Innovations in Drug Delivery for Chronic Wound Healing

Erfan    Rezvani    Ghomi; Mohamadreza       Shakiba; Ali    Saedi    Ardahaei; Mahsa   Akbari   Kenari; Mehdi       Faraji; Shahla       Ataei; Parisa       Kohansal; Iman       Jafari; Majid       Abdouss; Seeram      Ramakrishna
Abstract

Wound healing is a varied and complex process designed to restore normal skin structure, function, and appearance in a timely manner. To achieve this goal, different immune and biological systems participate in coordination through four separate steps, including homeostasis, inflammation, proliferation, and regeneration. Each step involves the function of different cells, cytokines, and growth factors. However, chronic ulcers, which are classified into three types of ulcers, namely vascular ulcers, diabetic ulcers, and pressure ulcers, are not able to heal through the mentioned natural stages. This, in turn, causes mental and physical problems for these people and, as a result, imposes high economic and social costs on the society. In this regard, using a system that can accelerate the healing process of such chronic wounds, as an urgent need in society, should be considered. Therefore, in this study, the innovations of drug delivery systems for the healing of chronic wounds using hydrogels, nanomaterials, and membranes are discussed and reviewed.
Keywords: Chronic wounds, drug delivery, wound healing, hydrogel, membrane, nanomaterials.
[1] 
Rezvani Ghomi E, Khalili S, Nouri Khorasani S, Esmaeely Neisiany R, Ramakrishna S. Wound dressings: Current advances and future directions. J Appl Polym Sci  2019; 136: 47738.
[http://dx.doi.org/10.1002/app.47738] 
[2] 
Md Abu T, Zahan KA, Rajaie MA, et al. Nanocellulose as drug delivery system for honey as antimicrobial wound dressing. Materials Today: Proceedings  2020; 31: 14-7.
[3] 
Ghaderi R, Afshar M, Akhbarie H, Golalipour MJ, Ghaderi R, Afshar M. Comparison of the efficacy of honey and animal oil in accelerating healing of full thickness wound of mice skin. Int J Morphol  2010; 28: 193-8.
[http://dx.doi.org/10.4067/S0717-95022010000100027] 
[4] 
Ghaderi R, Afshar M. Topical application of honey for treatment of skin wound in mice. IJMS  2004; 24(4): 185-8.
[5] 
Ma L, Cui J, Yao S, et al. Dendrite-free lithium metal and sodium metal batteries. Energy Storage Mater  2020; 27: 522-54.
[http://dx.doi.org/10.1016/j.ensm.2019.12.014] 
[6] 
Akhmetova A, Lanno G-M, Kogermann K, Malmsten M, Rades T, Heinz A. Highly elastic and water stable zein microfibers as a potential drug delivery system for wound healing. Pharmaceutics  2020; 12(5): 12.
[http://dx.doi.org/10.3390/pharmaceutics12050458] [PMID: 32443445] 
[7] 
Saghazadeh S, Rinoldi C, Schot M, et al. Drug delivery systems and materials for wound healing applications. Adv Drug Deliv Rev  2018; 127: 138-66.
[http://dx.doi.org/10.1016/j.addr.2018.04.008] [PMID: 29626550] 
[8] 
Malone M, Bjarnsholt T, McBain AJ, et al. The prevalence of biofilms in chronic wounds: A systematic review and meta-analysis of published data. J Wound Care  2017; 26(1): 20-5.
[http://dx.doi.org/10.12968/jowc.2017.26.1.20] [PMID: 28103163] 
[9] 
Frykberg RG, Banks J. Challenges in the treatment of chronic wounds. Adv Wound Care (New Rochelle)  2015; 4(9): 560-82.
[http://dx.doi.org/10.1089/wound.2015.0635] [PMID: 26339534] 
[10] 
Sood A, Granick MS, Tomaselli NL. Wound dressings and comparative effectiveness data. Adv Wound Care (New Rochelle)  2014; 3(8): 511-29.
[http://dx.doi.org/10.1089/wound.2012.0401] [PMID: 25126472] 
[11] 
Nussbaum SR, Carter MJ, Fife CE, et al. An economic evaluation of the impact, cost, and medicare policy implications of chronic nonhealing wounds. Value Health  2018; 21(1): 27-32.
