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Collagen Involvement in Health, Disease, and Medicine

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Bruno Silvestrini, Chuen Yan Cheng and Matteo Innocenti

Submitted: December 3rd, 2021Reviewed: December 12th, 2021Published: February 10th, 2022

DOI: 10.5772/intechopen.101978

IntechOpen
Collagen BiomaterialEdited by Nirmal Mazumder

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Collagen Biomaterial [Working Title]

Dr. Nirmal Mazumder and Dr. Sanjiban Chakrabarty

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Abstract

This chapter discusses the physiologic, metabolic, and clinical aspects of collagen, including the role of nutritional factors in a new nosographic entity, called “extended collagen carential disease.” Except water and possibly fats, carbohydrates, and other structural proteins, perhaps there is more collagen in the mammalian body than anything else. Moreover, collagen participates in almost all of the body functions, adjusting its structure constantly in response to changes in environment, development, growth, and external clues. Collagens found in bones and nails are different from collagens found in body fluids and other biological structures, such as basement membrane, skin, tendons, muscles, and hair. The ubiquity of collagen functions accounts for its phylogenetic ubiquity, involving any tissue, organ, and apparatus. This is shown by the so-called “collagen carential disease,” involving nails, hair, osteoarticular and gastrointestinal systems. For instance, the Ehlers-Danlos syndrome describes another group of genetic collagen disorders, affecting the collagen processing and structure. Some of them are inherited in an autosomal dominant manner, while others emerge in the absence of essential nutritional factors. It is the case of Vitamin C, which plays a critical role in the maintenance of a normal mature collagen network. Hence, the idea of an “extended collagen carential disease,” applicable to the absence of essential nutritional factors.

Keywords

  • collagen physiology
  • collagen pathology
  • collagen medicine
  • collagen physiopathology
  • collagen supplement

1. Introduction

The term collagen designates a family of proteins, which spread throughout the whole organism, linking its parts and carrying out a precise physiological role. In contrast to spherical globular, collagen is composed of linear, fiber-like structures. All cells and tissues are supported by a network of collagen fibers, the arrangement of which appears to be specifically site adaptive [1]. Its structural domain, namely tropocollagen, is a molecule of about 300 kDa, 300 nm long, and 1.5 nm in diameter and mainly composed of glycine (Gly) lysine (Lys) and proline (Pro).

The hydroxylation of Pro and Lys is catalyzed by prolyl 3-hydroxylase, prolyl 4-hydroxylase and lysil-hydroxylase, and these reactions all require free O2, ferrous iron, α-ketoglutarate, and ascorbic acid. Prolyl-hydroxylase hydroxylates the third carbon, whereas prolyl 4-hydroxilase hydroxylates the fourth carbon in the proline ring. An adequate amount of 4-hydroxyproline helps to stabilize the triple helix of collagen in the human body. Therefore, when its content is not enough, the newly synthetized collagen is denatured. It is the case of scurvy and local tissue hypoxia [2, 3]. This process increases the possibilities of hydrogen bonds, decreasing the steric hindrance of the molecule and improving its resistance to decay and disintegration.

In addition to the high content of Gly, Lys, and Pro, a distinctive feature of tropocollagen is the so-called α-chains, consisting of amino acid repeats of (Gly-X-Y)n, where X and Y are typically proline (Pro) or hydroxylated proline, 3-hydroxyproline or 4-hydroxyproline.

Like other proteins, collagen has primary, secondary, tertiary structural elements. It has also a quaternary structure similar to other complex oligomeric proteins, which are characterized by having multiple polypeptide chains or subunit [4]. To date, some XXVIII different types of collagens have been identified.

About 44 genes, which typically have the “COL” prefix, are associated with the biosynthesis of collagen, which begins with turning on genes, which are associated with the formation of an α peptide. Following the transcription into the collagen mRNA, it enters into the cytoplasm, where a translational process begins. Once the synthesis of the new peptide is finished, it goes into the rough end plasmatic reticulum (rER) for posttranslational process, forming a pre-pro-collagen. Removal of the signal peptide on the N-terminal and the glycosylation occur to transform the pre-pro-collagen into the procollagen, which is packaged into vesicle destined to Golgi apparatus. Herein, procollagen undergoes last posttranslational modification, representing by oligosaccharides addition, before being secreted out of the cell, wherein the action of collagen peptidase serves to obtain the formation of tropocollagen. Outside the cell, lysin oxidase acts on the amino acids lysines and hydroxylysines producing aldehyde groups, for covalent binding between tropocollagen polymer, forming the so-called collagen fibril.

