Scaffolds for lung tissue engineering

Scaffolds for lung tissue engineering

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Chaman Naeem1, Masoud Mozafari2,3,5, Farshid Sefat1,4,6,7 1Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford, United Kingdom; 2Bioengineering Research Group, Nanotechnology and Advanced Materials Department, Materials and Energy Research Center (MERC), Tehran, Iran; 3Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran; 4Interdisciplinary Research Centre in Polymer Science and Technology (IRC Polymer), University of Bradford, Bradford, United Kingdom; 5Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran; 6Department of Materials and Polymer Engineering, Hakim Sabzevari University, Sabzevar, Iran; 7Department of Biology, Faculty of Sciences, Hakim Sabzevari University, Sabzevar, Iran

51.1  Introduction The lungs are an essential organ, housing the alveoli which is where gas exchange occurs. The endurance of all the lungs over millions of respiratory cycles is a crucial component to the sustenance of human life, exhibiting just how remarkable the body is. With every organ or tissue, disease or damage is inevitable and environmental or genetic factors increase the risk of this damage. Current treatment options focus on making the patient’s life better rather than treating the problem or repairing damage, for example, oxygen therapy in those with lung cancer helps making breathing easier rather than treating the cancer. Lung transplants are a rarity as the donor is infrequently a live donor, and the demand of lung transplants far outweighs the supply; moreover, if a lung is transplanted, infection and rejection may occur, which present further problems. This global problem necessitates the need for tissue engineering to participate in the fabrication of lung tissue scaffolds to restore normal functionality to the lungs. To create 3D scaffold structures, extensive knowledge is required in the mechanical and biological properties of the native tissue so that the components are manufactured to mimic these properties, thus allowing essential functionality to be carried out in the correct physiological conditions [1]. The combination of biology with materials science, medicine with nanotechnology, and medical engineering with electronics allows scaffolds to be created that are biocompatible and biodegradable [2]. Tissue engineering is a future prospect that should be carefully studied as it could hold the potential to treating many diseases, which were historically untreatable.

Handbook of Tissue Engineering Scaffolds: Volume Two. https://doi.org/10.1016/B978-0-08-102561-1.00018-X Copyright © 2019 Elsevier Ltd. All rights reserved.

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51.2  Anatomy and physiology Paired organs of respiration that lie in the thoracic cavity, the lungs are separated by the heart and other edifices within the mediastinum [3]. Consequently, trauma to one lung may not affect the other lung, which can carry out function as normal and expand individually. Each lung is bound and protected by the pleural membrane, a doublelayered serous casing. The parietal pleura lines the walls of the thoracic cavity, and the final deep layer, the visceral pleura, encloses each lung [3]. The pleural cavity exists in a small space between the visceral and parietal pleurae, containing a small amount of lubricating fluid secreted by the membranes. This fluid reduces friction between the membranes, allowing them to easily slide over one another during breathing, and causes the membranes to stick to one another, in a phenomenon known as surface tension. The right and left lungs are surrounded by two separate pleural cavities [3]. Conical in shape, each lung has a blunt apex that spreads from above the sternal end of the first rib (slightly superior to the clavicles [3]) to a dipped base laying over the concave diaphragm, a lengthy costovertebral shape molded against the chest wall and a concave mediastinal exterior, which houses the pericardium [4]. Each lung lies on either side of the mediastinum enclosed by the right and left pleural cavities [5]. The mediastinal section of each lung contains an area known as the hilum, through which bronchi, lymphatic vessels, pulmonary blood vessels, and nerves enter and exit the lungs [3]. The lungs are composed mostly of respiratory airways, which lead to the alveoli, importantly the stroma, which the lung is composed of, is an elastic connective tissue allowing the lungs to coil and recoil during inspiration and expiration [6]. The right lung is slightly shorter than the left lung, because of the underlying diaphragm being pushed up by the inferior liver. Albeit, shorter, the right lung is in fact heavier and thicker as the overall size of the left lung is abridged by the indentation on the medial portion of the lung created by the heart, known as the cardiac notch [4]. The right lung is separated into three lobes: the upper, middle and lower lobes, which are divided by the oblique and horizontal fissures. The left lung has only an oblique fissure and thus only two lobes—an upper and lower lobe [4]. The oblique fissure, present in both lungs, extends anteriorly and inferiorly [3]. Fig. 51.1 shows the location of the oblique and horizontal fissures, the apex, and the cardiac notch. The pulmonary arteries serve the lungs with deoxygenated blood from the heart’s right ventricle [5], and both inferior and superior pulmonary veins return oxygenated blood to the left atrium of the heart [4]. The brachial arteries are small arteries, which provide huge clinical importance by ensuring the blood supply to the lung parenchyma after pulmonary embolism is conserved, as well as providing air passages, while the brachial veins drain the azygos system [4]. The lungs are principal respiration organs; respiration consists of two phases: inspiration and expiration, which are completed by the alternating increase and decrease of the thoracic cavities’ capacity [8]. During inspiration, oxygen-rich air travels into the body via the airways and into the lungs, and gas exchange occurs at the alveoli where oxygen is exchanged for carbon dioxide, which then travels out of the body during expiration. The oxygen-rich blood then travels to the many cells and tissues within the body. If the thoracic cavity is envisaged as a gas-filled box with a single entrance denoting the trachea, the total volume of this box can be increased by amplifying all the

