Airway Involvement in Sarcoidosis
\r\n\tmolecular and imaging methods for detection and identification of plant diseases have many limitations that will be discussed in this book. This sparked interest in the development of minimally invasive and substrate general spectroscopic
\r\n\ttechniques that can be used directly in the field for confirmatory plant disease diagnostics.
\r\n\tThis book will also discuss recent progress in development of reflectance, infrared, Raman and surface-enhanced Raman
\r\n\tspectroscopy for detection and identification of plant diseases. It will also present advantages and disadvantages of these optical spectroscopy methods compared to the most common molecular and imaging techniques.
\r\n\tThe book also aims to discuss specific plant diseases, their symptoms and available methods of treatment.
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[6] Pathognomic for sarcoidosis, Lupus pernio is a plaque-like lesion that is usually swollen, scaly or shiny. Typically, it occurs on the nose, cheeks, lips or ears. [7] Lupus pernio is most commonly observed in African-American women [8] and approximately 20% of all sarcoidosis patients with the lesion have co-morbid upper respiratory tract disease. [9] The skin lesion often involves the nasal mucosa and sometimes the underlying cartilage and nasal bones are destroyed. [7]
Nasal disease is usually associated with sinus disease. [10, 11] However, the clinical manifestations of nasal granulomas differ from sinus granulomas. Nasal mucus membrane granulomas may cause nasal obstruction, [11] epistaxis, crusting, rhinorrhea, post-nasal drip, pain and anosmia. [3] Obstruction is usually the most common presenting symptom when polypoid granulomatous lesions involve the nasal septum and the inferior turbinate. Fergie and colleagues retrospectively reviewed eight patients with nasal sarcoidosis and found that epiphora was present in 4 patients. [12]
On examination, the nasal mucosa is usually hypertrophic, erythematous and granular. It may also contain polyps, masses and/or asymmetric crust-like patches. The nasal bones may demonstrate a variety of radiographic abnormalities. [9, 10] Septal perforation is rare but granulomatous inflammation of the nasal cartilage (figure 2) may result in the classic “saddle nose” deformity. [13] Occasionally, granulomatous lesions may erode through the hard or soft palate, creating intraoral lesions or oral-nasal fistulae. [14]
Sarcoidosis patient with Lupus Pernio.
Bronchcoscopic appearance of endobronchial sarcoidosis demonstrating nodules and inflamed mucosa that narrows the right upper lobe bronchus.
The symptoms of nasal obstruction and chronic sinusitis often occur in patients concomitantly. [10, 11] The most common symptoms associated with sarcoidosis of the sinuses are recurrent infections, epistaxis, periorbital tenderness, post-nasal drip and headache. [15] Patients with sarcoidosis of the sinuses usually have involvement of multiple organ systems. [11] Sarcoidal lesions in the sinus mucosa are generally similar to those found in the nasal mucosa. Examination often demonstrates erythematous, friable, hypertrophied mucosa. Crusting, studding, plaque-like changes or polyps may also be visualized. Rarely, granulomatous lesions extend out of the sinuses and into the orbit, resulting in proptosis and/or decreased unilateral visual acuity. [16] Sarcoidosis of the sinuses is generally a chronic and recalcitrant form of the disease that requires prolonged systemic therapy. [6, 17, 18]
The epiglottis, aryepiglottic folds, arytenoids, false cords and subglottis are the most commonly affected regions in the larynx. The true vocal cords are relatively devoid of lymphatic tissue and are rarely ridden with disease. [19] Granulomatous involvement of the larynx may cause life-threatening stridor or dysphagia. [10] On examination, the involved laryngeal mucosa is typically pale pink, granular and edenomatous. Lesions vary in their size and shape. Localized submucosal induration, punctate nodules or polypoid masses may be present. In one review of 40 patients with laryngeal sarcoidosis, the presenting symptoms were: dysphagia (85%), hoarseness (63%), dyspnea or stridor (47%) and cough (13%). [20] Ulceration of the mucosa is rare. Patients also present with hoarseness, dysphonia, cough, dyspnea, a sensation of a lump in the throat and obstructive sleep apnea. [21]
Hoarseness is typically caused by granulomatous laryngitis. However, laryngeal sarcoidosis may cause hoarseness by two additional mechanisms. [22, 23] The first involves granulomatous infiltration of the vagus nerve, resulting in a polyneuropathy. Limited data suggests that vagal polyneuropathy is rare [24] and if present, is typically associated with other cranial neuropathies. [21] In rare cases, hoarseness may result from mediastinal lymphadenopathy that compresses the recurrent laryngeal nerve, resulting in vocal cord paralysis. The left recurrent laryngeal nerve is affected in more than 95% of cases. [21, 25] The predilection for left-sided injury results from the longer and more vulnerable course of the left recurrent laryngeal nerve through the mediastinum.
In one report, a young female presented with daytime hypersomnolence and snoring. [26]
Nasopharyngoscopy demonstrated an irregularly shaped and narrowed subglottis. Subsequent biopsy confirmed the presence of non-caseating granulomas. The patient was diagnosed with obstructive sleep apnea, secondary to laryngeal sarcoidosis. To determine the prevalence and risk factors for obstructive sleep apnea in sarcoidosis patients, 83 patients with sarcoidosis were prospectively evaluated. [27] The Epworth Sleepiness Scale was used to assess enrolled patients. A control group of 91 patients were similarly screened. Patients with a positive sleep questionnaire were referred for sleep studies. A total of 14 sarcoidosis patients (17%) were found to have sleep apnea, which was significantly higher than in the control group where 3/91 were found to have obstructive disease (3%, p < 0.001). [27] Lupus pernio was significantly more frequent in the sleep apnea group. [27] Although granulomatous laryngitis may be associated with obstructive sleep apnea, obstructive sleep apnea in patients with sarcoidosis usually results from obesity secondary to the administration of chronic corticosteroids.
Sarcoidal involvement of the trachea is rare [28] and the literature on tracheal sarcodosis is sparse. Tracheal stenosis and dystonia are the primary manifestations that have been described. [28, 29] Brandstetter and associates [30] described a patient who complained of deteriorating voice strength for 30 years and eventually, stridulent breathing that was refractory to corticosteriods. In 1949, Lemoine described tracheal dystonia (tracheal collapse most pronounced on expiration) in sarcoidosis. Ellefsen detailed a 44-year-old female who complained of progressive dyspnea for 4 years prior to admission to the hospital. [29] She eventually developed wheezing and a severe nonproductive cough. Physical exam showed stridor and wheezing.
