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How does human body deal with inert solid material in the bloodstream? For example, if there is a powder of glass injected into our bloodstream, will the white blood cells do anything or will kidney excrete these materials? Thanks.
Non-opsonized particles (Particles that can't be coated with opsonins like antibodies or complement proteins) can be engulfed by macrophages which could end up, for example, in the lung secretions and be coughed up one day. Note that a cell can only engulf a particle so large, so you'll not feel yourself coughing up anything out of the ordinary. Only tiny particles can be dealt with like this. Bigger particles can become trapped in fine vasculature (small veins; venules, and small arteries;arterioles). This can lead to abscess formation necessitating amputation of the affected limb.
Human Body Diagram
The human body is one complex network, universally accepted as the most intriguing construct. It is certainly the most widely studied structure the world over. Undermentioned are little- and well-known facts about the human body.
The human body is one complex network, universally accepted as the most intriguing construct. It is certainly the most widely studied structure the world over. Undermentioned are little- and well-known facts about the human body.
A vast array of aspects concerning the human body have been comprehended however, there are facets that await a treatment for thorough analysis. The head, neck, torso, a pair of arms and legs, respectively constitute the external view of the body, often described as the superficial, first-layer of the human body. However, internally, the structure is far complex and intricate. Know that there are 11 organ systems of the body: Circulatory System, Respiratory System, Immune System, Skeletal System, Excretory System, Urinary System, Muscular System, Endocrine System, Digestive System, Nervous System, and Reproductive System.
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The human head consists of the brain, a pair of eyes and ears, a nose and mouth, all of which help in various sensory functions, such as the ability to process thought, see, hear, smell, and taste.
Did You Know…
☛ The human eye has the ability to differentiate between 400+ shades of gray, and what’s more, it can identify approximately 10 million colors.
☛ Your ears never sleep. Sound is received even while you are asleep it’s the brain that does not process them.
☛ Our noses and ears continue to grow because of gravity (starts to droop/sag) and cartilage (which continues to grow as we age).
☛ Your taste buds are not only present on your tongue the palate and your throat passage, have taste buds too.
☛ Every day, the number of thoughts that human beings process are roughly estimated to be 70,000.
The neck is the junction between the head and the torso. It has been derived from the Latin word “cervical” which means “of the neck.” Our spinal cord has 33 small bones, which are called the vertebrae. Out of the 33, 7 bones are located in the neck region, known as the cervical curve.
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Did You Know …
☛ A free bone, indeed the hyoid bone (lingual bone) located below the Adam’s apple, is the only bone not attached to the human skeleton.
The human torso is also known as the ‘trunk’. It is the central part of the body, and it is from here that the neck and the limbs extend. Some of the most critical human body organs are situated within the torso. The upper part consists of the heart and the lungs these are protected by the rib cage. The middle region or the abdominal area consists mainly of organs which help in digestion. It has the liver, the large and the small intestine, the anus from where fecal waste is excreted, and the rectum where the feces is stored.
Then you have the gallbladder which stores bile produced by the liver, and concentrates it to produce chyme. Then there is the ureter, from where urine is passed to the urinary bladder and stored the urethra expels urine. Finally, comes the third part of the torso, the pelvic region. This has the male and female reproductive organs. The torso of the human body also consists of the major muscles of our body the pectoral muscles, the abdominal muscles, and the lateral muscle.
Did You Know…
☛ While the size of the human head right from birth won’t change drastically, it is the torso and the lower limbs that grow in length.
Of the two pairs of limbs that we have, our arms form the upper limbs, also known as forelimbs. In anatomical terms, the word ‘arms’ indicates the segment between the shoulder and the elbow, while ‘forearm’ is the segment between the elbow and the wrist. However, the term commonly refers to the entire limb, starting from the shoulder to the wrist. The arms help us perform a variety of tasks in a day.
Did You Know…
☛ When you wave your wrist, all the bones of your arm are at work.
The legs are also known as the lower limbs, and they help us bear the weight of the entire body besides facilitating movement.
Did You Know…
☛ The femur bone, also known as the thigh bone, is the longest bone in the body. It is deemed far stronger than concrete!
The brain aids us to think, comprehend, and create. Marked by folds that meander through the surface area of the brain, the signals in the form of information, are passed from the brain as they navigate through the spinal cord, and then transported to other parts of the body. Know that the brain has four sections: the cerebrum, cerebellum, diencephalon, and brain stem.
Regarded as the most vital organ of the respiratory system, a pair of lungs is located inside the chest, their primary function being the release of oxygen into the blood and extricating carbon dioxide from the blood. The trachea – also known as the windpipe – serves as the passageway for inhalation. When oxygen passes through the trachea into the lungs, it goes through tiny air sacs called alveoli. As oxygen penetrates the alveoli, the carbon dioxide is extricated from the blood as we exhale.
❒ Know This (?)
As astounding as it may sound, the lungs consist of over 300,000 capillaries. If they stretched into a line, placed end to end, the distance they would cover would be approximately 2400 km!
The heart is the most active muscular organ, residing marginally on the left section of the body that tirelessly supplies blood to the entire system. The heart pumps and circulates blood through the body, following a contraction-relaxation cycle. Blood is carried throughout the body through the capillaries, while the coronary arteries supply blood to the heart.
❒ Know This (?)
The heart can beat all by itself even after being separated from the body. The heart possesses its own electric impulse that causes it to function without the body, provided that it receives a constant supply of oxygen.
An important organ of the digestive system, the liver is located below the diaphragm and to the right of the stomach. The major function of the liver is to process and store substances ingested through the mouth, and those that we inhale and absorb via the epidermal layers. It essays an essential role in extricating matter that can be potentially toxic.
❒ Know This (?)
The liver is a very hardworking organ that filters more than a liter of blood per minute.
The stomach is another vital organ of the digestive system. The substances ingested will pass the esophagus and lead its way into the stomach. The stomach stores food for a short period while the lining releases hydrochloric acid to facilitate the break down of food. The digestive acid it secretes is very strong and thus kills the bacteria that may cause damage to the lining of the stomach. It is protected from the harmful effects of the acid, by a mucosal substance that lines the abdominal cavity. The process reduces solid food into soft, mush-like matter which is then transported to the small intestine, that continues the process of digestion.
❒ Know This (?)
A new stomach lining is formed within a period of three to four days. Why? Well, know that the digestive acids produced in the stomach are so strong, that they might as well burn a hole, quite literally, through your stomach wall.
The spleen is an organ that helps fight infection and balances bodily fluids. It cleanses the blood of bacteria and other harmful substances that may pose a threat to the smooth functioning of the entire system. The spleen also functions as the exterminator of toxicities along with unhealthy red blood cells.
❒ Know This (?)
In Ancient Greece, it was believed that the body consisted of fluids that may adversely affect an individual’s mood. The spleen was held responsible for making people feel sad or what was known as melancholia. It was believed that the spleen produced a black-colored fluid which interfered with the normal functioning of the system.
The pancreas is an organ located above the small intestine. It secretes digestive juices into the duodenum and aids in efficient digestion. Besides, it also controls sugar levels in the blood.
❒ Know This (?)
Researchers suggest that the pancreas consists of taste receptors that can identify sweet substances.
The gallbladder resides under the liver and collects bile produced in the liver. It releases the bile after extracting water content from it into the small intestine, to facilitate the breakdown of fat and protein ingested through the food we consume.
❒ Know This (?)
The gallbladder mimics the mechanism of a balloon. Before a meal, the gallbladder enlarges itself with bile. The bile is released into the small intestine to digest fat and protein this extraction of bile leads the gallbladder to deflate.
Located toward the rear of the body, the kidneys are a pair of organs that cleanse blood and regulate water levels in the body. The primary function of the kidney is to extract water accompanied with other constituents from the blood. Waste matter is extricated from the system in the form of urine. Besides, the kidneys are also responsible for filtering blood and regulating blood pressure.
❒ Know This (?)
Healthy kidneys work toward filtering approximately two gallons of blood every hour.
The bladder holds liquid waste matter — the urine. When the bladder starts to inflate, it triggers a signal to the brain indicating that its capacity is exhausted, and it needs to be relieved. The urine travels from the bladder through a tube called the urethra to be extricated from the body.
❒ Know This (?)
The urethra of a female’s is shorter, i.e., approximately 2.5 cm whereas, in men, the passage is approximately 15 cm.
The small intestine is a coiled organ where food passes through, beginning from the duodenum where the food intermixes with bile to facilitate the break down of fat and protein. The intestine is lined with microvilli they are tiny projections that help in the absorption of nutrients from the food ingested.
❒ Know This (?)
The length of the small intestine is 18 to 23 feet, and is longer than the large intestine. It’s diametrically smaller than the large intestine this is precisely the reason why the small intestine is regarded as “small.”
The large intestine constitutes the cecum and the colon. As the break down of food is a process conducted in the small intestine, the role of the large intestine is to absorb water and minerals, and process the remains of the digested food into fecal matter.
❒ Know This (?)
The large intestine houses more than 700 species of bacteria. They are a source of vitamins and are deemed essential for the body.
The appendix is a small, finger-like structure, attached to the large intestine. Thought to be useless, it is an organ much speculated for its role in the human body.
❒ Know This (?)
As mentioned, the appendix performs no apparent function in the human body. However, researchers are of the opinion that the appendix is a rather useful organ to deal with certain issues, with regard to digestion. Besides, researchers suspect that the appendix may save you from pernicious infections as well.
The uterus – also known as the womb – is a pear-shaped organ. The cervix forms the lower section of the uterus, that opens into the vagina. The other major section of the uterus is regarded as the corpus, and serves as an expandable vessel that has the capacity to hold a growing fetus. The uterus has two oval-shaped glands on either of its sides, known as the ovaries.
❒ Know This (?)
The uterus is 2 to 3 cm thick, while in length it is 6 to 8 cm, approximately.
The testes is the male gonad this being a part of the reproductive system. The function of the testes is to produce sperm and testosterone. The penis is a sexual organ, functioning as the passageway to pass urine and ejaculate
❒ Know This (?)
If the testes ache or have a dull pain in the vicinity, it is due to the prostate swelling with excess fluid. This is known as prostatic congestion.
Arranged here are ten body parts that surprisingly, you can live without.
The human body is marked by its structural complexity, and maintaining health with the right foods is of paramount importance. However, besides eating right, it’s eating smart that gains a stronger foothold in the health department. It is found that there are certain foods that share an uncanny resemblance with the parts of the human body, thereby deemed effective in maintaining the specific part of the body, too. Thus, in order to keep your body and mind healthy, undermentioned are foods that help maintain them.
Walnuts ⇆ Brain
Now this nut is a give away for sure. Walnuts, pound for pound, resemble the human brain. The folds and crevices, too, of the brain are mimicked perfectly by nature. Rich in omega-3 fatty acids, regular consumption of this nut facilitates the functions of the brain.
Carrots ⇆ Eyes
Health care providers perpetually recommend to nibble on carrots to keep your eyes healthy and active. Besides its befitting benefits, you must notice the radial pattern when the carrot is sliced diametrically. Get closer, and you are sure to find a striking resemblance between the human eye and the carrot slice. The pattern created looks like the pupil and iris. The most important component — beta-carotene — is potent in reducing the risk of cataracts.
Mushroom ⇆ Ears
Slice open a mushroom, and you’ll that it looks like the ears. You must know that mushrooms contain vitamin D in abundance which is deemed essential for effective hearing. Vitamin D is also essential in maintaining bone health in the ears, which include the malleus, incus, and strapes that aid in receiving sounds and transmitting the same to the brain.
Orange ⇆ Breasts
The relation between oranges and breasts may go well beyond the obvious factor of resemblance. Oranges and grapefruits, too, maintain breast health and facilitate the movement of lymph in the breasts. Besides, grapefruits have a component called limonoids that help in reducing the risk of developing breast cancer.
Tomato ⇆ Heart
Tomatoes look like the heart. It is red and when sliced into halves, it generally has four chambers — characteristics that resemble the heart. Tomatoes are known to be high in lycopene — a plant chemical that protects the heart and reduces its risks of succumbing to a cardiac arrest.
Ginger ⇆ Stomach
Ginger root is one spice that more or less resembles the stomach. Besides being added to enhance flavors of your dish, ginger also aids in effective digestion.
Kidney Beans ⇆ Kidneys
There is no doubt that kidney beans look like kidneys. They help to facilitate the smooth functioning of the kidneys.
Sweet Potato ⇆ Pancreas
A look at the sweet potato and it tells you what it’s meant for. Bearing resemblance to the pancreas, sweet potatoes are rich in beta-carotene that helps prevent the adverse effects of aging on the tissues of the body. Besides, it is also known to maintain one’s glycemic index, thus aiding those with diabetes.
Celery ⇆ Bones
Celery is one food that concentrates on bone density. Bones are known to consist of 23% sodium and coincidentally celery, too, contains 23% sodium.
Avocados ⇆ Uterus
Avocados along with pears, have an appearance that is strikingly similar to the womb and cervix of the female body. Besides, it corrects hormone imbalance and reduces the risk of succumbing to cervical cancer.
Clams ⇆ Testes
Rich in zinc and folic acid, clams resemble the testicles. It is known to improve the quality of semen in men.
These diagrams help you learn the basics and understand the human body better. Click on the images if you wish to have them printed.
AP Biology Final
For each property, identify and define the property and explain it in terms of the physical/chemical nature of water.
"Relative Amounts of Organelles in Three Cell Types"
Cell Type. Smooth ER. Rough ER. Mitochondria. Chloroplast. Golgi Bodies
A. Large Amount. Small Amt. Small #. Absent. Small Amt
B. Small Amt. Large Amt. Small #. Absent. Large Amt
C. Small Amt. Small Amt. Small #. Large Amt Small Amt
TIME (Sec). NaCl (mg/L)
Rect. solid. Length. Height. Width. SA. V. SA-V Ratio
1. 2.00 1 1 10 2 5
2. 2.67 .5 1.5 12.18 2 6.08
3. 4.00 .25 2 19 2 9.50
4. 6.05 .13 2.65 34.24 2 17.09
5. 10.68. .06. 3. 65.79. 2 32.85
FH is associated with a loss-of-function mutation of a gene that encodes LDL receptors in liver cells. Individuals who are heterozygous produce lower than normal amounts of the LDL receptors and individuals who are homozygous for the mutant allele have no LDL receptor function
Gray body, long wings ———— 42
Black body, apterous wings —- 41
Gray body, apterous wings —- 9
Black body, long winds ———— 8
|All others||< 0.1||< 0.3|
Almost 99% of the mass of the human body is made up of six elements: oxygen, carbon, hydrogen, nitrogen, calcium, and phosphorus. Only about 0.85% is composed of another five elements: potassium, sulfur, sodium, chlorine, and magnesium. All 11 are necessary for life. The remaining elements are trace elements, of which more than a dozen are thought on the basis of good evidence to be necessary for life.  All of the mass of the trace elements put together (less than 10 grams for a human body) do not add up to the body mass of magnesium, the least common of the 11 non-trace elements.