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Anterior view

Posterior view Horizontal fissure Cervical pleura

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Figure 51.1  Anterior and posterior view of the lungs, outlining components of lung anatomy. Reused with permission from R. Newell, Anatomy of the post-laryngeal airways, lungs and diaphragm, Surgery 29 (5) (2011) 199–203.

dimensions, thus decreasing the overall pressure within the box. This reduction in pressure then causes air into the box from the surrounding atmosphere because gases flow against the pressure gradient. In the lungs, this works with the diaphragm and intercostal muscles contracting during inspiration and relaxing during expiration although the diaphragm is the most superior muscle of the two for respiration.

51.3  Pulmonary diseases and treatments Diseases and disorders of the lungs can arise because of many reasons, including inherited and acquired factors. The symptoms presented by the following diseases are very similar with chest tightness and a shortness of breath appearing to be the most common. Diagnosis techniques include chest X-rays or ultrasounds and physical examinations with treatment options varying, although prolongation of the diseases presents the need for lung transplants. Below some of the problems associated with the lung will be discussed, showing the risk factors, symptoms, diagnosis, and treatment of the conditions.

51.3.1  Asthma Characterized by frequent episodes of coughing, wheezing, and chest tightness, which reverse after the use of medication or impulsively [9], asthma is noticeable by acute exacerbations followed by symptom-free periods [10]. Although the onset can start at any stage of one’s life, in most cases the first symptoms arise during early childhood [9]. Genetic predisposition, sex, ethnicity, pollution, allergens, and diet all have an effect on the occurrence and severity of asthma although it is not clearly known to which extent each factor affects asthma [11].

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A simple spirometry test can be used to diagnose asthma before and after the administration of an inhaled short-acting β2-antagonist. Moreover, peak flow meters can be used to diagnose asthma in the clinic or to monitor asthma at home. Treatment for asthma is typically in the form of inhaled mediations; these can be preventer or reliever inhalers; preventers (inhaled corticosteroids) are taken daily to control persistent asthma, whereas relievers (short-acting β2-antagonist) are taken to reverse symptoms during an attack [11].

51.3.2  Chronic obstructive pulmonary disease (COPD) Categorized by limited airflow, a cough, and sputum that arises suddenly and remains persistent, COPD is a common, yet preventable, disease [12]. COPD includes emphysema, which is damage to the alveoli, and chronic bronchitis, which is inflammation of the airways. Although any person can be affected by the disease, those greatest at risk are middle-aged or elderly smokers or former smokers [13]. Although tobacco smoking is the greatest etiological factor of COPD, the occurrence of COPD in nonsmokers is ever increasing, suggesting that additional risk factors are associated with the disease; such risk factors include prolonged exposure to harmful dusts and toxins [14]. Usually, COPD is diagnosed when the damage is irreversible, when patients present with symptoms, many respiratory tests, including spirometers and peak flow meters as well as X-rays, can be conducted to confirm the diagnosis. Currently, no treatment works to reverse the damage although the cessation of smoking and inhalers is recommended to improve the quality of one’s life [15]. In extreme cases, a lung transplant may be offered to some patients. Fig. 51.2 visually depicts the early-life events and additional risk factors associated with COPD and the advice and treatment prescribed to help patients achieve the best possible outlook.

51.3.3  Lung cancer In the United Kingdom, lung cancer is the most common cancer, presenting oncologists with serious problems [17]. Similar to other pulmonary conditions, the symptoms include a persistent cough where blood is coughed up, breathlessness, fatigue, weight loss, and aches around the thoracic cavity [88]. Two of the greatest contributors to lung cancer are tobacco smoke and environmental exposure, although nonsmokers are also at risk of developing lung cancer [18]. There are two types of lung cancer [88]: • Non–small cell lung cancer—the most common type that can be adenocarcinoma, squamous cell carcinoma, or large cell carcinoma • Small cell lung cancer—a less common type that spreads faster

Generally, symptoms are not displayed till the cancer has spread through the lungs or into other parts of the body, so the outlook is not good, diagnosis follows that of many other pulmonary conditions, and this includes spirometry and peak flow measurements, blood tests, chest X-rays, MRI scans, and clinical biopsy [19]. Treatment offered depends on the type of cancer, how far it is spread, and how the patient’s body

Risk factors for incidence and progress

Escalation of treatment

Clinical phenotypes of severe COPD

Consider emphysema intervention Consider non-invasive ventilation ● Genes ● Lung

function at adolescence and adulthood ● Exposure to other pollutants ● Infections ● Amount of cigarettes ● Physical inactivity

