Nanomaterials for the delivery of bioactive factors to enhance angiogenesis of dermal substitutes during wound healing

Abstract

Dermal substitutes provide a template for dermal regeneration and reconstruction. They constitute an ideal clinical treatment for deep skin defects. However, rapid vascularization remains as a major hurdle to the development and application of dermal substitutes. Several bioactive factors play an important regulatory role in the process of angiogenesis and an understanding of the mechanism of achieving their effective delivery and sustained function is vital. Nanomaterials have great potential for tissue engineering. Effective delivery of bioactive factors (including growth factors, peptides and nucleic acids) by nanomaterials is of increasing research interest. This paper discusses the process of dermal substitute angiogenesis and the roles of related bioactive factors in this process. The application of nanomaterials for the delivery of bioactive factors to enhance angiogenesis and accelerate wound healing is also reviewed. We focus on new systems and approaches for delivering bioactive factors for enhancing angiogenesis in dermal substitutes.

Keywords

Nanomaterials / Bioactive factors / Dermal substitute / Angiogenesis / Wound healing / Regeneration / Tissue engineering / Vascularization

References

[1] Jarbrink K, Ni G, Sonnergren H, Schmidtchen A, Pang C, Bajpai R, et al. The humanistic and economic burden of chronic wounds: a protocol for a systematic review. Syst Rev. 2017; 6: 15.

[2] Frueh FS, Menger MD, Lindenblatt N, Giovanoli P, Laschke MW. Current and emerging vascularization strategies in skin tissue engineering. Crit Rev Biotechnol. 2017; 37: 613-25.

[3] Novosel EC, Kleinhans C, Kluger PJ. Vascularization is the key challenge in tissue engineering. Adv Drug Deliv Rev. 2011; 63: 300-11.

[4] Wang X, Wu P, Hu X, You C, Guo R, Shi H, et al. Polyurethane membrane/knitted mesh-reinforced collagen-chitosan bilayer dermal substitute for the repair of full-thickness skin defects via a two-step procedure. J Mech Behav Biomed Mater. 2016; 56: 120-33.

[5] Hendrickx B, Vranckx JJ, Luttun A. Cell-based vascularization strategies for skin tissue engineering. Tissue Eng Part B Rev. 2011; 17: 13-24.

[6] Zheng YR, Feng ZZ, You CG, Jin YY, Hu XL, Wang XG, et al. In vitro evaluation of Panax notoginseng Rg1 released from collagen/chitosan-gelatin microsphere scaffolds for angiogenesis. Biomed Eng Online. 2013; 12: 134-150.

[7] Phelps EA, Garcia AJ. Update on therapeutic vascularization strategies. Regen Med. 2009; 4: 65-80.

[8] McCarty SM, Percival SL. Proteases and delayed wound healing. Adv Wound Care (New Rochelle). 2013; 2: 438-47.

[9] Allen DB, Maguire JJ, Mahdavian M, Wicke C, Marcocci L, Scheuenstuhl H, et al. Wound hypoxia and acidosis limit neutrophil bacterial killing mechanisms. Arch Surg. 1997; 132: 991-6.

[10] Oryan A, Alemzadeh E, Zarei M. Basic concepts, current evidence, and future potential for gene therapy in managing cutaneous wounds. Biotechnol Lett. 2019; 41: 889-98.

[11] Kim HS, Sun X, Lee JH, Kim HW, Fu X, Leong KW. Advanced drug delivery systems and artificial skin grafts for skin wound healing. Adv Drug Deliv Rev. 2019; 146: 209-39.

[12] Chen W, Palazzo A, Hennink WE, Kok RJ. Effect of particle size on drug loading and release kinetics of Gefitinib-loaded PLGA microspheres. Mol Pharm. 2017; 14: 459-67.

[13] Nissen NN, Polverini PJ, Koch AE, Volin MV, Gamelli RL, DiPietro LA. Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing. Am J Pathol. 1998; 152: 1445-52.

