Technological Advances in Infant Formula Ingredients

Abstract

The best source of nutrients for babies is breast milk. However, the baby formula offers a crucial alternative to nursing when it is not practical or viable to meet the growing child’s nutritional needs. Bovine milk has traditionally been used as a primary component in baby formula production. It is then prepared with additional nutrients and bioactive substances to resemble the makeup of human breastmilk closely. Bovine-based baby formula is the most accessible type of formula, but it is not appropriate for all newborns; thus, alternatives, including those based on caprine milk, soy, and rice protein, are becoming more readily available. The composition of baby formula made from soy, rice, caprine milk, and cow’s milk is thoroughly examined in this chapter. In addition, we cover the literature that is currently available on nutrient bio-accessibility and features of protein functioning that are pertinent to baby formula.

1. Introduction

Human milk (HM) plays a crucial role in newborns’ healthy growth and development of gastrointestinal (GI) tracts and immune systems. Therefore, breast milk is the best and only naturally designed food for babies [1]. In addition to the nutritional components, HM also contains essential physiologically active elements that help to reduce malnutrition risk. Sometimes, preterm babies do not get an adequate amount of their mother’s milk [2]. In that case, milk from the donor or HM bank is needed, which is not always available in many countries. However, infant formula is required to maintain a newborn’s normal physical, mental, and immunological development when breast milk is not available [3]. Therefore, it is formulated as a complete substitute for mother’s milk to support an infant’s necessary nutritional needs under 6 or 12 months [3]. Generally, infant formulas are prepared as a powder for bottle feeding, which is mixed with purified and sterile water [4]. The rehydrated mixture needs to be homogenized for adequate absorption in the infant’s stomach. Formulas are made with different ratios of 6 basic food components, which are carbohydrates, proteins, fats, vitamins, minerals, and prebiotics and probiotics [3]. Manufacturers claim that formulas are identical to the HM. Bovine milk (BM) is the primary source of proteins (whey and casein) in most infant formulas [5]. In addition, some manufacturers also use soy protein [6]. However, almost half of the calories in formulas made with cow’s milk come from a specific blend of fats designed to be easily absorbed by the body. Palm olein, soy, coconut, high-oleic sunflower, and safflower oils are frequent sources of fat [7]. Many infant formulas include omega fatty acids, which are long-chain polyunsaturated fatty acids (LCPUFAs) [8]. Studies reported that 20% of energy in a formula comes from carbohydrates or sugar. In milk-based products, lactose is the primary source of carbohydrates. The main benefit of lactose is that it is tolerable for almost all babies regardless of having protein allergy [9].

In the past half-century, there have been tremendous breakthroughs in infant formulas. During the middle of the 20th century, formula-fed infants typically received cow milk-based or homemade formulations with evaporated milk, sugar, and water [10]. However, technological advancements have changed formula preparation and nutritional compositions [11]. As a result, different formulas for different target groups are available in the market to support the infant’s dietary needs with special conditions. For example, there are currently soy, lactose-free, rice starch formulations and formulas for preterm babies and infants with specific disorders, such as metabolic problems [12]. As more constituents of HM are identified and their physiological functions described, new formulas continue to be developed, and established formulas are continually modified. Nevertheless, hormones, immunological components, and enzymes analyzed in breast milk cannot be added to infant formulas.

This chapter reviews the application of technologies in infant formulations. There are many challenges that manufacturers need to encounter during the preparation of formulas. Most of these challenges are nutrition related, to be specific, the improvement of the nutritional benefits of infant formulations. For example, there were many limitations in the past to increasing the level or fortifying the formulas with macronutrients (carbohydrates, proteins, and fats), bioactive compounds, and prebiotics or probiotics.