Type I, II, III, and IV collagens are the most abundant collagens found in several tissues.

Type I collagen is a fibrillar-type collagen and the most abundant in the composition of several tissues. It forms connective tissues, tendons, skin, artery walls, cornea, fibrocartilage, and the organic matrix of bone and teeth, serving to the deposit of the mineral matrix, conferring further stiffness and hardness to these tissues. Without its action, calcium salts would go unused. Type I collagen mutations occur in several genetic diseases, such as osteogenesis imperfecta and Ehlers-Danlos syndrome (EDS). In the adult, type II collagen, instead, is the major structural component of the hyaline cartilage, vitreous humor of the eye, and it is also found in other tissues, such as the nucleus pulposus of the intervertebral disc, whereas type III is the structural component in hollow organs, such as intestines and uterus. Lastly, type IV collagen is a type of collagen found primarily in the skin within the basement membrane zone and also the testis. It also forms basal lamina, eye lens, and also serves as part of the filtration system in capillaries and the glomeruli of nephron in the kidney. In essence, the tropocollagen represents a common matrix and the unifying element of the variegated collagen family.

Collagen has two fundamental biological properties: a mechanistic effect, of support and protection, and a trophic one. The first is comparable to the function of cement that composes and covers a building, supporting and protecting it from foreign elements. The mechanistic action is so strong to be used in the protection of marble monuments from acid rain [3]. A new in vitro test has been recently developed to measure the barrier effect of collagen against the erosive action of hydrochloric acid (HCl) [5]. This test showed that hydrolyzed collagen guarantees a consistent and dose-dependent barrier effect against high concentration of HCl, which correlated with the molecular weight and amino acid composition of the protein. As a matter of fact, partially hydrolyzed collagen (molecular weight 5.000–10.000 Da) was about fivefold more potent than totally hydrolyzed collagen (molecular weight 1.000–3.000 Da), whereas the different aminoacidic composition of bovine and fish collagen reflects a greater barrier effect for the latter.

The trophic effect of collagen overlaps the mechanistic one. It is typically used in cell cultures. For example, an addition of collagen to the culture medium enhances exponentially the growth rate of the fibroblast subpopulation [6]. This property of collagen is typically used in the wound healing management, taking part in the proliferative and maturation phases, leading to the epithelization of the damage tissue. In human living, the aforementioned actions are interconnected. In fact, after the mechanistic action, collagen disintegrates, nourishing the surrounding tissues with the products of this disruption, peptides, and free amino acids [7, 8].

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2. Metabolism of collagen in human body

The metabolism of collagen in the mammalian organism must take into account not only the molecular structure of collagen, but also its relation to other constituents of the tissue of which it is a part. Concerning the metabolic turnover of collagen, studies have shown that it is daily exposed on one side to a continuous loss, on the other side to an equally continuous newly synthesis. Nevertheless, when the loss overcomes the newly synthesis of collagen, it springs into a nosographic condition, comparable to avitaminosis, namely collagen carential disease [9]. Of the several conditions in which collagen structure or metabolism is disrupted, these changes lead to two pathological conditions: these are scurvy and lathyrism [10].

The loss of collagen is due both to the degradation implicit in the structural functions of the protein and to the products of its metabolism, which disperse outside the organism through the main route of elimination. The rate of the aforementioned loss has not been precisely determined, but its magnitude can be deduced from the daily protein requirement. It is in the order of 0.8 g/kg/day or about 55 g daily [11, 12]: in the organism collagen represents from 25 to 35% of the whole protein content [13], it derives a requirement of about 0.2–03 g/kg/day, corresponding to 14–18 g daily. This is the rate of the loss of collagen involved in the collagen carential disease.

Furthermore, pyridinoline (PYD) and deoxypyridinoline (DPD) are bone cross-linking compound of collagen fibers. PYD and DPD are formed during collagen maturation, thus their presence in both serum and urine is the result of collagen degradation, representing a useful diagnostic tool for the collagen carential disease.