[14] Mohle R, Green D, Moore MA, Nachman RL, Rafii S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci U S A. 1997; 94: 663-8.

[15] Jinnin M, Ihn H, Mimura Y, Asano Y, Yamane K, Tamaki K. Regulation of fibrogenic/fibrolytic genes by platelet-derived growth factor C, a novel growth factor, in human dermal fibroblasts. J Cell Physiol. 2005; 202: 510-7.

[16] Johnson KE, Wilgus TA. Vascular endothelial growth factor and angiogenesis in the regulation of cutaneous wound repair. Adv Wound Care (New Rochelle). 2014; 3: 647-61.

[17] Anisimov A, Tvorogov D, Alitalo A, Leppanen VM, An Y, Han EC, et al. Vascular endothelial growth factor-angiopoietin chimera with improved properties for therapeutic angiogenesis. Circulation. 2013; 127: 424-34.

[18] DiPietro LA. Angiogenesis and wound repair: when enough is enough. J Leukoc Biol. 2016; 100: 979-84.

[19] Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Jung S, et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell. 2006; 124: 175-89.

[20] Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Growth factors and cytokines in wound healing. Wound Repair Regen. 2008; 16: 585-601.

[21] Xiong S, Zhang X, Lu P, Wu Y, Wang Q, Sun H, et al. A Gelatin-sulfonated silk composite scaffold based on 3D printing technology enhances skin regeneration by stimulating epidermal growth and dermal neovascularization. Sci Rep. 2017; 7: 4288.

[22] Wu J, Ye J, Zhu J, Xiao Z, He C, Shi H, et al. Heparin-based Coacervate of FGF2 improves dermal regeneration by asserting a synergistic role with cell proliferation and endogenous facilitated VEGF for cutaneous wound healing. Biomacromolecules. 2016; 17: 2168-77.

[23] Ruthenborg RJ, Ban JJ, Wazir A, Takeda N, Kim JW. Regulation of wound healing and fibrosis by hypoxia and hypoxia-inducible factor-1. Mol Cells. 2014; 37: 637-43.

[24] Desmet CM, Preat V, Gallez B. Nanomedicines and gene therapy for the delivery of growth factors to improve perfusion and oxygenation in wound healing. Adv Drug Deliv Rev. 2018; 129: 262-84.

[25] Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003; 9: 677-84.

[26] Mazure NM, Brahimi-Horn MC, Pouyssegur J. Protein kinases and the hypoxia-inducible factor-1, two switches in angiogenesis. Curr Pharm Des. 2003; 9: 531-41.

[27] Jeong JW, Bae MK, Ahn MY, Kim SH, Sohn TK, Bae MH, et al. Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. Cell. 2002; 111: 709-20.

[28] Benjamin LE, Hemo I, Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development. 1998; 125: 1591-8.

[29] Diaz-Flores L, Gutierrez R, Madrid JF, Varela H, Valladares F, Acosta E, et al. Pericytes. Morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche. Histol Histopathol. 2009; 24: 909-69.

[30] Lindblom P, Gerhardt H, Liebner S, Abramsson A, Enge M, Hellstrom M, et al. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 2003; 17: 1835-40.

[31] Bjarnegard M, Enge M, Norlin J, Gustafsdottir S, Fredriksson S, Abramsson A, et al. Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development. 2004; 131: 1847-57.

[32] Teichert M, Milde L, Holm A, Stanicek L, Gengenbacher N, Savant S, et al. Pericyte-expressed Tie2 controls angiogenesis and vessel maturation. Nat Commun. 2017; 8: 16106.

[33] Gianni-Barrera R, Butschkau A, Uccelli A, Certelli A, Valente P, Bartolomeo M, et al. PDGF-BB regulates splitting angiogenesis in skeletal muscle by limiting VEGF-induced endothelial proliferation. Angiogenesis. 2018; 21: 883-900.

[34] Gainza G, Villullas S, Pedraz JL, Hernandez RM, Igartua M. Advances in drug delivery systems (DDSs) to release growth factors for wound healing and skin regeneration. Nanomedicine. 2015; 11: 1551-73.

