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The Immunity Crisis in America

Have you ever wondered WHY you get sick from different things, sometimes seemingly for no reason? Haven't you ever wished that you could find some way to stop yourself from getting sick and stay healthy all the time? Well, that might be more possible than you thought at first! Your immune system is an odd system, that many scientists are still struggling to understand. However, there have been some amazing breakthroughs! Once you get access to this detailed and helpful book, you will be able to find REAL and Applicable ways to improve your immune system and keep yourself from getting sick all of the time. This book teaches you everything that you never learned about your immune system Start learning what you can Really do to improve your immune system's health and keep your body healthier for longer! It's not hard at all Get started today!

Immunity Crisis Overview

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Mechanisms for how inhaled multiwalled carbon nanotubes suppress systemic immune function in mice

The potential health effects of inhaling carbon nanotubes are important because of possible exposures in occupational settings. Previously, we have shown mice that have inhaled multiwalled carbon nanotubes have suppressed systemic immune function. Here, we show the mechanisms for this immune suppression. Mice were exposed to 0, 0.3 or 1 mg m3 multiwalled carbon nanotubes for 6 h per day for 14 consecutive days in whole-body inhalation chambers. Only those exposed to a dose of 1 mg m3 presented suppressed immune function this involved activation of cyclooxygenase enzymes in the spleen in response to a signal from the lungs. Spleen cells from exposed animals partially recovered their immune function when treated with ibuprofen, a drug that blocks the formation of cyclooxygenase enzymes. Knockout mice without cyclooxygenase enzymes were not affected when exposed to multiwalled carbon nanotubes, further confirming the importance of this enzyme in suppression. Proteins from the lungs of...

Increasing Environmental Concern

ETC argues that mass production of nanomaterials poses a threat to human health for several reasons. First, large amounts of nanomaterials could accumulate in humans. Nanomaterials might be absorbed by bacteria and work their way through the food chain.4 Second, the substances may bind to common contaminants such as pesticides or polychlorinated biphenyls (PCBs). Since some nanoscale particles can enter cells without eliciting an immune response, they might enable toxins to more effectively penetrate the body's defenses.5 Third, carbon nanotube fibers may cause serious respiratory problems. Because of their unique, needle-like structure, detached fibers could wreak havoc and become the next asbestos.6 A casual glance at Figure 4.1 gives the impression that nanotubes resemble asbestos fibers, as viewed under a scanning electron microscope (SEM). (On closer inspection, however, the scale of the photographs reveals that the nanotubes shown are over 60 times smaller than the asbestos...

The Importance of Protein Nanotechnology

Proteins are major cellular components that play an essential role in maintaining the functioning of the cell. Proteins have a number of functions. They can function as enzymes, which are the driving force for biochemical reactions. Also, they can serve as antibodies that recognize invading elements and allow the immune system to neutralize and eliminate unwanted invaders. Proteins have functions within physiological as well as pathophysiological processes in a cell or organism. Because diseases, therapy, and drugs can alter protein profiles, a determination of protein profiles can provide useful information for understanding disease and designing therapy. Therefore, understanding the structure, metabolism, and function of proteins at the molecular (i.e., nanoscale) level is absolutely critical to our understanding of biological

Tissue engineering concept

The grafting of bone in skeletal reconstruction has become a common task of the orthopedic surgeon, with over 863 200 grafting procedures performed each year in the United States. For cartilage replacement, there are over 1000000 procedures of various types performed each year, and for ligament repairs, there are approximately 90000 procedures performed per year.1 Currently, autograft2,3 (tissue taken from the patient) and allograft4-6 (tissue taken from a cadaver) are the most common replacement sources for the treatment of musculoskeletal problems. In repair of anterior cruciate ligament injuries, a segment of the patellar tendon has frequently been used.3 For cartilage and bone repair, transplantation of autogenous grafts has been the current treatment of choice. Unfortunately, these gold standards possess certain disadvantages. For any type of autogenous tissue, the key limitations are donor site morbidity where the remaining tissue at the harvest site is damaged by removal of the...

And Nanoparticulate Matter

Similarly, inadvertent implants delivered to the lungs because of the retention of particles and microorganisms can initiate immune response in the lungs in terms of engulfment and degradation by alveolar macrophages and neutrophils. Respirable particles that resist degradation have a potential to form health hazards. Examples of such particles include asbestos, crystalline silica and silicon carbide whiskers.

Intracellular Uptake and Fate

Unless the nanoparticle carrying a chemotherapeutic agent can release it prior to the trafficking of these vesicles to destructive (lysosomal) pathways or it can avoid such a pathway once inside the cell, the effectiveness of the absorbed material may be dramatically reduced. Also, some new classes of anti-cancer agents have poor membrane permeability properties and would not readily leave the endosome after uptake. Furthermore, exposure of these materials to lysosomal environments would destroy their biological activity nucleic acid- or peptide protein-based therapeutics capable of marking a cancer cell for clearance by the immune system would be examples of this type of approach. In these cases, proper selection of the nanoparticle composition and characteristics allows these materials to escape the fate of this default uptake event. There are endogenous properties of some materials as well as the capacity to include specific intracellular targeting agents that can be matched with...