[http://dx.doi.org/10.1016/j.jval.2017.07.007] [PMID: 29304937] 
[12] 
Chhabra P, Chauhan G, Kumar A. Augmented healing of full thickness chronic excision wound by rosmarinic acid loaded chitosan encapsulated graphene nanopockets. Drug Dev Ind Pharm  2020; 46(6): 878-88.
[http://dx.doi.org/10.1080/03639045.2020.1762200] [PMID: 32338544] 
[13] 
Tronci G. 13 - the application of collagen in advanced wound dressings.Advanced textiles for wound care.  2nd. Woodhead Publishing 2019; pp. 363-89.
[14] 
Kumari M, Dhasmana A. Hydrogel as a prospective substance for wound healing and sealing. Adv Tissue Eng Regen Med Open Access  2020; 6: 20-4.
[15] 
Sen CK. Human wounds and its burden: An updated compendium of estimates. Adv Wound Care (New Rochelle)  2019; 8(2): 39-48.
[http://dx.doi.org/10.1089/wound.2019.0946] [PMID: 30809421] 
[16] 
Chaby G, Senet P, Vaneau M, et al. Dressings for acute and chronic wounds: A systematic review. Arch Dermatol  2007; 143(10): 1297-304.
[http://dx.doi.org/10.1001/archderm.143.10.1297] [PMID: 17938344] 
[17] 
Gorecka J, Kostiuk V, Fereydooni A, et al. The potential and limitations of induced pluripotent stem cells to achieve wound healing. Stem Cell Res Ther  2019; 10(1): 87.
[http://dx.doi.org/10.1186/s13287-019-1185-1] [PMID: 30867069] 
[18] 
Duceac IA, Verestiuc L, Dimitriu CD, Maier V, Coseri S. Design and preparation of new multifunctional hydrogels based on chitosan/acrylic polymers for drug delivery and wound dressing applications. Polymers (Basel)  2020; 12(7): 1473.
[http://dx.doi.org/10.3390/polym12071473] [PMID: 32630040] 
[19] 
Rezvani Ghomi E, Khosravi F, Neisiany RE, Singh S, Ramakrishna S. Future of additive manufacturing in healthcare. Curr Opin Biomed Eng  2021; 17: 100255.
[http://dx.doi.org/10.1016/j.cobme.2020.100255] 
[20] 
Lazarus GS, Cooper DM, Knighton DR, et al. Definitions and guidelines for assessment of wounds and evaluation of healing. Wound Repair Regen  1994; 2(3): 165-70.
[http://dx.doi.org/10.1046/j.1524-475X.1994.20305.x] [PMID: 17156107] 
[21] 
Werdin F, Tenenhaus M, Rennekampff HO. Chronic wound care. Lancet  2008; 372(9653): 1860-2.
[http://dx.doi.org/10.1016/S0140-6736(08)61793-6] [PMID: 19041788] 
[22] 
Rani S, Ritter T. The exosome - a naturally secreted nanoparticle and its application to wound healing. Adv Mater  2016; 28(27): 5542-52.
[http://dx.doi.org/10.1002/adma.201504009] [PMID: 26678528] 
[23] 
Fearns N, Heller-Murphy S, Kelly J, Harbour J. Placing the patient at the centre of chronic wound care: A qualitative evidence synthesis. J Tissue Viability  2017; 26(4): 254-9.
[http://dx.doi.org/10.1016/j.jtv.2017.09.002] [PMID: 28893459] 
[24] 
Dickinson LE, Gerecht S. Engineered biopolymeric scaffolds for chronic wound healing. Front Physiol  2016; 7: 341.
[http://dx.doi.org/10.3389/fphys.2016.00341] [PMID: 27547189] 
[25] 
O’Meara S, Al-Kurdi D, Ologun Y, Ovington LG, Martyn-St James M, Richardson R. Antibiotics and antiseptics for venous leg ulcers. Cochrane Database Syst Rev  2014; (1): CD003557.