Bronchial sarcoidosis was first described at autopsy by Bernstein and colleagues in 1929 and subsequently on bronchcoscopy by Benedict and Castleman in 1941. [31] Numerous case series have followed. [32-37] Granulomatous lesions typically occur in the bronchial submucosa. [37] The bronchial mucosa often appears inflamed with small or large nodules containing granulomas. [37] (Figure 2) Granulomatous involvement of the bronchi may cause edema and/or an endobronchial masses that results in reversible narrowing of the large airways. [33, 36, 37] Irreversible narrowing, especially of the right middle lobe bronchus, results from cicatricial stenosis. [33] Reversible or irreversible bronchial stenosis occurs more commonly in the presence of end-stage pulmonary fibrosis. But bronchostenosis may occur in milder stages of the disease. [33, 36, 37] Bronchial sarcoidosis may be isolated (one stenotic point) or diffuse (multiple stenotic points) involving the lobar or segmental bronchi. Compressive mediastinal and/or bronchopulmonary lymphadenopathy is rarely a cause of stenoses at these locations within the airway. [38, 39]
Patients with bronchial sarcoidosis present with dyspnea, cough and wheezing that is often misdiagnosed as asthma. [10] The symptoms generally progress and are refractory to bronchodilators and inhaled corticosteroids. Bronchial sarcoidosis is suggested by obstructive airways disease (a reduced ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC]) that may be accompanied by airways hyperreactivity on pulmonary function tests. Bronchoscopic inspection of the airways with or without biopsy of the parenchyma is the most efficient method to confirm the diagnosis. Endobronchial involvement is common in sarcoidosis. Endobronchial biopsy has a yield comparable to transbronchial biopsy and can safely increase the diagnostic value of fiberoptic bronchoscopy. Performance of endobronchial biopsies should routinely be considered in cases of suspected sarcoidosis.
Small airways disease is an underappreciated manifestation of pulmonary sarcoidosis. Regional air trapping, indicative of small airways disease, may be visualized on expiratory HRCT [40] and newer imaging modalities such as hyperpolarized 3-H MRI, [41, 42] in patients with pulmonary sarcoidosis who have obstructive airways disease. Peripheral airway obstruction with involvement of small airways may be caused by the formation of granulomas in a perilymphatic distribution along the bronchovascular bundles. [41, 43] Small airways dysfunction can be measured by forced expiratory flow during the middle half of the forced expiratory curve (MMEF25-75%), forced expiratory volume at 3 seconds (FEV3) ratio of the residual volume to the total lung capacity (RV/TLC). In one study, the extent of air trapping on HRCT correlated significantly with RV/TLC and MMEF25-75%. [41, 43] In other studies, however, these physiologic measurements were highly variable and provided limited clinical information. [43-45]
Patients with small airways disease typically present with progressive dyspnea, cough and wheeze. They may also exhibit stridulent breathing. Lung auscultation demonstrates wheezing, stridor or squeaks.
Skin of the Nose (Lupus Pernio) | \n\t\t
Nares | \n\t\t
Nasal Septum | \n\t\t
Sinuses | \n\t\t
Larynx | \n\t\t
Vocal Cords | \n\t\t
Trachea | \n\t\t
Bronchi | \n\t\t
Bronchioles | \n\t\t
Airway Involvement in Sarcoidosis
\n\t\t\t\tINFECTIOUS\n\t\t\t | \n\t\t\t\n\t\t\t\tNON-INFECTIOUS\n\t\t\t | \n\t\t
Tuberculosis | \n\t\t\tSarcoidosis | \n\t\t
Atypical Mycobacterial Disease | \n\t\t\tWegener’s Granulomatosis | \n\t\t
Syphilis | \n\t\t\tBerylliosis | \n\t\t
Leprosy | \n\t\t\tSilicosis | \n\t\t
Aspergillosis | \n\t\t\tHypersensitivity Pneumonitis | \n\t\t
Histoplasmosis | \n\t\t\tLymphoma | \n\t\t
Rhinoscleroma | \n\t\t\tCocaine | \n\t\t
Coccidioidomycosis | \n\t\t\tChurg-Strauss Syndrome | \n\t\t
Toxoplasmosis | \n\t\t\tTalc | \n\t\t
Actinomycosis | \n\t\t\tLymphoid Interstitial Pneumonia | \n\t\t
Cryptoccosis | \n\t\t\tRheumatoid Nodule | \n\t\t
Differential Diagnosis of Granulomatous Airways Diseases
“Reprinted from Mukhopadhyay, S. et al…, Granulomatous Lung Disease: An Approach to the Differential Diagnosis. May 2010, Vol. 134, No. 5, pp. 667-690 with permission from Archives of Pathology & Laboratory Medicine. Copyright 2010. College of American Pathologists.”
The incidence of airway hyperreactivity (AHR) in sarcoidosis is highly variable. Airway hyperreactivity has been observed in approximately 20%--50% of sarcoidosis patients. [46, 47] The statistical discrepancy probably results from different patient populations, study designs and different definitions of sarcoidosis and AHR.
Airway hyperreactivity has important clinical and prognostic implications in sarcoidosis. [47] Many patients with sarcoidosis exhibit normal pulmonary function and imaging but complain of cough, dyspnea and wheeze. The wall of the airway may be narrowed and thickened as a result of airway hyperreactivity or may collapse from an extrinsic pathologic process in the lung. Airway hyperreactivity in sarcoidosis may also cause chronic airflow obstruction, which has been associated with a poor prognosis. [47, 48] Fixed airway obstruction has been shown to nearly double the risk of mortality. [47]
The prevalence of AHR, as demonstrated by a positive methacholine challenge test, is significantly higher in sarcoidosis patients compared to normal controls. [1, 47] It is unclear whether AHR is a physiologic manifestation of endobronchial sarcoidosis or reversible airways disease in asthma. Rarely, asthma may be associated with sarcoidosis. [49] Airway hyperreactivity in sarcoidosis and reversible airways disease in asthma may often be distinguished by response to inhaled corticosteroids and/or beta-agonists. Asthmatic reactive airways disease usually improves with these medications. But AHR in sarcoidosis commonly requires treatment with oral corticosteroids. [33, 47] In many cases, AHR in sarcoidosis does not improve with systemic corticosteroids.
Importantly, cough and wheeze secondary to AHR (as demonstrated by positive methacholine challenge testing) should not be confused with cough and wheeze unrelated to AHR. Sarcoidal cough and wheeze\n\t\t\t\t\tunrelated to AHR responds favorably to inhaled corticosteroids and/or beta-agonists as does asthmatic cough and wheeze related to AHR. [47] Sarcoidal cough and wheeze associated with AHR, however, may require treatment with oral corticosteroids, which is often ineffective.
