Bone cells, their function, and locations [1, 2, 3, 4, 5, 6, 7].
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\r\n\tComputer graphics are not entirely an original topic, because it defines and solves problems using some already established techniques such as geometry, algebra, optics, and psychology. The geometry provides a framework for describing 2D and 3D space, while the algebraic methods are used for defining and evaluating equality related to the specific space. The science of optics enables the application of the model for the description of the behavior of light, while psychology provides models for visualization and color perception.
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\r\n\t3D computer graphics (or 3D graphics, three-dimensional computer graphics, three-dimensional graphics) is a term describing the different methods of creating and displaying three-dimensional objects by using computer graphics.
\r\n\tThe first types of graphic interpretations were put in the plane (two-dimensional 2D). Requirements for a universal interpretation led to a three-dimensional (3D) interpretation content. From these creations have arisen applied mathematics and information disciplines of graphic interpretation of content - computer graphics. It relies on the principles of Mathematics, Descriptive Geometry, Computer Science and Applied Electronics.
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\r\n\t3D computer graphics or three-dimensional computer graphics use a three-dimensional representation of geometric data (often in terms of the Cartesian coordinate system) that is stored on a computer for the purpose of doing the calculation and creating 2D images. The images that are made can be stored for later use (probably as animation) or can be displayed in real-time.
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\r\n\tObjects within the 3D computer graphics are often called 3D models. Unlike rendered (generated) images, data that are ""tied"" to the model are inside graphic files. The 3D model is a mathematical representation of a random three-dimensional object. The model can be displayed visually as a two-dimensional image through a process called 3D rendering or can be used in non-graphical computer simulations and calculations. With 3D printing, models can be presented in real physical form.
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\r\n\tComputer graphics have remained one of the most interesting areas of modern technology, and it is the area that progresses the fastest. It has become an integral part of both application software, and computer systems in general. Computer graphics is routinely applied in the design of many products, simulators for training, production of music videos and television commercials, in movies, in data analysis, in scientific studies, in medical procedures, and in many other fields.
Technological innovations, referred to as nanomedicine, is an exciting field of applications of nanotechnology to the diagnostic, treatment and/or prevention of traumatic injury or disease of the human body. This field holds the promise to deeply revolutionize the medicine to treatment and therapy areas such as imaging, drug delivery, cell therapy, tissue regeneration and development of new nanomedicine products. Due to its great importance, recent global marketed report expects that the applications of nanotechnology in medicine could reach $528 billion by 2019 [1]. Indeed, a broad range of nanoparticles (NPs) made of various materials (e.g., polymers, dendrimers, gold, silver, lipids, metals, and virus-like particles), differing in their size, architecture and surface properties, has been initially engineered to improve parameters such as the pharmacokinetics and biodistribution of therapeutic molecules and to reduce drugs’ toxicity side effects [2]. Additionally, NPs are also useful tools for body or organ imaging [3]. During the past few decades, NPs have been successfully developed as drug, gene and/or imaging delivery vehicles due to their key properties of enhancing water solubility of poorly water-soluble molecules, extending the plasma circulation time and targeting the site of disease, while avoiding nonspecific toxicity effects [4, 5].
In fact, NPs have provided remarkable progress in therapy and diagnostic imaging of several diseases. Since 1990, a high number of nanocarrier formulations have been approved by regulatory authorities for clinical use [6, 7]. There are five different applications of nanomedicine products on the market within healthcare – in vitro diagnostics; biomaterials; drug delivery; in vivo imaging and active implants [7]. Of these products, the type of NPs that exists on the market is diverse and it includes the following: (i) liposomes (e.g., Ambisome®, Albelcet®, DaunoXome®, Depocyt® and Myocet®); (ii) polymer-coated liposomes (e.g., Doxil® and Lipo-Dox®); (iii) polymeric drugs (e.g., Copaxone®); (iv) polymer-protein conjugates (e.g., Oncospar®, PEG-Intron® and Pegasys®); (v) nanoparticle containing paclitaxel (e.g., Abraxane™), (vi) antibodies (e.g., Avastin™ and Herceptin®) and (vii) antibody conjugates (e.g., Mylotarg®); (viii) aptamer conjugates (e.g., Macugen®); (viii) micelles (e.g., Estrasorb®); among others. These formulations are considered the first generation of nanomedicine, already bringing clinical benefits to patients [8].
Moreover, researches are constantly focusing on the development of NPs that can accumulate and deliver their cargo specifically at the diseased site, and these efforts are bringing important advances toward the development of NP-based targeted drug delivery systems. To increase the specificity of NPs to the targeted area, nanocarriers that can either passively or actively target the unhealthy site have been engineered. In passive targeting, the capacity of NPs to accumulate in the angiogenic site of tumors by the enhanced permeability and retention effect is explored [6, 9]. This strategy is achieved by recovering surface of NPs with some sort of coating with several compounds such as poly(ethylene glycol) (PEG) and poly(phosphoester) (PEEP) [10]. By binding PEG or PEEP to the surface of NPs, there occurs a change in the protein corona populations that adhere to the surface of NPs, reducing drastically the opsonization process of the nanocarriers thus preventing recognition by macrophages and monocytes and rapid clearance of NPs from the blood [10, 11]. Also, the accumulation and cellular uptake of NPs could be further enhanced by conjugating the NPs with molecules such as antibodies, peptides and aptamers that are able to bind to overexpressed receptor or antigens on the surface of targeted cells [12].
More recently, various researchers have been developing NPs able to perform two or more functions for the simultaneous or sequential delivery of single or multiple therapeutic active principles to the required targeted site in the body, overcoming multiple physiological barriers [13]. Multifunctional NPs often have the ability to: (i) encapsulate sufficient amount of drug or therapeutic macromolecules for a sufficient time; (ii) increase residence time in the blood through the use of soluble polymers such as polyethylene glycol (PEG); (iii) increase their accumulation at the desired site in the body by attaching to NPs, surface macromolecules such as antibodies, RNA aptamers and peptides; (iii) respond to several intrinsic or extrinsic stimuli for “on demand” delivery such as abnormal pH, temperature or magnetic and ultrasound fields and (iv) entrap concomitantly an imaging agent to enable the real-time monitoring of their biodistribution, targeted accumulation and/or therapy efficiency [2, 13].
Despite the exciting advances in the discipline of nanotechnology-based approaches, different challenges arise in their efficacy toward the treatment of neurodegenerative diseases. One of the major obstacles that limit the application of NPs for effective delivery of drugs and diagnostic imaging agents to the central nervous system (CNS) is the presence of the blood-brain barrier (BBB) [14]. As a result, new and innovative invasive and noninvasive NPs formulations have been engineered to provide efficacy in crossing the BBB, mainly by the functionalization of NPs’ surface with ligands. Invasive strategies show potential and are being explored for efficient NPs’ access to the brain. Some examples of invasive strategies are: convention-enhanced delivery, intracerebral or nasal injection and use of implants. With this in mind, it is important to understand the general concept of BBB, mechanisms of transport in and out of the brain and the BBB alterations in pathology.
The BBB is a formidable physiological structure that acts as an effective security system for the brain, letting in circulating compounds that this organ needs, but at the same time, these cells have evolved a system of biological pumps and if these pumps recognize molecules that should not be on their way to the brain, they will be pumped right back out into the vascular system [15]. The BBB is primarily composed of brain endothelial cells, which are cells that line microvessels and capillaries in the brain, and these are highly specialized cells that are knitted together very tightly by tight junctions, so there are no gaps between the cells (Figure 1). In fact, endothelial cells’ tight junctions control the flux of hydrophilic molecules and small lipophilic substances such as water and some gases, respectively, that go through the BBB [15, 16]. Also, the brain endothelial cells are surrounded by a structure known as basal lamina, composed of fibronectin, type IV collagen, heparin sulfate and laminin [16, 17].
The Blood-Brain Barrier. Schematic cross-sectional representation of the blood brain barrier (BBB) and other components of vascular unit like neurons, astrocytes, pericytes that are essential for the health function of the CNS. Also, depicted in the picture are the BBB mechanism of passage: (A) Water soluble agents; (B) Lipid solid agents; (C) Protein transport; (D) Receptor-mediated transport, and (E) Adsorptive transcytosis.
Other structures such as neurons, astrocytes, pericytes and extracellular matrix components constitute the neurovascular unit that is also part of the BBB structure (Figure 1). Neurons are electrically excitable cells responsible for processing and transmitting information throughout the mind and body. In the nervous system, chemical and electrical signals between neurons occur via synapses, or junctions, that connect these cells [18]. Astrocytes play a key role in providing nutrients to neurons by shuttling them from the blood vessels to neurons themselves; they also help to control the ion concentration in the brain; are part of the repair process that happens after brain injury and help neurons recycle their neurotransmitters [19]. Pericytes appear to play a key role in BBB endothelial cells barrier formation [20]. Finally, the extracellular matrix occupies 10–20% of brain volume and has a major role in its normal pathology [21]. Therefore, it is the vascular unit that controls permeability and cerebral blood flow throughout the CNS, ensuring physiological CNS functioning.