Concerning the process of newly synthesis of collagen, it must be considered that collagen is a protein and, unlike vitamins and other essential nutrients, cannot be introduced into the organism as such. If it happened, collagen would trigger an immune, potentially auto-disruptive, reaction. Therefore, the focus shifts from the collagen itself to the raw materials required for its synthesis, which mainly consist of peptides and free amino acids.

Limited to nonessential amino acids, the raw material is partly synthesized ex novo inside the organism, whereas the remainder is recycled from preexisting proteins. Nevertheless, the main source is presumably represented by the products of food digestion. The last way is the most relevant, depending merely on food supply and supplementation.

Typically, a balanced diet should guarantee the adequate supply of amino acids necessary to synthesize collagen to maintain its homeostasis across the human body. However, there are critical issues that deserve attention. Firstly, collagen has a unique amino acid composition, which is made up of 20 amino acids. Of the nine amino acids designed as essential for human body, only methionine is slightly present and tryptophan is completely absent. Typical for collagen is the presence of essential amino acids, but also modified amino acids, namely 3-hydroxyproline, 4-hydroxyproline, and 5-hydroxyproline. Collagen also contains carbohydrate units, linked to hydroxylysine residues via the hydroxyl functional group of the amino acid. Gly and Pro in collagen structure are at 10–20-fold concentration found in other proteins. In order to ingest the same amount of glycine that is contained in 10 g of gelatin, one would have to consume about 2.8 L of milk or 160 g of meat. In the case of proline, the equivalent amounts are 0.4 L and 110 g, respectively [4]. For this reason, the amino acid composition of collagen has no significant correspondence in other proteins, neither animal nor vegetable. Therefore, the protein dietary intake can help, but it is not enough. Moreover, beyond certain limits, it takes negative effects, favoring the urinary elimination of calcium, the absorption of undigested proteins, and the accumulation of toxic portions [14, 15, 16].

In essence, the only protein that guarantees a correct amino acids supply for the endogenous synthesis of collagen is collagen itself, except that it is slightly digestible.

In this way, we have arrived to talk about hydrolyzed collagen (HC), also known as gelatin, which is progressively affirming in the treatment of the collagen carential disease. Gelatin is typically obtained from type I bovine skin collagen and from type I fish skin collagen. In brief, the skin of the animal is cleansed and treated with alkali and acid to prepare it to the extraction process. It was done by increasing the temperature of water till boiling. Then, collagen was in water solution ready to be purified using ultrafiltration and ionic exchange resins. After that, the solution is concentrated under vacuum, to reach the right concentration for the drying step. Apart from acids and alkalis, enzymes, or a combination of enzymes and chemicals, are also used for cleaving the cross-links. Special proteolytic enzymes are used as pepsin, neutrase, alkalase, bromelain, or papain. The selection of enzyme(s) and hydrolysis conditions essentially determine the sensory properties of the final product. Lastly, gelatin is spray-dried to a powder [5].

This “pre-digestion” promotes the gastro-enteric digestion and absorption in the form of peptides and free amino acids, tripling the bioavailability of collagen [17, 18, 19]. Orally administered gelatin is digested in the gut, crosses the intestinal barrier, becoming available for the metabolic process in the tissues. It has been proposed that HC peptides are only digested reaching the blood by passing through the enterocyte (transcytosis) at a level of approximately 10% [20].

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3. Medical uses of hydrolyzed collagen via the oral and topical route

The term collagen derives from Greek κόλλα, meaning “glue,” and suffix -γέν, −gen, denoting “producing.” In fact, as early 3000 years ago, Egyptians used collagen solution as a biological glue to repair wooden articles. However, around 1800 A.D., collagen had its real development, being used as the main protein source in the diet of the French population who, due to the port blocks imposed by the British fleet, found themselves deprived of meat. The empiric uses of gelatin, for health protection, are widely documented since the Middle Age. Hildegard von Bingen was a German Benedictine abbess active as a writer, philosopher, composer, and medical writer during the High Middle Ages. In her book “Physica,” dated around 1150 A.D., she recommended frequent and abundant meals of broth produced with veal fragments, very rich in collagen, to give well-being to joint pain.