Techniques and Strategies

Any protein product designed to circulate through the body and perform some specific task on a certain class of cells must fulfill several criteria. It must first of all conform to a rigid set of specifications imposed by the body's immune system. It must also have some way of recognizing the target cells and, in some cases, some way of knowing when it has arrived at an appropriate location in the body. Foiling the Immune System The need to get past the immune system's detectors is a daunting requirement in view of that system's perpetual vigilance and almost devilish versatility. As we have learned more about the system's functioning, however, small chinks have begun to appear in its armor. Presumably these chinks will widen with further research, of which we can expect a considerable amount in the ten to twenty years that are likely to elapse before the first nanosurgical products appear. However, there is one surefire way to protect such a product from the immune system, even in...

Unique Class of Synthetic Polymers Dendrimers

Dendrimers have several advantages in drug delivery Dendrimers can hold a drug's molecules in their structure and deliver the drug to a particular part of the body such as a tumor. Dendrimers can enter cells easily and release drugs on target and don't trigger immune system responses.

How do nanotubes suppress T cells

Mice inhaling low levels of multiwalled carbon nanotubes show suppressed immune function. New studies suggest that this suppression originates from signals in the lungs. Previously, it was shown that MWNTs can suppress the immune system of mice when inhaled3. Following up on this study, on page 451 of this issue, Jacob McDonald and colleagues of the Lovelace Respiratory Research Institute in New Mexico report that this suppression originates from signals in the lung that turn on signals that directly affect the function of T cells in the spleen4. T cells are a class of white blood cells that coordinate the immune system to fight infections and diseases, and whether their suppression has long-term consequences remains unclear. The New Mexico team explored mechanistic aspects of the immune response by perturbing the cyclooxygenase-2 pathway a biochemical route to making compounds that are responsible for various inflammatory processes. By blocking the transmission of signals from the...

Evaluation of nanoparticle immunotoxicity

The pharmaceutical industry is developing increasing numbers of drugs and diagnostics based on nanoparticles, and evaluating the immune response to these diverse formulations has become a challenge for scientists and regulatory agencies alike. An international panel of scientists and representatives from various agencies and companies reviewed the limitations of current tests at a workshop held at the National Cancer Institute in Frederick, Maryland. This article outlines practical strategies for identifying and controlling interferences in common evaluation methods and the implications for regulation. As more nanoscale drugs and diagnostics are engineered to target the immune system (or to avoid interactions with it), it is increasingly important to understand the immune response to these nanoscale formulations. The challenge however, is that many nanoparticles can interfere with the assays traditionally used by immunologists, so it is necessary to develop new types of assays and or...

Science and Natural

Tradition of deliberate idea mutation, and a unique immune system for controlling the mutants. The results of evolution vary with the selective pressures applied, whether among test tube RNA molecules, insects, ideas, or machines. Hardware evolved for refrigeration differs from hardware evolved for transportation, hence refrigerators make very poor cars. In general, replicators evolved for A differ from those evolved for B. Memes are no exception.

In Vivo Characterization

In vivo studies must be conducted to better understand the safety and behavior of nanoparticles in a living organism. As with any new chemical entity (NCE), the nanoparticle formulations' pharmacological and toxicological properties (i.e., ADME Tox) need to be thoroughly characterized. In vivo studies should include examination of nanoparticles' effects on various organs and systems, such as the liver, heart, kidney, and immune system.

Holistic Approach to Problem Definition

A key element of this top-down approach is to consider the whole human being and not merely the immediate interface of nanobiotechnology with its target problem. The ability to view the needs in this area from a biomedical perspective that starts with the whole human and works down through organ and cellular levels to the molecular (nanoscale) level, will be an essential component of projects with successful outcomes in this field. There is little point in developing isolated, advanced technological systems or medical treatments to find that they solve one problem only to generate many others. For example, ingenious microdevices with nanoscale features that might patrol blood vessels or carry out tissue repairs have been suggested and designed (Moore 2001 Dario et al. 2000). However, there has been little detailed discussion or consideration at this stage regarding biocompatibility issues, particularly of the thrombogenicity (clot-forming potential) of these devices or of their...

Forces Energies and Kinetic Rates

Anibody-antigen interactions are of key importance for the function of the immune system. Their affinities are known to vary over orders of magnitudes. For single-molecule recognition AFM studies, the molecules were surface-coupled via flexible and distensible crosslinkers 16.4, 10, 13, 14 to provide them with sufficient motional freedom, so that problems of misorientation and steric hindrance that can obscure specific recognition are avoided. In 16.4,12 , the tips were functionalized with a low antibody density, so that on the average only a single antibody on the tip end could access the antigens on the surface. Hence, isolated single molecular antibody-antigen complexes could be examined. It was observed that the interaction sites of the two Fab fragments of the antibody (the antibody consists of two antigen-active Fab-fragments and one Fc-portion) are able to bind simultaneously and independently with equal binding probability. Single antibody-antigen binding events were also...

The Potential for Gene Therapy as a Validation Delivery Platform

On the other hand, the gain in gene-transfer efficiency associated with synthetic complexes must be balanced against the general lack of stability of polyplex and lipoplex vectors in vivo and the tendency of locally delivered cationic agents to cause tissue necrosis, which can be dramatic. Nonviral vectors are inefficient, and high doses may be required to achieve therapeutic effects. High-dose administration may be limited, however, by motifs in the vector backbone that stimulate the immune system (MacColl et al. 2001). While CpG-dependent immune stimulation is Thl-biased, SCID mice (Ballas, Rasmussen, and Krieg 1996) have shown increased levels of IFN- and IL-12 following plasmid-vector delivery (Klinman et al. 1996). Significantly, nonviral vector administration to animals has generated anti-DNA antibodies, leading to renal disease and premature death (Deng 1999). Relevant to the present application, Payette and colleagues (2001) recently showed that intramuscular delivery of a...