Other elements Edit
Not all elements which are found in the human body in trace quantities play a role in life. Some of these elements are thought to be simple common contaminants without function (examples: caesium, titanium), while many others are thought to be active toxins, depending on amount (cadmium, mercury, lead, radioactives). In humans, arsenic is toxic, and its levels in foods and dietary supplements are closely monitored to reduce or eliminate its intake. 
Some elements (silicon, boron, nickel, vanadium) are probably needed by mammals also, but in far smaller doses. Bromine is used abundantly by some (though not all) lower [ clarification needed ] organisms, and opportunistically in eosinophils in humans. One study has indicated bromine to be necessary to collagen IV synthesis in humans.  Fluorine is used by a number of plants to manufacture toxins (see that element) but in humans only functions as a local (topical) hardening agent in tooth enamel, and not in an essential biological role. 
Elemental composition list Edit
The average 70 kg (150 lb) adult human body contains approximately 7 × 10 27 atoms and contains at least detectable traces of 60 chemical elements.  About 29 of these elements are thought to play an active positive role in life and health in humans. 
The relative amounts of each element vary by individual, mainly due to differences in the proportion of fat, muscle and bone in their body. Persons with more fat will have a higher proportion of carbon and a lower proportion of most other elements (the proportion of hydrogen will be about the same). The numbers in the table are averages of different numbers reported by different references.
The adult human body averages
53% water.  This varies substantially by age, sex, and adiposity. In a large sample of adults of all ages and both sexes, the figure for water fraction by weight was found to be 48 ±6% for females and 58 ±8% water for males.  Water is
67% hydrogen by atomic percent, and these numbers along with the complementary % numbers for oxygen in water, are the largest contributors to overall mass and atomic composition figures. Because of water content, the human body contains more oxygen by mass than any other element, but more hydrogen by atom-fraction than any element.
The elements listed below as "Essential in humans" are those listed by the (US) Food and Drug Administration as essential nutrients,  as well as six additional elements: oxygen, carbon, hydrogen, and nitrogen (the fundamental building blocks of life on Earth), sulfur (essential to all cells) and cobalt (a necessary component of vitamin B12). Elements listed as "Possibly" or "Probably" essential are those cited by the National Research Council (United States) as beneficial to human health and possibly or probably essential. 
Of the 94 naturally occurring chemical elements, 61 are listed in the table above. Of the remaining 33, it is not known how many occur in the human body.
Most of the elements needed for life are relatively common in the Earth's crust. Aluminium, the third most common element in the Earth's crust (after oxygen and silicon), serves no function in living cells, but is toxic in large amounts, depending on its physical and chemical forms and magnitude, duration, frequency of exposure, and how it was absorbed by the human body.  Transferrins can bind aluminium. 
Periodic table Edit
The composition of the human body expressed in terms of chemicals:
The composition of the human body can be viewed on an atomic and molecular scale as shown in this article.
The estimated gross molecular contents of a typical 20-micrometre human cell is as follows: 
|Molecule||Percent of Mass||Mol.Weight (daltons)||Molecules||Percent of Molecules|
|Water||65||18||1.74 × 10 14||98.73|
|Other Inorganics||1.5||N/A||1.31 × 10 12||0.74|
|Lipids||12||N/A||8.4 × 10 11||0.475|
|Other Organics||0.4||N/A||7.7 × 10 10||0.044|
|Protein||20||N/A||1.9 × 10 10||0.011|
|RNA||1.0||N/A||5 × 10 7||3 × 10 −5|
|DNA||0.1||1 × 10 11||46*||3 × 10 −11|
|Cell type||% mass||% cell count|
|Erythrocytes (red blood cells)||4.2||85.0|
|Adipocytes (fat cells)||18.6||0.2|
Body composition can also be expressed in terms of various types of material, such as:
Composition by cell type Edit
There are many species of bacteria and other microorganisms that live on or inside the healthy human body. In fact, there are roughly as many microbial as human cells in the human body by number.     (much less by mass or volume). Some of these symbionts are necessary for our health. Those that neither help nor harm humans are called commensal organisms.
How is Chronic Kidney Disease Detected?
Early detection and treatment of chronic kidney disease are the keys to keeping kidney disease from progressing to kidney failure. Some simple tests can be done to detect early kidney disease. They are:
- A test for protein in the urine. Albumin to Creatinine Ratio (ACR), estimates the amount of a albumin that is in your urine. An excess amount of protein in your urine may mean your kidney's filtering units have been damaged by disease. One positive result could be due to fever or heavy exercise, so your doctor will want to confirm your test over several weeks.
- A test for blood creatinine. Your doctor should use your results, along with your age, race, gender and other factors, to calculate your glomerular filtration rate (GFR). Your GFR tells how much kidney function you have. To access the GFR calculator, click here.
It is especially important that people who have an increased risk for chronic kidney disease have these tests. You may have an increased risk for kidney disease if you:
- are older
- have diabetes
- have high blood pressure
- have a family member who has chronic kidney disease
- are an African American, Hispanic American, Asians and Pacific Islander or American Indian.
If you are in one of these groups or think you may have an increased risk for kidney disease, ask your doctor about getting tested.
Food's Journey Through the Digestive System
The mouth is the beginning of the digestive system, and, in fact, digestion starts here before you even take the first bite of a meal. The smell of food triggers the salivary glands in your mouth to secrete saliva, causing your mouth to water. When you actually taste the food, saliva increases.
Once you start chewing and breaking the food down into pieces small enough to be digested, other mechanisms come into play. More saliva is produced. It contains substances including enzymes that begin the process of breaking down food into a form your body can absorb and use. Chew your food more -- it also helps with your digestion.
Stop 2: The Pharynx and Esophagus
Also called the throat, the pharynx is the portion of the digestive tract that receives the food from your mouth. Branching off the pharynx is the esophagus, which carries food to the stomach, and the trachea or windpipe, which carries air to the lungs.
The act of swallowing takes place in the pharynx partly as a reflex and partly under voluntary control. The tongue and soft palate -- the soft part of the roof of the mouth -- push food into the pharynx, which closes off the trachea. The food then enters the esophagus.
The esophagus is a muscular tube extending from the pharynx and behind the trachea to the stomach. Food is pushed through the esophagus and into the stomach by means of a series of contractions called peristalsis.
Just before the opening to the stomach is an important ring-shaped muscle called the lower esophageal sphincter (LES). This sphincter opens to let food pass into the stomach and closes to keep it there. If your LES doesn't work properly, you may suffer from a condition called GERD, or reflux, which causes heartburn and regurgitation (the feeling of food coming back up).
Stop 3: The Stomach and Small Intestine
The stomach is a sac-like organ with strong muscular walls. In addition to holding food, it serves as the mixer and grinder of food. The stomach secretes acid and powerful enzymes that continue the process of breaking the food down and changing it to a consistency of liquid or paste. From there, food moves to the small intestine. Between meals, the non-liquefiable remnants are released from the stomach and ushered through the rest of the intestines to be eliminated.
Made up of three segments -- the duodenum, jejunum, and ileum -- the small intestine also breaks down food using enzymes released by the pancreas and bile from the liver. The small intestine is the 'work horse' of digestion, as this is where most nutrients are absorbed. Peristalsis is also at work in this organ, moving food through and mixing it up with the digestive secretions from the pancreas and liver, including bile. The duodenum is largely responsible for the continuing breakdown process, with the jejunum and ileum being mainly responsible for absorption of nutrients into the bloodstream.
A more technical name for this part of the process is "motility," because it involves moving or emptying food particles from one part to the next. This process is highly dependent on the activity of a large network of nerves, hormones, and muscles. Problems with any of these components can cause a variety of conditions.
While food is in the small intestine, nutrients are absorbed through the walls and into the bloodstream. What's leftover (the waste) moves into the large intestine (large bowel or colon).
Everything above the large intestine is called the upper GI tract. Everything below is the lower GI tract
Stop 4: The Colon, Rectum, and Anus
The colon (large intestine) is a five- to seven -foot -long muscular tube that connects the small intestine to the rectum. It is made up of the cecum, the ascending (right) colon, the transverse (across) colon, the descending (left) colon and the sigmoid colon, which connects to the rectum. The appendix is a small tube attached to the ascending colon. The large intestine is a highly specialized organ that is responsible for processing waste so that defecation (excretion of waste) is easy and convenient.
Stool, or waste left over from the digestive process, passes through the colon by means of peristalsis, first in a liquid state and ultimately in solid form. As stool passes through the colon, any remaining water is absorbed. Stool is stored in the sigmoid (S-shaped) colon until a "mass movement" empties it into the rectum, usually once or twice a day.
It normally takes about 36 hours for stool to get through the colon. The stool itself is mostly food debris and bacteria. These bacteria perform several useful functions, such as synthesizing various vitamins, processing waste products and food particles, and protecting against harmful bacteria. When the descending colon becomes full of stool, it empties its contents into the rectum to begin the process of elimination.
The rectum is an eight-inch chamber that connects the colon to the anus. The rectum:
- Receives stool from the colon
- Lets the person know there is stool to be evacuated
- Holds the stool until evacuation happens
When anything (gas or stool) comes into the rectum, sensors send a message to the brain. The brain then decides if the rectal contents can be released or not. If they can, the sphincters relax and the rectum contracts, expelling its contents. If the contents cannot be expelled, the sphincters contract and the rectum accommodates so that the sensation temporarily goes away.
The anus is the last part of the digestive tract. It consists of the muscles that line the pelvis (pelvic floor muscles) and two other muscles called anal sphincters (internal and external).
The pelvic floor muscle creates an angle between the rectum and the anus that stops stool from coming out when it is not supposed to. The anal sphincters provide fine control of stool. The internal sphincter is always tight, except when stool enters the rectum. It keeps us continent (not releasing stool) when we are asleep or otherwise unaware of the presence of stool. When we get an urge to defecate (go to the bathroom), we rely on our external sphincter to keep the stool in until we can get to the toilet.
Multiple Sugar Carbohydrates
Complex carbohydrates contain multiple sugar chains including polysaccharides like starch or oligosaccharides, which are high in fiber and indigestible. When you eat wheat bread or oatmeal, the sugar in the food breaks down into a single molecule dispersed as glucose into your bloodstream, but these types of foods also contain a high amount of indigestible fiber. Essentially, the sugar is digested the same way because it is turned into a monosaccharide before conversion to glucose. However, the complex carbohydrate-containing food has additional nutrients your body uses in the digestive process.
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Components of Blood
There are several major components of the seemingly uniform liquid that is our blood. When centrifuged, the components of different densities separate to look something like this:
Here we will discuss the most vital components of blood, including serum, white blood cells or “leukocytes,” red blood cells, and platelets.
Plasma is the liquid which carries the red blood cells, white blood cells, platelets, and other substances found in blood. More than half the volume of our blood is composed of this fluid.
Our blood plasma is mostly water, but it also contains salts proteins, and other substances, which can make it appear thick and syrupy even when the red and white cells have been filtered out.
One important protein, albumin, exists in part to keep the blood thick and syrupy. This ensures that the blood does not leak out of our vessels and into tissues, and slows bleeding when we are injured.
Other substances that can be found in the plasma include:
- Antibodies, which are proteins that attack invading pathogens
- Clotting factors, which prevent bleeding
- Hormones, which are chemical messages sent between different tissues in the body
- Electrolytes such as salt
- Nutrients such as sugar, vitamins, and minerals
- Lipids including cholesterol
So even this seemingly simple fluid is a veritable stew of the ingredients for life! But it could not do its job without…
Red Blood Cells
Red blood cells can be thought of as the cargo ships of the body. They are small, numerous cells which are specifically designed to carry oxygen from the lungs to cells, and carry carbon dioxide back to the lungs to be expelled when we exhale.
Red blood cells contain hemoglobin – a protein which is beautifully tailored to bind aggressively to oxygen in the lungs, and then release it and pick up carbon dioxide at a slow, steady rate as it passes through the body.
Hemoglobin is a pigment which changes color slightly, depending on whether it is bound to a molecule of oxygen or not. That’s why blood drawn from veins, which carry oxygen-depleted blood back toward the lungs, is a dark red that can appear almost brown. Blood drawn from arteries, which carry oxygen-rich blood from the lungs to the tissues, is a bright red.
White Blood Cells
White blood cells perform both immune and clean-up functions for the body. Like red blood cells, they are made by stem cells in the bone marrow.
There are many types of white blood cells, which play many different roles in immune response to infection and injury. Some types of white blood cells include:
- Neutrophils – Target bacteria and fungi.
- Eosinophils – Target larger parasites such as those which cause malaria. Also play a role in allergic inflammatory responses.
- Basophils – Release chemicals that enhance inflammatory responses.
- B Lymphocytes – Release antibodies and assist in activating T cell lymphocytes.
- T Lymphocytes – Different subtypes help the immune system learn to “recognize” new infection so it can target it help immune system to activate in response to infection, then return to normal after infection has passed target virus-infected and tumor cells.
- Natural Killer Lymphocytes – Target virus-infected and tumor cells for destruction.
- Monocyte – Migrate into tissues and mature into macrophages, literally “big eaters,” which engulf harmful cells and cellular debris and destroy them some mature into Kupffer cells, which live in the liver and break down and recycle dying red blood cells.
Platelets are cell fragments – bits of membrane-bound cytoplasm – which stop bleeding by clumping together to form clots and scabs seal wounds. Like red and white blood cells, they are made in the bone marrow. Cancer of the bone marrow may prevent production of properly functioning platelets.
Platelets have two states: active platelets, which are prepared to create blood clots, and inactive platelets that do not clot. Under normal circumstances, the endothelial lining of healthy blood vessels produces chemical messages that tells platelets to remain in their inactive form, so that they don’t form clots inside of healthy blood vessels.
Under normal circumstances, platelets are activated when a nearby injury starts a chemical cascade that urges platelets and other nearby clotting factors to activate. These factors then release clot-promoting messages of their own, encouraging more clotting factors to join their growing clot.
Platelets can sometimes be incorrectly activated when endothelial lining is damaged and does not produce the usual inhibitory messages for platelets. This can happen in people with some metabolic disorders and some forms of cardiovascular disease.
