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    Steven Ballestas, Andrea Ardila, Karen Muñoz, Yancarlos Ramos-Villegas, Yelson Alejandro Picon-Jaimes, Tariq Janjua1,
    Alfonso I. Pacheco-Hernandez, Luis Rafael Moscote-Salazar

    Colombian Clinical Research Group in Neurocritical Care, Bogota, Colombia
    1Department of Critical Care Medicine, Physician Regional Medical Center, Naples, Florida. USA

    Email: rafaelmoscote21 @

    Rev Electron Biomed / Electron J Biomed 2022;2:37-42.

    Dear editor:

    Wound healing is a complicated mechanism that aims to repair and heal injuries, however, if there is an inadequate process, it can lead to complications. These complications have an impact on the daily life of the individual, such as higher hospital costs, further procedures, and psychological impact1.

    Various factors influence healing, which can slow it down, and therefore increase morbidity and mortality and even poor cosmetic appearance in the individual. On the other hand, sometimes the wounds, and psychological sequelae that patients present can be undervalued and generate high costs2. Among the factors are the intrinsic ones, alluding to the state of health and others such as age, states of immunosuppression, and stress. On the contrary, extrinsic factors refer to situations such as malnutrition, infections, hypoperfusion, cancer, and radiation3.

    Immune activity may be influenced by sleep limitation, especially in the short term, and is related to the sympathetic system and the hypothalamic-pituitary-adrenal axis. This leads to a decrease in Natural Killer cells and an increase in circulating proinflammatory interleukins, increasing the risk of infection, pathologies, and impaired healing4.

    This document provides an overview of some factors that influence wound healing such as nutrition, oxygenation, stress, and, mainly, sleep. Mechanisms that are involved in these alterations are discussed.


    Pathological entities, intentional and accidental injuries to the skin, organic tissue, or mucosal surface, result in loss of tissue integrity leading to wound formation,2. Healing contains different sequential but overlapping phases, these are the hemostasis/inflammation phase, proliferation phase, and remodeling phase23. Once there is a tissue injury, platelet aggregation will be activated by the action of the exposed endothelium, collagen, and tissue factor, leading to degranulation, chemotaxis, and release of growth factors to form the clot and obtain correct hemostasis5.

    Different factors can intervene; intrinsic ones are referring to the individual's health status and if they have any predisposing elements or extrinsic ones such as malnutrition and infections3.

    Nutrition: Good nutrition plays an important role when it comes to tissue repair. It helps to create an environment to heal wounds that promote cell differentiation. For this reason, optimal amounts of nutrients and proteins are necessary to synthesize nucleic acids (DNA and RNA), proteins, and different elements involved in all these cellular processes6. Essential nutrients such as vitamin A promote healing because they participate in the epidermal growth factor, fatty acids, and omega-3 modulate the arachidonic acid pathway and carbohydrates in collagen formation2.

    Oxygenation: Adequate oxygenation is necessary to carry out correct healing, individuals under circumstances where the oxygen supply is not sufficient, lack optimal healing2. Oxygen is crucial in the process of inflammation, bactericidal action, angiogenesis, epithelial germination, and collagen deposition. Any interruption of oxygen supply such as cold, stress, or vasoconstriction by catecholamines or hypovolemia, can delay healing3.


    Stress is a condition in which environmental loads cannot be tolerated by the individual, causing negative repercussions on behavior, affectivity, and other physiological processes, being part of the etiology of multiple pathologies7. There is a negative link between stress and healing, this is associated with an alteration in healing and an inadequate regulation of cells and molecules involved in the said process8.

    The hypothalamic-pituitary-adrenal and sympathetic-adrenal-medullary axes can be activated by stress, leading to the upsurge of glucocorticoids and catecholamines, which influence the healing process, especially in the initial inflammatory phase1.

    In older adults, a decrease in the number of macrophages has been observed, therefore, the secretion of proinflammatory cytokines and growth factors is reduced, preventing the correct recruitment and activation of leukocytes, stimulation of fibroblasts and keratinocytes, and promotion of angiogenesis in the wound. This process slowdown the inflammatory and proliferative phases9.

    Many studies show the relationship between emotional and psychological stress with increased mortality and morbidity24-26. The inflammatory markers are frequently researched aspects of the impact of stress, however, more research is required on micro-changes of the immune system in pathological results8.


    Wound healing requires oxygen to interact with numerous cytokines, serve as a supply to actively proliferating cells, and provide an effector for the respiratory burst of neutrophils10-12. It is estimated that a wound needs at least a tissue oxygen tension of 20 mmHg to heal properly, and oxygen tensions as low as 5 mmHg have been measured in non-healing wounds1.