2. Protein

The first year of an infant’s life is a crucial time of rapid growth and development. Between birth and weaning, development and growth are required for long-term health [13]. Protein is a macronutrient that is necessary for the development of organ systems and bodily structures, as well as the regulation of several physiological processes. Protein synthesis must occur quickly to sustain the infant’s rapid development. As a result of their fast growth, babies and early children have more significant protein needs per kilogram of body weight than any other age group [14]. In babies, the protein synthesis and turnover rate are disproportionately high to their body weight. During the first month of life, infants require around 3.5 times more protein per kilogram of body weight than adults [15]. HM includes more than 400 proteins that may be roughly categorized into three groups: caseins, whey proteins, and mucins, which are found in the milk fat globule membrane (MFGM). Although it varies across mothers and throughout lactation, the macronutrient content of HM is consistent among populations, despite nationality and race variability [16]. Throughout the first year of breastfeeding, the total protein content and concentrations of different proteins in HM fluctuate to meet the demands of the newborn. Regardless of the moment of birth, protein levels in human milk drop throughout the first 4–6 weeks [17, 18]. HM is dominated by whey; however, the ratio of whey to casein fluctuates throughout lactation, from 90/10 in colostrum to 60/40 in mature HM.

Protein content in mature, full-term milk is expected to be between 0.9 and 1.2 g/dl on average [18, 19]. Significant levels of α-lactalbumin, lactoferrin, IgA (Immunoglobulin A), osteopontin (OPN), and lysozyme are found in the whey fraction. After intake, these proteins are swiftly degraded into amino acids that may be absorbed and used [20]. Many of these proteins have both bioactive and non-nutritive activities. For example, α-lactalbumin is needed for lactose production and Ca and Zn ion binding [21]. Casein aids calcium and phosphorus in bulk formation. Lactoferrin and lysozyme inhibit the spread of potentially dangerous germs, protecting newborns from disease. The IgA antibody eliminates microorganisms and protects the intestinal mucosa [20].

2.1 Cow’s milk formula and allergy

Cow’s milk is an excellent source of protein for the baby. It includes crucial amino acids for the healthy growth of the body and mental health [15]. For example, while cow’s milk has a protein level of 5 g/100 kcal, human milk has a protein content of just 1.5 g/100 kcal [18]. However, GI resistance to infant formulas manufactured with cow’s milk occurs frequently during the first several months of life. Lactose intolerance may also be impacted by sensitivity to milk protein, lactose, or both [9]. A cow’s milk allergy is a consistently unpleasant response to one or more milk proteins mediated by IgE and/or non-IgE pathways (CMA) [6]. Within one to two hours after consumption, gastrointestinal, respiratory, and cutaneous symptoms may manifest as IgE-mediated reactions. A skin rash or dermatitis as well as gastrointestinal (GI) symptoms like diarrhea, mucous stools, vomiting, and stomach discomfort may also be present [22]. Immune system-related, non-IgE mediated reactions can take up to 48 hours to develop but are immune system-delayed. Infants with ongoing issues may wheeze, become irritable, or underperform [22]. The majority of CMA cases occur in the first year of life, and hypoallergenic formula is the dietary treatment if the kid is not breastfed. For treating CMA, particularly in infants and young children, extensively hydrolyzed cow’s milk formula (eHF) with confirmed hypo-allergenicity can be advised [23]. Amino acid-based formulas (AAF) can also be recommended, particularly for patients with more severe symptoms or in patients who are not responding to the eHF. They offer 90% of infants with CMA effective therapy [24]. Infants with CMA, who cannot tolerate or prefer eHF should use soy- and hydrolyzed rice-based formulas (HRFs).

CMA is widespread, but it is frequently improperly diagnosed because of its ambiguous indications [23]. The baby and the parents will suffer; thus, it will be advantageous to prevent CMA. A partly hydrolyzed formula (pHF) is one method to stop CMA in newborns. Using a combination of thermal processing and enzymatic hydrolysis reduces the protein’s molecular weight and peptide lengths, which is created to lessen protein sensitivity [15]. pHFs typically have a molecular weight of around 5000 Da (range: 3–10,000 Da), whereas raw cow’s milk-based formula (CMF) has peptides ranging from 14,000 Da to 67,000 Da [15]. Sensitivity has been reported in around fifty percent of newborns with CMA; hence, pHF should not be used for treatment. The hypoallergenic formulation has been thoroughly hydrolyzed and includes no peptides with a molecular weight of more than 5000 Da [25]. The majority of recommendations call for pHFs to protect at-risk non-breastfed babies against allergy illnesses, namely, atopic dermatitis (AD) and CMA. However, according to epidemiological research, almost 50% of newborns who later acquired allergies did not belong to the at-risk category. This is because the non-at-risk population is substantially more significant than the at-risk group. There is a 15% chance that non-at-risk infants may acquire allergies [26]. According to evaluation, formulas that have been partly hydrolyzed are secure, well-tolerated, and promote healthy newborn growth. In addition, in comparison to intact proteins, partly hydrolyzed formulas are easier to digest and hasten the transit time in premature newborns [27].

