal stem cells induced microvessel and periosteal bone collar formation in a murine segmental fracture model.
Feng L, Wu H, E L, Wang D, Feng F, Dong Y, et al. Effects of vascular endothelial growth factor 165 on bone tissue engineering. PLoS One. 2013;8(12):e82945.
Hernandez-Hurtado AA, Borrego-Soto G, Marino-Martinez IA, Lara-Arias J, Romero-Diaz VJ, Abrego-Guerra A, et al. Implant composed of demineralized bone and mesenchymal stem cells genetically modified with AdBMP2/AdBMP7 for the regeneration of bone fractures in ovis aries. Stem Cells Int. 2016;2016:7403890.
Fernandes G, Wang C, Yuan X, Liu Z, Dziak R, Yang S. Combination of controlled release platelet-rich plasma alginate beads and bone morphogenetic protein-2 genetically modified mesenchymal stem cells for bone regeneration. J Periodontol. 2016;87(4):470–80.
Park SY, Kim KH, Shin SY, Koo KT, Lee YM, Seol YJ. Dual delivery of rhPDGF-BB and bone marrow mesenchymal stromal cells expressing the BMP2 gene enhance bone formation in a critical-sized defect model. Tissue Eng Part A. 2013;19(21–22):2495–505.
Persons DA. Lentiviral vector gene therapy: effective and safe? Mol Ther. 2010;18(5):861–2.
• Alaee F, Sugiyama O, Virk MS, Tang H, Drissi H, Lichtler AC, et al. Suicide gene approach using a dual-expression lentiviral vector to enhance the safety of ex vivo gene therapy for bone repair. Gene Ther. 2014;21(2):139–47. A lentiviral vector encoding for both BMP2 and a pharmacologically-activatable suicide gene could be used to reduce the oncogenic potential of lentiviral nuclear integration.
Pensak M, Hong S, Dukas A, Tinsley B, Drissi H, Tang A, et al. The role of transduced bone marrow cells overexpressing BMP-2 in healing critical-sized defects in a mouse femur. Gene Ther. 2015;22(6):467–75.
Alaee F, Bartholomae C, Sugiyama O, Virk MS, Drissi H, Wu Q, et al. Biodistribution of LV-TSTA transduced rat bone marrow cells used for “ex-vivo” regional gene therapy for bone repair. Curr Gene Ther. 2015;15(5):481–91.
Lu S, Wang J, Ye J, Zou Y, Zhu Y, Wei Q, et al. Bone morphogenetic protein 9 (BMP9) induces effective bone formation from reversibly immortalized multipotent adipose-derived (iMAD) mesenchymal stem cells. Am J Transl Res. 2016;8(9):3710–30.
• Guan J, Zhang J, Zhu Z, Niu X, Guo S, Wang Y, et al. Bone morphogenetic protein 2 gene transduction enhances the osteogenic potential of human urine-derived stem cells. Stem Cell Res Ther. 2015;6:5. Transfection of human urine-derived stem cells with BMP2 encoding lentiviruses results in osteogenic differentiation in vitro and bone formation in vivo in nude mice.
Gao X, Usas A, Tang Y, Lu A, Tan J, Schneppendahl J, et al. A comparison of bone regeneration with human mesenchymal stem cells and muscle-derived stem cells and the critical role of BMP. Biomaterials. 2014;35(25):6859–70.
Gao X, Usas A, Lu A, Tang Y, Wang B, Chen CW, et al. BMP2 is superior to BMP4 for promoting human muscle-derived stem cell-mediated bone regeneration in a critical-sized calvarial defect model. Cell Transplant. 2013;22(12):2393–408.
Zhang W, Zhang X, Ling J, Wei X, Jian Y. Osteo-/odontogenic differentiation of BMP2 and VEGF gene-co-transfected human stem cells from apical papilla. Mol Med Rep. 2016;13(5):3747–54.
Lin Z, Wang JS, Lin L, Zhang J, Liu Y, Shuai M, et al. Effects of BMP2 and VEGF165 on the osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells. Exp Ther Med. 2014;7(3):625–9.
Wang Y, He T, Liu J, Liu H, Zhou L, Hao W, et al. Synergistic effects of overexpression of BMP2 and TGFbeta3 on osteogenic differentiation of bone marrow mesenchymal stem cells. Mol Med Rep. 2016;14(6):5514–20.
Bougioukli S, Jain A, Sugiyama O, Tinsley BA, Tang AH, Tan MH, et al. Combination therapy with BMP-2 and a systemic RANKL inhibitor enhances bone healing in a mouse critical-sized femoral defect. Bone. 2016;84:93–103.
Lin CY, Chang YH, Sung LY, Chen CL, Lin SY, Li KC, et al. Long-term tracking of segmental bone healing mediated by genetically engineered adipose-derived stem cells: focuses on bone remodeling and potential side effects. Tissue Eng Part A. 2014;20(9–10):1392–402.
Liao JC. Bone marrow mesenchymal stem cells expressing baculovirus-engineered bone morphogenetic protein-7 enhance rabbit posterolateral fusion. Int J Mol Sci. 2016;17(7).
Waki T, Lee SY, Niikura T, Iwakura T, Dogaki Y, Okumachi E, et al. Profiling microRNA expression during fracture healing. BMC Musculoskelet Disord. 2016;17:83.
Waki T, Lee SY, Niikura T, Iwakura T, Dogaki Y, Okumachi E, et al. Profiling microRNA expression in fracture nonunions: potential role of microRNAs in nonunion formation studied in a rat model. Bone Joint J. 2015;97-B(8):1144–51.
