Overview of various stimuli responsive nano-carriers for smart drug delivery systems with mode of drug release applications
\r\n\tOver the past few decades, there has been a rationalization for better classification of dystonia and paying more attention to understanding the different causes of dystonic movements from the advanced study of genetics, neurophysiology, and functional imaging in various forms of dystonia.
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He has many publications and is a member of the Editorial board of multiple reputable journals. He has presented his work at worldwide conferences and symposia and ran workshops for spasticity management and the use of the ketogenic diet in treating epilepsy. Dr. Rizk is a member of the ICNA, the INA, and the BPNA.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"170531",title:null,name:"Tamer",middleName:null,surname:"Rizk",slug:"tamer-rizk",fullName:"Tamer Rizk",profilePictureURL:"https://mts.intechopen.com/storage/users/170531/images/system/170531.jfif",biography:"Tamer Rizk, MD FRCPCH MBPNA (UK) MINA (USA) MICNA (SWE) is currently Consultant Pediatric Neurologist and a Professor of Pediatric Neurology in NB, Canada. Dr. Rizk’s research focuses on various subspecialties in the field of pediatric neurology, specifically movement disorders and spasticity. His research has been directed at recent advances in management modalities. Dr. Rizk studied Medicine at the Faculty of Medicine, Alexandria University, Alexandria, Egypt. His pediatric neurology training was shared between KSA and the UK. Subsequently, he completed a CESR in Paediatric Neurology from the UK. Dr. Rizk has many publications and he is a member of the Editorial board of multiple reputable journals in the field of pediatric neurology. 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Especially in the field of smart drug delivery, polymer played a significant role because it can deliver therapeutic agents directly into the intended site of action, with superior efficacy. The ideal requirements for designing nano-particulate delivery system are to effectively be controlled particle size, surface character; enhance permeation, flexibility, solubility and release of therapeutically active agents in order to attain the target and specific activity at a predetermined rate and time. The smart drug delivery systems have been successfully made by the advances in polymer science in the bio-nanotechnology field. Recently, these advances have been found in various medical applications for nano-scale structures in smart drug delivery. The smart drug delivery systems should possess some important feature such as pre-scheduled rate, self controlled, targeted, pre-determined time and monitor the delivery. The smart drug delivery system enhances the polymer nanoparticle better stage to their therapy regimen. They are drug carriers of natural, semi-synthetic, and synthetic polymeric nature at the nano-scale to micro-scale range. The polymeric particles are collectively named as spheres and capsules. The most of the polymeric nanoparticles with surfactants offer stability of various forms of active drugs and have useful to smart release properties. There are numerous biological applications have been reported for the nano-scale to micro-scale sized particles, such as site-targeted, controlled, and enhanced bioavailability of hydrophobic drugs [1-4]. Due to the nanoparticles size the drugs have been targeting into various applications, such as, various cancers targeting has been shown to be promising [5]. Moreover, polymeric particles proved their effectiveness in stabilizing and protecting the drug molecules such as proteins, peptides, or DNA molecules from various environmental hazards degradation [2-4, 6, 7]. So these polymers are affording the potential for various protein and gene delivery. Numerous methods had been available to fabricate nanoparticles; it depends on the physical and chemical properties of polymer and active ingredients. Most of the formulation techniques involve different mechanisms such as using organic solvents, temperature, ultra-sonication and mechanical agitation which can degrade the pharmaceutical active ingredients. So the nano-particulate system can be developed to consider the formulation methodology should not damage the active pharmaceutical ingredients. There are numerous biodegradable and biocompatible polymers with different physicochemical characters are offered to prepare smart nanoparticles, those polymeric nano-carriers can be natural or semi-synthetic or synthetic. Those nanoparticles can enhance the systemic circulation half-life and minimize unwanted internalization and prevents the denaturation of the therapeutically active moiety and could use to deliver the target agents. Several polymer systems are approved by the U.S. Food and Drug Administration (FDA) for human use. It is the belief that when inventions in fabrication can catch up with those in materials, design and development of drug delivery system can enter a new generation of enhancing clinical healthcare.
The most recent advances in the uses of carriers for sustained and targeted delivery, micro and nano fabricated self-regulated devices [8], bio-recognizable systems; micro-needles for transdermal drug delivery have shown the flexibility and enhanced permeability of these polymeric materials. Ultimately the goal in smart drug delivery is the emergence of a micro and nano-fabricated therapeutic drug release device with the capacity to enough hold and release of various active agents on demand. In modern system the micro-electro-mechanical systems give a distinctive possibility to produce micro-fabricated biomedical devices for different intentions, from implantable systems to lab-on-a-chip systems. The constant and prolonged drug release micro-fabricated systems have the several benefits, such as many active ingredients could be stored in an nano form within the system and sustainably released, the drug release is initiated by the dissolution and disintegration of outer membrane barrier by an mechanical/electric stimuli, the most potential drugs could be released more specifically with this technique, the complex drug release system such as simultaneous stable and periodically could be attained for local therapy by the micro-fabricated system; it can be achieved in high or low dose of drugs at the targeted site and increase the stability of drugs by the membrane barrier for preventing water diffusion into the reservoirs [9]. Owing to the advanced scientific sophistication of the controlled drug release system that has been achieved till now, or that are in dynamic progress, this delivery model can be categorized into various classes. The controlled drug delivery systems can be categorize four main mode of drug delivery, such as (1) rate-programmed drug delivery, where drug diffusion from the system has follow a specific release rate profile, (ii) activation-modulated drug delivery, where the drug release is induced by various factors such as physical, chemical electrical or biochemical modules, (iii) feedback-regulated drug delivery, where the rate of release is determined by biochemical substance (triggering agent) concentrations, it is dependent on the concentration exhibit in the target and (iv) site-targeting drug delivery systems, this is a complex process that consists of multiple steps of diffusion rate and partitioning for the rate of drug release is regulated by the specific targeting moiety, solubilizer and drug moiety. This chapter will brief discussion on recent innovative nano-fabrication methods for novel drug delivery system. Also, highlights some of these new technologies and consider their possibility ongoing clinical transformation of nanoparticles, which the particles are well-controlled formulated. This chapter will be followed by a more detailed novel drug delivery system development from a polymeric material viewpoint and their various bio-applications will be covered without attempting to all the work that has been done in this field.
Over a decade, investigators have appreciated the enrichment of potential uses of bio-nanotechnology in offering huge advancements in novel drug delivery and targeting. The novel drug delivery platform that provides diminishes toxicity and enhances therapeutic efficacy gives most possible benefits to clinical levels. In approaches to drug delivery systems the route of administration is one of the crucial roles of drug targeting. These nanoparticles can be used for various routes, including oral, nasal, transdermal, parenterals, pulmonary, ocular, etc. Nonetheless, the oral route is most convenient, preferred, and in several cases, also its cost-effective, but it does not cross easily some biological barrier; also easily degraded by various body fluids, then rapid hepatic clearance and other organs. So the drug delivery systems focus on overcoming the various membrane barriers, such as the blood brain barrier, tight junction barrier, to achieve the effective drug target and enhance the efficacy. To find an alternative and satisfiable route of administration for the effective drug delivery system should overcome the digestive tract problems, where the degradation could take place via acid-hydrolysis, enzymatic degradation and bacterial fermentation in the alimentary canal. This chapter will cover the more detailed novel route of administration and development from a polymeric material viewpoint and their brief discussion will be covered without attempting to all the work that has been done in this field.
Recently, various kinds of polymers are used to prepare the polymeric nanoparticles, among this all polymer biodegradable polymers and their co-polymers such as di-block, tri-block, multi-block or radial block copolymer structures have been generally used to prepare polymeric nanoparticles and to encapsulate the active ingredients. These multi-functionalized polymeric nano-carriers include micelles, capsules, platelets, fibers, spheroids colloids, dendrimers, core-shells, nanoparticle incorporated polymer matrixes, etc. The first polymeric nanoparticles were developed between the year of 1960 to 1970 for the therapeutic application, and this were Micelles[10-12].The micelles are formed by polymerisation methods, commonly the formation of polymer nano-carriers during the polymerization of monomers [13-16]. Then the various advanced polymerization techniques have been developed for the preparation polymeric based nanoparticles, and the nanoparticles were stabilised using various surfactants [1, 9]. The stabilised drug loaded nanoparticles consist of drug and non-toxic biocompatible polymer with stabilizing agents, the biocompatible polymer is either biodegradable or non-biodegradable. Numerous techniques are available for the preparation of the polymeric nanoparticles and mainly top-down and bottom up processes. The polymer nanoparticle drug carriers can be further categorized into nano/micro-capsules and nano/micro-spheres depends on the size and structure [1, 9, 17-19]. The fine particles are 100 - 2,500 nm and ultrafine particles are 1 to100 nm in size, and are collectively known as nanoparticles. 50 to 300 nm sized nanoparticle have been prepared by emulsion polymerization method [20]. Drawbacks in polymerization techniques are evolving noxious factors such as toxic, reactive residues, un-reacted monomers, the risk of a chemical reaction and the formation of unwanted oligomers [1], and these drawbacks are overcome by using preformed polymers for the polymerization process [1]. Generally the drug loaded nanoparticles were prepared by dissolving the drug and polymer into the water-immiscible organic solvents and producing a nano-emulsion, as an example by probe-sonication method. The organic solvent is removed by using elevated temperature or reduced pressure [21-23], as an example of rotary evaporation method, and the nanoparticle is washed and collected by certification. Followed by various changes and improvements of the emulsification techniques have been reported [24-29]. For example, the sonication process is a crucial step in the preparation of the sensitive drug loaded nanoemulsion, and the sonication process can increase the temperature, that leads to inactivate the active ingredients. In order to avoid the problems researchers utilized an on/off cycle to maintain a low temperature. Other examples of general methods to prepare the drug polymer nanoparticle are described in the Figure 1. The biodegradable polymeric nanoparticles are commonly prepared by five different techniques such as emulsification-solvent evaporation, solvent displacement, salting-out, emulsification-solvent diffusion and double emulsion solvent evaporation. The synthesizing methods include salting-out method [1, 30, 31]; it is based on the separation of a water miscible solvent from aqueous solution through the salting out effect, solvent displacement method [1, 32-34], phase separation method [35], evaporation precipitation [36, 37], antisolvent precipitation and electrospray methods [38].
General methods of preparation of polymeric nanoparticles and their principle involved in the mechanisms
Also, many approaches have been developed for the drug particle size reduction (increase in the surface) to the nanometer size range. For size-reduction, high pressure homogenization or wet bead milling is frequently used technique to produce reduced size nanoparticle [39-43]. Among these the high-pressure homogenization has been shown to be effective methods to produce size reduction particle. Moreover, its need sophisticated equipment to resist increasing pressures and temperature. Then, in order to obtain dried polymeric nanoparticle formulations researchers used various drying techniques such as atmospheric freeze drying, spray freeze drying, vacuum freeze drying, and lyophilisation. The uniformity of spray-dried nanoparticle is better than a freeze-dried nanoparticle. Moreover the lyophilisation and spray-drying are used to prepare the nanoparticle [44, 45], these nanoparticles easily tends to aggregates. Also the polymeric nanoparticles have also been synthesized by supercritical fluid techniques [46-52]. This method can get a dry product without any solution, also no need additional drying stages, but the supercritical fluid can swell some of the polymers and act as a softener, extender, and lubricant, which lead to aggregation. Moreover, this method is not easy to get the mono-dispersed multi-component particles because of different kinetics [52]. Nanoparticles prepared by spray-drying technique are one-step based on the conversion of a droplet to a dry particle by evaporation [53-55]. These one-step techniques have been revealed that the nanoparticle could be prepared without any problems [56-58], and the drug content in the particles is almost high [59], but produce an amorphous residual structure. In all above technique induce some unwanted noxious factors, as well as the organic solvents used in the preparations are increasing the risk of pharmaceutical application, also the increased processing time leads to microbial contamination [60, 61, 62]. Understanding the all risk factors, recently the modern instrument provides a promising and viable platform for the preparation polymeric nanoparticles.
Recently, the polymeric nanoparticles have emerged as a most promising and viable technology platform for recognizing the targeted, environment-responsive and, multi-functional with navigated controlled drug delivery system. Polymer in smart drug delivery is a rapid-emerging new technological discipline in which various therapeutic applications of nano products are expected to overcome the patient complaints in healthcare. Smart delivery will give new solutions for therapeutic interventions. There is great interest from the beginning in smart medicine of advanced and well-characterized bionanotechnological products that will be especially effective in fighting diseases like cardiovascular diseases [63], diabetes [64], cancer [65, 66], aging [67, 68], some chronic metabolic syndrome and various degenerative diseases and disorders [69, 70]. For example, the innovative smart polymers with nano-particulate drug-delivery systems can obviously advances in therapeutics by guiding the drugs to target cells and reducing the adverse-effect/side-effect on well being. At present, some of the smart polymer with multi-functioned nanoparticle system approaches in clinical trials, and it shows promising outcome. Certainly the morbidity and mortality rate of disease affected patients could improve their lifestyle by the early course of smart therapeutic intervention. This smart intervention can be attained by developing high sensitivity and reliable smart drug delivery.
