Advances in Aerogels Formulations for Pulmonary Targeted Delivery of
Therapeutic Agents: Safety, Efficacy and Regulatory Aspects

Shristy      Verma; Pramod   Kumar   Sharma; Rishabha      Malviya; Sanjita      Das
Abstract

Aerogels are the 3D network of organic, inorganic, composite, layered, or hybrid-type materials that are used to increase the solubility of Class 1 (low solubility and high permeability) and Class 4 (poor solubility and low permeability) molecules. This approach improves systemic drug absorption due to the alveoli's broad surface area, thin epithelial layer, and high vascularization. Local therapies are more effective and have fewer side effects than systemic distribution because inhalation treatment targets the specific location and raises drug concentration in the lungs.
The present manuscript aims to explore various aspects of aerogel formulations for pulmonary targeted delivery of active pharmaceutical agents. The manuscript also discusses the safety, efficacy, and regulatory aspects of aerogel formulations. According to projections, the global respiratory drug market is growing 4–6% annually, with short–term development potential. The proliferation of literature on pulmonary medicine delivery, especially in recent years, shows increased interest.
Aerogels come in various technologies and compositions, but any aerogel used in a biological system must be constructed of a material that is biocompatible and, ideally, biodegradable. Aerogels are made via "supercritical processing". After many liquid phase iterations using organic solvents, supercritical extraction, and drying are performed. Moreover, the sol-gel polymerization process makes inorganic aerogels from TMOS or TEOS, the less hazardous silane. The resulting aerogels were shown to be mostly loaded with pharmaceutically active chemicals, such as furosemide-sodium, penbutolol-hemisulfate, and methylprednisolone. For biotechnology, pharmaceutical sciences, biosensors, and diagnostics, these aerogels have mostly been researched. Although aerogels are made of many different materials and methods, any aerogel utilized in a biological system needs to be made of a substance that is both biocompatible and, preferably, biodegradable.
In conclusion, aerogel-based pulmonary drug delivery systems can be used in biomedicine and non-biomedicine applications for improved sustainability, mechanical properties, biodegradability, and biocompatibility. This covers scaffolds, aerogels, and nanoparticles. Furthermore, biopolymers have been described, including cellulose nanocrystals (CNC) and MXenes. A safety regulatory database is necessary to offer direction on the commercialization potential of aerogelbased formulations. After that, enormous efforts are discovered to be performed to synthesize an effective aerogel, particularly to shorten the drying period, which ultimately modifies the efficacy. As a result, there is an urgent need to enhance the performance going forward.
Keywords: Aerogel, pulmonary drug delivery, sol-gel process, biocompatibility, safety and efficacy, regulatory, scaffolds.
Graphical Abstract

[1]
Gesser, H.D.; Goswami, P.C. Aerogels and related porous materials. Chem. Rev.,  1989, 89(4), 765-788.
 [http://dx.doi.org/10.1021/cr00094a003]

[2]
Pinelli, F.; Piras, C.; Rossi, F. A perspective on graphene based aerogels and their environmental applications. FlatChem,  2022, 36, 100449.
 [http://dx.doi.org/10.1016/j.flatc.2022.100449]

[3]
Venezuela, J.; Dargusch, M.S. The influence of alloying and fabrication techniques on the mechanical properties, biodegradability and biocompatibility of zinc: A comprehensive review. Acta Biomater.,  2019, 87, 1-40.
 [http://dx.doi.org/10.1016/j.actbio.2019.01.035] [PMID:  30660777]

[4]
Wei, S.; Ching, Y.C.; Chuah, C.H. Synthesis of chitosan aerogels as promising carriers for drug delivery: A review. Carbohydr. Polym.,  2020, 231, 115744.
 [http://dx.doi.org/10.1016/j.carbpol.2019.115744] [PMID:  31888854]

[5]
Nita, L.E.; Ghilan, A.; Rusu, A.G.; Neamtu, I.; Chiriac, A.P. New trends in bio-based Aerogels. Pharmaceutics,  2020, 12(5), 449.
 [http://dx.doi.org/10.3390/pharmaceutics12050449] [PMID:  32414217]

[6]
García-González, C.A.T.; Budtova, T.; Durães, L.; Erkey, C.; Del Gaudio, P.; Gurikov, P.; Koebel, M.; Liebner, F.; Neagu, M.; Smirnova, I. An opinion paper on aerogels for biomedical and environmental applications. Molecules,  2019, 24(9), 1815.
 [PMID:  31083427]

[7]
Soleimani, D.A.; Abbasi, M.H. Silica aerogel; synthesis, properties and characterization. J. Mater. Process. Technol.,  2008, 199(1-3), 10-26.
 [http://dx.doi.org/10.1016/j.jmatprotec.2007.10.060]

[8]
Guenther, U.; Smirnova, I.; Neubert, R. Hydrophilic silica aerogels as dermal drug delivery systems – Dithranol as a model drug. Eur. J. Pharm. Biopharm.,  2008, 69(3), 935-942.
 [http://dx.doi.org/10.1016/j.ejpb.2008.02.003] [PMID:  18423994]

[9]
García-González, C.A.; Jin, M.; Gerth, J.; Alvarez-Lorenzo, C.; Smirnova, I. Polysaccharide-based aerogel microspheres for oral drug delivery. Carbohydr. Polym.,  2015, 117, 797-806.
 [http://dx.doi.org/10.1016/j.carbpol.2014.10.045] [PMID:  25498702]

[10]
Athamneh, T.; Amin, A.; Benke, E.; Ambrus, R.; Leopold, C.S.; Gurikov, P.; Smirnova, I. Alginate and hybrid alginate-hyaluronic acid aerogel microspheres as potential carrier for pulmonary drug delivery. J. Supercrit. Fluids,  2019, 150, 49-55.
 [http://dx.doi.org/10.1016/j.supflu.2019.04.013]

[11]
Marin, M.A.; Mallepally, R.R.; McHugh, M.A. Silk fibroin aerogels for drug delivery applications. J. Supercrit. Fluids,  2014, 91, 84-89.
 [http://dx.doi.org/10.1016/j.supflu.2014.04.014]