Biomedical Nanotechnology: Introduction, Applications, Diagnostics and Therapy
Let us make an in-depth study of the biomedical nanotechnology. The below given article will help you to learn about the following things:- 1. Introduction to Biomedical Nanotechnology 2. Scientific and Application-Oriented Research 3. Diagnostics 4. Therapy and 5. Other Applications.
Introduction to Biomedical Nanotechnology:
Nanotechnology and Nano engineering stand to produce significant scientific and techno­logical advances in diverse fields including medicine and physiology. In a broad sense, they can be defined as the science and en­gineering involved in the design, synthesis, characterization, and application of materi­als and devices whose smallest functional organization in at least one dimension is on the nanometer scale, ranging from a few to several hundred nanometers.
A nanometer is one billionth of a meter or three orders of magnitude smaller than a micron, roughly the size scale of a molecule itself (e.g. a DNA molecule is about 2.5 nm long while a sodium atom is about 0.2 nm).
The potential impact of nanotechnology stems directly from the spatial and tempo­ral scales being considered: Materials and devices engineered at the nanometer scale imply controlled manipulation of individual constituent molecules and atoms in how they are arranged to form the bulk macroscopic substrate. This, in turn, means that Nano engineered substrates can be designed to exhibit very specific and controlled bulk chemical and physical properties as a result of the con­trol over their molecular synthesis and as­sembly.
For applications to medicine and physiol­ogy, these materials and devices can be de­signed to interact with cells and tissues at a molecular (i.e., subcellular) level with a high degree of functional specificity, thus allowing a degree of integration between technology and biological systems not previously attain­able. It should be appreciated that nano­technology is not in itself a single emerging scientific discipline but rather a meeting of traditional sciences such as chemistry, phys­ics, materials science, and biology to bring together the required collective expertise needed to develop these novel technologies.
The present review explores the significance of Nano science and latest nanotechnologies for human health (Fig. 11.1). Addressing the associated opportunities the review also suggests how to manage far-reaching develop­ments in these areas.
Scientific and Application-Oriented Research:
Living cells are full of complex and highly functional ‘machines’ at nanometer scale. They are composed of macromolecules, in­cluding proteins. They are involved in practi­cally every process in the cell, such as infor­mation transfer, metabolism and the transport of substances. Nanotechnologies offer new instruments for observing the operation of these machines at the level of individual mol­ecules, even in the living cell.
Using atomic force microscopes, it is possible, for example, to measure the bonding forces between trig­ger substances, such as hormones, and the as­sociated receptor proteins that act as switches in the cell membrane. Biomolecules can be labeled using quantum dots. The intense light of a specific wavelength that these Nano crystals emit enables the path followed by the biomolecules in the cell to be precisely traced. A great deal of this research is concerned with obtaining information on basic biochemical and biophysical processes in healthy and dis­eased cells.
This knowledge can provide the basis for the development of new prevention strategies and therapies. Besides this primarily knowledge-broadening research, research is also underway into numerous possible ap­plications for nanotechnologies in medicine.
Research efforts are particularly intensive in the search for new methods and tools for imaging, sensing, targeted drug and gene deliv­ery systems. More research is also underway into applications in fields such as, tissue med­ical implants and disinfection. Clinical applications are currently scarce partly because of stringent safety requirements. Nevertheless, experts expect a great deal from Nano medicine especially in the longer term (Fig. 11.2).
The enormous increase in knowledge of the human genome (genomics) and of expres­sion products, proteins (proteomics), makes it possible in an increasing number of cases to trace diseases to abnormalities at the molecu­lar level. In theory, this gives rise to the pos­sibility of making a diagnosis at a very early stage—and of possibly starting treatment— even before the initial symptoms of the dis­ease appear. Attention in medicine is therefore increasingly focusing on prevention.
Neona­tal screening (by means of a heel prick) for metabolic diseases is a good example of this. The medical profession has an ever increas­ing number of technical tools at its disposal for detecting these molecular bio marks. It is in this field that the impact of nanotechnology will probably be noticed first (by 2015). The diagnostic research can be conducted in the laboratory using samples taken from the human body (in vitro research) but it can also be carried out directly on the patient (in vivo). This distinction is important because, in the latter case, the tools/agents have to meet more stringent requirements.
In the Laboratory:
Research into patients’ genetic material (DNA) can be conducted to measure gene expression—the degree of RNA production in diseased tissue, or to ascertain which variant of a particular gene a person has. Many hu­man genes exist in several forms, which only differ in a single base pair. These are known as single nucleotide polymorphisms (SNPs).
The corresponding protein variants may dif­fer from each other in a single amino acid and then display a considerable difference in functionality. SNPs are the root of all kinds of genetic disorders but also affect a person’s sensitivity to chemical substances, includ­ing medicines. This refers to their therapeu­tic effect as well as their side-effects.
Genetic research offers major possibilities for iden­tifying gene types that predispose a person to certain diseases and for achieving better matches between individual patients and the medicines they are prescribed.
DNA chips used for analysing DNA have been available for a few years now. They are currently widely used in scientific, biomedi­cal research but they are rarely used in clini­cal practice. The chips comprise an inert sup­port which carries micro-arrays of hundreds to thousands of single-strand DNA molecules with different base sequences.
DNA from a tissue sample that has been labeled with a radioactive or fluorescent material can be identified on the basis of the place on the chip where it binds to the chip DNA. The Dutch Cancer Institute has been using a DNA chip since 2003 to predict the spread of breast tumors on the basis of gene expression pro­files.
This information makes it much easier than it was in the past to determine which patients would benefit from supplementary chemotherapy after the tumor has been sur­gically removed. Similar chips are being de­veloped for the diagnosis of leukemia’s and mouth and throat tumors. DNA chips and other biochips were originally an achieve­ment of micro technology but miniaturization is advancing here too, as with computer chips. Nanotechnologies are also increasingly playing a role in producing the chips and in increasing their detection sensitivity and reli­ability.
A new Nano technological analytical method uses quantum dots. DNA in a sample is identified on the basis of its bonding to DNA mol­ecules of a known composition embedded in micro-meter-sized polymer spheres contain­ing various mixtures of quantum dots, each of which provides a unique spectral bar code (colour code).
American researchers have used this-method to study SNPs in genes that code for enzymes of the cytochrome P450 family which are involved in the breakdown of substances (including medicines) in the body. The method is very suitable for study­ing large quantities of samples on many SNPs simultaneously (multiplex analyses).
In theory, the composition of DNA mole­cules can also be ascertained by pulling them through Nano-pores in a membrane by means of an electric potential difference. The base sequence can be deduced from the time pro­file of the electric current through the pores.
Researchers have now used this method to identify a mutation in a HIV gene that makes the virus resistant to a particular medicine. If this method, which is still being developed, can be perfected, it will result in a much fast­er way of determining the base sequence of DNA than has thus far been available. This would involve having to place hundreds of pores on a chip.
The aforementioned techniques would, in principle, also be suitable for identifying oth­er biopolymers, such as proteins and carbo­hydrates. Nevertheless, American research­ers have succeeded in developing a chip to detect prostate cancer. The chip contains around one hundred cantilever sensors (mi­cro-meter-sized, nanometers thick miniscule levers), which are coated on one side with an­tibodies to prostate-specific antigen (PSA), a biomarker for that disease.
Bonding of PSA from a sample placed on the chip bends the cantilevers several nanometers, which can be detected optically. This enables clinically relevant concentrations of PSA to be mea­sured. Antibodies placed on nanowires can be used in a similar way to detect viruses—in a blood sample for example. The bonding of a single virus particle to an antibody results in a change in the nanowires electric con­ductance.
The method is extremely sensitive, which means that an infection can be detect­ed at a very early stage. It is also suitable for multiplex analyses. Work is also underway on sensors based on carbon nanotubes, for use in micro-arrays. Detection methods based on cantilevers, nanowires or nanotubes offer the added advantage that it is not necessary to la­bel the sample.
Labs-on-a-chip are pocket-sized laborato­ries. They can be used for analysing biopo­lymers but also for research and for manip­ulating cells. They are expected to play an important role in the further development of biosensors for the detection of pathogen­ic bacteria. In due course there will also be possibilities for point-of-care applications, in which simple analyses can be made in the general practitioner’s surgery or in the pa­tients’ homes and carried out by the patients themselves.
Researchers of the University of Trinity are currently working on the develop­ment of a lab-on-a-chip for measuring lith­ium concentrations in the blood. A chip of this kind would enable patients who use psycho-pharmaceuticals based on lithium to keep the lithium concentration in their blood at the right level. The ease of use would be compa­rable with that of current devices that enable diabetic patients to measure glucose levels in their blood. Photonic explorers for bio-analysis with biologically localized embedding (PEBBLEs) are a final example.
These sensors are a few hundreds of nanometers in size and are composed of an inert capsule, made of polymers for example, containing an indica­tor colouring agent that emits light as soon as a substance being analysed diffuses through the capsule to the inside and binds with the colouring agent.
PEBBLEs were developed for measuring concentrations of small ions and molecules—such as ions of hydrogen, calcium, magnesium and zinc, or glucose—in living cells. Once the Nano capsules have been introduced into a cell, their light emis­sion (and cessation of emission) can be moni­tored using a microscope. Tools of this kind are useful when studying certain diseases. For example, an abnormal zinc balance is a characteristic of brain disorders such as Al­zheimer’s disease and Parkinson’s disease.
In Vivo Diagnostics and Imaging:
In the case of in vivo diagnostics, patients are given contrast agents or radiopharmaceuti­cals. Their specific properties mean that these agents are useful in imaging pathophysi­ological changes and functional changes such as changes in blood flow in cells, tissue and organs. The term molecular imaging is often used, as todays imaging techniques are in­creasingly concerned with making molecular biomarkers of disease processes visible, for instance a receptor protein on the surface of a cancer cell.
To this end, besides being given a contrast agent (the imaging component), a carrier molecule or particle is also given a molecule that specifically binds to the bio- marker, such as an antibody (the targeting component). Various techniques have been developed, each with its own contrast agents and imaging equipment: methods based on ultrasonic vibrations, radioactive substances (including positron emission tomography, PET), magnetic resonance imaging (MRI) and fluorescent substances. Each has its own possibilities for applications and its own re­strictions.
Imaging that focuses on molecular biomarkers makes early detection of diseases possible and provides information on appro­priate therapies. Imaging is also very suitable for monitoring, evaluating and optimizing treatment that is being provided. Nanotech­nologies offer numerous possibilities for im­proving existing and designing new imaging techniques.
Nanoparticles of perfluorohydrocarbons combined with a lipid layer have multiple uses. They are suitable as an ultrasonic con­trast agent. If gadolinium compounds or radioactive substances such as technetium- 99 are combined with the lipid layer of the nanoparticles, they are also suitable for MRI, or scintigraphic imaging.
Given the right targeting molecule, the particles can make pathogenic changes in blood vessels visible. The nanoparticles are currently being studied for use as a contrast agent for the diagnosis of atherosclerosis, thrombosis and (tumor) angiogenesis. A clinical study is expected to start by 2015. Super paramagnetic nanoparticles of iron oxide are-now being used clinically as an MRI contrast agent. They accumulate after intra­venous administration in the liver, the spleen and the lymph glands, thereby enabling stud­ies of those organs.
Patient-based research has indicated that they can also increase detectability of tumor metastases in lymph glands. Combined with dendrimers (Fig. 11.3), the particles can be used for marking living cells. Magneto dendrimers of this kind make it possible to, for example, monitor the migration and division of transplanted cells in the body.
The method, which has already been used successfully on laboratory animals, may prove to be of valuable assistance in the future in stem cell therapy. Gadolinium den­drimers are also being developed for use as contrast agents. The first of these agents are almost ready for introduction on the mar­ket. Depending on their size and solubility in water or fat, they are suitable for examining blood vessels, kidneys, liver or lymph glands.
Optical imaging techniques use fluorescent colouring agents which are taken orally or injected and then accumulate in a tumour, for example. The tumour cells fluoresce when irradiated with laser light. Because the laser light cannot penetrate deep into the body, this technique can only be used for imaging tumours in or just below the skin or in tissue that is accessible using an endoscope.
Intensive research has been underway for several years now into new optical methods based on the use of nanoparticles. Quantum dots are at the most advanced stage (Fig. 11.4) of development. These Nano crystals have the advantage over colouring agents that they fade less quickly over time and do not react with cell components.
Moreover, quantum dots of different colours can be made to fluo­resce with laser light of the same wavelength, which makes multiplex applications possible. Nanoparticles have already been successfully used in cell cultures and laboratory animals to colour biomarkers on the surface of can­cer cells, to monitor the development of cell lines in a frog embryo, to make blood vessels visible in mice and lymph glands in pigs.
The hope is that the latter application will in due course improve the possibilities for tracing tumour metastases. All these applications are based on the fact that Nano-materials because of their minute size can easily enter even the smallest compartment of the cell.
The quantum dots are provided with a layer of lipids or polymers, to prevent heavy metals from being released. However, before clinical applications can be considered, research will have to show that coatings of this sort are also effective in the long term.
Contrast agents can sometimes also act as a medicine. For example, under the influence of laser light of a certain wavelength and in the presence of oxygen, some fluorescent colouring agents produce toxic substances which can destroy tumour cells by oxidation.
In addition, it is theoretically possible to combine diagnosis and therapy by providing nanoparticles not only with targeting molecules and contrast agents but also active substances. The Nano-particle then also acts as a drug delivery sys­tem.
Many substances that could, in theory, be used as medicines have the disadvantage that they are hardly, if at all, able to reach the dis­eased organs or tissues in the body.
There are various possible reasons for this:
1. The substance is hardly, if at all, soluble in water
2. The substance is broken down in the body or inactivated before it reaches its target
3. The substance is hardly, if at all, capable of passing certain biological barriers (cell membranes, placenta, and blood brain bar­rier)
4. The substance distributes non-specifically to all kinds of tissues and organs.
Substances of this kind are, therefore, inef­fective or lead to undesirable adverse side- effects. The German microbiologist Paul Ehrlich conceived (in early 1900s) of the idea of using ‘magic bullets’ to direct medicines at their target more effectively. This idea was taken up again at the end of the 1960s and researchers have since been developing such drug delivery systems. Their miniscule di­mensions mean that all kinds of nanoparticles are suitable for use in systems of this kind.
Depending on the type of particle, the active substance can be encapsulated or attached to the surface. This means that even if they dis­solve poorly in water, they can be transported in an aqueous solution, such as blood and are better protected against degradation by enzymes, for example. A suitable coating on the nanoparticle can prevent identification and removal by the immune system.