    When other pathological factors come into play, such as an underlying disease state that can range from diabetes to cancer to malnutrition, a chronic wound can form10,13,14. The mechanism to reach this state can vary but includes factors that influence blood supply, alterations in immune function, metabolic diseases, medications, or local tissue damage10. External factors, such as sustained pressure, temperature, and humidity, also play an important role in allowing a wound to heal10,15.

    A sleep disorder characterized by instability of the upper airways during sleep, obstructive sleep apnea (OSA)10,13,14,16, consisting of repetitive episodes of partial or complete narrowing or closure of the airways higher during sleep while respiratory effort continues, causes intermittent desaturation during sleep, sleep interruptions, and excessive daytime sleepiness10,14,16. In parallel, intermittent hypoxia and subsequent reoxygenation can lead to hypoxia/reperfusion injury with subsequent increased oxidative stress and production of vascular growth factors that can further impair wound healing14. In vitro, intermittent hypoxemia frequency and magnitude cycling markedly altered wound healing responses. The cell response can be very complex with obstructive sleep apnea desaturations15.

    OSA has a high prevalence in people with diabetes but is significantly underdiagnosed13. In patients with diabetes and OSA, intermittent hypoxia increases sympathetic activation and thus oxidative stress, impaired microvascular function, and inflammation, which could contribute to worse outcomes from diabetic foot ulcers, one of the most common complications. of diabetes, associated with a high risk of lower limb amputation and increased mortality13,14,16. In a recently reported case series of three people with diabetic foot ulcers, it was hypothesized that severe undiagnosed or untreated OSA contributed to the failure of ulcer healing, and they reported improved healing after starting treatment of OSA in 2 patients, while the third declined treatment with continuous positive airway pressure and reported much slower healing despite receiving full care of both the wound and its comorbidities13. Infection, ischemia, and inadequate pressure offloading are the three classic risk factors for nonhealing, and results to date suggest that OSA is potentially another modifiable risk factor for improved healing14. Future intervention studies should focus on examining the impact of OSA treatment on the development and progression of chronic and poorly healing wounds13,14.


    The immune response differs between day and night17. The circadian rhythm, the coordination of the functions of the human body with the external cycles of light and darkness, is related to critical bodily changes such as hormone production, brain activity, heart, respiratory rates, body temperature, and tissue regeneration18-20. Cell division and protein synthesis reach their highest levels during sleep hours and decrease throughout the day, so the rate of healing of damaged tissues is higher during sleep11,19. Sleep is considered a restorative period in which the nervous system slows down its activity, leading to a state of partial unconsciousness18-20. A single sleep cycle is made up of 2 main phases, the non-rapid eye movement (non-REM) and rapid eye movement (REM) phases19.

    The first two stages of non-REM sleep involve changes in muscle and eye movement, respiratory rate, and body temperature19. These changes are followed by another two stages in which the decrease in brain delta waves results in deep sleep17,19. Growth hormone (GH), which is secreted after the delta stage of sleep, is responsible for growth in infancy and is crucial for ongoing tissue restoration and repair of damage incurred during waking hours18,19,21.

    Sleep disruption and neurosurgical wound healing are something not regularly brought up or discussed27. Prolonged duration of periodic desaturation can impact the wound healing process after neurosurgical procedures. Due to swings in intrathoracic pressure and obesity in combination with reduced central venous outflow, the wound healing can be slow and the risk of cerebrospinal leak can be present22. This is complicated with periodic desaturation. Further work is required to understand the interactions of these factors.


    Lack of sleep is one of the crucial factors among factors, both intrinsic and extrinsic, known to influence the wound healing process. However, entities associated with sleep disturbances are generally underdiagnosed and adequate sleep is often not considered an integral part of therapy for wound management and healing. In addition, continuous positive airway pressure can improve the healing of diabetic foot ulcers, but given the lack of studies on the subject, randomized controlled intervention studies with a significant sample are required to verify and subsequently consider their inclusion in the chronic wound management guidelines.


      1.- Gouin J, Kiecolt-Glaser JK. The Impact of Psychological Stress on Wound Healing: Methods and Mechanisms. Immunol Allergy Clin North Am. 2011;31(1):81-93.

      2.- Singh S, Young A, McNaught CE. The physiology of wound healing. Surg. 2017;35(9):473-477.

      3.- Gantwerker EA, Hom DB. Skin: Histology and Physiology of Wound Healing. Clin Plast Surg. 2012;39(1):85-97.

      4.- Smith TJ, Wilson M, Karl JP, Orr J, Smith C, Cooper A, et al. Impact of sleep restriction on local immune response and skin barrier restoration with and without "multinutrient" nutrition intervention. J Appl Physiol. 2018;124(1):190-200.

      5.- Wang P, Huang B, Horng H, Yeh C, Chen YJ. Wound healing. J Chinese Med Assoc. 2018;81(2):94-101.

      6.- Brown KL, Phillips TJ. Nutrition and wound healing. Clin Dermatol. 2010;28(4):432-439.

