Oral Wound Healing in Aging Population

Abstract

Background: Oral wound healing in the aging population is a multifaceted issue requiring a comprehensive approach, considering the physiological changes that come with aging and the frequent presence of comorbidities. Methods: This descriptive review summarizes the factors influencing oral wound healing in aging patients, including age-related physiological changes, hormonal modifications, multimorbidities, polypharmacy, oralome alterations, and nutritional status. Results: The aging population encounters numerous challenges in oral wound healing due to intrinsic factors, such as biological aging and hormonal changes, and extrinsic factors, such as medication use and lifestyle. Conclusion: Understanding these factors and their combined impact is essential for effective clinical management and improved outcomes in older adults.

1. Introduction

Wound healing is defined as a natural physiological reaction to tissue injury, is a complex and dynamic process, and comprises four ordered phases [1]:

• The first phase consists of hemorrhage and initiation of the coagulation cascade, involving the formation of immediate platelets;
• The second phase involves inflammation at the wounded site, with migration of inflammatory cells;
• The third phase consists of migration and proliferation of keratinocytes, endothelial cells, fibroblasts, angiogenesis, phagocytosis, and matrix synthesis with complete wound closure;
• The fourth phase is maturation, which involves tissue remodeling and reorganization.

Oral wounds are among the most common issues in everyday dental practice. Mostly, they occur after surgical procedures like extraction, periodontal, and implant surgery, or mouth ulcers.

Oral wound healing stages are similar, but compared with skin healing, it is more rapid and with minimal scar formation [2] due to the presence of excellent blood supply in the head and neck region, antibacterial and prohealing properties of saliva, presence of oral microbiota, as well as a more rapid turnover of the mucosal keratinocytes [3,4,5].

The oral mucosa is the only adult tissue with the potential to heal with minimal scar formation due to the following particularities: environment (saliva and microbiota), reduced inflammation, angiogenesis, keratinocyte proliferation, and fibroblasts [6]. Oral fibroblasts seem to possess unique characteristics and tightly controlled specific functions in wound healing and repair [7].

Moreover, there are more types of wounds due to different tissues under the mucosa in the oral cavity. Healing processes in the oral cavity differ depending on the type of tissue involved. The mucosa covering loose connective tissue and muscle heals differently compared to the attached gingiva that covers the alveolar bone. For the former, epithelial coverage of excisional wounds occurs rapidly and is largely independent of the underlying stromal healing. In contrast, healing in the attached gingiva is characterized by epithelial closure that coincides with substantial new connective tissue formation, which progresses slower.

Additionally, wounds over muscle and loose connective tissue typically heal through epithelial coverage and wound contraction [8]. Depending on the specific oral tissue type, wound healing may primarily involve reepithelialization, reepithelialization with substantial connective tissue formation, or a combination of both with new bone formation. Consequently, the cellular mechanisms and types of cells involved vary, and these processes are differentially affected by systemic diseases [8].

Oral wound healing is particularly important in the elderly due to several factors, including a slower healing process, a weakened immune response, chronic health conditions, and the impact of medications that interfere with the healing process. These multiple influences make this an essential topic to review, as promoting efficient oral wound healing in elderly patients is critical for maintaining oral health, preventing infections, and ensuring overall quality of life.

2. Impact of Aging on Oral Wound Healing

Causes of poor wound healing in the oral cavity are closely linked to the described phases of the wound healing process. One primary issue is the persistence of the inflammatory phase, which can extend beyond seven days. This prolonged inflammation is often characterized by delayed epithelialization and tissue necrosis [9].

Aging is a biological progressive process of functional decline with a decrease in cellular function derived from a gradual deficiency of the regenerative response [10,11]. This process is characterized by disequilibrium, and increased vulnerability, in addition to reduced adaptation [12].

Old age is considered a risk factor in the healing process, which leads to delay in healing but not inevitably in a deterioration of healing quality [13]. Delayed healing in aged patients is associated with an altered inflammatory response, a delay in angiogenesis, collagen synthesis, reepithelialization [14,15], and a disrupted balance between synthesis and degradation [16]. Impaired vascularization is related to delay wound healing of aged skin [17].