[12]
Steckel, H.; Eskandar, F. Factors affecting aerosol performance during nebulization with jet and ultrasonic nebulizers. Eur. J. Pharm. Sci.,  2003, 19(5), 443-455.
 [http://dx.doi.org/10.1016/S0928-0987(03)00148-9] [PMID:  12907295]

[13]
Xi, J.; Wang, Z.; Si, X.A.; Zhou, Y. Nasal dilation effects on olfactory deposition in unilateral and bi-directional deliveries: in vitro tests and numerical modeling. Eur. J. Pharm. Sci.,  2018, 118, 113-123.
 [http://dx.doi.org/10.1016/j.ejps.2018.03.027] [PMID:  29597042]

[14]
Kadota, K.; Sosnowski, T.R.; Tobita, S.; Tachibana, I.; Tse, J.Y.; Uchiyama, H.; Tozuka, Y. A particle technology approach toward designing dry-powder inhaler formulations for personalized medicine in respiratory diseases. Adv. Powder Technol.,  2020, 31(1), 219-226.
 [http://dx.doi.org/10.1016/j.apt.2019.10.013]

[15]
Zhang, Y.; Lu, P.; Qin, H.; Zhang, Y.; Sun, X.; Song, X.; Liu, J.; Peng, H.; Liu, Y.; Nwafor, E.O.; Li, J.; Liu, Z. Traditional Chinese medicine combined with pulmonary drug delivery system and idiopathic pulmonary fibrosis: Rationale and therapeutic potential. Biomed. Pharmacother.,  2021, 133, 111072.
 [http://dx.doi.org/10.1016/j.biopha.2020.111072] [PMID:  33378971]

[16]
Li, R.; Jia, Y.; Kong, X.; Nie, Y.; Deng, Y.; Liu, Y. Novel drug delivery systems and disease models for pulmonary fibrosis. J. Control. Release,  2022, 348, 95-114.
 [http://dx.doi.org/10.1016/j.jconrel.2022.05.039] [PMID:  35636615]

[17]
Ribeiro, N.; Soares, G.C.; Santos-Rosales, V.; Concheiro, A.; Alvarez-Lorenzo, C.; García-González, C.A.; Oliveira, A.L. A new era for sterilization based on supercritical CO 2 technology. J. Biomed. Mater. Res. B Appl. Biomater.,  2020, 108(2), 399-428.
 [http://dx.doi.org/10.1002/jbm.b.34398] [PMID:  31132221]

[18]
Peng, T.; Lin, S.; Niu, B.; Wang, X.; Huang, Y.; Zhang, X.; Li, G.; Pan, X.; Wu, C. Influence of physical properties of carrier on the performance of dry powder inhalers. Acta Pharm. Sin. B,  2016, 6(4), 308-318.
 [http://dx.doi.org/10.1016/j.apsb.2016.03.011] [PMID:  27471671]

[19]
Zhao, S.; Malfait, W.J.; Guerrero-Alburquerque, N.; Koebel, M.M.; Nyström, G. Biopolymer aerogels and foams: Chemistry, properties, and applications. Angew. Chem. Int. Ed.,  2018, 57(26), 7580-7608.
 [http://dx.doi.org/10.1002/anie.201709014] [PMID:  29316086]

[20]
Mosanenzadeh, S.G.; Karamikamkar, S.; Saadatnia, Z.; Park, C.B.; Naguib, H.E. PPDA-PMDA polyimide aerogels with tailored nanostructure assembly for air filtering applications. Separ. Purif. Tech.,  2020, 250, 117279.
 [http://dx.doi.org/10.1016/j.seppur.2020.117279]

[21]
Ulker, Z.; Erkey, C. An emerging platform for drug delivery: Aerogel based systems. J. Control. Release,  2014, 177(177), 51-63.
 [http://dx.doi.org/10.1016/j.jconrel.2013.12.033] [PMID:  24394377]

[22]
Schwertfeger, F.; Zimmermann, A.; Krempel, H. Use of inorganic aerogels in pharmacy. United States Patent US 6,280,744, 2001.

[23]
Li, T.; Ai, F.; Shen, W.; Yang, Y.; Zhou, Y.; Deng, J.; Li, C.; Ding, X.; Xin, H.; Wang, X. Microstructural orientation and precise regeneration: A proof-of-concept study on the sugar-cane-derived implants with bone-mimetic hierarchical structure. ACS Biomater. Sci. Eng.,  2018, 4(12), 4331-4337.
 [http://dx.doi.org/10.1021/acsbiomaterials.8b01052] [PMID:  33418828]

[24]
Maleki, H. Recent advances in aerogels for environmental remediation applications: A review. Chem. Eng. J.,  2016, 300, 98-118.
 [http://dx.doi.org/10.1016/j.cej.2016.04.098]

[25]
Al-Muhtaseb, S.A.; Ritter, J.A. Preparation and properties of resorcinol-formaldehyde organic and carbon gels. Adv. Mater.,  2003, 15(2), 101-114.
 [http://dx.doi.org/10.1002/adma.200390020]

[26]
Berg, A.; Droege, M.W.; Fellmann, J.D.; Klaveness, J.; Rongved, P. Medical use of organic aerogels and biodegradable organic aerogels. EP Patent 0707474A1, 1995.

[27]
Bakhori, N.M.; Ismail, Z.; Hassan, M.Z.; Dolah, R. Emerging trends in nanotechnology: Aerogel-based materials for biomedical applications. Nanomaterials,  2023, 13(6), 1063.
 [http://dx.doi.org/10.3390/nano13061063] [PMID:  36985957]

[28]
Lee, K.P.; Gould, G.L. Aerogel Powder Therapeutic Agents; Aspen Publishers Aerogels Inc., 2001. 

[29]
Kanamori, K. Aerogels; Klein, L.; Aparicio, M; Jitianu, A., Ed.; Springer International Publishing, 2016. 