[35] Berthet M, Gauthier Y, Lacroix C, Verrier B, Monge C. Nanoparticle-based dressing: the future of wound treatment? Trends Biotechnol. 2017; 35: 770-84.

[36] Golub JS, Kim YT, Duvall CL, Bellamkonda RV, Gupta D, Lin AS, et al. Sustained VEGF delivery via PLGA nanoparticles promotes vascular growth. Am J Physiol-Heart C. 2010; 298: H1959-65.

[37] Chereddy KK, Lopes A, Koussoroplis S, Payen V, Moia C, Zhu H, et al. Combined effects of PLGA and vascular endothelial growth factor promote the healing of non-diabetic and diabetic wounds. Nanomedicine. 2015; 11: 1975-84.

[38] Lai HJ, Kuan CH, Wu HC, Tsai JC, Chen TM, Hsieh DJ, et al. Tailored design of electrospun composite nanofibers with staged release of multiple angiogenic growth factors for chronic wound healing. Acta Biomater. 2014; 10: 4156-66.

[39] Claffey KP, Abrams K, Shih SC, Brown LF, Mullen A, Keough M. Fibroblast growth factor 2 activation of stromal cell vascular endothelial growth factor expression and angiogenesis. Lab Invest. 2001; 81: 61-75.

[40] Zhang J, Postovit LM, Wang D, Gardiner RB, Harris R, Abdul M, et al. In situ loading of basic fibroblast growth factor within porous silica nanoparticles for a prolonged release. Nanoscale Res Lett. 2009; 4: 1297-302.

[41] Li W, Lan Y, Guo R, Zhang Y, Xue W, Zhang Y. In vitro and in vivo evaluation of a novel collagen/cellulose nanocrystals scaffold for achieving the sustained release of basic fibroblast growth factor. J Biomater Appl. 2015; 29: 882-93.

[42] Arunkumar P, Dougherty JA, Weist J, Kumar N, Angelos MG, Powell HM, et al. Sustained release of basic fibroblast growth factor (bFGF) encapsulated Polycaprolactone (PCL) microspheres promote angiogenesis in vivo. Nanomaterials (Basel). 2019; 9: 1037.

[43] Xu HL, Chen PP, ZhuGe DL, Zhu QY, Jin BH, Shen BX, et al. Liposomes with silk fibroin hydrogel Core to stabilize bFGF and promote the wound healing of mice with deep second-degree scald. Adv Healthc Mater. 2017; 6: 1-13.

[44] Losi P, Briganti E, Errico C, Lisella A, Sanguinetti E, Chiellini F, et al. Fibrin-based scaffold incorporating VEGF-and bFGF-loaded nanoparticles stimulates wound healing in diabetic mice. Acta Biomater. 2013; 9: 7814-21.

[45] Hsieh PC, Davis ME, Gannon J, MacGillivray C, Lee RT. Controlled delivery of PDGF-BB for myocardial protection using injectable self-assembling peptide nanofibers. J Clin Invest. 2006; 116: 237-48.

[46] Zymek P, Bujak M, Chatila K, Cieslak A, Thakker G, Entman ML, et al. The role of platelet-derived growth factor signaling in healing myocardial infarcts. J Am Coll Cardiol. 2006; 48: 2315-23.

[47] Jin Q, Wei G, Lin Z, Sugai JV, Lynch SE, Ma PX, et al. Nanofibrous scaffolds incorporating PDGF-BB microspheres induce chemokine expression and tissue neogenesis in vivo. PLoS One. 2008; 3: e1729-36.

[48] Stratman AN, Schwindt AE, Malotte KM, Davis GE. Endothelial-derived PDGF-BB and HB-EGF coordinately regulate pericyte recruitment during vasculogenic tube assembly and stabilization. Blood. 2010; 116: 4720-30.