In Figure 1, a schematic overview of the mechanisms of transport through the BBB is depicted. Molecules that present either a high degree of lipophilicity and molecular weight smaller than 500 Da can penetrate the CNS by simple diffusion (Figure 1A). However, in the absence of these characteristics, other circulating molecules can cross the BBB by their interaction with specific transport proteins located at the brain endothelial surface. These proteins are classified into two main categories: (i) carrier-mediated transport and (ii) receptor-mediated transport. Carrier-mediated transport (CTM) systems are responsible for the transport of small-drug molecules or small nutrient molecules including monosaccharaides and amino acids with a molecular mass smaller than 600 Da. These molecules can cross the BBB endothelial cells via active transport mediated by specific proteins (Figure 2C). The diffusion of molecules from the blood to the brain may be passive or active. For example, the transport of neutral L-amino acids such as leucine, phenylalanine and tyrosine is mediated by the large neutral amino acid transport (LAT1), whereas cationic amino acid transporter (CAT1) mediates the transport of cationic amino acids such as lysine and histidine. Other examples of transporters of polar substances into the brain include the nucleoside transporter (CNT2), the glucose transporter (GLUT1) and the monocarboxylic acid transporter (MCT1) for nucleoside, glucose and carboxylic acids transport, respectively. Moreover, transporters presented at brain endothelial cells’ surface are also able to expel endogenous peptides such as Tyr-Pro-Trp-Gly or a multiplicity of drugs from the CNS to the blood are to be mediated, respectively, by peptide transport system-1 or P-glycoprotein, via active efflux transport (AET). In fact, if a drug is a substrate of any AET protein, multidrug resistance occurs, and this phenomenon is a great obstacle for therapeutic drug delivery to the CNS.
Schematic representation of a drug-loaded, multifunctional, stimuli-responsive NP. The structure of a nanocarrier allows the incorporation of one or multiple therapeutic molecules. These NPs can be found in different sizes and shapes. Increased blood circulation time can be achieved with soluble polymers such as polyethylene glycol (PEG). Nonspecifically target the intended site of action can be achieved by exploring, for example, leaky vessels of tumors. NPs can be actively targeted via the attachment of targeted-specific ligands such as antibody, antibody fragments, aptamers and peptides at their surface. Depending on the kind of application of NPs, various compounds can be added to turn the nanocarrier into a responsive device to a specific stimuli such as temperature, pH or magnetic and ultrasound fields. Imaging or contrast agents such as magnetic resonance imaging (MRI), near infrared (NIR) and/ or polyethylene terephthalate (PET) compounds can also be incorporated into a single platform to enable imaging and releasing of drugs from NPs.
Chemotherapy agents, natural, synthesized or recombinant peptides and proteins, nucleic acids, monoclonal antibodies and other pharmaceutical breakthroughs do not readily cross the BBB (Figure 2D). Nonetheless, there are some specific proteins that the brain needs to function correctly, so they can access the brain by attaching to receptors, which are transported across the barrier and subsequently release into the brain. This mechanism of transport is known as receptor-mediated transport (RMT) and the internalization of these relatively large compounds is done via endocytosis (Figure 2E). It is the most studied transport mechanism for drug delivery, since receptor-specific ligands such as peptides and antibodies against receptors that are expressed on brain endothelial cells surface can be attached to the surface of nanoparticles or drugs, enabling their accumulation and internalization by cells of vascular side and, consequently, being transported into the brain. In addition, adsorptive-mediated transport (AMT) is a kind of transport where endocytosis is induced by the binding of cationic substances to the negatively charged plasma membrane of brain endothelial cells interaction. Therefore, due to the electrostatic interaction between the negatively charged membranes, the cationic therapeutic compound takes the AMT to enter the CNS.
This becomes a problem when treating diseases of the brain because we need to be able to deliver drugs from the vascular system into the CNS [22]. Unfortunately, at the moment, there are no drug therapies for a wide range of CNS diseases, and these include neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) and cerebral ischemia (or stroke). Therefore, the objective of this chapter is to discuss how NPs can be modified to transport thousands of different drug molecules for the treatment of brain diseases. In essence, NPs for drug delivery into the brain is a method for transporting drug molecules across the BBB using nanocarriers. NPs, surface can be functionalized with molecules such as peptides, antibodies and RNA aptamers, and these macromolecules can be attached to the receptors present at the BBB endothelial cell surface, which allow the NPs across the barrier and subsequently deliver pharmaceuticals to the brain for the therapeutic and/or imaging of neurological disorders [14]. In fact, part of the difficulty in finding an effective treatment for these CNS disorders is that there is not yet an efficient delivery method for drug delivery across the BBB. However, over the last several years, researches have started to understand some of the design rules for efficient delivery of NPs to the brain.
As mentioned earlier, the BBB is a selective and dynamic barrier restricting the passage of a huge variety of compounds across this barrier, which is essential for the maintenance of homeostasis and functionality of the CNS. Therefore, the BBB is considered the major obstacle for the use of NPs as delivery systems to brain diseases. As shown in Figure 2, endothelial cells of the cerebral microvasculature are associated with perivascular cells form the BBB. The functional interaction between endothelial and perivascular cells and their response to injury have led to the concept of the neurovascular unit [15, 17]. Studying the mechanisms of uptake, transport and cytotoxicity of NPs through the BBB is an extremely challenging task in vivo because of the technical limitation to access the interface between the vascular system and the brain, since it is estimated that the brain capillary length is about 650 km [23]. To overcome this problem, in vitro BBB models have been built to reproduce as precise as possible the major BBB features, allowing investigation of cellular and molecular mechanisms that occur in the barrier; prediction of the transport of compounds across the BBB and performing high-throughput platform to test NPs transport through the barrier for the effective treatment of brain diseases. For example, it was observed that NPs can reach the capillaries into the brain of rats or mice 30 m after intravenous injection and, up to 5 h after NPs administration, they could go through the barrier, decreasing afterward [24, 25, 26, 27, 28, 29]. These studies of NPs across the brain tissue are in line with in vitro BBB models data reported [30, 31]. In addition, it was observed that in vitro BBB model facilitates the manipulation of some parameters that affects the barrier such as aglycemia, hypoxia, among others [32]. For decades, two-dimensional or three-dimensional in vitro models of BBB have been developed by cultivating either as a monolayer or in cocultivation with mouse brain microvascular endothelial cells and murine or human endothelial cells with pericytes or astrocytes or glial tissue among others in a way that mimics the barrier under physiological or pathological conditions such as Alzheimer’s and Parkinson’s diseases or stroke [33, 34, 35, 36, 37]. Models of BBB based on stem cells are also reported in the literature [38, 39]. Moreover, by taking permeability measurements on the cultured cells, it is possible to test the physiological relevance of the developed model. In addition, experiments such as gene expression analysis using real-time polymerase chain reaction (PCR), permeability analysis [40, 41] and immunocytochemistry can also be used to validate the BBB model obtained. Although we are still not able to make this platform available both in academic and industry setting, this kind of technology has been showing the importance of considering in vitro data together with in vivo studies to understand the transport process of NPs into the brain.
In addition, the BBB is not the only physiological barrier for drug delivery to the brain. If we consider the anatomic aspects of our body, the brain and the spinal cord are completely cushioned and protected by the cerebrospinal fluid (CSF) [42, 43]. This fluid is also responsible for carrying nutrients to and waste products away from the brain. The great majority of CSF is produced within ventricular areas of the brain, as a result of the specialized tissue known as choroid plexus. The choroid plexus is located in each of the four ventricles within the brain area: two lateral ventricles, and the third and fourth ventricles. Here, it is important to clarify that the cells of the choroid plexus do not produce the CSF; instead, this fluid is a filtrate of the blood that is performed by the highly specialized cells of choroid plexus known as cuboidal epithelial cells. Cuboidal epithelial cells are exactly located between the capillary and the ventricle. As all capillaries present within the brain, the capillaries of the choroid plexus have a wall formed by single cells responsible for ready transportation of ions and molecules to and from the choroid plexus capillary. Tight-gap junctions hold the choroid plexus epithelial cells together. These gap junctions prevent substances from entering or leaving the CSF; thus, the choroid plexus acts as a blood-CSF barrier. Lastly, although the CSF originates in the ventricles, this fluid flows through to the ventricles and then surrounds the brain and the spinal cord.
Over the last several years, researches have engineered a variety of NPs that can potentially deliver therapies and/or imaging agents directly into the brain [14, 42, 44, 45, 46, 47, 48]. It is really challenging to get these nanoparticles across the BBB to treat a CNS disease in sufficient amount and without causing major side effects on healthy brain cells. NPs are available in many sizes and shapes and they can have a positive, negative or neutral surface charge (Figures 2, 3). Their core can be made of a variety of materials such as biological, synthetic or energy receptive. NPs can also be coated with specialized molecules that allow them to interact with their environment. NPs can also be loaded with therapeutic molecules that are released in a controlled way and, at the same time, retain the drug stability and prevent them from degradation once in the blood. Therefore, for an efficient drug delivery into the CNS, it is very important to engineer NPs with the following properties: (i) small size (NP diameter should be smaller than 100 nm); (ii) biocompatible, biodegradable, nontoxic and noninflammatory; (iii) prolonged circulation time in the body; (iv) stable in the plasma; (v) protect the cargo such as small molecules, peptides [43, 49, 50, 51], proteins or nucleic acids from degradation; (vi) targetability to the BBB and (vii) controlled drug release [44].