Several studies suggests that AHR in sarcoidosis correlates with both the degree of alveolitis and angiotensin converting enzyme (ACE) levels in bronchoalveolar lavage (BAL) fluid and serum. [50] In addition, higher serum ACE levels were found in sarcodosis patients with hyperreactivity. [47] Finally, patients with AHR were more likely to have a positive endobronchial biopsy (9/9, 100%) compared to individuals without hyperreactivity (15/33, 45.5%), which suggests that AHR is present in patients with more pronounced bronchial inflammation. [47]
Lobar atelectasis may result from occlusion of a lobar bronchus. Bronchial obstruction may be caused by one of two mechanisms: endobronchial stenosis [37] or rarely, by extrinsic compression of the bronchus by enlarged lymph nodes. [51, 52] Atelectasis of the middle lobe is most common but atelectasis of the right upper lobe has also been reported. [53] The middle lobe is particularly susceptible to collapse because it has a small bronchial lumen, surrounded by many lymph nodes and emerges at a right angle from the bronchus intermedius. Collapse of the right upper lobe may result in the radiographic S-sign of Golden, which is commonly associated with cancer. Resolution of atelectasis is variable and it may occur even after several years. [54]
Chronic, progressive, end-stage, pulmonary fibrosis with traction bronchiectasis, often referred to as “honeycomb lung”, develops in approximately 25% of patients with chronic pulmonary sarcoidosis. [40, 55] The condition is characterized by parenchymal fibrosis, bronchiolectasis and enlarged, dilated air spaces. It usually occurs subpleurally within the upper regions of the lung [40, 56] (figure 3). Oxygenation and ventilatory function are impaired. Pulmonary function tests demonstrate severe restriction and gas transfer abnormalities. Importantly, fibrosis characterized by a stage IV radiographic pattern, rarely responds to treatment.
Sarcoidosis patient with granulomatous inflammation of the nasal cartilage
Bullea (thin-walled air spaces in the lungs) may develop in patients with advanced pulmonary sarcoidosis. Most sarcoidosis patients with bullous disease do not exhibit an extensive smoking history and have airflow obstruction on pulmonary function tests. [10, 57] Dilatation and rupture of bullae probably results from granulomatous bronchostenosis. [58] Bullae may develop secondary to destruction of alveolar walls by alveolitis. [58] Bullous rupture may cause pneumothorax.
Giant bullous changes in sarcoidosis may rarely cause the Vanishing Lung Syndrome. [59] First described by Burke in 1937, the Vanishing Lung Syndrome describes an end stage of diffuse panacinar emphysema in which large air spaces develop, further impairing lung function. [59] Miller and associates reported two cases of the Vanishing Lung Syndrome. Postmortem analysis of the lungs demonstrated that the bullae were quite different from the localized air spaces frequently seen in chronic pulmonary sarcoidosis. [10, 60]
Although the terms cyst and cavity have overlapping meanings and may be used interchangeably, the technical definitions of these terms are different. Cysts are clearly defined air-containing space surrounded by a relatively thin (≤ 4 mm) wall. A cavity, in contrast, is meant to describe an air-containing lesion with a relatively thick (> 4 mm) wall or within an area of a surrounding infiltrate or mass. The distinction is useful because there is a different diagnostic approach to these anatomic structures. [61]
True cavitary lung disease, which results from necrosis of granulomatous areas creating airspaces within thick walls or within a fibrotic mass, is rare in sarcoidosis. Sarcoidal cavities must be differentiated from those associated with mycobacterial infection. The radiographic cystic changes that occur in advanced sarcoidosis are typically consistent with saccular bronchiectasis, rather than true cavitations. [57, 61] Saccular or cylindrical bronchiectasis likely results from bronchial wall injury by granulomas, superimposed bronchial infection and radial traction by peribronchial scar tissue. Colonization of the bronchiectatic sacs by Aspergillus sp., may result in the development of an aspergilloma. Patients with aspergillomas complicating sarcoidosis may have life-threatening hemoptysis but, as a result of their advanced lung disease, are usually high-risk surgical candidates. [62]
Intracavitary instillation of antifungal agents is an alternative treatment in patients with severe pulmonary dysfunction who are poor operative risks. Percutaneous instillation of amphotericin B guided by CT scans may be effective for the treatment of aspergilloma. [63] In several cases, the intervention has led to resolution of hemoptysis. [63] The response to percutaneous injection of amphotericin B appears to be sustainable for several months. [63]
Israel and associates evaluated the role of surgery in 38 sarcoidosis patients with pulmonary aspergillomas, 10 of whom were considered satisfactory operative candidates. [64] Satisfactory candidates demonstrated a forced vital capacity greater than 50% predicted and a resting PaO2 greater than 80 mmHg. The indication for surgical resection in satisfactory and unsatisfactory candidates was recurrent hemoptysis. Seven satisfactory and 7 unsatisfactory candidates underwent segmental resection, lobectomy or bilobectomy. The authors did not specify the type of procedure that each patient received. Patients were followed postoperatively for an unspecified duration. Among the 7 satisfactory candidates who underwent resection, 1 patient died from empyema immediately after surgery. Three of 7 patients with unsatisfactory pulmonary function died of respiratory failure 1 month, 11 months and 27 months, respectively, after surgery. Twenty-one patients with poor pulmonary function did not have surgery. Four patients died of recurrent hemorrhage 4 months to 3 years after discovery of the aspergilloma. Eleven patients died of respiratory failure and 6 survived at the time of publication (1982) although it is unclear when these patients were diagnosed with their aspergilloma. The principle complications of surgical resection were prolonged air leaks, bronchopleural fistulae and empyema. The authors concluded that surgical resection should generally be avoided in patients with bilateral disease and compromised pulmonary function. The indication for surgery in all patients, especially those with poor pulmonary function, should be recurrent hemoptysis because it may cause exsanguinating hemorrhage, which poses a greater risk to the patient than surgical intervention. [64]
Computed tomography (CT) is often the imaging method of choice for sarcoidosis of the upper and lower respiratory tract. [40] Braun and associates analyzed the CT findings of 15 patients with sinonasal sarcoidosis. [20] A spectrum of abnormalities were evaluated: nodular lesions of the septum and/or inferior turbinates; mucosal thickening and complete or subtotal opacification of the ethmoidal, maxillary and/or sphenoid sinuses; obstruction of the ostiomeatal units and of the upper part of the nasal cavities; turbinoseptal synechiae; destruction or erosion of the turbinates, nasal bones, septum, ethmoid air cells and sphenoid sinus.
CT scan has a high sensitivity for detecting sarcoidosis of the larynx or trachea. [65] Typically, the CT demonstrates stenosis of the larynx and trachea.