The rapid advancement in the above direction has been made with the initiation and development of more advanced alternative nanofabrication techniques to produce structures in various nano-scales level of controlled manners. Drug loaded polymeric nano-systems can provide controlled release of both hydrophilic and hydrophobic drugs over a long period of time while minimizing unwanted side effects in the body. This involves the synthesis of various novel biocompatible polymers with well-defined nanometers to a few micro-meters structures using several modern techniques such as microelectromechanical systems [71] microfluidic systems [72-76], electrodropping system [77], microneedle based system [78-81], advanced high pressure homogenization, interfacial emulsion polymerization and combined systems. Figure 2 described the few modern techniques for polymeric nanoparticles preparation with various concepts. The physiochemical characters of polymeric nanoparticles have to be optimized based on the specific application. Various methods can be used to produce various nano-particulate systems with various polymers. The multifunctional polymeric nanoparticles developments such as environment-responsive micelles, colloids, nano hydrogel, core-shell nanoparticles, nano-spheres and core-shell nano-spheres with layer-by-layer assembly for single/dual or multi drug release have been achieved so far. In order to get the desired properties, the mechanism of formulation method plays a vital role. Thus, it is extremely beneficial to have synthesis mechanism at hand to approach multi-functional polymeric nanoparticles with exact physiochemical properties for a specific application.
Schematic diagrams represent the advanced techniques of preparation of polymeric nanoparticles
The smart delivery systems of target bio-molecules have been concentrated of recent researches for various interventions. Particularly, various proteins, peptide, growth factors and cytokine therapy for various diseases play a vital role in regulating cellular responses, and thus the design of multi-functional polymeric particles delivery vehicles are closely associated with the regulation of multiple cellular events, likewise a wide variety of target bio-molecules have been investigated in numerous literature reports [82, 83]. Also numerous of delivery vehicles have been studied and reported recently, this chapter will cover same viewpoint and their brief discussion will be covered without attempting to all the work that has been done in this field. Various concepts are utilized in the design of delivery vehicles that are capable of ferrying multiple active ingredients in a self-controlled manner, with different release profile kinetics. The distinctive self-assembly of multifaceted nanostructures from an easy colloidal system has been of interest to design a material with distinctive characters for the use of drug delivery vehicles. The inter-and intra-molecular linkage via van der Waals interaction leads to dense-packed self-assembly periodic nanostructures. These structures could be colloidal particle or clusters, based on the assembly [84, 85]. The natural or semi-synthetic polymer-based self-assembled nanostructures have inherent capacity of the nano-carrier for delivering many kinds of active ingredients, because of good biocompatibility and degradation/resorption properties [86]. In the sonication methods (Figure 2a), the self-assembled nanoparticle was achieved by probe sonication, the process has been done by cavitation, nucleation and reversible locking concept, the formed nanostructure have more flexibility in the nature [87]. In this self-assembled and core-shell particulate delivery systems, including water-soluble polymeric drug compounds conjugates [88], block polymeric micelles [89-93], long-circulating polymeric micelles [94, 95], nano encapsulations [96, 97], and core-shell nano-spheres [98, 99] have been synthesized by in situ two-step semi-batch emulsion polymerization technique (Figure 2b), as vehicle to target suitable dose of drugs in an accurate and controlled manner. Also the core-shell nano-spheres have been achieved for pH-responsive controlled release, and delivery of hydrophobic anticancer agents for acidic tumor tissues [100]. Recently Choi DH, et al have optimized electrodropping system to produce a homogeneous biocompatible core shell capsules for angiogenesis in dual delivery system [77], and they particularly focused on regenerative medicine. This electro-dropping system can overcome from the particle aggregation and drug encapsulation efficiency (Figure 2d). Coming to the micro-fluidics, the recent science and advanced technology of manipulating micro/nano-scale volumes in micro-fluidic channels have significant impact on the various applications. Advances and inventions in micro-fluidics are awaited to enhance the preparation of polymer nanoparticles and shifting to clinical evaluation [101] most of the micro-fluidic systems for synthesis, polymer nanoparticles are still under development and they have the widest possible to develop because they are highly reproducible, easily modifiable and can be incorporated with other techniques [102]. Recently, various micro-fluidic systems provide rapid mixing without any stimulator, such as stirring or electric force; have been originated [103]. Among these various systems the flow-focusing [104], droplet mixers [105] are widely utilized and it enables micro-mixing within the micro channel [106]. The flow focusing squeezes the solvent stream between two anti-solvent streams, resulting in a rapid solvent exchange via diffusion take place (Figure 2c). The effectuation of these rapid mixing methods for the development of nanoparticles in continuous flow; the micro-fluidic system has been achieved the continuous flow, narrow sized, mono dispersed with high drug entrapment and better batch-to-batch uniformity in compared with conventional methods [107].
The recent advances in smart drug delivery systems with rate-programmed drug delivery systems have been achieved by functionalization of rate-controlling surface. The transdermal drug delivery have been achieved a new rate pre-programmed drug delivery system, transdermal patch which delivers a particular concentration of drugs to the blood circulation via the skin, it provides the therapeutic advantage to clinical levels. The rate-programmed drug delivery systems, the release of drug molecules from the rate controlling membrane system has been pre-programmed at particular rate kinetics. The rate controlling membranes made from natural and semi-synthetic polymeric material and proves their ability to use as a rate controlling membranes in any dosage form even nano to micro-scale level particle embedded matrixes or implantable or transdermal patches. It must be simple, cost-effective, and flexible enough not to split or crack on bending or stretching. Recently, some of novel rate-controlling composite membranes have been developed as rate controlling barriers for transdermal application, with flexible and smooth surface nanoparticles embedded scaffold which could reduce the risk of wounding or being rubbed off during dressing, and thereby improves upon traditional dressings and its can provides better patient compliance [108, 109]. This is achieved by optimized system design, which determines the diffusivity of active agents across the membrane. This rate-programmed drug delivery system can be categorized by various controlling dependencies, such as (1): membrane permeation-controlled, (2): diffusion-controlled, (3): membrane/matrix hybrid-type and (4): reservoir partition-controlled systems. The recent advance in the smart rate-programmed drug delivery systems the polymer and their scaffolds play vital roles, such as greater drug-loaded nano/micro-particle encapsulation ability, overcome pre-systemic metabolism, enhanced bioavailability and environmental responsive properties for various applications. For selecting the polymers, need to consider some important key factors for pharmaceutical application such as reduced tensile strength [110], water vapor permeability rate, biocompatibility, non-toxic [111], anti-infective, controlled release [112, 113], flexibility, emollient, adhesion, spreadability and retention properties of the drug-loaded nano/micro-particle encapsulation scaffold or film preparation [114-116]. So it can prevent the immunogenesis, secondary damage to cells, disease recurrence and finally enhance patient compliance [117]. In this type of rate-programmed controlled drug delivery systems, a drug-loaded nano formulation or rate-controlled nano formulation can be either totally or partially loaded in the reservoir space whose surface is covered by the rate pre-programmed polymeric membrane. The pre-programmed polymeric membrane can be optimized and achieved by multi-functionalization with block copolymers. The scaffold or membrane can be produced by the homogeneous or heterogeneous non-porous polymeric compounds or a micro/nano-porous or semi-permeable material. The drug release profile should be at a constant pre-fixed rate. The release profile is controlled by a pre-programmed rate-controlling membrane; it\'s based on the molecules, diffusivity, partition co-efficient, and dimension of the outer membrane. Also the rate of release is determined by the cross-linking ratio of the polymer network. The rate controlled release profile exists in many kind therapeutic formulations such as intrauterine devices [118], ocular insert [119, 120], some transdermal therapeutic system [109], polymer matrix, sub-dermal [121] and subcutaneous implantation [122-125].
Schematic diagrams represent the rate controlled drug delivery systems of topical applications
The smart drug delivery with activation-modulated system has been achieved by external or environmental stimuli, these environmental responsive smart delivery systems achieved a lot more with double and multiple-responsive delivery system. The various activation/stimuli responsive drug delivery vehicles have been synthesized and tested, in various particle sizes, ranges from nanometers to a few micro-meters sized carriers for different routes of administration. The transdermal electro-activated or electro-modulated drug delivery has been established as an efficient model. In this group of activation-modulated controlled drug delivery system, the release of active agents from the systems is activated by some physical, chemical, electrical, environmental condition or biochemical processes and/or facilitated by an energy supplied externally. The release profile has been controlled by the input energy. Based on the activation/stimulation process applied or energy type used, this activation-modulated controlled drug delivery system can be categorized into the various classes which are given in the Table 1. These stimuli-responsive materials show changes in the physicochemical character during the environmental condition changes. These changing properties can be fully utilized in smart delivery system, which certainly similar to the biological response behavior. Different types of body organs, different tissues and various types of cellular compartments might have great differences in every stimulus with great response. So that all the important cases considered in this chapter, deal with various environmental responsive smart delivery systems. Any specific behavioral changes in the system lead to a phase transition, these transitions will be key factors for the stimuli-responsive drug delivery system and some selected examples of applications are described in the Figure 4. The preclinical and clinical studies have demonstrated that drug-loaded polymeric nanoparticles has been well tolerated, extended systemic circulation, higher accumulation in the tumor sites through enhanced permeability and retention effect, minimized side effects and adverse effect, and/or higher bioavailability [153-155]. And most of the drug delivery systems are based on biodegradable polymer [156, 157]. Most of the environment-sensitive polymeric nano-particulate systems are leading to degradation and or disintegration by the internal or external local environmental stimulus such as pH, glucose, low oxygen content, ions, redox potential, and lysosomal enzymes; and then temperature, magnetic field, electric, ultrasound, and light respectively (Table 1).
These activations grew to achieve smart, targeted drug release in a particular time (spatial and temporal control release) [158-160]. At this place we describe a few examples. Particularly, the acidic pH levels in the body vary according to the different body environments (site and the organ) such as tumor cells and tissues (pH 6.5-7.2), endosomes (pH 5.0-6.5), lysosomes (pH 4.5-5.0) and entire GI tract with different pH value as comparatively varied with normal physiological (pH of 7.4) conditions in blood and tissues. So, the pH-responsive nano system have been considered and formulated to release the active agents in pH sensitive targets such as cancer site or endo/lysosomal regions [161,162]. The cytosol and cell nuclei have surrounded with elevated redox potential (in reducing glutathione) it higher than normal body fluids and it have been developed for intracellular release of various active bio-molecules [163-165]. Additionally, the cancerous tissues are extremely low in oxygen content (hypoxia) with higher glutathione levels compared to normal tissues [166]. This has been targeted with hypoxia-responsive polymeric nanoparticles. These internal stimuli-responsive nanoparticles have their own benefit of self-regulated drug delivery and effective target in clinical therapeutics. Also the external activated nanoparticles provide their own advantages such as high reproducible nature, also remote controlled delivery possible, then the release profile can be pulsatile delivered (means that switched on and off) possible [167]. On the other hand, the various light-responsive polymeric nanoparticles system has been developed for activating antitumor drug release [168]. Also numerous of temperature-sensitive multi-functionalized polymeric and copolymers nanoparticles have been formulated based on thermally-responsive release [169, 170]. Magnetically guided nano-carriers have been developed for the remote controlled cancer therapy and diagnosis [171, 172]; also the core-shell nanoparticles have demonstrated for improved tumor accumulation and antitumor therapeutic efficacy in various models.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Physical stimuli | \n\t\t\tOsmotic pressure | \n\t\t\tControlled through the permeability of water Controlled through a gradient of osmotic pressure | \n\t\t\t[126] | \n\t\t
Hydrodynamic pressure | \n\t\t\tGenerate hydrodynamic pressure gradient Forces the drug to release through the orifice | \n\t\t\t[127] | \n\t\t|
Vapor pressure | \n\t\t\tPumping system contains vaporizable fluid Creates vapor pressure, vaporizes at body temperature | \n\t\t\t[128] [129] | \n\t\t|
A mechanical force | \n\t\t\tEquipped with a mechanically activated pump First-pass elimination and pressure-sensitive delivery | \n\t\t\t[130] | \n\t\t|
Magnetics | \n\t\t\tElectromagnetism-triggering vibration mechanism Magnetically activated, vibrate by an electromagnetic field | \n\t\t\t[131] | \n\t\t|
Sonophoresis | \n\t\t\tUtilizes ultrasonic energy to activate the delivery | \n\t\t\t[132] | \n\t\t|
Iontophoresis | \n\t\t\tElectrical current to activate and diffuse the charged drug | \n\t\t\t[133] | \n\t\t|
Hydration | \n\t\t\tUtilized swellable polymer matrix Activated by hydration-induced swelling delivery | \n\t\t\t[128] [126] | \n\t\t|
Electricity | \n\t\t\tElectric-sensitive capsule Electrically erodible matrix for delivery | \n\t\t\t[134] [135] | \n\t\t|
Chemical stimuli | \n\t\t\tpH | \n\t\t\tDeliver the drug in the intestinal tract not in the stomach Deliver the drug in the ulcer stomach by floating delivery | \n\t\t\t[136] [137] | \n\t\t
Salt concentration | \n\t\t\tPrepared by ionizable drug with ion-exchange resin Controlling the delivery of an ionic or an ionisable drug | \n\t\t\t[128] [138] | \n\t\t|
Hydrolysis | \n\t\t\tHydrolysis-induced degradation of polymer chains Hydrolysis activate the release of drug molecules | \n\t\t\t[139] | \n\t\t|
Biochemical stimuli | \n\t\t\tEnzyme | \n\t\t\tPolymer chains fabricated with biopolymers Deliver the drug by enzymatic hydrolysis of polymers | \n\t\t\t[140] [141] | \n\t\t
Biochemical | \n\t\t\tEnzymatic-activated, biodegradation Feedback-regulated delivery concept has been applied | \n\t\t\t[142] [143] | \n\t\t|
Environmental stimuli | \n\t\t\tTemperature | \n\t\t\tDepends on the transition temperature Shifting the hydrophilic/hydrophobic balance | \n\t\t\t[144] [145] | \n\t\t
Light | \n\t\t\tPolymers undergo isothermal phase transitions by photon Reversible phase separations through photo-irradiation | \n\t\t\t[146] [147] | \n\t\t|
Hypoxia | \n\t\t\tHydrophobically modified imidazole derivative was conjugated to the carboxymethyl dextran, it can release the hydrophobic agents under hypoxic conditions | \n\t\t\t[148] | \n\t\t|
Dual-stimuli | \n\t\t\tTwo different responses | \n\t\t\tBased on the polymer architecture Micelles are reported pH and thermo-responsive | \n\t\t\t[149] [150] | \n\t\t
Multi-stimuli | \n\t\t\tMore than two responses | \n\t\t\tFunctionalization of pyrene-quaternized segments form a light-responsive shell and the unquaternized segments form a temperature/pH-responsive core | \n\t\t\t[151] [152] | \n\t\t
Overview of various stimuli responsive nano-carriers for smart drug delivery systems with mode of drug release applications
Schematic diagrams represent the activation-modulated drug delivery systems, which the polymeric nanoparticle activated by various stimuli such as physical, chemical, biochemical, environment, and/or a combination of two or more.
