Examples of biomedical applications for currently used biomaterials.
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Implants are man-made devices that are fabricated for the implantation inside body to replace or support a biological structure, together with delivering drugs and monitoring body functions. They can remain in the body temporarily or permanently [1]. To date, biomedical implants are used not only as sensory devices [2]; brain and neural devices including neuronal, cochlear and retinal implants [3, 4]; subcutaneous implants [5]; cardiovascular devices such as vascular grafts, stent, heart valves, pacemakers [3]; sutures and wound dressings [6]; spinal [7] and dental implants [8]; cosmetic [9] and structural implants [10] including rods, braces, craniofacial, hip and knee replacements; but also as ophthalmic devices including glasses and contact lenses as well as insulin delivery devices [6].
In recent years, scaffolds made of synthetic or natural polymers were developed to regenerate damaged or deteriorated tissues, or to deliver drugs to specific locations. Scaffolds are three-dimensional (3D) structures that mimic the native extracellular matrix (ECM) of tissues and provide a substrate for cell adhesion and proliferation.
These biomedical implants can be made of bioactive materials. The term “bioactive” means that a material can affect its surrounding tissue biologically. Scaffolds can include molecules that promote a biological response in the region where they are implanted. Moreover, cells can be included in these scaffolds to promote healing and regeneration, as they naturally secrete growth factors and cytokines [11].
The risks related to the surgery during the placement or removal of the implant include infection and implant failure. Also, inflammation reaction against the material or rejection needs to be taken into consideration [1]. Here, we report what it is known about bioactive biomedical implants, their desired properties and their applications, focusing on the techniques and materials used for their fabrication. We further provide an overview of cell-based and drug-based implants, implant manufacture and its considerations.
To assist native tissue regeneration or/and replacement, implants are made of biomaterials, which support cell and tissue growth through cell adhesion, proliferation and differentiation, prevent unwanted cell and tissue growth, tailor tissue response and prevent immunological responses [12].
Biomaterials have been used for controlled drug delivery systems, sutures and adhesives including biodegradable and non-biodegradable materials, cardiovascular grafts, reconstructive and orthopaedic implants, ophthalmic devices such as corneas and contact lenses, and dental implants [13]. Various types of materials have been used to produce biomedical implants. These include bioceramics, polymers, metals and composites, which are further discussed below. Table 1 summarises current biomedical applications for biomaterials.
Ceramics are chemically inert and possess low thermal and electric conductivity as well as physical properties, which make them a suitable material glass for biomedical implants [34, 35]. Bioceramics are osteoinductive and osteoconductive and possess mechanical properties like native bone. Their use as biomedical implants prevents the transmission of diseases and immunogenicity. To date, bioceramics are utilised for dental, periodontal, maxillofacial and orthopaedic applications [36]. In comparison to non-resorbable bioceramics, degradable ceramics exhibit lower mechanical strength. Their chemical and physical composition determines their biological response [37].
Ceramics produced from aluminium, zirconium and titanium oxides possess bending, tensile and compressive strength at least 3 times higher than natural bone and are used mainly for pin-type dental implants and root- and endosteal plate forms [38]. The first zirconia implants were reported in the 1970s. These implants exhibited the ability to integrate into bone tissue, accumulate less plaque and provide improved aesthetics compared to titanium implants [39, 40]. Hence, titanium-zirconium alloys, also called Straumann Roxolid or Roxolit (TiZr1317), are often used as dental implants due to their enhanced mechanical properties and osseointegrative properties that are often used as dental implants [41].
Calcium phosphate-based bioceramics such as tricalcium phosphate (TCP) are similar in chemical composition to the inorganic phase natural bone tissue. TCP exhibits better biodegradation, restorability and bioactivity in vivo than hydroxyapatite and is commonly used for orthopaedic, dental and maxillofacial applications. Complete resorption of orthopaedic implants fabricated from TCP was reported after up to 2 years in the rat tibia and for the formation of cancellous bone [42].
Amorphous or low crystalline hydroxyapatite (HAp) is bioactive and bioresorbable. The preparation of synthetic HA at high temperatures results in high crystallinity. Biodegradation and resorbability of HAp are very slow. HAp bioceramics are commonly used for small defects in the case of bone loss or fractures of the tibia, calcaneus and vertebra. HAp is not employed for load-bearing bone applications because of its poor mechanical properties. The modification of HAp with strontium, magnesium and silicon ions resulted in enhanced mechanical and biological properties [43]. Improved bioresorbability was achieved by zinc—[44] and manganese—[45] substitution of HAp.
Dicalcium phosphates (DCP) are biodegradable ceramics composed of calcium phosphates and water. DCPs are widely added to material compositions to modify their physical properties. Dehydrated DCP is known as brushite, which is used in tibial plate and distal metaphysis bone fractures [46].
Historically, ceramics have been used as dental and orthopaedic implant materials. However, compared to other material classes, ceramics have not been used extensively as implant materials due to their limited load-bearing capacity [14].
Polymers are macromolecules that consist of covalently bonded repeating units, which can be of the same (homopolymers) or different (co-polymers) molecule type [27]. A variety of natural and synthetic polymers are used as soft tissue transplants, facial prostheses, denture, hip and joint replacements as well as medical adhesives, sealants and coatings [14].
Polymers are commonly selected based on their physical characteristics, composition, and mechanical properties; how easily they can be modified and moulded; their heat and electric conductivity as well as their ability to integrate into and attach to native tissue [47].
Natural polymers possess similar properties to native tissues. They are non-toxic and exhibit protein binding-sites and biochemical moieties that are important for tissue regeneration. However, natural polymers are often associated with immunological reactions, low mechanical strength and degradation at body temperature limiting their usability [14].
One of the most commonly used natural polymers is collagen. More than twenty different collagens are known in connective tissues such as bone, tendon, skin, cartilage and ligaments of the ECM of different species. Collagen type I is the main component in bone, skin and tendon, whereas type II is found in articular cartilage. Because of its abundance in nature, its importance for tissue homeostasis and growth, collagen has been investigated as material for bone, cartilage, tendon, skin and blood vessel regeneration [11]. In the clinic, collagen is used for the generation of dermal tissue, neo-tissue formation and wound healing [14]. Further natural polymers are chitosan, hyaluronic acid, fibrin and silk.
Silk, or silk fibroin, is a naturally occurring polymeric protein produced by insects and worms. The protein content gives rise to silk’s biocompatibility and its high tensile strength making it an ideal biomaterial for biomedical applications as gels, sponges and films [11, 48, 49, 50, 51, 52, 53]. Silk composites fabricated from silk-chitosan and silk-hydroxyapatite have been used to improve silk’s elasticity, degradation and porosity [54, 55].
Hyaluronic acid (HA), a non-adhesive glycosaminoglycan (GAG), occurs mostly in connective, epithelial, and neural tissue [56]. HA is commonly used as hydrogel for the regeneration of bone, cartilage and the vascular system and for drug delivery [11].
Chitosan is a biodegradable polysaccharide produced through partial deacetylation of chitin. Chitosan scaffolds exhibit similar properties to naturally occurring GAGs, leading to their bioactivity, and support cellular adhesion [11, 57]. It has been investigated as scaffold material in combination with collagen and HA, as well as PCL for bone, cartilage and nerve regeneration [11].
Synthetic polymers were developed with tailored physical and chemical properties depending on the desired application to overcome limitations of natural polymers. Synthetic polymers are linear, branched or cross-linked depending on their molecular arrangement [58] and possess amorphous or crystalline structures [27]. In addition, synthetic polymers are cheaper in production and enable improved functionality [11]. Commonly used synthetic polymers are poly(lactic acid-co-glycolic acid) (PLGA), polyglycolic acid (PGA), polylactic acid (PLA), polycaprolactone (PCL) and poly-hydroxybutyrate (PHB) [11, 27, 59, 60].
PGA, PLA and PCL are used for sutures, interference screws, fixation plates for meniscal repair and craniomaxillofacial fixtures and 3D scaffolds. However, they are known to induce inflammatory responses and are limited in mechanical integrity and controlled degradation. Hence, metal/polymer composites such as Mg/PCL have been developed [27]. Biodegradable synthetic polymers are chosen based on the required physical, chemical and mechanical material characteristics (Table 2).
Application | Material | References |
---|---|---|
Ophthalmic applications (contact lenses, intraocular lenses) | Silicones, hydrogels | [14] |
Cardiovascular applications (vascular prostheses, artificial valves, stents, cardiac-assisted pumps, blood bags and catheters) | Polymers, metals and ceramics; polyurethane (PU); polyesters (PE); polybutesters (PBE); polypropylene (PP) and PTFE; stainless steel | [15, 16, 17, 18, 19, 20, 21] |
Central nervous system and peripheral nervous system (scaffolds for nerve regeneration) | Polycaprolactone (PCL), silk, collagen | [11, 22, 23, 24, 25, 26] |
Orthopaedic applications (total hip replacement, hip arthroplasty, total knee arthroplasty, bone screws, orthodontic brackets and wires; bone fillers and scaffolds as bone replacements) | Chromium, cobalt, molybdenum, nickel, titanium and zirconium alloys, ultrahigh molecular weight polyethylene (UHMWPE), Ti-6Al-4V, ceramic-coated steels, stainless steel, copper; natural polymers like collagen, chitosan, alginates, synthetic polymers, ceramics like bioglasses, hydroxyapatite and beta-TCP; poly( | [11, 12, 14, 27, 28, 29, 30, 31, 32, 33] |
Examples of biomedical applications for currently used biomaterials.
