Nucleic acids and analogs for bone regeneration

Abstract

With the incidence of different bone diseases increasing, effective therapies are needed that coordinate a combination of various technologies and biological materials. Bone tissue engineering has also been considered as a promising strategy to repair various bone defects. Therefore, different biological materials that can promote stem cell proliferation, migration, and osteoblastic differentiation to accelerate bone tissue regeneration and repair have also become the focus of research in multiple fields. Stem cell therapy, biomaterial scaffolds, and biological growth factors have shown potential for bone tissue engineering; however, off-target effects and cytotoxicity have limited their clinical use. The application of nucleic acids (deoxyribonucleic acid or ribonucleic acid) and nucleic acid analogs (peptide nucleic acids or locked nucleic acids), which are designed based on foreign genes or with special structures, can be taken up by target cells to exert different effects such as modulating protein expression, replacing a missing gene, or targeting specific gens or proteins. Due to some drawbacks, nucleic acids and nucleic acid analogs are combined with various delivery systems to exert enhanced effects, but current studies of these molecules have not yet satisfied clinical requirements. In-depth studies of nucleic acid or nucleic acid analog delivery systems have been performed, with a particular focus on bone tissue regeneration and repair. In this review, we mainly introduce delivery systems for nucleic acids and nucleic acid analogs and their applications in bone repair and regeneration. At the same time, the application of conventional scaffold materials for the delivery of nucleic acids and nucleic acid analogs is also discussed.

Bone Regeneration: Nucleic acids and analogs in bone repair

Used with an appropriate delivery system, nucleic acids and nucleic acid analogs have excellent potential for bone repair and regeneration. Owing to various challenges with bone tissue regeneration, current research is largely focused on gene therapy, which employs genes to treat or prevent disease, and such new materials as nucleic acids (DNA and RNA) and nucleic acid analogs (compounds structurally similar to naturally occurring nucleic acids). A team headed by Yunfeng Lin at Sichuan University, China conducted a review of delivery systems for nucleic acids and nucleic acid analogs and their application in bone repair and regeneration. The authors identified the use of biomaterial scaffolds (which mimic living tissue) as one of the most important research areas for gene therapy, and that strategy has proven effective with all types of bone regeneration and repair.

References

[1] Tsiridis E, Gamie Z, Conaghan PG, Giannoudis PV. Biological options to enhance periprosthetic bone mass. Injury, 2007, 38:704-713

[2] Robling AG, Stout SD. Morphology of the drifting osteon. Cells Tissues Organs, 1999, 164:192-204

[3] Faingold A, Cohen SR, Reznikov N, Wagner HD. Osteonal lamellae elementary units: lamellar microstructure, curvature and mechanical properties. Acta Biomater., 2013, 9:5956-5962

[4] Terkeltaub R, Yang B, Lotz M, Liu-Bryan R. Chondrocyte AMP-activated protein kinase activity suppresses matrix degradation responses to proinflammatory cytokines interleukin-1β and tumor necrosis factor α. Arthritis Rheum., 2011, 63:1928-1937

[5] Sitara D, Aliprantis AO. Transcriptional regulation of bone and joint remodeling by NFAT. Immunol. Rev., 2010, 233:286-300

[6] Asafo-Adjei TA, Chen AJ, Najarzadeh A, Puleo DA. Advances in controlled drug delivery for treatment of osteoporosis. Curr. Osteoporos. Rep., 2016, 14:226-238

[7] Einhorn TA. Enhancement of fracture-healing. J. Bone Joint Surg. Am., 1995, 77:940-956

[8] Murphy PS, Evans GR. Advances in wound healing: a review of current wound healing products. Plast. Surg. Int., 2012, 2012:190436

[9] No YJ, Roohani-Esfahani SI, Zreiqat H. Nanomaterials: the next step in injectable bone cements. Nanomedicine, 2014, 9:1745-1764

[10] Jeong, S. Y., Kim, J. A. & Oh, I. H. The adaptive remodeling of stem cell niche in stimulated bone marrow counteracts the leukemic niche Stem Cells 36, 1617–1629 (2018).

