A Review on Different Approaches for Improving Cell Infiltration in Electrospun Nanofibrous Scaffolds

Authors
1 Department of Biomaterials and Tissue Engineering, Faculty of Biomedical Engineering, Amirkabir University of Technology, Tehran, Iran
2 Department of Biomaterials and Tissue Engineering, Faculty of Biomedical Engineering, Amirkabir University Technology, Tehran, Iran
3 Amirkabir Nanotechnology Research Institute, Amirkabir University Technology, Tehran, Iran
4 Faculty of Polymer Engineering, Amirkabir University Technology, Tehran, Iran
Abstract
In recent years, electrospinning that has the capability to form polymeric nano-/microfibers has gained substantial attention for fabrication of tissue engineering scaffolds. The morphological resemblance to native extracellular matrix (ECM), high surface to volume ratio, high porosity, and pore interconnectivity are amongst the brilliant features of electrospun structures. The high surface area to volume ratio and interconnected pores of these fibrous meshes confer desirable cell attachment and growth. However, due to small pore sizes and high packing density of electrospun nanofibers, cell penetration into a conventional electrospun mat is completely restrained. Scarce cell infiltration in turn prohibit cell migration into internal parts of the scaffold, cause inhomogeneous cell distribution throughout the structure, limit vascularization, and impede tissue ingrowth. In fact, traditional electrospun nanofibrous scaffolds in practice act as two-dimensional (2D) surfaces rather than three-dimensional (3D) microenvironments. Thus far, a number of approaches have been employed to solve this problem, which range from simple variations in electrospinning parameters to intricate post-processing modifications. Some efforts directly manipulate the electrospun mat characteristics to enhance cell penetration, while others combine cells with scaffolds or encourage cells to migrate into internal parts with different stimuli. In the present study, we have attempted to provide an overview of different approaches offered for improving cell infiltration in electrospun scaffolds.

Keywords


[1]  Sill TJ, von Recum HA. Electrospinning: applications in drug delivery and tissue engineering. Biomaterials 2008; 29(13): 1989-2006.
[2]  Gunn J, Zhang M. Polyblend nanofibers for biomedical applications: perspectives and challenges. Trends Biotechnol 2010; 28(4): 189-97.
[3]  Pezeshki-Modaress M, Zandi M, Mirzadeh H. Fabrication of gelatin/chitosan nanofibrous scaffold: process optimization and empirical modeling. Polym Int 2015; 64: 571-80.
[4]  Beachley V, Wen X. Polymer nanofibrous structures: Fabrication, biofunctionalization, and cell interactions. Prog Polym Sci 2010; 35(7): 868-892.
[5]  Shabani I, Haddadi-Asl V, Seyedjafari E, Soleimani M. Cellular infiltration on nanofibrous scaffolds using a modified electrospinning technique. Biochem Biophys Res Commun 2012; 423(1): 50-4.
[6]  Phipps MC, Clem WC, Grunda JM, Clines GA, Bellis SL. Increasing the pore sizes of bone-mimetic electrospun scaffolds comprised of polycaprolactone, collagen I and hydroxyapatite to enhance cell infiltration. Biomaterials 2012; 33(2): 524-34.
[7]  Greiner A, Wendorff JH. Electrospinning: a fascinating method for the preparation of ultrathin fibers. Angew Chem Int Ed Engl 2007; 46(30): 5670-703.
[8]  Khorshidi S, Solouk A, Mirzadeh H, Mazinani S, Lagaron JM, Sharifi S, Ramakrishna S. A review of key challenges of electrospun scaffolds for tissue-engineering applications. J Tissue Eng Regen Med 2015. [Epub ahead of print]
[9]  Koosha M, Mirzadeh H, Shokrgozar MA, Farokhi M. Nanoclay-reinforced electrospun chitosan/PVA nanocomposite nanofibers for biomedical applications. RSC Adv 2015; 5: 10479-87.
[10]             Agarwal S, Wendorff JH, Greiner A. Use of electrospinning technique for biomedical applications. Polymer 2008; 49(26): 5603-21.
[11]             Sun B, Long YZ, Zhang HD, Lia MM, Duvail JL, Jiang XY, Yin HL. Advances in three-dimensional nanofibrous macro-structures via electrospinning. Progress in Polymer Science 2014; 39(5): 862-90.
[12]             Garg K, Bowlin GL. Electrospinning jets and nanofibrous structures. Biomicrofluidics 2011; 5(1): 13403.