[49] Xie ZW, Paras CB, Weng H, Punnakitikashem P, Su LC, Vu K, et al. Dual growth factor releasing multi-functional nanofibers for wound healing. Acta Biomater. 2013; 9: 9351- 9.

[50] Chu Y, Yu D, Wang P, Xu J, Li D, Ding M. Nanotechnology promotes the full-thickness diabetic wound healing effect of recombinant human epidermal growth factor in diabetic rats. Wound Repair Regen. 2010; 18: 499-505.

[51] Gao XW, Xu ZP. Mechanisms of action of angiogenin. Acta Biochim Biophys Sin. 2008; 40: 619-24.

[52] Shi HF, Han CM, Mao ZW, Ma L, Gao CY. Enhanced angiogenesis in porous collagen-chitosan scaffolds loaded with Angiogenin. Tissue Eng Pt A. 2008; 14: 1775-85.

[53] Pan SC, Chiu HY. Response to Wang et al. Comments on "Angiogenin, an angiogenic factor with potential for tissue engineering applications". Wound Repair Regen 2014; 22: 289-9.

[54] Sun HF, Wang XG, Hu XL, Yu WJ, You CG, Hu H, et al. Promotion of angiogenesis by sustained release of rhGM-CSF from heparinized collagen/chitosan scaffolds. J Biomed Mater Res B. 2012; 100b: 788-98.

[55] Kohara H, Tajima S, Yamamoto M, Tabata Y. Angiogenesis induced by controlled release of neuropeptide substance P. Biomaterials. 2010; 31: 8617-25.

[56] Tang T, Jiang H, Yu Y, He F, Ji SZ, Liu YY, et al. A new method of wound treatment: targeted therapy of skin wounds with reactive oxygen species-responsive nanoparticles containing SDF-1 alpha. Int J Nanomedicine. 2015; 10: 6571-85.

[57] Zhang S, Chen S, Shen Y, Yang D, Liu X, Sun-Chi AC, et al. Puerarin induces angiogenesis in myocardium of rat with myocardial infarction. Biol Pharm Bull. 2006; 29: 945-50.

[58] Leung KW, Pon YL, Wong RNS, Wong AST. Ginsenoside-Rg1 induces vascular endothelial growth factor expression through the glucocorticoid receptor-related phosphatidylinositol 3-kinase/Akt and beta-catenin/T-cell factor-dependent pathway in human endothelial cells. J Biol Chem. 2006; 281: 36280-8.

[59] Hong SJ, Wan JB, Zhang Y, Hu G, Lin HC, Seto SW, et al. Angiogenic effect of Saponin extract from Panax notoginseng on HUVECs in vitro and zebrafish in vivo. Phytother Res. 2009; 23: 677-86.

[60] Xhindoli D, Pacor S, Benincasa M, Scocchi M, Gennaro R, Tossi A. The human cathelicidin LL-37 a pore-forming antibacterial peptide and host-cell modulator. BBA-Biomembranes. 2016; 1858: 546-66.

[61] Vandamme D, Landuyt B, Luyten W, Schoofs L. A comprehensive summary of LL-37, the factotum human cathelicidin peptide. Cell Immunol. 2012; 280: 22-35.

[62] Chereddy KK, Her CH, Comune M, Moia C, Lopes A, Porporato PE, et al. PLGA nanoparticles loaded with host defense peptide LL37 promote wound healing. J Control Release. 2014; 194: 138-47.

[63] Li XL, Fan RR, Tong AP, Yang MJ, Deng JJ, Zhou LX, et al. In situ gel-forming AP-57 peptide delivery system for cutaneous wound healing. Int J Pharm. 2015; 495: 560-71.

[64] Thomas CE, Ehrhardt A, Kay MA. Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet. 2003; 4: 346-58.

[65] Park HJ, Yang F, Cho SW. Nonviral delivery of genetic medicine for therapeutic angiogenesis. Adv Drug Deliv Rev. 2012; 64: 40-52.

[66] Lu CH, Chang YH, Lin SY, Li KC, Hu YC. Recent progresses in gene delivery-based bone tissue engineering. Biotechnol Adv. 2013; 31: 1695-706.