[http://dx.doi.org/10.1002/14651858.CD003557.pub5] [PMID: 24408354] 
[26] 
Beebe-Dimmer JL, Pfeifer JR, Engle JS, Schottenfeld D. The epidemiology of chronic venous insufficiency and varicose veins. Ann Epidemiol  2005; 15(3): 175-84.
[http://dx.doi.org/10.1016/j.annepidem.2004.05.015] [PMID: 15723761] 
[27] 
Abbade LPF, Lastória S. Venous ulcer: Epidemiology, physiopathology, diagnosis and treatment. Int J Dermatol  2005; 44(6): 449-56.
[http://dx.doi.org/10.1111/j.1365-4632.2004.02456.x] [PMID: 15941430] 
[28] 
Bergqvist D, Lindholm C, Nelzén O. Chronic leg ulcers: The impact of venous disease. J Vasc Surg  1999; 29(4): 752-5.
[http://dx.doi.org/10.1016/S0741-5214(99)70330-7] [PMID: 10194512] 
[29] 
Demidova-Rice TN, Hamblin MR, Herman IM. Acute and impaired wound healing: Pathophysiology and current methods for drug delivery, part 1: Normal and chronic wounds: Biology, causes, and approaches to care. Adv Skin Wound Care  2012; 25(7): 304-14.
[http://dx.doi.org/10.1097/01.ASW.0000416006.55218.d0] [PMID: 22713781] 
[30] 
Brem H, Stojadinovic O, Diegelmann RF, et al. Molecular markers in patients with chronic wounds to guide surgical debridement. Mol Med  2007; 13(1-2): 30-9.
[http://dx.doi.org/10.2119/2006-00054.Brem] [PMID: 17515955] 
[31] 
Bao P, Kodra A, Tomic-Canic M, Golinko MS, Ehrlich HP, Brem H. The role of vascular endothelial growth factor in wound healing. J Surg Res  2009; 153(2): 347-58.
[http://dx.doi.org/10.1016/j.jss.2008.04.023] [PMID: 19027922] 
[32] 
Liapis CD, Avgerinos ED, Kadoglou NP, Kakisis JD. What a vascular surgeon should know and do about atherosclerotic risk factors. J Vasc Surg  2009; 49(5): 1348-54.
[http://dx.doi.org/10.1016/j.jvs.2008.12.046] [PMID: 19394559] 
[33] 
Reiber GE, Vileikyte L, Boyko EJ, et al. Causal pathways for incident lower-extremity ulcers in patients with diabetes from two settings. Diabetes Care  1999; 22(1): 157-62.
[http://dx.doi.org/10.2337/diacare.22.1.157] [PMID: 10333919] 
[34] 
Nickinson ATO, Bridgwood B, Houghton JSM, et al. A systematic review investigating the identification, causes, and outcomes of delays in the management of chronic limb-threatening ischemia and diabetic foot ulceration. J Vasc Surg  2020; 71(2): 669-681.e2.
[http://dx.doi.org/10.1016/j.jvs.2019.08.229] [PMID: 31676182] 
[35] 
Thorud JC, Plemmons B, Buckley CJ, Shibuya N, Jupiter DC. Mortality after nontraumatic major amputation among patients with diabetes and peripheral vascular disease: A systematic review. J Foot Ankle Surg  2016; 55(3): 591-9.
[http://dx.doi.org/10.1053/j.jfas.2016.01.012] [PMID: 26898398] 
[36] 
Lindgren M, Unosson M, Fredrikson M, Ek A-C. Immobility--a major risk factor for development of pressure ulcers among adult hospitalized patients: A prospective study. Scand J Caring Sci  2004; 18(1): 57-64.
[http://dx.doi.org/10.1046/j.0283-9318.2003.00250.x] [PMID: 15005664] 
[37] 
Jaul E. Assessment and management of pressure ulcers in the elderly: Current strategies. Drugs Aging  2010; 27(4): 311-25.
[http://dx.doi.org/10.2165/11318340-000000000-00000] [PMID: 20359262] 
[38] 
Diegelmann RF. Excessive neutrophils characterize chronic pressure ulcers. Wound Repair Regen  2003; 11(6): 490-5.
