How Dietary Protein and Collagen Dipeptides Improve Wound Healing

Nutrition is a critical factor in the wound healing process, with adequate protein intake essential to successful healing. Patients with chronic and acute wounds, such as postsurgical wounds or pressure injuries, require increased protein to ensure complete and timely healing. Older patients with multiple comorbidities present a particular challenge. They often do not consume the necessary quality and quantity of dietary protein. In addition, this population may have a heightened stress response and resultant muscle loss due to a reduction in muscle protein synthesis. The all too frequent result is compromised wound healing, decreased ability to fight infections, and longer recovery time from illnesses and surgeries. It is imperative to address the increased protein needs of patients with wounds, especially older patients, to promote a full recovery.

STRUCTURE AND FUNCTION OF PROTEIN

The origin of the word protein, from the Greek protos, meaning “first” or “primary,” points to the fundamental need for this nutrient in the human body. Amino acids, the basic constituents of protein, are required for numerous and wide-ranging functions in the body. Proteins function in the body as enzymes for chemical reactions, hormones for chemical messaging, buffers to regulate acid–base balance, antibodies for the immune system, transporters of necessary substances in the blood (eg, albumin, hemoglobin, transferrin, retinol-binding protein), and acute-phase responders that guide the body’s response during acute critical illness.¹

Proteins also have structural roles in the body, such as the contractile proteins actin and myosin found in cardiac, skeletal, and smooth muscle, and as the fibrous proteins collagen, elastin, and keratin.¹ During the proliferative phase of wound repair, collagen deposition is crucial for closing the wound and increasing the tensile strength of the repaired tissue. Lean body mass, sometimes called muscle mass, decreases with age and critical illness. This significantly compromises the body’s ability to carry out all the necessary functions of protein. This is where nutrition intervention can play a dramatic role in wound healing and the overall well-being and functioning of the patient.

AMINO ACIDS

All amino acids have the same basic structure: a central carbon, at least one amino group (-NH₂), at least one carboxylic acid group (-COOH), and a side chain group that makes each amino acid unique and determines its functional role in the body.¹ Although sometimes classified by their properties, such as net charge and polarity, the 20 amino acids are commonly grouped into “essential” or “indispensable” amino acids, and “nonessential” or “dispensable” amino acids. The 9 essential amino acids (histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine) cannot be synthesized by the human body and therefore must be consumed in the diet.¹ The remaining amino acids are considered nonessential because they can be synthesized by the body using existing carbon skeletons and free amino groups.² However, some nonessential amino acids are considered conditionally essential for specific reasons, such as a genetic condition like phenylketonuria or immature organ function during infancy and childhood, which prevent the amino acid from being synthesized by the body.¹ For others, the demand increases during times of metabolic stress, such as in the presence of a chronic wound. Then the question is if the body's production can keep up with the increased demands. The requirements for the nonessential amino acid arginine are increased during wound healing for this reason.³ Arginine benefits wound healing by increasing collagen deposition and improving both nitric oxide (NO) production and nitrogen retention and immune function.³

There are some challenges with dietary arginine supplementation, so citrulline has been suggested as a more efficient alternative to raise plasma levels of NO. Citrulline is first converted to arginine in the bloodstream and then to NO in the cells. Arginine is largely metabolized by the liver, whereas the liver does not take up citrulline and therefore, nearly all the citrulline absorbed from the small intestine bypasses the liver and enters the systemic circulation.⁴ In addition, 40% of dietary arginine is catabolized by enterocytes in the first pass,⁵ whereas citrulline undergoes limited degradation.⁶ In real-life patient use, some have complained of gastrointestinal upset, namely nausea and diarrhea, and some clinicians are hesitant to administer arginine in critically ill patients, patients with renal disease, and patients with sepsis. Nutrition supplements are now available containing citrulline rather than arginine to address these concerns and achieve the same result, which is having enough arginine onboard for wound healing.