Existing FDA Regulations That Apply to Nanomaterial Containing Products

Within CDER, the preclinical requirements for approval to market pharmaceutical products include both short-term and long-term toxicity testing in rodent and non-rodent species. Specifically, the types of studies conducted by pharmaceutical manufacturers prior to New Drug Application (NDA) submission include pharmacology (mechanism of action), safety pharmacology (functional studies in various organ systems, most notably the cardiovascular system), absorption, distribution, metabolism, and excretion (ADME), genotoxicity (potential to cause mutations in both in vivo and in vitro assays), developmental toxicity (to assess effects on reproduction, fertility and lactation), irritation studies (to assess local irritation effects), immunotoxicology (to assess effects on the components of the immune system), carcinogenicity (to assess the capacity of drugs to induce tumors in animal models) and other possible studies (specific studies for a product being developed). The current battery of...

Breast Cancer and Nanoparticles

One preliminary plan includes using probes that inject special magnetic iron nanoparticles into a tumor and then heating the nano-particles. The nanoparticles destroy the cancer cells. In this probe, the magnetic iron nanoparticles, containing antibodies, are concealed in polymers. The polymers make the antibodies nearly invisible to the body's immune system. The reason for the polymer coating is that you do not want the antibodies to be attacked by the immune system. Inside the bloodstream, the antibodies go to work and attach themselves onto the surface of tumor cells. Then, outside the body, laboratory technicians apply a heat source to the magnetic particles in the tumor region of the body. By applying just the right amount of heat to the tumor region, the heated magnetic particles weaken and destroy the cancer cells.

Microbotics Nanoparticles Hitching a Ride on Bacteria

Areas of the world (at least where vaccines are available and affordable providing vaccines to many parts of the developing world still is one of the basic medical needs that is far from being met). The basic idea of vaccination is to inject weakened or killed forms of pathogens such as bacteria or viruses into the body in order for the immune system to develop antibodies against them. If the same types of microorganisms enter the body again, they will be recognized and destroyed by the antibodies.

Cleaning Up Organic Pollutants Using Nanotechnology

TCE can be absorbed through the lungs, mucous membranes, gastrointestinal tract, and the skin. Exposure to TCE happens mostly from breathing contaminated air and drinking contaminated water. Short-term exposure to high levels of this chemical can result in toxic effects on a number of organs and systems, including the liver, kidney, blood, skin, immune system, reproductive system, nervous system, and cardiovascular system. In humans, acute inhalation exposure to TCE causes central nervous system symptoms such as headache, dizziness, nausea, and unconsciousness. TCE has been linked to liver damage, impaired pregnancies, and cancer.

Binding Proteins and Peptides

Proteins that bind to various biological or inorganic molecules are useful in fabricating multiple-component biomolecular devices. The streptavidin-biotin protein-ligand system is probably the most used biomolecular adapter system in biotechnology, owing to the high affinity (> 1015 M_1) of biotin for streptavidin and its homolog avidin, the high specificity of the interaction, and the fact that both avidin and streptavidin are homotetrameric proteins with 222 point symmetry, which positions two pairs of biotin-binding sites on opposite faces of the (strept)avidin tetramer, so that they can be used for stepwise molecular assembly 104 . There are many other natural and engineered peptides (e.g., oligohistidine tag 105 , FLAG tag 106 , and S-tag 107 ) and proteins (e.g., maltose binding protein 108 , glutathione S-transferase 109,110 , and cellulose-binding domain 111,112 ) that have been developed as affinity tags in biotechnology, largely for the purification of recombinant...

Computers And Electronics

We learned in Chapters 9 and 10 that nanotechnology offers tons of possibilities for computing, electronics, sensors, and communications. Research in nanoscience and nanotechnologies has taken off in the last decade thanks to big chunks of governmental and industrial funding. But what happens if and when a more powerful, cost-effective computing architecture comes out of future nano labs How far will it go Some people think that nanotechnology can create nearly unimaginable computing power that will revolutionize medicine, energy, and transportation. It's even possible that the division between computing and human consciousness will narrow quite a bit. An implantable operating system (e.g., a souped-up immune system), for example, could even be on the far horizon.

Magnetic Drug Delivery

Further research interest in the use of targeted hybrid magnetic nanoparticles is in the field of gene therapy 219 . Gene therapy represents an exciting development in medical treatment 220 . The theory is that by insertion of plasmid DNA into target cells, it may be possible to rectify genetic disorders, and to produce therapeutic agents in the form of peptides and proteins to stimulate the immune system. Magnetofection is a method in which magnetic nanoparticles associated with a DNA vector are trans-fected into cells by the influence of an external magnetic field 221 .

