New Concepts for
Oral Wound Care

COURSE OBJECTIVES

1. Understand the Evolution and Principles of Wound Care:

   1. Participants will gain an in-depth understanding of the historical evolution of wound care, including traditional and modern approaches. They will explore the three fundamental principles of wound care: eliminating the cause of the wound, dressing the wound, and providing systemic support. Additionally, they will learn about the specific challenges and considerations unique to oral wounds.

2. Evaluate the Impact of Bioburden and Pain on Oral Wound Healing:

   1. Participants will examine the role of bioburden in oral wound healing, understanding the difference between infection and critical colonization. They will also study how pain and discomfort affect wound healing through mechanisms such as vasoconstriction and the stress response. The objective is to highlight the importance of addressing microbial load and pain for optimal wound care.

3. Explore Safe and Effective Wound Dressing Materials for Intraoral Use:

   1. Participants will be introduced to new advancements in intraoral wound dressings, focusing on materials that are both effective and safe to swallow. They will learn about the benefits of natural ingredients like acemannan, essential oils, and xylitol in promoting healing, providing pain relief, and protecting wounds from contamination. The course will cover the formulation and application of a new oral hydrogel wound dressing designed for use in dental practice.

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ABSTRACT

Oral wound care is woefully lacking in dentistry because most wound care products are designed to work outside the mouth. So, what new advances in oral wound care can enhance patient care and your practice today? Information will be presented on a new, simple means to SAFELY promote optimal healing, provide pain relief, and protect oral wounds, thus benefiting both the patient and the practice.

 

INTRODUCTION

Wound care is an important part of patient care in just about every discipline of medicine.  It has long been known that wounds heal better, with fewer complications, when they are dressed properly.  Wounds have been dressed as long as wounds have plagued mankind.  Ancient manuscripts from Egypt that date back more than 5000 years describe wound dressings made of animal grease, Aloe vera, and honey mixed together.1  It is noteworthy that this combination of materials is an excellent wound dressing, and in fact, far surpasses many products and techniques used in modern wound care today.

 

Wound dressings may consist of bandages and other materials to cover a wound; however, various ointments, creams, oils, and sprays are also considered to be wound dressings.2  Whatever the wound happens to be, wound dressings perform many important functions.  Three important functions include: 1) protect wounds from further damage, 2) prevent contamination, and 3) maintain an optimal healing environment.3

 

Today, wound dressing research focuses on developing products with bioactive components to offer more benefits, such as pain relief and direct antimicrobial activity.  Some progress has been made with pain relief and antimicrobial activity; however, little success has been realized in obtaining these benefits without the use of toxic or irritating agents.  Almost all drugs have inherent toxicity, so it is necessary to weigh the risk against the benefit of a particular treatment.   The “line” which represents an acceptable balance between safety and efficacy is determined by the use of a “therapeutic index (TI).”  Factored into what constitutes an acceptable TI is the condition being treated.  For example, a cancer patient is generally subjected to drugs with much smaller safety ranges, or narrower TIs, than are patients who are treated for acne.  Unfortunately, just about everything used in the mouth for various conditions carries with it certain toxicities.  As is well known, almost everything used for oral wound care, even oral hygiene products such as toothpaste and mouthwashes, should not be swallowed because of potential toxicity.  A real need exists for effective intraoral wound care agents that are free of toxicity, and are safe to be swallowed.

 

3 PRINCIPLES OF WOUND CARE

 

•  ELIMINATE THE CAUSE OF THE WOUND 

•  DRESS THE WOUND

•  PROVIDE SYSTEMIC SUPPORT AS NEEDED

 

One of the three principles of wound care is that wounds should be dressed.  The other two principles are: eliminate the cause of the wound, and provide systemic support as needed in the form of nutrition, antibiotics, analgesics, etc.4  Unfortunately, dentists are the cause of most intraoral wounds, so little can be done about principle #1 (see figure above).  Dentists are generally very good at fulfilling principle #3, and routinely provide nutritional guidance and systemic medications as needed.  Dentistry, however, has never been able to adequately address principle #2, for obvious reasons.  The environment of the mouth is not conducive to standard wound dressings. 

 

Because the mouth’s environment precludes the use of standard wound dressings, many dentists have never thought of caring for mouth wounds, and worse, do not even think of extraction sites, flap procedure sites, graft sites, etc., as wounds at all!  It should be understood that surgery produces surgical wounds, and wounds should be cared for.  Although intraoral wounds such as extraction sites almost always eventually heal, the same can be said for just about any other wound of the body.  The fact is that wounds heal faster, with less pain and fewer complications, when they are dressed.  A need has thus existed for a truly safe and effective wound dressing for intraoral wounds.