[13]   Agarwal S, Greiner A, Wendorff JH. Functional materials by electrospinning of polymers. Progress in Polymer Science 2013; 38(6): 963-91.
[14]             Koosha M, Mirzadeh H. Electrospinning, mechanical properties, and cell behavior study of chitosan/PVA nanofibers. J Biomed Mater Res A 2015; 103(9): 3081-93.
[15]             Pezeshki-Modaress M, Mirzadeh H2, Zandi M. Gelatin-GAG electrospun nanofibrous scaffold for skin tissue engineering: fabrication and modeling of process parameters. Mater Sci Eng C Mater Biol Appl 2015; 48: 704-12.
[16]             Pezeshki-Modaress M, Rajabi-Zeleti S, Zandi M, Mirzadeh H, Sodeifi N, Nekookar A, Aghdami N. Cell-loaded gelatin/chitosan scaffolds fabricated by salt-leaching/ lyophilization for skin tissue engineering: in vitro and in vivo study. J Biomed Mater Res A 2014; 102(11): 3908-17.
[17]             Guo B, Sun Y, Finne-Wistrand A, Mustafa K, Albertsson AC. Electroactive porous tubular scaffolds with degradability and non-cytotoxicity for neural tissue regeneration. Acta Biomater 2012; 8(1): 144-53.
[18]             Billiet T, Vandenhaute M, Schelfhout J, Van Vlierberghe S, Dubruel P. A review of trends and limitations in hydrogel-rapid prototyping for tissue engineering. Biomaterials 2012; 33(26): 6020-41.
[19]             Pezeshki Modaress M, Mirzadeh H Zandi M. Fabrication of a porous wall and higher interconnectivity scaffold comprising gelatin/chitosan via combination of salt-leaching and lyophilization methods. Iranian Polymer Journal 2012; 21(3): 191-200.
[20]             Agarwal S, Wendorff JH, Greiner A. Progress in the field of electrospinning for tissue engineering applications. Adv Mater 2009; 21(32-33): 3343-51.
[21]             Szentivanyi A, Chakradeo T, Zernetsch H, Glasmacher B. Electrospun cellular micro-environments: Understanding controlled release and scaffold structure. Adv Drug Deliv Rev 2011; 63(4-5): 209-20.
[22]             Pezeshki-Modaress M, Rajabi-Zeleti S, Zandi M, Mirzadeh H, Sodeifi N, Nekookar A, Aghdami N. Cell-loaded gelatin/chitosan scaffolds fabricated by salt-leaching/ lyophilization for skin tissue engineering: in vitro and in vivo study. J Biomed Mater Res A 2014; 102(11): 3908-17.
[23]             Reilly GC, Engler AJ. Intrinsic extra-cellular matrix properties regulate stem cell differentiation. J Biomech 2010; 43(1): 55-62.
[24]             Madden LR, Mortisen DJ, Sussman EM, Dupras SK, Fugate JA, Cuy JL, Hauch KD, Laflamme MA, Murry CE, Ratner BD. Proangiogenic scaffolds as functional templates for cardiac tissue engineering. Proc Natl Acad Sci U S A 2010; 107(34): 15211-6.
[25]             Marshall AJ, Irvin CA, Barker T, Sage EH, Hauch KD, Ratner BD, American Chemical Society. Biomaterials with tightly controlled pore size that promote vascular in-growth. Polymer Preprints -America 2004; 45: 100-1.
[26]             Lee BL, Jeon H, Wang A, Yan Z, Yu J, Grigoropoulos C, Li S. Femtosecond laser ablation enhances cell infiltration into three-dimensional electrospun scaffolds. Acta Biomater 2012; 8(7): 2648-58.
[27]   Zhong S, Zhang Y, Lim CT. Fabrication of large pores in electrospun nanofibrous scaffolds for cellular infiltration: a review. Tissue Eng Part B Rev 2012; 18(2): 77-87.
[28]             Wright LD, Andric T, Freeman JW. Utilizing NaCl to increase the porosity of electrospun materials. Materials Science and Engineering: C 2011; 31(1): 30-6.
[29]             Rnjak-Kovacina J, Weiss AS. Increasing the pore size of electrospun scaffolds. Tissue Eng Part B Rev 2011; 17(5): 365-72.