Airways sarcoidosis produces a variety of abnormalities on CT scan of the lungs. Several CT studies performed at near residual volume (end expiration) have demonstrated air-trapping in pulmonary sarcoidosis. [40, 66, 67] Davies and colleagues reported that air-trapping on expiratory CT was present in 95% of 21 sarcoidosis patients and correlated with physiologic obstruction by percentage predicted residual volume (RV)/ total lung capacity (TLC) (p < 0.05) and percentage predicted maximal mid-expiratory flow rate between 25% and 75% of the vital capacity (VC) (p < 0.05). [41] The CT may also demonstrate focal bronchial lesions, atelectasis, bullous disease, fibrosis/honeycombing, cavitary lung disease, bronchiectasis (saccular or cylindrical) and mycetomas
The respiratory tract is typically divided into the upper and lower airways at the level of the vocal cords. The physiology of obstruction to the upper airways depends on the location of the obstruction (intrathoracic or extrathoracic) and whether it is fixed or variable within the respiratory cycle. Granulomatous involvement of the larynx results in a fixed upper airway obstruction. When tracheal sarcoidosis results in stenosis, it may cause a fixed upper airway obstruction (figure 4) or a variable extrathoracic or intrathoracic obstruction (figure 4) depending on whether it is located above (extrathoracic) or below (intrathoracic) the thoracic inlet (level of the supra-sternal notch). In a fixed upper airway obstruction, there is flattening of the inspiratory and expiratory limbs of the flow volume loop. A variable extrathoracic obstruction causes flattening of the inspiratory portion of the flow volume loop, while a variable intrathoracic obstruction causes flattening of the expiratory portion of the loop. Spirometry commonly indicates restrictive ventilatory dysfunction. At least 50% of patients have concurrent obstructive airways disease, evidenced by a reduced ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC). [2, 68] Airway hyperreactivity assessed by methacholine challenge test occurs in 5-83% of patients. [47, 68]
Sarcoidosis patient with “honeycomb lung”.
Flow volume loops demonstrating various types of airways obstruction.
The diagnosis of sarcoidosis is confirmed by histologic evidence of non-caseating, epitheliod granulomas. Tissue is obtained from the upper airways by direct nasopharyngoscopy. Transbronchial and/or mucosal biopsies of the lower airways may be obtained by bronchocoscopy, the diagnostic procedure of choice for sarcoidosis.
There are no controlled studies that examine the variety of therapeutic agents, which are purported to be effective in the treatment of sarcoidosis. There is consensus by experienced physicians that corticosteroids are the most efficacious medication. None of the other therapies share this favorable level of support. Oral corticosteroids are given in the smallest possible dose to limit their adverse effects. Since upper airways obstruction occurs in chronic sarcoidosis, ‘steroid-sparring’ medications may be administered simultaneously to reduce the corticosteroid dose that would be needed if it is given for many months. Hydroxychloroquine has been used with some success for cutaneous sarcoidosis. [69] Minocycline is also effective for the treatment of skin lesions. [70, 71] Minocycline appears to inhibit metalloproteinases, angiogenesis, apoptosis and in vitro granuloma formation. [68, 72]
The treatment of sinus and nasal sarcoidosis should be tailored to the specific organ system or systems involved and to the extent of disease. [14, 16] Isolated sinonasal disease can be treated by topical corticosteroids and/or intra-lesional steroid injections. [73] Nasal irrigations and emollients may be used to ameliorate nasal crusting. Siltzbach and Teirstein used chloroquine to treat 14 pataients with intrathoracic and cutaneous sarcoidosis. All of the patients showed relative improvement in their cutaneous lesions and most exhibited radiographic improvement of their intrathoracic disease. Johns and colleagues used hydroxychloroquine, a drug with less ocular toxicity, to treat mucosal lesions. [74] Patients taking hydroxychloroquine must have an ophthalmic exam every 6 months. Hassid reported a patient with biopsy-proven sarcoidosis of the paranasal sinuses who was successfully treated with hydroxychloroquine 200 mg orally, twice daily for one month and 200 mg per day for an additional 7 months. [75] Despite these results, the overall response rate for antimalarial drugs is probably less than 50% [76] and the drugs are often reserved for patients with cutaneous or sinonasal sarcoidosis, in whom the response to treatment can be easily observed. [76]
Methotrexate may also be used for the treatment of cutaneous sarcoidosis. In several case reports, skin lesions improved in patients who were treated with methotrexate 10 mg to 15 mg per week. [77] Although azathioprine has been commonly used as a corticosteroid-sparing agent for many forms of sarcoidosis, it has rarely been reported for the treatment of skin sarcoidosis. [7] Tumor necrosis factor-a (TNF-a) antagonists have been reported to be useful in the treatment of sarcoidosis, including cutaneous sarcoidosis. [78] Inflixamab appears to be the most efficacious of the biologics. It may be especially useful in the treatment of lupus pernio. [78]
The indication for surgical intervention of sinonasal granulomatous lesions is controversial.
While surgery may reduce symptoms, it does not eradicate or prevent recurrence of disease. [14, 17, 79] Neville and associates evaluated 34 patients with sarcoidosis of the upper respiratory tract, [9] 3 of whom, underwent submucous resection. In 2 of 3 patients the resection was complicated by nasal septal perforation. Aubart and colleagues operated on 7 patients. [17] Nasal and sinus involvement recurred in all of them and sinus symptoms worsened in 1 patient after surgery. But two additional studies suggest that endoscopic sinus surgery may have a therapeutic role in patients with nasal obstruction or chronic sinusitis caused by anatomic blockage from sinonasal sarcoidosis. [18, 80] Removal of the obstructing lesion(s) may facilitate improved sinonasal hygiene by permitting endoscopic debridement, nasal irrigation and topical administration of medicines into the sinonasal tract. Surgical intervention should not be used to treat patients with symptoms related to crusting, atrophy or bleeding. While surgery may improve one’s quality of life by relieving severe symptoms and may even reduce the need for oral steroids, it is almost never curative.
Laryngeal sarcoidosis may cause life-threatening upper airway obstruction. As a result, early diagnosis and proper management is essential. The treatment of laryngeal sarcoidosis depends on the severity of the symptoms. Asymptomatic patients do not require therapy. [5, 19, 81] But close monitoring is warranted. It may be difficult to assess the efficacy of various treatment modalities because spontaneous remissions of disease punctuate the natural evolution of sarcodosis. [51, 67] Systemic corticosteroids are the mainstay of treatment for laryngeal sarcoidosis, especially for impending laryngeal obstruction. [1, 10] Methotrexate has been used with some success in the treatment of laryngeal sarcoidosis. One patient with granulomatous laryngitis responded to treatment with azathioprine. Intra-lesional steroid injections of the larynx for selected patients with well-circumscribed disease is modestly effective. [5, 21] When the airway is compromised and stridor is present, emergent tracheostomy should be performed. [21] Tracheostomy may also be an appropriate for patients who develop marked adverse effects from systemic corticosteroids. [82] Tracheostomy is often used as a temporizing measure until corticosteroids are able to effectively reduce granulomatous inflammation. Surgical intervention for laryngeal sarcoidosis is effective for patients with well-localized, life threatening lesions. [5] Typically, the goals of surgery are to create an adequate airway, avoid aspiration, avoid tracheostomy and preserve the voice. [5, 83] Low-dose external beam radiation therapy (3000 rads during 6 weeks) has been utilized in selected patients. [5, 84] It is generally reserved for patients in whom intra-lesional steroids or local excision of granulomatous tissue are not feasible and/or in those who are refractory to or cannot tolerate systemic corticosteroids. [5, 82]
Tracheal involvement in sarcoidosis is limited to the description of tracheal dystonia [29] and tracheal stenosis. [29, 30] Brandstetter and colleagues used high-dose systemic corticosteriods to treat a patient with tracheal stenosis. The patient failed to stabilize with the treatment but ultimately underwent successful bronchoscopic tracheal dilatation. [30] Tracheal stents have been used with limited success for tracheobronchial obstruction in pediatric patients. [85]
Patients with bronchostenosis respond poorly to treatment with systemic corticosteroids. [33, 37, 46, 47, 53] Fouty and associates used a flexible fiberoptic bronchoscope and a Fogarty embolectomy catheter to dilate multiple bronchial stenoses under direct vision. [86] The six patients who underwent the procedure were symptomatic and refractory to corticosteroids. All of them obtained subjective symptomatic benefit from the dilatation. Three of the patients required repeated dilatation on a long-term basis. Complications from the procedure were minimal. Collectively, these studies suggest that bronchial dilatation is a safe option for sarcoidosis patients with stenoses who are refractory to systemic corticosteroids.