[30]
Ulker, Z.; Erucar, I.; Keskin, S.; Erkey, C. Novel nanostructured composites of silica aerogels with a metal organic framework. Microporous Mesoporous Mater.,  2013, 170, 352-358.
 [http://dx.doi.org/10.1016/j.micromeso.2012.11.040]

[31]
Lee, K.P.; Gould, G.L. Aerogel Powder Therapeutic Agents; Aspen Publishers Aerogels Inc., 2001. 

[32]
Liu, Z.; Ran, Y.; Xi, J.; Wang, J. Polymeric hybrid aerogels and their biomedical applications. Soft Matter,  2020, 16(40), 9160-9175.
 [http://dx.doi.org/10.1039/D0SM01261K] [PMID:  32851389]

[33]
Salmaso, S.; Caliceti, P. Stealth properties to improve therapeutic efficacy of drug nanocarriers. J. Drug Deliv.,  2013, 2013, 1-19.
 [http://dx.doi.org/10.1155/2013/374252] [PMID:  23533769]

[34]
Sani, N.S.; Malek, N.A.N.N.; Jemon, K.; Kadir, M.R.A.; Hamdan, H. In vitro bioactivity and osteoblast cell viability studies of hydroxyapatite-incorporated silica aerogel. J. Sol-Gel Sci. Technol.,  2020, 96(1), 166-177.
 [http://dx.doi.org/10.1007/s10971-020-05386-w]

[35]
Tevlek, A.; Atya, A.M.N.; Almemar, M.; Duman, M.; Gokcen, D.; Ganin, A.Y.; Yiu, H.H.P.; Aydin, H.M. Synthesis of conductive carbon aerogels decorated with β-tricalcium phosphate nanocrystallites. Sci. Rep.,  2020, 10(1), 5758.
 [http://dx.doi.org/10.1038/s41598-020-62822-1] [PMID:  32238872]

[36]
Liu, X.; Zheng, H.; Li, Y.; Wang, L.; Wang, C. A novel bacterial cellulose aerogel modified with pgma via arget atrp method for catalase immobilization. Fibers Polym.,  2019, 20(3), 520-526.
 [http://dx.doi.org/10.1007/s12221-019-8650-4]

[37]
Liu, S.; Zhou, C.; Mou, S.; Li, J.; Zhou, M.; Zeng, Y.; Luo, C.; Sun, J.; Wang, Z.; Xu, W. Biocompatible graphene oxide–collagen composite aerogel for enhanced stiffness and in situ bone regeneration. Mater. Sci. Eng. C,  2019, 105, 110137.
 [http://dx.doi.org/10.1016/j.msec.2019.110137] [PMID:  31546424]

[38]
Franco, P.; Pessolano, E.; Belvedere, R.; Petrella, A.; De Marco, I. Supercritical impregnation of mesoglycan into calcium alginate aerogel for wound healing. J. Supercrit. Fluids,  2020, 157, 104711.
 [http://dx.doi.org/10.1016/j.supflu.2019.104711]

[39]
Guo, X.; Xu, D.; Zhao, Y.; Gao, H.; Shi, X.; Cai, J.; Deng, H.; Chen, Y.; Du, Y. Electroassembly of chitin nanoparticles to construct freestanding hydrogels and high porous aerogels for wound healing. ACS Appl. Mater. Interfaces,  2019, 11(38), 34766-34776.
 [http://dx.doi.org/10.1021/acsami.9b13063] [PMID:  31429547]

[40]
Alnaief, M.; Obaidat, R.M.; Alsmadi, M.M. Preparation of hybrid alginate-chitosan aerogel as potential carriers for pulmonary drug delivery. Polymers,  2020, 12(10), 2223.
 [http://dx.doi.org/10.3390/polym12102223] [PMID:  32992662]

[41]
Qin, L.; He, Y.; Zhao, X.; Zhang, T.; Qin, Y.; Du, A. Preparation, characterization, and in vitro sustained release profile of resveratrol-loaded silica aerogel. Molecules,  2020, 25(12), 2752.
 [http://dx.doi.org/10.3390/molecules25122752] [PMID:  32549204]

[42]
Bajpai, V.K.; Shukla, S.; Khan, I.; Kang, S.M.; Haldorai, Y.; Tripathi, K.M.; Jung, S.; Chen, L.; Kim, T.; Huh, Y.S.; Han, Y.K. A sustainable graphene aerogel capable of the adsorptive elimination of biogenic amines and bacteria from soy sauce and highly efficient cell proliferation. ACS Appl. Mater. Interfaces,  2019, 11(47), 43949-43963.
 [http://dx.doi.org/10.1021/acsami.9b16989] [PMID:  31684721]

[43]
Zhao, T.; Qiu, Z.; Zhang, Y.; Hu, F.; Zheng, J.; Lin, C. Using a three-dimensional hydroxyapatite/graphene aerogel as a high-performance anode in microbial fuel cells. J. Environ. Chem. Eng.,  2021, 9(4), 105441.
 [http://dx.doi.org/10.1016/j.jece.2021.105441]

[44]
Rostamitabar, M.; Subrahmanyam, R.; Gurikov, P.; Seide, G.; Jockenhoevel, S.; Ghazanfari, S. Cellulose aerogel micro fibers for drug delivery applications. Mater. Sci. Eng. C,  2021, 127, 112196.
 [http://dx.doi.org/10.1016/j.msec.2021.112196] [PMID:  34225849]

[45]
Anastasova, E.I.; Belyaeva, A.A.; Tsymbal, S.A.; Vinnik, D.A.; Vinogradov, V.V. Hierarchical porous magnetite structures: From nanoparticle assembly to monolithic aerogels. J. Colloid Interface Sci.,  2022, 615, 206-214.
 [http://dx.doi.org/10.1016/j.jcis.2022.01.154] [PMID:  35131501]

[46]
Egu, J.; Moldován, K.; Herman, P.; István, F.; Kalmár, J.; Fenyvesi, F. 6ER-017 prevention of extravasation by the local application of hybrid aerogel microparticles as drug delivery systems for cervical cancer chemotherapy. BMJ,  2022, 29, A172.1-A1A172.