Synthetic polymer | Application | References |
---|---|---|
Poly( | Sutures, drug delivery, vascular grafts, bone screws, fixation pins, dermal filler for facial atrophy (Scultra™) | [11, 61] |
Poly(lactic-co-glycolic acid) (PLGA) | Drug delivery | [11, 62] |
Polycaprolactone (PCL) | Long-term implant, maxillo-cranial facial implant; drug release | [11, 63] |
PCL-gelatin, PCL-chitosan, PCL-collagen | Tissue regeneration | [60, 64, 65] |
Poly-para-dioxanone (PPD) | Internal fracture fixation, medical implant as films, foams and moulded scaffolds | [47, 66, 67] |
Low-density polyethylene (LDPE), high-density polyethylene (HDPE) | Total hip arthroplasty and treatment of osteolysis as polymer-ceramic composites; rhinoplasty surgery | [68, 69, 70, 71] |
Poly(methyl methacrylate) (PMMA) | Orbital medical implants, rhinoplasty, cranioplasty, bone cement in hip joint replacement, dental implant for restoration and aesthetics | [72, 73, 74, 75, 76] |
Polydimethylsiloxane (PDMS) | Enclosing implantable electronic devices and sensors, medical implants, oesophagus substitutes, catheters, shunts, blood pumps and peacemakers | [77, 78, 79, 80] |
Polyamides (PA), e.g., nylon and nylon-composites | Sutures, fabrication of dentures; scaffold materials and nanofillers for bone regeneration | [81, 82] |
Carbon nanotubes (CNT) and composites | Metal coatings for load-bearing musculoskeletal implants to improve surface porosity, reduce metal ionisation and promote the formation of hydroxyapatite | [83] |
Synthetic polymers commonly used for the fabrication of biomedical implants.
Due to their mechanical properties, the ease of their processing and the possibility to sterilise them, metals and alloys are ideal materials for biomedical implants [34].
Metals are commonly used as load-bearing orthopaedic implants such as wires, screws, fixation plates, artificial joints for hips, knees, shoulders and ankles, as well as for dental, cardiovascular and craniofacial applications [14].
Novel magnesium alloys have been investigated for orthopaedic and cardiovascular applications [84, 85]. Combining magnesium alloys with aluminium or rare earth metals improves their mechanical properties [86, 87]. However, the accumulation of these elements is associated with neurotoxicity and hepatotoxicity [88]; hence, these alloys are not suitable for biomedical applications. Instead, extensive research is carried out to develop nontoxic magnesium alloys [89], such as Mg-Si and Mg-Sr alloys [90].
Titanium alloys are among the most commonly used metal alloys [91] due to their biocompatibility [92] and corrosion resistance [93]. Their composition and microstructure vary depending on their elemental composition [94]. The mechanical properties of B-titanium alloys have a Young’s modulus like bone but possess a low fatigue strength. Their mechanical properties can be enhanced through the addition of silicon dioxide, zirconium dioxide and Yttrium oxide. Furthermore, to increase their wear resistance, titanium alloys are surface treated. Pure titanium alloys are used in pacemaker cases, ventricular devices, implantable drug pumps, screws and staples in spinal surgery, dental implants and craniofacial implants. Ti-6Al-4V alloys are used in hip and knee replacements and dental implants. Due to the release of aluminium and vanadium ions, which can cause neurological conditions such as Alzheimer’s, Ti-6Al-4V alloys are not considered safe for long-term use. β-Titanium alloys substituted with stabilising elements like zirconium, tantalum and molybdenum are safer compared to Ti-6Al-4V [27], and alternative titanium alloys, vanadium free Ti-6Al-7Nb and Ti-5Al-2.5Fe, are being developed [95].
Titanium has become the material of choice for implants; however, components of prosthetics are still manufactured from gold alloys, stainless steel, nickel-chromium alloys and cobalt-chromium alloys [35]. Cobalt chromium alloys enable the fabrication of customised grafts including subperiosteal implants. They are mainly composed of cobalt, chromium and molybdenum, which give rise to corrosion resistance and mechanical properties [96, 97]. Stainless steel alloys such as iron-chromium-nickel-based alloys are used as orthopaedic implants such as ramus blade, ramus frame, stabiliser pins and some mucosal inserts. Due to its nickel content, these alloys possess a low corrosion resistance and induce immunological reactions in patients with nickel allergies [34, 38].
Implant materials should possess adequate chemical and physical properties to allow for host tissue infiltration and nutrient transport; biocompatibility to avoid immunological responses; and corrosion resistance, degradation and bioresorbability to enable normal cellular activity and controlled implant degradation [14, 27, 98]. In addition, temporary implants should possess a highly interconnected porous structure to allow cell migration and nutrient and waste transport, provide suitable surface topography to support cell adhesion and growth, as well as allow for the release of bioactive molecules if applicable [5, 11, 12].
Mechanical properties like Young’s Modulus, tensile, compressive and shear strength, yield strength and fatigue strength are required to ensure uniform stress distribution, to minimise the movement or fracture of the implant [34].
Surface properties influence cell adhesion and cellular and tissue responses. Surface tension determines the wettability by a wetting fluid, such as blood or water [11, 34]. Implant surfaces are also categorised by roughness, texture and the orientation of irregularities [38, 99]. The surface textures can vary from concave or convex. Concave surface textures occur due to additive treatments such as hydroxyapatite coatings, whereas convex surfaces are created through etching and blasting. Furthermore, implant surfaces can either be isotropic, meaning that implant properties are independent from the measurement direction, or anisotropic, which means properties are directionally dependent [12, 34].
Corrosion is the involuntary breakdown of metals by an electrochemical reaction and through the loss of ions from the metal surface in an acidic, an alkaline or a neutral environment. It is one of the most common reasons for implant failure [98]. Table 3 summarises the types of corrosions that have been observed in metal implants [98, 99, 100].
Corrosion type | Explanation | Biomedical implants |
---|---|---|
Crevice corrosion |
|
|
Pitting corrosion |
|
|
Galvanic corrosion |
|
|
Corrosion fatigue and fretting |
|
|
Types of corrosions observed in metallic biomedical implants.
Magnesium for example corrodes faster with an increase of impurities such as nickel, copper and iron [101]. The higher the purity of magnesium, the slower its corrosion rate. However, pure magnesium is not suitable for medical implants due to its mechanical characteristics. Instead, calcium is used for the grain refinement in magnesium alloys [102]. Orthopaedic implants fabricated from Mg-Ca alloys were observed to corrode over a 3-month period after bone formation [103]. Magnesium’s mechanical properties can also be enhanced through Mg-Zn with calcium, manganese, yttrium or zirconium [104, 105]. Mg-Zn alloys withstand galvanic corrosion and biocorrosion in vitro; however, biocorrosion in vivo resulted in a 2 mm/year reduction of a Mg-Zn alloy used as rods in femur shafts [106].
Polymer degradation, or biodegradation, occurs through a process called hydrolysis. The polymer surface is attacked by organisms, which secrete enzymes breaking down ester bonds in macromolecules. The resulting smaller polymer molecules are further converted into carbon dioxide and water. The process of biodegradation varies for each polymer [27, 107, 108]; however, all polymers lose their mechanical integrity. To date, PGA, PLA and PLGA among others have been explored for biomedical implants [27]. Their degradation into non-toxic by-products made them favourable materials for temporary biomedical implants [109]. Poly(
PLGA degrades into acidic moieties, which in higher concentrations can affect the microenvironment of the implant’s surrounding tissue. This can be especially important for drug delivery applications, where pH-sensitive drugs are used [11]. By increasing the amount of poly(glycolic acid) (PGA) compared to poly(lactic acid) (PLA) in PLGA, the degradation rate is reduced; hence, less acidic by-products are formed [11].
Biocompatibility indicates a desired response of the implant to its biological surrounding [34] and depends on biodegradability and corrosion. The ISO 10993 standard series is used to assess biocompatibility of medical grade materials and medical devices [112]. Test categories investigate the materials’ cytotoxicity, sensitization, irritation, toxicity, implantation and biodegradation [71]. Materials that meet these criteria include noble metals and titanium, their alloys, cobalt-based alloys, but also alumina, zirconia, quartz, fused silica, bioglass, silicon, biocompatible polymers like epoxies, silicones, polyurethanes, polyimides, silicon-polyimides, polycyclic-olefins, silicon-carbons, and liquid crystal polymers [113].
Foreign body response (FBR) is a non-specific immune reaction of the body to implanted materials. This inflammatory reaction can happen in response to surgical implantation of biodegradable or non-biodegradable materials present in medical devices or implants [114, 115]. FBR can modulate the safety and/or function of the implanted material. FBR is characterised by distinct phases, namely onset, progression and resolution [116] (Figure 1). The onset starts with the surgical implantation of the biomaterial, for example, subcutaneously, which causes local tissue damage [117]. Upon tissue damage, vessel permeation to cells and proteins increases and coagulation occurs where inflammatory mediators like vascular endothelial growth factor (VEGF) plays an important role along with neutrophils and macrophages to initiate the wound healing process. In parallel, angiogenic factors stimulate local vasculature.
Foreign body response to implant materials. Sequence of events and responses leading to the fibrous capsule formation and foreign body giant cell formation (adapted from [117]).
FBR comprises of a biomaterial-dependent and biomaterial-independent reaction (Figure 1). If biodegradable materials are present, the FBR will persist until the material is fully degraded. With non-degradable or long-term implants, a fibrotic capsule creating a barrier between the material and the body will form.
Progression of FBR depends on the material’s surface chemistry and wettability [118], where protein, antibody and macrophage adsorption can vary due to the material’s intrinsic properties. Additionally, fibrinogen can be adsorbed by the implant altering its structure. During FBR’s progression, leukocyte extraversion occurs from the blood vessels. These migrate towards the foreign body. Consequently, polymorphonuclear neutrophils (PMNs) are activated, which recruit cells including macrophages to the site. Macrophage activation leads to the recruitment of fibroblasts, monocytes and more PMNs [116], which ultimately increases production of extracellular matrix and hence implant encapsulation and fibrosis.