In this chapter, provide the recent proposes and formulations of dual and multiple-stimuli responsive multi-functionalized polymeric nanoparticles and their promising targets in smart drug delivery in specific to the cancer therapy. With the booster development of the smart drug release and increase therapeutic efficiency of intelligent drug loaded nano-particulate system, polymeric nanoparticles that respond to dual and multi-stimuli, which have been aggressively reported. The double-response and multiple-responsive nano-particulate systems were described in the Table 2. It must be mentioned that the stimuli and responses happened at the same time at the same site or different mode. These dual and multi-stimuli responsive polymeric nanoparticles can provide control over the drug release profile, which leads to greater anti-tumor efficiency in vitro and in vivo models, and on the other side the nanoparticle formulation and drug loading under moderate conditions. In this section we describe a few examples. Especially, redox-responsive drug release multi-functionalized nano-particulate system have been formulated based on temperature and reduction, dual responsive tri-block copolymers functionalized by increasing temperature above the lower critical solution temperature after that cross-linking [173, 174]. These multi-functionalized nano-particulate systems were targeted to cancer cells and triggered by reduction oxidation mechanism, which leads to dissociate to release the active agents by de-crosslinking followed by disruption and degradation of nano-particulate system. pH/redox dual-stimuli multi-functionalized disulfide cross-linked micelles have been developed for increased drug release and accumulation in the cancer target, due to endo/lysosomal pH and intracellular redox environment the drug release was taken place [175].
These multi-functional polymeric nanoparticles are capable to face the current problems of nanoparticle drug formulations including formulation and drug encapsulation, prolong stability, cellular internalization, site-targetability, enhanced cellular uptake, and inside cell target and drug release. These dual and multiple-activation responsive characteristics have provided novel and enthusiastic power over drug release kinetics and greater efficiency. All the described studies in dual and multiple-stimuli responsive drug delivery systems are mostly trial and error models, because most them non-biodegradable carriers, low encapsulation, and nonviable to clinical therapeutics. To overcome all the unfavorable conditions, immediate efforts could be focussed to improvement of dual and multiple-stimuli responsive biocompatible, biodegradable, non-toxic, and non-immunogenic smart polymeric nanoparticles that could effectively entrap and sustain the drug release in the systemic circulation, enhanced accumulation in the cancer target, and efficient release kinetics in response to more efficient external or internal stimuli. Moreover the smart polymeric nanoparticle system does not produce any secondary damage and any harmful to the healthy cells. In the case of clinical studies on dual and multiple stimuli responsive system shall be performed to obtain a real mechanism of action in anti-cancer target. In addition, the multi-functionalized smart polymeric nanoparticles system construct with targeting ligands and shall be incorporated into dual/multiple stimuli responsive nanoparticles to be achieved multidrug resistant cancers by site targeting, site-specific, and rapid/sustained release, and we sure that dual and multiple stimuli responsive smart nano-particulate system going to be a good future in cancer therapy.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Dual-stimuli | \n\t\t\tpH & Thermo | \n\t\t\tP(NIPAAm-co-DMAAm-co-UA) nanoparticles P(NIPAAm-co-AA)-b-PCL nanoparticles PLA-g-P(NIPAAm-co-MAA) nanoparticles P(NIPAAm-co-DMAAm)-b-PCL/PLA micelles PNIPAAm and PAA hollow nanogels | \n\t\t\t[176] [177] [178] [179] [180] | \n\t\t
pH & redox | \n\t\t\tPEG-SS-PDEA polymersomes DS-g-PEG/cRGD nanoparticles Poly(b-amino ester)s-PEG micelles PMAA-based nanogels mPEG-PAsp(MEA)-PAsp(DIP) micelles | \n\t\t\t[181] [182] [183] [184] [185] | \n\t\t|
pH & magnetic | \n\t\t\tFe3O4 nanocarrier with peptide mimic polymers DOX-tethered Fe3O4 conjugates nanoparticles mPEG-b-PMAA-b-PGMA-Fe3O4 nanoparticles Fe3O4-capped MSNs MCM-TAA-Fe3O4-capped MSNs | \n\t\t\t[186] [187] [188] [189] | \n\t\t|
T & redox | \n\t\t\tEO-PAA-PNIPAAm polymersomes | \n\t\t\t[190] [191] | \n\t\t|
Double pH | \n\t\t\tPPC-Hyd-DOX-DA nanoparticles Poly-b-amino ester ketal nanoparticles | \n\t\t\t[192] [193] | \n\t\t|
pH & diols | \n\t\t\tPEG-b-dendritic cholic acid telodendrimers nano-carriers containing boronic acid | \n\t\t\t[194] | \n\t\t|
T & magnetic | \n\t\t\tPluronic with Fe3O4 nanoparticles | \n\t\t\t[195] | \n\t\t|
T & enzyme | \n\t\t\tDNA-capped MSNs | \n\t\t\t[196] | \n\t\t|
Multi- stimuli | \n\t\t\tT/pH/redox | \n\t\t\tPNIPAAm-SS-P(THP-protected HEMA) micelles | \n\t\t\t[197] | \n\t\t
T/pH/magnetic | \n\t\t\tP(NIPAAm-co-MAA) coated magnetic MSNs | \n\t\t\t[198] | \n\t\t|
pH/redox/ magnetic | \n\t\t\tFe(II) loaded PMAA crosslinked by N,N-methylene-bisacrylamide and N,N-bis(acryloyl)- cystamine | \n\t\t\t[199] | \n\t\t|
T/redox/guest molecule | \n\t\t\tVesicles based on hosteguest complex formation between C4AS and MVC12 | \n\t\t\t[200] | \n\t\t|
T/pH/guest molecule | \n\t\t\tCucurbit(8)uril micelles, methylviologene-functionalize PNIPAAm and naphthalene-terminated PDMAEMA | \n\t\t\t[201] | \n\t\t|
Light/pH/T | \n\t\t\tPyrene-functionalized poly (dimethylaminoethyl methacrylate) | \n\t\t\t\n\t\t |
Overview of dual and multi-stimuli responsive materials for nano-carriers of various smart drug delivery systems
The recent advances in smart delivery systems with feedback-regulation of drug release. This self-regulated or feedback-controlled drug delivery comes under closed-loop systems. The self-regulated system drug release rate is controlled by feedback information, without any external stimulation, and utilized several approaches to control the release rate [202-205]. The feedback-regulated drug delivery concepts were schematically depicted in Figure 5. The feedback-regulated drug delivery concept has been applied to the development of various controlled delivery systems such as bio-erosion regulated, bio-responsive regulated and self-regulating drug delivery systems. Among this one of the concepts has been involved in the smart controlled delivery systems. For that various research efforts are also in progress to develop such nanoparticles that contain drugs capable of a feedback-modulated drug release. The drug release is activated by a triggering agent, such as a biochemical substance, in the body via some feedback mechanisms. The release rate has been determined by triggering agent concentration. When the triggering agent is above a certain level, the release is activated. This can induce and stop the drug release. It would be a high potential benefits if they were delivered by a system that recognized the particular warning signal caused by disease affected part, then they estimated the magnitude ratio of the signal, and then acted to release the exact quantity of active drugs in response. This kind of drug delivery system required to fulfil the physiological need by means of some feedback mechanism. The self-regulated drug delivery systems utilize several approaches for the rate-control release: pH-responsive polymers, temperature-responsive polymers, enzyme-substrate reactions, antibody interactions, enzyme-mediated, pH-dependent drug solubility nature, competitive binding mechanism and metal concentration-dependent hydrolysis. A hydrogel can swell in aqueous medium and retain their structure. The multi-functionalized polymer nanoparticle can be incorporated into hydrogel, such hydrogel used for the feedback-regulated drug delivery system. This hydrogels can protect the drug from dangerous environments such as enzymes and low pH in the stomach. This can control drug release through changing the network structure in response to particular stimuli, which can enable the sensor leads to reversible volume phase transitions upon small changes in the environment condition. For example, the polymers characterized by lower critical solution temperatures generally shrink, as the temperature is increased via lower critical solution temperature. Decreasing the temperature below lower critical solution temperature, the polymer can swell. Biomolecules can be encapsulated on or within the heat responsive polymers.
Schematic diagrams represent the feedback-regulated drug delivery systems
The sensor grafted in the delivery system can enable to mimic the recognition function of various bio-chemicals such as enzymes, cell mediated receptors and various proteins in human beings for maintaining the regulation and equilibrium. This approach is utilized for drug incorporated polymeric feedback controlled delivery systems, and this system approach is based on the observation that changes in control mechanisms, e.g.: pH or ionic strength or temperatures can affect large changes in drug solubility; this can be the main factor for control release rate. The external trigger molecule and polymer-bound enzyme can alter the pH inside the polymeric system. If the pH alteration happened inside the polymer system that can lead to changes in drug solubility, which is induces the diffusion or dissolution or disintegration, and rate of release has been changed accordingly. Many researchers have been developed a membrane to bypass the rumen but it allows the polymeric system to release the drug in the stomach via gastric retention mechanism [206]. Because of the polymer membrane it is impermeable to the rumen pH 7, but the swells and release at pH 4, which is the fourth stomach. Several studies have been performed on various polymers holding weakly acidic or basic functional groups in the polymeric backbone [207-112]. This polymeric system can swell or de-swell by changing the pH of the environments. By this way the drug will release from a matrix or device, which is developed by pH dependent polymers and this system can provides controlled release rates.
The bio-erosion controlled drug delivery system comprises of a drug-encapsulated bio-erodible scaffolds developed from biocompatible polymers (poly (vinyl methyl ether)), and were layered using immobilized urease. In a neutral pH the polymer erodes gradually, but in existing with urea, urea is metabolized by the system containing urea to form ammonia, it leads to increase the pH in the surrounding area, this increased pH degrade the polymer scaffolds then the drugs has been released [213], and some polymers require high pH to degrade.
The bio-responsive controlled drug delivery system, glucose-triggered insulin delivery has developed [214], the insulin is encapsulated within biocompatible polymer hydrogel scaffold comprising abundant NR2 functional groups present in the normal state. So in this state scaffolds are un-swollen and thus impermeable to insulin molecules. Enzymatically oxidized glucose is to form gluconic acid, this triggers the NR2 groups to form NR2 H+, it leads to swollen and insulin molecules deliver through the polymer membrane, and the amount of delivery has been controlled by glucose penetrating concentration.