[67] Okholm AH, Kjems J. DNA nanovehicles and the biological barriers. Adv Drug Deliv Rev. 2016; 106: 183-91.

[68] Jones MR, Seeman NC, Mirkin CA. Nanomaterials. Programmable materials and the nature of the DNA bond. Science 2015; 347: 1260901.

[69] Angell C, Xie S, Zhang L, Chen Y. DNA nanotechnology for precise control over drug delivery and gene therapy. Small. 2016; 12: 1117-32.

[70] Lee DS, Qian H, Tay CY, Leong DT. Cellular processing and destinies of artificial DNA nanostructures. Chem Soc Rev. 2016; 45: 4199-225.

[71] Kwon M, Firestein BL. DNA transfection: calcium phosphate method. Methods Mol Biol. 2013; 1018: 107-10.

[72] Wu X, Gong Y, Ding X, Cheng G, Yan W, She X, et al. Retrovirus-mediated transfection of the tissue-type plasminogen activator gene results in increased thrombolysis of blood clots. Biochem Genet. 2019; 57: 234-47.

[73] Deodato B, Arsic N, Zentilin L, Galeano M, Santoro D, Torre V, et al. Recombinant AAV vector encoding human VEGF165 enhances wound healing. Gene Ther. 2002; 9: 777-85.

[74] Galeano M, Deodato B, Altavilla D, Cucinotta D, Arsic N, Marini H, et al. Adeno-associated viral vector-mediated human vascular endothelial growth factor gene transfer stimulates angiogenesis and wound healing in the genetically diabetic mouse. Diabetologia. 2003; 46: 546-55.

[75] Brem H, Kodra A, Golinko MS, Entero H, Stojadinovic O, Wang VM, et al. Mechanism of sustained release of vascular endothelial growth factor in accelerating experimental diabetic healing. J Invest Dermatol. 2009; 129: 2275-87.

[76] Saaristo A, Tammela T, Farkkila A, Karkkainen M, Suominen E, Yla-Herttuala S, et al. Vascular endothelial growth factor-C accelerates diabetic wound healing. Am J Pathol. 2006; 169: 1080-7.

[77] Jazwa A, Kucharzewska P, Leja J, Zagorska A, Sierpniowska A, Stepniewski J, et al. Combined vascular endothelial growth factor-a and fibroblast growth factor 4 gene transfer improves wound healing in diabetic mice. Genet Vaccines Ther. 2010; 8: 6.

[78] Liu PY, Liu K, Wang XT, Badiavas E, Rieger-Christ KM, Tang JB, et al. Efficacy of combination gene therapy with multiple growth factor cDNAs to enhance skin flap survival in a rat model. DNA Cell Biol. 2005; 24: 751-7.

[79] Keswani SG, Katz AB, Lim FY, Zoltick P, Radu A, Alaee D, et al. Adenoviral mediated gene transfer of PDGF-B enhances wound healing in type I and type II diabetic wounds. Wound Repair Regen. 2004; 12: 497-504.

[80] Rah DK, Yun IS, Yun CO, Lee SB, Lee WJ. Gene therapy using hepatocyte growth factor expressing adenovirus improves skin flap survival in a rat model. J Korean Med Sci. 2014; 29: S228-36.

[81] Bitto A, Minutoli L, Galeano MR, Altavilla D, Polito F, Fiumara T, et al. Angiopoietin-1 gene transfer improves impaired wound healing in genetically diabetic mice without increasing VEGF expression. Clin Sci (Lond). 2008; 114: 707-18.

[82] Schaffer MR, Tantry U, Gross SS, Wasserburg HL, Barbul A. Nitric oxide regulates wound healing. J Surg Res. 1996; 63: 237-40.

[83] Ziche M, Morbidelli L, Masini E, Amerini S, Granger HJ, Maggi CA, et al. Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. J Clin Invest. 1994; 94: 2036-44.