Selective accumulation in the target organ or tissue can arise through various mechanisms. The first mechanism is passive. An example of this would be to use the high permeability of the walls of blood vessels and the reduced lymph drainage in tumor tissue. However, it is also possible to provide nanoparticles with ‘targeting molecules’ (e.g. specific antibodies or folic acid), which ensure that the delivery system primarily bonds to the diseased tissue (Fig. 11.5). However, this can aid detection by the immune system.
When provided with suitable targeting molecules, some nanoparti­cles are able to transport medicines across the blood-brain barrier to treat brain tumors, for example. The cells being treated can then take up the delivery system containing the ac­tive substance by means of endocytosis. Combining the delivery systems with con­trast agents, fluorescent or radioactive sub­stances also makes it possible to use imaging techniques to monitor how successful the se­lective transport to the destination has been.
Once it has reached the target area, the active substance has to be released from the carrier at the correct rate. This can occur spontane­ously by gradual diffusion, in combination with the delivery system’s degradation or oth­erwise.
It may also occur as a result of special conditions at the destination, such as a dif­ferent acidity level, salt concentration, tem­perature or the presence of certain enzymes. The accumulation of the delivery system and/ or the release of the active substance at the right place can also be controlled from out­side by influencing conditions in the target organ or tissue by means of magnetic fields, near-infrared radiation, ultrasonic vibrations or heat. The delivery system used and the ex­ternal treatment have to be precisely matched to each other for this purpose.
The requirements that delivery systems have to fulfil are:
1. Their residence time in the blood must be long enough to enable accumulation in the target tissue
2. They must be capable of containing suf­ficient active substance
3. The systems or their degradation products must have a favourable toxicity profile
4. They must have a shelf life that is long enough to allow storage and distribution
5. The effectiveness must be in proportion to the costs.
Research into the suitability of a large va­riety of nanoparticles for use as a delivery system is currently underway. Which parti­cles are most suitable depends on the active substance that has to be transported, the tar­get organ and the method of administration (oral, inhalation, dermal, by injection). Some particles, such as nanoparticles of polymer or of solid fat, appear to be usable for transport­ing a wide range of substances.
The scope for using other, especially inorganic, nanopar­ticles is smaller. Most delivery systems are currently being developed for transporting anti-tumour agents, genetic material (gene therapy) and proteins and peptides. Nano­particles of polymers as delivery systems for active substances have been taking place since the mid-1970s.
The usefulness of other sys­tems, such as nanoparticles of solid fat, dendrimers, fullerenes and Nano crystals of the active substance, only began to be studied in the early or mid-1990s. There are now various medicines with delivery systems on the mar­ket and many are in the clinical study phase.
The future for drug delivery systems is expect­ed to be bright, even if significant obstacles still have to be overcome. Obstacles include the development of methods to increase the specificity of delivery systems for target cells, to more precisely regulate the bio-availability of active substances in the target tissue and to get active substances to the destination within the cell more efficiently.
Nanoparticles as Medicines:
Besides acting as a delivery system, in some cases nanoparticles can act as an active sub­stance. Once they have found their way through the bloodstream into a tumour, or have been injected directly into it, metal- containing nanoparticles can be heated using near-infrared radiation or a rapidly oscillat­ing magnetic field so that the tumour cells die. As yet, this relates to research conducted using laboratory animals. It may also be pos­sible to use single-wall carbon nanotubes in a similar way.
In vitro studies have in fact shown that, if combined with folic acid as targeting molecules, the tubes are selectively taken up by cancer cells. These cells can then be killed by using near-infrared radiation to heat the tubes (Fig 11.5). Healthy cells appeared to take up few, if any, nanotubes and not to be affected by the near infrared radiation.
Recent in vitro and in vivo studies have revealed that some nanomaterial’s are en­dowed with innate anti-platelet properties thus indicating their potential as future anti­thrombotic drugs. Further studies are already underway to characterize the fibrinolytic behaviour of these nanomaterial’s in various pathological conditions like diabetes, stroke, and myocardial infarction [Shrivastava S. et al, unpublished data].
Passive Implants and Tissue Engineering:
Artificial joints, such as artificial hips, nor­mally have a life of around ten to fifteen years, after which complications occur, such as wear or implant loosening, and further operations are required. Nanotechnologies could help re­duce these problems. The implants, which are usually made of titanium or alloys of cobalt and chromium, can be provided with a thin layer of a Nano crystalline structure, which is harder and smoother and consequently more resistant to wear.
This would also result in less wear of the artificial socket, which is generally made of a special type of polyethylene. More­over, the layer would ensure that the body better tolerates the implant (better biocompatibility). The suitability of various materials for use as a coating is currently being studied: diamond, metal-ceramic and hydroxyapatite. The latter material is a natural component of bone, 70% of which consists of the mineral hydroxyapatite, with the remaining 30% con­sisting of organic fibers (collagen).
Hydroxy­apatite has been used as a coating in implants for some time but new production methods now make it possible to apply layers with a grain size in the nanometer, rather than the micro-meter scale. This makes their structure more like that of natural hydroxyapatite in bone, which likewise has a Nano crystalline structure (grain size less than 50 nm). This aids biocompatibility.
The layer can even en­courage the growth and bonding of the sur­rounding bony tissue. In vitro research has shown that bone-forming cells (osteoblasts) adhere better and deposit more calcium on materials with a grain size in the nanometer range than on conventional materials with a grain size in the micro-meter range. This is presumably related to the higher absorption of proteins that stimulate cell adhesion.
Bone re-sorbent cells (osteoclasts) also function better on these nanomaterial’s. Proper, coor­dinated function of both types of cells in es­sential for the formation and maintenance of healthy bony tissue and, therefore, for strong bonding between the implant and the sur­rounding bone.
This is extremely important for implants that are attached without the use of bone cement. Implants provided with a hy­droxyapatite layer with a nanostructure are currently being tested in patients, in 2000 a patient in the Maastricht University Hospital was the first to receive an artificial hip with such a coating.
Nanoparticles of hydroxyapa­tite can also be introduced directly into dam­aged bones to accelerate the repair of bony tissue. In recent years, a few medicines have been admitted that work according to this principle. Implant coatings with a nanostruc­ture based on diamond and metal-ceramic are still at the research stage. Their main ben­efits are hardness, smoothness, corrosion re­sistance and good bonding to the implant.
The mechanical properties and biocompat­ibility of implants can also be improved by providing the material that is used to make the implants with a nanostructure. This is possible by applying a thin layer of titanium dioxide with Nano pores. An added advantage of this approach is that the layer can be made in a way that metal ions with an antiseptic ef­fect such as copper ions are slowly released.
This reduces the likelihood of bacterial infec­tions, which are a frequent complication with implants. Another possibility is to make the implants from Nano powders of titanium di­oxide or aluminium oxide using a sinter pro­cess. Promising alternative materials include organic polymers with a nanostructure and composite materials of organic polymers into which Nano fibers of carbon or nanoparticles of titanium, aluminium or hydroxyapatite have been mixed.
The advantage of the or­ganic polymers is that they dissolve gradu­ally while new bony tissue is being formed. Studies are also underway of the possibilities of generating bone with the help of scaffolds of carbon nanotubes. The orthopedic applications are closest to being used on patients, but biodegradable scaffolds of Nano fibers consisting of natural or synthetic organic polymers are already used to cultivate other tissues, such as carti­lage, muscle tissue, nerve tissue and vascular tissue in vitro.
Here too, the goal of the Nano-structure is to imitate the natural extracel­lular matrix. Researchers recently succeeded in using Nano fibers to regenerate brain tis­sue in vivo. Young and adult hamsters that had been blinded as a result of intentionally caused brain damage had their sight restored within a few weeks of scaffold-forming Nano-material being injected into the brain. It may also be possible to use the method in the fu­ture to repair damaged human nerve tissue.
Stents are a completely different type of im­plant. They are small tubes of woven thread used to dilate blood vessels. Inflammatory reactions often occur and lead to the blood vessel closing again. This problem is dealt with using stents with a coating of aluminium oxide which is provided with Nano pores. A radioactive substance can be applied to them, which prevents the stent from clogging.
The pores ensure that sufficient radioactive ma­terial can be introduced and that it is released very gradually. The functionality and safety of these stents still has to be confirmed in ani­mal trials. Research is also underway into the possibility of using the lotus effect: a coating of titanium compounds is used to prevent clotting reactions owing to conformation changes in proteins in the blood caused by their contact with the stent wall.
Active implants are implants that contain a source of energy. They can be divided into two groups on the basis of their function. The first category comprises implants for administering medicines, such as insulin pumps and morphine pumps. They have been in use for a long time. Work has also been underway for several years on implantable microchips for the storage and controlled release of ac­tive substances. The benefits of this approach to administering medicines include the fact that the medicines go directly to the location where they are needed and can, if required, be administered at varying rates.
The release could also be controlled by a biosensor that responds to physiological parameters. The first system of this kind is soon due to be test­ed on patients. The second group comprises neural pros­theses, which are intended to repair or take over nerve functions. For instance, they bridge damaged nerve paths, provide impuls­es for muscles or replace senses.
This catego­ry includes cochlear implants (for restoring hearing), pacemakers and defibrillators (for regulating the heart beat), bladder stimula­tors (for controlled emptying of the urinary bladder by spinal cord lesion patients), deep- brain stimulators (to combat tremor in pa­tients with Parkinson’s disease), peroneus stimulators (to combat drop foot).
These are all currently used in patients and some have been in use for decades. On the other hand, retinal implants to restore the sight in patients with a damaged retina are still in development. In recent years, a great deal of research has been conducted into this in the United States, Germany and Japan. Although considerable advances are being made and the first clinical tests are already underway, some major obstacles still have to be overcome.
It will probably be years before ‘artificial retinas’ are as common as the other neural implants. For some years now, vari­ous research groups in the United States have also been working on Neuroprostheses that enable devices to be operated by thought. To this end, one or more chips with electrodes are fitted to the motor cerebral cortex, which register the electrical signals associated with thoughts.
These prostheses are also referred to as brain-machine interfaces. They have now succeeded in enabling rats to operate handles by ‘brain power’ and monkeys to operate the cursor of a computer or a robot arm. A few years ago, an ALS (Amyotrophic lateral scle­rosis) patient had an electrode implanted in the cerebral cortex, to enable him to operate a computer.
In 2004, a Neuroprosthesis was fitted to a paralyzed man. It enables him to operate the cursor of a computer by thought, play video games, and operate a light switch and to select a television channel. The findings were presented at the annual meeting of the American Academy of Physical Medicine and Rehabilitation, in Phoenix, in October 2004.
The ultimate goal, which is still far-off, is to enable patients to operate arm or leg pros­theses or even to restore their control of their paralyzed limbs. Conversely, it also possible to control rats remotely by administering electrical stimuli in the parts of the brain involved in touch and in experiencing pleasant feelings.
These so called ‘robot-rats’ could be used to search for victims underneath the rubble of collapsed houses, to detect landmines or be used as mobile biosensors. All these active implants are essentially products of micro technologies but nanotechnologies may play an impor­tant role in their improvement and further development.
Research is mainly concerned with increasing functionality, fixation in the surrounding tissue and biocompatibility by modify the surface at the Nano scale. For example, electrodes with a Nano porous sur­face are being developed for retinal implants. This nanostructure increases the electrodes’ surface area by a factor of one hundred, which is necessary for proper signal transfer from the electrodes to the tissue.
The micro- electrodes of Neuroprostheses that register electrical signals in the brain often only work for a few weeks. They do not usually become defective but the surrounding tissue gets damaged and non-conductive scar glial-cell tissue grows. In vitro research has shown that a Nano porous surface structure reduces glial- cell adhesion and promotes the formation of outgrowths of nerve cells. A possible expla­nation for the stimulating effect on the nerve cells is that they are naturally embedded in an extracellular matrix with a nanostructure of microtubuli and laminin.
To combat rejec­tion reactions or infections, coatings can be applied that release medicines gradually. An antiseptic layer based on silver nanoparticles is already being used in Germany on cochlear implants. Other examples of contributions made by nanotechnologies to active implants include the membranes with Nano pores in microchips for drug delivery and batteries with a higher energy-storage capacity.
The disinfectant effect of silver has long been known but the use of silver in combating pathogenic microorganisms decreased with the emergence of organic antibiotics. The increasing resistance of bacteria to antibiotics has resulted in renewed interest in silver as a disinfectant. The antiseptic effect is based on silver ions. They block the enzymes required for oxygen metabolism, destabilize the cell membrane and block cell division. Bacte­ria are not expected to develop resistance to silver, owing to the diversity of the working mechanisms.
Especially in the form of nano­particles, silver is extremely effective thanks to the large contact area with the environment. Moreover, the particles have the advantage that they can be readily integrated with other materials like (Fig. 11.6) globular or fibrous proteins [communicated data] and polymers. The nanoparticles then act as depots that continually release new silver ions.
When ap­plied to medical instruments or implants, an­timicrobial layers of this kind can help reduce the number of infections. Current research is studying uses on catheters, cochlear implants and in bone cement. Anti-microbial wound dressing containing Nano crystalline silver are already on the market.
Titanium dioxide nanoparticles also have a bactericidal effect. This is based on a photo- catalytic effect. Under the influence of ultra­violet radiation and in the presence of water and oxygen, the particles form extremely re­active molecules (radicals), such as hydroxyl and per-hydroxyl radicals, which kill micro­organisms. Titanium dioxide can be used to produce antiseptic surfaces that only work in the presence of UV radiation. Fullerenes also have an antimicrobial effect in the presence of light. Various antimicrobial products based on nanoparticles are already on the market.
Identification, Security and Logistics:
Radio frequency identification labels (RFID labels) consist of a microchip to which a ra­dio antenna is attached. The chip can contain information on a product that contains it or to which it is attached. A scanning device can activate the chip by means of the antenna, which, in turn, transmits the information stored in the chip. The labels are used for identification and security purposes and for following flows of goods. They have been in use for some time, for locating stolen cars bicycles, for example, and for identifying do­mestic pets and cattle.
The labels are a product of micro technology but nanotechnologies of­fer possibilities for making them smaller and cheaper. This is expected to increase their use considerably. RFID labels are already used in hospitals and care institutions. They are used to prevent newborns from being abducted or confused or demented patients from wander­ing away unnoticed.
They are also increasingly being used for identifying patients or samples taken from patients, alongside or instead of labels with bar codes. This is to enable an early response when the wrong patient is taken to an operating room, for example. They are also expected to reduce the number of wrong blood transfusions. The labels can also simplify the tracing and localization of expensive hospital equipment, make it easier to trace medicines and to help in combating drug counterfeiting. Implanting RFID labels in victims of disasters can facilitate their sub­sequent identification.