The reversible and competitive binding mechanism also has been reported to insulin delivery. This mechanism role is to activate and to regulate the release of drug in the target; also it depends upon the glucose level present in the systemic circulation. Insulin-sugar-lectin complex has been prepared and entrapped into the semi-permeable polymeric membrane to achieve controlled release. The diffused blood glucose has competitively bound to particular binding sites, then activates the complex to release insulin derivatives, and the release acted based on the concentration of glucose presented in the systemic circulation. By this way the self-controlled drug delivery has been achieved. A further improvement on insulin delivery, they used glycosylated insulin-concanavalin A complex and entrapped inside polymeric membrane and the release has been achieved by self-regulated mechanism, depends on the glucose concentration permeate into the system [215]. Again in the development of self-regulating insulin delivery has achieved by enzymatically controlled implantable glucose-dependent insulin delivery systems [216]. Followed by various researches developed the different kinds of glucose-responsive insulin delivery [217-223]. Also the molecular imprinting technology developed system able to identify the specific compounds on the cell surface, and this can be appropriate for further developing and targeting the delivery system to specific tissues or cells. Recently, the pH-Sensitive polymer multi-functionalized with block co-polymeric nanoparticles have been developed for the triggered release of paclitaxel within a tumor microenvironment which the polymer acted as a feedback-regulated drug delivery carrier [224], and this carrier have a reversed swelling behavior. Most recently, the feedback controlled drug delivery system has been developed for cerebral cortical disorders with a feedback controlled mechanism. Drugs have been delivered via subdural/subarachnoid space, then diffuse into neocortical tissue and this diffusion can be controlled by electrophysiological feedback, the cerebral cortical area is exposed to the drug, and they were optimized for the drug concentration, delivery, frequency of delivery [225]. Moreover, the molecular imprinting technology has a huge possibility for producing acceptable dosage forms in the feedback-regulated drug delivery systems. The application of molecular imprinting enables the design of new systems and also in polymer based device fabrications. The advances in the preparation of molecular imprinting as spherical uniform particles [226] and scaffolds [227] can increase the field application potentiality of several polymers in drug delivery system. Moreover, these imprinted delivery systems have not yet touched in clinical therapeutics.
The recent advances in the smart delivery systems with site-targeting drug release. A site targeted drug delivery systems are complex of multiple steps of diffusion and partitioning. Nowadays the site targeted drug delivery systems involve deep investigation as they are very eager to overcome the modern medical application [228]. A well-designed multi-functionalized polymeric carrier for site-targeted drug delivery in the interventions of various diseases such as colon disease, kidney/renal disease, nasal disease and genitourinary disease has been reported recently [229-234]. A variety of both natural and synthetic water-soluble polymers have been used for biomedical applications. These polymers have been used routinely in bio-pharmaceutics because of the effectiveness in controlled drug release. The traditional formulations are not significantly efficient at targeting molecules, thus the new and smart drug delivery systems are being studied to overcome the problem. The goal of the smart drug delivery systems is to allow a localized drug delivery, at the same time; it does not affect the healthy tissues and no unwanted effects. The drugs composed of micro-or nano-sized particulate system, which is able to spread through the systemic circulation, and transport through various body organs and body areas such as arteries, veins, and capillaries and even cross membrane barriers. The nanoparticle transport and targeting tissue are the complex process, so the transportation and communication have been viewed by the molecular communication paradigm. This transport of drug-loaded particles in the human body has been viewed, where the nanoparticle has transported this information is conveyed by signaling molecule. This communication system provides a clear reading of particle diffusion, distribution, disintegration over time throughout the biological system, which provides the importance to the invention of a smart particulate delivery system. Initially, the kinetic Monte Carlo method [235, 236], have been used computer simulation to solve the communication system. Lately, researchers developed an analytical approach based on the abstraction of targeted particulate delivery systems as a communication mechanism. This information is passed between sender and receiver by intracellular and intercellular signalling [237]. Different kinds of molecular communication have been analyzed so far, which involve passive or active transport of molecules [238, 239]). The smart site targeted delivery system takes an advantage of the systemic circulation for the distribution of active drug particle from where it’s ingested to the systemic circulation to a targeted site. Basically, the delivery systems have been made with purpose and intention to control the rate of release from the systems, but the transport of nanoparticle to the target site still needs more control. Preferably, the route of administration and nanoparticle transport should also be strong enough controlled.
In this section also provides a few examples of site-targeted drug delivery systems, The ideal example is that the kidney site-targeted drug delivery systems, it acted as a smart delivery to enhance drug efficacy and safety in the therapeutics of kidney diseases. By this smart drug delivery treatment provides that reduces inflammation and reduce the formation of excess fibrous to proximal tubular cells, it can protect systemic infection and renal tubular inflammations. So targeting the renal proximal tubular cells is the novel and efficient routes to cure kidney disease [240-244]. Kidney-targeted drug delivery system can overcome from the various obstacles such as kidney transplantation, ureteral obstruction, diabetes, and other some important kidney disease. Figure 6 shows the kidney drug delivery of nano-particulate systems. Among all drug carriers the macromolecular carriers are extremely powerful targeting the kidney, because of the selective accumulation in the kidneys. Macromolecular carriers with prodrugs play crucial roles in targeting drugs to particular target cells in the kidney. The molecular weight and electric charge of polymers is one of the crucial role for effective renal clearance [245, 246], thus the active polymeric system can uptake and exists in the renal cells [247]. Especially the multi-functionalized polymeric nanoparticles showed higher uptake in glomerular mesangial cells [248, 249]. For nasal site-targeting specificity, the multi-functional particulate system design is the main role for site-targeting. So, design and preparation method has to be controlled according to the needs, the materials should be with quality of properties such as biocompatible, biodegradable, modifiable, mucoadhesive, antimicrobial, tumor or particular cell recognition, and maintain the drug release. In the example, N,N,N-Trimethyl chitosan nanoparticles achieved controlled intra nasal delivery to treat various diseases including hepatitis B and allergic rhinitis [250]. Also the amine functionalized chitosan has been shown their eminent characters such as biocompatible, enhanced solubility, strength, porosity, absorption efficacy, chemical tolerance, non-immunogenic and non-antigenic properties, and it has been used for various nasal delivery.
Schematic diagrams represent the site-targeting specificity particulate drug delivery systems
Macromolecule is a very large molecule, which can accumulate in the kidneys. Generally, the molecular weight of the macromolecular vehicle is bigger than that of the prodrugs, so this kind of system can achieve the goal. Pro-drugs have the ability to select the target in the kidney because it can release the active drug by the action of renal enzymes. The various strategies of kidney-targeted drug delivery systems has to be considered such as biodynamical strategy of renal artery perfusion, macromolecular carriers which includes enzymes, immune proteins and peptide hormones, pro-drugs which includes folate, sugars, and amino acids, and other strategies including various nano-particulate systems. The molecular weight and charge [245, 246] of polymers is the main factor, it can influence their distribution in various organs including kidney. In general, increasing the molecular weight of polymers leads to decreases urinary clearance. Some of the polymers have been eliminated rapidly from the systemic circulation but it does not excrete from the kidney, and its accumulated in the renal systems. So it clearly proposed that the selection of effective and active multi-functionalized polymeric nanoparticles can uptake by the particular kidney cell types. So the selection of polymers is one of the prime strategies for consideration to achieve the efficient kidney targeting. These new possibilities to develop kidney targeting conjugates and other nano-particulate drug delivery systems. Including various polymers based nanoparticles give excellence strategies to achieve the goal of targeting drugs to the various renal diseases.
The ideal proposed model for site-targeting delivery is fabricated from a biocompatible, non-immunogenic and biodegradable polymer and acts as the central of support to three main characteristics of attachments such as site-specific targeting moiety, solubilizer and drug moiety, which should have drug delivery capacity, capable of transport and active molecule should bonded to the polymer via spacer, and the linkage is cleaved by particular enzyme(s) at the final targeted site respectively. In order to develop a new polymeric vehicle for a particular drug, the polymer distribution in the systemic circulation has to be analyzed since it’s right away affects on activity of drugs. For controlling the systemic distribution of drugs, we need to consider minimum two strategies which are active or passive targeting. Previously, the drug is delivered to target site using some specific antibodies, which are specific to target cell-surface [251-254]. This method gives efficient targeting to tumor site; however, the antibodies can produce immunogenic activity. But, the passive targeting with bio-polymers vehicles cannot produce immunogenicity or toxicity, this might enhance the active molecule efficacy, such as increased half-life by increased size of the nano-particulate complex, increased permeability at the targeted area and polymer vehicle interacts to the body organs. Those elements must be increase the absorption of the drug molecule; which minimize the dosage and low unwanted effects [255, 256]. Moreover, in the advanced fabrication of molecular imprinting technology can provide efficient smart polymeric systems with the ability to recognize specific bio active molecules. This advanced fabrication technology has tremendous possibility to meet the requirements for satisfactory dosage forms developments. Depends upon the particular application the fabricated systems can decide the delivery, efficiency, safety of the drugs, and when it should be reached. Described all above application strategies have a significant interest in targeting drugs into specific regions [257, 258].
Engineered materials have been utilized for developing smart drug delivery systems. Design and multi-functionalities fabricate of efficient smart drug delivery systems are vitally necessary for medicine and healthcare development. In the material science field provides biodegradable, biocompatible, environment-responsive, and highly effective novel polymeric system for targeted delivery. Nanotechnology provides bottom-up and top-down nanofabrication with size controlled and multi-functionality of particulate for targeted delivery. New materials invention and advanced technology have been synergistically achieved in drug delivery so far. The essential goals of medical pharmacology provide the right medicine, right dosage, and right route at the right time to the right patient, so more research need to optimize the therapeutic efficacy of the drug. This is the essential principles is behind the smart drug delivery. A smart, controlled delivery system needs synergistic consideration of several factors; these have been summarized in Figure. 7. It is difficult to get all consideration factors in a smart controlled delivery system due to other influencing factors. Also high quality, reliability, efficiency and reproducibility are the most significant issue while designing such a smart system. Also the smart systems have to induce the drug release and stop the release by their own manner. It would be highly benefited, if the system recognizes the disease affected part, estimated the disease affected ratio, and then acted to release the exact quantity of active drugs. This kind of drug delivery system can fulfil the medicine and healthcare requirements.
Requirements of several factors for simultaneous consideration to design a polymeric nanoparticle for the smart drug delivery system
In this section provides the recent research on the preparation and functionalization of various polymeric hybrid nano-materials including nanoparticles and microparticles by various techniques. Several techniques have been developed for the functionalization of polymeric nanoparticles with different therapeutic applications. The polymeric nanoparticles have been studied for their enriched properties in biological systems, with the nature of the materials and whether it has the specific properties for chemical modification and functionalization of the nanoparticle developed from various materials including bio-macromolecules. There are several researchers have been studied for functionalization and surface modification of nanoparticles and it would not cover all this in this section; so, this section covers some examples of nanoparticles functionalization and some important criteria to consider the fabrication process. In addition, the richness of surface chemistry and potential biomedical applications are described. The polymeric nanoparticles surface functionalization are mainly two types, one is functionalization with biological (macro)molecules such as peptides, carbohydrates, lipids, fatty acids, proteins, and nucleic acids (genes, oligomers, aptamers, and ribozymes/DNAzymes); another one is functionalization with specific ligands such as mono-or oligosaccharides (carbohydrates), folate receptor, antibodies and biotin are commonly used. This surface functionalization have been made by various modifications on preformed nanoparticles through adsorption, functional surfactants, emulsification, polymerization, covalently bounded functional molecules and various forms of bio-conjugation. There are few considerations for functionalization of polymeric nanoparticles properties such as: 1) the bio-molecule ratio should controlled by calculating the number of conjugate sites presents in the nanoparticles with different applications, 2) due to the environment and electrostatic interactions the alignment of functionalization has been varying, so the non specific attachment should be avoided in the performed nanoparticles, 3) depends on the applications requirements the nanoparticles bio-molecule distance should be maintained, 4) control the conjugation moiety attachment/linking affinity to the performed nanoparticles, 5) should maintain the optimal efficiency of physiochemical characters and 6) it should be high reproducible for all batches. The above all criteria can fulfil the requirement of design and functionalization of nanoparticles for a controllable release profile that satisfies the desired application. And better protection against environmental factors and maximum optimal control is achieved if drug loading is carried out by encapsulation instead of adsorption on to the particle surface. With the combinations of these above criteria in the fabrication of nanoparticles are potential to increase the clinical therapeutics by reducing unwanted effects.