Types of nanoparticles for brain delivery. Enhancing brain drug delivery with the use of several nanocarriers, able to carry the most diverse kind of molecules.
One of the most important and challenging characteristics in engineering NPs is their functionalization. Active targeting of NPs can be achieved by attaching onto their surface, in a highly controlled way, specific molecules such as monoclonal antibody, RNA aptamers, transferrin, lactoferrin and peptides (Figure 2). An example of such active NP is the extensive use of cell penetrating peptides such as SynB vectors, Tat and penetratin that were successfully used to target the BBB [52, 53, 54, 55]. In fact, a huge variety of molecules that increased targeting strategies to the BBB such as growth factors (e.g., vascular endothelial growth factor; epidermal growth factor) [56], albumin [57], insulin [58], lactoferrin [59], transferrin [60], angiopep-2 [61] and biotin-binding proteins has been reported [62]. Targetability is usually associated with nanoparticles with prolonged circulation time. This characteristic is achieved by coating the surface of NPs with hydrophilic polymers such a polyethylene glycol (PEG), poly(acryloylmorpholine), poly-N-vinylpyrrolidones, polyvinyl alcohol and poly[N-(2-hydroxypropyl) methacrylamide] [63] (Figures 2, 3). Among these polymers, PEG is still the most useful polymer in obtaining long circulating NP. The attachment of polymers onto the surface of NPs works by preventing NPs interaction with opsonins present at the plasma and, in this way, impeding their capture and subsequent clearance from the body. However, it was observed that the blood clearance phenomenon is accelerated after repetitive administration of clinically used PEGylated NPs due to the induction of production of antibodies (the NPs used in these studies were PEGylated liposomes) [64, 65]. Moreover, PEGylated NPs are particularly useful for neurological disease treatment, since the long-circulating NPs into the brain by diverse mechanisms were observed. Nevertheless, for brain tumors, reliance on the enhanced permeability and retention (EPR) effect for drug delivery strategies faces several challenges, since the accumulation of NPs at the tumor site is very low [66].
Due to their ability to carry hydrophilic, hydrophobic and/or lipophilic compounds and high specificity, the use of NPs provides a very efficient platform for drug delivery into the CNS. The most popular nanocarrier studied for brain drug delivery is liposomes and several liposomal formulations are clinically available or tested at different clinical trial phases [14]. Liposomes are spherical concentric vesicles, consisting of at least one lipid bilayer, enclosing an aqueous compartment. This nanocarrier has been employed for therapeutically active compounds delivery soon after its discovery by Bangham in the early 1960s. This NP has been successfully engineered for a variety of brain neurodegenerative disorders and brain tumors. For a detailed overview of liposome-based strategies to drug delivery across the BBB, we refer the reader to Vieira and Gamarra’s article [14].
One of the breakthroughs of nanoparticles formulations is to target the nanocarriers to deliver their cargo into the brain. The brain endothelial cells contain several targets as discussed earlier that are explored on the studies of nanoparticles for brain delivery. Each of these targets could be specific for a brain disease or brain diseases. For example, transferrin has been described as the BBB-targeting ligand in studies of nanoparticle formulations [67, 68]. Transferrin is a glycoprotein (80 kDa) that binds to the transferrin receptor and is taken across the BBB via Receptor mediated endocytosis (RME). Indeed, these studies demonstrated that transferrin conjugated to liposomes exhibited a significant increase in the concentration of therapeutic molecules delivered by NPs into the brain when compared to the administration of the drug alone. In addition, broad ranges of nanocarriers with different shapes, sizes and surface properties have been developed for the transport of therapeutic or imaging molecules across the BBB. These also include carbon nanotubes [69, 70], micelles [71], dendrimers [72, 73], nanofibers [74, 75], polymer [46, 76], gold [77] and iron oxide nanoparticles [78] NPs (Figure 3).
Although nanotechnology-based strategies to get into the brain have shown progress in animal models, the translation of passive- and active-targeting delivery strategies into clinical studies is still questionable. This might be due to the random nature of receptor-ligand interactions and/or ineffective release of drug from the nanocarrier at the targeted site [79]. Therefore, the development of multifunctional nanoparticles is becoming possible due to the engineering of stimuli-responsive systems that are able to control the release of their cargo and drug distribution in response to specific stimuli such as magnetic field, light, changes in pH, variations in temperature, among others (Figure 2).
Getting NPs into CNS is not an easy task. As discussed earlier, the BBB is the main structure responsible for brain protection and homeostasis. In addition, it is important to mention that in neurological diseases, several impairments of this structure occur, leading to the perpetuation of the inflammatory cycle that damages neuronal cells and neurodegeneration [80] Moreover, the BBB breakdown can occur, which is clearly a consequence of an ischemic stroke that occurred [81] due to an obstruction within a blood vessel that supplies the brain with oxygen and several nutrients, leading to brain cell death.
In other cases, especially in chronic neurological diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), it remains unclear how these diseases promote the BBB impairment [32]. Importantly, these modifications in the BBB structure should be taken into consideration when you are planning the engineering of effective multifunctional NPs for brain delivery. In this context, NPs have been designed to cross the BBB and this new technology has some applications so far in the treatment of Alzheimer’s and Parkinson’s diseases, stroke and brain tumors, which are discussed in the following section.
Stroke is a serious disease that occurs when some or all of the blood supply to a part of the brain is restricted or cut off and, therefore, this can lead to disability, brain injury or death. Thus, the loss of oxygen and nutrients provided by the blood causing the loss of brain function is a stroke also known as cerebral ischemia. There are two ways to disturb the blood supply to the brain (Figure 4). The most common type occurs when there is a stoppage of blood flow to a part of the brain due to a blood clot. This cause of strokes accounts for 85% of all cases and it is known as ischemic stroke. The second cause of stroke, that is not as common as the ischemic stroke, but still very serious, happens when one of the blood vessels that is a part of the cerebral circulation supplying the brain ruptures. This kind of stroke is called a hemorrhagic stroke. In addition, “hemorrhagic” refers to a sudden torrential bleeding outburst. However, regardless of whether it is an ischemic stroke or a hemorrhagic stroke, the brain cells start to malfunction after some minutes due to the lack of oxygen and nutrients owing to improper blood flow or improper blood supply.
Schematic representation of the main event causing ischemic stroke, Alzheimer’s and Parkinson’s disease. (Adapted from Alvarim et al. [82]) ischemic stroke is caused by the interruption of the blood flow, depriving the brain of oxygen and some nutrients. For Alzheimer’s disease, the main characteristic of this disease is the presence of neurofibrillary tangles and amyloid plaques in the brain, leading to shrinkage of some structures of the brain such as the hippocampus and the enlargement of the brain ventricles, resulting in neurodegeneration. In Parkinson’s disease, substantia nigra dopamine neurons are lost.
There is also a related condition called the transient ischemic attack (TIA), also known as a mini-stroke. It is essentially a temporary interruption of blood flow to a part of the brain often lasting between 30 m and several hours. Therefore, the symptoms of TIA and stroke are similar. However, the difference is that a TIA does not actually destroy brain cells and it does not cause permanent disability. Nevertheless, it is often a warning signal that an individual is at risk of having a stroke in the near future. One of the key differences is that a TIA will resolve, whereas, if an individual has a stroke, he/she may not gain normal functioning again for weeks or months, or maybe even for the rest of his/her life.
Nevertheless, the cellular and molecular mechanisms of a stroke episode have been very well known due to the development of several experimental animal models of ischemic stroke [83]. From the studies with these animal models, it was observed that during ischemic stroke, first occurs the opening of the BBB for a short time period. Then, occurs a refractory interval, followed by a reopening of the BBB, but this time for a long period [84] The reopening of the BBB is the step responsible for the activation of the endothelium, leukocyte recruitment, reactive oxygen species (ROS) and cytokine productions and edema formation [85], leading to an inflammatory response and the BBB breakdown and cell death upon stroke [86]. Moreover, dysregulation of tight-junction proteins is also observed during ischemic stroke, due to their degradation by matrix metalloproteinases, which are involved in the process of BBB extracellular degradation, leading to an increase in the permeability of the brain structure [32].
Therefore, besides the BBB itself being an excellent target for itself for treating ischemic stroke, the design of effective drug delivery systems has also to take into consideration the cellular and molecular mechanisms described earlier. One of the strategies described in the literature to overcome neuronal tissue damage after a stroke event is the use of multifunctional NPs to deliver neuroprotective drugs into the brain, since the majority of neuroprotective drugs do not cross the BBB in their free form. For example, the inactive caspase-3 activation in the brain cells likely decreases the probability of brain cell damage after a stroke event. Although it was shown that some peptide inhibitors of caspase are effective compounds in promoting neuroprotection, they cannot readily cross the BBB. For this purpose, a positively charged NP of chitosan conjugated with transferrin receptor was designed to deliver the relatively specific caspase-3 inhibitor N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone (Z-DEVD-FMK) across the BBB [36]. By clearly reducing the caspase 3-activity in vivo, this formulation was also readily transported across the BBB (less than 1 h) and it decreased neurological deficits and the infarcted area, proving to be a very promising formulation [27].