Meanwhile, RFID labels the sizes of a grain of rice are available for implantation under the skin. The Food and Drug Administration in the United States approved a label of this kind in 2004. A person’s medical records can be stored on the chip. The idea behind this is that faster availability of the right medi­cal information could save a person’s life in an emergency. Apart from health care these kinds of chips are also finding important role in agriculture and food technologies.
Hence, the multidisciplinary field of nano­technology s application for discovering new molecules and manipulating those available naturally could be dazzling in its potential to improve health care. The spin-offs of Nano-biotechnology could be utilized across all the countries of the world. In the future, we could imagine a world where medical Nano devices are routinely im­planted or even injected into the bloodstream to monitor health and to automatically par­ticipate in the repair of systems that deviate from the normal pattern.
The continued ad­vancement in the field of biomedical nano­technology is the establishment and collabo­ration of research groups in complementary fields. Such collaborations have to be main­tained not only on specialty field level, but internationally as well. The successful devel­opment and implementation of international collaborations fosters a global perspective on research and brings together the benefits to mankind in general. However, nanotechnolo­gy in medicine faces enormous technical hur­dles in those long delays and numerous failures are inevitable.
Likewise, we should be aware and take precautions against the dangers and negative consequences of Nano biotechnology when applied in warfare—in the hands of ter­rorists, and also disasters associated with its application in energy generation when and wherever it strikes or the risks associated with nanoparticles in blood circulation.
It should be appreciated that nanotechnology is not in itself a single emerging scientific disci­pline but rather a meeting point of traditional sciences—like chemistry, physics, biology and materials science—to bring together the required collective knowledge and expertise required for the development of these novel technologies.
A Pharmacological and Toxicological Profile of Silver as an Antimicrobial Agent in Medical Devices
Silver is used widely in wound dressings and medical devices as a broad-spectrum antibiotic. Metallic silver and most inorganic silver compounds ionise in moisture, body fluids, and secretions to release biologically active
. The ion is absorbed into the systemic circulation from the diet and drinking water, by inhalation and through intraparenteral administration. Percutaneous absorption of through intact or damaged skin is low. binds strongly to metallothionein, albumins, and macroglobulins and is metabolised to all tissues other than the brain and the central nervous system. Silver sulphide or silver selenide precipitates, bound lysosomally in soft tissues, are inert and not associated with an irreversible toxic change. Argyria and argyrosis are the principle effects associated with heavy deposition of insoluble silver precipitates in the dermis and cornea/conjunctiva. Whilst these changes may be profoundly disfiguring and persistent, they are not associated with pathological damage in any tissue. The present paper discusses the mechanisms of absorption and metabolism of silver in the human body, presumed mechanisms of argyria and argyrosis, and the elimination of silver-protein complexes in the bile and urine. Minimum blood silver levels consistent with early signs of argyria or argyrosis are not known. Silver allergy does occur but the extent of the problem is not known. Reference values for silver exposure are discussed.
Silver is a white lustrous transitional metallic element found widely in the human environment. Low concentrations of silver are present in the human body through inhalation of particles in the air and contamination of the diet and drinking water, but silver serves no trace metal value in the human body. Increasing use of silver as an efficacious chemotherapeutic antibacterial and antifungal agent in wound care products, medical devices (bone cements, catheters, surgical sutures, cardiovascular prostheses, and dental fillings), textiles, cosmetics, and even domestic appliances in recent years has lead to concern as to the safety aspects of the metal and potential risks associated with the absorption of the biologically active Ag + into the human body . Safety thresholds set by regulatory authorities including the World Health Organisation and U.S. Environmental Protection Agency are based mostly on scientific reports conducted before the introduction of the high standards of experimental and investigative procedures and tissue analysis expected nowadays and fail to recognise more recent work [2, 3].
Metallic silver is inert in the presence of human tissues but ionises in the presence of moisture, body fluids, and secretions to release the biologically active Ag + which shows a strong affinity for sulphydryl groups and other anionic ligands of proteins, cell membranes, and tissue debris . Ionisation of metallic silver is proportional to the surface area of particles release of Ag + from nanocrystalline particles of
20 nm being more than one-hundred-fold higher than that from silver foil or other metallic silver forms. Comparative studies have shown that nanocrystalline silver with higher solubility in water exhibits a sixfold or higher log reduction in Pseudomonas aeruginosa in culture . Ag + binds protein residues on cell membranes of sensitive bacteria, fungi, and protozoa and is absorbed intracellularly by pinocytosis. Subsequent denaturation and inactivation of proteins and essential enzymes including RNA- and DNA-ases forms the basis of the genetically regulated antimicrobial action of silver [5, 6]. Silver-sensitive strains of bacteria and fungi have been shown to absorb and concentrate Ag + from dilute solutions (1 ppm) by an oligodynamic action, first described by the Swiss botanist Von Nägeli in 1893 . Experimental studies suggest that concentrations of 60 ppm Ag + should be sufficient to control the majority of bacterial and fungal pathogens .
Recent advances in the biotechnology of medical devices and the ability to impregnate or coat alginates, polyurethane, silicones, and textile fibres with ionisable silver compounds now provide clinicians with efficacious means of overcoming infections in wound care and device-related infections which have proved costly in terms of hospital care and patient stress as well as being a major cause for fatalities [8–10]. Wound dressings, catheters, bone cements, dental devices, hygiene textiles, consumer products, and other products area treated with silver as antibiotic or preservative release bioactive Ag + to achieve antibacterial or antifungal action. Limited evidence is available currently to show that nanoparticulate silver is an efficacious antiviral agent [11, 12]. Lara et al. have shown that silver nanoparticles exert antiviral action against HIV-1 at noncytotoxic concentrations, but these mechanisms of action which have not been fully elucidated involve virion binding, inhibition of replication, and inactivation .
Silver should be classified as a xenobiotic metal in the human body. Available evidence suggests that much of the ion released precipitates with chloride or phosphate anions or becomes strongly bound in the form of inert complexes with albumins or macroglobulins some binds or is deposited in tissue debris [13, 14]. This bound ion is not available for antibiotic purposes but is of potential significance as a toxic factor [4, 15].
Clinical studies with antibiotic wound dressings have shown that most of the Ag + released into the wound bed is deposited superficially and that minimal levels are available for absorption . Proteins in the systemic circulation and at sites of contact avidly bind the lower concentrations of Ag + released from antibiotic in in-dwelling catheters, cardiovascular devices, and orthopaedic cements, pins, and fixation materials. Occupational health studies demonstrate that greatest risk of silver absorption is anticipated following chronic exposures to silver and silver oxide dusts or silver nitrate particles or aerosol droplets, each of which has been associated with deposition of inert silver sulphide or silver selenide precipitates in the form of argyria and argyrosis in the skin (dermis) and eye (cornea and conjunctiva), respectively [17, 18]. Argyria may present as a profound cosmetic disfigurement which is not readily removed by surgical (dermabrasion) or chemical means , but it is not associated with tissue damage or dysfunction. Long-term usage of unregulated and medically unsupervised colloidal silver formulations marketed as nasal decongestants, therapies for allergic rhinitis, and other complaints of infective and noninfectious aetiology are well documented causes of argyria [19–21].
The anti-inflammatory effects of silver nitrate or nanocrystalline silver have been recognised experimentally in wound care, treatment of allergic contact dermatitis ulcerative colitis, and cystitis [22–26]. In dinitrochlorobenzene-induced porcine or murine skin decreased inflammation following application of nanocrystalline silver was associated with lymphocyte apoptosis, decreased expression of pro-inflammatory cytokines, and reduced gelatinase activity. Silver nitrate (0.5%) evoked a wider level of cellular apoptosis but delayed wound healing. In a rat model of ulcerative colitis, administration of 4 mg
kg -1 nanocrystalline silver intracolonically or 40 mg kg -1 orally significantly reduced inflammatory changes, partly through suppression of matrix metalloproteinase (MMP-9), tumour necrosis factor (TNF), and interleukin-
(IL- ) and IL-12 . Other anti-inflammatory changes associated with intravesicular administration of nanocrystalline silver in murine cystitis included suppression of mast cells and urine histamine levels .
Wright et al. examining early events in a porcine wound-healing model noted that nanocrystalline silver in particular as used in wound dressings was an efficacious antibacterial agent and significantly promoted wound healing with rapid neovascularisation and suppression of metalloproteinases without compromising other essential events in the wound healing cascade . Further studies are now indicated to confirm this action of nanocrystalline silver in human wound repair.
The toxicology of silver is not well documented and much of the available information concerning the release of Ag + from medical devices and other products intended for human use is ambiguous and widely scattered. Few relevant experimental studies in animal models are reported openly whilst insufficient in predicting human risk from silver exposure, they do provide relevant information on cytotoxicity, intracellular management of Ag + , and routes of excretion [1, 14, 27–29]. It is my intention here to highlight progress on the safety assessment of silver in recent years and to emphasise the gaps in existing knowledge relevant to establishing realistic safety thresholds.
2. Absorption and Metabolism of Silver
Expressions of toxicity for any xenobiotic material are related directly to the amount absorbed into the body, its metabolism and accumulation in target organs, and cellular vulnerability to irreversible toxic change. Clinical and experimental studies have shown that metals absorbed into the body interact and compete for binding sites on carrier proteins, and that when protective mechanisms afforded by key metal-binding proteins like metallothioneins and the epidermal barrier function become saturated, toxic changes occur [30–32]. Silver is absorbed into the human body through ingestion, inhalation, intraparenteral insertion of medical devices, and through dermal contact, but the literature on silver absorption by all routes in humans is fragmentary, poorly correlated, and not strong statistically. Metabolic pathways are similar irrespective of route of uptake . Much information on the uptake of silver as a cause of argyria and raised blood silver is derived from occupational health studies where workers have been exposed to silver and silver compounds over many years [3, 17, 33, 34]. From this data it is rarely possible to identify how much silver is absorbed into the circulation from the gastrointestinal tract, lungs, or percutaneous absorption or how much is retained, but urinary or faecal silver excretion may be informative [17, 35–37]. The maximum carrying capacity of human blood for silver is not known but is expected to relate to albumin and macroglobulin concentrations. Armitage et al. studied the uptake of silver in the blood of workers exposed occupationally to silver and reported levels ranging from 0.1 to 23.0
g L -1 with the highest levels in silver reclaimers . Few objective studies on silver uptake and excretion are reported but Di Vincenzo et al. noted that in 37 workers exposed to silver in smelting and refining, mean silver concentrations in blood, urine, and faeces were 11 g L -1 , 0.005 g g -1 , and 15 g g -1 , respectively . Hair concentrations of silver were markedly higher at 130
160 g g -1 compared to 0.57 ± 0.56 g g -1 in controls.
2.1. Oral Administration and Gastrointestinal Absorption
Principle routes for buccal or gastrointestinal absorption of silver include (i) contaminated food, (ii) occupational exposures to metallic silver dust, silver oxide, and silver nitrate aerosols, (iii) drinking water (including use of silver : copper filters in water purification), (iv) silver nitrate or colloidal silver therapies in oral hygiene and gastrointestinal infection, (v) colloidal silver preparations labelled as “food supplements” or “alternative medicines”, (vi) silver acetate antismoking therapies, (vii) silver amalgams used in dentistry, (viii) accidental consumption of silver nitrate or other colourless silver compounds.
Silver absorption through buccal membranes and gastrointestinal mucosae is determined by the ionisation of the silver source and availability of “free” Ag + to interact with protein receptors on cell membranes. Passive uptake is not indicated on account of the high reactivity of the silver ion and its binding capacity of sulphydryl, carboxyl, hydroxyl, and protein ligands on mucosal surfaces and cell debris. Biologically active Ag + readily binds and precipitates with organic constituents of food (phytate, fibres, etc.) and inorganic cations like chloride and phosphate greatly, thereby reducing absorption. Current estimates suggest that less than 10% of the silver ingested by humans is absorbed into the circulation , but this can be expected to vary widely according to the age, health and nutritional status, and composition of the diet.
Individual case studies like that conducted in a severely argyric patient following silver acetate antismoking therapy indicate that the amount of silver absorbed is low but that 18% of this is retained in the body . After 2 years self administration of an antismoking remedy, this patient exhibited an estimated total body burden of 6.4 g silver with high levels of silver in forearm skin exposed to solar irradiation. Her blood silver levels increased marginally within 2 hours of administration of a radiolabelled (
g) silver acetate lozenge, and urinary silver excretion remained fairly constant over 7 days. Studies relating to the absorption and metabolism of silver from dental amalgams show good correlations between levels of silver eluting from dental amalgams and concentrations observed in soft tissues and in blood, hair, and urine [40, 41]. The famous “blue man” of Barnum and Bailey’s Circus was believed to contain as much as 90–100 g of silver in his body with deposits in bone (0.21%), muscle (0.16%), kidney (0.24%), and heart (0.15%) but the reliability of silver quantitation in tissues in 1927 is questioned .
Presently, toxic risks associated with silver ingestion are low since most products releasing Ag + for oral or gastrointestinal hygiene have been removed from current pharmacopoeias and permitted lists in most countries in view of the risks of argyria [2, 3]. Silver is widely used in the purification of drinking water, and in the form of silver copper filters, has a major role in cleansing hospital water systems . Average levels of silver in natural waters was at 0.2 g L -1 , and levels in drinking water (USA) that had not been treated with silver for disinfection purposes ranged from barely detectable to 5 g L -1 . Water treated with silver may have levels of 50 g L -1 , with most of this silver present in a nondissociated form as silver chloride. Estimates suggest that the silver absorbed from drinking water represents a relatively low proportion to that absorbed from the diet which ranged from 7 to 80 g daily. The World Health Organisation considered in 1996 that on the basis of present epidemiological and pharmacokinetic knowledge, a lifetime intake of about 10 g of silver can be considered the human No Observable Adverse Effect Level (NOAEL) and that the contribution of silver from drinking water would be negligible . Even in special situations as when silver is added to water for maintaining bacteriological quality, concentrations of silver of 0.1 mg L -1 (a concentration that gives a total dose over 70 years of 50% of the human NOAEL of 10 g) can be tolerated without risks to health [43, 44]. Greater risks are expected through uncontrolled use of colloidal silver products containing unspecified levels of ionisable silver which are commercially available in some countries as food additives, health supplements, breath fresheners, multipurpose antiseptics, topical therapies, and many other claims many of which are not substantiated by scientific or clinical evidence [45–47].