Surface Modification to Alter Biodistribution

The potential of injectable polymeric drug carriers (nanoparticles) is compromised by their accumulation in the tissues of the mononuclear phagocytic system (MPS). Thus, the therapeutic efficacy of the drugs associated with the nanoparticles is limited to the treatment of several liver diseases.90,91 Long-circulating nanoparticles can be obtained by their surface modification with dysopsonic polymers such as PEG.92,93 Indeed, these hydrophilic and flexible polymers can prevent the opsonin-nanoparticle interaction, which is the first step of the recognition by the immune system. In the tumor-bearing animal models, these long-circulating nanoparticles would be able to extravasate thorough the endothelium, allowing drugs to concentrate in the tumors.94 Recently, it was shown that the synthesis of amphiphilic PEGylated polymers allows the direct preparation of PEG-coated nanoparticles, ensuring the stability of the PEG coating layer because the PEG chains remain chemically linked to the...

Nanoparticles in foods

TiO2 was previously classified as biologically inert but recent investigations of in vitro cellular studies, epidemiology and animal experimentation revealed that TiO2 in nanoparticle form possesses potent biological toxicity (as briefly reviewed by Rahman et al, 2002). It was particularly disturbing to find that inhaled ultrafine TiO2 caused severe inflammation, impaired macrophage function, pulmonary damage, fibrosis and lung tumours in rats. The activated alveolar macrophages produced large amounts of oxygen radicals, growth regulators and increased levels of interleukin mRNAs and induced micronuclei formation and cell apoptosis in in vitro studies. Ultrafine TiO2 particles were also shown to cause chromosomal damage and to be strongly genotoxic (Rahman et al, 2002). Because of the similarities between the lung and intestinal epithelial tissues and the sharing of a common mucosal immune system, it may not be farfetched to propose that, based on the precautionary principle, the use...

Tactics for the Assembler Breakthrough

Replicators have already become possible. Design-ahead can help the leading force prepare, yet even vigorous, foresighted action seems inadequate to prevent a time of danger. The reason is straightforward dangerous replicators will be far simpler to design than systems that can thwart them, just as a bacterium is far simpler than an immune system. We will need tactics for containing nanotechnology while we learn how to tame it.

In vivo human and animal reactivity of nanoparticles for the respiratory system and systemic consequences

Aimed at finding out the mechanisms and physiological and immunological consequences of the nanoparticle uptake of the organs, apart from the general observation that lungs will be inflamed owing to the activation of the immune system. However, there has also been some progress in this respect. Thus, it was recently shown that polluted air containing ultrafine particles may increase biomarkers of inflammation in the brain of intranasally, oval-bumin-sensitized mice (an asthmatic model), such as the proinflammatory cytokines interleukin 1 alpha and tumour necrosis factor alpha and raise the levels of immune-related transcription factor NF-kB (Campbell et al, 2005 Calderon-Garciduenas, Azzarelli et al, 2002).

Interactions of nanoparticles with isolated cells

A major component in some of the reactions and responses to nanoparticles is the activation of the immune system. In some instances this can include the activation of the alternative complement system. Some features of these in vitro reactions may also be relevant in vivo. Thus, it was shown that in serum exposed to nanoparticle carbon black, the alternative complement pathway became activated and chemotactic factors were generated by a mechanism

DNA Nanovaccines Using Nanocapsules and Ultrasound Methods

The USDA is completing trials on a system for mass vaccination offish in fishponds using ultrasound. Nanocapsules containing short strands of DNA are added to a fishpond where they are absorbed into the cells of the fish. Ultrasound is then used to rupture the capsules, releasing the DNA and eliciting an immune response from the fish. This technology has so far been tested on rainbow trout by Clear Springs Foods (Idaho, US) a major aquaculture company that produces about one-third of all U.S. farmed trout.

Delivery of Drugs and Vaccines Gene Therapy

Well-established coupling strategies can now be applied to covalently link the functional groups of the nanotubes with peptides, maleimide linkers (for subsequent attachment of proteins via cysteine units), or the like. It is possible, for instance, to immobilize viral proteins (e.g., of the virus causing foot-and -mouth desease) while conserving their immunological properties (Figure 3.111). Thus the nanotube acts as a carrier for antigenes and might also be employed as a vehicle for vaccines. Nanotubes possess an important advantage over the carrier proteins commonly used for this purpose It is true that the correct immune response to the antigene is evoked in both cases, and also that in a mouse model an immunity against the actual virus is generated, but to the nanotubes themselves, there is no immune response at all. Carrier proteins, on the other hand, give rise to such a reaction by inducing the formation of unspecific antibodies. In gene therapy, suitable nanotube conjugates...

Microchameleons Reaction Diffusion for Amplification and Sensing

Although modern technology, especially optoelectronics, has used nonlinear amplification as a basis for such important devices as lasers or power and frequency amplifiers, it has not been able to apply it as broadly and flexibly as biological systems do. Indeed, in biology the coupling between inherently nonlinear (bio) chemical kinetics and the transport of chemicals makes nonlinear amplification phenomena ubiquitous at virtually all length scales. On the level of macromole-cules, various ultrasensitive protein gene regulatory cascades1 play the role of developmental 'programs' and amplify molecular events into spatial and or temporal patterns up to cellular2 or even organism3,4 scales. In humoral immune response, B lymphocytes recognize and respond to new antigens by amplifying the production of antibodies that ultimately help destroy the foreign invader.5 In collections of microorganisms, cAMP signaling between the individual members of an ensemble translates amplifies into their...