In the same way, several other compounds have been described to provide neuroprotection and to prevent neurodegeneration. One of these compounds is the Tanshinone IIA that has demonstrated neuroprotective effects against ischemic injury [87]. However, its use in the treatment of this disease is limited due to the compound’s low solubility in aqueous medium, short-half circulation in the plasma and inability to cross the BBB. To overcome these limitations, Tanshinone IIA was successfully conjugated to PEGylated-cationic bovine serum albumin. These nanoparticles were able to cross the BBB in vivo, as a significant decreasing in the infarcted volume was observed. In addition, a reduction in the neutrophil infiltration and neuronal apoptosis was observed [88]. The authors also explored the molecular mechanisms by which this formulation conferred neuroprotection. It seems that the mechanism of action of this formulation in the brain is related to the down-regulation of pro-inflammatory cytokines (mainly IL-8 and TNF-α), to the up-regulation of anti-inflammatory cytokines (mainly transforming growth factor-β1 and IL-10) and to the reduction or inhibition of mRNA and proteins (mainly GFAP, MMP-9, COX-2, p38MAPK, ERK1/2 and JNK) [88].
As a last example, adenosine is also a powerful molecule that has demonstrated neuroprotection to the brain after an ischemic stroke event. This molecule also presents as limitations short-life time in the plasma and inability to cross the BBB. Here, adenosine was conjugated to the lipid-squalene and, then, yielded negatively charged NPs, showing promising results [89]. In vivo experiments showed that this formulation was able to extend adenosine circulation time in the plasma, interact with the neurovascular unit, enhance animal neurological deficit scores and decrease the size of the infarcted area [89].
It has been estimated that AD, only in the USA, affects over 5.5 million people. Moreover, Alzheimer’s AD is the most common cause of dementia [90]. Dementia is a serious brain disease that has as major symptoms deterioration in memory, behavior and thinking. In 2015, dementia affected 47.5 million people worldwide. Most were over the age of 60. The United States data related to AD account that this disease was the sixth highest cause of death in 2005. It was also observed that 1 in 3 seniors who died had AD or other kinds of dementia. It is also expected that the number of people with Alzheimer’s will grow as the population of those over the age of 65 rises. In 2015, Alzheimer’s disease and other dementia cost the nation $226 billion and by 2050 this may rise to $1.1 trillion [90].
AD was named after the German physician Dr. Alois Alzheimer who presented a case history before an important medical meeting. In 1901, he was closely following a 51-year-old woman patient with a mental disorder, the manifestations of which were language problems and memory loss. After her death, Dr. Alzheimer took a serious examination of her brain and found the presence of plaques and tangles that today characterize AD [91]. This disease accounts for about 60–80% of the dementia cases. In most cases, Alzheimer’s clinical manifestations first appear after the age of 65. However, Alzheimer’s disease is not considered normal aging although the greatest risk factor of developing the disease is increased age. This is actually the greatest known risk factor for developing AD. However, as mentioned earlier, Alzheimer’s is not a normal part of aging. It was observed that a greater proportion of patients over 85 years have AD compared to those over 65 years as AD is more likely to affect older individuals. Dominant genes that are transmitted through generations cause less than 5% of Alzheimer’s. However, family risk is the second biggest factor for the development of AD after a certain age. In these families, individuals usually present symptoms of Alzheimer’s before the age of 65 and these symptoms sometimes appear in their 30s. This form of AD that is hereditary and marked by Alzheimer’s symptoms at an early age is called early-onset familial Alzheimer’s disease (EOFAD). To date, mutations in presenilin (PS1 on chromosome 14 and PS2 on chromosome 1) and the amyloid precursor protein gene (APP) on chromosome 21 have been associated with EOFAD. All these three gene mutations (PS1/PS2/APP) affect the pathway in amyloid precursor protein synthesis, which leads to the increase of production of Aβ, creating plaques in the brain [92]. Additionally, there are certain genes such as apoE gene on chromosome 19 that increase the susceptibility to AD. There are three forms of the apoE gene: APOE2, APOE3 and APOE4, the last one being the one associated with a high risk for developing AD. Actually, an individual with two copies of this gene is at three to eight more risk than people with one copy of this gene.
The human brain contains about 100 billion neurons that communicate to one another via synapses, when a burst of chemicals called neurotransmitters are released [93]. The neurotransmitters are synthesized into the synaptic gap. Then, neurotransmitters move across these synaptic gaps between neurons and bind to receptor sites on the dendrites of the next neuron. Unfortunately, neurons are the type of cells affected by AD. To date, scientists still do not know exactly the causes of AD and how this process begins. However, according to recent studies, it appears to be likely that astrocytes’ activation contributes to the neuroinflammatory component responsible for the damage of neurons decades before the issue becomes obvious [94].
Abnormal structures called β-amyloid plaques and neurofibrillary tangles are classical biological hallmarks of the disease [91]. The formation of extracellular β-amyloid plaques occurs when amyloid precursor protein in the neuron cell membrane is cleaved at different positions, releasing small fragments called amyloid β (Aβ) that are highly toxic to the neurons and also interfere with the function of the brain cells [95]. Neurofibrillary tangles, on the other hand, are aggregates of hyperphosphorylate of a microtubule-associated protein known as tau. Tau protein, which in normal cells is responsible for helping nerve cells transport nutrients and maintain their proper shape, is altered in AD and, as a consequence, the transport of nutrients and other essential supplies into the neuron is affected, causing its death. At the same time, the health neurons start working less effectively. After some time, these neurons start losing their capacity to function and communicate to one another and, eventually, they die. Then, the harm may spread to structures in the brain such as hippocampus and entorhinal cortex, which are crucial areas of the brain responsible for forming new memories, thus causing memory loss. As neurons continue to die, affected areas of the brain begin to shrinks and brain functions are lost (Figure 4).
The BBB impairment in AD has been controversial [96]. However, several studies carried out in AD patients or AD animal models have been suggesting that the cause of cerebrovascular alterations in the BBB of the diseased brains is the accumulation of Aβ peptide [97, 98, 99]. Nevertheless, there are also studies suggesting that the BBB impairment is the cause of neurodegeneration, since the dysfunction of the brain structure in AD animal models was observed before Aβ aggregates were accumulated [100]. In any case, both hypotheses for the dysfunction of the BBB consider as a secondary event the tauopathies. However, a study reported that the tau filaments alone are able to start the disruption of the BBB and when it was deregulated, the BBB integrity was recovered [101].
Currently, there are no drug treatments that can cure AD. For this reason, approaches for treating AD are focused more on therapeutic interventions that alleviate symptoms, slow down or delay the progression of the disease, improving the patient’s quality of life. To date, there are two types of medications for Alzheimer’s treatment: acetylcholinesterase inhibitors (Aricept, Reminyl, Exelon and Cognex) and N-Methyl-D-aspartate (NMDA) receptor antagonist (Namenda). Nevertheless, the administration of these therapeutic molecules is associated with severe side effects. Thus, it would be desirable to develop drugs that can efficiently deliver these drugs into the brain. Moreover, there are also several studies showing that neuroprotective peptides might be an excellent compound for AD therapy, since they have shown to be able to break down and degrade Aβ plaques.
Multifunctional NPs are a good option to carry these peptides, since nanocarriers can protect them from degrading into the plasma by proteolytic enzymes and increase their stability in the serum. For example, PEG-PLA NPs were able to protect the neuroprotective peptide NAPVSIPQ from degradation. However, just NPs modified with B6 peptide (similar to transferrin) were able to cross the blood-brain barrier in mice and successfully deliver the neuroprotective peptide into the brain [102]. Moreover, it was observed that the treatment with this formulation improved cholinergic function and ameliorated spatial learning of AD mouse model [102]. In the same way, the nerve growth factor (NGF) has also been explored as a good drug for treating AD, although it is not able to cross the BBB. For this purpose, NGF was encapsulated into PBCA NPs, decorated with polysorbate 80 [103]. These NPs presented very promising results, since they were able to reach the mice brain parenchyma in less than 1 h after administration and these nanocarriers also proved to be able to improve recognition and memory of mice and to reduce by almost 40% the PD symptoms such as rigidity, tremor and oligokinesia in animal models [103]. Coenzyme Q10, a powerful antioxidant macromolecule, has also been explored at AD therapy. In this way, this coenzyme was encapsulated within PLGA NPs decorated with trimethylates chitosan. The results showed that these nanoparticles were able to cross the BBB and accumulate in the choroid plexus, ventricles and cortex. Moreover, the authors also observed an improvement in the cognitive and spatial memory performance of AD mice models and a significant reduction of senile plaques and levels of ROS [104].
After Alzheimer’s, PD is the second most common disease in terms of neurodegenerative diseases. As the aging population increases, the number of people with this disease is expected to rise. It affects 0.3% and 1% of the population worldwide over the age of 40 years and 65 years, respectively. Pathologically, PD is characterized by progressive loss of muscle control, which leads to tremor of hands, bradykinesia, rigidity and postural instability [105] Motor impairment in PD can also cause hypomimia, which is the decreased degree of facial expression. Dysphagia and hypophonia, which are disruption of the swallowing process and lack of coordination in the vocal musculature, are also common features in PD. Other symptoms also include ophthalmologic complaints such as blurred vision and gate. It is important to mention that all these signs and symptoms are a result of affected areas that occur within the brain, especially in an area known as basal ganglia [105].