 

To develop a viable dressing for the mouth, several issues with wounds and wound care, in general, should be considered.  Then, specific issues related to the mouth must be addressed.

Issues With Wounds

 

•  BIOBURDEN 

•  DISCOMFORT OR PAIN

 

Bioburden is defined as the number of microbial organisms on a wound surface.5  This is important because the microbial load can affect the healing process.  Infection is one aspect of bioburden.  “Infected wounds don’t heal” is one dogmatic statement that is almost 100% accurate.  When a wound contains enough microbes to be truly infected, the body’s immune system is too busy dealing with the infection to have the time or energy to heal the wound.  Signs of infection include most, or all, of the cardinal signs of inflammation (pain, swelling, heat, and redness).  The hallmarks of infection, though, are the presence of pus (with concurrent foul odor) and the lack of healing.6

 

A step below infection is a condition known as “critical colonization.”7 Critical colonization is defined as the presence of microbes in a wound to the extent that healing is adversely affected.  These wounds may also have some of the signs of inflammation, mostly pain, and have a foul odor.  However, these slow-healing wounds do not produce pus.  A good example of critical colonization seen in dentistry is alveolar osteitis (dry socket).

 

Although some disagreement still remains, most authorities agree that a major component of dry socket is bioburden.  These wounds are not truly infected, but they definitely show the signs of critical colonization (pain, foul odor, delayed healing).  Studies that demonstrate the reduced incidence of dry socket with the use of antibiotics or antimicrobial rinses support this view.8,9

 

A major tenet of wound care is that open wounds (traumatic or surgical) should be dressed as soon as possible to deal with microbial pathogens, and to protect from further contamination. There are an estimated 20 billion microbes in the human mouth, so oral wounds are immediately contaminated. Bacteria can reproduce every 15-20 minutes in ideal conditions. In the mouth, however, because of the natural cleansing and antimicrobial activities of saliva, they reproduce only every 5 hours or so. Even so, after tooth extraction, for example, besides immediate contamination, the microbial population of the extraction site can increase by a factor of almost 5 every 24 hours. This obviously has a detrimental effect on the wound healing process, and can increase pain from
bacterial activity.

 

Unfortunately, the mouth is an “ideal” site for increased bioburden.  Close to 1000  species of bacteria have been identified.10  In addition, several species of fungi and viruses also inhabit the mouth.  Open wounds in this environment are obviously ideal candidates for various complications.  Besides potential critical colonization or infection, increased pain can result from microbial activity and byproducts.

 

The second issue that must be addressed in wound care is discomfort or pain.  Wounds tend to hurt.  Call it discomfort, pain, or whatever you like, but the fact is it has negative effects on wound healing.  Two mechanisms will be discussed here.  

 

First, healing is delayed because pain is a vasoconstrictor.11  Inflammation is one of the phases of the healing process and is important because of the increased blood supply that brings wound healing cells, nutrients, cytokines, and other important factors to the wound.  Pain obviously countermands this by causing vasoconstriction.  Pain is a cardinal sign of inflammation, so the natural tug of war between pain and enhanced blood flow is already at play.  It is thus important to try to achieve adequate pain relief.

 

Another mechanism by which pain hinders healing is the well-known connection between pain and the hypothalamo-hypophyseal-adrenal axis.12  Pain causes stress. The body’s natural protective response to stress is for the hypothalamus to secrete corticotropin-releasing hormone (CRH), which stimulates the anterior hypophysis (pituitary) to release adrenocorticotropic hormone (ACTH).  ACTH stimulates the adrenal cortex to produce and release corticosteroids.  Corticosteroids are, of course, immunosuppressants.  The immune system controls the healing process.  Suppress the immune system, suppress healing.

 

Delayed healing is an important reason to address discomfort or pain effectively.  Unfortunately, systemic drugs such as NSAIDs and narcotics do not always produce adequate pain relief.13  In addition, NSAIDs counter inflammation; inflammation is necessary for optimal healing.  

