Abstract:

Many
children around the world are undernourished. According to the World Health
Organization (WHO), about 1.3 million children die as a result of a nutrition
based deficiency. In addition, about 156 million children aged less than five
years are suffering from stunting, and about 50 million of the same age suffer
from wasting ⁽¹⁾. It is clear that many children worldwide have
inadequate nutrition, which makes them vulnerable to many diseases and
sometimes death. To protect kids from these serious consequences, their food
must contain essential nutrition supplements that includes vitamins and
minerals. This is because of the importance of minerals and vitamins in the
growth and development stages of children. Therefore, infant formulas must
contain the essential vitamins and minerals for the physiological functions in
the body of infants.  However, a number
of micronutrients should be suitable for the body’s needs, so that it does not
result in deficiency or of overdoses.

Food fortification means the adding of micronutrients to food during its manufacture ⁽²⁾. One must choose the appropriate method of infant formula fortification to ensure the preservation of micronutrients during processing and storage. Nanotechnology in food fortification has several benefits, including economic, practical, plus effective and healthy benefits for the body by increasing the supply of nutrients ⁽³⁾. Nanotechnology in food and dairy manufacture is divided into two categories; food additives (nano inside) and food and dairy packaging (nano outside).

Introduction:

According
to (WHO), 45% of children around the world die due to a lack of nutrition. In
2015, 156 million under the age of five years suffered from stunting (too short
compared to their age), 50 million of the same age suffered from wasting (too
thin compared to their age). In contrast, 42 million children around the world
were overweight and obese ⁽¹⁾. All these facts show that many
children worldwide do not receive adequate nutrition. Therefore, one must
support all sources of nutrition for children by providing the essential
nutrients, which are necessary for growth and which protect against diseases.

WHO
and UNICEF, recommend providing early breastfeeding during the first hour from
birth and to continue breastfeeding exclusively for six months. After six
months, one can begin to give children safe and complementary nutrition with
continued breastfeeding up to two years of age ⁽¹⁾. This is because
breastfeeding contains all the required nutrients for healthy growth and
development. Also, it contains antibodies, that protects the baby from common
childhood diseases like pneumonia and diarrhea. Moreover, breastfeeding is
easily available and affordable, which ensures that children receive adequate
nutrition ⁽⁴⁾. However, there are exceptional circumstances that may
prevent or reduce breastfeeding such as maternal exposure to some diseases,
teenage mothers and infants who suffer from malnutrition⁽¹⁾. For
these reasons, formula milk is an appropriate alternative.

“Infant
formula is defined as a breast milk substitute that can fulfil by itself all
the nutritional requirements of an infant from birth up to the introduction of
complementary feeding” ⁽⁵⁾. The aim of formula milk is to supply a
formula-fed infant the same growth and development as a breastfeed infant. So,
an infant formula must be prepared carefully to meet the needs of infants, not
only the macronutrients (carbohydrates, proteins and lipids), but also the
micronutrients (vitamins, minerals, etc.). Cow’s milk is the essential
ingredient for an infant formula, but it cannot be given to babies because of
the different composition of breast milk ⁽⁵⁾. Although, the milk is
rich in nutritional proteins, amino acids, minerals and vitamins, some of these
elements are lost during the manufacturing process. For example, vitamins in
food are susceptible to loss due to technological or cooking processes. Fat
soluble vitamins are destroyed by oxygen, whereas B vitamins are destroyed by
temperature and light ⁽⁶⁾. Therefore, there should be a careful selection
of vitamins and minerals to be added to an infant formula ⁽³⁾.

Fortification
is defined as the addition or enrichment of micronutrients to the diet, whether
these nutrients are normally present in the food or not. The goal of food
fortification is to prevent or correct a demonstrated deficiency. However, it
should be added in sufficient quantities to meet targets without causing a risk
of toxicity as a result of overdosing ⁽³⁾. In the process of
fortification one must choose the appropriate method to ensure the preservation
of the minerals and vitamins during processing and storage. Recently,
nanotechnology applications have played an important role in food
fortification, because of the increase in surface area in nano size when
compared with the bulk materials of the same components. Nanoparticles are
absorbed in the digestive tract easily, leading to the increased
bioavailability of nutrients in the body ⁽³⁾.

The
aim of this report is to discuss the importance of vitamins and minerals for
the physiological functions the body. Furthermore, this review will explain the
effects of a lack of micronutrients especially in infants, and the consequences
as a result of deficiency. These consequences could be reduced in infants by
improving the micronutrient value of infant formulas. This can be obtained by
using nanotechnology to fortify baby milk. This review contains three sections.
The first section will explain the importance of minerals for the human body
and diseases resulting from either shortage or excess (overdosing). In
addition, it will discuss the metabolism of minerals, and the factors that
could have an effect on their absorption. The second section will demonstrate
the importance of vitamins for the physiological functions, and it will show
the damages which can be caused by a deficiency or too high a dose. The last
section will explain the background of food fortification especially using
nanotechnology.