Smoking cessation Physical activity

Scaffolds for lung tissue engineering

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Vaccination Bronchodilatation Diagnosis and treatment of comorbidities

Oxygen palliative care

Pulmonary rehabilitition

Consider inhaled corticosteroids Consider roflumilast Consider macrolides

Figure 51.2  Life course of COPD and the effect of different factors that may affect disease incidence and severity along with treatments. Reused with permission from K. Rabe, H. Watz, Chronic obstructive pulmonary disease, Lancet 389 (10082) (2017) 1931–1940. 431

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would react to certain treatments. Early diagnosis entails surgical removal of part of the lung or radiotherapy to destroy the cancerous cells. If the diagnosis is confirmed at a later stage, chemotherapy is suggested, and if a suitable donor is available, the prospect of a lung transplant could be suggested [20,88].

51.3.4  Pneumothorax A collapsed or dropped lung is the entrance of air into the space between the chest wall and the lungs, known as the pleural space. Usually, a pneumothorax is instigated by trauma, for instance, a rib fracture or a gunshot or stab wound to the lung or chest region [21]. Smoking significantly increases the risk of a pneumothorax along with genetic predisposition and those with underlying pulmonary diseases [22]. A sudden increase in heart rate, chest pain, shortness of breast, and a persistent cough are all symptoms of pneumothorax, where diagnosis follows X-ray or ultrasound scans [21]. Treatment for a diagnosed pneumothorax is a complicated emergency procedure, the pressure in the chest cavity must be released urgently, and a needle thoracotomy must be performed [21]. A hospital stay is essential to ensure that recovery takes place under the care of medical professionals.

51.3.5  Pneumonia Caused by bacteria, fungi, or viruses, pneumonia is an infection and inflammation of the lung parenchyma, where the alveoli become inflamed and consequently fill with fluid [23]. In adults, most cases are caused by bacterial infections; however, in children younger than 5 years, viruses are the most common cause [24]. The symptoms, similar to other lung diseases, include difficulty breathing, chest pain, wet cough, fever, and fatigue [23]. Although any person can contract pneumonia, certain groups have an increased risk, which include the elderly, infants, those with chronic health problems, and those who smoke. Diagnosis of pneumonia consists of X-rays, blood tests, and phlegm culture; phlegm culture is highly vital in determining the cause of the infection as this establishes the treatment [23]. Bacterial pneumonia is treated with antibiotics, which can be intravenous or oral depending on the severity, and viral pneumonia usually improves without treatment; however, rest is important [25].

51.3.6  Acute pulmonary edema The accumulation of fluid in the lungs impairs gas exchange and overall lung function; hence a pulmonary edema is a medical emergency that requires instant intervention [26]. Symptoms include a cough (sometimes with froth), shortness of breath, chest pain and tightness, wheezing, and excessive sweating [27]. Primary causes of the impairment include arrhythmias (atrial fibrillation), acute valvular dysfunction, myocardial ischemia, and fluid overload; other causes are pulmonary embolisms, renal artery stenosis, and anemia [26]. A stethoscope may be used to listen to the lungs for abnormal sounds, such as crackles and rapid breathing; however, further diagnostic tests would be essential to

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diagnose. These include blood tests to measure the blood oxygen levels and electrolyte levels; electrocardiograms (ECG) to monitor the heart and chest X-rays to observe the fluid around the lungs are necessary to confirm the diagnosis [27]. Treatment for an acute pulmonary edema must be administered urgently to improve the chances of survival, continuous positive airway pressure supplied via a face mask improves ventilation; however, this can sometimes cause myocardial infarctions [28]. Furthermore, the treatment should be individually modified to the urgency of each situation. As with most pulmonary diseases, the prevention focuses on the cessation of smoking, and tobacco significantly increases the risk of lung disease, as well as contributing to heart disease and circulatory problems [27].

51.3.7  Pulmonary embolism Pulmonary embolism is a highly common disease that can cause death and disability if not detected early; early diagnosis is difficult as the symptoms appear similar to other lung diseases [29]. Essentially, a pulmonary embolism is a blood clot that blocks the blood vessels and thus prevents the supply of blood to the lungs [30]. A sudden blockage of blood to the lungs can cause chest pain, a shortness of breath, heart palpitations, leg swelling, and, in the most severe cases, death [30]. Risk factors consist of both inherited and acquired factors, such as protein deficiency, smoking, obesity, old age, pregnancy, major trauma, and many more [31]. Blood thinners, known as anticoagulants, prevent new blood clots forming, whereas the body breaks down the current embolism. Anticoagulants can be either intravenous (heparin, dalteparin, and fondaparinux) or oral (warfarin and rivaroxaban), and typical treatment lasts around 6 months or longer if the risk of recurrence is high [30]. More advanced treatment options including clot-dissolving medications and catheters, as well as lifestyle changes of regular exercise, a healthier diet, and the cessation of smoking [32].