[http://dx.doi.org/10.1046/j.1524-475X.2003.11617.x] [PMID: 14617291] 
[39] 
Sabapathy SR, Periasamy M. Healing ulcers and preventing their recurrences in the diabetic foot. Indian J Plast Surg  2016; 49(3): 302-13.
[http://dx.doi.org/10.4103/0970-0358.197238] [PMID: 28216809] 
[40] 
Grey JE, Enoch S, Harding KG. ABC of wound healing: Venous and arterial leg ulcers. BMJ  2006; 332: 0604140.
[http://dx.doi.org/10.1136/sbmj.0604140] 
[41] 
Gupta S, Ichioka S. Optimal use of negative pressure wound therapy in treating pressure ulcers. Int Wound J  2012; 9(Suppl. 1): 8-16.
[http://dx.doi.org/10.1111/j.1742-481X.2012.01012.x] [PMID: 22727135] 
[42] 
Xie T, Ye J, Rerkasem K, Mani R. The venous ulcer continues to be a clinical challenge: An update. Burns Trauma  2018; 6: 18.
[http://dx.doi.org/10.1186/s41038-018-0119-y] [PMID: 29942813] 
[43] 
Singh S, Young A, McNaught C-E. The physiology of wound healing. Surgery  2017; 35: 473-7.
[http://dx.doi.org/10.1016/j.mpsur.2017.06.004] 
[44] 
Garcia-Orue I, Pedraz JL, Hernandez RM, Igartua M. Nanotechnology-based delivery systems to release growth factors and other endogenous molecules for chronic wound healing. J Drug Deliv Sci Technol  2017; 42: 2-17.
[http://dx.doi.org/10.1016/j.jddst.2017.03.002] 
[45] 
Velnar T, Bailey T, Smrkolj V. The wound healing process: An overview of the cellular and molecular mechanisms. J Int Med Res  2009; 37(5): 1528-42.
[http://dx.doi.org/10.1177/147323000903700531] [PMID: 19930861] 
[46] 
Cañedo-Dorantes L, Cañedo-Ayala M. Skin acute wound healing: A comprehensive review. Int J Inflamm  2019; 2019: 3706315.
[http://dx.doi.org/10.1155/2019/3706315] [PMID: 31275545] 
[47] 
Li J, Chen J, Kirsner R. Pathophysiology of acute wound healing. Clin Dermatol  2007; 25(1): 9-18.
[http://dx.doi.org/10.1016/j.clindermatol.2006.09.007] [PMID: 17276196] 
[48] 
Teller P, White TK. The physiology of wound healing: Injury through maturation. Perioper Nurs Clin  2011; 6: 159-70.
[http://dx.doi.org/10.1016/j.cpen.2011.04.001] 
[49] 
Han G, Ceilley R. Chronic wound healing: A review of current management and treatments. Adv Ther  2017; 34(3): 599-610.
[http://dx.doi.org/10.1007/s12325-017-0478-y] [PMID: 28108895] 
[50] 
Menke NB, Ward KR, Witten TM, Bonchev DG, Diegelmann RF. Impaired wound healing. Clin Dermatol  2007; 25(1): 19-25.
[http://dx.doi.org/10.1016/j.clindermatol.2006.12.005] [PMID: 17276197] 
[51] 
Barrientos S, Brem H, Stojadinovic O, Tomic-Canic M. Clinical application of growth factors and cytokines in wound healing. Wound Repair Regen  2014; 22(5): 569-78.
[http://dx.doi.org/10.1111/wrr.12205] [PMID: 24942811] 
[52] 
Olczyk P, Mencner Ł, Komosinska-Vassev K. Diverse roles of heparan sulfate and heparin in wound repair. BioMed Res Int  2015; 549417.
[http://dx.doi.org/10.1155/2015/549417] [PMID: 26236728] 
[53] 
Laurens N, Koolwijk P, de Maat MPM. Fibrin structure and wound healing. J Thromb Haemost  2006; 4(5): 932-9.