2.2 Soy-based infant formula

Infant formulas containing soy have already been used for over a century. Despite few indicators, soy-based formula accounts for around 20% of the U.S. formula market [28]. Available formulas using extracted soy protein are currently devoid of cow milk protein and lactose and offer 67 kcal/dL [29]. The protein consists of a soy isolate supplemented with L-methionine, L-carnitine, and taurine to produce a protein level of 1.65 to 1.90 g/dL [6]. Among the several heat-stable components in soy formula, phytoestrogens are particularly important to health. Phytoestrogens include numerous categories of non-steroidal estrogens, such as isoflavones, often found in legumes, with soybeans having the most significant concentration [6]. Concerns about isoflavones’ possible adverse effects on reproductive development, neurobehavior, immunological performance, and hormone levels have been expressed [30]. However, the latest soy research indicates that phytoestrogens can lead to a reduced risk of coronary artery disease, cancer, and menopausal symptoms, all of which might be extra benefits of eating a soy-based diet at an early age [31]. Researchers are particularly concerned about the nutritional features of soy, especially as soy is the primary source of nutrition for many newborns for a minimum of six months during their growth. However, gas chromatography and mass spectrometry (GS/MS) were the traditional techniques for evaluating the isoflavone content of soy [28]. Recently, it was discovered that high-performance liquid chromatography (HPLC) was quicker, required less preparation time, and cheaper equipment.

Consequently, HPLC has been utilized in most research investigating the phytoestrogens content of soy formula [28]. Multiple experiments have extracted isoflavones from soy formula and compared these quantities to those found in the human milk collected following soy eating by the mother [6, 28, 32]. The decreased isoflavone content may give the advantages without causing as many of the dangers associated with high soy formula intake.

2.3 Hydrolyzed rice in infant formula

Formulas containing hydrolyzed rice have been used for decades in Europe, but they are still not widely accessible worldwide. A recent meta-analysis of 11 clinical trials using hydrolyzed rice formula in babies with CMA presented no cross-reactivity [33]. Another meta-analysis study of seven trials indicated that typically developing children and those with CMA could compensate for lost ground in height and weight. A skin prick test revealed rice-specific IgE levels in 4% of newborns in a multicenter trial of 100 infants with confirmed CMA; however, these infants showed no symptoms [25]. For children allergic to rice, hydrolysis of rice protein in the formula changes its allergenic characteristics and avoids an immunological response, as evidenced by negative Western blotting results [34]. Hydrolyzed rice formula’s unpleasant flavor and limited availability are two drawbacks that might impair the formula’s effectiveness in improving adherence. However, the taste scores of partially hydrolyzed rice formulas are comparable to those of soy formulas and are just as effective in treating CMA [27].

In choosing a formula substitute, factors like symptom intensity, preferences, cost, and effectiveness should be taken into account because all replacements to CMFs are nutritionally appropriate. Both substantially hydrolyzed formula and rice formula must be taken into consideration when nursing kids, who are allergic to CMF and soy-based formula. The effectiveness of HRFs as a choice for babies with CMA and soy allergy was investigated in a trial of 18 children, who were given SF but later experienced allergic responses after two to eighteen months of supplementation [34]. Skin prick test findings revealed that 8 and 2 children reacted to rice and rice hydrolysate, respectively. At the same time, 7 infants had antibodies in response to rice according to their serology tests [35].