[84] Yamasaki K, Edington HD, McClosky C, Tzeng E, Lizonova A, Kovesdi I, et al. Reversal of impaired wound repair in iNOS-deficient mice by topical adenoviral-mediated iNOS gene transfer. J Clin Invest. 1998; 101: 967-71.

[85] Breen AM, Dockery P, O’Brien T, Pandit AS. The use of therapeutic gene eNOS delivered via a fibrin scaffold enhances wound healing in a compromised wound model. Biomaterials. 2008; 29: 3143-51.

[86] O’Toole G, MacKenzie D, Lindeman R, Buckley MF, Marucci D, McCarthy N, et al. Vascular endothelial growth factor gene therapy in ischaemic rat skin flaps. Br J Plast Surg. 2002; 55: 55-8.

[87] Jeschke MG, Herndon DN, Baer W, Barrow RE, Jauch KW. Possibilities of non-viral gene transfer to improve cutaneous wound healing. Curr Gene Ther. 2001; 1: 267-78.

[88] Byrnes CK, Malone RW, Akhter N, Nass PH, Wetterwald A, Cecchini MG, et al. Electroporation enhances transfection efficiency in murine cutaneous wounds. Wound Repair Regen. 2004; 12: 397-403.

[89] Branski LK, Gauglitz GG, Herndon DN, Jeschke MG.A review of gene and stem cell therapy in cutaneous wound healing. Burns. 2009; 35: 171-80.

[90] Dileo J, Miller TE, Jr, Chesnoy S, Huang L. Gene transfer to subdermal tissues via a new gene gun design. Hum Gene Ther. 2003; 14: 79-87.

[91] Glasspool-Malone J, Somiari S, Drabick JJ, Malone RW. Efficient nonviral cutaneous transfection. Mol Ther. 2000; 2: 140-6.

[92] Liu L, Marti GP, Wei X, Zhang X, Zhang H, Liu YV, et al. Age-dependent impairment of HIF-1alpha expression in diabetic mice: correction with electroporation-facilitated gene therapy increases wound healing, angiogenesis, and circulating angiogenic cells. J Cell Physiol. 2008; 217: 319-27.

[93] Ferraro B, Cruz YL, Coppola D, Heller R. Intradermal delivery of plasmid VEGF(165) by electroporation promotes wound healing. Mol Ther. 2009; 17: 651-7.

[94] Lee PY, Chesnoy S, Huang L. Electroporatic delivery of TGF-beta1 gene works synergistically with electric therapy to enhance diabetic wound healing in db/db mice. J Invest Dermatol. 2004; 123: 791-8.

[95] Samal SK, Dash M, Van Vlierberghe S, Kaplan DL, Chiellini E, van Blitterswijk C, et al. Cationic polymers and their therapeutic potential. Chem Soc Rev. 2012; 41: 7147-94.

[96] Paliwal R, Palakurthi S. Zein in controlled drug delivery and tissue engineering. J Control Release. 2014; 189: 108-22.

[97] Guo R, Xu S, Ma L, Huang A, Gao C. The healing of full-thickness burns treated by using plasmid DNA encoding VEGF-165 activated collagen-chitosan dermal equivalents. Biomaterials. 2011; 32: 1019-31.

[98] Reckhenrich AK, Hopfner U, Krotz F, Zhang Z, Koch C, Kremer M, et al. Bioactivation of dermal scaffolds with a non-viral copolymer-protected gene vector. Biomaterials. 2011; 32: 1996-2003.

[99] McKnight CD, Winn SR, Gong X, Hansen JE, Wax MK. Revascularization of rat fasciocutaneous flap using CROSSEAL with VEGF protein or plasmid DNA expressing VEGF. Otolaryngol Head Neck Surg. 2008; 139: 245-9.

[100] Tokatlian T, Cam C, Segura T. Porous hyaluronic acid hydrogels for localized nonviral DNA delivery in a diabetic wound healing model. Adv Healthc Mater. 2015; 4: 1084-91.