Older studies document therapeutic administration or accidental consumption of high doses of silver nitrate as a cause of argyria and argyrosis, corrosive damage in the mouth or gastrointestinal tract, pain, and even fatality [48, 49]. Lethal oral concentrations of silver nitrate in humans have been estimated at approximately 10 g, but this is largely attributable to the strong acidity of the nitrate anion released and not Ag + absorbed . Blumberg and Carey reported a case of a chronically ill 33-years-old lady who had supposedly taken oral silver nitrate capsules (30 mg silver daily) on alternate periods of 2 weeks for over a year (total dose 6.4 g) and who showed greatly elevated blood silver of 0.5 mg/L (normal ca 2.3 g/L) . It is unclear whether ill health was in part due to the corrosive effects of the nitrate or to other causes but she developed generalised argyria even though her argyraemia declined slightly after 3 months following withdrawal of treatment. Several other cases are reported where intentional or accidental oral consumption of silver nitrate led to gastrointestinal lesions but where the actual amount of silver ingested is not known . The low systemic toxicity of oral metallic silver is illustrated by a study of 30 healthy volunteers who consumed silver leaf (50 mg/day) for 20 days . Apart from transitory changes in hepatic enzymes, the treatment was well tolerated without symptoms of argyria.
Animal models provide limited predictive information concerning the gastrointestinal absorption of silver. As in humans, silver nitrate solutions are highly irritant and potentially fatal at high doses in all species due to the anion, but the uptake of Ag + varies greatly. Thus rats, mice, and monkeys given silver nitrate ( g) in drinking water absorb less than 1% of the silver administered within 1 week whereas in dogs, up to 10% may be absorbed . From these experiments, the authors reasoned that a 70-kg man would retain approximately 4% of the dose administered. This extrapolation is seriously flawed on account of the imprecision of the experiments conducted and wide interspecies differences in gastrointestinal physiology and dietary requirements. Uptake and retention of silver was based upon patterns of intake and faecal excretion patterns but did not allow for secondary and tertiary excretion via the urine and hair [1, 17]. Biliary excretion is the principle route for elimination of silver from the human body.
Argyria and argyrosis provide unequivocal evidence for silver absorption following long-term inhalation of colloidal silver preparations or occupational exposures to silver or silver oxide dusts or silver nitrate [47, 52]. Detailed study of the uptake of silver through nasal and respiratory membranes has not been seen, but it is expected that inhaled silver or silver compounds ionise in mucoid secretions or alveolar pulmonary surfactants allowing Ag + to be absorbed through alveolar epithelia. Silver precipitates in lungs and is absorbed by alveolar macrophages, but it is unclear to what extent Ag + interacts with or is precipitated by the phospholipid content of this pulmonary surfactant, or whether this secretion acts as a barrier to absorption.
Di Vincenzo et al. evaluated 37 workers involved in silver industries and reported blood, urine, and faecal silver levels of 11 g L -1 , 0.005 g g -1 , and 15 g g -1 , respectively, compared to 0.5 g L -1 , 0.005 g g -1 , and 1.5 g g -1 in nonsilver-exposed subjects . They estimated that human exposure to the threshold limit values, set by the American Conference of Governmental Industrial Hygienists (ACGIH) and the European Union of 0.1 mg/m 3 could lead to faecal excretion of 1 mg of silver daily, but that argyria is unlikely to occur at these exposure levels. Other research demonstrates that blood silver is much influenced by the solubility and ionisation capacity of environmental silver exposures. Thus, Armitage et al. showed that blood silver levels in melters, refiners, and silver nitrate producers exposed to soluble silver salts were in the range from 0.1 to 23 g L -1 whereas those exposed to metallic silver with considerably lower ionisation potential showed argyraemias of 0.2–2.8 g L -1 (control 0.1 g L -1 ) . Neither group exhibited argyria. In a similar way, 27 silver reclamation workers exposed to airborne silver halides of low solubility at 0.005 to 0.240 mg/m 3 exhibited very low absorption with blood silver levels of 0.01 g L -1 .
Occupational health reports published before the introduction of stringent health and safety at work regulations show that inhalation of silver nitrate dust is a cause of bronchitis, squamous metaplasia, and pigmentation of the respiratory tract resembling anthracosis and siderosis . Rosenman et al. [33, 34] examined 27 workers in a silver plant exposed to metallic silver, silver oxide, silver chloride, and silver alloyed with other metals and reported that those exposed to environmental silver contamination levels exceeding the recommended 0.01 mg/m 3 (i.e., 0.04–0.35 mg/m 3 ) showed raised blood and urinary silver levels (blood Ag,
0.27 g 100 mL -1 urine Ag, 1.91 g L -1 ), but that blood or urine silver levels did not correlate well with levels of environmental silver in work areas. A 29-years-old man accidentally inhaled dust containing g and 65 Zn in a minor nuclear reactor incident . He was assumed to have inhaled about 100 nCi of each element, the specific activities being approximately 15 Ci and 3 Ci per gram respectively. Radio labelled silver was monitored in his lungs, urine, and faeces for up to 200 days. Faecal excretion persisted for at least 300 days. The half-life of silver in this patient was estimated to be 52 days.
Greater occupational risk may be experienced by those exposed to inhalation of airborne silver particles as used in impregnation of biomaterials and in plating. As Burrell demonstrated, nanocrystalline particles ( 20 nm diam.) with a large surface to volume ration are expected to be dissolved more rapidly in moisture and achieve greater absorption . This implies that increased silver dissolving in alveolar fluid will lead to greater lung volumes. Alveolar macrophages (dust cells) sequester a large proportion of silver particles inhaled, thereby limiting the amount available to dissolve in alveolar moisture or to invoke inflammatory changes. Reference values have not been set on this problem but some hygienists place the risk of nasal and pharyngeal inflammation at exposures as low as 0.1 mg/m 3 with particles of grain size 20 nm diameter . Much research is needed in this area.
Extrapolation of human risk from inhalation toxicity studies of silver in animal models is complex in view of major interspecies differences in respiratory patterns and relative lung volumes . Whereas absorption of silver in a dog’s lung following intratracheal administration (equivalent to 1 gAg per cm 2. daily) is low, rats exposed to nanoparticulate silver exhibited a rapid clearance pattern . Alveolar macrophages were involved in mobilisation of silver released from silver nitrate, and silver precipitates were seen in alveolar phagolysosomes. Physiopathological evaluations have indicated that in subacute (90 days) inhalation studies, rats exposed to nanosilver (18 nm diameter) for 6 hours daily the lung function was markedly depressed, and female rats exhibited a dose-related increase in inflammatory responses . Thickening of alveolar membranes and granulomatous changes were reported after prolonged exposure to silver nanoparticles, but fatalities were not recorded.
2.3. Dermal Contact and Percutaneous Absorption
The majority of products containing silver or silver compounds for antibiotic purposes come into contact with human skin at some time, but clinical and experimental studies indicate that percutaneous absorption of silver is exceedingly low. Epidermal keratin and phospholipids of the epidermal barrier function provide effective barriers with exposed sulphydryl groups irreversibly binding free Ag + , in much the same way as other metallic elements [30, 60]. Where severe generalised argyria has been reported in occupational situations, it is expected that the greatest proportion of the Ag + absorbed occurs through inhalation or through contamination of contaminated food and drinking water .
The increasing use of metallic silver, silver thread, or silver impregnates in textile fibres designed for hygiene purposes might be expected to lead to percutaneous absorption, increased blood silver, and some accumulation of silver precipitates in the skin in chronic exposures. However, risks of argyria through the use of silver antibiotics in textiles and hygiene clothing are negligible even where the skin is warm and hydrated . As discussed in the recent conference “Biofunctional Textiles and the Skin” , concentrations of Ag + released for controlling dermatophytes and superficial bacterial infections were exceedingly low and sustained. Whilst more clinical research is necessary in this area, it is noteworthy that when a wound dressing containing 85 mg 100 cm -1 was applied to the skin of patients with chronic ulcers for 4 weeks, blood levels of silver were not significantly different from control patients .
Tracer studies using 111 Ag indicate that 4% of the total Ag + released from topically applied silver nitrate solution is absorbed through intact skin . Very low but perceptible penetration of nanoparticulate silver was demonstrated in human skin in vitro with in Franz perfusion cells . Median silver concentrations of 0.46 ng/cm 2 and 2.32 ng/cm 2 (range 0.43–11.6) were found in the receiving solutions of cells where the solution of nanoparticles was applied on intact skin and damaged skin, respectively. Granules of inert silver precipitate were detected in the stratum corneum and the outer layers of the epidermis by electron microscopy. Silver flux in damaged skin after 24 hours was 0.62 0.2 ng/cm 2 with a lag phase of 1 hour. Penetration of silver through guinea pig skin, which is similar in thickness to human skin, was estimated to be 1% in 5 hours .
Clinical studies have shown that silver sulphadiazine (100 g) in an amphiphilic formulation (Flamazine) is not noticeably absorbed through intact skin but in burned patients ( 5% total body surface) and that percutaneous absorption increased in line with the severity of the wounds, their depth and vascularity, and the concentration applied [35, 65]. Patients with 20% burns exhibited blood silver levels exceeding 200 g L -1 with the highest concentrations at 310 g L -1 , without argyria. Blood silver levels increased twentyfold within 6 hours to at least 40 g/L, rising to plateau after 4–7 days. Silver nitrate is appreciably more astringent than silver sulphadiazine and ionises more rapidly when applied topically as Strong Silver Nitrate (75%), silver nitrate sticks/pencils, or douches to remove warts, callus or undesirable granulations, but Ag + penetration is very low. Ag + binds to epidermal keratin and blackens on exposure to solar radiation to give characteristic brown-black discoloration. Local skin discolorations rarely occur following application of sustained silver-release wound dressings and occupational contact with silver oxide and other ionisable silver compounds, but are not representative of true argyria which is long lasting. Experimental studies have demonstrated that silver precipitates in epidermal wound debris, proteins (albumins and macroglobulins) in wound exudates, or as relatively insoluble silver chloride in the skin surface exudates to be lost in normal repair processes .
2.4. Miscellaneous Routes of Silver Absorption
Silver is employed in catheters for renal drainage, central vascular insertion, intraventricular drainage in patients with hydrocephaly and cerebrospinal fluid disorders, and in in-dwelling intraperitoneal use . A sustained release of Ag + from metallic silver, silver sulphadiazine, or other silver compounds is necessary to achieve antimicrobial efficacy, but the amount released into the circulation for binding plasma albumins and macroglobulins is not known. Schierholz et al.  considered that most of this irreversibly bound silver has no toxicological, physiological, or antimicrobial significance and that silver-coating or impregnation of medical devices is only effective clinically when the concentration of free Ag + is increased and the effect of contact with serum proteins and inorganic anions minimised.
Isolated cases are reported where abnormally high blood or tissue silver levels has been associated with the use of silver in patients implanted with silver-containing heart valves, bone cements, and acupuncture needles but none show silver or Ag + -binding to be a cause of tissue damage. A 76-year-old patient implanted with total hip replacement was shown to have blood silver 1000 times higher than normal, but this declined rapidly following the removal of the prosthesis and silver-containing bone cement [66, 67]. During the following 2 years, her serum silver concentrations decreased from 60 to 20 times higher than normal, and the patient partially recovered from an idiopathic muscle paralysis. A second interesting case of raised blood silver related to the use of silver as an antibiotic or anticalcification additive in bioprosthetic heart valves . The valve was withdrawn from clinical use for reasons other than the silver inclusion or Ag + release, but sheep implanted with silvered valves exhibited transitory increases in argyraemia to 40 ppb within 10 days of implant with decline to normal 30 days after surgery. Silver accumulated in the liver (16.75 mg g -1 dry wt.), kidney (8 mg g -1 ), lung, brain, and spleen ( 5 mg g -1 ) without evidence of toxicity.
Silver and gold acupuncture needles used in ancient Japanese “Hari therapy” for relief of muscular pains, fatigue, and other discomforts are potential causes of macular or more generalised argyria-like symptoms [69, 70]. Blood silver levels are not known from either report but the extent of argyria was related to the duration of acupuncture therapy and the number of needles inserted, and hence the quantity of Ag + released directly into the dermis. One 57-year-old lady is recorded as implanting 2,500 needles in 13 years to alleviate symptoms of rheumatic fever.
2.5. Silver Metabolism
Silver absorbed into the body as Ag + readily binds to intracellular proteins, notably serum albumins and macroglobulins for metabolism and distribution to bone and soft tissues. Experimental studies have demonstrated that Ag + actively absorbed from silver nitrate or silver sulphadiazine induces and binds the cysteine-rich proteins—metallothioneins (MTs) I and II in metabolically active cells of the wound margin [14, 71]. MTs are major metal carrier proteins but also serve as cytoprotectants in binding toxic metal ions thereby reducing risks of cytoplasmic damage.
Controversies exist on the predominant routes of silver metabolism in the human body, its transitory or longer-term accumulation in kidney, liver, and bone, and its excretion patterns in bile, urine, hair, and nail [36, 39]. The biliary route of excretion predominates over the urinary route but urinary silver measurement may provide a convenient index of silver absorption by all routes and serve as a guide to the total silver content of the body at blood levels of 100 g L -1 [36, 65]. At higher concentrations, patterns of urinary excretion are irregular. Biological monitoring of workers exposed to long-term environmental silver residues has shown raised silver concentrations in hair, blood, urine, and faeces [17, 35], but faecal silver represents that excreted in bile plus the 90% or more ingested with food and not absorbed into the circulation. From their examination of 37 silver workers, Di Vincenzo et al. concluded that at recommended environmental concentrations of 0.1 mg/m 3 (TLV), faecal excretion of silver would be about 1 mg daily . Critical evaluation of reported clinical and experimental studies has shown that silver is not absorbed into neurological tissue but is bound as inert precipitates in lysosomal vacuoles of the blood brain barrier and blood-CSF barrier [72, 73].
3. Manifestations of Silver Toxicity
Argyria is the principle manifestation of chronic inhalation or ingestion of metallic silver or ionisable silver compounds. Excessive absorption of Ag + over a long period leads to a state of silver “overload” in the circulation, where absorption exceeds the capacity of the liver or kidney to eliminate the metal in bile and urine, respectively. Argyria is characterised by the deposition of inert precipitates of silver selenide and silver sulphide in the connective tissue surrounding the vascular tissue and glands of the papillary layer of the dermis but not epidermis [52, 69, 70]. The fine deposits are inert, intracellular (lysosomally bound) or intercellular in distribution, and long lasting or permanent. The mild to profound blue-grey discolorations of the skin and nail bed occur mainly in light-exposed areas and on occasions may be severely disfiguring . There is no evidence to associate argyria with cellular damage or altered sensory perception in the skin, and even in cases of profound discoloration, argyria is not life threatening. In severe cases of generalised argyria, the discolorations may be psychologically disturbing since they are not readily removed chemically or by surgical dermabrasion. Fatalities in patients with profound argyria or argyrosis have been attributed to pre-existing medical conditions and not silver-related aetiology. Argyrosis more specifically denotes silver precipitation in the cornea or conjunctiva of the eye and is regarded by some as a more sensitive indicator of silver exposure . Whilst argyria is an unequivocal manifestation of chronic exposure to silver, on occasions, raised blood silver levels (argyraemias) are reported in silver workers where overt discoloration of the skin, eyes, mucus membranes, or nail bed are not recognised [35, 53].