[47]
Long, L.Y.; Weng, Y.X.; Wang, Y.Z. Cellulose aerogels: Synthesis, applications, and prospects. Polymers,  2018, 10(6), 623.
 [http://dx.doi.org/10.3390/polym10060623] [PMID:  30966656]

[48]
Del Castillo, A.M.P. Nanomaterials and Workplace Health & Safety: What Are the Issues for Worker?; European Trade Union Institute: Brussels, 2013. 

[49]

Workplace Safety & Prevention Services, Silica in the Workplace;; Ontario, 2011. 

[50]
Feldmann, K. D.; Musolin, K.; Methner, M. M. Evaluation of Aerogel Insulation Particulate at a Union Trading Facility; United States Department of Health and Human Services, Centers for Disease Control and Prevention & National Institute for Occupational Safety and Health 2015.

[51]
The Uk NanoSafety Partnership Group. Working Safely with Nanomaterials in Research & Development. Nano; Safety Partnership Group, 2012. 

[52]
Chew, N.Y.K.; Chan, H.K. The role of particle properties in pharmaceutical powder inhalation formulations. J. Aerosol Med.,  2002, 15(3), 325-330.
 [http://dx.doi.org/10.1089/089426802760292672] [PMID:  12396421]

[53]
Seifelnasr, A.; Talaat, M.; Si, X.A.; Xi, J. Delivery of agarose-aided sprays to the posterior nose for mucosa immunization and short-term protection against infectious respiratory diseases. Curr. Pharm. Biotechnol., 2023.
 [PMID:  37533243]

[54]
Seheult, J.N.; Costello, S.; Tee, K.C. Investigating the relationship between peak inspiratory flow rate and volume of inhalation from a diskus™ inhaler and baseline spirometric parameters: A cross-sectional study. Springerplus,  2021, 3, 496.

[55]
Lavorini, F. Inhaled drug delivery in the hands of the patient. J. Aerosol Med. Pulm. Drug Deliv.,  2014, 27(6), 414-418.
 [http://dx.doi.org/10.1089/jamp.2014.1132] [PMID:  25238005]

[56]
Laba, T.L.; Jan, S.; Zwar, N.A.; Roughead, E.; Marks, G.B.; Flynn, A.W.; Goldman, M.D.; Heaney, A.; Lembke, K.A.; Reddel, H.K. Cost-related underuse of medicines for asthma—opportunities for improving adherence. J. Allergy Clin. Immunol. Pract.,  2019, 7(7), 2298-2306.e12.
 [http://dx.doi.org/10.1016/j.jaip.2019.03.024] [PMID:  30928659]

[57]
Melani, A.S.; Bonavia, M.; Cilenti, V.; Cinti, C.; Lodi, M.; Martucci, P.; Serra, M.; Scichilone, N.; Sestini, P.; Aliani, M.; Neri, M. Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir. Med.,  2011, 105(6), 930-938.
 [http://dx.doi.org/10.1016/j.rmed.2011.01.005] [PMID:  21367593]

[58]
Westerik, J.A.M.; Carter, V.; Chrystyn, H.; Burden, A.; Thompson, S.L.; Ryan, D.; Gruffydd-Jones, K.; Haughney, J.; Roche, N.; Lavorini, F.; Papi, A.; Infantino, A.; Roman-Rodriguez, M.; Bosnic-Anticevich, S.; Lisspers, K.; Ställberg, B.; Henrichsen, S.H.; van der Molen, T.; Hutton, C.; Price, D.B. Characteristics of patients making serious inhaler errors with a dry powder inhaler and association with asthma-related events in a primary care setting. J. Asthma,  2016, 53(3), 321-329.
 [http://dx.doi.org/10.3109/02770903.2015.1099160] [PMID:  26810934]

[59]
The European Commission. Commission Regulation (EU). Off. J. Eur. Union 2018/1881 of amending Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) as regards, 2018 (L308), 4.12.2018, 1–20. 2018.

[60]

Occupational Exposure Limits in mg/M3; Vol. 8 hours TWA –
Respirable dust;; European Network on Silica: EU 27 + Norway &
Switzerland,, 2019. 

[61]

Workplace Exposure Limits; 4th ed.; Health and Safety Executive, 2020. 

[62]

Directive (EU) 2017/2398 of the European Parliament and of the Council of 12 December 2017 Amending Directive 2004/37/EC on the Protection of Workers from the Risks Related to Exposure to Carcinogens or Mutagens at Work - Document 32017L2398;; The European Parliament and Council, 2017. 

[63]
Occupational Safety and Health Standards OSHA Laws & Regulations – Regulations (Standards – 29 CFR), 1910, 1910.1000. Occupational Safety and Health Administration,  1910, 3, 1910.

[64]
Council Directive 89/391/EEC of 12 June 1989 on the introduction of measures to encourage improvements in the safety and health of workers at work. 1989. Available from: http://data.europa.eu/eli/ dir/1989/391/oj

[65]
Regulation (EU) No 305/2011 of the European Parliament and of the Council of 9 March 2011 laying down harmonised conditions for the marketing of construction products and repealing Council Directive 89/106/EEC Text with EEA relevance. 2011. Available from: http://data.europa.eu/eli/reg/2011/305/oj

[66]
Feldmann, K. D.; Musolin, K.; Methner, M. M. Evaluation of Aerogel Insulation Particulate at a Union Trading Facility; United States Department of Health and Human Services, Centers for Disease Control and Prevention & National Institute for Occupational Safety and Health 2015.

[67]
Aegerter, M.A.; Leventis, N.; Koebel, M.M. Aerogel Handbook. In: Advances in Sol–Gel Derived Materials and Technologies; Aegerter, M.A.; Prassas, M., Eds.; Springer, 2011. 