[30]             Blakeney BA, Tambralli A, Anderson JM, Andukuri A, Lim DJ, Dean DR, Jun HW. Cell infiltration and growth in a low density, uncompressed three-dimensional electrospun nanofibrous scaffold. Biomaterials 2011; 32(6): 1583-90.
[31]             Zhang Y, Ouyang H, Lim CT, Ramakrishna S, Huang ZM. Electrospinning of gelatin fibers and gelatin/PCL composite fibrous scaffolds. J Biomed Mater Res B Appl Biomater 2005; 72(1): 156-65.
[32]             Eichhorn SJ, Sampson WW. Statistical geometry of pores and statistics of porous nanofibrous assemblies. J R Soc Interface 2005; 2(4): 309-18.
[33]             Balguid A, Mol A, van Marion MH, Bank RA, Bouten CV, Baaijens FP. Tailoring fiber diameter in electrospun poly(epsilon-caprolactone) scaffolds for optimal cellular infiltration in cardiovascular tissue engineering. Tissue Eng Part A 2009; 15(2): 437-44.
[34]             Sisson K, Zhang C, Farach-Carson MC, Chase DB, Rabolt JF. Fiber diameters control osteoblastic cell migration and differentiation in electrospun gelatin. J Biomed Mater Res A 2010; 94(4): 1312-20.
[35]             Rnjak-Kovacina J, Wise SG, Li Z, Maitz PK, Young CJ, Wang Y, Weiss AS. Tailoring the porosity and pore size of electrospun synthetic human elastin scaffolds for dermal tissue engineering. Biomaterials 2011; 32(28): 6729-36.
[36]             Pham QP, Sharma U, Mikos AG. Electrospun poly(epsilon-caprolactone) microfiber and multilayer nanofiber/ microfiber scaffolds: characterization of scaffolds and measurement of cellular infiltration. Biomacromolecules 2006; 7(10): 2796-805.
[37]   Zander NE, Orlicki JA, Rawlett AM, Beebe TP Jr. Electrospun polycaprolactone scaffolds with tailored porosity using two approaches for enhanced cellular infiltration. J Mater Sci Mater Med 2013; 24(1): 179-87.
[38]             Vaquette C, Cooper-White JJ. Increasing electrospun scaffold pore size with tailored collectors for improved cell penetration. Acta Biomater 2011; 7(6): 2544-57.
[39]             Yokoyama Y, Hattori S, Yoshikawa C, Yasuda Y, Koyama H, Takato T, Kobayashi H. Novel wet electrospinning system for fabrication of spongiform nanofiber 3-dimensional fabric. Materials Letters 2009; 63(9-10): 754-6.
[40]             Yang W, Yang F, Wang Y, Both SK, Jansen JA. In vivo bone generation via the endochondral pathway on three-dimensional electrospun fibers. Acta Biomater 2013; 9(1): 4505-12.
[41]             Kim TG, Chung HJ, Park TG. Macroporous and nanofibrous hyaluronic acid/collagen hybrid scaffold fabricated by concurrent electrospinning and deposition/ leaching of salt particles. Acta Biomater 2008; 4(6): 1611-9.
[42]             Baker BM, Gee AO, Metter RB, Nathan AS, Marklein RA, Burdick JA, Mauck RL. The potential to improve cell infiltration in composite fiber-aligned electrospun scaffolds by the selective removal of sacrificial fibers. Biomaterials 2008; 29(15): 2348-58.
[43]             Whited BM, Whitney JR, Hofmann MC, Xu Y, Rylander MN. Pre-osteoblast infiltration and differentiation in highly porous apatite-coated PLLA electrospun scaffolds. Biomaterials 2011; 32(9): 2294-304.
[44]             Simonet M, Schneider OD, Neuenschwander P, Stark WJ. Ultraporous 3D polymer meshes by low‐temperature electrospinning: use of ice crystals as a removable void template. Polymer Engineering & Science 2007; 47(12): 2020-6.
[45]             Leong MF, Rasheed MZ, Lim TC, Chian KS. In vitro cell infiltration and in vivo cell infiltration and vascularization in a fibrous, highly porous poly(D,L-lactide) scaffold fabricated by cryogenic electrospinning technique. J Biomed Mater Res A 2009; 91(1): 231-40.
[46]             Lee JB, Jeong SI, Bae MS, Yang DH, Heo DN, Kim CH, Alsberg E, Kwon IK. Highly porous electrospun nanofibers enhanced by ultrasonication for improved cellular infiltration. Tissue Eng Part A 2011; 17(21-22): 2695-702.