[http://dx.doi.org/10.1111/j.1538-7836.2006.01861.x] [PMID: 16689737] 
[54] 
Sen CK, Gordillo GM, Roy S, et al. Human skin wounds: A major and snowballing threat to public health and the economy. Wound Repair Regen  2009; 17(6): 763-71.
[http://dx.doi.org/10.1111/j.1524-475X.2009.00543.x] [PMID: 19903300] 
[55] 
Briquez PS, Hubbell JA, Martino MM. Extracellular matrix-inspired growth factor delivery systems for skin wound healing. Adv Wound Care (New Rochelle)  2015; 4(8): 479-89.
[http://dx.doi.org/10.1089/wound.2014.0603] [PMID: 26244104] 
[56] 
Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: Mechanisms, signaling, and translation. Sci Transl Med  2014; 6(265): 265sr6.
[http://dx.doi.org/10.1126/scitranslmed.3009337] [PMID: 25473038] 
[57] 
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 (Lond)  2015; 11(6): 1551-73.
[http://dx.doi.org/10.1016/j.nano.2015.03.002] [PMID: 25804415] 
[58] 
Mustoe TA, O’Shaughnessy K, Kloeters O. Chronic wound pathogenesis and current treatment strategies: A unifying hypothesis. Plast Reconstr Surg  2006; 117(7)(Suppl.): 35S-41S.
[http://dx.doi.org/10.1097/01.prs.0000225431.63010.1b] [PMID: 16799373] 
[59] 
Boateng JS, Matthews KH, Stevens HNE, Eccleston GM. Wound healing dressings and drug delivery systems: A review. J Pharm Sci  2008; 97(8): 2892-923.
[http://dx.doi.org/10.1002/jps.21210] [PMID: 17963217] 
[60] 
Chi J, Zhang X, Chen C, Shao C, Zhao Y, Wang Y. Antibacterial and angiogenic chitosan microneedle array patch for promoting wound healing. Bioact Mater  2020; 5(2): 253-9.
[http://dx.doi.org/10.1016/j.bioactmat.2020.02.004] [PMID: 32128464] 
[61] 
Xu Z, Han S, Gu Z, Wu J. Advances and impact of antioxidant hydrogel in chronic wound healing. Adv Healthc Mater  2020; 9(5): e1901502.
[http://dx.doi.org/10.1002/adhm.201901502] [PMID: 31977162] 
[62] 
Yin M, Wang X, Yu Z, et al. γ-PGA hydrogel loaded with cell-free fat extract promotes the healing of diabetic wounds. J Mater Chem B Mater Biol Med  2020; 8(36): 8395-404.
[http://dx.doi.org/10.1039/D0TB01190H] [PMID: 32966542] 
[63] 
Sosnik A, Seremeta KP. Polymeric hydrogels as technology platform for drug delivery applications. Gels  2017; 3(3): 25.
[64] 
Hu H, Xu F-J. Rational design and latest advances of polysaccharide-based hydrogels for wound healing. Biomater Sci  2020; 8(8): 2084-101.
[http://dx.doi.org/10.1039/D0BM00055H] [PMID: 32118241] 
[65] 
Vashist A, Vashist A, Gupta YK, Ahmad S. Recent advances in hydrogel based drug delivery systems for the human body. J Mater Chem B Mater Biol Med  2014; 2(2): 147-66.
[http://dx.doi.org/10.1039/C3TB21016B] [PMID: 32261602] 
[66] 
Kurakula M, Rao GSNK, Kiran V, Hasnain MS, Nayak AK. Chapter 13 - alginate-based hydrogel systems for drug releasing in wound healing.Alginates in Drug Delivery.  Academic Press 2020; pp. 323-58.
[67] 
Lin Y, Wu J, Gu W, et al. Exosome-liposome hybrid nanoparticles deliver crispr/cas9 system in mscs. Adv Sci (Weinh)  2018; 5(4): 1700611.
[http://dx.doi.org/10.1002/advs.201700611] [PMID: 29721412] 
[68] 
Elkhoury K, Koçak P, Kang A, Arab-Tehrany E, Ellis Ward J, Shin SR. Engineering smart targeting nanovesicles and their combination with hydrogels for controlled drug delivery. Pharmaceutics  2020; 12(9): 849.