Phagocytosis occurs from the onset when antibodies are non-specifically adsorbed by the biomaterials, thus recruiting phagocytes. During progression, phagocytosis by macrophages is continuously promoted through the degradation of the material through biodegradation.
Material particles too large to be phagocyted cause the formation of larger multinucleated cells by fusion of macrophages. These so-called foreign body giant cells possess an irregular shape with more than 20 nuclei dispersed randomly. Giant cells will usually disappear once the foreign body is fully degraded. Surface roughness and surface/volume ratio of the implant can influence the adhesion of macrophages or prevalence of fibrosis [114].
As part of FBR, fibrosis is critical in tissue engineering, since capsule formation can prevent the diffusion of molecules (e.g., drugs) and continuous fibrosis formation can lead to capsule shrinkage thus affecting the implant structure [119]. It has been shown that inhibition of TGF-β can reduce capsule formation [120].
Finally, resolution of the foreign body response involves the degradation of the biomaterial or removal of the non-degradable material.
Biomaterials’ characteristics partly determine the body’s immune response to the implant. Implant pore size and morphology are critical since they can allow immune cells and macromolecules to interact with the implant. In addition, degradation products derived from implants like scaffolds and medical devices, as well as their constantly changing surfaces, can trigger the immune response [121]. Recent implants can carry therapeutic cells. These cellular implants provoke an immune response due to encapsulated cells, posing further challenges besides biomaterial compatibility and design [122, 123, 124].
Polymers such as collagen, alginate, chitosan, polyethylene glycol, polyvinyl alcohol and polyurethane are used in several implantable products that may have an inherent biocompatibility. Understanding how these polymer’s chemical and physical properties can be used to either avoid immune response or modulate it, while improving their functionality, is crucial for the advancement of these systems [121].
Strategies to circumvent the FBR include changing the biomaterial’s surface properties like wettability, its chemical moieties, and surface charge, because they affect protein adhesion to the biomaterial [121, 125].
To create more hydrophilic surfaces, monolayers of hydrophilic polymers such as polyethylene glycol (PEG) and polyethylene oxide (PEO) are added, thus preventing protein adsorption altogether [126]. The deposition of chemical moieties like amino (▬NH2), carboxyl (▬COOH), hydroxyl (▬OH), and methyl (▬CH3) groups allows the modulation of cellular adhesion influencing inflammatory cell infiltration and macrophage response affecting the fibrotic capsule thickness around the implant [121]. Surface charge is important for the FBR immunomodulation. There have been contradicting reports on how exactly neutral, positive or negative charges reduce the inflammatory response connected to the FBR. Generally, negatively charged surfaces tend to inhibit the immune response through reduced cell adhesion [127].
Moreover, implant topography including texture, shape and size has shown to trigger an FBR [121]. Therefore, several manufacturing techniques like particles, assembled monolayers and photolithography are used to create variety of shapes, sizes and surface topographies [128, 129]. Surface roughness at the nanoscale can modulate protein adsorption [130], while variations in surface roughness at microscale affect cells directly [131]. For example, the inflammatory response of titanium used for dental or orthopaedic applications can be decreased by altering its surface nano-and microstructures via physical or chemical procedures [121].
Macrophage interaction with differently shaped biomaterials demonstrated preferred internalisation of nanorods via pinocytosis compared to nanospheres. Additionally, sharper cornered surfaces led to more acute immune responses than smoother surfaces [121, 132]. Moreover, spherical alginate capsules of 1.5 mm or greater were reported to be more biocompatible than their smaller, non-spherical comparators, demonstrating that larger, rounder, smoother capsules could diminish the FBR [133].
The use of decellularised ECM as scaffolds by removing immunogenic components to avoid an acute response but keeping the original structure has been studied. While decellularised ECMs contribute to a pro-regenerative environment [134], it has been discussed that the immune response modulation still depends on the original tissue from which the ECMs have been obtained. Therefore, this option still presents a potential solution with more research needed to advance its understanding, manufacturing and impact [134].
The incorporation of bioactive molecules such as adhesion molecules, drugs and growth factors to promote immunological interaction with the host attenuating its response has been investigated. Bioactive molecules bound to the biomaterial for controlled release aiding tissue regeneration [125] include proinflammatory molecules like prostaglandins [135] and anti-inflammatory molecules like cytokines [136]. Combining their delivery with glucocorticoids improved tissue regeneration and attenuation of inflammation [137]. In recent years, the encapsulation of immune cells that act as producers or inducers of specific biological responses to reduce inflammation and/or induce repair has been investigated as immunomodulation strategy [125]. Examples include the encapsulation of MSCs to decrease the fibrosis in FBR [138] or the encapsulation of macrophages to mediate pro-angiogenic activation [139].
Overall, understanding the fundamental biological systems associated with FBR and the structural, physical and chemical properties of biomaterials will lead to new designs and strategies allowing to circumvent or work together with the natural body’s response towards implants.
Implants can be bioactive, inducing an alteration to the surrounding tissue, by their own biomaterials imparting this alteration to the surrounding tissue, by releasing a drug (or drugs) inducing bioactivity, or by containing cells that can produce bioactive molecules. In the following sub-sections, we discuss the implant bioactivity induced by drugs and cells implicating in drug delivery and in tissue regeneration.
Bioactive implants may incorporate active substances including small chemicals, peptides, proteins, hormones and even cells, which will have a therapeutic function in the human body. For drug delivery, these systems are commonly administered via parenteral route by injection or implantation. There are also implantable drug delivery systems that can be administered via ocular administration or via surgical procedures such as brain implants (e.g., Gliadel®). Implantable drug delivery systems are designed to slowly release the active substance(s) that they carry, thus avoiding repetitive injection. The active substance is delivered at a consistent predictable rate creating a drug release profile. This avoids peaks and troughs in the drug-blood level, which is common for non-long acting injectable products (e.g., intravenous solutions). Implantable drug delivery systems can be also injected subcutaneously, intramuscular or via other sites including intra-articular. They include implants and suspensions of micro- or nano-particles. Typically, these systems are preferred when the active substance has a poor absorption by other means of administration or a short half-life. The major advantages of such systems are improved pharmacokinetics, control of the drug release rate, and enhanced patient acceptability due to the reduction of side effects by maintaining the drug-blood level constant and by decreasing administration frequency [140, 141].
Sustained drug release is obtained via diffusion of the active substance through a biomaterial matrix, or released through biomaterial biodegradation, or a combination of both mechanisms. To date, commonly used biomaterials for drug delivery are either biodegradable like PCL and PLA or non-biodegradable like polydimethylsiloxane, polyethyl vinyl acetate, or titanium alloy [141]. Several approaches have been developed to produce implantable drug delivery systems [142] and to control the drug release. These include (i) using diffusion via membrane permeation, either porous or semi-porous membranes; (ii) controlling drug release by matrix diffusion using porous polymers; (iii) reservoir systems, where the drug is encapsulated in an inner reservoir; and (iv) actively releasing the drug from the implant via osmotic pressure, electric current, vapour pressure, hydrolysis or ultrasound activation.
Typically, simple rod-like solid implants, produced by hot melt extrusion processes using biodegradable polymers like PLA, PCL, PLGA and PEVA, often display a biphasic drug release kinetics showing a burst release due to the drug being deposited on the surface or near the surface of the implant, followed by a zero-order kinetics reflected by drug diffusion, matrix erosion, or a combination of both depending on the polymeric biomaterial used. Table 4 summarises drug release systems that are currently commercially available or under development. There are numerous advantages to using implants in drug delivery such as the possibility of removal after treatment, the consistent and predictable drug release, and versatility in manufacture using various biomaterials. However, there are potential disadvantages of this dosage form, where often a specialised device (e.g., trocar) and technique are needed for implantation and removal requires minor surgical procedures. Additionally, there may be complications in locating the implant for removal since it can migrate from its original location. From a commercialisation point of view, this type of bioactive implant may require complex regulatory and commercial strategies for market approval [154].
System | Product | Drug | Manufacturer | Indication | Clinical status |
---|---|---|---|---|---|
Implants [143, 144, 145, 146, 147, 148] | Zoladex® (PLGA solid rod, 1 × 10 mm) | Goserelin (up to 3 month release) | AstraZeneca | Prostate cancer | Approved by FDA |
Nexplanon® (radiopaque PEVA solid rod) | Etonogestrel (release up to 3 years) | Merck | Contraception | Approved by FDA | |
ITCA 650 (Medici technology, former Duros®) | Exenatide (release up to 2 years) | Ipsen | Type 2 diabetes | Clinical Phase III/NDA | |
MK-8591 (PCL solid implant) | EFdA (long-term release) | Merck | HIV treatment and prevention | Pre-clinical/Phase I | |
Microparticles [149, 150, 151] | Risperdal Consta® (PLGA microspheres) | Risperidone | Janssen | Antipsychotic | Approved by FDA |
Decapeptyl SR® (PLGA microspheres) | Triptorelin | Debiopharm/Ferring/Ipsen | Prostate cancer | Approved by FDA | |
Sandostatin LAR® (PLGA microspheres) | Octreotide | Novartis | Acromegaly | Approved by FDA | |
Bydureon® (PLGA microspheres) | Exenatide | Amylin/AstraZeneca | Type 2 diabetes | Approved by FDA | |
Vivitrol® (PLGA microspheres) | Naltrexone | Alkermes | Opioid/alcohol dependence | Approved by FDA | |
In situ hydrogels [152, 153] | Eligard® (Atrigel® technology) | Leuprolide acetate | Sanofi-Aventis | Prostate cancer | Approved by FDA |
Posidin® (Sabre® technology) | Bupivacaine | Durect/Sandoz | Postoperative pain | Clinical Phase III/NDA | |
Relday® (Sabre® technology) | Risperidone | Durect/Zogenix | Schizophrenia/bipolar disorder | Phase I | |
Sublocade® (Atrigel® technology) | Buprenorphine | Indivior | Severe opioid use disorder | Approved by FDA |
Injectable drug delivery systems, such as particulate suspensions or hydrogels like in situ forming gel depots, are designed from biodegradable biomaterials, injected (e.g., subcutaneous, intramuscular), form a depot, erode when in contact with body fluids, and release the drug by diffusion and erosion [149]. Injectable depots are not designed to be retrieved. Examples of injectable depots are micro- or nano-scale particles, where the drug is encapsulated within the polymer matrix. The polymeric particles are commonly prepared from biodegradable materials (e.g., PLGA, PCL, or silica) since the intent is to deliver the depot system once by injection, let it erode and release the drug with time.