[68]
Xie, H.; He, Z.; Liu, Y.; Zhao, C.; Guo, B.; Zhu, C.; Xu, J. Efficient antibacterial agent delivery by mesoporous silica aerogel. ACS Omega,  2022, 7(9), 7638-7647.
 [http://dx.doi.org/10.1021/acsomega.1c06198] [PMID:  35284760]

[69]
Gorshkova, N.; Brovko, O.; Palamarchuk, I.; Bogolitsyn, K.; Ivakhnov, A. Preparation of bioactive aerogel material based on sodium alginate and chitosan for controlled release of levomycetin. Polym. Adv. Technol.,  2021, 32(9), 3474-3482.
 [http://dx.doi.org/10.1002/pat.5358]

[70]
Simonson, A.W.; Umstead, T.M.; Lawanprasert, A.; Klein, B.; Almarzooqi, S.; Halstead, E.S.; Medina, S.H. Extracellular matrix-inspired inhalable aerogels for rapid clearance of pulmonary tuberculosis. Biomaterials,  2021, 273, 120848.
 [http://dx.doi.org/10.1016/j.biomaterials.2021.120848] [PMID:  33915409]

[71]
García-González, C.A.; Smirnova, I. Use of supercritical fluid technology for the production of tailor-made aerogel particles for delivery systems. J. Supercrit. Fluids,  2013, 79, 152-158.
 [http://dx.doi.org/10.1016/j.supflu.2013.03.001]

[72]
Tønnesen, H.H.; Karlsen, J. Alginate in drug delivery systems. Drug Dev. Ind. Pharm.,  2002, 28(6), 621-630.
 [http://dx.doi.org/10.1081/DDC-120003853] [PMID:  12149954]

[73]
Lee, K.Y.; Mooney, D.J. Alginate: Properties and biomedical applications. Prog. Polym. Sci.,  2012, 37(1), 106-126.
 [http://dx.doi.org/10.1016/j.progpolymsci.2011.06.003] [PMID:  22125349]

[74]
Mehling, T.; Smirnova, I.; Guenther, U.; Neubert, R.H.H. Polysaccharide-based aerogels as drug carriers. J. Non-Cryst. Solids,  2009, 355(50-51), 2472-2479.
 [http://dx.doi.org/10.1016/j.jnoncrysol.2009.08.038]

[75]
Veronovski, A.; Novak, Z.; Knez, Ž. Synthesis and use of organic biodegradable aerogels as drug carriers. J. Biomater. Sci. Polym. Ed.,  2012, 23(7), 873-886.
 [http://dx.doi.org/10.1163/092050611X566126] [PMID:  21457617]

[76]
Del Gaudio, P.; Auriemma, G.; Mencherini, T.; Porta, G.D.; Reverchon, E.; Aquino, R.P. Design of alginate-based aerogel for nonsteroidal anti-inflammatory drugs controlled delivery systems using prilling and supercritical-assisted drying. J. Pharm. Sci.,  2013, 102(1), 185-194.
 [http://dx.doi.org/10.1002/jps.23361] [PMID:  23150457]

[77]
Haimer, E.; Wendland, M.; Schlufter, K.; Frankenfeld, K.; Miethe, P.; Potthast, A.; Rosenau, T.; Liebner, F. Loading of bacterial cellulose aerogels with bioactive compounds by antisolvent precipitation with supercritical carbon dioxide. Macromol. Symp.,  2010, 294(2), 64-74.
 [http://dx.doi.org/10.1002/masy.201000008]

[78]
Rosenholm, J.M.; Lindén, M. Towards establishing structure–activity relationships for mesoporous silica in drug delivery applications. J. Control. Release,  2008, 128(2), 157-164.
 [http://dx.doi.org/10.1016/j.jconrel.2008.02.013] [PMID:  18439699]

[79]
Stergar, J.; Maver, U. Review of aerogel-based materials in biomedical applications. J. Sol-Gel Sci. Technol.,  2016, 77(3), 738-752.
 [http://dx.doi.org/10.1007/s10971-016-3968-5]

[80]
Murillo-Cremaes, N.; López-Periago, A.M.; Saurina, J.; Roig, A.; Domingo, C. Nanostructured silica-based drug delivery vehicles for hydrophobic and moisture sensitive drugs. J. Supercrit. Fluids,  2013, 73, 34-42.
 [http://dx.doi.org/10.1016/j.supflu.2012.11.006]

[81]
Rao, V.; Kalesh, R. Comparative studies of the physical and hydrophobic properties of TEOS based silica aerogels using different co-precursors. Sci. Technol. Adv. Mater.,  2003, 4(6), 509-515.
 [http://dx.doi.org/10.1016/j.stam.2003.12.010]

[82]
Rao, A.V. Superhydrophobic Silica Aerogels Based on Methyltrimethoxysilane Precursor. J. Non-Cryst. Solids,  2003, 330(1–3), 187-195.

[83]
Lee, K.H.; Kim, S.Y.; Yoo, K.P. Low-density, hydrophobic aerogels. J. Non-Cryst. Solids,  1995, 186, 18-22.
 [http://dx.doi.org/10.1016/0022-3093(95)00066-6]

[84]
Wen, J.; Wilkes, G.L. Organic/inorganic hybrid network materials by the sol−gel approach. Chem. Mater.,  1996, 8(8), 1667-1681.
 [http://dx.doi.org/10.1021/cm9601143]

[85]
Leventis, N.; Sadekar, A.; Chandrasekaran, N.; Sotiriou-Leventis, C. Click synthesis of monolithic silicon carbide aerogels from polyacrylonitrile-coated 3D silica networks. Chem. Mater.,  2010, 22(9), 2790-2803.
 [http://dx.doi.org/10.1021/cm903662a]

[86]
Boday, D.J.; DeFriend, K.A.; Wilson, K.V., Jr; Coder, D.; Loy, D.A. Formation of polycyanoacrylate−silica nanocomposites by chemical vapor deposition of cyanoacrylates on aerogels. Chem. Mater.,  2008, 20(9), 2845-2847.
 [http://dx.doi.org/10.1021/cm703381e]