[11] Raftery RM et al. Delivering nucleic-acid based nanomedicines on biomaterial scaffolds for orthopedic tissue repair: challenges, progress and future perspectives. Adv. Mater. Deerfield., 2016, 28:5447-5469

[12] Gong T et al. Nanomaterials and bone regeneration. Bone Res., 2015, 3:15029

[13] Hutmacher DW. Scaffolds in tissue engineering bone and cartilage. Biomaterials, 2000, 21:2529-2543

[14] Zhang Y et al. Programmable and multifunctional DNA-based materials for biomedical applications. Adv. Mater. Deerfield., 2018, 30:e1703658

[15] Shi S et al. Effects of tetrahedral DNA nanostructures on autophagy in chondrocytes. Chem. Commun., 2018, 54:1327-1330

[16] Garzon R, Marcucci G, Croce CM. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat. Rev. Drug. Discov., 2010, 9:775-789

[17] Zhang, Y., Ma, W. & Zhu, Y. Inhibiting methicillin-resistant Staphylococcus aureus by tetrahedral DNA nanostructure-enabled antisense peptide nucleic acid delivery. Nano Lett. 18, 5652–5659 (2018).

[18] Fernandez-Yague MA et al. Biomimetic approaches in bone tissue engineering: Integrating biological and physicomechanical strategies. Adv. Drug Deliv. Rev., 2015, 84:1-29

[19] Gacanin, J., et al. Spatiotemporally controlled release of rho-inhibiting C3 toxin from a protein-DNA hybrid hydrogel for targeted inhibition of osteoclast formation and activity. Adv. Healthcare Mater. 6, 1700392 (2017).

[20] Crane GM, Ishaug SL, Mikos AG. Bone tissue engineering. Nat. Med., 1995, 1:1322-1324

[21] Nie L et al. The healing of alveolar bone defects with novel bio-implants composed of Ad-BMP9-transfected rDFCs and CHA scaffolds. Sci. Rep., 2017, 7

[22] Nandi SK et al. Converted marine coral hydroxyapatite implants with growth factors: in vivo bone regeneration. Mater. Sci. Eng. C Mater. Biol. Appl., 2015, 49:816-823

[23] Zhou T et al. Electrospun poly(3-hydroxybutyrate-co-4-hydroxybutyrate)/graphene oxide scaffold: enhanced properties and promoted in vivo bone repair in rats. ACS Appl. Mater. Interfaces, 2017, 9:42589-42600

[24] Li G et al. Poly(3-hydroxybutyrate-co-4-hydroxybutyrate) based electrospun 3D scaffolds for delivery of autogeneic chondrocytes and adipose-derived stem cells: evaluation of cartilage defects in rabbit. J. Biomed. Nanotechnol., 2015, 11:105-116

[25] Basu S, Pacelli S. Harnessing the noncovalent interactions of DNA backbone with 2D silicate nanodisks to fabricate injectable therapeutic hydrogels. ACS Nano., 2018, 12:9866-9880

[26] Li J et al. Functional nucleic acid-based hydrogels for bioanalytical and biomedical applications. Chem. Soc. Rev., 2016, 45:1410-1431

[27] Griffin MF et al. Chemical group-dependent plasma polymerisation preferentially directs adipose stem cell differentiation towards osteogenic or chondrogenic lineages. Acta Biomater., 2017, 50:450-461

[28] Khader A, Sherman LS, Rameshwar P, Arinzeh TL. Sodium tungstate for promoting mesenchymal stem cell chondrogenesis. Stem. Cells Dev., 2016, 25:1909-1918

[29] Shi S et al. Promote adipose-derived stem cell migration via lncRNA XLOC 010623 and RHOA/ROCK2 signal pathway. ACS Appl. Mater. Interfaces, 2016, 8:19353-19363

[30] Lukasova V et al. Osteogenic differentiation of 3D cultured mesenchymal stem cells induced by bioactive peptides. Cell. Prolif., 2017, 50:e12357

[31] Liu C et al. The effect of the fibre orientation of electrospun scaffolds on the matrix production of rabbit annulus fibrosus-derived stem cells. Bone Res., 2015, 3:15012

[32] Tan J et al. Decreased osteogenesis of adult mesenchymal stem cells by reactive oxygen species under cyclic stretch: a possible mechanism of age related osteoporosis. Bone Res., 2015, 3:15003

[33] Mehrabani M et al. Deferoxamine preconditioning to restore impaired HIF-1alpha-mediated angiogenic mechanisms in adipose-derived stem cells from STZ-induced type 1 diabetic rats. Cell. Prolif., 2015, 48:532-549

[34] Zuk PA et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tiss. Eng., 2001, 7:211-228

[35] Lin Y et al. Molecular and cellular characterization during chondrogenic differentiation of adipose tissue-derived stromal cells in vitro and cartilage formation in vivo. J. Cell. Mol. Med., 2005, 9:929-939

[36] Hollinger JO, Hart CE, Hirsch SN, Lynch S, Friedlaender GE. Recombinant human platelet-derived growth factor: biology and clinical applications. J. Bone Jt. Surg. Am., 2008, 90:48-54 Suppl 1

[37] Zhang, Q., Deng, S., Sun, K., Lin, S. & Lin, Y. MMP-2 and Notch signal pathway regulate migration of adipose-derived stem cells and chondrocytes in co-culture systems Cell Prolif. 50, e12385 (2017).