COLLAGEN DIPEPTIDES

In the simplest sense, a collagen dipeptide is two amino acids bonded together. Certain combinations of amino acids have been shown to have beneficial effects on wound healing. Prolyl-hydroxyproline (PO) and hydroxyprolyl glycine (OG) are two such combinations. These dipeptides are bonded in a way that prevents degradation and allows them to reach the wound site. PO is a low-molecular-weight, growth-initiating factor for specific fibroblasts involved in the wound healing process.⁷ Specifically, it triggers the growth of p75NTR-positive fibroblasts,⁷ which is beneficial during the proliferative phase of wound healing.⁸

PO and OG have been studied to determine if nutritional supplementation can affect the rate of wound healing. In a randomized trial, improved Pressure Ulcer Scale for Healing and Pressure Sore Status Tool scores were observed in the group that received nutrition supplementation containing PO and OG.⁹ According to the study’s authors, their findings suggest that the PO and OG absorbed into the blood act on fibroblasts in the dermal layers of pressure injuries and might also affect stem cells, resulting in reepithelialization and improved healing.⁹

ASSESSING DIETARY PROTEIN NEEDS

Adequate protein is essential for proper wound healing, but it has not been established how much more protein is required in patients with wounds.  The recommended amount of 0.8 grams of protein per kilogram of body weight is based on the needs of healthy adults. Elderly patients may require a higher baseline protein intake of 1.0 g/kg. In addition, many patients, including patients with wounds, do not fall into the category of “healthy adult” and have even further increased protein needs.

Postsurgically, 1.0 to 1.5 g/kg is the recommended amount but may vary depending on the extent of the surgical wound.¹⁰The recommendation for patients with pressure injuries who are malnourished or at risk of malnutrition is 1.25 to 1.5 g/kg.¹¹ Additional factors, such as preexisting protein-energy malnutrition, renal impairment, or other critical illnesses, must also be considered when determining a wound patient’s protein needs. The best policy is to evaluate the patient as a whole, use clinical judgment, and perform a nutrition-focused physical examination that includes signs and symptoms of malnutrition, dietary history to determine typical dietary protein intake, weight history to determine if unintended weight loss has occurred, and laboratory tests to determine the extent of inflammation.

MEETING PROTEIN NEEDS

If patients are not consuming a well-balanced diet, they are not consuming an adequate amount of protein to heal their wounds. Consuming enough dietary protein is particularly problematic in elderly patients for various reasons. The increased cost of high-protein foods, strong food preferences and intolerances, difficulty chewing or swallowing fibrous foods, and fear of consuming high-fat and high-cholesterol foods contribute to the decreased protein intake seen in this population.¹² In addition, loneliness, fatigue, depression, polypharmacy, dental problems, and a host of other problems interfere with meal preparation and oral intake.

To promote your patient’s intake of dietary protein, encourage flexibility in their diet and the consumption of foods that they enjoy, are easy to prepare, and are economically feasible. A diet that is too restrictive can be unappealing and may result in decreased intake and unintended weight loss. It is important to note that for wound healing to occur, adequate calories as well as adequate protein must be consumed; otherwise, protein calories will be used to provide glucose for energy production instead of being used for tissue repair.

Whole eggs, with their complete amino acid profile, are the gold standard protein against which all other sources of protein are compared. Luckily, eggs are generally cheaper than other high-protein foods, making their consumption a convenient and easy-to-prepare choice. Other good protein choices include beef, poultry, and fish as well as dairy products such as milk, cheese, and yogurt. Soy products are unique among plant foods in that they are also sources of complete protein. Most plant proteins are considered incomplete proteins because they have too little of one or more essential amino acid, which is termed the limiting amino acid.¹ The quality of plant sources of protein can be improved by combining foods with different limiting amino acids, such as combining grains with legumes, or legumes with seeds. It is unnecessary to combine incomplete proteins at each meal, but they should be eaten on the same day. The table lists the protein content of common food groups.