The majority of patients with sarcoidosis improve with therapy. However, 10-30% of patients develop progressive pulmonary fibrosis, which may result in advanced airways disease such as bronchiectasis, bullae and cavitation. Rarely, patients with bronchiectasis will improve with corticosteroids, antibiotics and/or nonsteroidal anti-inflammatory medications. [87] If patients do respond, it is generally short-lived. Bullectomies performed for bullous sarcoidosis may improve pulmonary function and symptoms. [57, 58] Surgical resection of the cavity and removal of the fungus ball is the mainstay of treatment for aspergilloma(s). [88] The primary indication for resection is recurrent hemoptysis. Bronchial artery embolization is modestly effective in inoperable patients. [89] Taken together, advanced involvement in sarcoidosis is seldom responsive to medical therapy, moderately responsive to surgical therapy depending on the type of underlying disease and has an ominous prognosis. Finally, sarcoidosis patients with fibrotic lung disease and/or airways dysfunction often develop pulmonary hypertension, which often has an unfavorable prognosis.
Sarcoidosis is a chronic granulomatous disease of undetermined etiology that can involve any organ system within the body. Greater than 90% of patients with sarcoidosis have interstitial lung disease. [2] But the upper and lower respiratory tract is also affected. Sarcoidosis is one of a few interstitial lung diseases that involves the entire respiratory tract; beginning at the nose and ending at the terminal bronchioles.
Although many patients are asymptomatic, most complain of dyspnea, cough and/or wheezing, Patients with sarcoidosis of the upper respiratory tract present with a variety of symptoms, which are primarily determined by the anatomic location of the granulomatous inflammation and/or scarring that may result from chronic disease. The diagnosis of upper or lower respiratory tract disease is frequently ascertained by bronchoscopy.
Computed tomography (CT), the imaging method of choice for sarcoidosis of the upper and lower respiratory tract, may demonstrate lesions within the sinonasal tract, larynx and trachea, large and small airways or parenchyma. It may also reveal mediastinal and/or hilar lymphadenopathy.
The physiology of airways obstruction depends on the location of the obstruction (intrathoracic or extrathoracic) and whether it is fixed or variable within the respiratory cycle. Granulomatous involvement of the larynx results in a fixed upper airway obstruction. Tracheal sarcoidosis may cause a fixed upper airway obstruction, or a variable extrathoracic or intrathoracic obstruction, depending on whether the lesion is located above (extrathoracic) or below (intrathoracic) the thoracic inlet (level of the supra-sternal notch).
Patients with pulmonary sarcoidosis may exhibit obstructive, restrictive, restrictive and obstructive, or gas transfer abnormalities. Corticosteroids are the mainstay of therapy for upper respiratory tract disease. However, other immunosuppressive treatments may be effective for the treatment of skin and sinonasal sarcoidosis. Patients with endobronchial or tracheal stenoses who are refractory to steroid therapy may derive some benefit from mechanical dilatation of the airways. [86] Surgical intervention may be required for treatment of bullous sarcoidosis and aspergilloma. [57, 58]
3D printing is an additive manufacturing (AM) process that enables the manufacturing of components with complex geometries in a layer-by-layer fashion. 3D printing became popular after the first machine was introduced to the market in 1986 by Hull [1]. Charles Hull created the first stereolithography (SLA) manufacturing method which he used for the rapid design and manufacturing of small prototype plastic parts. Stereolithography uses light to activate polymers within a resin (photopolymerization) to create 3D, complex shapes [2, 3]. This SLA system was commercialized in 1987 by the company 3D Systems. Since this breakthrough invention, there has been great effort in producing machines that can process a variety of plastics. Some of the machines currently in the market are fused deposition modeling (FDM) [4, 5] and direct ink write (DIW) for extrusion-based processes [6, 7]. Powder bed fusion (PBF) and laser sintering (SLS) are used for processes requiring a laser to cure or fuse polymeric materials [8]. Inkjet printers also use light to photopolymerize ink drops into complex shapes [9]. Extensive reviews on these processing and 3D printing technologies have been published elsewhere [4, 5, 10, 11, 12, 13, 14]. This chapter focuses on applications that use AM for the 3D printing of polymeric materials.
\nSince the 1980s, 3D printing has become very popular as a result of the rapid manufacturing of components with architectures designed to meet specific applications. AM allows for the manufacturing of a variety of shapes in a layer-by-layer fashion, often without the need of post-processing such as machining. As a general scheme, AM starts with the design of a virtual object using CAD (computer-aided design) software that generates a STL (stereolithography, named after Charles Hull’s SLA process) file format [15]. A slicer program interprets the STL file and converts it into g-code (e.g. Slic3r, 3DPrinterOS, MakerBot Print, and others). The computer controls the stage and dispenser of the 3D printer allowing prototypes to be manufactured. Rapid prototyping allows one to refine product ideas while saving significant time and money because it allows for iterations prior to creating a final product. Optimization via an iterative process involves touching and feeling the prototype, in real time, in order to finalize the shape and geometry, leading to a final product. Characterization methods during iterations and on the final design include optical microscopy, SEM, and mechanical tests. Others methods, such as bio-compatibility (cell-adhesion and proliferation) and electrical performance are performed depending on the application. Figure 1 demonstrates a general scheme for the AM process. Despite the many advances in AM, the technology still has many challenges that need to be addressed. These challenges are related to the speed of the processes (which in many cases is slower than injection molding processes and machining), cost of the machines, and limited feedstock. However, advantages outweigh the challenges due to the fact that AM allows for compositional flexibility, complex macro and microstructures, and easy modeling and optimization. As a result, industries including biomedical engineering, transportation, and the military have adopted AM as the main manufacturing method for the printing of prototypes and final parts [16, 17].
\nGeneral scheme for the use of additive manufacturing processes, from the choice of material to the final product. The 3D printing of parts involves the use of a computer-assisted design software that generates a STL file format that is then sliced and formatted into gcode. The computer controls the stage and dispenser to generate materials with specific architectures, e.g. faced-centered tetragonal cushion using direct ink writing (a) and diamond structure using FDM (b).