[38] Zhang Q et al. MMP-2 and Notch signal pathway regulate migration of adipose-derived stem cells and chondrocytes in co-culture systems. Cell. Prolif., 2017, 50:e12385

[39] Shao, X. et al. A potential promoter for cartilage tissue regeneration via regulating chondrocyte phenotype and proliferation. Small 13, 1602770 (2017).

[40] Zhong J et al. Crosstalk between adipose-derived stem cells and chondrocytes: when growth factors matter. Bone Res., 2016, 4:15036

[41] Min J et al. Designer dual therapy nanolayered implant coatings eradicate biofilms and accelerate bone tissue repair. ACS Nano, 2016, 10:4441-4450

[42] Salazar VS, Gamer LW, Rosen V. BMP signalling in skeletal development, disease and repair, Nature reviews. Nat. Rev. Endocrinol., 2016, 12:203-221

[43] Hankenson KD, Gagne K, Shaughnessy M. Extracellular signaling molecules to promote fracture healing and bone regeneration. Adv. Drug Deliv. Rev., 2015, 94:3-12

[44] An SY et al. Milk fat globule-EGF Factor 8, secreted by mesenchymal stem cells, protects against liver fibrosis in mice. Gastroenterology, 2017, 152:1174-1186

[45] Luchetti F et al. Melatonin regulates mesenchymal stem cell differentiation: a review. J. Pineal Res., 2014, 56:382-397

[46] Lu CH, Chang YH, Lin SY, Li KC, Hu YC. Recent progresses in gene delivery-based bone tissue engineering. Biotechnol. Adv., 2013, 31:1695-1706

[47] Lieberman JR, Daluiski A, Einhorn TA. The role of growth factors in the repair of bone. Biology and clinical applications. J. Bone Jt. Surg. Am. Vol., 2002, 84-a:1032-1044

[48] Lieberman JR et al. The effect of regional gene therapy with bone morphogenetic protein-2-producing bone-marrow cells on the repair of segmental femoral defects in rats. J. Bone Jt. Surg. Am., 1999, 81:905-917

[49] Chang PC et al. Adenovirus encoding human platelet-derived growth factor-B delivered to alveolar bone defects exhibits safety and biodistribution profiles favorable for clinical use. Hum. Gene Ther., 2009, 20:486-496

[50] Pinto UM, Pappas KM, Winans SC. The ABCs of plasmid replication and segregation. Nat. Rev. Microbiol., 2012, 10:755-765

[51] Lee H et al. Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery. Nat. Nanotechnol., 2012, 7:389-393

[52] Raper SE et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol. Genet. Metab., 2003, 80:148-158

[53] Sun Y et al. Osteoblast-targeting-peptide modified nanoparticle for siRNA/microRNA delivery. ACS Nano, 2016, 10:5759-5768

[54] Smith JO, Aarvold A, Tayton ER, Dunlop DG, Oreffo RO. Skeletal tissue regeneration: current approaches, challenges, and novel reconstructive strategies for an aging population. Tissue Eng. Part B Rev., 2011, 17:307-320

[55] Verma IM, Weitzman MD. Gene therapy: twenty-first century medicine. Annu. Rev. Biochem., 2005, 74:711-738

[56] Oliveira PH, Mairhofer J. Marker-free plasmids for biotechnological applications - implications and perspectives. Trends Biotechnol., 2013, 31:539-547

[57] Ferreira E et al. Sustained and promoter dependent bone morphogenetic protein expression by rat mesenchymal stem cells after BMP-2 transgene electrotransfer. Eur. Cell. Mater., 2012, 24:18-28

[58] Li H et al. Accelerated bony defect healing based on chitosan thermosensitive hydrogel scaffolds embedded with chitosan nanoparticles for the delivery of BMP2 plasmid DNA. J. Biomed. Mater. Res. A., 2017, 105:265-273

[59] Zinchenko A, Miwa Y, Lopatina LI, Sergeyev VG, Murata S. DNA hydrogel as a template for synthesis of ultrasmall gold nanoparticles for catalytic applications. ACS Appl. Mater. Interfaces, 2014, 6:3226-3232