The mechanism for dermal argyria is not fully understood but is thought to relate to imbalances in the local concentrations of soluble and insoluble complexes of silver in the middle or upper dermis and the action of lysosomal reductase . Buckley and Terhaar argued that in the mid-dermis, insoluble silver appears to be in an equilibrium with a variety of soluble forms of silver such as Ag + and silver mercaptides rich in cysteine and homocysteine, both of which are soluble at pH 7. They considered that an increase in soluble silver content involves the formation of more insoluble silver by a reductive process represented by the equilibrium
Formation of insoluble silver precipitate in dermal granules has been attributed to lysosomal action with the concentration of silver in lysosomes estimated to be 10 -5 M. They estimated that this molar concentration is “similar to the amount required to maintain oxidative stability of silver in dispersions such as Argyrol (a colloidal mild silver protein)”. They also suggested that a critical concentration of soluble silver exists, below which any lysosomal reductase is inactive, and where silver remains solubilised. Whilst these assertions have not been challenged, more recent work implicates selenium as a central factor in the production of insoluble silver complexes in argyric states. Microanalytical studies have revealed a tenfold increase in selenium in skin biopsies of argyric patients and have implicated the element in the “detoxification” of silver . X-ray emission spectroscopy of inert silver deposits in the kidney of a patient with generalised argyria showed that the particles were composed of silver selenide (Ag2Se) and not silver sulphide, suggesting that selenium was replacing the sulphide moiety [76, 77]. Silver selenide is a highly insoluble nontoxic material and not associated with reactive changes in tissue biopsies.
Despite electron microscopic evidence to the contrary [74, 78], silver deposited in connective tissue around hair follicles, and sebaceous or eccrine glands do not migrate across the dermoepidermal interface to be excreted in desquamated keratinocytes or in glandular secretions . Small amounts of silver sulphide deposited intercellularly in the dermis can be expected to be phagocytosed by dermal macrophages or eliminated through normal tissue repair process [79, 80], but in cases of generalised argyria the discolorations of the skin, buccal membranes, and hair and nail bed are expected to be long lasting or permanent. Whereas blood silver levels are usually greatly elevated in clinical argyria, argyraemia is not a reliable guide. Thus, Coombs et al. showed that patients treated with silver sulphadiazine for severe burns and showing blood silver of 300 g L -1 failed to show skin discoloration  whereas other cases of overt argyria failed to show correlation with elevated blood silver .
Melanin granules in the skin may protect against argyria by absorbing solar energy, but silver is not known to influence either melanocyte function or melanogenesis . On rare occasions where argyric discolorations have been erroneously identified as melanoma-like lesions, silver sulphide (or silver selenide) deposits were attributable to Ag + leaching from silver sutures used earlier in eye surgery [82, 83].
3.2. Argyrosis (Argyrosis Conjunctivae)
Argyrosis is defined as a dusky grey/blue pigmentation of the cornea and conjunctiva resulting from deposition of inert silver precipitates following chronic occupational, therapeutic, or environmental exposure to silver or soluble silver salts [33, 81, 84]. It is frequently a more sensitive outward sign of silver exposure than argyria, but like argyria it is not associated with pathological damage in any tissue. Therapeutic argyroses may have been known since the 17th Century when silver nitrate was used to treat epilepsy and venereal diseases and in the late 19th century when Credé et al. introduced silver nitrate as a prophylactic for neonatal eye disease , but more recent reports relate more to chronic occupational exposures to silver or the use of colloidal silver preparations for ocular infections [81, 84, 86, 87]. Exposure to silver in soldering, in particular, is held to be a common cause of argyrosis, but less commonly the use of silver in eyelash tints, jewellery work, therapeutic use of silver nitrate or colloidal silver preparations (notably 1% Argyrol, mild silver protein in eye drops), and industrial accidents are reported [88–93]. In each case, silver precipitates in the form of sulphide or selenide have been reported in the cornea, conjunctiva, lens, and lachrymal tissues with the severity reflecting the duration and severity of exposure, the ionisation of the silver compounds involved, and the nature of the exposure. The occupational risks of argyrosis and the toxicophysiological significance of the cytological changes are well illustrated in a study of 30 workers in silver nitrate and silver oxide manufacture [33, 81]. The conjunctiva was most frequently involved (20/30) with corneal pigmentation in 15 workers following a mean exposure period of 5 years. Slit lamp and visual acuity tests revealed more profound pigmentation of the caruncle and semilunar folds of the conjunctiva, and with corneal changes affecting the limbus, Descemet’s membrane and peripheral cornea. Lens changes were noted in 4 patients. Electrophysiological tests revealed a lack of retinal damage in all volunteers, but 10 reported decreased night vision and a significant association between this nyctalopia and pigmentation of the conjunctiva/cornea. Cauterisation using lunar caustic and the use of silver nitrate to stem haemorrhages have been associated with corrosive damage and corneal opacities mainly attributable to the caustic action of the nitrate anion [92, 94]. On occasions, discolorations attributable to silver precipitates in conjunctiva, cornea, or lachrymal gland tissues have simulated melanoma, but correct diagnoses have been provided by biopsy examination and records of patients’ clinical histories [82, 83, 95].
Correct diagnosis of argyrosis has been aided by confocal and specular microscopy, X-ray analysis, and electron-microscopy, but the deposition of silver precipitates in various circumstances has varied greatly according to the type of exposure and the ionisation patterns of the silver compounds implicated. In a study simulating Credé’s preventive therapy with 1% silver nitrate therapy for neonatal eye infections (ophthalmia neonatorum), a lamellar keratectomy from a very young treated child revealed electron dense granules 100–300 nm in diameter deep in the corneal stroma . In contrast, in an accident victim exposed to silver nitrate in an explosion, silver precipitates were more widely distributed in the eyelids, conjunctiva, and superficial layers of the cornea with diffuse particles located in the epithelial basement membrane, Bowman’s layer, and Descemet’s membrane . Silver-rich particles in the deep corneal stroma were lysosomally bound in connective tissues or free within intercellular spaces and associated with tissue debris, similar to those reported in silver-related dermal injuries. The mechanism of argyrosis has not been investigated in detail, but it is expected to follow a similar pattern to that in argyria [86, 87]. High-selenium and silver-intracellular precipitates were prominent in the region of the rough endoplasmic reticulum as demonstrated using X-ray microanalysis with energy dispersive technology (EDAX) .
3.3. Silver in Soft Tissues
The skin (and its appendages), eye, brain, liver, kidney spleen, and bone marrow are listed as principle target tissues for silver deposition following systemic absorption [3, 17, 21, 33, 42]. Critical analysis of published literature revealed that despite claims of neurological damage in clinical and experimental studies, silver is not absorbed into the brain and central or peripheral nervous systems, and there is no substantive evidence that it passes across either the blood brain barrier or blood-CSF barrier in any species [72, 73]. Silver acetate when used as deterrent to smoking evokes a bitter taste in the presence of tobacco smoke but is otherwise safe and effective . Elsewhere, Westhofen and Schafer  presented a case of a patient with generalised argyrosis associated with progressive taste and smell disorders, vertigo, and hypesthesia. The findings were ratified by chemosensory and electrophysiological tests, and hypogeusia and hyposomia were checked using subjective and olfactory tests but apart from electron-dense deposits of silver sulphide in macrophages and along perineuria and nerve tracts no histological damage was recorded using light or electron microscopy.
Clinical and experimental studies regularly list the liver as the principle organ for silver accumulation and elimination, but apart from transitory changes in certain metabolising enzymes, no evidence is seen to show that even in patients with blood silver of 200 g L -1 or advanced argyria, silver is a cause of irreversible pathological hepatic damage [65, 97, 98]. Daily administration of 50 mg silver leaf to 30 healthy volunteers for 20 days led to transitory increases in blood phospholipid, triglycerides, cholesterol, glycaemia, and associated enzymes, but no functional changes in the tissue . Electron microscopy has confirmed that in patients with high hepatocellular silver deposition (up to14 g. -1 wet weight), the precipitates are inert, lysosomally bound, and presumably extruded into bile ducts as a normal physiological process [65, 99]. Experimental studies in animal models have shown variations in hepatic management and biliary excretion of silver. Intravenous injection of dilute silver nitrate was associated with biliary excretion patterns of 0.25 g kg -1 /min. in rats, 0.05 g kg -1 /min. in rabbits, and 0.005 g/.kg -1 /min. in dogs . As in other tissues, Ag + evokes and binds MT-1 and MT-2 and is eliminated innocuously in bile without morphological change . Subacute (28 day) toxicity tests showed that rats tolerated massive doses of 1000 mg kg -1 nanoparticulate silver (60 mn) without significant changes in body weight, but that at doses of 300 mg kg -1 , increased alkaline phosphatase and cholesterol levels may reflect functional liver changes in the tissue . Klaassen confirmed that faecal excretion is greatly superior to biliary elimination for silver and that in g-labelling experiments, bile concentrations within 2 hours of intravenous administration were 16–20 times higher than in plasma, reflecting clear dose-related plasma to bile gradients . Faecal excretion accounted for 70% of the administered dose compared to 1% in urine. The study also emphasised marked interspecies differences in silver metabolism and excretion, with rabbits excreting the metal at a tenth of the rate seen in rats and dogs at one hundredth of the rate. Experimental studies in rats have also demonstrated that copper and the antioxidants selenium and vitamin E can influence the hepatobiliary transport and retention of silver in the liver [104–106]. Copper and silver are known to interact in MT and caeruloplasmin binding whereas selenium exhibits a strong tendency to precipitate silver as silver selenide, thereby promoting silver retention in the tissue .
Urinary excretion of silver is appreciably lower than biliary elimination and provides a less accurate measure of silver absorption by all routes. Clinical studies in burn-wound patients treated chronically with silver sulphadiazine suggest that a “threshold” of about 100 g L -1 blood silver exists and that above this level urinary secretion is variable [36, 65]. In a severely argyric patient, 18% of an oral dose of g was retained in the body for up to 30 weeks . The argyraemia in this patient 2 hours after treatment was low (4.5
10 –4 % of the dose administered), and a small proportion of the original dose was excreted in urine over the next 7 days. Neither study provided evidence of renal damage or functional impairment in a total of 23 patients subjected to known concentrations of silver. In contrast, mild increases in renal N-acetyl-B,D -glucosaminidase were reported in 4 of 27 workers exposed to silver occupationally, but the significance of this change is unclear . Other occupational health studies confirm renal management and excretion of silver with no obvious pathological effects [17, 33, 34, 53].
Renal pathology is an expected risk where silver nitrate is instilled into the renal pelvis or ureter as a therapy for filarial worm infestations like Wuchereriay brancrofti (chyluria), which represent major health risk in Southeast Asian countries [107–109]. Renal and hepatic failure, acute necrotizing ureteritis, obstructive nephropathy, and papillary necrosis have been reported following injection of up to 3% silver nitrate, although practitioners consider that the therapy is a “safe and minimally invasive treatment” for chyluria [107, 110].
The low nephrotoxicity of silver in the urinary tract has been confirmed in experimental studies in rodents given silver nitrate intravenously or in drinking water . Silver precipitates have been observed on glomerular basement membranes, arteriolar endothelia and elastic laminae, without obvious structural damage [112, 113]. Berry et al. noted high levels of renal selenium sulphur and silver in the precipitates in renal membranes and interpreted the role of selenium as a cytoprotective agent . As in human studies, precipitates of silver sulphide or silver selenide were lysosomally bound. Renal toxicity was not recorded in mice given high doses of 65 mg kg -1 silver nitrate daily for up to 14 weeks .
The ability of silver sulphadiazine (SSD) and silver nitrate to evoke changes in white blood cell populations (WBC) following therapy in burn wounds is equivocal [114, 115]. Since its introduction in 1968 and clinical marketing in the USA in 1973 , SSD has been frequently documented as a cause of leukopenia and lowered granulocyte counts, but these changes have normalised when therapy has been discontinued. Thus, Thomson et al.  recorded reduced white blood cell counts (WBC) of ≤5000/mm 3 in burn-wound patients treated with either SSD or silver nitrate within 3 days of injury (40 of 84 after SSD and 13 of 30 following silver nitrate therapy). Choban and Marshall confirmed this risk in patients with 15% total body surface burn wounds, but demonstrated that WBC normalised when SSD or silver nitrate therapy was withdrawn with no further complications . In their view, SSD-induced leukopenia should be viewed as a “self-limiting phenomenon that does not increase the incidence of infectious complications nor affect the final outcome”. Nevertheless, burn-wound strategies should predict that where WBC fall to less than 2000/mm -3 , SSD therapy be terminated as a precaution . The mechanism for postburn leukopenia is imperfectly understood. Whilst in vitro and experimental studies in mice indicate that SSD can suppress leukocyte progenitor cells in the bone marrow [120, 121], in a clinical situation SSD may be just one contributory factor. Burn stress or silver allergy may be partly responsible [121–123]. Leukopenia/neutropenia was reported in nine patients with a mean WBC of 2,680/mm 3 where SSD was associated with immature band forms in peripheral blood, but WBC normalised within 2-3 days . Prospectively, a survey of opinion in 101 burn clinics in North America and review of published case reports indicated that postburn leukopenias attributable to SSD, silver nitrate, or other causes “hold little risk for the burn patient” .
Methaemaglobinaemia is a supposedly rare complication of 0.5% silver nitrate therapy in burn clinics, particularly in children . The condition is attributable to alterations in the oxygen-carrying capacity of haemoglobin resulting from oxidation of ferrous iron (Fe ++ ) to the ferric state (Fe +++ ) through the action of the nitrate anion , and not through Ag + absorption. Nitrate is reduced to nitrite by nitrate reductase activity of intestinal flora as a preliminary to methaemoglobin formation. The condition may be life threatening, but normal blood oxygenation is restored with intravenous therapy with methylene blue .