 

ISSUES WITH CURRENT WOUND CARE

 

RESISTANCE TO ANTIBIOTICS

ALLERGY

CYTOTOXICITY/TOXICITY

 

Three major issues with current wound care should be addressed.  First is the ever-increasing problem of resistance to antibiotics.  Antibiotics generally work by one of five major mechanisms:  1) they interfere with the synthesis of a) nucleic acids, b) folate or c) cell walls; 4) they bind ribosomes and interfere with protein synthesis, and 5) they interfere with cell membrane permeability.14(a)

 

Bacteria and fungi can resist antibiotics by inactivating or modifying drugs, such as with ß-lactamases in penicillin resistance.  They can also alter antibiotic target sites, as seen with penicillin-binding proteins, which are necessary for cell wall synthesis, and thus render the antibiotic ineffective. Bacteria and fungi can also alter normal metabolic pathways, such as for nucleic acids and folic acid, and thus sidestep antibiotic activity.  The means by which resistance occurs is by the production of various enzymes, or by the presence of plasmids, which are small DNA molecules that can carry genes for resistance.14(b)

 

Clinicians have known for years about the problem of resistance, and have been advised not to use antibiotics indiscriminately.  Clinicians often think that this applies only to systemic antibiotics; however, topical antibiotics also contribute significantly to the problem of resistance.  This is a major reason the World Health Organization recommends that topical antibiotics not be used in infected wounds.  In addition, topical antibiotics cannot reach the source of infection and contribute to resistance.  For these reasons, many wound care specialists recommend that topical antibiotics not be used at all.15  If antibiotics are needed, they recommend that clinicians use systemic antibiotics, and apply topical antiseptic agents to wounds.  In spite of these recommendations, the use of topical antibiotics persists, and is still considered a standard of care by most physicians. 

 

Allergy is the second problem with current wound care practice, and its prevalence is rising.  As with resistance, allergies to various topical antibiotics continue to rise.  For example, both bacitracin and neomycin, popular topical antibiotics, were recognized as allergens of the year (2003 and 2010, respectively).  Some argue that, in addition to the issue of resistance,  topical antibiotics should not be used because the risk-to-benefit ratio is too high.16   In addition, allergies to preservatives, such as benzalkonium chloride, benzethonium chloride, and propylene glycol, commonly used in wound care products, continue to increase.  Not only are localized allergic reactions a problem, but many agents, such as chlorhexidine, can cause anaphylaxis.

 

The third issue is toxicity to the cells of wound healing caused by agents used in wound care.  Most, if not all, agents used to treat wounds, whether to prevent or treat infection or provide pain relief, are extremely cytotoxic.  Sodium hypochlorite, the active ingredient in chlorine bleach, is a common agent used as a wound cleanser.  Dakin’s solution, developed during World War I, is a very diluted solution of sodium hypochlorite (0.5%).17  It is used daily as a wound cleanser.  However, it is very toxic to the cells of wound healing.  For example, Dakin’s solution diluted 2000 times (0.00025 %) produces toxic effects to cells such as fibroblasts.  Chlorhexidine, an antimicrobial agent used in dentistry, is commonly used at a concentration of 0.12%.  However, a concentration of 0.005% (24X dilution) causes total cell death to human dermal fibroblasts, and a concentration of 0.001% (120X dilution) depletes ATP in human dermal fibroblasts over time.18,19

 

Agents used as antiseptics, topical antibiotics, and preservatives all have cytotoxicity to some extent.  The fact is, almost all these agents are much more effective at killing the good cells than they are at killing the bad cells.  The bottom line is, optimal healing cannot occur when so much damage is done to the cells of wound healing.

 

Added to the problem of cytotoxicity is the issue of toxicity itself.  Almost everything used to prevent tooth decay, periodontal disease, infections, mouth ulcers, etc., (toothpaste, mouthwash, antimicrobial rinses) have inherent toxicities and should not be swallowed.  This can be a problem because just about everything that goes into the mouth (or at least some of almost everything) is eventually swallowed.

 

ISSUES RELATED TO THE MOUTH

 

The mouth is a unique environment and presents its own set of challenges related to wound care.  First, the mouth is wet.  This presents the age-old “good news vs bad news” situation.  First, the good news is that wounds heal faster, with fewer sequelae, in a moist environment.  This fundamental concept has been known for 2000 years, and research since 1962 has proven this time and again.20 Proper wound care includes dressing wounds in such a way as to maintain a moist environment.  Hundreds of hydrogel wound dressings are on the market for that very reason.  Application of a hydrogel, followed by an occlusive dressing to maintain the moist environment, provides an optimal environment that promotes healing.  Regardless, many (most?) physicians and nurses still instruct their patients to keep wounds dry.  At any rate, the inherent moist environment of the mouth helps to enhance the healing of oral wounds.

 

The bad news is that this same moist environment precludes the use of standard wound dressings.  In addition, the mouth is a busy place.  The tongue, which tends to invest its time with talking and eating would tend to dislodge anything placed in the mouth to serve as a wound dressing.

 

Another important consideration is that some, or even all, of just about everything that goes in the mouth, ends up being swallowed.  This presents a totally different problem, that of toxicity.  Almost all products used to treat extraoral wounds are not safe to use in the mouth.  These include agents for cleansing wounds, such as hypochlorites, iodine, and others, as well as antibiotic/antiseptic preparations.  Even everyday products used in oral hygiene, such as toothpaste and mouthwashes, should not be swallowed.  The list of potential toxic outcomes can be sobering! 