Essential minerals and vitamins for babies:

Minerals to be fortified:

Minerals
are inorganic elements that are necessary for normal growth and development of
the body ⁽³⁾.  Although,
minerals are essential for several biological processes, the body needs only
small amounts of them to complete the vital functions.

Calcium:

It
is known that, calcium is the essential ingredient for building bones, which is
considered the main cation of bone mineralization. Also, calcium plays other
important roles in the body including a signaling role and as an intrasellar
messenger in many systems and cells ⁽⁷⁾.

There
are two routes for absorbing calcium through the intestine; transcellular and
paracellular. The transcellular route is saturable and it mainly depends on
vitamin D, while the paracellular route is non-saturable and is the transport
mechanism for most calcium absorption ⁽⁷⁾⁽⁸⁾. The process of
transcellular calcium transport in the intestine is affected by vitamin D. The
calcium intake recorded in formula-fed infants during the first year of life is
up to 900mg/day; it is higher than the calcium intake in breast-fed infants
which is about 200 mg/day. The absorption fraction in this range is between 30%
and 60% at the lowest intake. There is no evidence of damage at the highest
intake of calcium. There is no evidence of damage to the high intakes of
calcium ⁽⁹⁾.

There
are several factors affecting calcium absorption. For example, calcium
absorption in a formula containing lactose is about 60%, which is greater than
from a lactose-free formula ^(9)(10).

A deficiency
of calcium could lead to osteomalacia and osteoporosis due to inadequate
mineralization of the bone matrix, inaccessibility of peak bone mass, a higher
risk of colon cancer, growth stoppage and high blood pressure ⁽³⁾. Rickets
is a common disease among children resulting from a lack of vitamins and
calcium intake. However, there are many cases of rickets in children due to low
calcium in the presence of sufficient vitamin D intake. For example, in rural
villages of South Africa, the cause of rickets is attributed to low calcium
intakes, where the children’s meals were free of milk and milk products. It has
been estimated that their calcium intake is about 200mg. This amount of calcium
intake was very small when compared with the children’s needs ⁽¹¹⁾. In
contrast, overdoses of calcium intake may cause hypercalcemia (kidney stones, nausea,
constipation). In extreme cases, it might lead to coma and death ⁽³⁾.

Copper:

In
general, dairy products are considered poor sources of copper. However, copper concentration
in human milk is higher than in cows’ milk. Over the past 25 years most infant
formulas have been fortified with copper by 90-12mcg/100 kal (approx. 110-160
mcg/kg/d). This requirement has changed to 120-150 mcg/kg/d or between 100-130
mcg/kg/d⁽¹³⁾.

Copper
is required for growth and development, where it works as a significant
catalytic cofactor to oxidize proteins which perform many fundamental
biological functions ⁽¹⁴⁾. “Further studies confirmed these findings
and established that copper was required for infant growth, host defense
mechanisms, bone strength, red and white cell maturation, iron transport,
cholesterol metabolism, myocardial contractility, glucose metabolism, and brain
development” ⁽¹⁵⁾.

In
humans, copper is absorbed into the small intestine and stomach in small
proportions.

The
proteins in blood plasma and interstitial fluid play an important role in
uptake and transport of copper by affinity copper binding. These proteins
include albumin which is bound to 10-12% of the total copper in plasma. But it
is not required for the absorption of copper in the liver and kidney.
Ceruloplasmin is likely the major source of copper for other types of tissues.
Due to the nature of highly reactive copper, it is possible to interact with
cell membrane proteins and nucleic acids in the cells and damage them. Thus,
copper (Cu) is delivered to the cells as copper chaperone proteins instead of
free ions ⁽¹⁴⁾.