Research in periodontal healing capacity changes demonstrated that each phase of the healing process undergoes age-related changes: increased platelet aggregation, increased secretion of inflammatory mediators, late lymphocytic infiltration, decreased growth factor secretion, and a reduced collagen turnover rate [18,19].

In the aging process appears gingival atrophy and an inverse report between fibroblasts and collagen fibers [20], which is prone to delayed healing. Another factor implicated in delayed healing is the presence of senescent cells in oral epithelial and connective tissue [21]. These cells could appear due to the aging process, inflammation, infection, or mechanical stress [22,23]. Senescent cells lead to a deterioration of tissue homeostasis and impaired wound healing [24].

A significant delay in mucosal wound healing was observed in middle-aged and aged rats associated with aged blood factors, which decrease cellular responses [25]. In aged fibroblasts, cell migration, myofibroblastic differentiation, collagen remodeling, and proliferation are decreased [26].

Intriguingly, an in vivo study in rats has proved complete wound closure was faster in the old rats [27]. A reduced initial tissue damage due to decreased and delayed inflammatory response in the old rats, which led to faster clinical wound healing, may be responsible for the differences [27].

Understanding the impact of aging on the healing process is crucial for developing advanced tissue engineering strategies that aim to promote more effective wound healing. New strategies can be designed to address the specific challenges with the aging process by incorporating the underlying biological mechanisms that facilitate healing.

The integration of clinical health technologies into treatment protocols for elderly patients can significantly reduce the risk factors associated with impaired wound healing [28]. These technologies, which may include advanced diagnostics, personalized treatments, and regenerative therapies, can help mitigate the effects of aging on wound healing. By tailoring these interventions to the unique needs of older adults, it is possible to enhance their overall health outcomes and promote more efficient recovery processes.

Not only the aging process might impair wound healing, but also conditions associated with advancing age: hormonal changes, systemic disease, medication, modification of oral microbiota, and nutrition.

3. Hormonal Changes and Genetics

Furthermore, sex hormones influence mucosal wound healing. Regarding the level of estrogen and testosterone, it seems that for women, menopause, rather than age, may serve as a better indicator of risk for impaired healing in oral surgical procedures in women [29].

Oral wound healing in the older menopausal population is a complex and multifaceted process, heavily influenced by hormonal changes, genetic predispositions, and past medical history [30,31]. The significant decline in estrogen levels during menopause adversely affects key physiological processes, including collagen synthesis, immune function, and tissue regeneration, resulting in slower and often compromised healing of oral wounds [32,33]. These challenges are particularly pronounced in postmenopausal women who have experienced pregnancy complications, where the long-term effects of these conditions, compounded by genetic factors, necessitate a nuanced and individualized approach to clinical care.

The role of estrogen in maintaining oral health is well-documented, with its influence extending to the regulation of collagen production, immune responses, and vascularization of oral tissues [34]. As women transition into menopause, the sharp decline in estrogen levels leads to diminished collagen synthesis and a reduction in gingival blood flow, both of which are critical for effective wound healing [32]. Albandar highlights that postmenopausal women are at an increased risk of periodontal diseases, primarily due to these hormonal changes, which impair the body’s ability to repair and regenerate oral tissues efficiently [35].

Genetic factors play a crucial role in determining the efficiency of wound healing [36]. Specific genetic polymorphisms associated with collagen synthesis, immune modulation, and inflammatory responses can significantly impact the healing process [37]. For instance, variations in the COL1A1 gene, which is responsible for producing type I collagen, have been linked to reduced collagen production and delayed wound healing [26,38,39]. Additionally, the IL-1β +3954 gene polymorphism, known for its association with an exaggerated inflammatory response, has been identified as a significant risk factor for severe periodontal breakdown and slower healing rates following dental procedures [40,41].

Table 1. Genetic Variants Affecting Oral Wound Healing in Postmenopausal Women.