      7.- Vileikyte L. Stress and wound healing. Clin Dermatol. 2007;25(1):49-55.

      8.- Walburn J, Vedhara K, Hankins M, Rixon L, Weinman J. Psychological stress and wound healing in humans: A systematic review and meta-analysis. J Psychosom Res. 2009;67(3):253-271.

      9.- Koschwanez H, Vurnek M, Weinman J, Tarlton J, Whiting C, Amirapu S, et al. Stress-related changes to immune cells in the skin prior to wounding may impair subsequent healing. Brain Behav Immun. 2015;50:47-51.

      10.- Han G, Ceilley R. Chronic Wound Healing: A Review of Current Management and Treatments. Adv Ther. 2017;34(3):599-610.

      11.- Hoyle NP, Seinkmane E, Putker M, Feeney KA, Krogager TP, Chesham JE, et al. Circadian actin dynamics drive rhythmic fibroblast mobilization during wound healing. Sci Transl Med. 2017;9(415):eaal2774.

      12.- Briançon-Marjollet A, Henri M, Pépin J, Lemarié E, Lévy P, Tamisier R. Altered in vitro Endothelial Repair and Monocyte Migration in Obstructive Sleep Apnea: Implication of VEGF and CRP. Sleep. 2014;37(11):1825-1832.

      13.- Vas PRJ, Ahluwalia R, Manas AB, Manu CA, Kavarthapu V, Edmonds ME. Undiagnosed severe sleep apnoea and diabetic foot ulceration - a case series based hypothesis: a hitherto under emphasized factor in failure to heal. Diabetes Med. 2016;33(2):e1-4.

      14.- Maltese G, Fountoulakis N, Drakatos P, Shah D, Patel K, Sharma A, et al. Elevated obstructive sleep apnoea risk score is associated with poor healing of diabetic foot ulcers: a prospective cohort study. Diabetes Med. 2018;35(11):1494-1498.

      15.- Brown SA. Circadian clock-mediated control of stem cell division and differentiation: beyond night and day. Development. 2014;141(16):3105-3111.

      16.- Gupta MA, Simpson FC, Vujcic B, Gupta AK. Obstructive sleep apnea and dermatologic disorders. Clin Dermatol. 2017;35(3):319-327.

      17.- Del Gallo F, Opp MR, Imeri L. The reciprocal link between sleep and immune responses. Arch Ital Biol. 2014;152(2-3):93-102.

      18.- Sipahi M, Zengin K, Tanik S, Arslan E, Çubukçu A. Effects of circadian rhythm disorders on wound healing and strength of bowel anastomosis in rats. Wounds a Compend Clin Res Pract. 2014ov;26(11):317-322.

      19.- Elkhenany H, AlOkda A, El-Badawy A, El-Badri N. Tissue regeneration: Impact of sleep on stem cell regenerative capacity. Life Sci. 2018 ;214:51-61.

      20.- Weger M, Diotel N, Dorsemans AC, Dickmeis T, Weger BD. Stem cells and the circadian clock. Dev Biol. 2017;431(2):111-123.

      21.- Cable EJ, Onishi KG, Prendergast BJ. Circadian rhythms accelerate wound healing in female Siberian hamsters. Physiol Behav. 2017;171:165-174.

      22.- Yancey KL, Manzoor NF, Kelly PD, Yawn RJ, O'Malley M, Rivas A, et al. Impact of Obesity and Obstructive Sleep Apnea in Lateral Skull Base Cerebrospinal Fluid Leak Repair. Laryngoscope. 2020;130(9):2234-2240.

      23.- B H Cohen, L A Lewis, S S Resnik. Would healing: a brief review. Int J Dermatol. 1975;14(10):722-726.

      24.- Carrà G, Crocamo C, Bartoli F , Riboldi I, Sampogna G, Luciano M, Were anxiety, depression and psychological distress associated with local mortality rates during COVID-19 outbreak in Italy? Findings from the COMET study. J Psychiatr Res. 2022;152:242-249.

      25.- Adeyemi OJ , Gill TL, Paul R, Huber LB. Evaluating the association of self-reported psychological distress and self-rated health on survival times among women with breast cancer in the U.S. PLoS One. 2021;16(12):e0260481.

      26.- Bedi M, Varshney VP, Babbar R. Role of cardiovascular reactivity to mental stress in predicting future hypertension. Clin Exp Hypertens. 2000;22(1):1-22.

      27.- Khalyfa A, Gozal D, Kheirandish-Gozal L. Plasma Extracellular Vesicles in Children with OSA Disrupt Blood-Brain Barrier Integrity and Endothelial Cell Wound Healing in Vitro. Int J Mol Sci. 2019;20(24):6233.

    Luis Rafael Moscote, MD
    Colombian Clinical Research Group in Neurocritical Care,
    Bogota, Colombia

    Received: 28/08/2022
    Published: 13/09/2022