Copper
deficiency is often seen in infants, during the first five months – the liver
stores provide a sufficient quantity of copper for both preterm infants and
full-term infants. Copper deficiency in this period is due to a decrease in copper
deposits at birth, malabsorption, inadequate dietary intake of copper or
increase of the copper loss ⁽¹⁵⁾. However, preterm infants are more
susceptible to copper deficiency, and this is because of the lack of copper in
the liver stores and their high requirements, which are necessary for rapid
growth. Copper deficiency might occur in other cases, such as where formula milk
is not fortified with copper, or there are high intakes of iron, zinc or
ascorbic acid, which reduces the copper absorption rate. However, most cases of
copper deficiency occur in children who are malnourished, whether due to low
birth weight, a short breast feeding period, diarrheal disease or other
deficiency factors ⁽¹⁵⁾. All these cases of decreases of copper in
the body lead to hypochromic anemia not responding to iron, a defect in the
production of heme and depigmentation of skin and hair ⁽³⁾. In contrast,
a high intake of copper could lead to toxicity. Although copper overload is
likely to happen in only a few cases compared with copper deficiency, it might
lead to vomiting, hepatic necrosis, nausea and cellular oxidative stress. High
doses of copper could be more dangerous for patients who suffer from genetic
diseases. These diseases have a higher risk of accumulating of copper, such as
Wilson’s disease (WD) ^(16)(3).

Fluoride:

Fluoride
plays an important role in bones and teeth. In the bone, it can stimulate bone
cells and increases the distribution of new mental in cancellous bone. Also, it
reduces the solubility of the bone (apatite) by the merger of fluoride with
bone crystals, which become bigger and more resistant to osteoclastic attack ⁽¹⁷⁾.
In teeth, the basic role of fluoride is to protect the teeth from decay. This
occurs because of the fermentation of carbohydrates to acids, which
demineralize tooth enamels, by colonies of bacteria on tooth surfaces ⁽¹⁷⁾.

As with
most nutrients, fluoride is absorbed significantly through the digestive system
but the absorption ratio is variable (ranging 10-90%) and depends on
influential factors ⁽¹⁸⁾. During the first year, fluoride
supplements for children should consider other sources such as fluoridated water
to avoid the risk of dental fluorosis, and an increase of the brittleness of
bones and ligament ^(17)(3).

Tooth
decay is one of the most common health problems among children around the world
even in the developed countries. In 2013, for example, about 31% of British
children who were aged 5 years and about 46% of 8 years olds were suffering
from decay in primary teeth ⁽¹⁹⁾. Dental caries could be a serious
health problem at all stages of life, due to severe pain in the mouth resulting
from tooth decay. Desire and ability to eat will be reduced which can lead to
malnutrition ⁽¹⁷⁾.

Iodine:

Milk
and its products are a great source of iodine. The most important functions of
iodine in human bodies are helping in the body’s growth and development, and participation
in the formation of thyroid hormones⁽³⁾. Most of the iodine that is found
in food is inorganic. This inorganic iodine is mostly absorbed through the
gastrointestinal tract, whilst other types of iodine are converted to inorganic
forms before absorption. Iodide ions are linked with plasma proteins, where they
are oxidized to iodine in the thyroid gland. The thyroid hormones are formed by
the interaction of the tyrosine components of thyroglobulin with iodine ⁽⁸⁾. 

A deficiency
of iodine has several negative impacts on growth and development in humans. Iodine
deficiency leads to inadequate thyroid hormone production and all iodine deficiency
disorders are called panel. Health problems caused by iodine deficiency are
hypothyroidism, stillbirths, abortions, congenital anomalies dwarfism, impaired
mental function, and delayed physical development in adults. Thus, this element
is an essential nutrient especially in pregnancy because of the increase in
production of thyroid hormones and its transfer with iodine to the fetus ^(3)(20).

Iron:

Iron
is one of the trace minerals which are necessary for growth and development. It
has a significant role in electron transport, DNA synthesis and oxygen
transport. The basic physiological functions of iron in the body are the
metalloproteins such as, hemoglobin, myoglobin and oxidases ^(3)(21).
The free radical form of iron leads to tissue damage. Therefore, it should be
kept in the trivalent redox state or linked to proteins. Most iron in food
exists as ferric iron or heme iron ⁽²¹⁾. As with the majority of
metals in food, iron is absorbed in the duodenum and the mucosal cells of the
small intestine. There are three pathways to insert the three forms of iron
(heme, ferric and ferrous) to the mucosal cells. These cells can either store
the iron temporarily as heme, which is released and enters as non-heme, combined
with ferritin, which transports iron in the blood, or these cells can be
combined with ferro protein to transfer iron via body cells^(8)(10).
There are significant factors influencing the bioavailability of iron. For
example, ascorbate and citrate have an important effect in enhancing iron
absorption in the duodenum. This boost occurs because of the ability of
ascorbate and citrate to reduce ferric to ferrous at low PH and due to its
chelating properties. Although ascorbic acid has a negative effect on the
absorption of iron in all inhibitors such as proteins and calcium in phytate
and polyphenols, it increases the fortification of iron and native iron ^(8)(22).
On the other hand, there are many factors inhibiting iron absorption including
calcium, phytates, polyphenols, calcium some proteins such as portions from
soybean, egg proteins, albumin and milk proteins. Other several types of metals
could share the pathway of iron absorption in the intestine such as manganese,
cobalt and zinc ⁽²²⁾.