[60] Li J et al. Nanoparticle superlattices as efficient bifunctional electrocatalysts for water splitting. J. Am. Chem. Soc., 2015, 137:14305-14312

[61] Szpalski C, Barr J, Wetterau M, Saadeh PB, Warren SM. Cranial bone defects: current and future strategies. Neurosurg. Focus, 2010, 29:E8

[62] Field LD, Delehanty JB, Chen Y, Medintz IL. Peptides for specifically targeting nanoparticles to cellular organelles: quo vadis? Acc. Chem. Res., 2015, 48:1380-1390

[63] Hilgenbrink AR, Low PS. Folate receptor-mediated drug targeting: from therapeutics to diagnostics. J. Pharm. Sci., 2005, 94:2135-2146

[64] Ma W et al. Promote neural stem cell proliferation and neuronal. Differentiation, 2018, 10:7892-7900

[65] Shi, S., et al. Modulation of chondrocyte motility by tetrahedral DNA nanostructures. Cell. Prolif. 50, e12368 (2017).

[66] Pei H, Zuo X, Zhu D, Huang Q, Fan C. Functional DNA nanostructures for theranostic applications. Acc. Chem. Res., 2014, 47:550-559

[67] Zhou M et al. Effect of tetrahedral DNA nanostructures on proliferation and osteo/odontogenic differentiation of dental pulp stem cells via activation of the notch signaling pathway. Nanomedicine, 2018, 14:1227-1236

[68] Ye D, Zuo X, Fan C. DNA nanotechnology-enabled interfacial engineering for biosensor development. Annu. Rev. Anal. Chem., 2018, 11:171-195

[69] Peng Q et al. Understanding the biomedical effects of the self-assembled tetrahedral DNA nanostructure on living cells. ACS Appl. Mater. Interfaces, 2016, 8:12733-12739

[70] Zhou F et al. Programmably shaped carbon nanostructure from shape-conserving carbonization of DNA. ACS Nano, 2016, 10:3069-3077

[71] Shao XR et al. Effect of tetrahedral DNA nanostructures on osteogenic differentiation of mesenchymal stem cells via activation of the Wnt/beta-catenin signaling pathway. Nanomedicine, 2017, 13:1809-1819

[72] Lin S et al. IGF-1 promotes angiogenesis in endothelial cells/adipose-derived stem cells co-culture system with activation of PI3K/Akt signal pathway. Cell Prolif., 2017, 50:e12390

[73] Strem BM et al. Multipotential differentiation of adipose tissue-derived stem cells. Keio J. Med., 2005, 54:132-141

[74] Zhang, Q. et al. Curved microstructures promote osteogenesis of mesenchymal stem cells via the RhoA/ROCK pathway. Cell Prolif. 50, e12356 (2017).

[75] Wang S et al. DNA orientation-specific adhesion and patterning of living mammalian cells on self-assembled DNA monolayers. Chem. Sci., 2016, 7:2722-2727

[76] Zhang, T., et al. Effect of matrix stiffness on osteoblast functionalization. Cell Prolif. 50, e12338 (2017).

[77] Liao J et al. The fabrication of biomimetic biphasic CAN-PAC hydrogel with a seamless interfacial layer applied in osteochondral defect repair. Bone Res., 2017, 5:17018

[78] Xue, C., et al., The JAK/STAT3 signalling pathway regulated angiogenesis in an endothelial cell/adipose-derived stromal cell co-culture, 3D gel model. Cell. Prolif. 50, e12307 (2017).

[79] Shao XR et al. Independent effect of polymeric nanoparticle zeta potential/surface charge, on their cytotoxicity and affinity to cells. Cell. Prolif., 2015, 48:465-474

[80] Bakopoulou A et al. Comparative analysis of in vitro osteo/odontogenic differentiation potential of human dental pulp stem cells (DPSCs) and stem cells from the apical papilla (SCAP). Arch. Oral. Biol., 2011, 56:709-721

[81] Zhang W, Walboomers XF, Shi S, Fan M, Jansen JA. Multilineage differentiation potential of stem cells derived from human dental pulp after cryopreservation. Tiss. Eng., 2006, 12:2813-2823

[82] Lei M et al. Mesenchymal stem cell characteristics of dental pulp and periodontal ligament stem cells after in vivo transplantation. Biomaterials, 2014, 35:6332-6343

[83] Mumm, J. S. & Kopan, R. Notch signaling: from the outside in. Dev. Biol. 228, 151–165 (2000).