Thus, PD is a result of problems that occur within the basal ganglia. The basal ganglia is a collection of nuclei located deep beneath the cerebral cortex and it is responsible for the correct execution of voluntary muscle movements and learned movement patterns. The components of basal ganglia are caudate nucleus and putamen (dorsal striatum); nucleus accumbens and olfactory tubercule (ventral striatum), ventral pallidum, globus pallidus, subthalamic nucleus and substantia nigra. In PD, the basal ganglia is disrupted, causing degeneration of dopaminergic neurons located at the substantia nigra. Essentially, it is considered a disease of the basal ganglia because what happens is that when the cerebral cortex wants to initiate a movement, the basal ganglia receives these signals and sends it back the motor cortex via the thalamus. Through various pathways, the substantia nigra is connected with nuclei in basal ganglia. The basal ganglia plays an essential role in integrating multiple input signals to modulate the output of the motor cortex. Inhibitory or excitatory connections can occur in this process. Thus, the loss of dopamine from substantia nigra in this process underlies the symptoms described earlier [105].
At the beginning, researches believed that the BBB did not suffer any kind of alteration during the disease development [106]. Surprisingly, tracking compounds such as [11C]-verapamil and benserazide in the brain of PD patients or PD animal models, it was observed that the concentration of these compounds in the brain was increased, what does not happen in the brain of health patients or animals since these drugs are not able to cross the BBB [107]. In addition to this, a good correlation between the albumin ratio and progressive BB integrity loss in the brain of patients with PD was observed [107]. Moreover, other signals of the BBB impairment such as vascular alterations and blood flow deficiencies were reported [108]. Most important, the increased expression of vascular endothelial growth factor (VEGF) was directly correlated with the high amount of blood vessels presented in the damaged dopaminergic neurons in the brain of monkeys [109]. Later, it was observed that the injection of VEGF into the substantia nigra in the brain of rats disrupted the BBB, leading to a strong inflammation response and loss of dopaminergic neurons [110]. Lastly, alpha-synuclein aggregates are the central hallmark of PD and their accumulation seems to be correlated with the downregulation of the P-glycoprotein (Figure 4) [111]. Moreover, higher concentration of some metals like iron was found in the brain of PD patients and PD animal models because of the higher levels of lactoferrin receptor in the substantia nigra dopaminergic neurons of the diseased brain [32].
Currently, there is no cure for PD. However, there are drugs that work to decrease and relieve the symptoms of PD and maintain the quality of life of the patient. The most effective treatment for PD is the use of the drug levodopa—also called L-dopa—or dopamine that is both able to restore or increase the concentration of dopamine in the basal ganglia. But here, we want to discuss an article that explored the increased expression of lactoferrin in some region of the brain in PD patients [112]. In this way, a PAMAM and PEG NPs were developed, coated with lactoferrin to the delivery of a plasmid of human glial cell line-derived neurotrophic factor plasmid (GDNF), since GDNF is a promising factor in treating PD, but as all plasmids are unable to cross the BBB. These multifunctional nanoparticles were able to not only cross the brain barrier but also effectively deliver the plasmid into the brain, since a neuroprotective effect on dopaminergic neurons and improvement of locomotor activities in AD animal models was observed [113]. Another example is the encapsulation of urocortin (hormone-related peptide) in PEGylated-PLGA NPs covered by lactoferrin. From the results presented, this formulation was able to quickly cross the BBB and to promote protection to the dopaminergic neurons and improve locomotor functional deficits [114].
Nanotechnology in the field of medicine has brought a variety of new ways to treat and/or detect diseases [13, 115, 116]. Currently, engineered pharmaceutical NPs demonstrated abilities such as long blood circulation time in the body fluids for their accumulation at disease sites with leaky vasculature [117]; specific targeted drug delivery to the pathological area due to the surface functionalization of NPs with ligands such as antibodies [118]; contrast properties due to their unique capacity of carrying contrast agents allowing their tracking in vivo [119]; drug delivery from the particles responsive to a specific stimuli [79] and others. The tremendous advances in nanomedicine during the past decade have significantly advanced on the engineering of nanoparticles that combine several of these characteristics, known as multifunctional NPs. Long-circulating and target-specific NPs capable of prolonged circulation time in the blood and targeted delivery of drug to the brain and in vivo imaging represent one example of a multifunctional nanocarrier [44].
Moreover, we hope this chapter was a bridge between nanotechnology and central nervous systems disorders, since multifunctional NPs have a great potential in the treatment of neurological disorders in the near future [14, 44, 120]. However, as discussed, the BBB is one of the major obstacles to the delivery of drugs into the brain and, consequently, for the treatment of neurological diseases [48, 121]. The BBB is composed of very tightly connected endothelial cells and a variety of transporters [15, 17, 120, 122]. This results in a highly selective permeability barrier that separates the circulating blood from the cerebral parenchyma, thus limiting the entry of drugs into the brain. As discussed earlier, several multifunctional NPs for delivering therapeutic and/or imaging molecules into the brain have been developed [44, 47, 123]. Thus, this part of the chapter was organized in a way to carry the reader through the fundamentals of common neurological diseases such as Alzheimer’s, Parkinson’s and cerebral ischemia and their potential treatments with these kinds of NPs [44, 68, 88, 102, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139]. The purpose was to analyze some of the major scientific data indexed in PubMed, Web of Science and Scopus to explore different approaches engineered to transport and deliver imaging or therapeutic molecules to the brain by using multifunctional NPs technology. In this way, our gathered data on different strategies for the delivery of drugs across the BBB using multifunctional NPs were reviewed, discussed and grouped in self-explanatory figures. Results of our analysis from some research articles on our search showed that several strategies have been used to deliver several therapeutic compounds to the brain by these NPs. Functionalization of the surface of these NPs by covalent ligation of macromolecules such as antibodies, RNA aptamers as well peptides is an effective method for receptor targeting nanocarriers, which allows their BBB-penetration and the efficient delivery of their cargo specifically to the disease site. Additionally, methods for the development of multifunctional NPs that can respond to external stimuli were employed, concluding that the development of multifunctional NPs for treating neurological disorders still is at its infancy, although these systems have a huge chance to revolutionize the ways that brain diseases are treated.
Bone is living tissue that is the hardest among other connective tissues in the body, consists of 50% water. The solid part remainder consisting of various minerals, especially 76% of calcium salt and 33% of cellular material. Bone has vascular tissue and cellular activity products, especially during growth which is very dependent on the blood supply as basic source and hormones that greatly regulate this growth process. Bone-forming cells, osteoblasts, osteoclast play an important role in determining bone growth, thickness of the cortical layer and structural arrangement of the lamellae.
Bone continues to change its internal structure to reach the functional needs and these changes occur through the activity of osteoclasts and osteoblasts. The bone seen from its development can be divided into two processes: first is the intramembranous ossification in which bones form directly in the form of primitive mesenchymal connective tissue, such as the mandible, maxilla and skull bones. Second is the endochondral ossification in which bone tissue replaces a preexisting hyaline cartilage, for example during skull base formation. The same formative cells form two types of bone formation and the final structure is not much different.
Bone growth depends on genetic and environmental factors, including hormonal effects, diet and mechanical factors. The growth rate is not always the same in all parts, for example, faster in the proximal end than the distal humerus because the internal pattern of the spongiosum depends on the direction of bone pressure. The direction of bone formation in the epiphysis plane is determined by the direction and distribution of the pressure line. Increased thickness or width of the bone is caused by deposition of new bone in the form of circumferential lamellae under the periosteum. If bone growth continues, the lamella will be embedded behind the new bone surface and be replaced by the haversian canal system.
Bone is a tissue in which the extracellular matrix has been hardened to accommodate a supporting function. The fundamental components of bone, like all connective tissues, are cells and matrix. Although bone cells compose a small amount of the bone volume, they are crucial to the function of bones. Four types of cells are found within bone tissue: osteoblasts, osteocytes, osteogenic cells, and osteoclasts. They each unique functions and are derived from two different cell lines (Figure 1 and Table 1) [1, 2, 3, 4, 5, 6, 7].
Osteoblast synthesizes the bone matrix and are responsible for its mineralization. They are derived from osteoprogenitor cells, a mesenchymal stem cell line.
Osteocytes are inactive osteoblasts that have become trapped within the bone they have formed.
Osteoclasts break down bone matrix through phagocytosis. Predictably, they ruffled border, and the space between the osteoblast and the bone is known as Howship’s lacuna.
Development of bone precursor cells. Bone precursor cells are divided into developmental stages, which are 1. mesenchymal stem cell, 2. pre-osteoblast, 3. osteoblast, and 4. mature osteocytes, and 5. osteoclast.
The balance between osteoblast and osteoclast activity governs bone turnover and ensures that bone is neither overproduced nor overdegraded. These cells build up and break down bone matrix, which is composed of:
Osteoid, which is the unmineralized matrix composed of type I collagen and gylcosaminoglycans (GAGs).
Calcium hydroxyapatite, a calcium salt crystal that give bone its strength and rigidity.
Bone is divided into two types that are different structurally and functionally. Most bones of the body consist of both types of bone tissue (Figure 2) [1, 2, 8, 9]:
Compact bone, or cortical bone, mainly serves a mechanical function. This is the area of bone to which ligaments and tendons attach. It is thick and dense.