During
the first six weeks of life the average hemoglobin synthesis decreases from
about 170g/l to 120g/l. Iron is transferred from hemoglobin resulting from
recirculation of iron in senescent red cells to iron stores. Thus, the size of
infant doubled up during the 4-6 months in normal birth weight. Due to the
rapid growth of infants between 6-24 months, iron requirements of the body will
rise per kilogram weight from 300-600mg/k during this period ⁽²³⁾.

The
main reason for iron deficiency in the body is the depletion of iron stores.
Iron deficiency could lead to anemia where the level of hemoglobin in blood is
low when compared with normal levels ⁽⁸⁾. According to WHO there are
about two billion people around the world who are suffering from anemia, and
50% of this anemia is caused by iron deficiency. It affects all ages but is
more prevalent in women and young children⁽²²⁾.

To
minimize the risk of iron deficiency, infant food and milk should be supported
by iron fortification. Even in the case of breastfeeding, infants should be
supplemented with iron. Because of the influence of proteins in human milk on
the absorption of iron in the body and due to the influence of protein, one
should not use whole milk for formula-fed infants before one year of age.

Magnesium:

Magnesium
has two significant properties which are competing with calcium to bind with membranes
and proteins and its ability of forming chelates with ATP. For these properties
magnesium plays a great role in physiological functions of the body including,
carbohydrate metabolism, proper functioning in different organs such as nerves,
muscles and cardiovascular systems, and growth and proper maintenance of bones.
Also, more than 300 enzymes need magnesium for them to be active ^(3)(25).

The
absorption of magnesium from milk is better than from other types of food. The
solubility ratio of magnesium is different between the different types of milk.
In human milk, 92% of total magnesium is soluble, whilst in infant formulas,
83% is soluble in whey and 70% to 90% is soluble in casein ⁽⁸⁾. Magnesium
is observed basically in the small intestine. The rise in absorption decreases
with increasing of the dose. Magnesium uptake is kept either for the growth of
tissue or stored in the skeleton, where 60% of magnesium in the human body
occurs in bones. When the intake of magnesium is high, the kidney maintains
balance because of its effectiveness in conserving magnesium ^(8)(25).

A deficiency
of magnesium in humans does occasionally happen, and it can cause
hypomagnesemia, weakness, respiratory disorders, high blood pressure, anxiety,
nausea, tremors and muscle cramps⁽⁸⁾⁽³⁾.

Manganese:  

Manganese
is one of the heaviest metals and a neurotoxicant, which is necessary for human
health. The physical function of manganese in the body includes bone
development, the immune function, wound healing, antioxidant defense and a great
role in metabolism of cholesterol, amino acids and carbohydrates ^(3)(26).

The absorption
of manganese is general relatively small, and it could be less than 5%.
Homeostatic manganese is primarily regulated by excretion via bile and not
through the absorbent. The most absorbed manganese is as Mn⁺²
transported through CC-2-macroglobulin and manganese as Mn⁺³ through
transferrin. Manganese contains the enzyme arginase, which is responsible for
pyruvate carboxylase catalysis and urea formation ⁽⁸⁾. High amounts
of iron in food might reduce the absorption of manganese. This is because of the
rivalry between iron and manganese on the same absorption sites and binding.
Unlike the absorption of iron, manganese absorption is not affected by phytate,
phosphate or ascorbic acid⁽⁸⁾. The deficiency and disorders of
manganese is that rarely it causes Hypocholesterolemia, weight loss and
dermatitis ⁽³⁾.

Selenium:

Selenium
is an essential trace mineral and an important part of most of the antioxidant
enzymes like peroxidase and selenoprotein. In addition, it has several
physiological functions including maintaining homeostasis, protection from
radiation damage and contributing to the formation of triiodothyronine from
thyroxine ^(3)(27).

The
absorption of selenium compounds in the body varies depending on the chemical
formula, where 80% in case of seleniteand selenomethionine is 90%. By
intestinal cells in the duodenum, selenium is absorbed via amino acid transport
systems. Selenium is decomposed into elemental selenium, which gets included in
glutathione peroxidase (GPx) to give selenoproteins. In the liver selenoproteins
are changed into selenoprotein P (SePP) and distributed to the various organs
of the body such as the heart, brain, muscles, kidney, gonads and spleen ⁽²⁷⁾.