Careful attention is imperative when choosing a material to print a given part. While there are a variety of commercially available polymers, not one polymer is inclusive and will give one the properties needed for a specific application. Furthermore, a single AM technique is not capable of printing any one individual polymer available in the market. The selection of material depends on the application and the customers’ needs. Figure 2 lists the decision criteria for the selection of a material. One must take into consideration the environment at which the part will be exposed and the properties required (e.g. temperature, mechanical load, humidity, chemical exposure, radiation, UV light), the processability, 3D printing method, and availability.
\nMaterial selection chart for product design and manufacturing.
Polymers have become consumer goods, for they are used to manufacture bottles, toys, tools, bags, phones, computers, tools, cushions, electronics and transportation components [18]. Thus, it makes sense that efforts have focused on developing materials that can be 3D printed, which allows for rapid manufacturing [2, 3, 4, 17]. Table 1 lists commercially available polymers used in some of the AM processes. Polycarbonate (PC), acrylonitrile butadiene styrene (ABS), poly ether ester ketone (PEEK), polyetherimide (ULTEM) and Nylon are common polymers used in processes requiring thermoplastics, or plastics that are processed by heating to a semi-liquid state and close to the melting point. Upon extrusion, the printed layers fuse and solidify. AM techniques that use thermoplastics are Fused-Deposition Modeling (FDM), Jetting (InkJet), and Selective Laser Sintering (SLS). SLA and Direct Ink Writing (DIW) use thermosetting polymers in their liquid state, or polymers that become solids after curing. A chemical reaction occurs prior to the melting point, resulting in a solid-state material. In SLA and DIW, polymers are formulated to meet specific properties, most importantly rheological. For example, each layer should be self-supporting and should allow for the printing of multiple layers while retaining the designed geometry [14, 19, 20, 21]. Rheologically, this corresponds to a resin that has a yield stress at high oscillatory stresses, such that the resin is solid-like at rest (low stress) and liquid like during flow (high stress) [7]. One of the main challenges in the polymer 3D printing industry is the limited feedstock available for purchase. Polymers listed in Table 1 cannot be used in all applications. Particularly, polymers in the pure state lack mechanical strength for load-bearing applications. The addition of fillers, such as silica [22, 23] and carbon fibers [24, 25], is often used to generate materials with high mechanical strength. Furthermore, the incorporation of additives enhances materials properties by adding functionality to the parts that include getter [20], UV and radiation resistance [26, 27, 28], and anti-fouling properties [29, 30, 31].
\nAM technology | \nProcess | \nPhysical state of starting material | \nFeedstock | \n
---|---|---|---|
FDM | \nMelting-solidifying | \nSolid | \nPC, ABS, PLA, ULTEM, Nylon, Carbon-filled Nylon, ASA | \n
SLA | \nPhotocuring | \nLiquid | \nThermosetting- acrylates and epoxy | \n
SLS | \nMelting-solidifying | \nSolid | \nPCL, PLA | \n
Jetting | \nPhotocuring | \nSolid | \nABS, ASA, PCL, PLA, Vero | \n
Direct Writing | \nExtrusion-heat/UV curing | \nliquid | \nThermosetting- any material with adequate viscosity | \n
List of polymers used for 3D printing applications.
The biomedical market represents 11% of the total AM market share today, and will be a strong driver for AM development and growth [32]. Since the early 2000s, there has been increased interest in using 3D printing to fabricate hard tissues (bones, teeth, cartilage) and soft tissues (organs, skin, and others) [2, 3, 4, 16, 33]. The manufacturing of prostheses and scaffolds with complex geometries is especially important for regenerative medicine, where a porous scaffold is implanted into the patient to serve as a template for tissue to regenerate while the implant degrades slowly in the body. Other implants need to stay in place for the lifetime of the patient. 3D printing allows for the rapid manufacturing of customized prosthetics and implants with controlled architectures. The structure can be designed through the translation of x-ray, MRI, and CT images into STL file formats. The STL file can be processed by software and a design can be generated based on the patient’s specific needs. Metals are commonly used to generate prosthetics for bone reconstruction. ABS and PLA are the most suitable non-biodegradable polymers used for the manufacturing of scaffolds. However, materials used in medicine must enable cell adhesion, growth, and differentiation. Current feedstock for biomaterials is limited to collagen, gelatin, fibrin, and chitosan, which are similar to natural tissue, have high affinity to cells and are highly hydrated. The main challenge with these soft natural polymers is their low mechanical strength [33]. In biomedical engineering, the main focus has been on the development of biopolymeric materials for tissue and scaffold generations with improved flexibility, strength, and patient compatibility in order to prevent implant rejection and toxicity. Some polymeric mixtures include living cells isolated from the patient and grown in the laboratory. These types of polymers are often hydrogels suitable for ink jet 3D printing technologies. Table 2 shows various polymers used for biomedical applications. Some examples of biomedical devices developed using 3D printing are implants, prosthetics, dental, orthodontics, hearing aids, and drug release tissues.
\nMaterial | \n3D printing techniques | \nComments | \n
---|---|---|
PLA, PCLA, PLGA | \nFDM | \nScaffolds. Biodegradable. Can add fillers, e.g. HA, for improved cell adhesion and mechanical properties | \n
Collagen, alginate, PEG, fibrin, chitosan | \nInkjet, extrusion | \nBiodegradable scaffolds. Can add fillers and cells for improved cell adhesion and mechanical properties | \n
PCL, methacrylate copolymers | \nSLS | \nBiodegradable scaffolds. Improved mechanical properties | \n
Polymers and processes used for the additive manufacturing of biomedical devices.
Polymers used for tissue and organ fabrication need to have various functions in order to (1) allow for cell attachment and migration, (2) transfer growth factors and waste products, (3) maintain its shape while cells are growing and (4) maintain adequate mechanical properties. Wu et al. [34] reported the generation of a biopolymeric material based on chitosan dissolved in an acid mixture of acetic acid, lactic acid, and citric acid. This biomaterial was 3D printed using an ink-writing technique, then dried under vacuum and neutralized to remove any acid residue. The structure of the scaffold was characterized using confocal laser scanning microscopy and the images showed wrinkles attributed to the volume change. Tensile mechanical tests show that the printed material exhibits a strain to failure of 400% under tensile load and a 7.5 MPa ultimate strength when in its neutralized form. Furthermore, the 3D printed material allows for excellent cell adhesion, growth, and proliferation, as demonstrated using the Live-Dead staining method, fluorescence microscopy, and SEM.