With the field of bio-nanotechnology, enormous new research on the synthesis of polymeric nanoparticle based top-down or bottom-up approaches have been recently developed. Recent developed polymeric systems engrafted nanoparticles provide the optimal characteristic of the functionalized nanoparticles for various therapeutic approaches in harsh environments such as in the acidic and alkali environment [259]. Also polymer nanoparticles are broadly used in several therapeutic applications, mostly cancer targeting and therapeutics. And we provide some examples of various nanoparticles with different functionalization and different therapeutic uses based on the target, shown in Table 3. Therefore, the multi-functionalized nanoparticle over comes from the drawbacks of conventional therapy. In the latest study provided that more than 26 nanoparticle based therapeutic system have been approved for clinical treatment and several nanoparticles are under consideration [281]. In order to achieve the efficient nano-particulate system based therapeutics the nanoparticle synthesis and functionalization methods have to consider very carefully. Although several surface modified methods for various bio-applications have been reported previously, in this section highlight particular examples where this type of functionalization has been used.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Human serum albumin | \n\t\t\tAmino/acid group | \n\t\t\tDoxorubicin | \n\t\t\tAntineoplastic | \n\t\t\t[260] | \n\t\t
Trimyristin | \n\t\t\tSterically stabilized | \n\t\t\tPaclitaxel | \n\t\t\tOvarian, lung, breast cancer | \n\t\t\t[261] | \n\t\t
PLLA-b-PEG | \n\t\t\tFolate targeted | \n\t\t\tDoxorubicin | \n\t\t\tSolid tumors | \n\t\t\t[262] | \n\t\t
PEG-PE | \n\t\t\tLipid conjugated | \n\t\t\tPaclitaxel | \n\t\t\tVarious cancers | \n\t\t\t[263] | \n\t\t
PEG | \n\t\t\tLipid conjugated | \n\t\t\tTamoxifen | \n\t\t\tLung carcinoma | \n\t\t\t[264] | \n\t\t
Polymer-lipid hybrid | \n\t\t\tLipid conjugated | \n\t\t\tDoxorubicin | \n\t\t\tSolid cancer | \n\t\t\t[265] | \n\t\t
PCL-b-trimethylene carbonate-PEG | \n\t\t\tSerum protein | \n\t\t\tEllipticin | \n\t\t\tAnticancer | \n\t\t\t[266] | \n\t\t
PAMAM dendrimers | \n\t\t\tFolic acid | \n\t\t\tethotrexate | \n\t\t\tEpithelial cancer | \n\t\t\t[267] | \n\t\t
PEG | \n\t\t\tAlbumin bound | \n\t\t\tDoxorubicin | \n\t\t\tVarious cancers | \n\t\t\t[268] | \n\t\t
Micelles | \n\t\t\tBiotin-antibody-conjugated | \n\t\t\tDaunomycin | \n\t\t\tBrain tumor | \n\t\t\t[269] | \n\t\t
PLGA | \n\t\t\tAlendronate | \n\t\t\tEstrogen | \n\t\t\tBone-osteoporosis | \n\t\t\t[270] | \n\t\t
Poly(DEAP-Lys)-b-PEG -b-PLLA | \n\t\t\tPoly(lysine) | \n\t\t\tDoxorubicin | \n\t\t\tpH sensitive tumor | \n\t\t\t[271] | \n\t\t
PLGA-b-PEG-COOH | \n\t\t\tPSMA | \n\t\t\tAnti cancer | \n\t\t\tProstate- cancer | \n\t\t\t[272] | \n\t\t
PEG or PE particles | \n\t\t\tTransferrin | \n\t\t\tOligonucleotide | \n\t\t\tBrain- gene | \n\t\t\t[273] | \n\t\t
PLLA-PEG | \n\t\t\tBiotin | \n\t\t\tAnti cancer | \n\t\t\tCancer therapy | \n\t\t\t[274] | \n\t\t
Polystyrol | \n\t\t\tSc-TNF | \n\t\t\tAnti cancer | \n\t\t\tCancer therapy | \n\t\t\t[275] | \n\t\t
PLA | \n\t\t\tAptamer | \n\t\t\tAnti cancer | \n\t\t\tProstate cancer | \n\t\t\t[276] | \n\t\t
PE | \n\t\t\tRGD peptides | \n\t\t\tsiRNA | \n\t\t\tVasculature cancer | \n\t\t\t[277] | \n\t\t
mPEG/PLGA | \n\t\t\tPeptidomimetics | \n\t\t\tAnti cancer | \n\t\t\tBrain cells cancer | \n\t\t\t[278] | \n\t\t
PLA | \n\t\t\tGalactose | \n\t\t\tRetinoic acid | \n\t\t\tHepatocytes | \n\t\t\t[279] | \n\t\t
PLGA | \n\t\t\tMP lipid A | \n\t\t\tAnti cancer | \n\t\t\tDentritic cells | \n\t\t\t[280] | \n\t\t
Examples of various nanoparticles with different functionalization and therapeutic uses based on the target
Functionalization is defined as the improving performance of nanoparticle by a chemical functional group on their surface. Some basic components of functionalized nanoparticle are enabling to increasing the multifunctional applications in the field of biomedicine; the basic components are diagnostic agent, targeting ligand, spacer group, therapeutic agents, and polymer nano-carrier with proper functionalization. Here we introducing two strategies for surface functionalization, first one is direct functionalization, where the functional ligand is a bi-functional compound. In this method, one of the reactive groups is used to bind to the nanoparticle surface and the second group contains the required active functionality. Another one is post-functionalization, here the strategy is not changeable and the nature of the functionalizing group cannot be compatible with good control over the size and dispersion of the nanoparticles in the solvent used for the fabrication. Commonly, the nano-carriers have been functionalized with various chemical functional groups such as thiols, disulfides, amines, nitriles, carboxylic acids, phosphines and bio-macromolecules [282-287], based on their application. The functionalization of nanoparticle is to modify their outer surface with other specific chemical agents based on the desired application. After functionalization the particle physiochemical character has been changed. Also, it is a very important step for control because it can change their size and self-organization during the formation and should not promote aggregation. The prepared polymeric nanoparticles have emerged promising technology platform for recognizing the target with navigated controlled drug delivery system. Figure 8 shows the various functionalizations of the nano-engines for the development of smart drug delivery systems (Left side) and pre-regulated nanoparticle recognizes the tumor cells not the healthy (right side). This therapeutic drug concentration reaches the tumor site not in the normal cells or tissues. Polymer base smart drug delivery can overcome the patient complaints in healthcare.
In polymeric based nano-composites fabrication, the nanoparticles is used as backbone to enhance the physiochemical characters [288-290] such as flexibility, smoothness, enough strength and stiffness, which are much essential in the field of tissue engineering and bio-medical applications. The mechanical strength of polymer based nanocomposites is low due to the poor linkage between nanoparticles and the polymer, which leads to artificial defects in the composites [291-293]. It could be engineered with the appropriate interface to enhance the flexibility, smoothness, strength, stiffness and compatibility of the composite character [294]. The advanced functionalization of the nanocomposite have been prepared with suitable surface active agents, including anionic and non-ionic surfactants, it can lead to strong linkage between the nanoparticle and the polymer. The multi-functionalized nanocomposite enhances the physicochemical properties and no untoward effect on the biological system had been reported [295]. For the hydrophobic drug the phage display technique has been used for the functionalization [296], and the bioavailability have enhanced by post-polymerization. Additionally, the post-polymerization with copolymer produces efficient targeting in the extracellular compartment of the biological system [297-300]. With the nanoparticles the polymers like PEG establishes for prolonged systemic circulation [301, 302]. For the stimuli responsive targeted drug delivery has been achieved by the functionalization of suitable materials (light or magnetic or thermal or ionic responsive material). Particularly, the magnetic induction systems have been used with functionalized magnetic nanoparticles for cell or tissue specific targeted delivery. For targeting brain delivery system the nanoparticles has been functionalized for specific or nonspecific binding mechanisms [303]. The fabrication and functionalization science has merged with software oriented technology for the development of controlled and targeted nanoparticle loaded micro-device system [304]. The recent trends in novel polymer and block co-polymer synthesis methods like radical polymerization and click chemistry has been provide well-desired multi functionality polymeric structures [305-312]. This is the potential method to fabricate the desired molecular weight polymer with well-defined characteristic features. This unique method of polymer synthesis gives the successful nano formulation for potential bio-application. The functionalized nanoparticles have been synthesized with potential biochemical moieties. Then these multi-functionalized nanoparticles have been examined for desired physicochemical property and biocompatibility.
Schematic diagrams represent the various functionalizations of the nano-engines for smart drug delivery systems, which the pre-regulated nanoparticle recognizes the tumor cells not the healthy.
The route of administration of therapeutics is crucially important to cure the disease. Despite the invention of potential therapeutic moieties, the inefficient drug targeting by pills or injection on the appropriate site of the body limits therapeutics values to a larger extend. There are multiple barriers involve in the anatomical and physiological system to lack the drug efficiency, including enzymatic degradation in the stomach, absorption across the intestinal epithelium, hepatic clearance, and accumulation in non-targeted tissues. These barriers also involve a range of complexities from the tissue to the organelle level along with the time that mismatch the drug potency in vivo. Collectively, these conditions challenge the active utilization of potent therapeutic molecules for disease treatment or prevention. Extensive research has been carried out in the field of drug delivery to overcome these challenges and thus to contribute a significant role in the overall drug-development process. After the evolution of nanotechnology and vast increment in knowledge about the human body, advances have been achieved in the drug delivery field as targeted delivery and sustained/controlled delivery system. By tuning the kinetic properties of therapeutics, the potentiality could be secured until it reaching the targeted organ and this factor is considered to be the most important in the field of pharmacology. Progresses in the nanomaterials development have been fruitful to fulfil the goals of drug delivery. Pharmacologically, the drug delivery is better explained based on the routes of drug administrations. Development of alternative drug delivery methods is crucially important to overcome the challenges experienced throughout the history of medicine. Scientists have been working on the creation of the smart drug delivery system and such approaches could provide an easy route of administration, ensuring patient compliance, decreasing toxicity, improving bioavailability and achieving precise therapeutic targeting. Creation of smart drug carrier as delivery systems and the discovery of new pharmacological compounds will potentially advance disease diagnosis and treatment beyond expectation. A variety of novel drug delivery systems have been developed using various nanomaterials during the last decade and several of them are already marketed. Nanotechnology manipulates the multiple properties including the size and other physical characteristics and thus achieves both controlled and targeted delivery of drugs. The bio-adaptability and multi-functional properties of smart delivery system minimize the undesirable properties of drugs in various routes of administration, including oral, rectal, nasal, ocular, topical route such as transdermal, and dermal, parenteral route such as intravenous/intravascular, intramuscular, subcutaneous, intradermal/intracutaneous, intraperitoneal and intrathecal. Figure 9 depicts the tremendous applications of new nanomaterials for the development of various routes of administration and targeting for therapeutics such as transdermal vaccine delivery, intranasal vaccine delivery and lung targeted delivery. Nasal mucosa offers numerous benefits as a target tissue for drug delivery, particularly for brain targeting because drug penetration through the BBB is favored by lipophilicity.
Schematic diagrams represent the recent developments of various significance routes of administration and targeting strategies
In particular, the non-invasive intranasal delivery offers large interests in the targeted route of administration. Nasal delivery helps drugs to bypass the blood-brain barrier and hence acts as an excellent platform for brain targeting. The intranasal drug delivery several approaches should be considered, attending, specifically, to the nature of pathological condition (acute or chronic) and intended effects of drug treatment (local, systemic or at CNS). Local delivery, nasal vaccines, systemic delivery and CNS delivery through nasal route is the prime route for drug administration to treat the various diseases. So the nasal vaccination is a promising alternative to the classic parenteral route because the nasal mucosa possesses abundant nasal associated lymphoid tissue (NALT), dentritic cells, large surface area, and low proteolytic enzymes that serve as a primary defense system against pathogens. It can exhibit high drug concentration, permeation, no first-pass effect and compliance administration without enzymatic destruction. Moreover, antigens encapsulated nanoparticles ensure enhanced uptake and controlled release of antigens from the nasal vasculature membrane with strong immunogenicity and improved systemic therapeutic responses. Also, the bio-nanotechnology applied to the parenteral administrations techniques such as microneedles, jet-injections, ultrasound, iontophoresis, and electrophoresis. Theses systems extend painless, patient-friendly alternatives to injections for the delivery of molecule [313-317]. Drug administration using microneedles for the transdermal delivery routes have been reported elsewhere [318-320]. Microneedles are arrays of micrometer-sized shallow needles that penetrate only into the superficial layers of skin, thereby eliminating the pain associated with standard hypodermic needles [321]. Microneedles have been made from a variety of materials and in particular the polymers have been shown to be effective. They have also been produced in solid and as well as in hollow forms. Solid microneedles are used to render skin permeable, whereas hollow microneedles actively deliver drugs into the skin at a controlled rate. In contrast, jet injectors deliver a high-velocity liquid jet stream into the skin, delivering drugs into various skin layers, depending on the jet parameters [322]. Jet injectors have a long history, particularly in the delivery of vaccines, insulin, and growth hormone. Ultrasound enhances skin permeability by cavitation, which temporarily disrupts skin structure [323]. Iontophoresis and electroporation use electric fields to alter the skin structure and/or provide additional driving force for drug penetration through the skin [324]. These new routes of administration of therapeutics with improved responses have been achieved by high drug concentration in target, permeation, no first-pass effect, high bioavailability and compliance administration without enzymatic destruction [325, 326].
The uses of bio-nanotechnology in therapeutics a number of unexpected inventions have been done recently on polymer based nanometers, which have great attention in the field of smart drug delivery applications. The biomaterials including protein based polymers, polysaccharide based polymers, natural or synthetic or semi-synthetic polymers, various biomaterials and combination of polymer have utilized to prepare various kinds of nano-formulations towards the smart drug delivery applications. Several polymeric nanoparticle-based therapeutic systems have been established for the treatment of various diseases. Several nanoparticle based drug delivery systems have been approved in clinical trials, some of them in under pre-clinical trial levels, this nanoparticle based system can provide the increased half-life, high biocompatibility, and minimum immunogenicity, site targeting and overcome the membrane barriers. Also the last era, major and new identifications have been drastically established in the smart material that alter its own structure and function in response to the environment. This performance has been used for the fabrication smart drug delivery systems, Smart polymer matrices release drugs by environment responses this system have been successfully achieved. In parallel the new method of bottom-up and top-down nanofabrication technologies provided precisely controlled size and shaped nano-particulate delivery system. Simultaneously, various advanced significant routes of targeting have developed and successfully achieved to the site of action. At present, the field of microfluidics for synthesis, micro-needle for transdermal and site targeted delivery is still in its infancy. So the pharmaceutical industry has to bring these products into industry-led investigation and the improvement in this would possibly to quicken their progress.