A
deficiency of selenium causes cardiovascular diseases. In addition, there are
many complex health outcomes due to a lack of selenium including abnormalities
of gastrointestinal and nervous systems, a defect of the immune system and the
thyroid, fertility and type 2 diabetes ⁽²⁷⁾. In contrast, high doses
of selenium lead to neuropathy, alteration in mental status, diarrhea, nausea
and loss of hair and nails ⁽³⁾.

Sodium:

Sodium
is an important nutrient for the human body. It is extracellular caution, which
has significant physiological functions including maintaining osmotic pressure
which controls water balance, preserve heartbeat, ease of conducting nerve
impulses, muscle contraction and various membrane transport proteins ^(3)(28).

Sodium
is easily and mainly absorbed into the upper part of the small intestine.
Glucose transfers the sodium across the intestinal epithelium, which depends on
passive leaks and pumps located in the membranes of cells. Sodium is also
absorbed in the rumen and in most parts of the digestive tract. It seems that,
there is no control of sodium absorption, and where it is absorbed about 80% of
sodium intake is by the digestive system ⁽²⁹⁾.

The
deficiency and disorders of sodium in the body lead to headache, vomiting,
nausea, seizures, coma, cramps, fatigue, muscle weakness and short-term memory
loss ⁽³⁾. Since there is no control of the absorption of sodium, there
is a great possibility for high sodium intake. High sodium intake is one of the
serious factors for hypertension in children. High blood pressure in the early
stages of growth and development increases the proportion of risk for
cardiovascular disease and death. In addition, it predisposes children to
hypertension in adulthood ⁽³⁰⁾.

Zinc:

The
physiological roles of zinc are dependent on its biochemical mechanisms. Unlike
iron which is found in defined cellular components, zinc is ubiquitous
intracellularly. Zinc has three functions in biology: structural, catalytic and
regulatory functions ⁽³¹⁾.

Carrie-mediated
is the mechanism that contributes to zinc absorption in the small intestine.
Zinc is also secreted in the small intestine. Zinc is also secreted in the large
intestine, so it is difficult to determine zinc uptake. High or low zinc uptake
in the body depends on dietary zinc. There are some dietary factors affecting
bioavailability of zinc absorption. Iron and calcium might have negative
effects upon zinc absorption, unlike proteins which can have positive impacts ⁽³¹⁾.

The
deficiency and disorders of zinc lead to growth arrest, chronic diarrhea, behavioural
changes, stunted growth, poor wound healing, hypogonadism and infertility. By
contrast, an overdose of zinc causes weakness, diaphoresis, nausea, gastric
erosions low HDL, epigastric pain and impaired cellular immunity⁽³⁾.

Vitamins:

Vitamins
are a set of organic compounds, which are chemically heterogeneous. They are
present in small quantities in natural foodstuffs and are considered very
essential for growth and metabolism in the human body ⁽³²⁾. Vitamins
are classified into two groups according to their solubility, the fat-soluble
vitamins: A, D, E, K, and the water-soluble vitamins: Thiamine, Riboflavin,
Niacin, Pantothenic acid, Pyridoxine, Biotin, Folic acid, Cobalamin and
Ascorbic acid ^(3)(32).

Figure 1 Classification of Vitamins⁽³⁾.

Water-Soluble Vitamins:

Vitamin B group.

B
vitamins are soluble in water. They are significant cofactors to the
interaction of enzymes. B vitamins have an important role in energy production
through the processing of fats and carbohydrates ⁽³²⁾.

Vitamin B1 (Thiamine)

The
physiological functions of Thiamin are: maintains proper functioning of
digestive system and nervous system, works as a coenzyme for enzymes such as
transketolase and ketoglutarate dehydrogenase ⁽³⁾. Thiamine
pyrophosphate is the active form of this vitamin. The deficiency and disorders
of vitamin B₁ cause: Beriberi (70% of patients who suffer from this
disease have ocular abnormalities like optic atrophy, dry eyes and epithelial
changes in the conjunctiva. Since vitamin B₁ deficiency is often
caused by a lack of nutrition, it could result in an imbalance of the cardiac
muscle, skeletal muscle and the nervous system. This may lead to reduced blood
pressure, muscle weakness, hypothermia, paresthesia and anorexia ⁽³²⁾.

Vitamin B2 (Riboflavin)

Riboflavin
has important effects in the body, where it works as a prosthetic set of
flavoproteins, as a coenzyme in reduction reactions and as a coenzyme in
oxidation. Riboflavin deficiency causes normochromic anemia, normocytic anemia,
stomatitis, cheilosis, edema of the nasopharyngeal mucosal, hyperaemia,
seborrhoeic dermatitis and lesions at the corner of tongue, lips and mouth ⁽³⁾.