51.3.8  Oxygen therapy Although oxygen cannot stop damage to the lung, it can make breathing easier and improve the blood oxygen levels. Oxygen therapy is an easily applied, painless, and inexpensive procedure that can be administered at home [33]. Literature suggests an improved survival in patients with oxygen therapy compared with those without oxygen therapy especially for those with chronic obstructive pulmonary disease [34].

51.3.9  Lung transplant A lung transplant is a highly sophisticated, lifesaving procedure for many patients at end-stage lung disease. Lungs that are transplanted are often injured or diseased and either one or both lungs can be transplanted [35]. As with any procedure, a lung transplant presents many risks including infection although the survival rates after transplantation are exceptional. Complications include graft failure, airway complications, and rejection, which could be potentially fatal for patients if not dealt with urgently [36].

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Lung transplantation surgery is conducted by opening up the chest, cutting the main airways and blood vessels, and then removing the diseased lung. The diseased and damaged portion of the lungs is entirely removed, and then the lung transplant is fitted into the lung, ensuring it is correctly fitted to the airways and vessels to resume pulmonary function.

51.4  Fabrication techniques Because adult lung tissue has limited regeneration ability, the primary procedure for damaged lungs is lung transplantation [37]. Because of the lack of available donors, lung transplants are a rare procedure, thus making the need for tissue-engineered lungs gain clinical importance. Before lungs can be tissue engineered, the cell source must be acknowledged and utilized, and the scaffold must be fabricated to mimic the biological and mechanical properties of the native tissue; the lung and procedures for creating and implanting the scaffold must be standardized [38]. Electrospinning is a new and developing fiber production technique, which has, in recent years, gained approval in the biomedical and health-care sector because of the unlimited possibilities. The scaffolds produced during electrospinning fabricate fibers within the nanometer scale; nanotechnology has been acknowledged as a vital scientific endeavor for future applications [39]. Additionally, the scaffolds produced can mimic the native tissue because of modifications in the electrospinning process, creating scaffolds with architectural similarities to the extracellular matrix [40]. The scaffolds act as a temporary environment for cells to renew via attachment and differentiation till the tissue has regenerated. The simple setup is relatively low cost and easily tunable; it involves the feeding of a polymer solution through a needle of a specific size that is set at a nominated height from the grounded collector. The addition of a voltage applied to the needle tip creates an electrostatic force within the solution; this force must be overcome by surface tension, which resultantly causes a liquid jet to release from the needle. The polymer jet then undergoes a bending stability that causes stretching and thinning of fibers as the solvent evaporates. The resultant fibers gather on the collector plate in the form of aligned, random, or woven fiber meshes depending on the setup [40]. Processing parameters, such as flow rate, needle thickness, polymer composition, applied voltage, and distance to collector plate, can be modified to produce scaffolds that can exhibit different mechanical or biological properties. Once the scaffold has been created, it must be sterilized before cell seeding; the most widely used sterilization method is using gamma radiation. Gamma radiation does not harm the scaffolds architecture and ensures that the properties of the scaffold are not altered. The addition of cells, growth reactors, and cell culture media allows the cells to multiply in a sterilized environment. Biodegradable polylactic acid and hydrosoluble collagen dissolved in a solvent of hexafluoroidopropanol were fabricated using a template electrospinning technique. The flow rate was set to 0.5 mL/h, a 15 kV voltage was applied, and the needle was 20 cm above the collector plate. Once the scaffold was sterilized and submerged in a

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phosphate-buffered saline solution for 24 h, the scaffold was implanted into female New Zealand rabbits. The organs were stained with hematoxylin and eosin, subsequently observed with a microscope, and neither abnormal changes nor damages were observed on the lung, demonstrating the scaffolds were clinically success [41]. Ref. [42] electrospun gelatin/oxycellulose nanofibers modified with sodium and calcium salt, biocompatibility was tested using human lung adenocarcinoma cell line NHI-H441, as it is considered to be a suitable model for the human distal lung epithelial barrier. It was found that the cells and biomaterials displayed a nontoxic nature as there was no red staining when observing under a microscope, which can be seen in Fig. 51.3. Overall, they found that the selection of materials exhibited outstanding biocompatibility, which presents potential use of drug testing [42]. A solution of 35 mg/mL pig lung extracellular matrix and a 400 mg/mL of poly l-lactic acid were electrospun on a rotating mandrel, with a poly l-lactic acid sample as a control. With the needle set at 27 cm away from the collector, a flow rate was 4.5 mL/h with an applied voltage of 27 kV. The voltage applied to poly l-lactic acid was set to 15 kV; the difference in voltages was due to the presence of a Taylor cone. It was found that using these parameters, fibers in similar size to the decellularized lung tissue were created, as well as displaying mechanical properties, which were similar to the native lung. Moreover, the subsequent extracellular matrix creates a porous matrix that allows for cell division and nutrient transport throughout the tissue. Many properties displayed show the possibility of success of lung tissue engineering [43]. The combination of natural and synthetic polymers has been used for lung tissue engineering, showing this as an extensive field where there are no limitations. It is clear that further research is required on electrospinning tissue for lung engineering. Medical applications for tissue engineering are massively expanding and expected to modernize current health care, one such application is that for lung tissue engineering. Despite the current advances, many challenges persist and must be transformed in order for this method to provide unlimited opportunities, in cases of customization, drug delivery, and cost-effectiveness [44]. 3D printing is another procedure in which products are made of plastics, metals, ceramics, powders, liquids, or even living cells as individual layers stacked above one another to produce a 3D object, which can mimic the functionality of the object that it is to replace [45], for example, lungs can be fabricated using biomaterials and cells. Usually, the design is created in a computer-aided design (CAD) software, the foundations of the structure are printed in the x/y plane, and then the z-axis is used to build the object in 3D in the horizontal direction [44]. There are three types of bioprinting: microextrusion, ink-jet, and laser-assisted printing, each presents many strengths and limitations; hence careful selection of a technique should be dependent on the organ that is to be printed [46]. Current literature shows that 3D lung transplantation has not been carried out in humans; however, Li et al. [47] implanted a 3D-printed lung into a dog and found that after 1 year the mortality and morbidity of lung complications significantly decreased. Nevertheless, Quiñones et al. [48] attempted to create a 3D-printed simulator, which can detect moveable tumors in the lung; however, a 3D-printed lung has never been implanted into humans.