[87]
Hoffmann, F.; Cornelius, M.; Morell, J.; Fröba, M. Silica-based mesoporous organic-inorganic hybrid materials. Angew. Chem. Int. Ed.,  2006, 45(20), 3216-3251.
 [http://dx.doi.org/10.1002/anie.200503075] [PMID:  16676373]

[88]
Veres, P.; López-Periago, A.M.; Lázár, I.; Saurina, J.; Domingo, C. Hybrid aerogel preparations as drug delivery matrices for low water-solubility drugs. Int. J. Pharm.,  2015, 496(2), 360-370.
 [http://dx.doi.org/10.1016/j.ijpharm.2015.10.045] [PMID:  26484894]

[89]
López-Periago, A.M.; Domingo, C. Features of supercritical CO2 in the delicate world of the nanopores. J. Supercrit. Fluids,  2018, 134, 204-213.
 [http://dx.doi.org/10.1016/j.supflu.2017.11.011]

[90]
Seeni Meera, K.M.; Murali Sankar, R.; Jaisankar, S.N.; Mandal, A.B. Physicochemical studies on polyurethane/siloxane cross-linked films for hydrophobic surfaces by the sol-gel process. J. Phys. Chem. B,  2013, 117(9), 2682-2694.
 [http://dx.doi.org/10.1021/jp3097346] [PMID:  23394610]

[91]
Talebi Mazraeh-shahi Z.; Mousavi Shoushtari, A.; Bahramian, A.R.; Abdouss, M. Synthesis, pore structure and properties of polyurethane/silica hybrid aerogels dried at ambient pressure. J. Ind. Eng. Chem.,  2015, 21, 797-804.
 [http://dx.doi.org/10.1016/j.jiec.2014.04.015]

[92]
Duan, Y.; Jana, S.C.; Lama, B.; Espe, M.P. Reinforcement of silica aerogels using silane-end-capped polyurethanes. Langmuir,  2013, 29(20), 6156-6165.
 [http://dx.doi.org/10.1021/la4007394] [PMID:  23611433]

[93]
Duan, Y.; Jana, S.C.; Lama, B.; Espe, M.P. Self-crosslinkable poly(urethane urea)-reinforced silica aerogels. RSC Advances,  2015, 5(88), 71551-71558.
 [http://dx.doi.org/10.1039/C5RA11769K]

[94]
Gonçalves, V.S.S.; Gurikov, P.; Poejo, J.; Matias, A.A.; Heinrich, S.; Duarte, C.M.M.; Smirnova, I. Alginate-based hybrid aerogel microparticles for mucosal drug delivery. Eur. J. Pharm. Biopharm.,  2016, 107, 160-170.
 [http://dx.doi.org/10.1016/j.ejpb.2016.07.003] [PMID:  27393563]

[95]
Abe, K.; Iwamoto, S.; Yano, H. Obtaining cellulose nanofibers with a uniform width of 15 nm from wood. Biomacromolecules,  2007, 8(10), 3276-3278.
 [http://dx.doi.org/10.1021/bm700624p] [PMID:  17784769]

[96]
Zhang, Y.; Lim, C.T.; Ramakrishna, S. Recent development of polymer nanofibers for biomedical and biotechnological applications. J. Mater, Medico. Mater. Sci.,  2005, 16, 933-946.

[97]
Shaikh, R.P.; Pillay, V.; Choonara, Y.E.; du Toit, L.C.; Ndesendo, V.M.K.; Bawa, P.; Cooppan, S. A review of multi-responsive membranous systems for rate-modulated drug delivery. AAPS PharmSciTech,  2010, 11(1), 441-459.
 [http://dx.doi.org/10.1208/s12249-010-9403-2] [PMID:  20300895]

[98]
Shukla, A.; Fang, J.C.; Puranam, S.; Hammond, P.T. Release of vancomycin from multilayer coated absorbent gelatin sponges. J. Control. Release,  2012, 157(1), 64-71.
 [http://dx.doi.org/10.1016/j.jconrel.2011.09.062] [PMID:  21939701]

[99]
Afrashi, M.; Semnani, D.; Talebi, Z.; Dehghan, P.; Maheronnaghsh, M. Novel multi-layer silica aerogel/PVA composite for controlled drug delivery. Mater. Res. Express,  2019, 6(9), 095408.
 [http://dx.doi.org/10.1088/2053-1591/ab3097]

[100]
Krogman, K.C.; Lowery, J.L.; Zacharia, N.S.; Rutledge, G.C.; Hammond, P.T. Spraying asymmetry into functional membranes layer-by-layer. Nat. Mater.,  2009, 8(6), 512-518.
 [http://dx.doi.org/10.1038/nmat2430] [PMID:  19377464]

[101]
Gunasekaran, L.X.; Eleya, M.M.O. Whey protein concentrate hydrogels as bioactive carriers. J. Appl. Polym. Sci.,  2023, 140(46), 2470-2476.

[102]
Alnaief, M.; Antonyuk, S.; Hentzschel, C.M.; Leopold, C.S.; Heinrich, S.; Smirnova, I. A novel process for coating of silica aerogel microspheres for controlled drug release applications. Microporous Mesoporous Mater.,  2012, 160, 167-173.
 [http://dx.doi.org/10.1016/j.micromeso.2012.02.009]

[103]
Donius, A.E.; Liu, A.; Berglund, L.A.; Wegst, U.G.K. Superior mechanical performance of highly porous, anisotropic nanocellulose–montmorillonite aerogels prepared by freeze casting. J. Mech. Behav. Biomed. Mater.,  2014, 37, 88-99.
 [http://dx.doi.org/10.1016/j.jmbbm.2014.05.012] [PMID:  24905177]

[104]
Wicklein, B.; Kocjan, A.; Salazar-Alvarez, G.; Carosio, F.; Camino, G.; Antonietti, M.; Bergström, L. Thermally insulating and fire-retardant lightweight anisotropic foams based on nanocellulose and graphene oxide. Nat. Nanotechnol.,  2015, 10(3), 277-283.
 [http://dx.doi.org/10.1038/nnano.2014.248] [PMID:  25362476]

[105]
Munier, P.; Gordeyeva, K.; Bergström, L.; Fall, A.B. Directional freezing of nanocellulose dispersions aligns the rod-like particles and produces low-density and robust particle networks. Biomacromolecules,  2016, 17(5), 1875-1881.
 [http://dx.doi.org/10.1021/acs.biomac.6b00304] [PMID:  27071304]

[106]
ASTM F2792-12a.Standard Terminology for Additive Manufacturing Technologies; ASTM International: West, 2012. 