\nLuo et al. [35] reported the 3D printing of a bioceramic hollow struts-packed scaffold using an extrusion typ. 3D printer and a shell/core nozzle. The ink contained Ca7Si2P2O16, alginate and Pluronic F-127. After printing, the ink was dried overnight and sintered for 3 hours at 1400°C to remove the alginate and F-127 materials. The morphology was analyzed using an optical microscope. The micropores and the microstructure of the pores were characterized using SEM. The fabricated scaffolds (16/23 shell/core size) were subjected to mechanical testing and exhibited a compressive strength of 5 MPa, comparable to cancellous bone (2–12 MPa), and a modulus of 160 MPa. The scaffold had high porosity (65–85%), adjusted with the core/shell size nozzles. The high porosity and surface area (up to 6500 mm2/g) allowed for cell adhesion and proliferation on the outer and inner surface of the scaffold, as determined by SEM. Finally, the in-vivo bone formation study in a rabbit demonstrated that the bioceramic implant allows for good cell integration and bone formation was detected with micro-CT.
\nLewis’ team at Harvard University 3D printed a tympanic membrane scaffold composed of PDMS, PLA, and PCL based materials using a DIW technique [36]. The team demonstrated that it is possible to design and fabricate materials with similar properties when compared to human specimens. The high frequency displacement and acoustics were organized by concentric rings for each 3D printed graft, and it was very dependent on the patterns and mechanical properties, characterized via digital opto-electronic holography, laser Doppler vibrometry, and dynamic mechanical analysis. In a different study, the team 3D printed cellular materials with vascular networks for flow [37]. The 3D printed structure was fabricated using an ink composed of Pluronic F-127, GelMA (gelatin methacrylate to allow for UV curing) and fibroblast cell culture. After curing, the Pluronic F-127 was removed by cooling to 4°C, yielding open channels that represent the vascular networks. Lewis’ team demonstrated that blood and other cellular liquids can flow through the channels with minimal death of cells.
\nPatients with skin burns and thick wound injuries often suffer from long term recovery and extensive and expensive treatments. The autologous split-thickness skin graft (ASSG) is the technique most often used to treat large wounds [38]. A skin tissue is place in the injured area and assists with the wound closure and healing. This technique relies on the removal of a piece of skin from a different part of the patient’s body and reapplying it on the place of injury. The drawback with ASSG is that it is limited by the size of donor sites and also creates another place of injury [38]. 3D printing of biomaterials would alleviate the problems related to ASSG. Skin cells are cultured in a laboratory and mixed with biocompatible polymers for bioprinting. In 2012, Koch Singh et al. [39] reported the 3D printing of skin using a laser-based inkjet printing method. The inks were composed of blood plasma/alginate solution and fibroblast/keratinocytes/collagen biomaterials. Collagen is the main component of the extracellular matrix (ECM) in skin. The team proved that the laser-based printing method does not harm the cells by performing proliferation of the cells in histologic sections 10 days after printing. Ki-67 staining, which includes the protein present in cells during their active cell cycle phases, shows that proliferating cells can be found in all regions, verifying vitality. In addition, a build-up of basal lamina, cell adhesion and proliferation- sign of tissue generation was observed.
\nThe dental industry is taking advantage of 3D printing technologies for restoratives, implants, and orthodontics purposes. Currently, professionals in the dental field have access to 3D printers and it is possible to print designs in a clinical environment. A CT scan is used to generate a defined shape based on the patient’s morphology and quickly fabricate and replace a missing tooth [40]. 3D printing is used for the manufacturing of aligners, braces, dental implants, and crowns [40]. Biocompatible materials are used for the fabrication of dental parts using 3D printing, e.g. polylactic acid, polycaprolactone and polyglycolide, and acrylates [3]. It is possible to fabricate dental implants with antibacterial properties by the incorporation of additives, such as quaternary ammonium salts [41, 42, 43]. At the age of 23, Amos Dudley fabricated his own orthodontic aligners while he was a student at New Jersey Institute of Technology [44]. He used equipment available at the institute to scan and print models of his teeth. A non-toxic plastic was used to mold and eventually generate 12 clear aligners. Amos had access to a Stratasys Dimension 1200 3D printer and used a mixture of alginate powder and PermaStone as the resin to print the aligners, which were tested by fitting them on his teeth. While it was not a trivial problem to solve, Amos proved the ability of 3D printing orthodontic materials for teeth alignment.
\nAM has been widely used in the biomedical industry and will continue to impact work in the future. Some challenges will persist, such as regulatory issues, limited materials, and inconsistent quality [45]. AM biomedical products require FDA approval, which can be time consuming and difficult to obtain [46]. Biocompatibility will require the development of new techniques and materials to produce high quality, high performing AM materials [47]. Furthermore, mechanical properties of AM materials need to be well assessed such that final properties can have reliable and reproducible behaviors. Further development for on-demand and patient-specific applications will be exciting work in this field. For example, designing patient-specific implants following a CT-scan will result in quick results [48]. Complex parts with specific mechanical properties and biocompatibility can be constructed on demand and with multifunctional components if needed. AM Research and development may help to improve bio-printed scaffolds and tissues for clinical applications to reduce cost for tissue engineering [49]. Manufacturing AM artificial organs, which includes multifunctionality (i.e. bionic ear [50]), will revolutionize the field of 3D printing for biomedical applications.
\nOne of the most promising fields in the future of AM is the aerospace industry. According to Wohlers’ report, this industry account for almost 20% of the total AM market today [32]. Aerospace applications typically require light weight and high strength materials. The importance of AM relies on the reduced cost, increased flexibility of design, and increase in a variety of products to meet customer needs. Additive manufacturing is an important technology that enables the design and manufacturing of complex structured products with improved mechanical strength and lower weight, at a lower cost and reduced lead-time. The aerospace industry has replaced the conventional manufacturing methods of molding and machining with 3D printing technology for small scale production. At a small production scale, AM offers effectively low-cost design and assembly [17].
\nThe aerospace industry implemented the use of AM approximately 20 years ago [51]. The main use for 3D printing has been focused on prototyping, modeling and producing jigs, fixtures and tools [17]. Furthermore, AM is used to build replacement parts on-demand when required. The ability to build on-demand spare components reduces costs for the production of parts that may never be used due to them becoming obsolete to new technology, which also saves warehouse storage space. For example, BAE Systems is currently 3D printing window breather pipes used in jetliners [52]. These pipes cost 40% less than pipes manufactured using injection molding processes and are manufactured on an as-needed basis.
\nRecently, NASA designed a rover, named Desert RATS, that can support humans in a pressurized cabin in space [53]. The rover is intended to transport humans to Mars. It contains 70 3D printed parts that include flame-retardant vents and housings, camera mounts, large pod doors, front bumpers, complex electronics, and others. The materials used for the 3D printing of the part used in the rover were ABS, PCABS and PC, and were printed using a FDM Stratasys 3D printer. Piper Aircraft manufactures tools using PC that can withstand hydroforming pressures of 3000 to 6000 psi. Aurora Flight Science additively manufactured wings that weigh one third of the fully dense metal components [54]. Some wings have integrated electronics. Lepron generated 200 different designs for use in piloted helicopters [17]. It is foreseen that aerospace companies will replace small components with 3D printed parts, thus reducing the weight of the machines. Some examples are arm rests, seat belts, food trays, and many others [17].