[http://dx.doi.org/10.3390/pharmaceutics12090849] [PMID: 32906833] 
[69] 
Tao S-C, Rui B-Y, Wang Q-Y, Zhou D, Zhang Y, Guo S-C. Extracellular vesicle-mimetic nanovesicles transport LncRNA-H19 as competing endogenous RNA for the treatment of diabetic wounds. Drug Deliv  2018; 25(1): 241-55.
[http://dx.doi.org/10.1080/10717544.2018.1425774] [PMID: 29334272] 
[70] 
Elkhoury K, Russell CS, Sanchez-Gonzalez L, et al. Soft-nanoparticle functionalization of natural hydrogels for tissue engineering applications. Adv Healthc Mater  2019; 8(18): e1900506.
[http://dx.doi.org/10.1002/adhm.201900506] [PMID: 31402589] 
[71] 
Biondi M, Borzacchiello A, Mayol L, Ambrosio L. Nanoparticle-integrated hydrogels as multifunctional composite materials for biomedical applications. Gels  2015; 1(2): 162-78.
[http://dx.doi.org/10.3390/gels1020162] [PMID: 30674171] 
[72] 
Liu H, Wang C, Li C, et al. A functional chitosan-based hydrogel as a wound dressing and drug delivery system in the treatment of wound healing. RSC Adv   2018; 8: 7533-49.
[http://dx.doi.org/10.1039/C7RA13510F] 
[73] 
Singh B, Kumar A. Graft and crosslinked polymerization of polysaccharide gum to form hydrogel wound dressings for drug delivery applications. Carbohydr Res  2020; 489: 107949.
[http://dx.doi.org/10.1016/j.carres.2020.107949] [PMID: 32050103] 
[74] 
Xu K, An N, Zhang H, et al. Sustained-release of PDGF from PLGA microsphere embedded thermo-sensitive hydrogel promoting wound healing by inhibiting autophagy. J Drug Deliv Sci Technol  2020; 55: 101405.
[http://dx.doi.org/10.1016/j.jddst.2019.101405] 
[75] 
Li Y, Xu T, Tu Z, et al. Bioactive antibacterial silica-based nanocomposites hydrogel scaffolds with high angiogenesis for promoting diabetic wound healing and skin repair. Theranostics  2020; 10(11): 4929-43.
[http://dx.doi.org/10.7150/thno.41839] [PMID: 32308759] 
[76] 
Kao CH. Use of concentrate growth factors gel or membrane in chronic wound healing: Description of 18 cases. Int Wound J  2020; 17(1): 158-66.
[http://dx.doi.org/10.1111/iwj.13250] [PMID: 31661727] 
[77] 
Morgado PI, Lisboa PF, Ribeiro MP, et al. Poly (vinyl alcohol)/chitosan asymmetrical membranes: Highly controlled morphology toward the ideal wound dressing. J Membr Sci  2014; 469: 262-71.
[http://dx.doi.org/10.1016/j.memsci.2014.06.035] 
[78] 
Jackson EA, Hillmyer MA. Nanoporous membranes derived from block copolymers: From drug delivery to water filtration. ACS Nano  2010; 4(7): 3548-53.
[http://dx.doi.org/10.1021/nn1014006] [PMID: 20695511] 
[79] 
Mazzeo L, Bianchi M, Cocchi M, Piemonte V. Chapter 10 - drug delivery with membranes systems.Current trends and future developments on (bio-) membranes.  Elsevier 2019; pp. 291-309.
[80] 
Feng Y, Wang Q, He M, Zhang X, Liu X, Zhao C. Antibiofouling zwitterionic gradational membranes with moisture retention capability and sustained antimicrobial property for chronic wound infection and skin regeneration. Biomacromolecules  2019; 20(8): 3057-69.
[http://dx.doi.org/10.1021/acs.biomac.9b00629] [PMID: 31306012] 
[81] 
Mabrouk M, Rajendran R, Soliman IE, et al. Nanoparticle- and nanoporous-membrane-mediated delivery of therapeutics. Pharmaceutics  2019; 11(6): 11.