[107]
Huang, S.H.; Liu, P.; Mokasdar, A.; Hou, L. Additive manufacturing and its societal impact: A literature review. Int. J. Adv. Manuf. Technol.,  2013, 67(5-8), 1191-1203.
 [http://dx.doi.org/10.1007/s00170-012-4558-5]

[108]
Yao, B.; Chandrasekaran, S.; Zhang, H.; Ma, A.; Kang, J.; Zhang, L.; Lu, X.; Qian, F.; Zhu, C.; Duoss, E.B.; Spadaccini, C.M.; Worsley, M.A.; Li, Y. 3D‐printed structure boosts the kinetics and intrinsic capacitance of pseudocapacitive graphene aerogels. Adv. Mater.,  2020, 32(8), 1906652.
 [http://dx.doi.org/10.1002/adma.201906652] [PMID:  31951066]

[109]
Smirnova, I.; Gurikov, P. Aerogels in chemical engineering: Strategies toward tailor-made aerogels. Annu. Rev. Chem. Biomol. Eng.,  2017, 8(1), 307-334.
 [http://dx.doi.org/10.1146/annurev-chembioeng-060816-101458] [PMID:  28375771]

[110]
Lee, H.; Kim, G. Cryogenically fabricated three-dimensional chitosan scaffolds with pore size-controlled structures for biomedical applications. Carbohydr. Polym.,  2011, 85(4), 817-823.
 [http://dx.doi.org/10.1016/j.carbpol.2011.04.001]

[111]
Lacey, S.D.; Kirsch, D.J.; Li, Y.; Morgenstern, J.T.; Zarket, B.C.; Yao, Y.; Dai, J.; Garcia, L.Q.; Liu, B.; Gao, T.; Xu, S.; Raghavan, S.R.; Connell, J.W.; Lin, Y.; Hu, L. Extrusion‐based 3D printing of hierarchically porous advanced battery electrodes. Adv. Mater.,  2018, 30(12), 1705651.
 [http://dx.doi.org/10.1002/adma.201705651]

[112]
Mohammed, A.K.; Usgaonkar, S.; Kanheerampockil, F.; Karak, S.; Halder, A.; Tharkar, M.; Addicoat, M.; Ajithkumar, T.G.; Banerjee, R. Connecting microscopic structures, mesoscale assemblies, and macroscopic architectures in 3D-printed hierarchical porous covalent organic framework foams. J. Am. Chem. Soc.,  2020, 142(18), 8252-8261.
 [http://dx.doi.org/10.1021/jacs.0c00555] [PMID:  32279483]

[113]
Lei, D.; Yang, Y.; Liu, Z.; Chen, S.; Song, B.; Shen, A.; Yang, B.; Li, S.; Yuan, Z.; Qi, Q.; Sun, L.; Guo, Y.; Zuo, H.; Huang, S.; Yang, Q.; Mo, X.; He, C.; Zhu, B.; Jeffries, E.M.; Qing, F.L.; Ye, X.; Zhao, Q.; You, Z. A general strategy of 3D printing thermosets for diverse applications. Mater. Horiz.,  2019, 6(2), 394-404.
 [http://dx.doi.org/10.1039/C8MH00937F]

[114]
Xiong, Z.; Yan, Y.; Wang, S.; Zhang, R.; Zhang, C. Fabrication of porous scaffolds for bone tissue engineering via low-temperature deposition. Scr. Mater.,  2002, 46(11), 771-776.
 [http://dx.doi.org/10.1016/S1359-6462(02)00071-4]

[115]
Nazarov, R.; Jin, H.J.; Kaplan, D.L. Porous 3-D scaffolds from regenerated silk fibroin. Biomacromolecules,  2004, 5(3), 718-726.
 [http://dx.doi.org/10.1021/bm034327e] [PMID:  15132652]

[116]
Tetik, H. 3D freeze printing of functional aerogels. Doctoral Dissertation; Kansas State University, 

[117]
Zhang, Q.; Zhang, F.; Medarametla, S.P.; Li, H.; Zhou, C.; Lin, D. 3D printing of graphene aerogels. Small,  2016, 12(13), 1702-1708.
 [http://dx.doi.org/10.1002/smll.201503524] [PMID:  26861680]

[118]
Yan, P.; Brown, E.; Su, Q.; Li, J.; Wang, J.; Xu, C.; Zhou, C.; Lin, D. 3D printing hierarchical silver nanowire aerogel with highly compressive resilience and tensile elongation through tunable poisson’s ratio. Small,  2017, 13(38), 1701756.
 [http://dx.doi.org/10.1002/smll.201701756] [PMID:  28834394]

[119]
Zhang, F.; Yang, F.; Lin, D.; Zhou, C. Parameter study of three-dimensional printing graphene oxide based on directional freezing. J. Manuf. Sci. Eng.,  2017, 139(3), 031016.
 [http://dx.doi.org/10.1115/1.4034669]

[120]
Brown, E.; Yan, P.; Tekik, H.; Elangovan, A.; Wang, J.; Lin, D.; Li, J. 3D printing of hybrid MoS2-graphene aerogels as highly porous electrode materials for sodium ion battery anodes. Mater. Des.,  2019, 170, 107689.
 [http://dx.doi.org/10.1016/j.matdes.2019.107689]

[121]
Ma, C.; Wang, R.; Tetik, H.; Gao, S.; Wu, M.; Tang, Z.; Lin, D.; Ding, D.; Wu, W. Hybrid nanomanufacturing of mixed-dimensional manganese oxide/graphene aerogel macroporous hierarchy for ultralight efficient supercapacitor electrodes in self-powered ubiquitous nanosystems. Nano Energy,  2019, 66, 104124.
 [http://dx.doi.org/10.1016/j.nanoen.2019.104124]