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Microscopic visualisation of crosslinked nanofibers

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Figure 51.3  SEM visualization of cross-linked nanofibers: (a) in situ cross-linked Gel/CaOC2:1 with EDC/NHS, (b) DHT treatment of Gel/CaOC2:1; (c) in situ cross-linking and DHT treatment of Gel/CaOC2:1, (d) in situ cross-linked Gel/NaOC2:1 with EDC/NHS, (e) DHT treatment of Gel/CaOC2:1, (c) in situ cross-linking and DHT treatment of Gel/CaOC2:1 with EDC/NHS, (e) DHT treatment of Gel/NaOC2:1, and (f) in situ cross-linking and DHT treatment of Gel/NaOC2:1. Morphological features of cells growing on nanofibrous materials visualized by fluorescence microscopy (a–d), where red color stains actin and the blue visualized chromatic and SEM (e–h), where red arrows are cells and blue arrows depict supporting material. Growing cells on samples: XDHT Gel/NaOC2:1 for 1 day (a, e) and 3 days (b, f) and on in situ/DHTGel/NaOC2:1 for 1 day (c, g) and 3 days (d, h). This test indicated that the cells growing in contact with the materials had the same appearance as the cells growing under standard culture conditions. In addition, the cells had regular shaped nuclei without protrusions, frequent occurrence of mitotic figure dominating normal cell division and well-developed network of actin. There were no signs of blebbing of cytoplasmic membrane, regular microvilosity of cell surface, and firm contacts with supporting nanofibrous structures. Reused with permission from V. Švachová, L. Vojtová, D. Pavliňák, L. Vojtek, V. Sedláková, P. Hyršl, M. Alberti, J. Jaroš, A. Hampl, J. Jančář, Novel electrospun gelatin/oxycellulose nanofi­ bers as a suitable platform for lung disease modeling, Mater Sci Eng C 67 (2016) 493–501.

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51.5  Biomaterials for lung tissue engineering Biomaterials have been used in tissue engineering applications for more than 20 years; however, more recently the modification of biomaterials has allowed for tissue regeneration to occur with or without the presence of cells. When an organ or tissue becomes diseased, the extracellular matrix (ECM) is damaged and biomaterial scaffolds create a microenvironment that resembles the native ECM, providing signals that promote tissue regeneration. Synthetic biomaterials, such as polylactic acid, polycaprolactone, and poly lactic-co-glycolic acid, can be accurately modified to create the desired mechanical properties, scaffold architecture, and degradation rate [49]. Mechanical properties include elasticity, hardness, and Young’s modulus, and scaffold architecture comprises fiber diameter and orientation, as well as pore size and percentage porosity. Natural biomaterials, such as elastin, collagen, silk, and keratin, already contain specific proteins such as cell adhesion ligands and are predisposed to cell adhesion and differentiation [50]. The careful selection of a biomaterial is important for the application intended to achieve the desired function; modern approaches also focus on the blend of natural and synthetic biomaterials. Table 51.1 highlights a few biomaterials listing their properties and reason for selecting a biomaterial in tissue engineering applications. Natural biomaterials, because of their derivation and physical and chemical architecture, can fill essential requirements in the field of tissue engineering. In pulmonary applications, they are increasingly utilized for various applications because of their clear advantage over synthetic biomaterials [49]. Scaffolds fabricated for pulmonary applications must be highly elastic and robust to complete function of the lung and last long term.