Genetic Polymorphism	Gene	Associated Function	Mechanism	Impact on Oral Wound Healing	Reference
COL1A1 +1245G/T	COL1A1	Type I Collagen Production	Polymorphism affects collagen fibril formation, leading to weaker collagen fibers.	Reduced collagen synthesis impairs wound healing and increases susceptibility to periodontal disease.	[26,38]
IL-1β +3954C/T	IL-1β	Pro-inflammatory Cytokine	Increases IL-1β expression, amplifying the inflammatory response and promoting tissue destruction.	Exaggerated inflammation contributes to alveolar bone destruction and slower healing.	[40,41]
MMP-1 -1607 1G/2G	MMP-1	Matrix Metalloproteinase Activity	Enhances MMP-1 expression, increasing extracellular matrix (ECM) degradation.	Increased ECM breakdown delays wound healing and accelerates periodontal tissue destruction.	[42]
TNF-α -308G/A	TNF-α	Pro-inflammatory Cytokine	Leads to higher TNF-α production, heightening inflammatory responses and tissue damage.	Increased inflammation slows healing and causes more extensive tissue damage.	[43]
IL-6 -174G/C	IL-6	Pro-inflammatory Cytokine	Alters IL-6 expression, affecting inflammation and interaction with tissue inhibitors of metalloproteinases (TIMPs).	Imbalanced inflammation reduces healing efficiency and increases chronic oral infections.	[41,44]
MMP-9 -1562C/T	MMP-9	Matrix Metalloproteinase Activity	Increases MMP-9 expression, leading to excessive ECM degradation.	Excessive ECM breakdown delays wound closure and worsens tissue destruction in periodontal disease.	[42]
APOE ε4	APOE	Apolipoprotein E Production	Impairs lipid metabolism and promotes inflammation.	Impaired tissue repair and increased inflammation result in prolonged healing and greater risk of periodontal disease.	[45]

summarizes the genetic variants affecting oral wound healing in postmenopausal women.

These genetic predispositions, when combined with the hormonal changes of menopause, can lead to more severe oral health challenges. For example, women carrying these genetic variants may experience exacerbated periodontal disease and prolonged wound healing times [46].

In women who have experienced pregnancy complications, such as late labor, the birth of malformed fetuses, or stillbirth, the challenges of oral wound healing are often exacerbated by genetic factors [47]. For instance, delayed delivery can impose significant physiological stress, leading to long-lasting systemic effects that may interact with genetic predispositions to influence wound healing [48]. Similarly, the birth of malformed fetuses or stillbirths, which often involve genetic components, may necessitate complex medical interventions that disrupt normal hormonal and immune responses, further complicating wound healing later in life [47,49].

Additionally, residual effects of pregnancy-related complications, such as gestational diabetes, can significantly impact oral wound healing [8,50]. Diabetes is known to induce long-term systemic inflammation and metabolic disturbances, which, when combined with the hormonal changes of menopause, can lead to more severe oral health outcomes [51]. For example, gestational diabetes has been shown to increase the risk of developing type 2 diabetes later in life, which is closely associated with impaired wound healing [52,53].

Oral wound healing in the older menopausal population is shaped by a confluence of hormonal changes, genetic predispositions, and the long-term effects of pregnancy-related complications. The decline in estrogen levels during menopause, coupled with these genetic and historical factors, necessitates a personalized and vigilant approach to dental care. As the understanding of these dynamics continues to evolve, it is imperative that clinicians apply this knowledge to enhance treatment strategies and outcomes for postmenopausal women.

4. Multimorbidity and Polypharmacy

Delayed oral wound healing is influenced by various systemic factors, particularly in the aging population. Common contributors include stress, smoking, alcohol consumption, diabetes mellitus, and obesity [13,54]. Among these, diabetes mellitus is notably linked with delayed oral wound healing, especially after tooth extraction, due to impaired blood flow and immune dysfunction [55,56,57].

However, older adults frequently have multiple chronic conditions that can further complicate the healing process.

Numerous systemic diseases, medications, and other medical treatments can adversely affect oral health in older adults [12]. Geriatric patients often suffer from chronic conditions such as hypertension, arthritis, heart disease, pulmonary disease, cancer, and diabetes, or have a history of stroke [58]. The medications used to manage these conditions, particularly in the context of polypharmacy, can impair wound healing. Drugs that reduce appetite, increase nutrient loss, or interact with other medications can lead to malnutrition, further interfering with the healing process [59].