The first therapeutic application of hydrolyzed collagen dates back to the second half of the last century, when in the United States it was mainly used to treat affections of the skin appendages, which typically concerned nail weakness, improving nail growth and strength. Hence, the idea to use HC in a method for treating disorders of the scalp, such as thinning or fall of hair. In 1976, Scala et al. did not observe an effect from HC treatment on the growth of hair, but it was due to the short duration of treatment, which was 4–8 weeks for the cat and dog. In the patent titled “Method for treatment of disorders of the piliferous system in mammals,” the author reported that the administration of gelatin in the dosage of 100–500 mg/Kg increases the growth of hair in the rat, the dog, the rabbit, and the cat [21]. After due consideration to the different life span between these animal species and human, it was considered appropriate a period of three months’ administration of 8–16 g of gelatin per day in order to obtain important results in the hair growth in human [22]. Thus, we arrive in 1998 when the use of hydrolyzed collagen was described for the preparation of food supplements, as a source of essential amino acids for the trophism of the scalp and the treatment of dystrophic disease in humans and animals [17].

Clinically, the signs and symptoms of the collagen carential disease present a dystrophic-degenerative character. The pathological conditions due to its deficiency involve, practically, the whole organism, based on the ancient criterion ex juvantibus, which dates back to the diagnosis of a disease through its treatment. As a matter of fact, this criterion has been used to diagnose avitaminosis and the other deficiency pathologies so far known. We can find the clearest expression of collagen carential disease in the osteoarticular, cutaneous, and mucous systems, nowadays the most documented systems.

Several scientific studies have demonstrated that a diet containing gelatin can improve the structure and health of the skin, bone, hair, and fingernails. Osteoarthritis is one of the main joint diseases, characterized by breakdown of joint cartilage and underlying bone. Its degeneration causes pain, lower mobility, and decrease of the quality of life. The main goal of prevention and treatment of osteoarthritis is related to decrease the degradation of joint cartilage, protecting it from further damage. The chondrocytes, the main cellular elements of cartilage, have to be supplied with structural elements necessary during the renewal phase. The administration of substances that are capable of supporting the cartilage with suitable nutrients promotes the cartilage to regenerate itself. Jiang et al. confirmed that hydrolyzed collagen improves joint health in patients with osteoarthritis. A prospective, randomized, double-blind, placebo-controlled study was performed in elderly woman with moderate knee osteoarthritis, and it showed that oral intake of gelatin for 6 months significantly reduces joint pain, improving mobility as assessed by two well-established scoring system (WOMAC and Lysholm score) [23].

Osteoporosis, like osteoarthritis, is a worldwide disease. It reduces drastically the bone density and the bone’s structure becomes porous and weak, decreasing the capacity of bones to guarantee their structural function. Osteoporosis is easier to prevent than to treat. Typically, its prophylaxis and treatment are based on supplies of calcium. However, the primary structural element of bone is collagen, and the loss of minerals also means increased loss of collagen. This can be measured by analyzing the urine. By administering collagen hydrolysate, the building blocks required for renewing bone collagen are provided, and the body then uses them for this purpose [4]. To date, many clinical studies have evaluated its effects on bone metabolism. In most studies, hydrolyzed collagen is applied in association with other drugs, whereas in other studies, it is used as a single therapeutic element. In a first study, Adam et al. showed the effects of calcitonin, alone or in combination with a hydrolyzed collagen, on bone metabolism in postmenopausal women. The results underlined that a daily ingestion of 10 g of hydrolyzed collagen, in association with intramuscular injection of calcitonin (100 UI) twice a week for 24 weeks, enhanced and prolonged the effect of the drug as shown by a fall in urinary pyridinoline cross-link levels [20].

In a prospective, randomized, double-blind, placebo-controlled study, postmenopausal woman received 5 g/daily of collagen peptides for 12 months to evaluate its effects on bone mineral density (BMD) of the lower spine and the femoral neck. Daily intake of collagen reflected a positive shift in bone markers. As a matter of fact, the amino-terminal propeptide of type 1 procollagen (P1NP) significantly increased in the study group, indicating a stimulation of bone formation, whereas no changes in bone degradation markers could be determined. BMD increased significantly in the spine (3%) and in the femoral neck (6.7%), whereas no significant changes were determined in the placebo group [24].