51.6  Cell type for lung regeneration The lung is composed of over 40 different cell types, including cells of the epithelium, interstitial connective tissue, alveolar cells, mucous cells, smooth muscle cells, stem cells, fibroblasts, and many more. Resident lung cells are cells, which are involved with pathogenic conditions, for example, glandular cells of the lung give rise to adenocarcinomas, an accumulation of eosinophils could potentially lead to pneumonia, minute meningothelioid cells are present in lung biopsies, and for inflammatory diseases such as asthma and emphysema, multiple cell types are involved [68]. This section will discuss some of the cell types used for lung tissue engineering, mentioning the success of the cell life if plausible. Daly et al. [69] explored the possibility of using stem and progenitor cells for the recellularization of decellularized mouse lungs after inoculation of bone marrow– derived mesenchymal stromal cells. The decellularized lungs preserved features of the native lungs, for example, the ability to undergo ventilation, vascularization, and

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Table 51.1  Comparison of natural (collagen, elastin, silk fibroin, and keratin) and synthetic (PLA, PGA, PLGA and PCL) biomaterials. Natural biomaterials Collagen

Elastin

Silk fibroin

Keratin

In mammals, collagens are the most profuse proteins; they are deposited in the extracellular matrix and play an integral in the organization and shape of tissues as well as the mechanical properties the tissue demonstrates. Collagen interacts with cells via many receptors, amending their proliferation, migration, and differentiation [51]. As a biomaterial, collagen provides exceptional biocompatibility, tuneable biodegradability, adequate mechanical characteristics, flexibility, and the ability to work in physiological conditions, making it an ideal choice for many tissue engineering applications [52]. Elastin is a major component of many tissues, endowing them with long-range elasticity required for their physiological function. Elastin fibers have been found to be intricate in structure and composition containing an assortment of microfibrillar proteins. Moreover, it is one of the most stable components that form part of the extracellular matrix, albeit compromised mechanical properties are associated with aging and diseases [53]. Biomaterials composed of elastin and elastin-derived molecules are proving to be a highly popular choice for tissue engineering application; the extraordinary properties such as elasticity, long-term stability, self-assembly, and biological activity are further fueling this response [54]. Silks are fibrous proteins that are produced by silkworms and spiders, exhibiting remarkable mechanical properties. The chemical manipulation through amino acid side chains can alter the surface properties, thus immobilizing cellular growth factors. A myriad of cells and cell lines have been successfully seeded on silk scaffolds, expressing a range of biological outcomes. In vivo and in vitro testing shows that the biocompatibility and biodegradability of silk is exceptional [55] A ubiquitous material, keratin, represents a group of insoluble protein constituting many epidermal appendages such as nails, hair, claws, breaks, horns, and feathers. These keratinous materials are considered “dead tissue” although they are among the toughest biomaterials in the mammalian body. Keratin displays an intricate hierarchical structure consisting of polypeptide chains at the nanoscale, layered structures at the microscale, and compact sheaths at the macroscale, producing a wide range of mechanical properties allowing keratin to serve a variety of functions [56]. The sulfur molecules within keratin are substantial to the functionality of keratin within naturally occurring substances or in chemically synthesized biomaterials. Moreover, the proteins characteristics can be easily manipulated, leading to several novel uses of the material in tissue engineering applications [57].

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Table 51.1 Continued Natural biomaterials Synthetic biomaterials Polylactic Acid PLA is a bio-based polymer that exhibits many properties, including (PLA) strength, stiffness, and gas permeability, although the degradation rate is slow, and the toughness is low [58]. In terms of tissue engineering, PLA is considered a gold standard for many applications because of its versatility in fabrication, compatibility with molecules and cells, and its ability to blend with other polymers (natural/synthetic) to create scaffolds that display desired mechanical and biological properties [59]. PLA is also highly considered because of its high surface area and biomimicry of native extracellular matrix architecture, all of which are significant influences when designing a scaffold. Additionally, the use of PLA scaffolds as drug delivery mechanisms is gaining countless approval because the drug release kinetics can be controlled based on the fabrication parameters of PCL [60]. Polyglycolic Acid A desired material for both physicians and engineers because of the (PGA) exception properties displayed, especially the degradation behavior, which can be easily tuneable depending on application [61]. A high Young’s modulus is presented because of its thermal and morphological properties; however, the loss of tensile strength over a period of time and its poor solubility significantly limit the use of PGA in soft tissue engineering. Subsequently, many PGA-based copolymers have been synthesized to broaden the functionality of PGA [62]. Polylactic-coDepending on the molecular weight of PLGA, the rate of biodegradaglycolide Acid tion can be modified making PLGA one of the primary choices for (PLGA) many tissue engineering applications; as well as the biocompatibility and the ability to modify surface properties enhancing interactions with biological materials make this polymer a primary choice [86]. The European Medicine Agency and the US Food and Drug Administration have approved the use of PLGA for drug delivery systems confirming the safety and immense properties of the polymer [63]. One of the most common uses of PLGA in medical applications is the controlled drug release and targeted drug delivery [64]. Polycaprolactone Among synthetic biomaterials, PCL is regarded as one of the easiest to (PCL) manipulate and process into a large array of shapes and size because of its excellent viscoelastic properties, absence of isomers, and low melting point [65]. Moreover, the biocompatibility and biodegradability of PCL is considered acceptable [66], as well as the polymer demonstrating bioresorbable properties [87]. PCL is soluble in many solvents such as chloroform, acetone, and dimethylformamide, proving a 3D structure upon fabrication that enables cells to adhere and proliferate [87]). Disadvantages of using PCL for regenerative purposes are based around the hydrophobic nature of the polymer, causing poor wettability and the lack of cell attachment [67].