[101] Thiersch M, Rimann M, Panagiotopoulou V, Ozturk E, Biedermann T, Textor M, et al. The angiogenic response to PLL-g-PEG-mediated HIF-1alpha plasmid DNA delivery in healthy and diabetic rats. Biomaterials. 2013; 34: 4173-82.

[102] Ramsay E, Hadgraft J, Birchall J, Gumbleton M. Examination of the biophysical interaction between plasmid DNA and the polycations, polylysine and polyornithine, as a basis for their differential gene transfection in-vitro. Int J Pharm. 2000; 210: 97-107.

[103] Zaitsev S, Cartier R, Vyborov O, Sukhorukov G, Paulke BR, Haberland A, et al. Polyelectrolyte nanoparticles mediate vascular gene delivery. Pharm Res. 2004; 21: 1656-61.

[104] Lee H, Jeong JH, Park TG. PEG grafted polylysine with fusogenic peptide for gene delivery: high transfection efficiency with low cytotoxicity. J Control Release. 2002; 79: 283-91.

[105] Jeschke MG, Klein D. Liposomal gene transfer of multiple genes is more effective than gene transfer of a single gene. Gene Ther. 2004; 11: 847-55.

[106] He S, Xia T, Wang H, Wei L, Luo X, Li X. Multiple release of polyplexes of plasmids VEGF and bFGF from electrospun fibrous scaffolds towards regeneration of mature blood vessels. Acta Biomater. 2012; 8: 2659-69.

[107] Raftery R, O’Brien FJ, Cryan SA. Chitosan for gene delivery and orthopedic tissue engineering applications. Molecules. 2013; 18: 5611-47.

[108] Raftery RM, Tierney EG, Curtin CM, Cryan SA, O’Brien FJ. Development of a gene-activated scaffold platform for tissue engineering applications using chitosan-pDNA nanoparticles on collagen-based scaffolds. J Control Release. 2015; 210: 84-94.

[109] Hwang BW, Kim SJ, Park KM, Kim H, Yeom J, Yang JA, et al. Genetically engineered mesenchymal stem cell therapy using self-assembling supramolecular hydrogels. J Control Release. 2015; 220: 119-29.

[110] Chen X, Nomani A, Patel N, Nouri FS, Hatefi A. Bioengineering a non-genotoxic vector for genetic modification of mesenchymal stem cells. Biomaterials. 2018; 152: 1-14.

[111] Chen J, Wang Q, Zhou J, Deng W, Yu Q, Cao X, et al. Porphyra polysaccharide-derived carbon dots for non-viral co-delivery of different gene combinations and neuronal differentiation of ectodermal mesenchymal stem cells. Nanoscale. 2017; 9: 10820-31.

[112] Lee YH, Wu HC, Yeh CW, Kuan CH, Liao HT, Hsu HC, et al. Enzyme-crosslinked gene-activated matrix for the induction of mesenchymal stem cells in osteochondral tissue regeneration. Acta Biomater. 2017; 63: 210-26.

[113] Peng B, Chen Y, Leong KW. MicroRNA delivery for regenerative medicine. Adv Drug Deliv Rev. 2015; 88: 108-22.

[114] Kowalczewski CJ, Saul JM. Surface-mediated delivery of siRNA from fibrin hydrogels for knockdown of the BMP-2 binding antagonist noggin. Acta Biomater. 2015; 25: 109-20.

[115] Ma W, Shao X, Zhao D, Li Q, Liu M, Zhou T, et al. Self-assembled tetrahedral DNA nanostructures promote neural stem cell proliferation and neuronal differentiation. ACS Appl Mater Interfaces. 2018; 10: 7892-900.

[116] Zhang Y, Ma W, Zhu Y, Shi S, Li Q, Mao C, et al. Inhibiting methicillin-resistant Staphylococcus aureus by tetrahedral DNA nanostructure-enabled antisense peptide nucleic acid delivery. Nano Lett. 2018; 18: 5652-9.