3. Carbohydrates

Early childhood is a time of high-speed development. Babies who do not get enough nutrients and calories cannot maintain their predicted growth and maturation throughout this time; therefore, better nutrition is crucial. During such a critical phase, dietary carbohydrates, mainly lactose, are an essential primary source of food-derived energy [36]. Moreover, sugar and polysaccharides are some other significant sources of energy. Lactose is the primary carbohydrate source in baby formula made from caprine and bovine milk (BM). These formulas contain around 7–7.5 g of lactose per 100 mL. BM and caprine milk (CM) primarily include lactose, which has a mass of 44–56 g/L and 32–50 g/L, respectively [36]. Since many decades back, lactose intolerance has been acknowledged as a widespread issue affecting most adults and children. Although lactose intolerance symptoms are seldom fatal, they can cause severe pain and negatively impact the quality of life [37]. Therefore, the goal of treatment is to reduce or eliminate lactose, the provoking ingredient, either by removing it from the diet or by “predigesting” it with an additional lactase-enzyme replacement whose diarrhea may be exacerbated by formulas containing lactose while benefiting from formulas devoid of lactose [37]. However, the particular need for lactose has not been established, and formulations with decreased or no lactose have become more popular recently.

The growing worry about newborn lactose intolerance has been the key factor behind the rise in the usage of formulas that incorporate different carbohydrate groups [9]. Glycemic and non-glycemic are the two main kinds of carbohydrates. In newborn and follow-up formulas, some permitted glycemic carbohydrates, such as pre-cooked starch, gelatinized starch, corn syrup solids (CSS), and maltodextrin, are frequently used as substitute sugar [38]. Glycemic carbohydrates are digested and absorbed in the small intestine, followed by a rise in blood glucose [39]. A reduced-sweet saccharide polymer made of D-glucose molecules primarily connected linearly with α-1,4 bonds, where maltodextrin also contains a complex structure with α −1,6 linkages [40]. Maltodextrin is used as the primary source of sugars in non-allergenic infant formula. It has a nearly equivalent energy content to lactose of 4 kcal/g with a dextrose equivalent (DE) of ≤20 [41]. In baby formula made with soy and rice protein, maltodextrins are often used as the primary carbohydrate source [42]. That is why newborns with genetic lactose intolerance may consume these infant formulas. In the lactose-free formula, glucose syrup or dried glucose syrup may also be used when DE ≤ 32 [36]. In addition, other lactose-free formulas based on animal milk protein have been prepared by membrane screening or enzymatic hydrolysis. As a result, up to 30% of the total carbohydrates in baby formulas may contain pre-cooked or gelatinized starches [43]. This makes baby formula intended for babies with gastroesophageal reflux viscous. Additionally, they are frequently added to infant formulas that contain hydrolyzed proteins because this process raises the osmolarity of the formula.

Human milk oligosaccharides (HMOs) are hypothesized to have prebiotic effects by acting as nutrients for good bacteria like bifidobacteria. Compared to human milk, which includes 5–15 g/L of oligosaccharides, BM only contains 0.03–0.12 g/L of these sugars [44, 45]. In comparison to BM, CM has an oligosaccharide content that is over ten times higher and includes molecules that are functionally more comparable to HMOs. 2′-Fucosyllactose (20FL) and Lacto-N-neotetrose (LNnT), two structurally isoforms of HMOs, have been created by microbial fermentation for inclusion in the newborn formula [46]. Moreover, as an alternative to mimic many of the positive benefits of HMOs, producers are now adding non-digestible carbohydrates such as fructooligosaccharides (FOS) and galactooligosaccharides (GOS) to newborn formula [47].

4. Lipids

Lipid content in breast milk is significantly more different compared to the other macronutrients. In matured milk, lipid concentrations range from 3.5 to 4.5/100 g, although they vary depending on the mother’s duration of nursing and throughout each meal [3]. High levels of medium-chain fatty acids (MCFA) and triacylglycerols are present in breast milk fat, which is dissolved by a phospholipid membrane. Lipids provide 40–50% of a newborn’s energy needs and are the main energy source in baby formula [48]. The key ingredients of infant formula are long-chain fatty acids (LCFA), which are emulsified with dairy proteins, and soy lecithin (SL), which lacks sphingomyelin [16]. The amount of lipid hydrolysis products in the intestine are altered by changes in the sphingomyelin content and saturation level of phospholipids, which ostensibly influences the advantage of the certain gut microbiome [49].