Although there are considerable amount researches have been done in the field of drug delivery so far. In the polymeric nanoparticle based drug therapy has to be enhanced by incorporating by the combination therapies, Smart delivery has been achieved successfully in the case of cancer, but need to be concentrating more on other pathologies, also numerous challenges remain. From the material viewpoint, most of the smart delivery systems mechanism do well in vitro studies but flops the in vivo studies. So the research has to be re-considering to come up with simple, straightforward, efficient and reasonably accurate preparations with broadly applicable strategies, the pharmacologically active agent targeting to pathological sites, for the development of smart drug delivery systems. In technology vice the research has to focus into the fusion technologies. Although several specific specialized technologies have been shown to in polymer synthesis, functionalization, analysis, in vitro and in vivo study in the field of polymer science, the combinations of two or more techniques are often more effective than single technologies like a combination of controlled radical polymerization with click chemistry. The fusion technologies can fulfil the various existing drawbacks of some individual technologies, and this has the high potentiality, synergistic enhancement in safest nanoparticle based drug delivery. Consider merging and adopting two or more right technologies for getting a high-throughput technology by selecting the right combinations is a fruitful area for research that is still largely unexplored. This new understanding must be incorporated into the future of newer polymeric based nanoparticle synthesis development and evaluation of smart drug delivery. Also the next generation of polymeric nanoparticle based delivery systems with drugs like growth factors, hormones, antibodies, genes, peptides, etc.; should also enhance the efficiency and minimize the unwanted effects.
This work was supported by the R&D Program for Society of the National Research Foundation(NRF) funded by the Ministry of Science, ICT & Future Planning (2013M3C8A3078806 and 2013M3C1A8A01072922).
Modern energy supply systems, primarily electricity, heat and gas systems represent a developed energy infrastructure that provides consumers in the economic and social sectors with various energy types with the required reliability, the required quality and at an affordable price. The development and opposition of these energy systems is under the influence of a new paradigm of customer-oriented energy supply. Recently, the requirements for the reliability of power supply and the quality of the types of energy supplied to consumers have significantly increased due to computerization and digitalization of consumer production processes and the expansion in the use of “high” production technologies by the consumer.
The design and operation of these energy systems tend to consider them independently of each other. The systems under discussion however interact quite closely with each other, for example, when electricity and heat is generated using gas as fuel at cogeneration under normal and emergency conditions, when electric heaters are used by consumers in the case of accidents in the heating system, etc.
The new conditions for the development and computerization of the infrastructure energy systems contribute to the expansion of interaction between them as many new actors appear that can provide ancillary services. The consumers with controlled load, managing their energy load, can have self-generation sources and energy storage units, and simultaneously, depending on the current conditions, be involved in conversion, storage and generation of the required type of energy; electric vehicles can deliver stored electricity to the power supply system during peak hours, etc.
The development of information and telecommunication technologies bring about additional opportunities for joint coordinated management of the expansion and operation of the energy systems under consideration.
All the above features increase significantly the interest in the research of virtually new facilities, i.e., integrated energy systems (IESs) [1, 2]. The primary basic problem here is the technology of modeling the sophisticated IESs. This chapter focuses on the main principles of the IES simulation technology relying on the capabilities of the Matlab/Simulink system and the energy hub concept.
The further presentation is structured as follows. Section 2 presents basic information about the features of IES and the history of research in this strand. Section 3 provides an overview of the energy hub concept. Section 4 contains a description of the nature of mathematical models of IES based on the integration of traditional models of the components of the considered IES of power supply systems. Section 5 discusses the principles of energy hub modeling used in most of the studies conducted, and the advantages and disadvantages of the models. Section 6 analyzes the capabilities of the Matlab/Simulink system for IES modeling. Section 7 presents a new approach to building a simulation model of an energy hub developed by the authors. Section 8 discusses the proposed technology for constructing an IES simulation model. Section 9 contains a description of one of the problems solved using the developed simulation model. The conclusion to this Сhapter summarizes the results of the studies performed.
Objective trends in energy systems development (electric power, heat, gas, oil, oil products supply systems, etc.) lead to creation of integrated multi-carrier energy systems. These tendencies are determined by strengthening of technological integration not only during production of energy (for example, electric power and heat on the co-generation plants (CGP) by using gas as the fuel), but also under energy consumption based on implementing different kinds of energy for the same objectives. For example, it is possible to use heat from centralized heating system based on CDP or from individual electric boilers, electric or gas individual furnaces, and so on. In these cases individual energy systems (electric power, gas and heat supply systems) acquire the interdependences not only between production plants and consumption of individual systems, but also between load flows in networks of these systems. Particularly significant interrelations between individual energy systems we can meet in emergency conditions. Taking into account above mentioned peculiarities we have to consider joint operation and expansion of individual energy systems [1, 2].
In [2], the authors explain the elements of the concept of integrated energy systems as a three-layer structure in three dimensions, similar to Rubik’s cube (see Figure 1). The groups of layers can be defined as follows:
Layers of systems - power systems, heating/cooling systems, gas systems;
Layers of scale - super-systems, mini-systems, micro-systems;
Layers of functions - energy, communication and management, decision making.
Three-layer structure of integrated energy systems in three dimensions.
Integrated multi-carrier energy systems, as well as their individual energy supply systems, especially electric power, heat and gas supply systems, have important infrastructural role in the enhancement of optimal operation of different economy sectors and acceptable life of citizens in any country. There are concrete requirements to necessary level of power supply reliability to consumers and high quality of supplied energy, and also to effectiveness of operation and development of above mentioned infrastructural energy systems. It is necessary to note, that the requirements to increase reliability and quality of energy supply first of all are forming under the influence of digitalization and computerization in technological processes of consumers [3, 4].
In 1999 actually the first research project started concerning energy delivery systems from production of different kinds of energy to retail markets [5]. End use energies included electricity and heat. Such kinds of energy were studied, as electric power, gas, oil, as well as conversion between different kinds of fuel (gas power plants, hydro power plants, co-generations, heating pumps, plants for production of liquid natural gas, and so on). The possibilities of alternative storages were studied, for example hydro accumulating plants and liquid natural gas storages. This project was as the stimuli for preparation of methodology of comprehensive analysis of complicate energy delivery systems with several kinds of energy including technological, economic and ecology aspects. It was planned, that such methodology will be very flexible and will allow the integrated energy companies to make comprehensive analysis their investments and general optimization of their energy supply systems.
The project “Vision of Future Energy Networks (VFEN)” was proposed by group of authors and supported by industry [6, 7]. Horizon of planning is since 30 up to 50 years. Economic, ecology and technological aspects localize the research conditions. General hybrid approach includes different kinds of energy, which consider the synergy between electrical, chemical and heat energies (it is possible, between the other kinds of energy).
An integration of different energy systems into technologically joint body gives new functional possibility, using complex innovative technologies for integrated energy system operation and creation of smart integrated multi-carrier energy systems (SIES). Such systems have many dimensional structures of functional possibilities and development properties. They consider big number of factors: intelligence, effectiveness, reliability, controllability, flexible use of technologies for energy transformation, transportation and preservation, active demand. Protection and control systems have to react to emergency and unreal behavior and to ensure SIES after such events. It is important to develop the models and software for on-line decision making, especially in the conditions of large disturbances [8, 9, 10].
Tendency towards technological integration of energy supply systems gave birth to the notion of an energy hub [1, 8], that implies an integrated facility with multiple inputs and outputs, which represent different types of energy. This facility has internal elements for the support of some functions, i.e., transformation, conversion and storage of different kinds of energy. It is necessary to note [10], that the energy hub concept can be used rather wide – from representing some individual transmission element to a building or a part of the city.
Following [7], we will consider an example of the energy hub shown in Figure 2. The Figure shows the inputs and outputs of the energy hub, as well as its internal components and their interconnections (electric transformer, electric battery, micro-turbine, heat exchanger, furnace, cooler and hot water storage).
Example of a specific energy hub containing a transformer, microturbine, heat exchanger, furnace, cooler, battery, and hot water storage.
In [11], an overview of the main provisions of the energy hub concept is presented. Four main functionalities of the energy hub concept are identified, including the input, conversion, storage and output of the considered types of energy. At the same time, most of the studies discussed in the overview, use electric and gas networks as the studied facilities of the energy hub. Various types of power plants especially those based on renewable energy resources, and those relying on promising innovative technologies, such as, fuel cells, for example, were studied as sources of generation.
It is necessary to take into account, that technological and market strengthening of individual energy systems requires more intensive studies of modeling integrated multi-carrier energy systems for the investigation and control of their operating conditions and expansion planning. There are two basically different approaches for modeling integrated multi-carrier energy systems: based on conventional mathematical models of individual energy systems [12, 13] and to use energy hub concept [14, 15].
Let us represent as the example conventional mathematical model of integrated multi-carrier energy system, including electric power and heat supply systems, in following form (1)–(6) [13]:
subject to:
and balance between electricity and heat production is:
where
References [14, 16, 17] present a system of algebraic equations that relate input variables of the energy hub into output variables. Both variables present different kinds of energy:
or, in matrix presentation,
Energy in the input and output ports is represented by vector-columns
In case of solving the inverse problem, a matrix of inverse conversions is introduced
Relations between coefficients of inverse and direct transformations have a unique form:
Should there be N output ports and one input port, the energy through each output channel would be distributed following the equation:
It is necessary to note, that the most part of references, which deal with the energy hub modeling, including dissertations [18, 19] for different problems investigations concerning integrated multi-carrier energy systems, are using linear energy hub models. These studied problems include calculation and optimization of power flow in integrated multi-carrier energy systems, reliability of electric power and heat supply to consumers, optimization of integrated energy system expansion, and some others [1, 10, 12, 14, 15, 16, 17].
Above mentioned studies showed potentials of considered approach to use the linear energy hub model and at the same time the problems of its application. The matter is, that it is necessary to determine the matrix coefficients in (7), which relate inputs and outputs of the energy hub. But this determination faces some difficulties even for linear case. Really these coefficients can have complicate structure including non-linearities. Moreover, above mentioned energy hub models allow to solve only stationary problems in integrated multi-carrier energy systems. Dynamic problems consideration based on energy hub concept had not been studied yet, what had noted as the favorite direction of further investigations [18].
It is necessary to draw the attention on the first known results of dynamic problems study in [20] using conventional mathematical model of integrated energy system based on technique of the theory of singular perturbations (small parameters). This technique was used for presentation of individual energy systems in the integrated multi-carrier energy system.
The above mentioned peculiarities of energy hub modeling stimulate to search the other possibilities to solve these problems. Next Section allows such possibilities.
The simulation modeling approach can be as the basic technology for construction of integrated multi-carrier energy system model. Let us use the capabilities of Matlab/Simulink software for suggested technology development. The following components of necessary simulation model construction procedure of integrated multi-carrier energy systems we will have to take into account:
The initial information about modeled integrated energy system includes the topology and parameters of different kinds of elements (objects) of individual energy systems. We have to note the initial element in every individual energy system, which will as the start point for topological model creation of every individual energy system.
Current versions of Matlab/Simulink software include rather developed library of models for elements of different technological systems – electric power, pneumatic, hydraulic ones, and the others. These models of elements are presented using transfer functions and can be implemented for dynamic processes study in different technological systems. We deal with steady state conditions, therefore it is necessary to convert initial dynamic models into the static form.
The above mentioned library of Matlab/Simulink software does not contain complicated elements with multi-input and multi-output structure. Such elements are energy hubs. The co-generation plant can be as the example of such complicated element (object) with one input (gas) and two outputs (electric power and heat). At the level of consumption such elements of integrated multi-carrier energy system include conversion function of one kind of energy into the other. The energy hub models are forming the specific additional library. These models also implement such functions as energy storages and summation of different kinds of energy.
It is necessary to note, that there are two kinds of energy conversion elements: 1) they change the characteristics of the energy channel without conversion of energy form into the other one (for example, electrical transformer, heat exchanger, and so on); 2) they change not only characteristics of the energy channel, but also convert one kind of energy into the other one.
Different kinds of energy in integrated multi-carrier energy system have different measurement units (kWh, Gcal, etc.). Therefore Joule (J, W.s) is considered as a basic unit of measurement. The transformation function of different unit to the basic one was implemented using Matlab/Simulink software.
After the creation of topological models of different individual energy systems networks using above mentioned procedures it is necessary to connect them each other. Energy hub models of energy production plants (co-generation plants, heating plants, etc.) and complex consumers with several kinds of consumed energy (electric power, heat, etc.) play the role of such connectors.