Vitamin B3 (Niacin)

The
physiological functions of Niacin are as active part of NAD+ and NADP+, in
addition to being a coenzyme in reduction reactions and oxidation ⁽³⁾.
Niacin deficiency occurs for two reasons. The main reason is due to low
nicotinamide and tryptophan in the diet. The second reason can be as a result
of cirrhosis, chronic diarrhea, and also because of intensive parenteral
nutrition fluids and cirrhosis ⁽³²⁾. Niacin deficiency leads to
Pellagra (it does not affect infants and children) ⁽³³⁾,  stomatitis, glossitis, burning dysesthesias
and vertigo. Overdoses of this vitamin can cause hyperglycemia, hyperuricemia,
parenchymal and vasomotor phenomenons (flushing) ⁽³⁾.

Vitamin B5 (Pantothenic Acid)

Pantothenic
acid mainly exists in the human body as coenzyme A. It is essential for several
metabolic processes, especially the metabolism of fat, proteins and carbohydrates
⁽³²⁾. In addition, vitamin B₅ has a role in the formation
of vitamins A and D ⁽³⁾. A deficiency of vitamin B₅ could
lead to vomiting, diarrhea, insomnia, fatigue, high insulin sensitivity,
abdominal pain, paresthesia of the extremities, mental depression and
neuromotor disorders ⁽³⁾.

Vitamin B6 (Pyridoxine)

Pyridoxine has
an important role as a coenzyme in decarboxylation of amino acids,
transamination and in glycogen phosphorylase. Also it is involved in the
formation of Niacin from tryptophan, compilation of many neurotransmitters,
formation of δ-aminolevulinic acid, a remedy for regulating

steroid
activity and discouraging receptor affinity to DNA⁽³⁾. A deficiency
of vitamin B₆ in infants might lead to convulsions, anemia,
hyper-irritability, weight loss and growth retardation ⁽³²⁾. High
doses of this vitamin cause photosensitivity and peripheral neuropathy ⁽³⁾.

Vitamin B7 (Biotin)

Biotin
is synthesized by bacterial action in the intestine and is a factor in the
formation of fatty acids. Biotin improves the condition of hair, nails and skin
cells. In addition, it supports the synthesis of keratin processes. A
deficiency of Biotin is rare and might cause localized infections of the skin
around the mouth, nose, eyes, conjunctivitis and abnormalities in fat metabolic
⁽³²⁾.

Vitamin B9 (Folic Acid, Folate)

The
physiological function of folate is as a coenzyme in the transfer of single
carbon in the formation of nucleotides and the metabolism of amino acids. A
deficiency of vitamin B₉ can cause: neural tube disorders in
children, glossitis, diarrhea, megaloblastic anemia and cell hyperplasia in the
bone marrow that creates blood with immature nuclei, resulting in ineffective
DNA consists⁽³⁾.

Vitamin B12 (Cyanocobalamin)

Vitamin
B₁₂ is one of the essential vitamins for the health of the body,
where it has physiological functions in the metabolism of folic acid and
transfer of the fragments of single carbon ⁽³⁾. Thus, it is
necessary for the proper functioning of the nervous system and affects the
synthesis of blood cells ⁽³²⁾. A deficiency of vitamin B₁₂
cause pernicious anemia, loss of absorption in the intestine, atrophic
gastritis, pancreatic insufficiency, demyelination of nerves in the brain,
peripheral nerves and nerves within lateral columns and posterior of the spinal
cord, depression, mental distress, psychoses and complications in neurology and
hematology ⁽³⁾.

Vitamin C (Ascorbic Acid)

Ascorbic
acid has an active role in many functions of the body. Especially, it is
essential to the formation of collagen. Also, it produces noradrenaline and
neurotransmitters. In addition, vitamin C improves the function of the hepatic
oxygenase system, promotes iron absorption and increases the intake of non-heme
iron in the intestine. Another function is biosynthesis of carnitine,
norepinephrine and bile acids. Moreover, ascorbic acid works as an
antioxidant.  Vitamin C deficiency occurs
due to incorrect nutrition and could lead to Scurvy, defects in bone growth (in
infants) and ossification. In contrast, overdoses of vitamin C cause a higher
risk of oxalate kidney stones ^(3)(32).

Table 8 Recommended Daily Allowances of Water-soluble
Vitamins for Children ⁽³⁾.

Fat-soluble Vitamins:

“Fat-soluble
vitamins are polar molecules that are hydrophobic derivatives of isoprene”
⁽³²⁾. They are soluble in fats and are stored in chylomicrons (fat
globules). These chylomicrons travel via the lymphatic system to the adipose
tissue, where they are then stored. A deficiency of these types of vitamins
might be the result of a lack of intake. Also it could be as a result of a
defect in absorption resulting from the overlapping of certain kinds of drugs
or diseases. High doses of fat-soluble vitamins cause a risk of poisoning in
the human body ⁽³⁾.