Choosing the polymer grade, type and combining polymer types can help tune the drug release as necessary [149, 154]. Key points in preparing these bioactive depots are the choice of the biomaterial (biodegradable/erodible), the physico-chemical properties of drug to be encapsulated (i.e., hydrophobic or hydrophilic), the drug loading needed to deliver the therapeutic dose, and the inherent pharmacokinetics of the drug. This will inform the choice of manufacturing methods, often by emulsification. Common polymers used in these preparations are PLGA and PLA, where their long safety records deem these polymers as preferred, even though some minor inflammatory responses can still be reported [150].
Hydrogels, prepared from different types of biomaterials (e.g., hyaluronic acid, polyesters and chitosan) have been extensively investigated as carriers for sustained drug release [152, 155]. In situ forming hydrogels as injectable depots pose major advantages over other drug release systems since they allow for rapid, painless and easier administration through smaller needle sizes. These biodegradable in situ depots are of low viscosity prior injection and solidify into a gel or solid depot after injection, typically due to a specific trigger depending on the chemistry of the chosen biomaterial [153].
Before commercialising a cellular implant, it needs to be approved by FDA’s Cellular, Tissue and Gene Therapies Advisory Committee. The Committee evaluates the safety and effectiveness of cellular implants for the reconstruction, repair or replacement of damaged tissues [156].
Cell-based drug delivery systems can be defined as technologies capable of treating diseases using living cells to deliver the therapeutic bioactive molecules in the body, as either transport system or as production units [157]. Some examples of commercially available or under development cell-based implants are shown in Table 5. These cell-based drug delivery systems are used as constant producers of bioactive molecules in the form of implant devices. Judging by the current developments in this technology, a major driving force behind this type of delivery is the improvement in treatment of insulin-dependent diabetes mellitus. The biggest challenge in cell-based drug delivery systems is avoiding immune response.
Company | Product | Application | Method of action | Manufacture |
---|---|---|---|---|
Neurotech | Encapsulated cell therapy (ECT) | Ophthalmology | Ciliary neurotrophic factor (CNTF) has neuroprotective effects on photoreceptors. | Encapsulated human cells producing CNTF into the back of the eye. |
VIaCyte | Encaptra® | Stem cell delivery for treatment of diabetes mellitus | Human stem cells are isolated and differentiated into β islet cells contained into a pouch, which is implanted. | PTFE porous membrane device filled with cells. |
Sernova | Cell PouchTM with SertolinTM | Diabetes/haemophilia/thyroid disease | Therapeutic cells are inserted into a pouch made of medical-grade materials inserted subcutaneously; Sertolin® is a patented immune protection system. | Pouch made of medical-grade materials. |
PharmaCyte | Cell-in-a-box® | Pancreatic cancer/breast cancer/diabetes | Uses cotton cellulose to encapsulate cells. | Single cell encapsulation in proprietary polymer, freeze-drying process to keep cells viable in the long term. |
Beta-O2 | βAir® bioartificial pancreas | Diabetes, adrenal insufficiency | Device using alginate—high guluronic acid and high mannuronic acid—to encapsulate cells and impregnate a PTFE porous membrane, respectively. Also comprises an oxygen-providing chamber, which needs refilling. | Single cell encapsulation in proprietary polymer, freeze-drying process to keep cells viable in the long term. |
Sigilon | Afibromer™ | Diabetes | Human stem cells differentiated to β islets encapsulated in modified alginate spheres, which suppress immune system response and FBR. | |
Encapsulife | Encapsulation system for the immunoisolation of living cells | Diabetes | Cellulose-based polymer encapsulation of cells. | Pancreatic islets encapsulated are stimulated to produce insulin. |
Organogenesis incorporated | GINTUIT | Mucogingival conditions | Keratinocytes and fibroblasts produce cytokines and growth factors that promote healing and regeneration of the tissue. | Allogeneic keratinocytes and fibroblast in bovine collagen. |
Examples of commercially available cell-based implants for drug delivery.
When damages due to disease, injury or trauma lead to the degeneration of tissues, it is necessary to provide support for their repair, replacement or regeneration. Common approaches include tissue transplantation, both from the patient’s own body (autograft) and from a donor (allograft). However, harvesting autografts is expensive and invasive and the patient may experience infections and hematomas. While for the allografts, there are risks of rejection along with the infections due to the surgery or the transplanted tissue [158]. With tissue engineering, biological implants are developed that restore, maintain and improve the tissue function [159]. Implants provide the environment for cell adhesion and proliferation to grow new tissues. They can also include active substances like growth factors and drugs as well as cells to aid tissue regeneration [11]. Cell-based scaffolds are either cultured in vitro with the aim of synthetizing tissues that can be implanted, or to be implanted directly in the damaged region [158]. Table 6 summarises some of the recent studies about cell-based implants tested on in vivo models.
Application | Cell type | Implant | Outcome | Reference |
---|---|---|---|---|
Tendon regeneration | Rat tendon stem/progenitor cells | Asymmetric chitosan-based sponges |
| [160] |
Neural tissue engineering | Schwann cells, human bone marrow mesenchymal stem cells (BMSCs) | Polyvinyl alcohol (PVA)/sulphate alginate nanofibers |
| [161] |
Wound healing and skin regeneration | Wharton’s jelly mesenchymal stem cells (MSCs) | Poly(ε-caprolactone) (PCL)/gelatin nanofibers |
| [162] |
Mandible defects repair | Endothelial progenitor cells (EPCs), BMSCs | Biodegradable bioactive glass ceramic scaffold |
| [163] |
Acute kidney injury | Human placenta-derived mesenchymal stem cells (hP-MSCs) | Self-assembling peptide hydrogel |
| [164] |
Spinal cord regeneration | Neural stem cells (NSCs) | Elastic poly(sebacoyl diglyceride) (PSeD) scaffolds coated with poly(sebacoyl diglyceride)-isoleucine-lysinevaline-alanine-valine-serine (PSeD-IKVAVS) |
| [165] |
Examples of recent studies on cell-based implants.
The advantage of using cell-based scaffolds is the possibility to customise the construct using cells derived from the patient (primary cells). In this way, there is no risk of rejection due to immunological incompatibility. Cells can be isolated from biopsies and then seeded on the scaffold (Figure 2). However, primary cells are differentiated, post-mitotic cells. This leads to a limited lifespan, where after a limited number of cell doubling, they will enter in senescence and stop dividing, but are still viable [166, 167]. Moreover, primary cell types are difficult to culture, because they have difficulties adhering and proliferating in vitro [168].
Source of cells used for cell-based implants. Image adapted from [168].
To overcome problems associated with primary cells, stem cells have been be used. Stem cells are present in most if not all tissues and, according to their origin, they can be classified into embryonic and adult stem cells. Stem cells are able to both duplicate (self-renew) and differentiate in one or more cell types [167].
Embryonic stem cells (ESCs) are isolated from inner cell mass of embryo at the blastocyst stage. They can differentiate in any cell type (pluripotency) and have a high rate of self-renewal. Unfortunately, they can cause an immune response, as they are derived from a different body, so immunosuppression is necessary to avoid rejection. Moreover, the injection of undifferentiated ESC can lead to the formation of teratoma [169].
Adult stem cells (ASCs) are multipotent cells that can differentiate in a limited number of cell types, which reside in a specific microenvironment, the stem cell niche. Their role is to replace damaged and dead cells in the tissue to maintain homeostasis [170].
ASCs can be isolated from bone marrow, blood, adipose tissue, liver and skin [169]. Compared to ESCs, ASCs proliferate more slowly and have limited expansion capacity in vitro. Like primary cells, they can enter in senescence [171]. With age, their regenerative potential, growth and divisions are affected [172]. The most commonly used type of ASCs is mesenchymal stem cells (MSCs). These cells can differentiate into musculoskeletal cells, marrow and other cells of connective tissue, and they can provide trophic support and modulate the immune response [173]. They can migrate to a damaged region and promote healing by secreting molecules involved in angiogenesis and cell proliferation and inhibit oxidative stress and apoptosis [174, 175].
Induced pluripotent stem cells (iPSCs) originate from fully differentiated somatic cells, which are dedifferentiated to form iPSCs by a process called reprogramming. The methodology was developed in 2006 [176] and involves the stimulation of genes that are active during the embryogenesis. Thanks to the cell derivation, the implantation of these cells does not lead to rejection. However, as with ESCs, iPSCs can form teratoma. Moreover, some of the genes that are activated are also associated with tumour development [177].
To generate tissue replacements, it is essential to resemble the native extracellular matrix (ECM). Therefore, the matrix composition, shape and physical properties are crucial. Nanofibers, sponges or gels have been fabricated using numerous different techniques or combinations of techniques to mimic the native ECMs. Some of these techniques and their biomedical applications are presented in Table 7.