[47]             Stankus JJ, Guan J, Fujimoto K, Wagner WR. Microintegrating smooth muscle cells into a biodegradable, elastomeric fiber matrix. Biomaterials 2006; 27(5): 735-44.
[48]             Stankus JJ, Soletti L, Fujimoto K, Hong Y, Vorp DA, Wagner WR. Fabrication of cell microintegrated blood vessel constructs through electrohydrodynamic atomization. Biomaterials 2007; 28(17): 2738-46.
[49]             Yang X, Shah JD, Wang H. Nanofiber enabled layer-by-layer approach toward three-dimensional tissue formation. Tissue Eng Part A 2009; 15(4): 945-56.
[50]             Canbolat MF, Tang C, Bernacki SH, Pourdeyhimi B, Khan S. Mammalian cell viability in electrospun composite nanofiber structures. Macromol Biosci 2011; 11(10): 1346-56.
[51]             Seil JT, Webster TJ. Spray deposition of live cells throughout the electrospinning process produces nanofibrous three-dimensional tissue scaffolds. Int J Nanomedicine 2011; 6: 1095-9.
[52]             Lee J, Yoo JJ, Atala A, Lee SJ. The effect of controlled release of PDGF-BB from heparin-conjugated electrospun PCL/gelatin scaffolds on cellular bioactivity and infiltration. Biomaterials 2012; 33(28): 6709-20.
[53]             Sell SA, Wolfe PS, Ericksen JJ, Simpson DG, Bowlin GL. Incorporating platelet-rich plasma into electrospun scaffolds for tissue engineering applications. Tissue Eng Part A 2011; 17(21-22): 2723-37.
[54]             Nerurkar NL, Sen S, Baker BM, Elliott DM, Mauck RL. Dynamic culture enhances stem cell infiltration and modulates extracellular matrix production on aligned electrospun nanofibrous scaffolds. Acta Biomater 2011; 7(2): 485-91.
[55]             Park SH, Kim TG, Kim HC, Yang DY, Park TG. Development of dual scale scaffolds via direct polymer melt deposition and electrospinning for applications in tissue regeneration. Acta Biomater 2008; 4(5): 1198-207.
[56]             Moroni L, Schotel R, Hamann D, de Wijn JR, van Blitterswijk CA. 3D Fiber‐Deposited Electrospun Integrated Scaffolds Enhance Cartilage Tissue Formation. Advanced Functional Materials 2008; 18(1): 53-60.
[57]             Ekaputra AK, Prestwich GD, Cool SM, Hutmacher DW. Combining electrospun scaffolds with electrosprayed hydrogels leads to three-dimensional cellularization of hybrid constructs. Biomacromolecules 2008; 9(8): 2097-103.
[58]             Hsieh A, Zahir T, Lapitsky Y, Amsden B, Wan W, Shoichet MS. Hydrogel/ electrospun fiber composites influence neural stem/progenitor cell fate. Soft Matter 2010; 6(10): 2227-37.
[59]             McMahon RE, Qu X, Jimenez-Vergara AC, Bashur CA, Guelcher SA, Goldstein AS, Hahn MS. Hydrogel-electrospun mesh composites for coronary artery bypass grafts. Tissue Eng Part C Methods 2011; 17(4): 451-61.
[60]             Yang Y, Wimpenny I, Ahearne M. Portable nanofiber meshes dictate cell orientation throughout three-dimensional hydrogels. Nanomedicine 2011; 7(2): 131-6.
[61]             Ju YM, Choi JS, Atala A, Yoo JJ, Lee SJ. Bilayered scaffold for engineering cellularized blood vessels. Biomaterials 2010; 31(15): 4313-21.
[62]             Joshi VS, Lei NY, Walthers CM, Wu B, Dunn JC. Macroporosity enhances vascularization of electrospun scaffolds. J Surg Res 2013; 183(1): 18-26.
[63]             Kurpinski KT, Stephenson JT, Janairo RR, Lee H, Li S. The effect of fiber alignment and heparin coating on cell infiltration into nanofibrous PLLA scaffolds. Biomaterials 2010; 31(13): 3536-42.
[64]             Li L, Qian Y, Jiang C, Lv Y, Liu W, Zhong L, Cai K, Li S, Yang L. The use of hyaluronan to regulate protein adsorption and cell infiltration in nanofibrous scaffolds. Biomaterials 2012; 33(12): 3428-45.