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an extracellular matrix composed of collagens I and IV, laminin, and fibronectin. The mesenchymal stem cells in these regions multiplied in type I and IV of collagen and laminin but not for fibronectin. The cells were cultured in either basal media or small airways growth media; it was found that those cells cultured in basal media increased, whereas the others decreased after 1 month. The study highlighted the power of decellularized whole lung scaffolds, which were recellularized with mesenchymal stem cells. In a recent study, O’Neill et al. reported that lung extracellular matrix (LECM) can hold a great potential as a scaffold for lung tissue engineering because it retains the complex architecture, biomechanics, and topological specificity of the lung. They examined porcine lung as a substitute for human lung to study tissue engineering therapies. They indicated that decellularization with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) could show the best maintenance of both human and porcine lung extracellular matrix (LECM), with similar retention of LECM proteins except for elastin. They found that human and porcine LECM could efficiently support the cultivation of pulmonary cells in a similar way, except that the human LECM was stiffer and resulted in higher metabolic activity of the cells than porcine LECM [70] (Fig. 51.4). Epithelial and endothelial cells were seeded into the lungs to generate gas exchange tissue; before cell seeding, the lungs were decellularized by detergent perfusion. To inaugurate functionality of the lungs, the seeded cells were perfused in a bioreactor stimulating the physiological environment of the developing lung. Five days after, the lungs were tested for functionality, and it was shown that they generated gas exchange comparable with that of the native lungs, the in vitro testing showed that the seeding was successful. For in vivo testing, the lungs were transplanted into rats and perfused with the circulation and ventilated with the airways and respiratory muscles; it was found that they did provide successful gas exchange [71]. Lungs from adult rats were treated using a method to remove the cellular components of lungs but leave behind the structure of the extracellular matrix that preserves epithelium and vascular endothelium on the acellular lung matrix. The seeded epithelium scaffolds exhibited outstanding hierarchical organization within the matrix, whereas the seeded endothelium cells effectively repopulated the vascular region. The mechanical properties of the scaffold were tested in vitro, and results showed that the characteristics were similar to those of the native lung tissue; in vivo implantation showed the scaffolds participated in lung testing [37]. The seeding of cells can be done in a manifold of ways, including passive seeding using pipettes, dynamic seeding where the scaffolds are submerged in cell suspension, sheet-based cell seeding, electrostatic cell seeding, magnetic cell seeding, and photopolymerized hydrogels for cell seeding. The methods can be used individually or as a combination of techniques such as rotational systems, vacuums, pressure differential system, and bioreactor systems [72].

Comparison of decellularized human and porcine lung etracellular matrix

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Figure 51.4  Part (a): An overall approach of the decellularized scaffolds from human and porcine lungs. Three different methods of decellularization and three different types of human cells (lung fibroblasts, small airway epithelial cells, mesenchymal cells) were evaluated. Part (b): Ultrastructure of decellularized lung tissue and representative scanning electron micrographs are shown for all experimental groups, indicating that there were no major differences in ultrastructural morphology between human and porcine LECM. Native lung scaffolds showed smooth surfaces that were disrupted after decellularization, resulting in a more fibrillar structure and a rougher topographic profile. Decellularization using SDS showed the most fibrillar ultrastructure of all the methods. Part (c): Viability and metabolic activity of three human cell types on lung scaffolds decellularized by 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CHAPS). (i,ii): Cell viability (live cells stained green for calcein-AM, dead cells stained red for ethidium homodimer-1) for human lung fibroblasts (hMRC-5s), human small airway epithelial cells (hSAECs), and human adipose-derived mesenchymal stem cells (hMSCs) after 1 and 7 days of culture on decellularized lung scaffold. (iii,iv) Metabolic cell activity measured after 1 and 7 days of culture. (CHAPS = 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate; SDS = sodium dodecyl sulfate). Reused with permission from J. O’Neill, R. Anfang, A. Anandappa, J. Costa, J. Javidfar, H. Wobma, G. Singh, D. Freytes, M. Bacchetta, J. Sonett, G. Vunjak-Novakovic, Decellularization of human and porcine lung tissues for pulmonary tissue engineering, Ann Thorac Surg 96 (3) (2013) 1046–1056.

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51.7  Biological properties of lung scaffolds Tissue engineering seeks to repair diseased or damaged organs that are unable to carry out the necessary function using novel approaches. One such way that the functionality can be restored is by ensuring that the biological properties of the scaffold mimic those of the native organ; additionally upon implantation, the scaffold must live in coordination with the body. Below, the properties explained exhibit the importance of carefully selecting an appropriate biomaterial (discussed above), which is capable of displaying these properties.