Nanoscale Biostructures

Nanoscale Biostructure

One example of a nanoscale biostructure is provided by a self-assembling artificial bone, very recently developed in Stupp's group. Figure 5.2 shows the general notion the molecules that make up the bone are held together by chemical bonds. These molecules, in turn, have interactions among them that are weaker than true bonds (more like those that create surface tension in water), but that hold the molecules together with each other in a particular shape, in this case a cylinder. The molecules in the bone are designed to occupy space in a particular way so that they will assemble spontaneously to form the desired shape, and, once assembled, so that they will be packed densely enough for the bone to be very strong. The structure of packed molecules can be made compatible with the human immune system by properly choosing the head groups of the molecule, the groups of atoms that ultimately form the outer shell of the artificial bone template. The outer shell is also designed so that...

Monitoring Tissue Healing Through Nanosensors

Abstract Nanotechnology is the use of materials with at least one dimension less than 100 nm. Nanotechnology has already revolutionized numerous fields, from construction to computers. Recently, nanotechnology has also been used to improve disease detection and treatment by developing wireless in situ sensors. Importantly, the use of wireless technologies in medicine, such as wireless body area networks and wireless personal area networks, is not new as they provide many promising applications in medical monitoring systems to measure physiological data from specific anatomical areas. Nanotechnology can aid in the functioning of wireless medical devices since it can provide for materials smaller in size (thus, minimally interacting with tissues to invoke an immune response), better in properties (such as electronic), and more similar to those of natural tissues since natural tissues are composed of nano-scale entities. In fact, studies have demonstrated increased tissue growth,...

Nanowireassisted Gene Delivery

To test the potential utility of multifunctional nanowires for genetic immunization applications, an in vivo study was done to measure the immune response in mice to cutaneous delivery via gene gun bombardment of nanowires functionalized with the model antigen ovalbumin and a DNA plasmid that further stimulates the immune response 43 . Both a strong antibody response in the bloodstream and a strong CD8+ T-cell response in the spleen were observed. A comparison of the antibody response for the nanowires with that obtained using 1.6 m gold particles as the carriers is shown in Figure 1.18. These gold particles are the state of the art in inorganic carriers

The Cytoskeleton and Medicine

The pathway to understanding MT led through the disease gout, a painful swelling of joints caused by the body's response to accumulation of urate crystals. Lymphocytes and macrophages, the body's immune cells, leave the bloodstream and migrate by amoeboid locomotion towards the urate crystals which often lodge in a joint of the big toe. Gout may be precipitated by purine containing foods which are metabolized to urate. The urate crystals are not particularly harmful except for the painful inflammatory immune response they trigger. By luck, a drug called colchicine was found to be helpful in relieving the pain and tenderness. Later it was discovered that colchicine worked by depolymerizing microtubules and preventing the locomotion and engulfment behavior of the lymphocytes and macrophages.

Contributing to the Fight against Alzheimers

There is currently no cure for Alzheimer's disease, and its ultimate cause is still unknown. The disease affects millions of people around the world. Experts predict that this figure is expected to rise dramatically as the population, especially in developed countries, ages. Genetic factors are known to be important in causing the disease and dominant mutations in different genes have been identified that account for both early-onset and late-onset Alzheimer's. For a number of years, researchers have been working on alleviating neurodegenerative disorders such as Alzheimer's or Parkinson's disease through gene therapy. In this type of treatment, a gene's DNA is delivered to the neurons in individual cells, allowing them to produce their own therapeutic proteins. Gene therapy typically aims to supplement a defective mutant allele (the location of DNA codings on a chromosome) with a functional one. Currently, the most common carrier vehicles to deliver the therapeutic genes to the...

Drug Delivery Applications Of Nanogels

Recently, there has been significant interest in developing nonviral vectors for synthetic vaccines designed to prime the adaptive immune system that are sought for a broad range of infectious diseases and for the treatment of cancer in both prophylactic and therapeutic settings 250-252 . However, many obstacles associated with the successful delivery of synthetic vaccines remain such as antigen loading capacity, maintaining the integrity of encapsulated proteins, and minimizing the nonspecific antigen-antibody reaction. Therefore, the delivery system that can effectively carry the protein antigens to antigen-presenting cells is most desirable. The feasibility of achieving these goals has been demonstrated using submicron-sized hydrophilic particles, which were loaded with high doses of protein 253 .

Current Scenario of Bone Grafting

Allografting is another kind of bone grafting method, which can be defined as tissue transplantation between individuals of the same species but of nonidentical genetic composition. Lexer carried out the first clinical use of allograft in 1908 32 . The materials used as allografts are mostly cancellous, cortical, or a combination of each. The bone banks stock this type of grafts, which are usually harvested from cadavers. Typically, they are frozen or freeze-dried bones. However, after sterilization, most of them seem to lose much of their strength and, of course, they will not be resorbed absolutely after implantation therefore they often remain as dead tissue or act as a foreign body. The dead portion then gradually becomes brittle and gives further medical complications with surrounding tissues. The advantages of allografting are the elimination of harvesting a surgical site, the related postoperative pain, and the added expense of a second operative procedure. The disadvantages...

Implantable Drug Delivery

Nanoporous membranes are microfabricated with well-defined pores (diameters in the tens of nanometers). The membranes can be used to deliver small-molecule, peptide, or protein drugs (Figure 16-5). One application under investigation involves encapsulation of pancreatic islet cells for insulin delivery. The reproducible and uniform pore size precisely controls the material exchange across nanoporous membranes Nutrients for the cells and secreted insulin can pass through the pores, but proteins and cells from the immune system that may attack the implanted islet cells are restricted from entering the biocapsules due to their size.