The lipid content of baby formula must fall between the range of 4.4–6.0 g/100 kcal [36]. Due to significant changes in their fatty acid profiles from HM, which has a higher proportion of unsaturated fatty acids (C18:1, C18:2, and C18:3) and LCPUFAs (C20:4 and C22:6), BM and CM are not suitable as the only source of lipids in infant formula [36]. In newborn formula manufactured from BM and CM, vegetable oils are combined in a way comparable to human milk because of these discrepancies. The LCPUFAs, for example, arachidonic acid (ARA) (C20:4ω6) and docosahexaenoic acid (DHA) (C22:6ω3), are not present in the blends of vegetable oils [50]. Infant formulas are presently required by EU law to include 20–50 mg/100 kcal DHA [51]. Fish oils, microbe oil, and egg-yolk-produced lipids are all acceptable sources of LCPUFAs to add to baby formula. However, using unfractionated fish oil is not recommended since it contains eicosapentaenoic acid (EPA), which is hostile to the actions of ARA [52]. Triglyceride structure in baby formula is crucial because it influences lipid hydrolysis and, in turn, the bioavailability of fatty acids. The precise esterification of fatty acids to glycerol at the outer sn-1 and sn-3 and inner sn-2 locations of a triglyceride is known as triglyceride synthesis. Over 70% of the palmitic acid (C16:0) in HM is found at the sn-2 position on the triglyceride backbone. Because of this, structured triglycerides containing 17–25% palmitic acid and more than 40% of it esterified at the sn-2 position have been created by enzymatic procedures [53]. When added to the newborn formula, these structured triglycerides have been linked to altered intestinal microbiota, decreased colic incidence, enhanced bone growth, and lower intestinal inflammation.

During the manufacturing process, infant formula often goes through a homogenization stage. Consequently, globules are created in plant-based oil (approximately 0.4–0.5 μm), which are then solidified by protein [3]. Casein and whey proteins served as stabilizers in baby formula made from BM and CM, whereas soy and hydrolyzed rice proteins serve as the main emulsifiers of fat globules in formulas made from soy and rice, respectively [3, 54]. It has been reported that the characteristics of the lipid/water (L/W) interface and the globules’ diameter influence how easily newborn formula digest. Consequently, efforts have been made to alter the structure of the L/W interface. One method involves adding BM’s phospholipids to baby formula to change its concentration [20]. On the other hand, palmitic acid is abundant in human and animal milk, making up around 70% and 45%, respectively. However, less than 20% of vegetable oils are esterified with palmitic acid at the sn-2 position [50]. Compared to newborn formulas containing milk fat or β-palmitate, formulas using just plant-based oils had a lower percentage of palmitic acid in the sn-2 place of triglycerides. According to Prosser et al., who studied the fatty acid profile of a CM-based formula product in which goat milk accounted for 55% of the total fat and a vegetable oil mix for the rest, this blend provided the necessary fatty acids profile for the babies [55].

5. Prebiotics and probiotics

Probiotics in formula help infants maintain a healthy proportion of microbes in their gut and inhibit the development of “unfriendly” microorganisms that may otherwise cause illness and irritation [56]. Probiotics and prebiotics are included in baby formula to establish good gastrointestinal bacteria similar to those of breastfed babies in order to support optimal growth and minimize illnesses. Breastfeeding newborns have a higher proportion of bifidobacteria in their gut microbial population and a lower number of pathogens than those who are formula-fed [57]. Prebiotics are indigestible components of some foods that promote the development of probiotics in the digestive system. Prebiotics may be found naturally in foods, including human milk, fruits, and vegetables. Probiotics are live microorganisms that mimic the microflora typically present in the body and are included in certain meals. Probiotics are useful for better digestion since they assist in moving food through the gastrointestinal tract, maintaining a healthy digestive system [58]. Numerous substances included in human milk influence the infant’s gut flora. Although it is impossible to trace breastfeeding’s effects on the gut microbiota to a single substance, mounting research suggests that human milk oligosaccharides play a key role. Human milk oligosaccharides (HMOs), which have distinct nutritional and functional qualities, are a common and significant group of components [46]. Prebiotic oligosaccharides (OS), which are essentially missing in cow’s milk, are the third most common substance in a mother’s milk, which is made with complex combination of glycan [57].