51.7.1  Biocompatibility Defined as the performance of a medical device or scaffold after implantation, biocompatibility refers to the ability of such implanted devices to provide an appropriate response while living in harmony with the body [73]. Once an appropriate biomaterial is selected, it must be tested to ensure no toxic or harmful agents will be released into the bloodstream; moreover, it must be able to function in physiological conditions causing no reaction or adverse side effects to the native organ or to neighboring tissues. After implantation, the tissue-engineered scaffold must stimulate a negligible immune response to ensure that no severe inflammatory response is caused; if an immune response was demonstrated, then healing would be affected with rejection appearing to be likely [74]. Scaffolds fabricated for lung tissue engineering must be highly biocompatible, any toxicity could prove fatal as the lungs are vital respiratory organs, and bordering the lungs is the heart which is an important organ so adverse side effects must be kept insignificant [75].

51.7.2  Biodegradability Biodegradation is an important feature of scaffold fabrication, warranting the precise breakdown of the scaffold over time, which should, in turn, be replaced with newly regenerated tissue; also biodegradation is dependent on the molecular architecture and average molecular weight of the biomaterial [76]. A quicker degradation rate can improve cell proliferation and the mechanical properties of the scaffold [77]; for lung tissue engineering, mechanical properties are of great interest so biodegradation must be considered highly. Many biomaterials, both natural and synthetic, are available, which can be used in varying combination to provide the desired degradation rates [78]. Furthermore, biodegradable scaffolds provide adequate structural support to the native tissue although they provide limited permeability, which can hinder the success of the scaffold [79].

51.7.3  Pore size Pore size is a vital component of scaffolds, providing a region where cells can adhere, attach, migrate, and differentiate to recreate the extracellular matrix and an area for adequate nutrient transport and cell waste management. Pore size is critical for suitable

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cell infiltration and vascularization, enhancing the biological response of the scaffold. When the relevant pore size is small, the cell infiltration into the scaffold is slow as the seeded cells often remain on the border, which delays overall scaffold breakdown [80]. The flow rate during the electrospinning process can have an effect on the pore size; higher flow rate presents a greater pore size, subsequently creating scaffolds with a higher tensile strength [81]. Scaffold characterization was done using a scanning electron microscope, which allows for the surface of the scaffold to be analyzed [80]. As well as pore size, it is also important to consider average pore diameter, porosity, pore volume, and pore interconnectivity, which all have an effect on the aforementioned biological properties of the scaffold, along with the success of the scaffold in terms of functionality.

51.8  Mechanical properties of lung scaffolds The design of scaffolds necessitates the deliberation of mechanical properties as a central factor in the development of materials for tissue engineering [82]. Lung tissue is highly elastic and mechanically robust over thousands of millions of respiratory cycles during one’s life; appropriate respiration entails a subtle balance between strength and elasticity to allow for lung expansions during inspiration and expiration. The extracellular matrix of the lung parenchyma is composed of mainly collagen, elastin, and lamina; these structural proteins have a significant effect on the mechanical properties of the lungs [83]. The mechanical properties of scaffolds are reliant on the processing parameters, which can be modified for different organs and applications. Elastic modulus is regulated by the fiber diameter and orientation; thus, the scaffold architecture plays an integral role in the overall performance of the scaffold [84]. To create scaffolds suitable for lung tissue, the fiber diameter and orientation must be revised to create scaffold that replicates the properties of the lung.

51.9  Summary and future directions Tissue engineering is a rapidly evolving interdisciplinary disciple, which involves medicine, bioelectrics, biomaterials, and biomechanics. Because of a lack of suitable donors available, the need for tissue-engineered organs is currently a huge demand and necessitates the need for further research into this field. Selecting an appropriate biomaterial, suitable cell for cell seeding and adequate fabrication technique are essential to produce a scaffold that can resemble the organ or tissue, which is to be replaced. Electrospinning is the most advanced technique, although others are closely following; these include 3D bioprinting and freeze drying to fabricate tissue-engineered components. Organ-on-a-chip techniques are promptly developing to create biomimetic chips that imitate the obligatory function; in terms of lung, tissue engineering microsystems have been developed, which reconstruct the function of the lung [85].

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Existing research suggests that tissue-engineered scaffolds have not, as of yet, been trialed and implanted in humans; however, animal trials have proved to be a success. The need for human trials promotes ethical reasons; nevertheless it is necessary for production of scaffolds for humans to become widely available and, if possible, commercialization. Other organs have been used for medical applications and have ascertained the huge success of this method; such organs include the cornea, the skin, the kidney, the bladder, and many more. Lung tissue engineering requires further research, which can widen the procedure and allow scaffolds to be fabricated for a major organ.

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Further reading [1] L. Júnior, D. Silva, M. de Aguiar, C. de Melo, K. Alves, Preparation and characterization of polypyrrole/organophilic montmorillonite nanofibers obtained by electrospinning, J Mol Liq 275 (2019) 452–462.