Biomedical Properties 61 Introduction

Nanoparticles used in drug delivery are solid, colloidal particles consisting of macromolecular substances that vary in size from 10 to 1000 nm. The drug is dissolved, entrapped, adsorbed, attached, or encapsulated in the macromolecular materials. Nanoparticles, also called nanopellets or nano-capsules, can have a shell-like wall, called a nanosphere, or a polymer lattice. However, it is often difficult to determine whether nanoparticles have a shell-like wall or a continuous matrix. Nanocapsules present a liquid core surrounded by a polymeric shell, while so-called nanospheres consist of a dense polymeric matrix, in which the drug can be dispersed. Compared to other colloidal carriers, polymeric nanocapsules present a higher stability when in contact with biological fluids, and their polymeric nature allows one to obtain the desired controlled and sustained drug release. Nanocapsules represent drug delivery systems suitable for most of the administration routes, even if rapid...

Biosensors

Antibody Bioreceptors An antibody is a complex biomolecule, made up of hundreds of individual amino acids arranged in a highly ordered sequence. Antibodies are biological molecules that exhibit very specific binding capabilities for specific structures. For an immune response to be produced against a particular molecule, a certain molecular size and complexity are necessary proteins with molecular weights greater then 5000 Da are generally immunogenic. The way in which an antigen and its antigen-specific antibody interact may be understood as analogous to a lock and key fit, by which specific geometrical configurations of a unique key enables it to open a lock. In the same way, an antigen-specific antibody fits its unique antigen in a highly specific manner. This unique property of antibodies is the key to their usefulness in immunosensors where only the specific analyte of interest, the antigen, fits into the antibody binding site.

Of mice and men

When a foreign material enters the body, our immune system detects, isolates and destroys it in a number of ways. Some of these tasks are performed by specialized cells called macrophages, which engulf and neutralize the material in a process called phagocytosis, but if this fails, the foreign material can cause inflammation and other problems. The emergence of new properties in nanoparticles, which are not found in bulk materials, has led to numerous calls for further research into the toxicity of engineered nanomaterials, but the scale of the challenge is enormous. Recently it was estimated that it could take between 34 and 53 years, and cost between 249 million and 1.18 billion dollars, to perform toxicity tests on existing nanomaterials in just the United States1. Testing for toxicity involves a number of considerations the duration and route of exposure (which could be by inhalation, ingestion, injection or skin absorption), the dosage, the formulation of the test material, the...

Complicating Aspects

By their eponymous descriptor, nanoparticles have physical dimensions in the nanometer size scale similar to viruses and other materials that are either recognized by the body as pathogens or are elements associated with an infective event. Toll-like receptors (TLR) present on monocytes, leukocytes, and dendritic cells play a critical role in innate immunity with the capacity to recognize organized patterns present on viruses and bacteria.49 TLR proteins are present on the surface of cells in the lung, spleen, prostate, liver, and kidney. Because the patterned surfaces of nanoparticles can look like pathogen components recognized by TLR proteins such as DNA, RNA, and repeating proteins like flagellin, it is possible that a number of cell types might non-selectively interact with some nanoparticles. If such an interaction occurs, there are several potential outcomes that might produce complicating aspects for nanoparticle targeting to cancers. Nanoparticle materials might be...

Dan Garcia

Ho's group, Garcia conducted immunology research in the laboratory of Dr. Genhong Cheng. Garcia's work helped clarify the interaction between a novel protein, TRAF3-interacting JunN-terminal kinase (JNK)-activating modulator (T3JAM), and tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3), two proteins that play important roles in the CD40 signal transduction pathway. The CD40 signaling pathway plays a role in the adaptive immune response, atherosclerosis, and the body's response to transplants.

Selecting Ideas

Parasites have forced organisms to evolve immune systems, such as the enzymes that bacteria use to cut up invading viruses, or the roving white blood cells our bodies use to destroy bacteria. Parasitic memes have forced minds down a similar path, evolving meme systems that serve as mental immune systems. The oldest and simplest mental immune system simply commands believe the old, reject the new. Something like this system generally kept tribes from abandoning old, tested ways in favor of wild new notions such as the notion that obeying alleged ghostly orders to destroy all the tribe's cattle and grain would somehow bring forth a miraculous abundance of food and armies of ancestors to drive out foreigners. (This Your body's immune system follows a similar rule it generally accepts all the cell types present in early life and rejects new types such as potential cancer cells and invading bacteria, as foreign and dangerous. This simple reject-the-new system once worked well, yet in this...

Basic Immunology

Specific immune responses are directed to individual macromolecules or assemblages of them and can be cat egorized into cellular responses, mediated by cytotoxic T-lymphocytes (CTLs), and humeral responses, mediated by soluble proteins (found in blood serum and other biological fluids) secreted by B-cells (antibodies). Regardless of the effector (CTLs or antibodies), specific responses are directed to individual molecular features of antigens called epitopes. The three types of epitopes are cytotoxic T-cell (CTL) epitopes, helper T-cell epitopes, and B-cell epitopes. The first two types are peptides that must be presented on cell surfaces in the context of the class I (in the case of CTL epitopes for CTL responses) or class II (in the case of T-helper epitomes, involved in both antibody and CTL responses) major histocom-patibility complex (MHC) molecules. B-cell epitopes are a chemically and structurally heterogeneous group of epitopes and include synthetic molecules as well as...