Multimorbidity and polypharmacy are common in the aging population, and oral side effects of medication are frequently ignored. Polypharmacy, a common issue in the aging population, can lead to adverse drug reactions and exacerbate patient conditions, including those affecting oral health [60]. Given these challenges, personalized care plans tailored to the specific needs of elderly patients are crucial for effective clinical management.

Among the medications commonly prescribed to older adults are antihypertensives, anticoagulants, and corticosteroids, each with implications for oral wound healing.

Xerostomia, or dry mouth, is prevalent in the aging population, often resulting from the use of anticholinergics and diuretics rather than aging itself [61,62]. Xerostomia and hyposalivation are commonly observed among patients suffering from hypertension [63]. These could be due to the medications such as calcium antagonist-type antihypertensive drugs that have been cited as a contributing factor to the xerostomia [64] effect, or ACE inhibitors (angiotensin-converting enzyme inhibitors) that can lead to dehydration and electrolyte imbalances, further exacerbating conditions hyposalivation [65].

Diuretics reduce salivary flow and impair wound healing by reducing the protective and antimicrobial functions of the saliva [66,67].

Anticoagulants increase the likelihood of bleeding and the formation of hematomas. Consequently, excessive bleeding could complicate the healing process. Anticoagulants impede hemostasis that initiates wound healing, making it harder for wounds to heal efficiently. In addition, by interfering with platelet function, anticoagulants can lead to delayed or impaired wound healing [68].

Despite these risks, studies have shown that anticoagulated geriatric patients do not have a higher in-hospital mortality rate from low-severity falls compared to non-anticoagulated peers. Although, the risk of oral complications remains due to maxillofacial trauma [69].

Finally, long-term corticosteroid use, common in older adults, can inhibit collagen synthesis and impair immune responses, essential for efficient wound healing [70,71].

The combined effects of these medications, alongside the presence of chronic diseases, underscore the need for careful management of oral health in the aging population.

5. Oral Microbiota

The oral microbiota, organized in many different microbiomes called oralome according to Radaic and Kapila [72], plays a critical role in maintaining oral health by ensuring a balanced ecosystem that supports normal biological processes, including wound healing.

Homeostasis within this microbiome is essential, as disruptions or dysbiosis can adversely affect healing processes. When the balance shifts, favoring pathogenic bacteria over beneficial ones, it can impede cell migration, osteogenic differentiation, and cell proliferation, which are crucial for effective wound healing [73]. This is evidenced by findings that antibiotic treatments, which significantly alter the oralome, can impair oral wound healing [74].

As individuals age, their oral microbiome undergoes significant changes, often driven by systemic diseases [75], nutritional status [76,77], and the aging process [78]. For example, systemic diseases such as diabetes or cardiovascular conditions can disrupt oral microbiome balance, leading to poorer wound-healing outcomes. Nutrition also plays a role, with deficiencies or imbalances potentially exacerbating dysbiosis. Age-related shifts in the oralome are characterized by a decrease in microbial diversity and an increase in pathogenic species, which contribute to chronic inflammation and may be indicators of frailty [79,80,81].

The relationship between oral microbiota and overall health is bidirectional; oral health can influence systemic health, and vice versa. Despite these changes recognized in older adults, research examining the oralome in geriatric populations, particularly with healthy control groups, is limited. However, existing studies suggest that the decline in microbial diversity and the rise in pathogenic species in the aging population leads to chronic inflammation, thereby complicating wound-healing processes and overall health [82].

Table 2. Oralome Changes with Aging.