Constructed simulation model of integrated multi-carrier energy system really is the basic part of any full simulation model for solving some concrete problem of integrated energy system. The statement of concrete solved problem requires additional procedures for problem formalization and results interpretation. For example, the solving loss minimization problem in electrical network requires load flow calculation as the basic procedure and optimization algorithm formalization for solving full necessary problem.
After above mentioned procedures the simulation model of integrated multi-carrier energy system is ready to usage for solving different problems.
Figure 3 shows general structure of the energy hub simulation model, which was constructed by Matlab/Simulink software capabilities [21]. This structural scheme presents three energy supply channels: 1 - electric power; 2 - heat; 3 - gas. The model implements the functions of transformation, conversion and storage of energy, and an additional summation function whose concept is understandable from Figure 3.
General structure of the energy hub simulation model. (channels: 1 - electric power supply; 2 - heat supply; 3 - gas supply).
Figure 4 presents detail structure of the energy hub simulation model for the electric power supply channel using representation of elements by images of Matlab/Simulink software. Here 1 and 6 present direct and inverse transformations of state variables; 2 and 4 present the electricity transfer; 3 presents the transformer sub-station model; 5 presents the energy storage device model.
Flow chart of electric power supply channel for the energy hub simulation model.
Figure 4 takes into account the peculiarities of simulation modeling procedures of Matlab/Simulink software, including propagation and conversion of presented system.
Figure 5 gives an example of an integrated scheme based on two energy supply channels. A black line here denotes a channel of a heat network; gray one denotes a channel of an electric network. A squares denote hubs locations, which represent electricity and heat consumers.
An integrated scheme based on two energy supply channels.
The example in Figure 5 shows, that two energy channels (electric power and heat) go to one consumer. Taking into account storage systems and systems for conversion of electric power into heat we will have complex energy hub based on presented consumer.
Rather simple elements of electric power and heat supply systems can be presented by simulation models from Matlab/Simulink library. According to above noted approach, it is necessary to create additionally the library of energy hubs simulation models. Figure 6 presents the integrated simulation model of energy supply systems (electric power and heat) including energy hub with two energy supply channels.
Construction of integrated simulation model with two energy supply channels in Matlab/Simulink.
The simple elements of individual energy supply systems are used from the basic library of Sim Power Systems which is sub-system of Matlab/Simulink.
WEI and WS elements represent energy consumption and storage, which connected by electric power supply channel. WH is the energy consumption by heat supply channel. KP1 - KP4 are the elements, which works taking into account efficiency of the energy conversion. WE-WH represent electricity converted into the heat energy.
A general approach to constructing a simulation model of an integrated multi-carrier energy system and to solution of different problems with its help can be represented as follows [21, 22] (see Figure 7).
Flow chart of algorithm for constructing basic part of integrated energy system simulation model.
Input data about the studied integrated multi-carrier energy system is prepared including the matrices of parameters of individual energy systems (their network topologies, electric and hydraulic resistances of electric lines and pipelines), as well as vectors of nodes parameters (electric power and heat generations, loads, storages, etc.).
The necessity to use of two libraries of integrated energy system elements was noted earlier in Section 6. An algorithm for simulation model construction of integrated multi-carrier energy system selects required model of the next element from the point of view of individual energy system topology (depending on the element type) either from library of typical elements in Matlab/Simulink software or from additional library, which includes the energy hubs models. After that required model attaches to necessary node (nodes for energy hub model) of integrated energy system. As it is noted in Section 6, the energy hub model has several inputs and several outputs, which connect different individual energy systems into integrated multi-carrier energy system.
As we said in Section 6, above mentioned procedure creates so called basic part of integrated energy system simulation model. It is necessary to work out an additional part for simulation model, which represents the specifics of concrete calculated problem (see Section 6).
Matlab/Simulink software contains the object-oriented programming language, which has used for construction of integrated multi-carrier energy system simulation model. Figure 7 represents simplified flow chart of the basic part of discussed algorithm taking into account three individual energy systems: electric power, heat and gas supply systems.
An integrated energy system is considered including the electricity and heat supply systems of a block of 9 dormitories of a University campus. The diagram of the electric network of the integrated energy system is shown in Figure 8, the diagram of the heat network is topologically about similar, since each dormitory is a consumer of both electricity and heat. The diagram of the heat network is not given, since the load of heat pipelines in the problem solved does not including, but, on the contrary, decreases, i.e., there are no network constraints on heat transfer.
Diagram of the electrical supply system.
In Figure 8 FS is feeding substation, the nodes 11, 12, 13, 14, 15 are transformer substations 6/0.4 kV.
Figures 9 and 10 indicate the total annual electricity and heat consumption curves for the entire block of dormitories, respectively. We assume that thermal energy is consumed only for heating. The daily heat load curve is uniform. The irregularity factor of daily electrical load curve is 0.4 (the ratio of the load value during the night minimum period from 23:00 to 7:00 to the peak load value). Daily curves of heat and electrical load are the same for all dormitories.
Electricity consumption of 9 dormitories.
Heat consumption of 9 dormitories.
We consider the conditions for preventing overload of the electrical network. To this end, the total load power during the night minimum of the daily load curve, including its power level plus the amount of power consumed to convert electricity into heat, should not exceed the daily maximum load. In this case, the load flow in the electrical network will not change and there will be no overloads.
Table 1 shows monthly data on the parameters of electricity supply to consumers on the University campus.
Power consumption of 9 dormitories, kWh | Night zone (from 23 to 7), kWh | Payment for electricity consumption at night without conversion, $ | Daily peak load, kW | Maximum electricity consumption per month, kWh | The amount of electricity (potential) to convert to heat per month, kWh | 50% of electricity for conversion to heat per month, kWh | |
---|---|---|---|---|---|---|---|
Jan. | 122000 | 47000 | 519 | 476 | 343000 | 67900 | 34000 |
Feb. | 134000 | 50000 | 547 | 459 | 331000 | 65500 | 33000 |
Mar. | 142000 | 53000 | 583 | 418 | 301000 | 59600 | 30000 |
Apr. | 131000 | 48000 | 526 | 392 | 282000 | 55900 | 28000 |
May | 135000 | 50000 | 552 | 489 | 352000 | 69700 | 35000 |
June | 123000 | 48000 | 525 | 441 | 318000 | 62900 | 31000 |
July | 83600 | 33000 | 361 | 324 | 233000 | 46200 | 23000 |
Aug. | 92300 | 36000 | 401 | 344 | 248000 | 49100 | 25000 |
Sep. | 123600 | 48000 | 533 | 443 | 319000 | 63100 | 32000 |
Oct. | 130000 | 51000 | 561 | 410 | 295000 | 58500 | 29000 |
Nov. | 125000 | 49000 | 536 | 450 | 324000 | 64200 | 32000 |
Dec. | 130000 | 51000 | 559 | 489 | 352000 | 69700 | 35000 |
University campus power consumption data.
The values of daily maximum load are used to calculate the values of conventional maximum possible electricity consumption of the campus per month with the formula:
where
The amount of electricity that can be converted into heat (conversion potential) is determined by:
where
Conversion of electricity into heat is carried out according to the relationship:
In Table 1, the last two columns indicate two options for the amount of electricity to be converted to heat: the entire (100%) conversion potential and 50% of this potential.
Following the current pricing system for electricity and heat, electricity rates are differentiated throughout the day: a preferential night rate from 23:00 to 7:00 is $ 0.011 per kWh. Heat rate is $ 20.6 per Gkal.
In general terms, the following relations are valid:
The following relations are valid:
where
The results of the calculations of the considered options are presented in Figures 11 and 12.
Comparison of payment with electricity conversion into heat factored in 100%.
Comparison of payment with electricity conversion into heat factored in 50%.
Let us return to the condition of preventing the electrical network overloads, formulated above. An analysis of the transfer capability and loading of individual ties lines in the case of electricity conversion into heat, according to the condition assumed, shows that this loading is not the same (see Table 2).
Ties numbers | 10–11 | 10–12 | 10–14 | 12–13 | 14–15 |
Transfer capabilities of ties, kW | 2100 | 2100 | 2100 | 2100 | 2100 |
Load flow, kW | 980 | 1470 | 1960 | 980 | 980 |
Required parameters of electrical network and basic load flow.
It is important to estimate some limiting volume of conversion of electricity into heat at night taking into account the possibilities of electrical network. These possibilities depend on free transfer capabilities of ties and permissible loading of transformers on feeding substation. Required parameters of electrical network and basic load flow calculation without consideration of active losses you can see on the Table 2. Consumption load at night which found on the previous stage (basic load flow) for each consumer is 490 kW. The permissible loading of transformers on feeding substation is 6000 kW. Let us consider, that cable lines from transformer substations 6/0.4 kV to import of electricity into building do not have the limits of transfer capabilities. As for limiting volume of heat supply for each consumer, let us to consider 380 kW after re-calculation into converted electricity.
Let us formalize optimization problem as following:
Objective function:
Subject to:
where
Several beginning steps of optimization are along the ray 10–11 to use the possibility for additional conversion of electricity into heat. The results of these iterations are 380 kW for consumer 2 and 380 kW for consumer 3 as the additional converted volumes of electricity. These volumes along the ray 10–11 are top volumes for additional conversion. One next iteration deals with the ray 10–12, where it is possible to use 380 kW for consumer 5 and the rest on this ray 250 kW (2100–1470 – 380 = 250) for consumers 1 or 4. The iteration along the ray 10–14 allows to use 140 kW additional converted electricity (2100–1960 = 140) for consumers 6 or 7 or 8 or 9.
It is possible to see, that we could use more electricity for additional conversion into heat, but the problem is in hhe electrical network limitation.
Creation of the integrated multi-carrier energy systems is progressive trend in development of energy supply systems. Joint expansion of individual energy systems leads to enhancement of economic efficiency and reliability of energy supply to consumers. It is necessary to have the efficient tools for expansion planning and operation management and control of integrated multi-carrier energy systems. Energy hub concept is progressive way for modeling and simulation of integrated energy systems, but there are some problems in determination of the coefficients of connection of each individual input and each individual output of the energy hub simulation model.
This Chapter represents new approach to solve above mentioned problems based on the possibilities of Matlab/Simulink software taking into account the elements of energy hub concept. The main idea of suggested approach deals with the construction of simulation model of integrated multi-carrier energy system considering the models of simple typical elements from the Matlab/Simulink library and complicate energy hub models from additional library, which is created based on Matlab/Simulink software possibilities.
Illustrative case study shows the efficiency of suggested approach.
This study was performed according to project # FWEU-2021-0002 of State Assignment of Fundamental Investigation Program of Russian Federation for 2021-2030.