Particulate Vaccines

The immune system, through dendritic cells (DCs), other antigen presenting cells (APCs), and immune effectors, performs ongoing surveillance for non-self antigens using the MHC antigen presentation system described above 10.1 . It has long been known that APCs sample serum for antigens that they process and present using the MHC class II pathway for antibody production 10.1 . Research of the last few years has shown that DCs, macrophages, and other APCs also take up partic-ulate materials and process and present the constituent peptide epitopes via the MHC class I pathway to trigger specific CTL responses. Previous dogma held that only endogenous antigens (such as those produced in virally infected cells) could be presented through the class I MHC pathway. Both soluble and particulate antigens can be presented via the class I pathway, but particulate antigens are orders of magnitude more potent than the same immunogens formulated in soluble form 10.125-128 .

Silicon Nanowires

When an individual virus connects with a receptor, it sparks an electrical change that announces its presence. Researchers have found that the detectors can even distinguish between several different viruses with great selectivity. Using nanowire sensors, physicians will soon be able detect viral infections at very early stages. The immune system would still be able to squash small virus populations, but for particularly dangerous viruses, medical intervention would be available long before the infection would normally be detected by traditional methods.

October 17 2000

Acquired Immune Deficiency Syndrome (AIDS) continues to exact an enormous toll throughout the world, in both human and economic terms. In the United States, an estimated 650 000 to 900 000 people are currently infected with HIV, of whom more than 200 000 are unaware of their infection. Through 1998 there were 688 200 cases of AIDS-related deaths reported to the Center for Disease Control and Prevention (CDC) in the United States. Despite enormous progress in the treatment of HIV, new drugs with unique modes of action are desperately needed. This is because of the rapid mutations

Immunotoxicity

Onset and development of various disorders, including cancer and autoimmune diseases.137-139 Nevertheless, it was not until recently that this relatively new field of toxicology emerged as an important interface between the fields of novel drug design and pharmacology. Recognition of immunosuppressive properties of new pharmaceuticals during early drug development phase is very important to eliminate potentially dangerous substances from the drug pipelines. For example, treatment of patients diagnosed with Crohn's disease and rheumatoid arthritis with inflix-imab and etanercept (both drugs represent neutralizing anti-TNF antibodies) resulted in increased incidence of tuberculosis and histoplasmosis.140-143 Although these data did not result in withdrawal of any of the products from the pharmaceutical market, they helped initiate the strategy of preparing patients for anti-TNF therapy by screening for, and treatment of, latent tuberculosis prior to administration of anti-TNF...

Immunogenicity

This issue of immune stimulation by pharmaceuticals came into the forefront when biotechnology-derived products, especially recombinant proteins, moved toward clinical trials. Today it is evident that the immune system can effectively recognize biological therapeutics as foreign substances and build up a multi-level immune response against them. A number of factors result in the immune system responding to the administration of a pharmacological product, such as structure, formulation, folding architecture, but also degradation byproducts.170 In addition, the route of administration and the dosage were shown to influence the staging and the amplitude of the immune system's response. In general, immune responses to biological products could be classified as benign in the sense that they affect only the pharmacological efficacy of the administered compound. The greatest concern is the robust immune response to certain biotechnology-derived products that are fraught with serious clinical...

Bioreceptors

The antigen-antibody (Ag-Ab) binding reaction, which is a key mechanism by which the immune system detects and eliminates foreign matter, provides the basis for specificity of immunoassays. Antibodies are complex biomolecules, made up of hundreds of individual amino acids arranged in a highly ordered sequence. Antibodies are produced by immune system cells when such cells are exposed to substances or molecules, which are called antigens. The antibodies appearing following antigen exposure have recognition binding sites for specific molecular structures (or substructures) of the antigen. The way in which an antigen and an antigen-specific antibody interact is analogous to a lock and key fit, in which specific configurations of a unique key enable it to open a lock. In the same way, an antigen-specific antibody fits its unique antigen in a highly specific manner, so that the three-dimensional structures of antigen and antibody molecules are complementary. Due to this three-dimensional...

Nanopores

Nanopores are essentially nanoparticles whose surface contains pores, which can be used for containing drugs. Uniformly spaced holes are created on the surface in which a drug molecule is contained. The pore size imposes a restriction on the size of the biomolecules present. This means that small molecules like oxygen, glucose, insulin, neurotransmitters, etc. can move across the pore surface while large immune system molecules like immunoglobulin cannot. The released molecule can therefore be used in disease treatment, e.g. the use of insulin in diabetes treatment, use of neurotransmitters in neural disorders, etc. (Refs 9, 10).

Labona Chip Diagnosis

Laboratory-on-a-chip technology for earlier and quicker diagnosis of a disease is being developed. Lab-on-a-chip has become possible because nanotechnology lets scientists manipulate extremely small materials, on the scale of atoms and molecules. The lab-on-a-chip is a miniaturized, portable version of a blood-count machine. The lab-on-a- chip can be designed for many applications. One example is that it could be a diagnostic tool for cancer detection by searching in blood plasma for certain molecules that could be early indicators of the disease. The handheld device also has advantages since it requires only a little sample of blood to analyze the blood chemistry of a patient. Analyzing the composition of blood is how doctors test for infections and deficiencies in the immune system.