[117] Ge Y, Tian T, Shao X, Lin S, Zhang T, Lin Y, et al. PEGylated protamine-based adsorbing improves the biological properties and stability of tetrahedral framework nucleic acids. ACS Appl Mater Interfaces. 2019; 11: 27588-97.

[118] Ma W, Zhan Y, Zhang Y, Xie X, Mao C, Lin Y. Enhanced neural regeneration with a concomitant treatment of framework nucleic acid and stem cells in spinal cord injury. ACS Appl Mater Interfaces. 2020; 12: 2095-106.

[119] Fu W, You C, Ma L, Li H, Ju Y, Guo X, et al. Enhanced efficacy of Temozolomide loaded by a tetrahedral framework DNA nanoparticle in the therapy for glioblastoma. ACS Appl Mater Interfaces. 2019; 11: 39525-33.

[120] Zhang M, Zhu J, Qin X, Zhou M, Zhang X, Gao Y, et al. Cardioprotection of tetrahedral DNA nanostructures in myocardial ischemia-reperfusion injury. ACS Appl Mater Interfaces. 2019; 11: 30631-9.

[121] Cui W, Zhan Y, Shao X, Fu W, Xiao D, Zhu J, et al. Neuroprotective and Neurotherapeutic effects of tetrahedral framework nucleic acids on Parkinson’s disease in vitro. ACS Appl Mater Interfaces. 2019; 11: 32787-97.

[122] Liu N, Zhang X, Li N, Zhou M, Zhang T, Li S, et al. Tetrahedral framework nucleic acids promote corneal epithelial wound healing in vitro and in vivo. Small. 2019; 15: 1907-21.

[123] Qin X, Li N, Zhang M, Lin S, Zhu J, Xiao D, et al. Tetrahedral framework nucleic acids prevent retina ischemia-reperfusion injury from oxidative stress via activating the Akt/Nrf2 pathway. Nanoscale. 2019; 11: 20667-75.

[124] Zhu J, Zhang M, Gao Y, Qin X, Zhang T, Cui W, et al. Tetrahedral framework nucleic acids promote scarless healing of cutaneous wounds via the AKT-signaling pathway. Signal Transduct Target Ther. 2020; 5: 120.

[125] Zhao D, Liu M, Li J, Xiao D, Peng S, He Q, et al. Angiogenic Aptamer-modified tetrahedral framework nucleic acid promotes angiogenesis in vitro and in vivo. ACS Appl Mater Interfaces. 2021; 13: 29439-49.

[126] Nunan R, Harding KG, Martin P. Clinical challenges of chronic wounds: searching for an optimal animal model to recapitulate their complexity. Dis Model Mech. 2014; 7: 1205-13.

[127] Veith AP, Henderson K, Spencer A, Sligar AD, Baker AB. Therapeutic strategies for enhancing angiogenesis in wound healing. Adv Drug Deliv Rev. 2019; 146: 97-125.

[128] Muller M, Trocme C, Lardy B, Morel F, Halimi S, Benhamou PY. Matrix metalloproteinases and diabetic foot ulcers: the ratio of MMP-1 to TIMP-1 is a predictor of wound healing. Diabet Med. 2008; 25: 419-26.

[129] Boniakowski AE, Kimball AS, Jacobs BN, Kunkel SL, Gallagher KA. Macrophage-mediated inflammation in normal and diabetic wound healing. J Immunol. 2017; 199: 17-24.

[130] Dunnill C, Patton T, Brennan J, Barrett J, Dryden M, Cooke J, et al. Reactive oxygen species (ROS) and wound healing: the functional role of ROS and emerging ROS-modulating technologies for augmentation of the healing process. Int Wound J. 2017; 14: 89-96.

[131] Li N, Luo HC, Yang C, Deng JJ, Ren M, Xie XY, et al. Cationic star-shaped polymer as an siRNA carrier for reducing MMP-9 expression in skin fibroblast cells and promoting wound healing in diabetic rats. Int J Nanomedicine. 2014; 9: 3377-87.