[122]
Zu, G.; Shen, J.; Wei, X.; Ni, X.; Zhang, Z.; Wang, J.; Liu, G. Preparation and characterization of monolithic alumina aerogels. J. Non-Cryst. Solids,  2011, 357(15), 2903-2906.
 [http://dx.doi.org/10.1016/j.jnoncrysol.2011.03.031]

[123]
Li, J.; Rossignol, F.; Macdonald, J. Inkjet printing for biosensor fabrication: Combining chemistry and technology for advanced manufacturing. Lab Chip,  2015, 15(12), 2538-2558.
 [http://dx.doi.org/10.1039/C5LC00235D] [PMID:  25953427]

[124]
Zhao, G.; Lin, D.; Zhou, C. Thermal analysis of directional freezing based graphene aerogel three-dimensional printing process. J. Micro Nano-Manuf.,  2017, 5(1), 011006.
 [http://dx.doi.org/10.1115/1.4035392]

[125]
Wang, G.; Wang, Z.; Liu, Z.; Xue, J.; Xin, G.; Yu, Q.; Lian, J.; Chen, M.Y. Annealed graphene sheets decorated with silver nanoparticles for inkjet printing. Chem. Eng. J.,  2015, 260, 582-589.
 [http://dx.doi.org/10.1016/j.cej.2014.09.037]

[126]
Shin, W.J.; Lee, H.; Sohn, Y.; Shin, W.G. Novel inkjet droplet method generating monodisperse hollow metal oxide micro-spheres. Chem. Eng. J.,  2016, 292, 139-146.
 [http://dx.doi.org/10.1016/j.cej.2016.02.021]

[127]
Scoutaris, N.; Ross, S.; Douroumis, D. Current trends on medical and pharmaceutical applications of inkjet printing technology. Pharm. Res.,  2016, 33(8), 1799-1816.
 [http://dx.doi.org/10.1007/s11095-016-1931-3] [PMID:  27174300]

[128]
Daly, R.; Harrington, T.S.; Martin, G.D.; Hutchings, I.M. Inkjet printing for pharmaceutics – A review of research and manufacturing. Int. J. Pharm.,  2015, 494(2), 554-567.
 [http://dx.doi.org/10.1016/j.ijpharm.2015.03.017] [PMID:  25772419]

[129]
Mueannoom, W.; Srisongphan, A.; Taylor, K.M.G.; Hauschild, S.; Gaisford, S. Thermal ink-jet spray freeze-drying for preparation of excipient-free salbutamol sulphate for inhalation. Eur. J. Pharm. Biopharm.,  2012, 80(1), 149-155.
 [http://dx.doi.org/10.1016/j.ejpb.2011.09.016] [PMID:  22001519]

[130]
Sharma, G.; Mueannoom, W.; Buanz, A.B.M.; Taylor, K.M.G.; Gaisford, S. In vitro characterisation of terbutaline sulphate particles prepared by thermal ink-jet spray freeze drying. Int. J. Pharm.,  2013, 447(1-2), 165-170.
 [http://dx.doi.org/10.1016/j.ijpharm.2013.02.045] [PMID:  23454848]

[131]
Alnaief, M.; Alzaitoun, M.A.; García-González, C.A.; Smirnova, I. Preparation of biodegradable nanoporous microspherical aerogel based on alginate. Carbohydr. Polym.,  2011, 84(3), 1011-1018.
 [http://dx.doi.org/10.1016/j.carbpol.2010.12.060]

[132]
Healy, A.M.; Amaro, M.I.; Paluch, K.J.; Tajber, L. Dry powders for oral inhalation free of lactose carrier particles. Adv. Drug Deliv. Rev.,  2014, 75, 32-52.
 [http://dx.doi.org/10.1016/j.addr.2014.04.005] [PMID:  24735676]

[133]
Sathishkumar, K.; Kumaresan, C. Development of an inhaled sustained release dry powder formulation of salbutamol sulphate, an antiasthmatic drug. Indian J. Pharm. Sci.,  2016, 78(1), 136-142.
 [http://dx.doi.org/10.4103/0250-474X.180261] [PMID:  27168692]

[134]
López-Iglesias, C.; Casielles, A.M.; Altay, A.; Bettini, R.; Alvarez-Lorenzo, C.; García-González, C.A. From the printer to the lungs: Inkjet-printed aerogel particles for pulmonary delivery. Chem. Eng. J.,  2019, 357, 559-566.
 [http://dx.doi.org/10.1016/j.cej.2018.09.159]

[135]
Basit, A.W.; Gaisford, S. 3D Printing of Pharmaceuticals; Springer, 2018. 
 [http://dx.doi.org/10.1007/978-3-319-90755-0]

[136]
Azizi Machekposhti, S.; Mohaved, S.; Narayan, R.J. Inkjet dispensing technologies: Recent advances for novel drug discovery. Expert Opin. Drug Discov.,  2019, 14(2), 101-113.
 [http://dx.doi.org/10.1080/17460441.2019.1567489] [PMID:  30676831]

[137]
Chung, J.H.; Naficy, S.; Wallace, G.G.; Naficy, S.; O’Leary, S. Inkjet‐printed alginate microspheres as additional drug carriers for injectable hydrogels. Adv. Polym. Technol.,  2016, 35(4), 439-446.
 [http://dx.doi.org/10.1002/adv.21571]

[138]
de Gans, B.J.; Duineveld, P.C.; Schubert, U.S. Inkjet printing of polymers: State of the art and future developments. Adv. Mater.,  2004, 16(3), 203-213.
 [http://dx.doi.org/10.1002/adma.200300385]
Cite As
Current Pharmaceutical Biotechnology

Advances in Aerogels Formulations for Pulmonary Targeted Delivery of Therapeutic Agents: Safety, Efficacy and Regulatory Aspects

Abstract

Graphical Abstract