Targeted Group	Microbiome Changes	Influence on Oral Health and Wound Healing	Reference
75–99 years of age community-dwelling healthy elderly	Significant association between denture use and increased fungal load in saliva, especially in complete denture wearers.	The denture appliance restricts the cleansing action of the tongue and saliva, which are part of the host defense mechanism.Oral candidiasis has been associated with hyposalivation, which promote an unhealthy oral environment.	[83]
Elderly living in nursing homes and healthy controls	Oral samples obtained from the present nursing home residents showed greater levels of Selenomonas, Veillonella, and Haemophilus, and lower levels of Fusobacterium.	Frailty is associated with oral microbiota formation and composition.	[79]
38–80 years	Younger participants were more likely to have a similar microbiota composition, whereas older participants demonstrated wider difference.	Salivary microbiota was associated with age and frailty.	[84]
Three age groups 20–40; 40–60; 60+ years	Low bacterial diversity with aging.Commensal Neisseria had declined after the age of 40. Opportunistic pathogens Streptococcus anginosus and Gemella sanguinis gradually rose with age.	Prone to disease formation in the oral cavity as well as in distant body sites.	[85]
35–70 years	Changes in microbiota with age.The abundance of Veillonella was reduced in both males and females, whereas increases in Corynebacterium appeared specific to males and Aggregatibacter, Fusobacterium, Neisseria, Stomatobaculum, and Porphyromonas specific to females.	Age and frailty are differentially associated with measures of microbial diversity and composition.	[86]
Elderly adults receiving community support and home care service	High-density fungal population co-occurs with poor oral and systemic health status.	Dysbiosis of the bacterial community, and the overgrowth of non-albicans Candida species might worsening oral and systemic health.	[87]

highlights the oralome changes with advancing age and influence on oral and systemic health with impact on wound healing.

6. Nutrition

The 2015 World Report on Ageing and Health by the World Health Organization (WHO) underscores that healthy aging is not merely about the absence of disease but also about preserving the functional abilities necessary for older adults to live meaningful and independent lives. Central to achieving this are nutritional and oral health, both recognized as crucial determinants of overall well-being in aging population.

This comprehensive understanding of oral health highlights its critical role in ensuring adequate nutrition, essential for preventing and managing chronic diseases [88]. Therefore, maintaining oral health and proper nutrition is fundamental to promoting healthy aging.

Poor nutritional status is associated with inadequate wound healing, and medical nutrition therapy is a way to improve the healing of wounds [89]. In

Table 3. Important Food Ingredients Benefiting Oral Wound Healing.

Food Ingredient	Health Benefits	Impact on Oral Wound Healing	Reference
Vitamins
Vitamin D	Supports calcium absorption and bone health.	Enhances wound healing by interacting with the vitamin D receptor and maintaining healthy gums.	[90]
Vitamin B12	Maintains energy levels and cognitive function.	Deficiency can impair tissue regeneration, leading to conditions like glossitis and mouth sores.	[91]
Vitamin C	Provides antioxidant properties and supports immune health.	Crucial for gum health and promotes collagen synthesis, essential for effective wound healing.	[92]
Vitamin E	Acts as an antioxidant and supports immune function.	Antioxidant properties help in healing wounds and reducing inflammation, particularly in diabetics.	[93]
Vitamin K	Supports blood clotting and bone health.	Plays a critical role in wound healing by promoting proper clot formation and tissue regeneration.	[94]
Minerals and Elements
Calcium	Maintains bone density and prevents osteoporosis.	Vital for normal skin physiology, tissue regeneration, and enamel quality, supporting wound healing.	[95]
Magnesium	Supports muscle and nerve function and bone health.	Improves wound healing and helps prevent tooth decay and periodontal disease.	[96,97]
Zinc	Supports immune function and wound healing.	Essential for healing oral wounds and maintaining gum health, aiding recovery after oral surgery.	[98,99]
Fatty Acids and Antioxidants
Omega-3 Fatty Acids	Reduces inflammation and supports cardiovascular health.	Enhances wound healing by reducing inflammation and improving gum health.	[100,101]
Coenzyme Q10 (CoQ10)	Supports cellular energy production and cardiovascular health.	Reduces gingival inflammation and accelerates healing after tooth extractions.	[102,103]
Proteins and Fibers
Proteins	Maintains muscle mass and supports overall health.	Crucial for tissue repair and chronic wound healing; deficiency affects gum and teeth health.	[104]
Fibers	Aids digestion and prevents constipation.	Supports oral hygiene by cleaning teeth naturally and contributes to improved wound healing.	[105]
Other Important Ingredients
Probiotics	Supports gut health and modulates immune function.	Enhances oral wound healing by balancing the oral microbiota and reducing inflammation.	[106]
Collagen	Supports joint health and skin elasticity.	Promotes oral tissue integrity and aids in wound healing by maintaining gum health.	[107,108]
Folic Acid	Supports red blood cell production and prevents anemia.	Helps maintain oral tissue health and promotes wound healing by reducing oxidative stress.	[41]
Lutein and Zeaxanthin	Protects against age-related macular degeneration	Contributes to oral health by improving skin tone	[109,110]

, we summarized health supplements with positive effects on oral wound healing.