[http://dx.doi.org/10.3390/pharmaceutics11060294] [PMID: 31234394] 
[82] 
Jeon G, Yang SY, Kim JK. Functional nanoporous membranes for drug delivery. J Mater Chem  2012; 22: 14814-34.
[http://dx.doi.org/10.1039/c2jm32430j] 
[83] 
Russo J, Fiegel J, Brogden NK. Rheological and drug delivery characteristics of poloxamer-based diclofenac sodium formulations for chronic wound site analgesia. Pharmaceutics  2020; 12(12): 12.
[http://dx.doi.org/10.3390/pharmaceutics12121214] [PMID: 33333773] 
[84] 
McQuilling JP, Vines JB, Mowry KC. In vitro assessment of a novel, hypothermically stored amniotic membrane for use in a chronic wound environment. Int Wound J  2017; 14(6): 993-1005.
[http://dx.doi.org/10.1111/iwj.12748] [PMID: 28370981] 
[85] 
Morgado PI, Miguel SP, Correia IJ, Aguiar-Ricardo A. Ibuprofen loaded PVA/chitosan membranes: A highly efficient strategy towards an improved skin wound healing. Carbohydr Polym  2017; 159: 136-45.
[http://dx.doi.org/10.1016/j.carbpol.2016.12.029] [PMID: 28038742] 
[86] 
Zaman HU, Islam JM, Khan MA, Khan RA. Physico-mechanical properties of wound dressing material and its biomedical application. J Mech Behav Biomed Mater  2011; 4(7): 1369-75.
[http://dx.doi.org/10.1016/j.jmbbm.2011.05.007] [PMID: 21783147] 
[87] 
He R, Wang K, Ren J, et al. Efficacy of a synthetic biomimetic skin substitute of PLLA/gelatin nanofiber membrane in facilitating chronic cutaneous wound healing. Mater Technol  2020; 35: 872-80.
[http://dx.doi.org/10.1080/10667857.2019.1709286] 
[88] 
Morgado PI, Aguiar-Ricardo A, Correia IJ. Asymmetric membranes as ideal wound dressings: An overview on production methods, structure, properties and performance relationship. J Membr Sci  2015; 490: 139-51.
[http://dx.doi.org/10.1016/j.memsci.2015.04.064] 
[89] 
Bou Haidar N, Marais S, Dé E, et al. Chronic wound healing: A specific antibiofilm protein-asymmetric release system. Mater Sci Eng C  2020; 106: 110130.
[http://dx.doi.org/10.1016/j.msec.2019.110130] [PMID: 31753364] 
[90] 
Momeni S, Rezvani Ghomi E, Shakiba M, et al. The effect of poly (ethylene glycol) emulation on the degradation of pla/starch composites. Polymers (Basel)  2021; 13(7): 13.
[http://dx.doi.org/10.3390/polym13071019] [PMID: 33806074] 
[91] 
Chen Y, Yan L, Yuan T, Zhang Q, Fan H. Asymmetric polyurethane membrane with in situ-generated nano-TiO2 as wound dressing. J Appl Polym Sci  2011; 119: 1532-41.
[http://dx.doi.org/10.1002/app.32813] 
[92] 
Felgueiras HP, Teixeira MA, Tavares TD, Homem NC, Zille A, Amorim MTP. Antimicrobial action and clotting time of thin, hydrated poly (vinyl alcohol)/cellulose acetate films functionalized with LL37 for prospective wound-healing applications. J Appl Polym Sci  2020; 137: 48626.
[http://dx.doi.org/10.1002/app.48626] 
[93] 
Poonguzhali R, Khaleel Basha S, Sugantha Kumari V. Novel asymmetric chitosan/PVP/nanocellulose wound dressing: In vitro and in vivo evaluation. Int J Biol Macromol  2018; 112: 1300-9.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.02.073] [PMID: 29447972] 
[94] 
Teo W, Ramakrishna S.  A review on electrospinning design and nanofibre assemblies. In:  Nanotechnology 2006; 17(14): R89-R106.
[95] 
Chen S, Li R, Li X, Xie J. Electrospinning: An enabling nanotechnology platform for drug delivery and regenerative medicine. Adv Drug Deliv Rev  2018; 132: 188-213.