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Examples of IKS such as Ayurveda from India and Acupuncture from China are well known. IK covers diverse areas of importance for society, spanning issues concerned with the quality of life - from agriculture and water to health. The IK resident in India and China have high relevance to rural life, especially given the level of engagement with agricultural and health technologies. The goal is to establish a heuristic whereby IK can be reviewed and evaluated within particular contexts to determine if the IKS can lead to the development of appropriate technology (AT) addressing that need sustainably. Although much work on cataloguing and documenting IKS has been completed in these two countries, a paucity of attention has been paid to the scientific rationale and technological content of these IKS. Evaluation of many indigenous technologies reveal that many of these technologies can be classified as ‘appropriate’, focused on basic needs of water, sanitation and agriculture, and many have origins in IKS that survived. Thus, IKS must be validated, exploited and integrated into AT innovation and development.",book:{id:"5866",slug:"indigenous-people",title:"Indigenous People",fullTitle:"Indigenous People"},signatures:"John Tharakan",authors:[{id:"198534",title:"Prof.",name:"John",middleName:null,surname:"Tharakan",slug:"john-tharakan",fullName:"John Tharakan"}]},{id:"56510",doi:"10.5772/intechopen.69890",title:"Role of Traditional Ethnobotanical Knowledge and Indigenous Institutions in Sustainable Land Management in Western Highlands of Kenya",slug:"role-of-traditional-ethnobotanical-knowledge-and-indigenous-institutions-in-sustainable-land-managem",totalDownloads:2594,totalCrossrefCites:4,totalDimensionsCites:5,abstract:"The objective of this chapter is to elucidate the relevance of indigenous knowledge and institutions in natural resource management using western highlands of Kenya as a case study. The research design was a mixed method, combining qualitative and quantitative methods. A total of 350 individuals (comprising farmers, herbalists and charcoal burners) from households were interviewed using a structured questionnaire, 50 in-depth interviews and 35 focus group discussions. The results show that indigenous knowledge and institutions play a significant role in conserving natural resources in the study area. There was gender differentiation in knowledge attitude and practice (KAP) of indigenous knowledge as applied to sustainable land management. It is recommended that deliberate efforts should be put in place by the County Governments to scale up the roles of indigenous institutions in managing natural resources in the study area.",book:{id:"5866",slug:"indigenous-people",title:"Indigenous People",fullTitle:"Indigenous People"},signatures:"Chris A. Shisanya",authors:[{id:"200734",title:"Prof.",name:"Chris",middleName:null,surname:"Shisanya",slug:"chris-shisanya",fullName:"Chris Shisanya"}]},{id:"67479",doi:"10.5772/intechopen.86677",title:"Exploring Aboriginal Identity in Australia and Building Resilience",slug:"exploring-aboriginal-identity-in-australia-and-building-resilience",totalDownloads:1337,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"This chapter will discuss the challenges faced by Aboriginal people seeking recognition of their identity as Indigenous Australians. It will explore government policies, their impact on identity formation and the ongoing impact of colonisation on education and health outcomes for Indigenous people in Australia. The issues raised will include historical and contemporary experiences as well personal values and attitudes. The strategies and programs introduced within educational settings as part of an inclusive practice regime will be highlighted. Aboriginal people have faced many challenges, and continue to do so in postcolonial times, including challenges to their identity.",book:{id:"8522",slug:"indigenous-aboriginal-fugitive-and-ethnic-groups-around-the-globe",title:"Indigenous, Aboriginal, Fugitive and Ethnic Groups Around the Globe",fullTitle:"Indigenous, Aboriginal, Fugitive and Ethnic Groups Around the Globe"},signatures:"Clair Andersen",authors:[{id:"296447",title:"Associate Prof.",name:"Clair",middleName:null,surname:"Andersen",slug:"clair-andersen",fullName:"Clair Andersen"}]},{id:"68484",doi:"10.5772/intechopen.88118",title:"Journey to America: South Asian Diaspora Migration to the United States (1965–2015)",slug:"journey-to-america-south-asian-diaspora-migration-to-the-united-states-1965-2015-",totalDownloads:1212,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"This chapter examines the immigration of South Asian and Indian populations to the United States between 1820 and 2015. More specifically, this effort scrutinizes legislative changes in immigration policy enabling this group to become the second largest immigrant group after Mexicans in the United States. These changes include the following: the removal of national origin quotas, the introduction of temporary skilled worker programs, and the creation of employment-based permanent visas. Because of these policy changes, by 2015, South Asian immigrants, primarily Indians, had become the top recipients of high-skilled H-1B temporary visas and were the second-largest group of international students in the United States. All told, this study will answer the following questions: What are the origins and demographics of these emigrants who make up the South Asia diaspora? What fields of endeavor are they drawn to by their prior education and skill sets? To what geographic locations have they migrated? And how successful are they in assimilating into their new surroundings?",book:{id:"8522",slug:"indigenous-aboriginal-fugitive-and-ethnic-groups-around-the-globe",title:"Indigenous, Aboriginal, Fugitive and Ethnic Groups Around the Globe",fullTitle:"Indigenous, Aboriginal, Fugitive and Ethnic Groups Around the Globe"},signatures:"John P. Williams",authors:[{id:"264648",title:"Prof.",name:"John",middleName:null,surname:"Williams",slug:"john-williams",fullName:"John Williams"}]},{id:"56426",doi:"10.5772/intechopen.70104",title:"Indigenous Resource Management Practices and the Local Social-Cultural Context: An Insight towards Self-Directed Resource Management by People who ‘Coexist’ with Supernatural Agents",slug:"indigenous-resource-management-practices-and-the-local-social-cultural-context-an-insight-towards-se",totalDownloads:1774,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"In recent arguments in the governance of natural resource management, effectiveness and desirability of collaborative management among various stakeholder including indigenous people has been recognized. In the context of Indonesia, the reformation movement has stimulated the growth of a new perception of indigenous people’s rights to their land in the country. This recent transition presents a growing opportunity for indigenous people who live in nature-rich areas (national parks, etc.) to collaborate with ‘outside stakeholders’ such as governmental agencies, scholars and environmental NGOs in natural resource management. In such situations, it is necessary to deeply understand the value of indigenous resource management (IRM) practices to promote self-directed and effective resource management. This chapter focuses on local forest resource management and its suitability in the local social-cultural context in central Seram, east Indonesia. First, I describe how the well-structured forest resource use is constructed and maintained through the indigenous resource management practices based on ‘supernatural enforce mechanism’. After that, I investigate what social-ecological roles the IRM in Amanioho has, and how IRM practices relate to the social-cultural context of an upland community in central Seram. Then, I discuss the possible future applications for achieving self-directed resource management by people who ‘coexist’ with supernatural agents.",book:{id:"5866",slug:"indigenous-people",title:"Indigenous People",fullTitle:"Indigenous People"},signatures:"Masatoshi Sasaoka",authors:[{id:"198898",title:"Dr.",name:"Masatoshi",middleName:null,surname:"Sasaoka",slug:"masatoshi-sasaoka",fullName:"Masatoshi Sasaoka"}]}],mostDownloadedChaptersLast30Days:[{id:"56426",title:"Indigenous Resource Management Practices and the Local Social-Cultural Context: An Insight towards Self-Directed Resource Management by People who ‘Coexist’ with Supernatural Agents",slug:"indigenous-resource-management-practices-and-the-local-social-cultural-context-an-insight-towards-se",totalDownloads:1774,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"In recent arguments in the governance of natural resource management, effectiveness and desirability of collaborative management among various stakeholder including indigenous people has been recognized. In the context of Indonesia, the reformation movement has stimulated the growth of a new perception of indigenous people’s rights to their land in the country. This recent transition presents a growing opportunity for indigenous people who live in nature-rich areas (national parks, etc.) to collaborate with ‘outside stakeholders’ such as governmental agencies, scholars and environmental NGOs in natural resource management. In such situations, it is necessary to deeply understand the value of indigenous resource management (IRM) practices to promote self-directed and effective resource management. This chapter focuses on local forest resource management and its suitability in the local social-cultural context in central Seram, east Indonesia. First, I describe how the well-structured forest resource use is constructed and maintained through the indigenous resource management practices based on ‘supernatural enforce mechanism’. After that, I investigate what social-ecological roles the IRM in Amanioho has, and how IRM practices relate to the social-cultural context of an upland community in central Seram. Then, I discuss the possible future applications for achieving self-directed resource management by people who ‘coexist’ with supernatural agents.",book:{id:"5866",slug:"indigenous-people",title:"Indigenous People",fullTitle:"Indigenous People"},signatures:"Masatoshi Sasaoka",authors:[{id:"198898",title:"Dr.",name:"Masatoshi",middleName:null,surname:"Sasaoka",slug:"masatoshi-sasaoka",fullName:"Masatoshi Sasaoka"}]},{id:"56259",title:"Indigenous Knowledge Systems for Appropriate Technology Development",slug:"indigenous-knowledge-systems-for-appropriate-technology-development",totalDownloads:4093,totalCrossrefCites:7,totalDimensionsCites:8,abstract:"Indigenous knowledge systems (IKS) comprises knowledge developed within indigenous societies, independent of, and prior to, the advent of the modern scientific knowledge system (MSKS). Examples of IKS such as Ayurveda from India and Acupuncture from China are well known. IK covers diverse areas of importance for society, spanning issues concerned with the quality of life - from agriculture and water to health. The IK resident in India and China have high relevance to rural life, especially given the level of engagement with agricultural and health technologies. The goal is to establish a heuristic whereby IK can be reviewed and evaluated within particular contexts to determine if the IKS can lead to the development of appropriate technology (AT) addressing that need sustainably. Although much work on cataloguing and documenting IKS has been completed in these two countries, a paucity of attention has been paid to the scientific rationale and technological content of these IKS. Evaluation of many indigenous technologies reveal that many of these technologies can be classified as ‘appropriate’, focused on basic needs of water, sanitation and agriculture, and many have origins in IKS that survived. Thus, IKS must be validated, exploited and integrated into AT innovation and development.",book:{id:"5866",slug:"indigenous-people",title:"Indigenous People",fullTitle:"Indigenous People"},signatures:"John Tharakan",authors:[{id:"198534",title:"Prof.",name:"John",middleName:null,surname:"Tharakan",slug:"john-tharakan",fullName:"John Tharakan"}]},{id:"56510",title:"Role of Traditional Ethnobotanical Knowledge and Indigenous Institutions in Sustainable Land Management in Western Highlands of Kenya",slug:"role-of-traditional-ethnobotanical-knowledge-and-indigenous-institutions-in-sustainable-land-managem",totalDownloads:2594,totalCrossrefCites:4,totalDimensionsCites:5,abstract:"The objective of this chapter is to elucidate the relevance of indigenous knowledge and institutions in natural resource management using western highlands of Kenya as a case study. The research design was a mixed method, combining qualitative and quantitative methods. A total of 350 individuals (comprising farmers, herbalists and charcoal burners) from households were interviewed using a structured questionnaire, 50 in-depth interviews and 35 focus group discussions. The results show that indigenous knowledge and institutions play a significant role in conserving natural resources in the study area. There was gender differentiation in knowledge attitude and practice (KAP) of indigenous knowledge as applied to sustainable land management. It is recommended that deliberate efforts should be put in place by the County Governments to scale up the roles of indigenous institutions in managing natural resources in the study area.",book:{id:"5866",slug:"indigenous-people",title:"Indigenous People",fullTitle:"Indigenous People"},signatures:"Chris A. Shisanya",authors:[{id:"200734",title:"Prof.",name:"Chris",middleName:null,surname:"Shisanya",slug:"chris-shisanya",fullName:"Chris Shisanya"}]},{id:"56296",title:"Empowering Namibian Indigenous People through Entrepreneurship: The Case from the Nama People",slug:"empowering-namibian-indigenous-people-through-entrepreneurship-the-case-from-the-nama-people",totalDownloads:1609,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The challenge emanating from the colonial and apartheid regimes on the Nama people of Namibia have not only resulted in them losing nearly half of its population, but they also appeared to have lost their social identity. To that end we continually find convergences and divergences in clothing and accessories, food, traditional dances, homes, and traditional beauty cosmetics, between the past and present. This chapter seeks to explore whether the Nama people have always used money to acquire the aforementioned past? If not, what have they done right in the past to acquire all these items? These are one of the few questions this chapter seeks to explore and understand, and the role Nama entrepreneurial activities play for their own socio-economic advancement. Critical discourse can lead to a better understanding and appreciation of entrepreneurship among indigenous people in Namibia. This will in turn result in an enhanced understanding of the role entrepreneurship and culture can play in both a local and international context. After a brief introduction to Namibia and the Nama people, the cultural values and entrepreneurial initiatives of the Nama people are discussed, followed by discussions, recommendations and conclusions. Research methods employed were in-depth interviews and participant observation.",book:{id:"5866",slug:"indigenous-people",title:"Indigenous People",fullTitle:"Indigenous People"},signatures:"Wilfred Isak April, Daniel Ileni Itenge, Josef Petrus Van der\nWesthuizen and Lazarus Shimwaningi Emvula",authors:[{id:"110034",title:"Dr.",name:"Wilfred",middleName:"Isak",surname:"April",slug:"wilfred-april",fullName:"Wilfred April"},{id:"204208",title:"Mr.",name:"Daniel",middleName:"Ileni",surname:"Itenge",slug:"daniel-itenge",fullName:"Daniel Itenge"},{id:"204209",title:"Mr.",name:"Lazarus",middleName:null,surname:"Emvula",slug:"lazarus-emvula",fullName:"Lazarus Emvula"},{id:"204916",title:"Mr.",name:"Josef",middleName:"P.",surname:"Van Der Westhuizen",slug:"josef-van-der-westhuizen",fullName:"Josef Van Der Westhuizen"}]},{id:"55689",title:"Usages and Customs of the Indigenous Communities in Favour of the Reduction of the Digital Divide: A Case Study of the Ñuu Savi People",slug:"usages-and-customs-of-the-indigenous-communities-in-favour-of-the-reduction-of-the-digital-divide-a-",totalDownloads:1282,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This research is of ethnographic nature, focusing on the study of the Ñuu Savi people (people of the rain), also called the Mixtec people, of pre-Columbian origin belonging to the Mixteca Region of the state of Oaxaca, Mexico. On the basis of sociocultural theory and the theory of the diffusion and adoption of technological innovations, the study on the cultural identity of the ethnolinguistic group, whose social platform is the “uses and customs,” is carried out. As a result of this research, the descriptive analysis is presented, detailing the effect of information and communication technologies (ICTs) on the situation of the vulnerable and disadvantaged group. Likewise, cultural elements have been identified that allow the formulation of a model for the development and inclusion of the ethnic minority. An educational strategy is designed and implemented through the model. However, in the process of implementing the educational strategy, it was observed that the Ñuu Savi people experience a conjunctural stage where technological adoption coexists with some beliefs, aptitudes, and attitudes, characteristic of its form of government of “uses and customs,” which create sociocultural barriers that make social and digital inclusion difficult.",book:{id:"5866",slug:"indigenous-people",title:"Indigenous People",fullTitle:"Indigenous People"},signatures:"Olivia Allende-Hernández and Jesús Salinas",authors:[{id:"198235",title:"Dr.",name:"Olivia",middleName:null,surname:"Allende-Hernández",slug:"olivia-allende-hernandez",fullName:"Olivia Allende-Hernández"},{id:"201435",title:"Dr.",name:"Jesús",middleName:null,surname:"Salinas",slug:"jesus-salinas",fullName:"Jesús Salinas"}]}],onlineFirstChaptersFilter:{topicId:"1330",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:31,numberOfPublishedChapters:314,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:18,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:14,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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