Technique | Material | Application | Outcome | References |
---|---|---|---|---|
Solvent casting—particulate leaching | Poly( | Articular cartilage regeneration |
| [178] |
Phase separation—particulate leaching | Poly(lactic acid) (PLA) | Bone tissue engineering |
| [179] |
Freeze-drying | Poly(ε-caprolactone) (PCL) and zein | Drug delivery |
| [180] |
Freeze-drying and self-assembly | Collagen | Tissue engineering |
| [181] |
Freeze-drying | Silk fibroin-chitosan | Cartilage regeneration |
| [182] |
Electrospinning | Poly(ε-caprolactone) (PCL)/poly( | Vascular tissue engineering |
| [183] |
Electrospinning | SiO2CaO | Wound healing |
| [184] |
3D printing | Copper/tetrakis (4-carboxyphenyl) porphyrin/β-tricalcium phosphate (Cu-TCPP-TCP) | Bone tumour ablation and osteogenesis |
| [185] |
E-jet 3D printing | Poly(lactic-co-glycolic acid) and drugs (5-fluorouracil and NVP-BEZ235) | Drug delivery in orthotopic breast cancer |
| [186] |
Techniques used for the fabrication of bioactive implants.
Solvent casting particulate leaching is a technique developed in 1993 by Mikos et al., where a polymer is dissolved in an organic solvent and the polymer solution is mixed with an insoluble porogen. The solvent is evaporated by solvent casting or freeze-drying techniques. The evaporation leads to a porogen-polymer compound, which is washed to remove the porogen leaving a porous polymer matrix behind [187, 188]. This method is relatively easy to use and inexpensive [189]. Pore size, porosity and interconnectivity can be controlled selecting the right polymer, porogen and their concentration [190].
Phase separation employs temperature changes that separate the polymeric solution in two phases: the lean phase (low polymer concentration) and the rich phase (high polymer concentration). Briefly, the polymer is dissolved in a solvent, then, the temperature is rapidly decreased to have a liquid-liquid separation and two-phase solid is formed [191]. Finally, the liquid is removed by extraction, evaporation or sublimation [192].
Freeze-drying technique or lyophilisation [193] is based on a sublimation process that will produce a porous scaffold. A polymer is added to a mixture of water and organic solvent and moved into a mould. The mixture is quickly frozen and, by lowering the pressure to few millibars, the water and the organic solvent sublimate. The complete removal of the liquid phase takes place under vacuum [189, 194, 195]. To control porosity and pore size, polymer/water ratio, ionic concentration, viscosity and pH, together with freezing rate and temperature, can be changed [194, 195].
Electrospinning is used to produce micro- and nanofibers. It is widely used as it can produce matrix that can resemble the native ECMs. Nanofiber scaffolds offer mechanical support and a nanoscale environment for the cells [196, 197]. A polymer solution is added to a syringe. Then, high voltage is applied, and the solution accelerates to a collector of opposite charge. The solution-air interface changes from rounded to conical, due to the repulsive electrostatic forces between the polymer molecules in solution and the attractive force between the polymer solution and the collector. The polymer solution is ejected from the syringe when the electrostatic forces are higher than the surface tension of the solution. Then, the solvent evaporates, and the solid polymer is deposited on the collector. By changing the voltage, collector, polymer concentration and solvent, it is possible to control the size of the fibres [196, 198].
Additive manufacturing (AM) techniques, or solid freeform fabrications (SFFs), are based on the use of computer-aided design (CAD) to fabricate scaffolds. The CAD controls the layer-by-layer deposition of material. The advantage of these methods is the full control of the topography of the construct [196, 198].
Three-dimensional (3D) printing is a commonly used AM technique that was developed at the Massachusetts Institute of Technology in 1990s [198, 199]. The CAD is converted in a stereo lithography (STL) file and exported to the 3D printer to control the movement and deposition of the material.
This technique allows the inclusion of cells within the scaffold, as high temperature or solvents are not required for its production [200]. In recent years, 3D printing has been used to produce scaffolds and anatomically customised implants based on MRI and CT scans. The AM can be classified in three different approaches [201], namely laser-based (stereolithography, selective laser sintering, electron beam melting and binder jetting) [202, 203, 204], nozzle-based (fused deposition modelling and melt electrospinning writing) [204, 205, 206, 207, 208] and indirect 3D printing [209, 210, 211].
Injection moulding is one of the most commonly used techniques for large-scale production of thermoplastic items. The plastic is melted and injected into a mould of desired shape. When the material solidifies, the mould is removed, and the finished part is extracted [212]. Metal constructs can also be fabricated with this technique. Metal injection moulding uses fine metal powders mixed with a binder and is injected with a conventional thermoplastic moulding machine. The binder is then removed, and the product is formed. This method allows the production of constructs with a sophisticate shape and higher mechanical properties [213].
Self-assembly is the spontaneous formation of molecular units in supramolecular structures, without external intervention. These molecules interact through hydrogen bonding, van der Waals and electrostatic forces. Due to their biocompatibility and biodegradability, peptides are commonly used for self-assembly. Specific structure can be created by modifying the amino-acidic composition of the peptides [189, 214]. These nanostructures can be used in drug delivery and tissue engineering [215].
The manufacturing of bioactive implants, whether these are for tissue engineering or for drug delivery purposes, includes several common aspects. These include the manufacturing methods that are employed, the biomaterial source, use of solvents, scalability, the need for aseptic facilities or if final product sterilisation is preferred, and if a specifically designed device is needed to administer the implant.
Most importantly, the regulatory strategy for filing needs to be in place soon in product development to define all the data that are needed for submission. It is important to define if the bioactive implant will be considered a drug product, a medical device, or a combination product (drug-device), and in which markets should it be launched, as different markets have different regulations and requisites for the different categories.
Comprehensive reviews and discussions on the regulatory aspects for filing medical devices, and combination products in the biomedical field were reviewed [216, 217, 218]. Ragelle et al. provide an excellent perspective for nanoparticle-based biomaterials, its manufacture and regulatory outlook for biomedical engineering [219].
To enable the use in animals and humans, the sterilisation process is important. If the manufacturing method is simplified enough, the use of aseptic technique for manufacturing, using filters and a particulate-free environment, will be possible although costly and complex for significantly large-scale manufacturing. For devices where metals are used, sterilisation by moist or dry heat may be possible.
However, for implants that involve polymers or heat-sensitive bioactive molecules, the preferred sterilisation method is gamma-irradiation. The drawback of using this technique is the potential risk to polymer and/or bioactive molecule degradation, changing the release rate and potentially compromising the efficacy of the implant [150]. Depending on the biomaterial and bioactive molecule involved, there may be ways to avoid degradation upon gamma-irradiation, such as using an antioxidant mixed with the drug. Apart from aseptic conditions, gamma-irradiation of the final product remains the best solution but exposes one of the disadvantages of developing bioactive implants as it is still a costly technique bringing its own risks [220].
In this chapter, we reviewed the current literature about bioactive biomedical implants applicable to regenerative therapies and used in drug delivery. To generate new biomedical implants, biomaterials are continuously developed, either through entirely new or by combining advantageous properties of well-known and safe biomaterials to improve the application and effectiveness of implants. Thus, materials that enhance the natural response of the body and simultaneously provide support for cell adhesion and proliferation are required. Another field that has developed in recent years is cell-induced bioactivity, where cells are used in implants for tissue regeneration and disease treatment. While there are several manufacturing techniques to create application-specific bioactive implants, new technologies, such as additive manufacturing, bring advantages and versatility to the field.
Extremophile organisms capable of growing in extreme conditions draw considerable attention since they show that life is robust and adaptable and help us understand its limits. In addition, they show a high biotechnological potential [1, 2]. Most of the best-characterized extreme environments on Earth are geophysical constraints (temperature, pressure, ionic strength, radiation, etc.) in which opportunistic microorganisms have developed various adaptation strategies. Deep-sea environments, hot springs and geysers, extreme acid waters, hypersaline environments, deserts, and permafrost or ice are some or the most recurrent examples of extreme environments [3]. However, the atmosphere is rarely thought of as an extreme habitat. In the atmosphere, the dynamics of chemical and biological interactions are very complex, and the organisms that survive in this environment must tolerate high levels of UV radiation, desiccation (wind drying), temperature (extremely low and high temperatures), and atmospheric chemistry (humidity, oxygen radicals, etc.) [4]. These factors turn the atmosphere (especially its higher layers) into one of the most extreme environments described to date and the airborne microorganisms into extremophiles or, at least, multiresistant ones [5].
\nIt is known that airborne cells can maintain viability during their atmospheric residence and can exist in the air as spores or as vegetative cells thanks to diverse molecular mechanisms of resistance and adaptation [2, 6]. The big question is whether some of them can be metabolically active and divide. Bacterial residence times can be several days, which facilitate transport over long distances. This fact, together with the extreme conditions of the atmosphere, has led researchers to think for years that they do not remain active during their dispersion. However, recent studies strongly suggest that atmospheric microbes are metabolically active and were aerosolized organic matter and water in clouds would provide the right environment for metabolic activity to take place. Thus, the role played by microorganisms in the air would not only be passive but could also influence the chemistry of the atmosphere. In any case, only a certain fraction of bacteria in the atmosphere would be metabolically active [2, 7].
\nDespite recognizing its ecological importance, the diversity of airborne microorganisms remains largely unknown as well as the factors influencing diversity levels. Recent studies on airborne microbial biodiversity have reported a diverse assemblage of bacteria and fungi [4, 8, 9, 10, 11, 12], including taxa also commonly found on leaf surfaces [13, 14] and in soil habitats [15]. The abundance and composition of airborne microbial communities are variable across time and space [11, 16, 17, 18, 19]. However, the atmospheric conditions responsible for driving the observed changes in microbial abundances have not been thoroughly established. One reason for these limitations in the knowledge of aerobiology is that until recently, microbiological methods based on culture have been the standard, and it is known that such methods capture only a small portion of the total microbial diversity [20]. In addition, because pure cultures of microorganisms contain a unique type of microbes, culture-based approaches miss the opportunity to study the interactions between different microbes and their environment.