[http://dx.doi.org/10.1016/j.addr.2018.05.001] [PMID: 29729295] 
[96] 
Garcia-Orue I, Gainza G, Gutierrez FB, et al. Novel nanofibrous dressings containing rhEGF and Aloe vera for wound healing applications. Int J Pharm  2017; 523(2): 556-66.
[http://dx.doi.org/10.1016/j.ijpharm.2016.11.006] [PMID: 27825864] 
[97] 
Thakkar S, Misra M. Electrospun polymeric nanofibers: New horizons in drug delivery. Eur J Pharm Sci  2017; 107: 148-67.
[http://dx.doi.org/10.1016/j.ejps.2017.07.001] [PMID: 28690099] 
[98] 
Pachuau L. Recent developments in novel drug delivery systems for wound healing. Expert Opin Drug Deliv  2015; 12(12): 1895-909.
[http://dx.doi.org/10.1517/17425247.2015.1070143] [PMID: 26289672] 
[99] 
Whittam AJ, Maan ZN, Duscher D, et al. Challenges and opportunities in drug delivery for wound healing. Adv Wound Care (New Rochelle)  2016; 5(2): 79-88.
[http://dx.doi.org/10.1089/wound.2014.0600] [PMID: 26862465] 
[100] 
Grip J, Engstad RE, Skjæveland I, et al. Beta-glucan-loaded nanofiber dressing improves wound healing in diabetic mice. Eur J Pharm Sci  2018; 121: 269-80.
[http://dx.doi.org/10.1016/j.ejps.2018.05.031] [PMID: 29864585] 
[101] 
Frenot A, Henriksson MW, Walkenström P. Electrospinning of cellulose-based nanofibers. J Appl Polym Sci  2007; 103: 1473-82.
[http://dx.doi.org/10.1002/app.24912] 
[102] 
Su Y, Mainardi VL, Wang H, et al. Dissolvable microneedles coupled with nanofiber dressings eradicate biofilms via effectively delivering a database-designed antimicrobial peptide. ACS Nano  2020; 14(9): 11775-86.
[http://dx.doi.org/10.1021/acsnano.0c04527] [PMID: 32840361] 
[103] 
Xu H, Li H, Ke Q, Chang J. An anisotropically and heterogeneously aligned patterned electrospun scaffold with tailored mechanical property and improved bioactivity for vascular tissue engineering. ACS Appl Mater Interfaces  2015; 7(16): 8706-18.
[http://dx.doi.org/10.1021/acsami.5b00996] [PMID: 25826222] 
[104] 
Ren X, Han Y, Wang J, et al. An aligned porous electrospun fibrous membrane with controlled drug delivery - An efficient strategy to accelerate diabetic wound healing with improved angiogenesis. Acta Biomater  2018; 70: 140-53.
[http://dx.doi.org/10.1016/j.actbio.2018.02.010] [PMID: 29454159] 
[105] 
McClure MJ, Sell SA, Simpson DG, Walpoth BH, Bowlin GL. A three-layered electrospun matrix to mimic native arterial architecture using polycaprolactone, elastin, and collagen: A preliminary study. Acta Biomater  2010; 6(7): 2422-33.
[http://dx.doi.org/10.1016/j.actbio.2009.12.029] [PMID: 20060934] 
[106] 
Chen Q, Wu J, Liu Y, et al. Electrospun chitosan/PVA/bioglass Nanofibrous membrane with spatially designed structure for accelerating chronic wound healing. Mater Sci Eng C  2019; 105: 110083.
[http://dx.doi.org/10.1016/j.msec.2019.110083] [PMID: 31546466] 
[107] 
Dodero A, Alloisio M, Castellano M, Vicini S. Multilayer alginate-polycaprolactone electrospun membranes as skin wound patches with drug delivery abilities. ACS Appl Mater Interfaces  2020; 12(28): 31162-71.
[http://dx.doi.org/10.1021/acsami.0c07352] [PMID: 32573197] 
Cite As
Current Pharmaceutical Design

Innovations in Drug Delivery for Chronic Wound Healing

Abstract