Trabecular bone, also known as cancellous bone or spongy bone, mainly serves a metabolic function. This type of bone is located between layers of compact bone and is thin porous. Location within the trabeculae is the bone marrow.
Structure of a long bone.
Long bones are composed of both cortical and cancellous bone tissue. They consist of several areas (Figure 3) [3, 4]:
The epiphysis is located at the end of the long bone and is the parts of the bone that participate in joint surfaces.
The diaphysis is the shaft of the bone and has walls of cortical bone and an underlying network of trabecular bone.
The epiphyseal growth plate lies at the interface between the shaft and the epiphysis and is the region in which cartilage proliferates to cause the elongation of the bone.
The metaphysis is the area in which the shaft of the bone joins the epiphyseal growth plate.
Bone macrostructure. (a) Growing long bone showing epiphyses, epiphyseal plates, metaphysis and diaphysis. (b) Mature long bone showing epiphyseal lines.
Different areas of the bone are covered by different tissue [4]:
The epiphysis is lined by a layer of articular cartilage, a specialized form of hyaline cartilage, which serves as protection against friction in the joints.
The outside of the diaphysis is lined by periosteum, a fibrous external layer onto which muscles, ligaments, and tendons attach.
The inside of the diaphysis, at the border between the cortical and cancellous bone and lining the trabeculae, is lined by endosteum.
Compact bone is organized as parallel columns, known as Haversian systems, which run lengthwise down the axis of long bones. These columns are composed of lamellae, concentric rings of bone, surrounding a central channel, or Haversian canal, that contains the nerves, blood vessels, and lymphatic system of the bone. The parallel Haversian canals are connected to one another by the perpendicular Volkmann’s canals.
The lamellae of the Haversian systems are created by osteoblasts. As these cells secrete matrix, they become trapped in spaces called lacunae and become known as osteocytes. Osteocytes communicate with the Haversian canal through cytoplasmic extensions that run through canaliculi, small interconnecting canals (Figure 4) [1, 2, 8, 9]:
Bone microstructure. Compact and spongy bone structures.
The layers of a long bone, beginning at the external surface, are therefore:
Periosteal surface of compact bone
Outer circumferential lamellae
Compact bone (Haversian systems)
Inner circumferential lamellae
Endosteal surface of compact bone
Trabecular bone
Bone development begins with the replacement of collagenous mesenchymal tissue by bone. This results in the formation of woven bone, a primitive form of bone with randomly organized collagen fibers that is further remodeled into mature lamellar bone, which possesses regular parallel rings of collagen. Lamellar bone is then constantly remodeled by osteoclasts and osteoblasts. Based on the development of bone formation can be divided into two parts, called endochondral and intramembranous bone formation/ossification [1, 2, 3, 8].
During intramembranous bone formation, the connective tissue membrane of undifferentiated mesenchymal cells changes into bone and matrix bone cells [10]. In the craniofacial cartilage bones, intramembranous ossification originates from nerve crest cells. The earliest evidence of intramembranous bone formation of the skull occurs in the mandible during the sixth prenatal week. In the eighth week, reinforcement center appears in the calvarial and facial areas in areas where there is a mild stress strength [11].
Intramembranous bone formation is found in the growth of the skull and is also found in the sphenoid and mandible even though it consists of endochondral elements, where the endochondral and intramembranous growth process occurs in the same bone. The basis for either bone formation or bone resorption is the same, regardless of the type of membrane involved.
Sometimes according to where the formation of bone tissue is classified as “periosteal” or “endosteal”. Periosteal bone always originates from intramembranous, but endosteal bone can originate from intramembranous as well as endochondral ossification, depending on the location and the way it is formed [3, 12].
The statement below is the stage of intramembrane bone formation (Figure 5) [3, 4, 11, 12]:
An ossification center appears in the fibrous connective tissue membrane. Mesenchymal cells in the embryonic skeleton gather together and begin to differentiate into specialized cells. Some of these cells differentiate into capillaries, while others will become osteogenic cells and osteoblasts, then forming an ossification center.
Bone matrix (osteoid) is secreted within the fibrous membrane. Osteoblasts produce osteoid tissue, by means of differentiating osteoblasts from the ectomesenchyme condensation center and producing bone fibrous matrix (osteoid). Then osteoid is mineralized within a few days and trapped osteoblast become osteocytes.
Woven bone and periosteum form. The encapsulation of cells and blood vessels occur. When osteoid deposition by osteoblasts continues, the encased cells develop into osteocytes. Accumulating osteoid is laid down between embryonic blood vessels, which form a random network (instead of lamellae) of trabecular. Vascularized mesenchyme condenses on external face of the woven bone and becomes the periosteum.
Production of osteoid tissue by membrane cells: osteocytes lose their ability to contribute directly to an increase in bone size, but osteoblasts on the periosteum surface produce more osteoid tissue that thickens the tissue layer on the existing bone surface (for example, appositional bone growth). Formation of a woven bone collar that is later replaced by mature lamellar bone. Spongy bone (diploe), consisting of distinct trabeculae, persists internally and its vascular tissue becomes red marrow.
Osteoid calcification: The occurrence of bone matrix mineralization makes bones relatively impermeable to nutrients and metabolic waste. Trapped blood vessels function to supply nutrients to osteocytes as well as bone tissue and eliminate waste products.
The formation of an essential membrane of bone which includes a membrane outside the bone called the bone endosteum. Bone endosteum is very important for bone survival. Disruption of the membrane or its vascular tissue can cause bone cell death and bone loss. Bones are very sensitive to pressure. The calcified bones are hard and relatively inflexible.
The stage of intramembranous ossification. The following stages are (a) Mesenchymal cells group into clusters, and ossification centers form. (b) Secreted osteoid traps osteoblasts, which then become osteocytes. (c) Trabecular matrix and periosteum form. (d) Compact bone develops superficial to the trabecular bone, and crowded blood vessels condense into red marrow.
The matrix or intercellular substance of the bone becomes calcified and becomes a bone in the end. Bone tissue that is found in the periosteum, endosteum, suture, and periodontal membrane (ligaments) is an example of intramembranous bone formation [3, 13].
Intramembranous bone formation occurs in two types of bone: bundle bone and lamellar bone. The bone bundle develops directly in connective tissue that has not been calcified. Osteoblasts, which are differentiated from the mesenchyme, secrete an intercellular substance containing collagen fibrils. This osteoid matrix calcifies by precipitating apatite crystals. Primary ossification centers only show minimal bone calcification density. The apatite crystal deposits are mostly irregular and structured like nets that are contained in the medullary and cortical regions. Mineralization occurs very quickly (several tens of thousands of millimeters per day) and can occur simultaneously in large areas. These apatite deposits increase with time. Bone tissue is only considered mature when the crystalized area is arranged in the same direction as collagen fibrils.
Bone tissue is divided into two, called the outer cortical and medullary regions, these two areas are destroyed by the resorption process; which goes along with further bone formation. The surrounding connective tissue will differentiate into the periosteum. The lining in the periosteum is rich in cells, has osteogenic function and contributes to the formation of thick bones as in the endosteum.
In adults, the bundle bone is usually only formed during rapid bone remodeling. This is reinforced by the presence of lamellar bone. Unlike bundle bone formation, lamellar bone development occurs only in mineralized matrix (e.g., cartilage that has calcified or bundle bone spicules). The nets in the bone bundle are filled to strengthen the lamellar bone, until compact bone is formed. Osteoblasts appear in the mineralized matrix, which then form a circle with intercellular matter surrounding the central vessels in several layers (Haversian system). Lamella bone is formed from 0.7 to 1.5 microns per day. The network is formed from complex fiber arrangements, responsible for its mechanical properties. The arrangement of apatites in the concentric layer of fibrils finally meets functional requirements. Lamellar bone depends on ongoing deposition and resorption which can be influenced by environmental factors, one of this which is orthodontic treatment.
Intramembranous bone formation from desmocranium (suture and periosteum) is mediated by mesenchymal skeletogenetic structures and is achieved through bone deposition and resorption [8]. This development is almost entirely controlled through local epigenetic factors and local environmental factors (i.e. by muscle strength, external local pressure, brain, eyes, tongue, nerves, and indirectly by endochondral ossification). Genetic factors only have a nonspecific morphogenetic effect on intramembranous bone formation and only determine external limits and increase the number of growth periods. Anomaly disorder (especially genetically produced) can affect endochondral bone formation, so local epigenetic factors and local environmental factors, including steps of orthodontic therapy, can directly affect intramembranous bone formation [3, 11].
During endochondral ossification, the tissue that will become bone is firstly formed from cartilage, separated from the joint and epiphysis, surrounded by perichondrium which then forms the periosteum [11]. Based on the location of mineralization, it can be divided into: Perichondral Ossification and Endochondral Ossification. Both types of ossification play an essential role in the formation of long bones where only endochondral ossification takes place in short bones. Perichondral ossification begins in the perichondrium. Mesenchymal cells from the tissue differentiate into osteoblasts, which surround bony diaphyseal before endochondral ossification, indirectly affect its direction [3, 8, 12]. Cartilage is transformed into bone is craniofacial bone that forms at the eigth prenatal week. Only bone on the cranial base and part of the skull bone derived from endochondral bone formation. Regarding to differentiate endochondral bone formation from chondrogenesis and intramembranous bone formation, five sequences of bone formation steps were determined [3].