\nAnother limitation for the study of aerial microbial ecology at higher altitudes or in open ocean areas is the difficulty of repeated and dedicated use of airborne platforms (i.e., aircraft or balloons) to sample the air. Most studies to date on the atmospheric microbiome are restricted to samples collected near the Earth’s surface (e.g., top of mountains or buildings). Aircraft, unmanned aerial systems (UASs), balloons or even rockets, and satellites could represent the future in aerobiology knowledge [5, 21, 22]. These platforms could open the door to conducting microbial studies in the stratosphere and troposphere at high altitudes and in open-air masses, where long-range atmospheric transport is more efficient, something that is still poorly characterized today. The main challenge in conducting these kinds of studies stems from the fact that microbial collection systems are not sufficiently developed. There is a need for improvement and implementation of suitable sampling systems for platforms capable of sampling large volumes of air for subsequent analyses using multiple techniques, as this would provide a wide range of applications in the atmospheric, environmental, and health sciences.
\nIn aerobiology, dust storms deserve special mention. Most of them originate in the world’s deserts and semideserts and play an integral role in the Earth system [23, 24]. They are the result of turbulent winds, including convective haboobs [25]. This dust reaches concentrations in excess of 6000 μg m−3 in severe events [26]. Dust and dust-associated bacteria, fungal spores, and pollen can be transported thousands of kilometers in the presence of dust [9].
\nIn this chapter, we approach the atmosphere as an extreme environment and make use of some advanced data from an example of an in situ study of the atmosphere: the analysis of bacterial diversity of the low troposphere of the Iberian Peninsula during an intrusion of Saharan dust using a C-212 aircraft adequately improved for aerobiological sampling.
\nIt is well known that there is a biota in the atmospheric air. The first study dates back to the nineteenth century, which speak about the presence and dispersion of microorganisms and spores in the atmosphere [27, 28]. Although the atmosphere represents a large part of the biosphere, the density of airborne microorganisms is very low. Estimates suggest that from the ground surface up to about 18 km above sea level (troposphere), there is less than a billionth of the number of cells found in the oceans, soils, and subsurface. Between approximately 18 and 50 km above sea level (stratosphere), temperature, oxygen, and humidity decrease and with them the number of cells. Above the ozone layer (between 18 and 35 km into stratosphere), ultraviolet (UV) and cosmic radiation become lethal factors. Once in the mesosphere (above 50 km), life is difficult to imagine; however microorganisms of terrestrial origin could arrive to the stratosphere from lower layers via different phenomena (human activity, thunderstorms, dust storms, or volcanic activity), and bacteria have been found isolated up to 41 km or in dust samples from the International Space Station (\nFigure 1\n) [6, 29]. Therefore, airborne microbes are always present in the atmosphere [11, 30, 31], and their permanence is dynamic, resulting in an environment with enormous variability. Estimates calculate that over 1021 cells are lifted into the atmosphere every year, leading to considerable transport and dispersal around the atmosphere, with a large portion of these cells returning to the surface due to different atmospheric events as part of a feedback cycle. Undoubtedly, airborne microbes play an important role in meteorological processes. They have been linked to the nucleation phenomena that lead to the formation of clouds, rain, and snow and to the alteration of precipitation events [32, 33, 34]. Their presence is essential to understand long-range dispersal of plant and potential pathogens [7, 35, 36] and maintain diversity in ground systems and could interfere with the productivity of natural ecosystems [17, 18]. On the other hand, airborne bacteria can have important effects on human health, being responsible for different phenomena such as seasonal allergies and respiratory diseases. Based on data from terrestrial environments, the global abundance of airborne bacteria has been estimated to range between 104 and 106 m−3 [37]. However, more recent studies incorporating direct counting by microscopy or quantitative PCR have provided more accurate estimates of the number of airborne microbes, which apparently point to a higher number of cells present in the atmosphere [38, 39, 40, 41].
\nDiagram displaying atmosphere layers, temperature and airborne emission sources. Yellow line marks atmospheric temperature. Bottom of the figures shows the common sources of aerosolized bacteria, with special attention to dust storms.
There is a great variety of airborne microorganism sampling systems, allowing us to select the most suitable one depending on our objectives [42]. On the other hand, no standardized protocols exist, which is a major pitfall when developing our objectives. This fact has led some authors to propose the creation of consortiums of interested parties for establishing standardized protocol reproducibility [20], as well as the need to establish global networks of aerobiological studies [11]. Two approaches are proposed: particles or cells can be collected passively or directly from the atmosphere. Passive media usually involves decanting [43] and collecting particles over snow [44] or through the collection of atmospheric water [45]. On the other hand, active methodologies entail three major approaches: filtration, impaction, and liquid impingement. All three approaches are very efficient when developing culture-dependent techniques. In contrast, culture-independent approaches produce some serious problems that make the work difficult: the high variability of the system and the low biomass mean that sampling campaigns are, in many cases, extremely inefficient [20]. Lastly, the use of airborne platforms is not very extended, but they represent a good opportunity to conduct a more direct study of the atmosphere [5, 19, 31].
\nFiltration is a simple and cheap method that is often efficient. It involves pumping air through a filter where the mineral and biological particles are trapped. Filters of different materials and porosity are available made of cellulose, nylon, polycarbonate or fiberglass, or quartz. Sizes used range from 0.2 to 8 μm, depending on the size of the particles to be captured and the capacity of the pump. In many cases, a PM10 filter can give better results when collecting smaller bacteria, as it allows greater airflow. Airflow filtration rates generally range between 300 and 1000 L/minute [4, 46]. Microorganisms trapped in the filter can be cultured, or the filters can be directly used for DNA extraction. In addition, filters are a very suitable support for microscopy, and countless holders for filters are available (an example is shown in \nFigure 2A\n).
\nThree different samplers of airborne microorganisms. (A) Filter holder and a filter (PALL Corporation). (B) Impinger sampling of bioaerosols (BioSampler, SKC, Inc.). (C) Six-stages Andersen Cascade Impactor (Thermo Fisher Scientific).
In impingement, particles are collected in a liquid matrix [20]. Normally a buffer is used such as phosphate buffer saline (PBS) that helps maintain the viability of the cells. One of the more widely used liquid impingers is BioSampler SKC (\nFigure 2B\n). In this case, the tangential movement of the particles inside the flow impinger retains the particles in the collecting liquid. The suspension obtained could be used for culturing or for molecular ecology assays [20]. One of the advantages of impingement collection is that it facilitates quantitative techniques such as flow cytometry or in situ hybridization [47].
\nIn this system, the particles generally impact into a petri dish with an enrichment medium. It is, possibly, the most efficient and most used method to conduct studies based on culture. Airflow impacting onto the plates is controlled by slots that allow the homogeneous distribution of the air. The system can be single stage or several stages in cascade, causing the particles to be distributed by size in the different petri dishes [20]. Some variants replace petri dishes with agarose filters or Vaseline strips, in order to carry out independent culture methodologies, but efficiency is very low. The original and more popular impactor is the Andersen cascade impactor (\nFigure 2C\n) [48].
\nSeveral studies explain and compare sampling methodologies in aerobiology, but most of them focus on the surface of the Earth (e.g., on top of mountains or buildings) or indoors [42, 49, 50, 51, 52, 53, 54]. However, small studies have been conducted at higher altitudes or in open sea areas. The use of airborne platforms (balloons, aircraft, rockets, etc.) for aerobiology sampling would allow conducting a direct study of the microbial ecology of the atmosphere. Another advantage of airborne platforms is the possibility of studying the vertical distribution of airborne microbial communities. In addition, some aircraft allow us to develop studies in the upper troposphere or in the stratosphere. Unfortunately, atmospheric microbial collection instruments have not been developed enough for airborne platforms.
\nAmong the different airborne platforms, aircraft, due to their versatility and access, are particularly interesting. Some studies have been conducted, but not enough samples have been developed yet, and efficiency is still very low. As already mentioned, the efficiency of samplers in soil-level aerobiology faces a series of problems (low biomass, high variability of populations, lack of standardized protocols). In the case of airplanes, in addition to these intrinsic problems associated with atmospheric microbial ecology, other additional ones exist: (1) the high velocity of the aircraft in relation to the relative quiescent air mass. This makes it difficult to obtain an isokinetic sampler and, therefore, one that is sufficiently efficient that would allow us to obtain a correct quantification of the incoming air [55]; (2) the sampler must be in a location on the airplane that avoids chemical contamination from the operation of the device. Previous studies have used wing-mounted air samplers or the roof of the aircraft to reduce the possibility of in-flight contamination [21, 22, 56, 57, 58]. Similarly, it should allow the aseptic collection of samples, avoiding microbiological contamination during the process. This operation, which can be very simple in the laboratory or at ground level, becomes tremendously complicated on an airplane, since air intakes that are part of the fuselage of the aircraft are often difficult to sterilize. It is therefore necessary to develop robust sterilization protocols. The spectacular work of DeLeon-Rodríguez of 2013 has been criticized in this aspect [40, 59]; (3) sampling time. A possible solution to the low biomass of the atmosphere is to increase sampling time, but in the case of flights, we are limited to the flight autonomy of the aircraft. Although scarce, some studies from airplanes have been conducted. The first studies that were conducted in airplanes were carried out by impaction on a petri plate with enrichment means, which allowed isolating microorganisms from the upper troposphere and even from the stratosphere [21, 57, 60]. However, advances in molecular ecology have caused the most recent studies to favor filtration [40, 58].