Cell Targeting

As discussed in Chapter 7, buckyballs can be used to deliver a therapeutic drug to a specific target, minimizing side effects. They have been constructed into shapes that fit tightly into specific cell surface receptors. When treated with enzymes or proteins that disrupt a cell's reproductive cycle, buckyballs will serve as disease interceptors, similar to the human immune system. These nanotechnology

Domesticated Viruses

The capabilities of viruses may be harnessed (Scott, 1985). Two hundred years ago Edward Jenner began to develop safe and effective anti-viral vaccines, a technique which amplifies the body's immune system. Slopek and co-workers (1983) have treated patients afflicted with drug resistant bacterial infection by using viral bacteriophages selected for their effectiveness against the resistant organism. British scientists (Williams, Smith and Huggins, 1983) have used bacteriophages to treat intestinal infections in animals and direct use of viruses to combat bacterial infections in humans have also been attempted. Bacteriophages have potential advantages over modern drugs they are highly specific, can leave the host cells unharmed with minimal side effects, and could be produced inexpensively. However, bacteria could develop resistances to bacteriophages as they do to some drugs.

Delivery Systems

The mode of delivering a drug substance can have a tremendous impact on its efficacy. Key challenges for better clinical practice include maximizing the drug loading, stability in the bloodstream, specific targeting to deseased cells, circulation lifetime against the immune system, controlled release of drug molecules, and diffusion of drug molecules through cell membranes. A target delivery vehicle based on liposomes (Figure 14.16) is one system that can address these issues quite all together. It also shows how nanofabrication that is based on self-assembly principles can work to formulate delivery systems. For example, after the self-assembly of liposomes with drug substances, they can be further decorated with targeting agent, attached with channel protein for drug release, coated with polyethylene glycol (PEG) for stealth function, and stabilized with polymer-

In Vivo Studies

Nanoparticle use in cosmetics (especially sunscreen) is widespread, with the primary materials being nanoscale TiO2 and ZnO. The primary barrier to absorption through the skin is physical the outer layer of the epidermis, which contains mostly dead skin cells. There is less information about dermal toxicity nanoparticles than about other types, and specific skin conditions may affect greatly the penetration of nanoparticles however, the primary toxic mechanism appears to be generation of ROS. Whether the nanoparticles penetrate the epidermis depends on a number of factors. Movement of the skin or damaged skin can allow the penetration of microscale beads to the dermis and may allow movement to regional lymph nodes, where chemical reactions with proteins can affect the autoimmune system 96,97 . There is evidence that submicron particles penetrate the skin shallowly and may penetrate more deeply via hair follicles 98,99 . Smaller particles may penetrate far...

The Debate Heats Up

I would point out to Smalley that earlier critics also expressed skepticism that either world-wide communication networks or software viruses that would spread across them were feasible. Today, we have both the benefits and the vulnerabilities from these capabilities. However, along with the danger of software viruses has emerged a technological immune system. We are obtaining far more gain than harm from this latest example of intertwined promise and peril.

Biodefenses

A totally different field that has received some attention lately, but probably not enough, is the area of edible vaccines.4 Synthetically coding for receptor sites on the protein coats of pathogens, and then inserting these DNA strings into a plant genome has produced interesting early results. Workers at the Boyce-Thompson Plant Research Institute at Cornell, in collaboration with researchers at Baylor University, have found immune response in human subjects generated by eating the potatoes that result from such genetic manipulation. Since we have experienced such difficulties in producing a vaccine in large quantity just for anthrax, a totally different path might be in order. Side effects should be minimized by this technique. One could even imagine, eventually, a cocktail, a V-8, of tomatoes, bananas, or some other food, bred to protect against a variety of pathogens. The doses could be easily distributed and delivered, and, in remote or poor areas, would need a minimum of...

The Practical Need

Biology has followed an observational and reductionistic approach of accumulating large bodies of information about the parts of biological systems and looking for interpretations of system behavior in terms of these parts. It has become increasingly clear that biological systems are intricate, spatially structured, biochemically based networks. The role of information in biological action and the relationships of structure and function are only beginning to be probed by mathematicians, physicists, and engineers who are interested in biological systems as systems designed by nature for their functional capabilities. While biologists are increasingly looking to mathematical approaches and perspectives developed in physics and engineering, engineers are increasingly looking to biological systems for inspiration in designing artificial systems. Underlying these systems are a wealth of design principles in areas that include the biochemical networks (Gallagher and Appenzeller 1999 Service...

Virosomes

A key issue in the development of second-generation vaccines involves targeting and delivery of antigens to antigen-presenting cells (APCs). Remarkable advances have been achieved in vaccine preparation techniques and among them, virus-mimicking nanoparticles (virosomes) have demonstrated potency in eliciting immune responses while minimizing side effects. reconstituted viral envelopes mimic the outer surface of a virus, virosomes can be used for mild induction of antibody responses against a native virus (for example, influenza virosomes can be used as a flu vaccine). Antigen delivery using virosomes is efficient enough to elicit a measurable immune response, and this approach has been developed into two commercially available vaccines Epaxal for hepatitis A and Inflexal V for influenza from Berna Biotech in 1994 and 1999, respectively. The incorporation of cationic lipids has been the main approach to entrap DNA. Many cationic lipids have been used successfully, and the two most...