The statements below are the stages of endochondral bone formation (Figure 6) [4, 12]:
Mesenchymal cells group to form a shape template of the future bone.
Mesenchymal cells differentiate into chondrocytes (cartilage cells).
Hypertrophy of chondrocytes and calcified matrix with calcified central cartilage primordium matrix formed. Chondrocytes show hypertrophic changes and calcification from the cartilage matrix continues.
Entry of blood vessels and connective tissue cells. The nutrient artery supplies the perichondrium, breaks through the nutrient foramen at the mid-region and stimulates the osteoprogenitor cells in the perichondrium to produce osteoblasts, which changes the perichondrium to the periosteum and starts the formation of ossification centers.
The periosteum continues its development and the division of cells (chondrocytes) continues as well, thereby increasing matrix production (this helps produce more length of bone).
The perichondrial membrane surrounds the surface and develops new chondroblasts.
Chondroblasts produce growth in width (appositional growth).
Cells at the center of the cartilage lyse (break apart) triggers calcification.
The stage of endochondral ossification. The following stages are: (a) Mesenchymal cells differentiate into chondrocytes. (b) The cartilage model of the future bony skeleton and the perichondrium form. (c) Capillaries penetrate cartilage. Perichondrium transforms into periosteum. Periosteal collar develops. Primary ossification center develops. (d) Cartilage and chondrocytes continue to grow at ends of the bone. (e) Secondary ossification centers develop. (f) Cartilage remains at epiphyseal (growth) plate and at joint surface as articular cartilage.
During endochondral bone formation, mesenchymal tissue firstly differentiates into cartilage tissue. Endochondral bone formation is morphogenetic adaptation (normal organ development) which produces continuous bone in certain areas that are prominently stressed. Therefore, this endochondral bone formation can be found in the bones associated with joint movements and some parts of the skull base. In hypertrophic cartilage cells, the matrix calcifies and the cells undergo degeneration. In cranial synchondrosis, there is proliferation in the formation of bones on both sides of the bone plate, this is distinguished by the formation of long bone epiphyses which only occurs on one side only [2, 14].
As the cartilage grows, capillaries penetrate it. This penetration initiates the transformation of the perichondrium into the bone-producing periosteum. Here, the osteoblasts form a periosteal collar of compact bone around the cartilage of the diaphysis. By the second or third month of fetal life, bone cell development and ossification ramps up and creates the primary ossification center, a region deep in the periosteal collar where ossification begins [4, 10].
While these deep changes occur, chondrocytes and cartilage continue to grow at the ends of the bone (the future epiphyses), which increase the bone length and at the same time bone also replaces cartilage in the diaphysis. By the time the fetal skeleton is fully formed, cartilage only remains at the joint surface as articular cartilage and between the diaphysis and epiphysis as the epiphyseal plate, the latter of which is responsible for the longitudinal growth of bones. After birth, this same sequence of events (matrix mineralization, death of chondrocytes, invasion of blood vessels from the periosteum, and seeding with osteogenic cells that become osteoblasts) occur in the epiphyseal regions, and each of these centers of activity is referred to as a secondary ossification center [4, 8, 10].
There are four important things about cartilage in endochondral bone formation:
Cartilage has a rigid and firm structure, but not usually calcified nature, giving three basic functions of growth (a) its flexibility can support an appropriate network structure (nose), (b) pressure tolerance in a particular place where compression occurs, (c) the location of growth in conjunction with enlarging bone (synchondrosis of the skull base and condyle cartilage).
Cartilage grows in two adjacent places (by the activity of the chondrogenic membrane) and grows in the tissues (chondrocyte cell division and the addition of its intercellular matrix).
Bone tissue is not the same as cartilage in terms of its tension adaptation and cannot grow directly in areas of high compression because its growth depends on the vascularization of bone formation covering the membrane.
Cartilage growth arises where linear growth is required toward the pressure direction, which allows the bone to lengthen to the area of strength and has not yet grown elsewhere by membrane ossification in conjunction with all periosteal and endosteal surfaces.
Membrane disorders or vascular supply problem of these essential membranes can directly result in bone cell death and ultimately bone damage. Calcified bones are generally hard and relatively inflexible and sensitive to pressure [12].
Cranial synchondrosis (e.g., spheno ethmoidal and spheno occipital growth) and endochondral ossification are further determined by chondrogenesis. Chondrogenesis is mainly influenced by genetic factors, similar to facial mesenchymal growth during initial embryogenesis to the differentiation phase of cartilage and cranial bone tissue.
This process is only slightly affected by local epigenetic and environmental factors. This can explain the fact that the cranial base is more resistant to deformation than desmocranium. Local epigenetic and environmental factors cannot trigger or inhibit the amount of cartilage formation. Both of these have little effect on the shape and direction of endochondral ossification. This has been analyzed especially during mandibular condyle growth.
Local epigenetics and environmental factors only affect the shape and direction of cartilage formation during endochondral ossification Considering the fact that condyle cartilage is a secondary cartilage, it is assumed that local factors provide a greater influence on the growth of mandibular condyle.
Chondrogenesis is the process by which cartilage is formed from condensed mesenchyme tissue, which differentiates into chondrocytes and begins secreting the molecules that form the extracellular matrix [5, 14].
The statement below is five steps of chondrogenesis [8, 14]:
Chondroblasts produce a matrix: the extracellular matrix produced by cartilage cells, which is firm but flexible and capable of providing a rigid support.
Cells become embed in a matrix: when the chondroblast changes to be completely embed in its own matrix material, cartilage cells turn into chondrocytes. The new chondroblasts are distinguished from the membrane surface (perichondrium), this will result in the addition of cartilage size (cartilage can increase in size through apposition growth).
Chondrocytes enlarge, divide and produce a matrix. Cell growth continues and produces a matrix, which causes an increase in the size of cartilage mass from within. Growth that causes size increase from the inside is called interstitial growth.
The matrix remains uncalcified: cartilage matrix is rich of chondroitin sulfate which is associated with non-collagen proteins. Nutrition and metabolic waste are discharged directly through the soft matrix to and from the cell. Therefore, blood vessels aren’t needed in cartilage.
The membrane covers the surface but is not essential: cartilage has a closed membrane vascularization called perichondrium, but cartilage can exist without any of these. This property makes cartilage able to grow and adapt where it needs pressure (in the joints), so that cartilage can receive pressure.
Endochondral ossification begins with characteristic changes in cartilage bone cells (hypertrophic cartilage) and the environment of the intercellular matrix (calcium laying), the formation which is called as primary spongiosa. Blood vessels and mesenchymal tissues then penetrate into this area from the perichondrium. The binding tissue cells then differentiate into osteoblasts and cells. Chondroblasts erode cartilage in a cave-like pattern (cavity). The remnants of mineralized cartilage the central part of laying the lamellar bone layer.
The osteoid layer is deposited on the calcified spicules remaining from the cartilage and then mineralized to form spongiosa bone, with fine reticular structures that resemble nets that possess cartilage fragments between the spicular bones. Spongy bones can turn into compact bones by filling empty cavities. Both endochondral and perichondral bone growth both take place toward epiphyses and joints. In the bone lengthening process during endochondral ossification depends on the growth of epiphyseal cartilage. When the epiphyseal line has been closed, the bone will not increase in length. Unlike bone, cartilage bone growth is based on apposition and interstitial growth. In areas where cartilage bone is covered by bone, various variations of zone characteristics, based on the developmental stages of each individual, can differentiate which then continuously merge with each other during the conversion process. Environmental influences (co: mechanism of orthopedic functional tools) have a strong effect on condylar cartilage because the bone is located more superficially [5].
Cartilage bone height development occurs during the third month of intra uterine life. Cartilage plate extends from the nasal bone capsule posteriorly to the foramen magnum at the base of the skull. It should be noted that cartilages which close to avascular tissue have internal cells obtained from the diffusion process from the outermost layer. This means that the cartilage must be flatter. In the early stages of development, the size of a very small embryo can form a chondroskeleton easily in which the further growth preparation occurs without internal blood supply [1].
During the fourth month in the uterus, the development of vascular elements to various points of the chondrocranium (and other parts of the early cartilage skeleton) becomes an ossification center, where the cartilage changes into an ossification center, and bone forms around the cartilage. Cartilage continues to grow rapidly but it is replaced by bone, resulting in the rapid increase of bone amount. Finally, the old chondrocranium amount will decrease in the area of cartilage and large portions of bone, assumed to be typical in ethmoid, sphenoid, and basioccipital bones. The cartilage growth in relation to skeletal bone is similar as the growth of the limbs [1, 3].
Longitudinal bone growth is accompanied by remodeling which includes appositional growth to thicken the bone. This process consists of bone formation and reabsorption. Bone growth stops around the age of 21 for males and the age of 18 for females when the epiphyses and diaphysis have fused (epiphyseal plate closure).
Normal bone growth is dependent on proper dietary intake of protein, minerals and vitamins. A deficiency of vitamin D prevents calcium absorption from the GI tract resulting in rickets (children) or osteomalacia (adults). Osteoid is produced but calcium salts are not deposited, so bones soften and weaken.