\nThe European Facility for Airborne Research (EUFAR) program brings together infrastructure operators of both instrumented research aircraft and remote sensing instruments with the scientific user community. However, it lacked aircraft prepared for microbiological sampling. The National Institute for Aerospace Technology (INTA) belonging to the Spanish Ministry of Defence has two CASA C-212-200 aircraft that were suitably modified to be used as flying research platforms. Now, these two aircraft are a unique tool for the study of atmospheric microbial diversity and the different environments of the EUFAR program. Our research group has a CASA-212 aircraft with an air intake located on the roof of the aircraft. A metal tube fits the entrance and is fitted inside the aircraft to a filter holder, a flowmeter, and a pump (\nFigure 3\n). This simple system is easy to sterilize, and both the metal tube and the filter holder can be replaced in flight by other sterile ones if we want to take different samples. Using PM10 fiberglass filters, we can obtain isokinetic conditions and pass 1800 L of air per hour through the filter, as indicated by the flowmeter.
\nAirborne microorganisms sampler installed in INTA’s CASA C-212-200 aircraft.
In a series of recent experiments, we tried to install a multi-sampler system in our aircraft, where we had five systems in parallel and connected to the same intake of the plane: one filter holder, two impingement systems, and two impactors (\nFigure 4\n). The results clearly showed that in the case of our aircraft, filtration was more efficient (data not shown).
\nMulti-sampler system tested in INTA’s CASA C-212-200 aircraft. (A) Impinger sampler, design and manufacture own. (B) Impactor sampler (Impaktor FH6, Markus Klotz GmbH). (C) Coriolis μ (Bertin Technologies SAS) a impinger biological air sampler. (D) Filter holder (PALL Corporation). (E) Six-stages Andersen Cascade Impactor (Thermo Fisher Scientific).
Aerobiology studies have traditionally focused on the collection of bacterial cells and the analysis of samples by total counting and culture-based techniques. It is known that such methods capture only a small portion of the total microbial diversity [61]. The almost exclusive use, for years, of these methodologies is one of the reasons for these limitations in the knowledge of aerobiology. In addition, culture-dependent methods do not allow us to study the interactions between different species of microorganisms. Culture-independent methods have been used to assess microbial diversity, increasing the specificity of microbial identification and the sensitivity of environmental studies, especially in extreme environments. These methods have recently been applied to various areas of airborne microbiology [62, 63, 64, 65] revealing a greater diversity of airborne microorganisms when compared to culture-dependent methods. Some good studies approach the challenges and opportunities of using molecular methodologies to address airborne microbiology [20, 66]. Although molecular ecology methods allow the rapid characterization of the diversity of complex ecosystems, the isolation of the different components is essential for the study of their phenotypic properties in order to evaluate their role in the system and their biotechnological potential. A combination of culture-dependent and culture-independent methods is ideal to address the complete study of the system.
\nModern culture-independent approaches to community analysis, for example, metagenomics and individual cell genomics, have the potential to provide a much deeper understanding of the atmospheric microbiome. However, molecular ecology techniques face several particular challenges in the case of the atmospheric microbiome: (1) very low biomass [20]; (2) inefficient sampling methods [20]; (3) lack of standard protocols [9, 20]; (4) the composition of airborne microbes continuously changes due to meteorological, spatial, and temporal patterns [7, 62, 67, 68, 69, 70]; and (5) avoidance of the presence of foreign DNA in the system [59]. Because these issues are not yet resolved, most of the non-culturing approaches focus on microbial diversity, where they are highly efficient.
\nThe most recurrent techniques are those based on DNA extraction, gene amplification of 16S/18S rRNA, and next-generation sequencing (NGS) technologies. Often, this approach is more efficient due to the greater efficiency and sensitivity of this process, as opposed to gene cloning and Sanger sequencing; thus some authors are inclined toward metagenomics instead of amplification. This provides more information and avoids an intermediate step, but bioinformatic processing is tedious and often only provides data in relation to diversity, making the annotation of the rest of the information very complicated [20]. These approaches can be complemented with quantitative methods such as qPCR, flow cytometry, or fluorescence in situ hybridization (FISH) [41, 47, 66, 71]. FISH is surely the best and most specific cell quantification methodology that exists. However, in the case of aerobiology, it cannot always be used. A minimum number of cells must exist so that we can observe and count them under a fluorescence microscope. Due to the variability of microbial populations in the air, this is not always achieved. In our research group, we have obtained very good results in this regard, optimizing cell concentration. \nFigure 5\n shows epifluorescence micrographs of bacteria from an air sample. On this occasion, sampling was performed using a biological air sampler (Coriolis μ, Bertin Technologies SAS), where biological particles are collected and concentrated in a liquid (PBS). Sampling was conducted for 2 hours at ground level, pumping a total of 36,000 L of air. After this time, the sample was paraformaldehyde fixed and filtered through a 0.2 μm pore size, hydrophilic polycarbonate membrane, 13 mm diameter (GTTP, Millipore). A half sample was hybridized with the universal Bacteria domain probe, EUB338I-III [72], following a conventional protocol [73]. The second half was hybridized with the probe NON338 [74] as negative control. In this case, an average of 140 cells per liter of air was counted. Occasionally, FISH also allows to observe bacteria attached to mineral particles (\nFigure 5C\n–\nD\n).
\nEpifluorescence micrographs of bacteria from an air sample. (A and C) DAPI-stained cells; (B and D) same fields a A, and C, respectively, showing cells hybridized with probes EUB338I-III (Cy3 labeled), specific for Bacteria domain. All micrographs correspond to the same hybridization process, performed with a sample obtained after 4 hours sampling at ground. C and D show microorganisms attaches to a mineral particles (arrow sign). Bars, 5 μm.
DNA gives us much information about the diversity of the system, but if we wish to obtain information about the metabolic activity that is taking place in the ecosystem, metabolomic and metatranscriptomic approaches are needed [50, 66]. In the case of the atmosphere, this is crucial, since we are not fully certain if the cells present are active. Some studies indicate that a part of the microorganisms in the atmosphere are developing an activity [6], but until we conduct RNA-based and metabolite-based studies, we will not have the certainty that this is the case. The big problem is that it is very difficult to carry out these studies using the current microbial capture systems.
\nScanning electron microscopy (SEM) also provides much information of the aerobiology [7]. Specifically, it allows the characterization of eukaryotic cells (e.g., diatoms) and, above all, pollens and fungal spores, from which we can obtain great information with good images alone. \nFigure 6A\n shows pine tree pollen observed via SEM in a sample obtained after a 30 minutes flight of the C-212 aircraft.
\nSEM images of different airborne samples. (A) Pinus pollen. Ground sample after 2 hours sampling. (B) Air sample collected from C-212-200 aircraft during a Saharan dust intrusion (February 24, 2017). Filter appear completely cover of mineral particles. (B and C) Biological particles sampled using C-212-200 aircraft. (E) Diatomea sampled by C-212-200 aircraft in a fligth along the northern coast of Spain (9 March 2017). (F) Cell attached to mineral particles and organic matter.
As mentioned above, factors, such as the shortage of nutrients and substrates, high UV radiation, drying, changes in temperature and pH, or the presence of reactive oxygen species, make the atmosphere an extreme environment. However, it is possible that the high variability of its conditions is the one characteristic that makes this environment more extreme [1, 20]. Among the cells present in the atmosphere, a considerable portion appears in the resistance forms capable of withstanding low-temperature and high-radiation conditions. This is what probably happens with fungi and gram-positive bacteria. Bacillus strains recurrently isolated from the atmosphere have characteristics and a capacity to sporulate very similar to strains isolated from the soil. Undoubtedly, another part of the cells will be in the form of latency and may even suffer modifications of the cell wall and slow down or stop their metabolic activity [75, 76]. These transformations can improve resistance to physical stresses, such as UV radiation [58]. On the other hand, some of the bacteria present in the atmosphere, such as Geodermatophilus, show pigmentation that undoubtedly protects it from excessive radiation. The microorganisms that are usually detected in the atmosphere originate mainly from the soil, which means they will share similar mechanisms of resistance. In some strains, metabolic adaptations have been observed to lack nutrients such as cytochrome bd biosynthesis to survive iron deprivation [77]. Deinococcus is also a recurrent genus in the atmosphere, which, like those in soil, has multiresistance mechanisms based on high DNA-repair efficiency. Bacteria that do not form spores and certain archaea, in contrast, often have genomes rich in G + C, which may increase tolerance to UV rays and overall survival [78].
\nAnother strategy of resistance could be cell clustering and adhesion to particles. Several studies have confirmed the loss of viability and shielding or the reflective properties of the mineral particles as an important role for the protection of UV radiation [19, 31]. In that sense, it is very possible that many cells have mechanisms that promote aggregation. In our samples, we often find the cells adhered to each other or to minerals, which undoubtedly makes them more resistant (\nFigure 6\n).
\nGlobal and regional models have been used to explain bioaerosol emission, transport, and atmospheric impact [17, 18, 79, 80, 81, 82, 83, 84]. Even so, it is not an easy phenomenon to explain, since it depends on a large number of factors. On the one hand, there are numerous sources of tropospheric aerosols, which include sea salt, volcanic dust, cosmic dust, industrial pollutants, and desert and semidesert areas [6, 85]. We must also consider the factors that make the transfer of particles possible, for example, meteorological phenomena, solar radiation, temperature, tides, erosion, etc. [85]. On the other hand, anthropogenic activities can also affect dust emissions indirectly, by changing the climate and the hydrological cycle. In these aerosols, microorganisms will be included in a greater or lesser number. The degree of richness in cells of tropospheric aerosols will depend largely on the source of emission. Thus, the large wooded masses or fields of crops provide the atmosphere with a good number of microorganisms due to the effect of air or the aerosols produced by rain. Similarly, anthropogenic activity contributes large amounts of bacteria to the environment, treatment plants, and composting areas being sources of airborne microorganisms [85].