7. Suggestions for Future Research

Future research in oral wound healing in the aging population should be directed toward several critical areas to address the complex challenges identified in this review. One key area involves the investigation of the molecular mechanisms underpinning the altered wound-healing process in aged tissues. Specifically, studies should focus on the impact of systemic conditions prevalent in elderly populations, such as diabetes and cardiovascular diseases, on the cellular and molecular dynamics of oral wound repair.

Secondly, the role of the aging immune system in wound healing should be a priority. Research should explore how immunosenescence and chronic low-grade inflammation, commonly observed in the elderly, affect the different phases of wound healing. This could lead to the development of targeted therapies that modulate immune responses to enhance healing in older adults.

Additionally, longitudinal studies are needed to delineate the causal relationships between hormonal changes, especially during menopause, and the dynamics of oral wound healing. This could include the assessment of hormonal replacement therapy and its impact on oral tissue repair capabilities in postmenopausal women.

New tissue engineering strategies could also play a significant role in promoting wound healing. By focusing on the underlying mechanisms that facilitate the healing process, these strategies could enhance the regenerative capabilities of oral tissues in the elderly.

The use of clinical health technology represents another promising avenue, potentially reducing overall risk factors associated with elderly subjects. These technologies could streamline the management of wound care, monitor healing progress in real time, and optimize treatment protocols based on dynamic patient data.

The interplay between nutrition, microbiota, and wound healing presents a fertile ground for exploration. Future studies should aim to elucidate how nutritional interventions, probiotics, and prebiotics can optimize oral microbiota composition to support better wound-healing outcomes in the elderly. Controlled clinical trials investigating the efficacy of such interventions will be crucial.

Technological advancements in regenerative medicine, including the development of novel biomaterials for wound dressing and drug delivery systems that can locally modulate the wound environment, also deserve attention. These innovations could be particularly beneficial for managing wounds in elderly patients, who often suffer from multiple comorbidities that complicate standard care.

The potential of personalized treatment plans based on genetic predispositions and individual health profiles could address the distinctive needs of geriatric patients. Research should focus on the development of predictive models based on genetic, epigenetic, and proteomic profiles to tailor wound care strategies to individual patients. This approach ensures that each patient receives care that is specifically aligned with their unique biological characteristics and health conditions.

These research directions will not only advance our understanding of oral wound healing in the aging population but also translate into more effective, personalized treatment strategies that can significantly improve outcomes for elderly patients.

8. Limitation of the Study

While this study offers valuable insights as a descriptive review of current research in oral wound healing among the aging population, it faces several inherent limitations. Primarily, its main objective was to present the current state of scientific research without focusing on methods of data selection and analysis from the literature, which could affect the depth and reliability of the findings.

The broad scope, encompassing diverse factors like hormonal changes and comorbidities, may also limit the depth of analysis for each specific aspect. Additionally, the review relies on existing literature that might exhibit publication bias, favoring more significant or positive outcomes.

The generalizability of the results is another concern, as the diverse genetic backgrounds and health conditions within the aging population can influence outcomes. To overcome these limitations, future research should integrate primary research and systematic reviews. This approach will provide more robust insights and align findings with the latest advancements in medical technology and treatments.

9. Conclusions

The aging population faces several challenges in oral wound healing due to intrinsic and extrinsic factors associated with aging. Understanding these factors and their impact is crucial for effective clinical management and improved outcomes in older adults.

Wound care in older adults should be tailored to address the specific challenges associated with aging. This includes managing underlying systemic conditions, optimizing nutritional status, and potentially using new therapies to enhance healing.