At the length of the long bones, the reinforcement plane appears in the middle and at the end of the bone, finally produces the central axis that is called the diaphysis and the bony cap at the end of the bone is called the epiphysis. Between epiphyses and diaphysis is a calcified area that is not calcified called the epiphyseal plate. Epiphyseal plate of the long bone cartilage is a major center for growth, and in fact, this cartilage is responsible for almost all the long growths of the bones. This is a layer of hyaline cartilage where ossification occurs in immature bones. On the epiphyseal side of the epiphyseal plate, the cartilage is formed. On the diaphyseal side, cartilage is ossified, and the diaphysis then grows in length. The epiphyseal plate is composed of five zones of cells and activity [3, 4].
Near the outer end of each epiphyseal plate is the active zone dividing the cartilage cells. Some of them, pushed toward diaphysis with proliferative activity, develop hypertrophy, secrete an extracellular matrix, and finally the matrix begins to fill with minerals and then is quickly replaced by bone. As long as cartilage cells multiply growth will continue. Finally, toward the end of the normal growth period, the rate of maturation exceeds the proliferation level, the latter of the cartilage is replaced by bone, and the epiphyseal plate disappears. At that time, bone growth is complete, except for surface changes in thickness, which can be produced by the periosteum [4]. Bones continue to grow in length until early adulthood. The lengthening is stopped in the end of adolescence which chondrocytes stop mitosis and plate thins out and replaced by bone, then diaphysis and epiphyses fuse to be one bone (Figure 7). The rate of growth is controlled by hormones. When the chondrocytes in the epiphyseal plate cease their proliferation and bone replaces the cartilage, longitudinal growth stops. All that remains of the epiphyseal plate is the epiphyseal line. Epiphyseal plate closure will occur in 18-year old females or 21-year old males.
Oppositional bone growth and remodeling. The epiphyseal plate is responsible for longitudinal bone growth.
The cartilage found in the epiphyseal gap has a defined hierarchical structure, directly beneath the secondary ossification center of the epiphysis. By close examination of the epiphyseal plate, it appears to be divided into five zones (starting from the epiphysis side) (Figure 8) [4]:
The resting zone: it contains hyaline cartilage with few chondrocytes, which means no morphological changes in the cells.
The proliferative zone: chondrocytes with a higher number of cells divide rapidly and form columns of stacked cells parallel to the long axis of the bone.
The hypertrophic cartilage zone: it contains large chondrocytes with cells increasing in volume and modifying the matrix, effectively elongating bone whose cytoplasm has accumulated glycogen. The resorbed matrix is reduced to thin septa between the chondrocytes.
The calcified cartilage zone: chondrocytes undergo apoptosis, the thin septa of cartilage matrix become calcified.
The ossification zone: endochondral bone tissue appears. Blood capillaries and osteoprogenitor cells (from the periosteum) invade the cavities left by the chondrocytes. The osteoprogenitor cells form osteoblasts, which deposit bone matrix over the three-dimensional calcified cartilage matrix.
Epiphyseal plate growth. Five zones of epiphyseal growth plate includes: 1. resting zone, 2. proliferation zone, 3. hypertrophic cartilage zone, 4. calcified cartilage zone, and 5. ossification zone.
When bones are increasing in length, they are also increasing in diameter; diameter growth can continue even after longitudinal growth stops. This is called appositional growth. The bone is absorbed on the endosteal surface and added to the periosteal surface. Osteoblasts and osteoclasts play an essential role in appositional bone growth where osteoblasts secrete a bone matrix to the external bone surface from diaphysis, while osteoclasts on the diaphysis endosteal surface remove bone from the internal surface of diaphysis. The more bone around the medullary cavity is destroyed, the more yellow marrow moves into empty space and fills space. Osteoclasts resorb the old bone lining the medullary cavity, while osteoblasts through intramembrane ossification produce new bone tissue beneath the periosteum. Periosteum on the bone surface also plays an important role in increasing thickness and in reshaping the external contour. The erosion of old bone along the medullary cavity and new bone deposition under the periosteum not only increases the diameter of the diaphysis but also increases the diameter of the medullary cavity. This process is called modeling (Figure 9) [3, 4, 15].
Appositional bone growth. Bone deposit by osteoblast as bone resorption by osteoclast.
Recent research reported that bone microstructure is also the principle of bone function, which regulates its mechanical function. Bone tissue function influenced by many factors, such as hormones, growth factors, and mechanical loading. The microstructure of bone tissue is distribution and alignment of biological apatite (BAp) crystallites. This is determined by the direction of bone cell behavior, for example cell migration and cell regulation. Ozasa et al. found that artificial control the direction of mesenchymal stem cell (MSCs) migration and osteoblast alignment can reconstruct bone microstructure, which guide an appropriate bone formation during bone remodeling and regeneration [16].
Bone development begins with the replacement of collagenous mesenchymal tissue by bone. Generally, bone is formed by endochondral or intramembranous ossification. Intramembranous ossification is essential in the bone such as skull, facial bones, and pelvis which MSCs directly differentiate to osteoblasts. While, endochondral ossification plays an important role in most bones in the human skeleton, including long, short, and irregular bones, which MSCs firstly experience to condensate and then differentiate into chondrocytes to form the cartilage growth plate and the growth plate is then gradually replaced by new bone tissue [3, 8, 12].
MSC migration and differentiation are two important physiological processes in bone formation. MSCs migration raise as an essential step of bone formation because MSCs initially need to migrate to the bone surface and then contribute in bone formation process, although MSCs differentiation into osteogenic cells is also crucial. MSC migration during bone formation has attracted more attention. Some studies show that MSC migration to the bone surface is crucial for bone formation [17]. Bone marrow and periosteum are the main sources of MSCs that participate in bone formation [18].
In the intramembranous ossification, MSCs undergo proliferation and differentiation along the osteoblastic lineage to form bone directly without first forming cartilage. MSC and preosteoblast migration is involved in this process and are mediated by plentiful factors in vivo and in vitro. MSCs initially differentiate into preosteoblasts which proliferate near the bone surface and secrete ALP. Then they become mature osteoblasts and then form osteocytes which embedded in an extracellular matrix (ECM). Other factors also regulate the intramembranous ossification of MSCs such as Runx2, special AT-rich sequence binding protein 2 (SATB 2), and Osterix as well as pathways, like the wnt/β-catenin pathway and bone morphogenetic protein (BMP) pathway [17, 19].
In the endochondral ossification, MSCs are first condensed to initiate cartilage model formation. The process is mediated by BMPs through phosphorylating and activating receptor SMADs to transduce signals. During condensation, the central part of MSCs differentiates into chondrocytes and secretes cartilage matrix. While, other cells in the periphery, form the perichondrium that continues expressing type I collagen and other important factors, such as proteoglycans and ALP. Chondrocytes undergo rapid proliferation. Chondrocytes in the center become maturation, accompanied with an invasion of hypertrophic cartilage by the vasculature, followed by differentiation of osteoblasts within the perichondrium and marrow cavity. The inner perichondrium cells differentiate into osteoblasts, which secrete bone matrix to form the bone collar after vascularization in the hypertrophic cartilage. Many factors that regulate endochondral ossification are growth factors (GFs), transforming growth factor-β (TGF-β), Sry-related high-mobility group box 9 (Sox9) and Cell-to-cell interaction [17, 19].
Osteogenesis/ossification is the process in which new layers of bone tissue are placed by osteoblasts.
During bone formation, woven bone (haphazard arrangement of collagen fibers) is remodeled into lamellar bones (parallel bundles of collagen in a layer known as lamellae)
Periosteum is a connective tissue layer on the outer surface of the bone; the endosteum is a thin layer (generally only one layer of cell) that coats all the internal surfaces of the bone
Major cell of bone include: osteoblasts (from osteoprogenitor cells, forming osteoid that allow matrix mineralization to occur), osteocytes (from osteoblasts; closed to lacunae and retaining the matrix) and osteoclasts (from hemopoietic lineages; locally erodes matrix during bone formation and remodeling.
The process of bone formation occurs through two basic mechanisms:
Intramembranous bone formation occurs when bone forms inside the mesenchymal membrane. Bone tissue is directly laid on primitive connective tissue referred to mesenchyma without intermediate cartilage involvement. It forms bone of the skull and jaw; especially only occurs during development as well as the fracture repair.
Endochondral bone formation occurs when hyaline cartilage is used as a precursor to bone formation, then bone replaces hyaline cartilage, forms and grows all other bones, occurs during development and throughout life.
During interstitial epiphyseal growth (elongation of the bone), the growth plate with zonal organization of endochondral ossification, allows bone to lengthen without epiphyseal growth plates enlarging zones include:
Zone of resting.
Zone of proliferation.
Zone of hypertrophy.
Zone of calcification.
Zone of ossification and resorption.
During appositional growth, osteoclasts resorb old bone that lines the medullary cavity, while osteoblasts, via intramembranous ossification, produce new bone tissue beneath the periosteum.
Mesenchymal stem cell migration and differentiation are two important physiological processes in bone formation.
The author is grateful to Zahrona Kusuma Dewi for assistance with preparation of the manuscript.
The authors declare that there is no conflict of interests regarding the publication of this paper.
alkaline phosphatase biological apatite bone morphogenetic protein extracellular matrix growth factors mesenchymal stem cells runt-related transcription factor 2 special AT-rich sequence binding protein 2 sry-related high-mobility group box 9 transforming growth factor-β
Authors are listed below with their open access chapters linked via author name:
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