The best policy for increasing dietary protein intake in patients is to treat them as individuals and find out what foods would be accepted and preferred. Supplementation may be necessary to reach the higher level of protein required for wound healing. The most common way to supplement is with an oral nutrition supplement beverage or protein modular, such as protein powder or liquid protein. Variety in supplementation is key because most patients tire quickly of the same supplement day after day. Take advantage of the many protein supplement products available, such as high-protein cookies, gelatins, and nutrition bars. Protein powders can be added to soups, sauces, milkshakes, and other foods. Liquid protein supplements usually have a small 1- or 2-ounce dose and are easy to administer.

PRACTICE POINTS

Clinicians must emphasize the importance of protein in wound healing to achieve the highest level of diet adherence and the best clinical outcomes.

If increased needs cannot be met through dietary intake alone, oral nutrition supplements can be used to fill in nutritional gaps. High-calorie, high-
protein supplements are available in many forms and flavors to meet individual tastes.

Wound-specific nutrition supplements are becoming more refined and advanced as we learn more about the role of nutritional components such as citrulline and collagen dipeptides prolyl-hydroxyproline and hydroxyprolyl glycine, which have direct action on fibroblasts. 

REFERENCES

1. Gropper S, Smith J. Advanced Nutrition and Human Metabolism. 6th ed. Cengage Learning; 2013.

2.  Mahan, LK, Escott-Stump S, Raymond J. Krause’s Food and the Nutrition Care Process. 13th ed. WB Saunders; 2012.

3. Nelms M, Sucher KP, Lacey K, Roth SL. Nutrition Therapy & Pathophysiology. 2nd ed. Brooks/Cole Cengage Learning; 2011.

4. Morris SM Jr. Regulation of enzymes of the urea cycle and arginine metabolism. Annu Rev Nutr. 2002;22:87-105. doi:10.1146/annurev.nutr.22.110801.140547

5.  Wu G. Intestinal mucosal amino acid catabolism. J Nutr. 1998;128(8):1249-1252. doi:10.1093/jn/128.8.1249

6.   Wu G. Urea synthesis in enterocytes of developing pigs. Biochem J. 1995;312:717-723. doi:10.1042/bj3120717

7. Sato K, Asai TT, Jimi S. Collagen-derived di-peptide, prolylhydroxyproline (Pro-Hyp): a new low molecular weight growth-initiating factor for specific fibroblasts associated with wound healing. Front Cell Dev Biol. 2020.8:548975. doi:10.3389/fcell.2020.548975

8. Shigemura Y. Effect of Prolyl-hydroxyproline (Pro-Hyp), a food-derived collagen peptide in human blood, on growth of fibroblasts from mouse skin. J Agric Food Chem. 2009;57(2):444-449. doi:10.1021/jf802785h

9. Sugihara F, Inoue N, Venkateswarathirukumara S. Ingestion of bioactive collagen hydrolysates enhanced pressure ulcer healing in a randomized double-blind placebo-controlled clinical study. Sci Rep. 2018;8:11403 (2018). doi:10.1038/s41598-018-29831-7

10. Escott-Stump S. Nutrition and Diagnosis-Related Care. 7th ed. Lippincott Williams & Wilkins; 2012.

11. European Pressure Ulcer Advisory Panel, National Pressure Injury Advisory Panel, Pan Pacific Pressure Injury Alliance. Prevention and Treatment of Pressure Ulcers/Injuries: Clinical Practice Guideline. EPUAP/NPIAP/PPPIA; 2019.

12. Chernoff R. Protein and older adults. J Am Coll Nutr. 2004;23(suppl 6):627S-630S. doi:10.1080/07315724.2004.10719434

Dr Collins is a wound care-certified registered dietitian based in Las Vegas, NV. She is well known for her expertise in the complex relationships among malnutrition, body composition, and tissue regeneration. She can be reached through her website, www.drnancycollins.com.
The opinions and statements expressed herein are specific to the respective authors and not necessarily those of Wound Management & Prevention or HMP Global. This article was not subject to the Wound Management & Prevention peer-review process.