Vitamin A (Retinol, ß-Carotene)

There
are several biological functionsof
vitamin A including sensory performance, cell differentiation, immune
functions, hematopoiesis, embryonic development, development of tumor
resistances, reproduction and growth. Retinol is created inside the body from
carotene, the majority of which is manufactured by plants and to lesser extent
manufactured by microorganisms ⁽³²⁾. Vitamin A deficiency is one of
the most common nutritional deficiency diseases and is a major threat to
children of preschool age. In addition, it is one of the diseases where the
necessary treatments should be carried out immediately, because it is
considered the main cause of blindness in children of developed countries
⁽³²⁾. Also, it can lead to keratomalacia (degeneration of the cornea),
skin keratomalacia and follicular hyperkeratosis xerophthalmia ⁽³⁾.
High doses of vitamin A lead to skin exfoliation, hypertension, ataxia,
dermatitis, alopecia, cheilitis, conjunctivitis, hyperlipidemia and pain in the
muscles and bone ⁽³⁾.

Vitamin D (Cholecalciferol)

Vitamin
D is produced naturally in the skin by exposure to sunlight. Also, it is
obtained from foods, whether they contain vitamin D naturally or are fortified
with vitamin D ⁽³⁴⁾. There are several physiological functions of
vitamin D in the body. The most important one is to maintain the concentration
of calcium and phosphorus levels in the blood, that have a significant role in
bone metabolism, transcription regulation and a variety of metabolic functions
⁽³⁴⁾. In addition, vitamin D has an essential impact in increasing the
efficiency of calcium and phosphorus absorption in the small intestine through
the interaction with vitamin D receptor (VDR). Moreover, vitamin D motivates
the absorption of calcium from the glomerular filtrate in the kidneys ⁽³⁴⁾.
A deficiency of vitamin D is one of the most prevalent health problems
worldwide, and occurs in about 30-50% of the world’s population and in all age
groups ⁽³²⁾. Vitamin D deficiency leads to Rickets in children and
osteomalacia in adults. Also it causes pathological fractures, bone deformation
and low calcium and phosphate concentration in serum ⁽³⁾.

Vitamin
D deficiency is one of the most common causes of rickets in children. The
appearance of clinical signs of rickets in children begins between 6 months to
1.5 years, which include widening of the epiphyseal plates at the end of long
bones, rachitic rosary and bowing deformities of the legs in newborns. Sweating
is the most common symptom, which is because of neuromuscular irritability
⁽³⁴⁾.

Rickets
in Europe was common in the mid-twentieth century and was known as the English
disease, due to its large spread within England. Because of public awareness,
supplements and clean air legislation, the cases of rickets have become very
few in the UK. In contrast, recently several cases of rickets in the UK have
been recorded amongst children of migrant families from Asia and Africa, and
there are fears of increased cases in the future ⁽³⁵⁾. This is maybe
due to the lack of awareness of rickets in these cultures. On the other hand,
despite the abundant sunshine in the Middle East and Africa, rickets rates are
also too high in these areas. Low levels of vitamin D are caused by low
socioeconomic status, the winter season and conservative clothing style
⁽³⁶⁾. For these reasons, one should not rely on the natural formation of
vitamin D from sunlight, and it should added to by fortified nutrition with this
vitamin especially for kids.

Figure
2 Prevalence rates of vitamin D deficiency in infants around the world. It has
been found in 12 studies: 1 in Europe, 3 in America, 6 in Asia, 1 in Oceania
and 1 in Africa. The highest prevalence rate of vitamin D deficiency has been
found in newborn infants in the Middle East ⁽³⁾.

Vitamin E (Tocopherol)

Vitamin
E has an essential role in protecting polyunsaturated fatty acids (PUFAs),
low-density lipoproteins and other cell membrane contents. The deficiency of
this vitamin occurs very little in humans, except in certain circumstances
relating to the metabolism of vitamin E ⁽³²⁾. Vitamin E deficiency
could lead to hemolytic anemia, ophthalmoplegia, peripheral neuropathies and
serious neurological disorders (rarely happens). However, overdoses of vitamin
E are dangerous and could lead to rise in the occurrence of hemorrhagic strokes
⁽³⁾.

Vitamin K (Phylloquinone)

Vitamin
K is necessary to posttranslational chemical correction of glutamic acid
residues in a group of proteins. In addition, vitamin K acts as a coenzyme for
blood clotting enzymes. A deficiency of vitamin K causes a defect in blood
clothing, fat malabsorption in adults and hemorrhagic diseases in newborn
babies. In contrast, high doses of this vitamin lead to flushing collapse of
the cardiovascular system and dyspnea ⁽³⁾.