The presence of growth factors (HMOs) in HM and their absence in baby formula have been cited as the main reasons why breastfed babies have a large proportion of bifidobacteria in GI microflora as opposed to formula fed babies [59]. Because of this, prebiotics are usually added to baby formula today to improve its functional qualities. Infant formula has been supplemented with oligosaccharides more often in recent years, primarily a combination of fructo and galacto-oligosaccharides (FOS) (GOS) and polydextrose [57]. Prebiotic functions have been reported to enhance immunity and resemble the bifidogenic action of HMOs [60]. Breastfed babies have a predominance of Bifidobacterium and Lactobacillus in their feces. However, by producing organic acids, hence reducing the level of pH, Bifidobacterium and Lactobacillus may prevent the development of harmful microbes in the intestine. In addition, these gut microflorae emulate harmful microorganisms for resources and epithelial attachment sites [61]. Recent research on prebiotics in a formula examined if adding probiotics or prebiotic FOS to the milk-based formula would alter the fecal bacteria of babies compared to breastfed infants. On the other hand, the fortification of the GOS/FOS combination to newborn formula was shown to have an influencing impact on the proliferation of Bifidobacterium and the digestion characteristics of the whole GI microflora [57].

Moreover, 1,3-olein-2-palmitin (OPO), a triacylglycerol that may be produced from plant-based oil (palm oil) and added to baby formula, is the most prevalent in HM. OPO may smooth and boost the frequency of stools in newborns without causing diarrhea and raising the percentage of Bifidobacterium in feces. However, it is uncertain how prebiotics and OPO may affect feeding results comparable to breast milk [62].

6. Bioactive compounds

An increasing number of research indicates that the numerous components in human milk, referred to as functional or bioactive components, cause the short- and long-term advantages of breastfeeding [18, 46, 63]. These bioactive compounds include various components such as macronutrients, nucleotides, minerals, and Igs [64]. Due to the essential nutrients and bioactive components in HM that are lacking or not present in sufficient quantity in the newborn formula, ingesting human milk has more health advantages than feeding infant formula. Human milk is utilized as a model for potentially adding new bioactive compounds to baby formula. There is little proof that one baby formula is superior to another, and most commercially available infant formulas are nutritionally equivalent [3]. However, potential sources of such bioactive components must be investigated. They may be added to baby formulas in order to make them equal to the HM. Due to rigorous regulations on baby formula content in many nations, this is not a simple task [20]. Clinical studies in newborns are necessary to assess changes in nutritional content, but they are expensive and time-consuming. Including bioactive components necessitates that they are both safe and provide the recipient babies with clear advantages. The ingredients’ cost, quality, and origins will also impact whether it is practical to use them.

6.1 α-lactalbumin

In cow’s milk, just 3.5% of the total protein is α-lactalbumin (α-La), while it makes up 22% in HM. The homology of the amino acid patterns of BM and HM α-La is quite close (73.9%), and they both have a similar length [65]. Since it contains relatively large amounts of tryptophan (Trp) and cysteine (Cys), α-La has primarily been used to supplement baby formula. Bioactive peptides from α-La are a significant source and may impact GI health. The presence of Trp and Cys, which are thought to be the source of these advantages, is supported by evidence [20]. In addition to serving as a nutrient, α-La contains a unique calcium receptor and another for iron and zinc, making it easier for the body to absorb [63]. By preventing pathogens from adhering to the intestine because lactosamine, which is required for its adherence, is absent when α-La is lactosylated, it may reduce the risk of contamination. It has been anticipated that several peptides produced from α-La when it is digested will have biological effects [65]. Data comparing the development of breastfed and formula-fed (α-La enriched) newborns showed that children’s growth trends were identical. According to these clinical investigations, α-La, a source abundant in essential amino acids, may serve as an appropriate dietary component [20].