3.4. Silver in Bone
Bone toxicity is not widely recognised in the safety evaluation of silver and silver-containing products, but there are strong indications from in vitro models that Ag + interacts with and binds to the hydroxyapatite complex and can displace calcium and magnesium ions [128, 129]. Other research has demonstrated that Ag + induces calcium release from the sarcoplasmic reticulum in skeletal muscle by acting on the calcium-release channels and calcium-pump mechanisms, presumably through oxidising sulphydryl groups . Although this suggests that bone and possibly cartilage are vulnerable to prolonged release of Ag + used as an antibiotic in bone cements, orthopaedic pins, dental devices, and so forth, this has not been established so far. No cases of osteoporosis have been reported following long-term ingestion or inhalation of silver or -implantation of silver-coated or impregnated orthopaedic devices. Osteoblasts cultured in the presence of silver wire failed to show a statistically significant reduction in cell growth after 48 hours, although alkaline phosphatase activity was markedly depressed . Silver salts of varying solubility—oxide, chloride, sulphate, or phosphate—were entirely biocompatible with osteogenesis in cultured rabbit bone, and foreign body reactions were minimal . With the exception of the oxide, all seemed to maintain the compressive strength of rabbit bone, following implantation in paraspinal muscles (Silver-coated orthopaedic fixing pins designed for external fixation were entirely compatible with bony and periosseous tissues . In a clinical situation, inappropriate use of a silver-impregnated bone cement led to a 1000-fold increase in argyraemia and silver in acetabular cavity of 103.3 g L -1 , but these high systemic and local silver concentrations were not associated with osteological damage in this patient [66, 67].
3.5. Contact Allergy and Delayed Hypersensitivity
Metal allergies present major problems in diagnosis in dermatology clinics since most metals and metal salts are impure and contaminated by other metals like nickel, chromium, and cobalt with recognised risk [134, 135]. Allergy to silver is a known adverse effect of silver exposure in coinage, cosmetics, and in patients treated with silver nitrate, SSD, and sustained silver-release wound dressings to control wound infections, but a proportion of predisposed metal workers, jewellers, photographers, and other persons exposed to silver or silver salts occupationally may exhibit symptoms of delayed contact hypersensitivity . The true extent of the problem is not known as diagnostic standard patch tests using 2% aq. silver nitrate are not routinely conducted except in health threatening situations.
Argyria or overt skin reactions do not arise through contact with metallic silver, but small amounts of Ag + released in the presence of skin exudates or moisture are sufficient to evoke symptoms of contact sensitivity in predisposed persons . Aged solutions of silver nitrate with greater ionisation were shown to be appreciably more allergenic than freshly prepared reagents . Although argyria as a response to silver and colloidal silver preparation had been reported from the beginning of the 20th Century [137, 138], the first reported case of true allergy was seen in a 26-year-old man following use of colloidal silver (Argyrol) to treat asthma and hay fever . Silver allergy was confirmed using scratch tests and intradermal injection of 0.05 ml of 1% silver nitrate. In more recent times, contact allergies to Ag + have been confirmed in occupational situations, and such conditions as “silver-workers finger”, “silver-fulminate itch” (in explosives industry), and “silver coat dermatitis” have been recognised [140–142]. Numerous cases are reported of SSD-related allergic dermatoses, with confirmation using patch and photopatch testing [143, 144].
4. In Vitro Cytogenicity, Mutagenicity, and Carcinogenicity
Cell culture systems have been developed in recent years as inexpensive means of examining intracellular metabolism of xenobiotic materials and mechanisms of cellular toxicity. In vitro tests have limited value in relation to in vivo assays discussed above for concentrations exceeding 5 ppm, and as far as I am aware, full preliminary screening for mutagenicity and carcinogenicity for silver and silver compounds has not been completed . Published cytotoxicity tests and in vivo experience indicate unequivocally that silver is not carcinogenic in any tissue and should be placed in a “No Risk” category . A large number of in vitro toxicity studies demonstrating the cytotoxic effects of metallic silver, silver sulphadiazine, or other silver compounds have been published in recent years, but observations in cultured fibroblasts, keratinocytes, and other human cell lines reflect the ability of Ag + to react with sulphydryl groups, other protein residues, and enzymes associated with cell membranes leading to denaturation, structural damage, and mitochondrial dysfunction, in much the same way to that seen in bacterial and fungal cells . Fibroblasts tend to be more sensitive to Ag + than keratinocytes, but silver toxicity in cultured cells may be influenced by the age of the donor and the composition of the culture medium . Human diploid fibroblasts and fresh human donor dermal fibroblasts were inhibited by short-term exposure to silver sulphadiazine and impaired proliferation was associated with marked changes in cell morphology including cytoplasmic deterioration and degeneration of nuclei and cell organelles . Growth factors including platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and basic fibroblast growth factor ( -FGF) which modulate cell proliferation, migration, and functional maturation in epidermal repair following injury have been shown to cytoprotect dermal fibroblasts from injury by silver sulphadiazine, suggesting that cells activated by growth factors are more resistant to the toxic effects of silver antibiotic , but this is unconfirmed by clinical or in vivo studies.
5. Reproductive Toxicity and Teratogenicity
Insufficient evidence is available presently to show that administration of silver or ionisable silver compounds in pregnancy is a cause of infertility, impaired foetal growth, or abnormal development in any species. Silver nitrate (1%) administered by intrauterine injection to 13 cynomolgus monkeys between 27 and 43 days of pregnancy caused early vaginal bleeding and termination of pregnancy but two of seven animals re-mated became pregnant again and delivered healthy offspring . It is not known whether Ag + passes transplacentally to accumulate in the foetus.
6. Nanotechnology and Nanocrystalline Silver
The antibacterial and antifungal efficacy of silver in medical devices, clothing, wound dressings, and so forth is directly proportional to the release of Ag + and its availability to interact with cell membranes leading to lethality and inactivation of toxins produced . Burrell has clearly identified the ionizing properties of metallic silver and silver compounds and shown that nanocrystalline particles ( 20 mn diameter) exhibit a solubility of 70–100 g mL -1 , that is, up to 100-fold greater than metallic silver. He is of the opinion that these nanoparticles show specific physical and chemical properties which may influence their biological action. In his view, the “grain boundary region of crystals of <20 nm may represent a new state of solid matter” . Differences in biological effect are illustrated in the antibacterial effects against Pseudomonas aeruginosa in culture and in the anti-inflammatory action of microcrystalline silver and silver nitrate in rodent models discussed above. Wound care products containing nanocrystalline silver (e.g., Acticoat, Smith & Nephew) have an acclaimed success in controlling infections in chronic wounds and ulcers . However, further studies are necessary to determine whether the antibacterial and physiological effects are attributable to the silver ion per se or to the unique biological properties of the silver microcrystals.
Workers involved in production of nanocrystalline silver over an extended period are potentially at risk of inhaling microparticles leading to argyria and argyrosis unless stringent safety precautions (air filters, personal respirators, etc.) are followed . Workers may be exposed to silver in the workplace unintentionally through hand to mouth transfer of materials or swallowing particles cleared from the respiratory tract. The National Institute of Safety and Health (NIOSH) is currently conducting research to determine the extent to which nanocrystalline silver poses a threat to exposed workers and under what circumstances and emphasising that presently no international standards have been introduced in the USA or elsewhere .
Specific toxicity studies and clinical trials have been conducted in relation to wound dressings including Acticoat containing nanocrystalline silver, where burn-wound patients exposed for up to 9 days exhibited increases in blood silver (56.8 g L -1 ), which normalised to 0.8 g L -1 after 6 months . Clinical studies are urgently required to examine the occupational risks associated with the use of highly dispersed nanocrystalline silver in general-purpose biocides, consumer products, electronics, metallurgy, and chemical catalysis [152, 153].
Laboratory evaluations of the toxicity of nanocrystalline silver are not numerous. Some have been discussed above in relation to the cytotoxicity and genotoxicity of silver particles in cultured lung fibroblasts and glioblastoma cells . Silver is absorbed into cultured cells by a pinocytic mechanism, and as in bacteria and fungi, can be expected to interact with and precipitate with cytoplasmic proteins leading to cell death. Minimal cytotoxic concentrations reflect the subcellular proteins and Ag + -binding sites. Cultured cells exposed to silver particles at 6.25–50 g mL -1 showed altered cell shape and showed evidence of oxidative stress and increased lipid peroxidation . Inhalation toxicity studies in rats conducted for Samsung Electronics Co. (Korea) have shown that the lungs and liver are principle target organs but that no effects were observable at environmental concentrations of 100 mg/m 3 [58, 59, 156]. Exposures at 133 mg/m 3 or 515 mg/m 3 evoked inflammatory and granulomatous changes in the lung and bile duct hyperplasia.
The present paper emphasises that health risks associated with systemic absorption of silver as Ag + are low. Argyria and argyrosis are the principle observable changes associated with long-term exposure to ingestion or inhalation of metallic silver or ionisable silver compounds, but neither is life threatening or associated with irreversible tissue damage. It is debatable therefore whether these conditions should be classified as “toxic changes”, but it should be emphasised that severe long-lasting argyria and argyroses arising from unprotected occupational exposures to silver or unregulated consumption or inhalation of unregulated colloidal silver preparations can be profoundly disfiguring and a cause of serious psychological and personal problems and should not be dismissed as irrelevant observations [18, 19, 38, 157, 158]. I have seen no unequivocal evidence to show that silver exerts morphological damage on neurological tissues [72, 73].
Clinical experience has shown that transitory changes in hepatic and renal enzyme systems in patients exposed to high clinical or environmental silver are of minimal toxic significance [17, 33, 65]. At the moment, there is no good evidence to show that silver accumulates preferentially in bone, influences significantly calcium-modulated events in the heart, skin, and other tissues, or is a putative cause of osteoporosis, but further clinical research is required. On the other hand, there is irrefutable evidence that silver like most other xenobiotic metals, can evoke delayed contact hypersensitivity reactions and allergy in predisposed persons and this should be viewed as potential toxic hazard, albeit that the extent of the risk is not known . Animal models have provided little guidance as to potential risks associated with silver exposure or sensitivity to argyria in humans, but some have provided useful information on cellular management of the metal and the role of silver-binding and carrier proteins in cytoprotection and metabolism [1, 14, 31, 71, 72]. In vitro toxicity studies with silver exposed to fibroblasts, keratinocytes, or other cell lines have minimal relationship to in vivo experiments using recognised animal models, but they are useful in confirming the lack of mutagenicity or carcinogenic change attributable to silver.
Regulatory authorities have evaluated reference standards and exposure limits to metallic silver and soluble silver compounds in occupational health situations, drinking water, medical devices, wound dressings, and consumer products based on published data on argyria and/or argyrosis as the only tangible evidence of silver exposure [2, 3, 44, 100, 146, 150]. At the moment, there are no clear guidelines from case studies or occupational health reports to indicate a clear relationship between clinical or occupational exposure to silver, blood silver levels, or minimal body silver concentrations consistent with early signs of the condition. As East et al.  showed in only one patient, profound argyria resulting from 2 years exposure to silver acetate antismoking device was associated with total body accumulation of 6.4 g of silver, much of which was deposited in the skin 71.7 g g -1 . Although dermal silver concentrations were 8000-fold higher than normal reference values , the patient remained in apparent good health. Elsewhere, argyria in a burn patient treated with a sustained silver-release wound dressing was associated with blood silver levels of 107 g kg -1 and urinary silver of 28 g kg -1 , but no other changes . Other studies claim that total body silver concentrations of 4-5 g can produce the clinical picture of argyria . Fung and Bowen noted that in reported cases up to 1973, 365 cases of argyria had been referred to the US Food and Drug Administration and that a total body burden of 3.8 g elemental silver was required to evoke argyria . It is emphasised that estimations of tissue and body silver in these older studies are considerably less accurate than those available these days using flameless thermal atomic absorption spectrophotometry or mass spectrometry with sensitivity of 1 g L -1 tissue silver measurement or lower (B. Sampson, personal communication) .
Opportunities these days to study silver intake as a cause of detectable argyric change are few, since silver compounds are not legally available for oral or enteric administration (other than silver acetate in antismoking devices) in many countries, and introduction of far-reaching international health and safety standards at work regulations greatly reduces the risk of chronic occupational exposure. Current exposure limits for metallic silver and ionisable silver compounds of 0.01 mg/m 3 in air (silver levels in drinking water 0.10 mg L -1 ) set by the National Institute for Occupational Safety and Health and the American Conference on Governmental Industrial Hygienists in environmental exposures and drinking water regulations of 0.10 mg. Ag L -1 (EPA) indicates that humans are unlikely to be exposed to sufficient silver in their food, drinking water, workplace, or in therapeutics in their lifetime to provoke symptoms of argyria [2, 3, 44, 161]. The amount of Ag + released from catheters, textiles, and wound dressings using silver for permitted antibiotic purposes is very low and probably of no toxicological significance, other than being a cause of allergy [1, 61]. However, indiscriminate ingestion or inhalation of colloidal silver preparations (with unspecified concentrations of ionisable silver) for infective and non-infective conditions still presents a real risk for argyria and argyrosis and associated psychological problems [162, 163]. Older studies frequently cited in calculating reference values for silver such as those conducted by Gaul and Staud  and Hill and Pillsbury  should be viewed with caution. The former discussed incidences of argyria in a total of 70 patients exposed intravenously to varying doses of the highly toxic antisyphilitic drug silver arsphenamine (for which the chemical formula and ionisation potential are still not resolved) and undisclosed colloidal silver preparations claimed that argyria developed after a total dose equivalent to 1.84 g of silver. Since the actual formulation of colloidal silver products available these days is not known, it is even less likely that the silver content of those available in 1935 was known. Hill and Pillsbury gave a lucid account of the clinical picture of argyria , but lacked the facility to examine fully the implications of silver exposure and the pathological features of the condition.
Silver should not be regarded as a cumulative poison . Only in cases of chronic systemic silver overload situations where excretory mechanisms become saturated, does silver deposit in an inert fashion in lysosomal or intercellular sites, unrelated to tissue damage. In these situations, selenium serves as a major protective factor in precipitating the silver in a highly insoluble and hence inert form of silver selenide. Although some of this may be taken up in lysosomes in macrophages, the deposits are essentially long lived or permanent. Available knowledge indicates that in normal healthy people, argyraemias of 3 g L -1 are usual , and that raised levels are seen in persons occupationally exposed to the metal without suitable protective measures (face masks, etc.) [17, 33, 34, 53]. The inherent human risks of argyria through entering food chains presenting health risks to people living in areas highly polluted with silver residues from factory wastes as in the San Fransisco Bay region require urgent attention .
The author is grateful to Ciba Ag and BASF GmbH for their support.
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