Table 9 Recommended Daily Allowances of Fat-soluble
Vitamins for Children ⁽³⁾.

Vitamins and Minerals Fortification:

According
to The Codex Alimentarius, “which is part of the Food and Agriculture
Organization / World Health Organization Food Standardization Program”,
consolidated general principles of adding nutrients to the food in countries ⁽³⁷⁾
:

1. Basic nutrients
   must be present in the specified levels, without resulting in excess or
   deficiency. 
2. Adding the
   essential nutrients for food should not adversely affect the metabolism of
   other nutrients.
3. The basic
   nutrients should be stable enough in the food during usual conditions of
   packing, distribution, storage and use.
4. The basic
   nutrients in the food must be biologically available.
5. The basic
   nutrients must not add undesirable properties, and must not unduly restrict the
   shelf life.
6. Processing
   facilities and technology used to add nutrients in a satisfactory manner should
   be available.
7. Adding any
   essential nutrients to the diet should not be used in consumer deception in
   regards to nutrient merits of the product.
8. The cost of
   adding nutrients must be suitable for the intended recipients.
9. It is necessary
   to provide ways to measure and monitor the levels of essential nutrients which
   are added to the food.
10. When food standards require adding essential nutrients for food and
    they are available, specific provisions must be inserted to determine the
    required nutrients and their concentrations which must be present in the food
    to achieve the desired goals.

There
are many challenges facing food fortification. For example, mineral
fortification of milk is difficult because at the normal PH of its soluble
phase it is saturated. So, adding more minerals is challenging. Therefore, it
is very important to choose the appropriate source of mineral for a particular
application. In dairy applications mineral salts are mostly used ⁽³⁸⁾.

Table 10 Some salts of Calcium, Magnesium and Zinc
Approved for Fortification in Europe ⁽³⁸⁾.

Soluble
mineral salts can affect the taste and increase the PH where there is a high
level of fortification. While insoluble mineral salts can influence mouth
feeling which includes chalkiness and grittiness, in addition, they could lead
to sedimentation in some products. To solve these problems, micronised mineral
salts are considered as a great option. For example, reducing the particle size
to ultrafine particles can decrease the speed of sedimentation. Thus, one could
achieve higher levels of fortification by using particles smaller than 20µm
than by using dissolved minerals ⁽³⁸⁾

Nanotechnology
is one of the modern methods which are essential for food and dairy
manufacturers. Nanotechnology has a significant impact on the development of
functional foods. “Nanotechnology is defined as the design, production and
application of structures, devices and systems through control of the size and
shape of the material at the nanometer (10^-9 of a meter) scale where
unique phenomena enable novel applications” ⁽³⁹⁾. Nanotechnology
applications in the food and dairy industry are divided into two main sections:
food additives (nano inside) and food and dairy packaging (nano outside).

Food additives (nano inside):

The
different physical and molecular forms (polarities, molecular weight, physical
state) of functional ingredients (such as vitamins) are pure forms. Therefore,
it is rare to utilize these ingredients directly. Instead, they are mostly
combined into a delivery system, which includes association colloids, biopolymeric
nanoparticles and nanoemulsion ⁽³⁹⁾.

Methods of fortification:

1 – Encapsulation

Encapsulation
is a type of technology which forms a capsule by coating an active
micronutrient, in order to enhance the retention time of micronutrients in the
food and allow control of its release in the gastrointestinal tract. In
addition, it can hide the disgusting flavor of some minerals and vitamins and
increase their stability during the food storage process ⁽³⁾.
Nanoencapsulation is a type of technology that protects the bioactive compounds
and drugs from inappropriate conditions such as degradation through coating by
a core material. Methodologies of encapsulation can be divided into physical
processes, physicochemical processes and chemical processes^(3).

Figure
3 Schematic Representation of Nanoencapsulation and Fortification Processes ⁽³⁾.

2 – Direct Addition:

It is one of the alternative methods that can protect the effective functional micronutrients from some conditions. In this method, nutrients are added directly to the food before consumption. Also, in this way, the degradation of micronutrients through heat processing of food is avoided, while it is added to the final product ⁽³⁾.

Conclusion:

Since
milk is a staple food for infants during the first two years of life, it must
contain all the essential minerals and vitamins for normal growth and
development. For this reason, the most appropriate method of fortification must
be chosen for adding micronutrients, so that, it will be effective and inexpensive
in order to ensure its use in various parts of the world, especially in
developing countries.

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