6.2 Lactoferrin

In different research studies, lactoferrin (LF) was initially discovered in cow’s milk and later from HM. Bovine lactoferrin (BLF), with a weight of 80 kDa and peptides that are quite comparable to those of human lactoferrin (HLF), has around 70% sequence similarity [20]. LF has versatile components, which have a role in the immune system and as an anti-inflammatory. It is widely recognized that lactoferrin has iron-binding properties and is the first line of defense against microbial contamination. It is extraordinarily resistant to proteolytic enzymes, allowing it to perform all these activities [63]. Additionally, LF may have biological effects that are not caused by the interaction of its receptor. Similar bioactive characteristics exist in commercially added LF and HLF. It was discovered that the prevalence of respiratory infections dropped while hematocrit rose when LF was added to the newborn formula [66]. However, since BLF does not attach to HLF receptors, enhanced lactoferrin did not increase iron absorption. However, equivalent bioactivity has been shown in both in vitro and animal models, including improved growth, similar effects against a variety of pathogenic organisms, and antioxidant activity [21]. In research, formulas enhanced with BLF at levels comparable to those found in mature HM were given to healthy newborns to assess their development and tolerance [63]. The study found that breastfed newborns grew at the same rate as formula-fed infants. Nowadays, BLF is widely accessible and comparatively proteolysis resistant. In a previous research, commercial BLF was added to baby formula and investigated its outcomes comparing with HLF in an intestinal enterocyte model [20]. In addition, Similar to the HLF, market-available BLF has been demonstrated to enhance cell proliferation. However, the findings revealed no appreciable impact on the microbiota of feces, pathogens, or iron status [63]. Synthesized LF sometimes contains lipopolysaccharides, which likewise have a strong attraction for LF receptors and inhibit their roles as a bioactive compound. Studies conducted in vitro on the bioactivity of BLF without the presence of lipopolysaccharides produced encouraging findings [20].

6.3 Milk fat globule membrane

The milk fat globule membrane (MFGM) is made of lipids and proteins, which surround the fat globule released by the alveolar epithelial cells of humans and other animals [67]. MFGM and its components are a significant source of bioactive substances. Because of their nutritional, physiological, and health advantages, they have recently attracted the attention of nutritionists in baby feeding. In addition, clinical research studies on humans and animals have shown benefits for immunological and GI health and cognitive function [20]. A whey protein concentrate high in MFGM may thus aid in guarding against diarrhea of both bacterial and viral origin [68]. In addition, several proteins in MFGM have been demonstrated to have inhibitory effects against different infections. Since the MFGM fraction is now marketed, it could be possible to include it in a newborn formula [69]. Clinical studies on MFGM are required to investigate impacts on essential outcomes in newborns because in vitro experiments have shown bioactivities and because the components of the bovine MFGM are comparable to those in human milk. In randomized controlled research in Peru, babies aged 6 to 8 months were given supplemental food containing bovine MFGM twice daily for six months. The incidence of diarrhea, especially bloody diarrhea, was shown to be lower [70]. Young babies were given MFGM-based or conventional formula from 6 weeks up to 6 months of age in a recent experiment in Sweden. Babies who had been breastfed were also used as a comparison group. However, results showed no difference in cognitive scores between the formula-fed and breastfed groups [71]. This implies that adding MFGM to baby formula may provide formula-fed babies with nutrients that assist brain development.

6.4 Polyunsaturated fatty acids

PUFAs have been introduced to baby formula to serve as bioactive components that promote eye and brain development. PUFAs like docosahexaenoic acid (DHA) and arachidonic acid (ARA), present in human milk, are crucial for forming the proteins that make up plasma membranes [20]. Globally, human milk produced by mothers is estimated to include an average amount of DHA and ARA of 0.32% and 0.47% of total fatty acids, respectively [72]. Due to the sluggish and ineffective elongation and desaturation processes, which result in a relatively low conversion rate, DHA and ARA are substituted for the formula’s corresponding n-6 and n-3 precursors. The membranes of the cells in the central nervous system and retina are structural components made up entirely of DHA and ARA. While DHA builds up throughout the first few years of life, the infant’s brain must develop normally [73]. Together, DHA and ARA make up around 25% of the total fatty acids profile in the brain, and they are both essential for a baby’s neurological development [20]. Newborns who are breastfed or given formulas without PUFA supplements have lower amounts of DHA and ARA in plasma or red blood cells than infants fed formulas with PUFA supplements. Upper respiratory infections are less common in infants given formula supplemented with DHA and ARA. Compared to a baby formula containing ARA, the lack of ARA impacts circulating T lymphocytes, macrophages, and B cells activation markers. Clinical studies have been conducted to evaluate the effectiveness of adding DHA and ARA to infant formula [74]. Infants who consumed formulas lacking LCPUFAs had significantly lower concentrations of DHA and ARA in their plasma and red blood cells compared to breastfed infants [48]. These results were compared to those of babies who received formula with DHA and ARA, and it was found that they have a satisfactory amount of these LCPUFAs. Moreover, it has been demonstrated that breastfed infants have far higher quantities of DHA in their brains than newborns who are given formula.