\nDesert dust storms play a major role in particle emissions and with them that of microorganisms. In this way, most of the material reaching the atmosphere from the surface comes from desert and semidesert areas, which is known as desert dust. The Sahara-Sahel desert, the Middle East, central and eastern Asia, and Australia are the major sources of desert dust, although all the arid zones of the world are emission sources [9, 86]. Dust storms are atmospheric events typically associated with dry lands due to the preponderance of dried and unconsolidated substrates with little vegetation cover. The strong and turbulent winds that blow on these surfaces raise fine-grained material, a large part of which consists of particles the size of silt (4–62.5 μm) and clay (<4 μm), reducing visibility to less than 1 km. The atmospheric concentrations of PM10 dust exceed 15,000 μg/m3 in severe events [87], although the concentrations naturally decrease with the distance from the areas of origin, extending hundreds of kilometers. The dust particles and cells associated with them are transported in this manner and will be deposited finally, by the effect of rain, snow, or other meteorological phenomena. Therefore, there is a continuous transfer of mineral and biological matter through the atmosphere that moves from the air to the terrestrial environment and changes its geographical area [7, 24].
\nThe Sahara-Sahel desert located in northwestern Africa is one of the major sources of windblown dust in the world [9]. This phenomenon has an impact on the Mediterranean coastline, but Saharan dust has been transported toward the north of Europe and has been found on numerous occasions in the Alps [88, 89] or blown toward the Atlantic and Caribbean [8, 90]. It has been estimated that 80–120 tons of dust are transported annually through the Mediterranean toward Europe [23, 91, 92]. In particular, dust transported by the winds can reach an elevation of up to 8 km in the atmosphere over the Mediterranean basin [93]. Because of its geographic position, the Iberian Peninsula is often affected by these dust events. Specifically, the Sahara-Bodele depression, located at the southern edge of the Sahara desert, has been described as the richest dust source reaching the Iberian Peninsula. Southern Spain is the main area affected, but dust can reach the Pyrenees and even France [43]. Different researchers have studied the mineralogical and chemical composition of Saharan dust, which has been observed to contain calcite, dolomite, quartz, different clay minerals, and feldspars as the main mineral components [94]. The intrusion of big amounts of these components is an important influence on nutrient dynamics and biogeochemical cycling in the atmosphere of the Iberian Peninsula.
\nDespite the large number of studies on dispersion, geochemistry, and mineralogy of African dust, few are focused on microbiology. All these studies conclude that there are microbes associated with dust because there are higher concentrations of aerosolized microorganisms during dust events [43, 90, 93, 94, 95, 96]. However, the magnitude of the concentrations and the specific microbes associated with dust events remain the subject of debate. On the other hand, the viability of these microorganisms is another big question. The United States Geological Survey (USGS) develops the Global Dust Program to investigate the viability of microorganisms transported in dust masses. USGS authors using DNA sequencing of the ribosomal gene were able to isolate and identify more than 200 viable bacteria and fungi in St. John’s samples in the USA [8, 36, 90]. Fungi and bacteria associated with atmospheric dust can be recovered and cultivated, but they must be gram-positive bacteria and many spore formers, which makes them resistant to the extreme conditions of the atmosphere.
\nTherefore, fungi and bacteria associated with dust may have been isolated from dust intrusions, but a percentage of the viable ones already remains an unanswered question. Another big question is the activity of these cells in the atmosphere. It is clear that they are resistant to extremophile conditions, but the question is whether they are developing their life cycle in this particular environment. This question could be answered by molecular ecology methodologies based on the isolation and sequencing of mRNA, but low atmospheric biomass and high variability are, once again, the great problem when developing this type of RNA-based methodologies. On the other hand, clinical records point to many of the viable microorganisms identified in the Saharan dust as the cause of respiratory diseases (asthma and lung infections or allergic reactions), cardiovascular diseases, and skin infections [7, 90, 97, 98]. It is known that other microbes associated with dust in the air are pathogenic to humans, including those that cause anthrax and tuberculosis, or to livestock (such as foot and mouth disease) or plants [7, 90, 97, 98]. Characterization, quantification, and feasibility studies are vital to address these problems.
\nIt is common to find fungal spores belonging to the genus Aspergillus, Nigrospora, Arthrinium, and Curvularia associated with Saharan dust. Bacterial taxa comprised a wide range of phyla, including Firmicutes, Proteobacteria, Actinobacteria, and Bacteroidetes. Generators of genus spores such as Clostridium and Bacillus are very common, along with other gram-positive ones such as Geodermatophilus or Streptococcus. Also, Alphaproteobacteria, a very common bacterium class in soils (e.g., the family Sphingomonadaceae), are associated with dust [4, 9]. As regards Archaea, there are few studies of the atmosphere, in general, and of dust, in particular, that focus on this domain. Surely, reduced cases of pathogenic archaea have been studied to a lesser extent. Aeropyrum is the most detected genus of airborne archaea, but it is related to marine aerosols [11]. On the other hand, studies of pollen associated with dust are widespread. An interesting study investigated pollen transported from North Africa to Spain through Saharan dust and found that pollen from five non-native plant species was detected exclusively during dust events [99]. Lastly, viruses and virus-like particles have a great interest in the emission of dust. One study mentions virus-like particles associated with a transoceanic dust event. This report is based on epifluorescent microscopy of filters stained with a specific nucleic acid stain. An increase in the order of magnitude of virus-like particles was observed, from 104 to 2105 m−3 between the baseline condition and dust conditions in the Caribbean [41]. It is speculated that free airborne viruses show worse resistance to high ultraviolet radiation and dry air associated with long-distance transport in dust events resist worse than others [9].
\nFour aerobiology sampling flights took place during February and March 2017 using the CASA C-212-200 aircraft from INTA. The study focused on microbial diversity in the atmosphere of the Iberian Peninsula during and after a Saharan dust intrusion. Flights took place under four different conditions: (1) during a strong Sahara dust storm that reached the north of the Iberian Peninsula, from February 22 to 24, 2017 (February 23, 2017) (\nFigure 7\n); (2) following precipitation (February 28, 2017); (3) following a dry period (March 8, 2017); and (4) along the northern coast of Spain (March 9, 2017). In each flight, samples were collected at different altitudes, and air samples were obtained simultaneously at ground level. A total of 20 samples were collected and are being analyzed. Cell presence was observed by scanning electron microscopy (SEM), and bacterial diversity is being studied by DNA extraction, 16S rRNA gene amplification, and Illumina MiSeq sequencing. Results are being analyzed via bioinformatics and biostatistical software (MOTHUR, SPSS, STAMP, CANOCO, and PAST) which will allow us to compare the results between the different flows and scenarios.
\nSaharan dust intrusion. Dust pours off the northweat Afrincan coast and blankets the Iberian Peninsula, 23 February, 2016. NASA satelital imagen via MODIS.
Although this study is not yet finished, some data can be advanced in this chapter. \nFigure 6\n shows SEM microphotographs obtained from samples in different scenarios. In general, the samples obtained during the days of dust intrusion (flight of February 23) appear completely covered with mineral particles. In these cases, more biological cells were detected than in the rest of the days. In the particular case of samples from the marine coast flight, more diatoms were observed (\nFigure 6E\n).
\nThe analysis of diversity using the Shannon index showed that, in all cases, diversity was greater on days of Saharan dust intrusion, both in the samples taken from the ground and those taken at higher altitudes with the aircraft. This indicates that Saharan dust contributes microorganisms that are not present in the atmosphere on a daily basis. Diversity analysis showed phylum characteristics of soils, being Alpha- and Betaproteobacteria the most abundant classes. All of the analyses performed showed that bacterial diversity detected at ground level and in-flight samples during the dust intrusion event were similar among one another. The genus taxonomic levels of Sphingomonas, Geodermatophilus, Methylobacter, Rhizobiales, Bacillus, or Clostridium were present in every sample, but their sequences were more abundant in the case of ground samples and dust intrusion samples collected during the day flight. However, sequences of the genus Flavobacterium, Streptococcus, or Cupriavidus were most abundant in the case of samples collected during flight.
\nPreliminary conclusions show that bacterial diversity of airborne bacteria during days of dust intrusion is higher and similar to bacterial diversity commonly detected in soil samples. Further analyses are being conducted with these samples to obtain a complete description of the evolution of bacterial diversity during those days.
\nIntense UV radiation, low pressure, lack of water and nutrients, and freezing temperatures turn the atmosphere into an extreme environment, especially its upper layers. However, it is widely known that airborne bacteria, fungal spores, pollen, and other bioparticles exist. Numerous bacteria and fungi have been isolated and can survive even at stratospheric altitudes. Microbial survival in the atmosphere requires extremophilic characteristics, and therefore airborne microbiota is potentially useful for biotechnological applications. The role of airborne microbial communities is vital in the Earth, including interactions among the atmosphere, biosphere, climate, and public health. Airborne microorganisms are involved in meteorological processes and can serve as nuclei for cloud drops and ice crystals that precede precipitation, which influences the hydrological cycle and climate. Furthermore, their knowledge is essential in understanding the reproduction and propagation of organisms through various ecosystems. Furthermore, they can cause or improve human, animal, and plant diseases.
\nAirborne platforms that allow conducting a direct study of microorganisms in the atmosphere and molecular methodologies (e.g., “omics”) could represent a major opportunity for approaching this question. Nevertheless, some challenges must yet be solved, such as low biomass, efficiency of sampling methods, the absence of standard protocols, or the high variability of the atmospheric environment.
\nDeserts and arid lands are one of the most important sources of aerosol emissions. Clouds of dust generated by storms mobilize tons of mineral particles, and it is known that microorganisms remain attached to the particles being transported over long distances. The large number of mineral particles and microorganisms thus placed into the atmosphere has global implications for climate, biochemical cycling, and health. North African soils, primarily the Sahara Desert, are one of the major sources of airborne dust on Earth. Saharan dust is often transported to southern Europe and could even reach high altitudes over the Atlantic Ocean and the European continent. Again, airborne platforms could be a perfect opportunity for conducting a direct study of the microbiology of this kind of events.
\nThis work has been supported by grants from the Spanish government (
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. 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