[84] Wang L et al. Notch-RBP-J signaling regulates the mobilization and function of endothelial progenitor cells by dynamic modulation of CXCR4 expression in mice. PLoS One, 2009, 4:e7572

[85] Hashimoto-Torii K et al. Interaction between Reelin and Notch signaling regulates neuronal migration in the cerebral cortex. Neuron, 2008, 60:273-284

[86] Sohn S et al. The role of ORAI1 in the odontogenic differentiation of human dental pulp stem cells. J. Dent. Res., 2015, 94:1560-1567

[87] Alam MI, Asahina I, Seto I, Oda M, Enomoto S. Prefabricated vascularized bone flap: a tissue transformation technique for bone reconstruction. Plast. Reconstr. Surg., 2001, 108:952-958

[88] Zeng D et al. DNA tetrahedral nanostructure-based electrochemical miRNA biosensor for simultaneous detection of multiple miRNAs in pancreatic carcinoma. ACS Appl. Mater. Interfaces, 2017, 9:24118-24125

[89] Mattick JS. Challenging the dogma: the hidden layer of non-protein-coding RNAs in complex organisms. Bioessays, 2003, 25:930-939

[90] Elbashir SM et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature, 2001, 411:494-498

[91] Hammond SM, Bernstein E, Beach D, Hannon GJ. An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature, 2000, 404:293-296

[92] de Kouchkovsky Y. Study of the chlorophyll fluorescence in chloroplasts and algae with the plastoquinone antagonist dibromothymoquinone. Biochim. Biophys. Acta, 1975, 376:259-267

[93] Elbashir SM, Lendeckel W, Tuschl T. RNA interference is mediated by 21- and 22-nucleotide RNAs. Genes Dev., 2001, 15:188-200

[94] Moretti J et al. STING senses microbial viability to orchestrate stress-mediated autophagy of the endoplasmic reticulum. Cell, 2017, 171:809-823.e13

[95] Schwarz DS, Hutvagner G, Haley B, Zamore PD. Evidence that siRNAs function as guides, not primers, in the Drosophila and human RNAi pathways. Mol. Cell, 2002, 10:537-548

[96] Frith JE, Kusuma GD. Mechanically-sensitive miRNAs bias human mesenchymal stem cell fate via mTOR signalling. Nat. Commun., 2018, 9

[97] Monaghan M, Browne S, Schenke-Layland K, Pandit A. A collagen-based scaffold delivering exogenous microrna-29B to modulate extracellular matrix remodeling. Mol. Ther., 2014, 22:786-796

[98] James EN, Delany AM, Nair LS. Post-transcriptional regulation in osteoblasts using localized delivery of miR-29a inhibitor from nanofibers to enhance extracellular matrix deposition. Acta Biomater., 2014, 10:3571-3580

[99] Yang L, Engeland CG, Cheng B. Social isolation impairs oral palatal wound healing in sprague-dawley rats: a role for miR-29 and miR-203 via VEGF suppression. PLoS One, 2013, 8:e72359

[100] Liao YH et al. Osteogenic differentiation of adipose-derived stem cells and calvarial defect repair using baculovirus-mediated co-expression of BMP-2 and miR-148b. Biomaterials, 2014, 35:4901-4910

[101] Lin L et al. Synergistic inhibition of endochondral bone formation by silencing Hif1alpha and Runx2 in trauma-induced heterotopic ossification. Mol. Ther., 2011, 19:1426-1432

[102] Li Y et al. The promotion of bone regeneration through positive regulation of angiogenic-osteogenic coupling using microRNA-26a. Biomaterials, 2013, 34:5048-5058

[103] Hu R et al. Targeting miRNAs in osteoblast differentiation and bone formation. Expert. Opin. Ther. Targets, 2010, 14:1109-1120

[104] Yamada Y et al. S1P-S1PR2 axis mediates homing of muse cells into damaged heart for long-lasting tissue repair and functional recovery after acute myocardial infarction. Circ. Res., 2018, 122:1069-1083

[105] Nguyen MK et al. RNA interfering molecule delivery from in situ forming biodegradable hydrogels for enhancement of bone formation in rat calvarial bone defects. Acta Biomater., 2018, 75:105-114

[106] Zhang J et al. Topography of calcium phosphate ceramics regulates primary cilia length and TGF receptor recruitment associated with osteogenesis. Acta Biomater., 2017, 57:487-497

[107] Li Y et al. MiR-26a rescues bone regeneration deficiency of mesenchymal stem cells derived from osteoporotic mice. Mol. Ther., 2015, 23:1349-1357

[108] Li Y et al. Estimation of the reliability of all-ceramic crowns using finite element models and the stress-strength interference theory. Comput. Biol. Med., 2013, 43:1214-1220