\nCompanies have adopted AM for fast production without making substantial changes to their products [17]. This modification is mostly due to the fast-changing market and low cost of generating such small builds. Several challenges would have to be overcome to facilitate the growth of AM. Some of these challenges include: (1) current speed of AM machines is slow for bulk production; (2) few polymeric material options; and (3) current machines do not allow for the manufacturing of large components [17, 55]. In the future, it is expected that companies will pursue a completely different business model by performing product customization for end-product while maintaining the on-demand part supply. Future work will focus on the development of multifunctional structures with complex geometries, which allows for novel solutions for complicated problems. AM techniques, such as using functionally graded materials, can be used in order to tailor the mechanical and/or thermal response of components [56]. Furthermore, on-demand manufacturing will reduce costs and eliminates potential damage caused by storage [45].
\nElectronic devices require suitable mechanical, geometrical, and optical functionalities to allow for miniaturization, low energy consumption, and smart capabilities [57]. The production of prototypes and end-products has to rapidly change due to the fast-changing technology. The conventional method for manufacturing electronic devices is using subtractive methods that involve masking and etching of sacrificial materials [58]. AM allows for the reduction of material waste, energy consumption and processing time and steps. 3D printing is being used to substitute steps for mounting and assembling electronic devices [59]. The additive process deposits material in a controlled layer-by-layer process allowing the manufacturing of complex geometries and dimensions. In addition, it enables 3D orientation of important components to improve performance. With miniaturization, AM allows for the manufacturing of small parts that would otherwise be difficult to obtain. AM has found application for thin films [60], inductors [61], solar cells [62], and others. The most common 3D printing techniques for electronics are inkjet and direct writing of conductive inks.
\nJennifer Lewis and colleagues fully 3D printed a quantum-dot (QD) light-emitting diode (LED) system, including green and orange-red light emitters embedded in a silicone matrix [63]. The printed device exhibits a performance of 10–100-fold below the best processed QD-LEP but could potentially be optimized with the addition of an electron-transport layer. A copper nanoparticle stabilized with polyvinyl pyrrolidine was mixed with 2-(2-butoxyethoxy)ethanol to prepare ink for inkjet printing [64]. The ink was printed onto a polyimide subtracted and sintered at 200°C. The prepared electronic device resulted in low electrical resistivity (≥ 3.6 μΩcm, or ≥ 2.2 times the resistivity of bulk copper). Bionic ears were printed using an inkjet printer [50]. The inks were composed of cell-cultured alginate and chondrocytes hydrogel matrix and a conductive polymer consisting of silicone and silver nanoparticles. The 3D printed ears exhibit enhanced auditory sensing for radio-frequency reception allowing the ear to listen to stereo music. This result demonstrates that bioengineering and electronics can be merged, resulting in advanced technologies. Students from Northwest Nazaren University and Caldwell High School designed the 3D printed CubeSat [65]. The CubeSat was launched aboard Delta II rocket as part of a NASA mission in 2013. It carries miniaturized electronics and sensors and is intended to collect real-time data on the effects of the harsh environments of space (oxygen, UV, radiation, temperature and collisions) on the polymeric materials- ABS, PLA, Nylon, and PEI/PC ULTEM.
\nFuture research and development in the electronics field will take advantage of low cost methods, flexibility in design, and fast speed of 3D printers for designing and prototyping new products. For example, printing circuit boards will offer superior accuracy and flexibility, with potential cost savings, environmental impacts, faster production times, and increased design versatility. Furthermore, adaptive 3D printing, which takes advantage of a closed-loop method that combines real-time feedback control and DIW of functional materials to construct devices on dynamic surfaces, is an exciting field of research [66]. This method of 3D printing may lead to new forms of smart manufacturing technologies for directly printed wearable devices. New possibilities will emerge in the wearable device industry, in biological and biomedical research, and in the study and treatment of advanced medical treatments.
\nUnsurprisingly, the amount of plastic pollution on the planet is alarming [67]. Plastics have dominated our marketplace due to their utility and versatility and make up at least 10% by mass of our waste streams. Plastics are designed to be durable and to withstand harsh environmental conditions. Therefore, the amount of plastic waste is only expected to increase in the future. Currently, 91% of plastic is not being recycled. The negative impact plastics have on our ecosystem is well recognized and researchers are using this as a business model and opportunity [68, 69]. Considerable efforts are being placed on recycling and reusing plastic waste. Prof. Sahajwalla at the University of New South Wales Sydney and her team work on turning plastic waste into usable polymers, including 3D printing polymers [70]. The company Reflow is collecting polyethylene terephthalate (PET) waste bottles and turning them into filaments suitable for 3D FDM printers [71]. A company in Belgium, Yuma, is using recycled plastics for the 3D printing of sunglasses [72]. The U.S. Army Research Laboratory and the U.S. Marine Corps are working together to repurpose plastic waste by printing items from recycled plastic useful for soldiers [73]. This process allows for a decrease in transportation costs and manufacturing of parts on demand. This large effort is expected to have a positive impact on both the environment and communities by turning polymer 3D printing into income for waste collectors and removing waste from the streams.
\nIndustries are moving toward the implementation of 3D printing as a manufacturing process because it facilitates the design of complex structures and rapid production of prototypes. AM utilizes a computer-aided design software that allows for the design of architectures with defined porosity and structures at a microscopic level. Because of the easy production of 3D printed prototypes, modeling based on a specific application can be performed to further improve the design of the end product and potentially reduce failure risks. The 3D printing of polymers and polymer composites has significantly progressed over the last 40 years and is expected to increase in the near future. Thermoplastic materials are readily commercially available for use in FDM, SLS, and inkjet processes. Materials like PC, ABS, PLA, ULTEM, and PCLA are commonly used for the manufacturing of tools, prototypes, and items used in the aerospace industry. However, these polymers are not one-size-fits-all types of polymers and are not necessary a good choice for all applications. Thus, research efforts are focused on developing materials that are capable of meeting specific applications. For examples, polymers blended with cultured cells can be used for scaffolds and implants on biological systems. Cells can be obtained from the patient and cultivated in the laboratory, thus producing a material that is less likely to be rejected by the patient. Fillers and additives can be used to generate multifunctional materials with improved mechanical properties. Fillers, such as CNTs and graphene, can be incorporated into the polymer to produce a material that is electrically conductive.
\nDespite all of the advances in the design and development of new polymeric materials for AM applications, challenges still remain. The availability of polymeric inks suitable for extreme applications, such as low temperature environments, high load pressures, and radiation resistance, is very limited. The development of new materials is necessary to increase the usefulness of polymer 3D printing technologies. Ideally, some of these composites are recyclable and/or biodegradable to reduce the negative impact plastics have on our environment.
\nWe thank the US Department of Energy’s National Nuclear Security Administration contract DE-AC-52-06NA25396 for providing financial support.
\nThe authors declare no conflict of interest.
IntechOpen publishes different types of publications
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