Regarding the effects of hydrolyzed collagen on cutaneous diseases, 89 patients with stage II, III, or IV pressure ulcers were enrolled in a double-blinded, placebo controlled, randomized, multicenter trial. Hydrolyzed collagen intake was provided for 8 weeks at the dose of 15 g in a 45-mL unit dose. For the first time, results indicate that orally administration of hydrolyzed collagen can promote healing of pressure ulcers in addition with standard care [25]. Additionally, the oral administration of gelatin increased skin hydration after 8 weeks of supplementation; whereas ex vivo experiments demonstrated that collagen peptides induce collagen as well as glycosaminoglycan production [26]. This is due to its amino acid composition that activates the synthesis of collagen and glycosaminoglycan in the human body. Furthermore, hydrolyzed collagen helps to improve the strength and hardness of nails and hair. For instance, in one study, based on 14 g/daily diet of gelatin treatment for three months, the mean hair diameter increased by an average of 10%. Increases in the size of the hair stalk and the hair density were also reported as noted in a three-month application study, fingernails became firmer and less brittle [4]. Hexsel et al. investigated the daily ingestion of hydrolyzed collagen for 24 weeks increasing nail growth and improving brittle nails with a notable decrease in the frequency of broken nails [27], whereas Chen et al. found the essential relationships between collagen and hair follicle regeneration. It confirmed that collagen could be a therapeutic target for hair loss as well as skin-related diseases [28].

Recently, the medical use of collagen has also been extended to gastric diseases [29, 30]. two pathogenetic factors play an important role in dyspepsia: an excessive secretion of hydrochloric acid by parietal cells and a reduction of the mucus that covers and protects the internal surface of the stomach. Ulcerative forms from non-steroidal anti-inflammatory drugs (NSAIDs) are a typical example of the second factor, resulting in part from the reduction of prostaglandin activity, in part from a contact action, which occurs locally on the gastrointestinal wall. Antacids and antisecretors, particularly the proton pump inhibitors (PPIs), have found to be important in the treatment of dyspepsia, but they are displaying some unwanted toxicity that limits their use. It is due to a drastic reduction of gastric acidity, which decreases digestibility and absorption of essential nutrients, representing a risk factor for cognitive decline, such as suggested in recent observational studies and systemic reviews of the literature. Moreover, the excessive reduction of stomach pH increases the vulnerability to infection. As such, there is an emerging interest in developing medications to treat dyspepsia not by reducing gastric acidity, but by increasing mucosal protection toward hydrochloric acid. This approach thus preserves the positive effects of sterilization, digestion, and absorption of food [5]. Hydrolyzed collagen is a main candidate, showing both a mechanistic action, which protects as a biological veil the gastric mucosa against hydrochloric acid injury, then a trophic one, nourishing and regenerating the suffering mucosa.

International Patent US 10,973,850 discloses a novel composition comprising tricalcium phosphate and gelatin for use in a method for the treatment of dyspepsia and related disorders [29].

Furthermore, United States Food and Drug Administration recently approved the use of Hemospray, a collagen powder administered through endoscopy, for the management of GI bleeding [30].

Thus, we arrive to talk about another property of collagen, that is, its involvement in platelet adhesion and activation, triggering phase of the coagulation. As a matter of fact, when the endothelium is damaged, collagen is exposed to circulating platelets, which bind directly to collagen through collagen-specific glycoprotein Ia/IIa surface receptors. This bound is strengthened by von Willebrand factor (vWF), which is released from platelets and from the endothelium. These interactions lead to the platelet activation, which changes shape from discoidal to spherical, favoring the aggregation process to the site of injury. Collagen also accelerates reparative processes and initiates wound healing through activation of inflammatory cells and tissue vascularization. Collagen has also been shown to stimulate angiogenic growth factors and epithelial cell migration and proliferation, leading to re-epithelialization [31].

In addition to the oral supplementation, hydrolyzed collagen also manifests its biological effects by topical route. Fore et al. concluded that the use of a topical hydrolyzed collagen is an acceptable adjunct therapy for the treatment of Pyoderma gangrenosum (PG) lesions. A topical mixture of hydrolyzed collagen powder with equal volumes of 4 mg/ml dexamethasone phosphate liquid and 40 mg/ml gentamycin liquid compounded to a paste consistency was applied to the wound, with additional application of a compression dressing once a week. The lesions are healed in 4 months. Hydrolyzed collagen helps granulation and epithelization acting as an absorbable reservoir for anti-inflammatory and antimicrobial agents. The association of hydrolyzed collagen and antibiotic agents provides an effective topical treatment for this hard wound [32].