He B, Zhang ZK, Liu J, He YX, Tang T, Li J, Guo BS, Lu AP, Zhang BT, Zhang G. Bioinformatics and microarray analysis of miRNAs in aged female mice model implied new molecular mechanisms for impaired fracture healing. Int J Mol Sci. 2016;17(8).
Weilner S, Skalicky S, Salzer B, Keider V, Wagner M, Hildner F, et al. Differentially circulating miRNAs after recent osteoporotic fractures can influence osteogenic differentiation. Bone. 2015;79:43–51.
Sun Y, Xu J, Xu L, Zhang J, Chan K, Pan X, et al. MiR-503 promotes bone formation in distraction osteogenesis through suppressing Smurf1 expression. Sci Rep. 2017;7(1):409.
Xie Q, Wang Z, Zhou H, Yu Z, Huang Y, Sun H, et al. The role of miR-135-modified adipose-derived mesenchymal stem cells in bone regeneration. Biomaterials. 2016;75:279–94.
Xie Q, Wei W, Ruan J, Ding Y, Zhuang A, Bi X, et al. Effects of miR-146a on the osteogenesis of adipose-derived mesenchymal stem cells and bone regeneration. Sci Rep. 2017;7:42840.
Murata K, Ito H, Yoshitomi H, Yamamoto K, Fukuda A, Yoshikawa J, et al. Inhibition of miR-92a enhances fracture healing via promoting angiogenesis in a model of stabilized fracture in young mice. J Bone Miner Res. 2014;29(2):316–26.
Kocijan R, Muschitz C, Geiger E, Skalicky S, Baierl A, Dormann R, et al. Circulating microRNA signatures in patients with idiopathic and postmenopausal osteoporosis and fragility fractures. J Clin Endocrinol Metab. 2016;101(11):4125–34.
Evans CH, Huard J. Gene therapy approaches to regenerating the musculoskeletal system. Nat Rev Rheumatol. 2015;11(4):234–42. Available from: https://clinicaltrials.gov/ct2/home
De Ugarte DA, Morizono K, Elbarbary A, Alfonso Z, Zuk PA, Zhu M, et al. Comparison of multi-lineage cells from human adipose tissue and bone marrow. Cells Tissues Organs. 2003;174(3):101–9.
Seebach C, Henrich D, Tewksbury R, Wilhelm K, Marzi I. Number and proliferative capacity of human mesenchymal stem cells are modulated positively in multiple trauma patients and negatively in atrophic nonunions. Calcif Tissue Int. 2007;80(4):294–300.
Leskelä H-V, Risteli J, Niskanen S, Koivunen J, Ivaska KK, Lehenkari P. Osteoblast recruitment from stem cells does not decrease by age at late adulthood. Biochem Biophys Res Commun. 2003;311(4):1008–13.
Siegel G, Kluba T, Hermanutz-Klein U, Bieback K, Northoff H, Schafer R. Phenotype, donor age and gender affect function of human bone marrow-derived mesenchymal stromal cells. BMC Med. 2013;11:146.
Corsi KA, Pollett JB, Phillippi JA, Usas A, Li G, Huard J. Osteogenic potential of postnatal skeletal muscle-derived stem cells is influenced by donor sex. J Bone Miner Res. 2007;22(10):1592–602.
Meszaros LB, Usas A, Cooper GM, Huard J. Effect of host sex and sex hormones on muscle-derived stem cell-mediated bone formation and defect healing. Tissue Eng Part A. 2012;18(17–18):1751–9.
Taylor K, Vallejo-Giraldo C, Schaible N, Zakeri R, Miller V. Reporting of sex as a variable in cardiovascular studies using cultured cells. Biol Sex Differ. 2011;2(11):152.
Clayton JA, Collins FS. NIH to balance sex in cell and animal studies. Nature. 2014;509(7500):282–3.
Liebergall M, Schroeder J, Mosheiff R, Gazit Z, Yoram Z, Rasooly L, et al. Stem cell-based therapy for prevention of delayed fracture union: a randomized and prospective preliminary study. Mol Ther. 2013;21(8):1631–8.
Morshed S. Current options for determining fracture union. Adv Med. 2014;2014:708574.
O'Halloran K, Coale M, Costales T, Zerhusen T Jr, Castillo RC, Nascone JW, et al. Will my tibial fracture heal? Predicting nonunion at the time of definitive fixation based on commonly available variables. Clin Orthop Relat Res. 2016;474(6):1385–95.
Conflict of Interest
Dan Gazit reports grants from California Institute for Regenerative Medicine (CIRM) and the NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI.
Gadi Pelled reports grants from California Institute for Regenerative Medicine (CIRM), the USAMRMC/TATRC, IDF Medical Corps, the Milgrom Family Fund, and the NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI.
Dan Gazit and Gadi Pelled are co-founders and shareholders at GamlaStem Medical Inc., and have patents pending (one for a method of endogenous stem cell activation for tendon/ligament osseointegration, and another for a novel transfection and drug delivery device).
Human and Animal Rights and Informed Consent
All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).
This article is part of the Topical Collection on Orthopedic Management of Fractures
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Shapiro, G., Lieber, R., Gazit, D. et al. Recent Advances and Future of Gene Therapy for Bone Regeneration. Curr Osteoporos Rep 16, 504–511 (2018). https://doi.org/10.1007/s11914-018-0459-3
- Gene therapy
- Gene-activated matrix
- Regenerative medicine