7. Technology of infant formula production

Infant formula was first made using customized cow’s milk around the start of the 20th century, but more modern formulas have come to closely resemble HM as a result of advances in our understanding of infant nutrition and production technology. The amounts of essential nutrients are the primary distinctions between HM and BM. LCPUFAs and choline are crucial elements that must be included in formulas [3]. The sterilized combination of required ingredients is then homogenized and evaporated before spray-drying. Thermal processes, such as component rearrangement, may take place throughout any step of this process [75].

Using a ribbon blender, the raw and dried materials collected from the vendor are combined in bulk until the ingredients are evenly redistributed everywhere in the mixture. Next, the ingredients are sorted via a fine mesh to remove large and unwanted particles. The powder is subsequently moved from the screened material to the packing line, which is then shifted to a filler hopper [3]. After that mixture is fed further into the can-filling chamber from the filler hopper, noble gas is used to rinse the cans. The dry blending method has several benefits, one of which is that it consumes less energy and needs less financial investment for the infrastructure, the machinery, and the operation [76]. Because the powder-forming technique does not include the use of any water, the potential for microbial contamination is drastically reduced.

Currently, the wet mixing-spray drying procedure is the most commonly used technique for making powdered baby formula. One benefit of this drying method is that all quality parameters may be more successfully controlled than they can be with the dry mix method [77]. Water-soluble components are mixed with milk in a high-shear mixer before being added to the mixture. Once fully hydrated, the mixture is then kept in a tank. Minerals that may dissolve in water are incorporated into the blend after being individually hydrated in warm water. To add oil-soluble vitamins to the mixture, they must first be dissolved in oil [76]. Evaporation, which uses less energy than spray drying, is, therefore, a required stage in the water removal process. In vacuum evaporators, evaporation is always performed. As a result, the components are shielded from heat damage since the pressure is lowered, allowing boiling to occur at a lower temperature. A continuous multiple-effect evaporator, often of the tubular form, concentrates milk before it is dried [77]. The drying method is to blame for the variation in maximum concentrations that might occur during evaporation. Milk is often dried using a hot air stream or a roller dryer. Both systems need to have the application modified for industrial usage. Because roller-dried goods are less soluble in water, spray drying is often used for baby formula. A solution is sprayed into a compartment with heated air flowing within it in the form of tiny droplets according to the drying concept. Expanding the surface area enables quick mass transfer. Before being exposed to the hot air in the chamber, evaporated milk must first be divided into tiny droplets. Different types of drying chambers exist. They typically consist of a cylindrical cone that is tilted between 40 and 60°, allowing the powder to escape the chamber by gravity. Additionally, the bottoms of these compartments are flat so that suction or scraper devices may be added to remove the powder. There are certain spray drying chambers with fixed nozzles. For the comparatively big milk droplets to be released in counterflow to the drying air, they are utilized in low spray towers and are situated in a lower location inside the chamber. The milk is released from the stationary nozzle in the identical airflow direction. In the chamber, generally, the air temperature range is between 170 and 250° C, whereas the formula mixture has a temperature below 100° C. Due to the fast heat transfer caused by the temperature differential, quick and homogenized drying is accomplished. However, the drying procedure might be carried out in phases, with each step having a distinct time-temperature profile to limit the destruction of delicate items, such as baby formula [77].

8. Conclusion

In conclusion, baby formula is still undergoing modifications, and these changes often lead to products with properties and compositions that are more similar to those of human milk. New formula is also being created to satisfy the demands of newborns who have specific nutritional requirements. Data show that formulas with PUFAs added in quantities comparable to those in human milk may help the visual system’s development. According to many studies, bioactive compounds in formula promote the development of the immunological and gastrointestinal systems. According to multiple studies, catch-up growth was higher in newborns given this novel formula than in those fed regular term-infant formulas. Formulas for preterm infants are created to satisfy the demands of a population at risk of developing growth and nutritional deficits. The complex components of human milk and the unique dietary requirements of various groups of newborns will continue to be characterized by researchers via continuing investigations. It is necessary to conduct lengthy research with large newborn cohorts to ascertain if the biochemical effects of formula changes are related to functional results.

Conflict of interest

The authors declare no conflict of interest.