In recent years, collagen has found widespread para-pharmaceutical uses, typically in the form of food supplements, cosmetics, and medical devices, with defined physiological effects and without adverse reaction. Of particular interest is the use of HC for skin through topical application, in consideration of the physiological role recognized to this apparatus. The skin performs functions of protection, self-repair, thermoregulation, control, secretion, absorption, and sensory activity. According to a recent discovery, moreover, it acts as a solar panel. Unlike photovoltaics, it does not turn light into simple electricity, which requires complex processes to translate into a consumer product. The skin is capable of transforming solar power directly into hormones, vitamins, neurotransmitters, and other products crucial to the functioning of the skin per se, but also for the whole body including different organs. Indeed, these new observations provide explanation of more complex phenomena, such as the correlation between mood and sun exposure [33].

The Ehlers-Danlos syndrome (EDS) describes another group of genetic collagen disorders, affecting the collagen processing and structure. It is a rare disorder comprising a group of related inherited disorders of connective tissue, resulting from underlying abnormalities in the synthesis and metabolism of collagen, which is characterized by joint hypermobility and susceptibility to arthritis, skin, and vascular problems. EDS occurs due to variations of more than 19 genes that are present at birth. The specific gene affected determines the type of EDS. Actually, no cure is known, and the treatment is only a palliative one. Physical therapy and bracing may help strengthen muscles and support joint [34].

The novel aspect proposed in this work is that its pathogenesis once thought to result from defective genes alone could be influenced, in some cases, by food deficiencies, which in the case of Ehlers-Danlos syndrome concern the amino acids suitable for the endogenous synthesis of collagen. In essence, nutrient deficiencies could unmask and highlight the underlying genetic malformations; in the same way food supplement could be a valid aid not only for the containment and prevention of these diseases but also as a treatment. Likewise, it is known that spina bifida is caused by a combination of genetic and nutritional factors. Whereas it is produced by an acid folic deficiency during pregnancy, a dietary supplementation of folic acid has been shown to reduce the incidence of spina bifida.

Hence, the idea of an “extended collagen carential disease,” applicable to the absence of essential nutritional factors in the Ehlers-Danlos syndrome, plays an important role in the pathogenesis and treatment of genetic diseases.

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4. Conclusion

In conclusion, collagen is a family of proteins present in the whole organism, linking its parts and carrying out precise physiological roles. The tropocollagen, a protein of about 300 kDa genetically predetermined, is its progenitor and carrier. The various types of collagens, which characterize its presence and tangible functions in the body, take shape after an essentially posttranscriptional process. Around the backbone of tropocollagen, XXVIII different types of collagens take shape, with essentially posttranslational modalities. After its biosynthesis by fibroblasts and their subpopulations, the tropocollagen is glycosylated in the Golgi apparatus. Then it goes outside the cell. Through cross-links and the assumption of other molecules by Van der Waals forces, it takes the definitive conformations that distinguish its functions in the single organs and tissues. The tropocollagen represents, therefore, the common matrix and the unifying element of the variegated collagen typology.

Collagen has two distinct but interconnected properties: first, a mechanistic effect of support and protection; second, a trophic effect that nourishes the tissues, favoring the production of new collagen. Collagen is also subject to an important turnover, due both to its catabolism and to the end products of its biological cycle poured out in the form of hairs, desquamations, and secretions. This cycle, if not adequately integrated with components from the outside, results in a deficit of collagen leading to the collagen carential disease.

Our organism reproduces collagen at the expense of the amino acids obtained from food or newly synthesized. A high-protein diet can help in the treatment of collagen carential disease, but is not enough, mainly for the particular amino acid composition of collagen, which does not match in other proteins. The only protein capable of ensuring a correct amino acids supply would be native collagen, except that it is not digestible. The solution is offered by hydrolyzed collagen, which is more digestible and ingestible than the native one.

Twenty years ago, a famous physiologist stated that the understanding of the physiology of collagen was rudimentary [1]. In the meantime, a huge amount of knowledge has accumulated, opening the way to the treatment of the “collagen carential disease,” with involves the whole organism. This chapter draws attention on the Ehlers-Danlos syndrome, suggesting a carential role aside the genetic one.

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Written By

Bruno Silvestrini, Chuen Yan Cheng and Matteo Innocenti

Submitted: December 3rd, 2021Reviewed: December 12th, 2021Published: February 10th, 2022