 

The end result is, therefore, that one of the three principles of wound care, the use of wound dressings, has never been a real option in the mouth.   And shockingly, as mentioned above, many dentists, in fact, do not even recognize oral wounds as true wounds!  For example, this author, countless times, has heard dentists deny that a tooth extraction site is a wound!!  An extraction site is indeed a wound (a surgical wound), as are sites involved in implants, frenectomies, biopsies, flap procedures, grafting, etc.  Like it or not, much of dentistry is about wounding.  It’s what we do.  DDS does stand for doctor of dental SURGERY, after all!  And wounds, even oral wounds, should receive appropriate care.

 

So, what is the best way to develop a safe, yet effective, wound dressing for the mouth?  If something goes into the mouth, some of it is going to be swallowed.  What things are designed by nature to be swallowed?  And, which of these things could also provide the benefits of a wound dressing; that is, protect wounds from contamination, provide relief from discomfort or pain, and promote healing?

 

FOODS/NUTRIENTS IN WOUND CARE

 

As mentioned earlier, mankind has known for thousands of years that wounds need to be cared for (dressed).  Of course, all the ancients had to work with were various naturally occurring agents.  As often as not, these agents were foods.  For example, certain populations have used, and still use, banana or potato peel, and certain leaves, to cover and protect wounds, with very good results.21,22  Wine and oil (olive oil) was used 2000 years ago in the Mediterranean (story of the Good Samaritan).  Already mentioned was the combination of honey, animal fat, and Aloe vera by the ancient Egyptians.  Gums (complex carbohydrates) have been used worldwide for thousands of years to dress wounds.  All of these have been, and are still, used as foods.  

 

Foods as wound care agents may sound strange, but research has validated the value of certain foods and/or nutrients in wound care.  And, when it comes to the mouth, use of food makes sense from a safety standpoint, since food, unlike just about everything else used in wound care, is designed to be taken by mouth and swallowed.

 

Aloe vera has been used for wounds for thousands of years.  Research dating back to the 1930s demonstrates the capacity of Aloe to provide pain relief and promote healing, even of chronic, non-healing wounds.23  The specific molecule in Aloe that provides these benefits was identified more than 30 years ago.  It is a long-chain, ß-linked, acetylated mannan called acemannan.24  Mannans are polysaccharides of mannose, a hexose very similar to glucose.  Mannans differ from glucans (polymers of glucose) in that they do not stimulate an insulin response to the degree that glucose and its polymers do, and have been used in the dietary management of diabetes.25,26

 

Another benefit of mannans is their ability to enhance wound healing.  Mannans stimulate macrophage activity, including phagocytosis and wound healing.  Wound healing is an extremely complex process.  Macrophages are recognized as the single most important cell in wound healing, and may be considered the “conductor” of the wound healing “symphony.”  Stimulation of macrophage activity can thus produce significant results in both prevention of microbial colonization and in healing.27

 

Macrophages can be stimulated by acemannan in two ways.  First, macrophages can phagocytize acemannan.  This process provides the added benefit of the macrophage also using the internalized sugar as an energy source.  Secondly, macrophages can recognize acemannan by means of various receptors located on their cell membranes.  The act of chemically recognizing these sugars stimulates macrophage activities.  This occurs naturally in wounds when the macrophage is called in during the inflammatory phase.  Bacterial and fungal cell walls contain various sugars, including mannans.  When these sugars come in contact with the membrane receptors, macrophage activity, including phagocytosis and production of cytokines (by which macrophages control healing) is enhanced.28  

 

By introducing acemannan to the wound site, macrophages are stimulated by a natural process; however, the sugars are not “attached” to microbes, and macrophages do not have to expend time and energy killing pathogens, but rather can concentrate on healing wounds.  

 

Studies with acemannan have demonstrated faster healing in both animals and humans.29(a),30  In addition, wounds heal with a much higher tensile strength than normally seen, thus a higher quality of healing occurs.29(b) Wound contamination has also been significantly reduced, equivalent to that of standard topical antibiotic therapy, but without the significant delay in healing caused by cytotoxicity of these agents (see figs).  Acemannan has also been shown to interfere with bacterial colonization, which is a function shared with other carbohydrates, such as xylitol.31  

 

Xylitol is an alcohol sugar that has been used for years as a sugar substitute because it does not promote dental caries.  Xylitol is found in various fruits and vegetables.  It is also a normal, non-toxic metabolic product in humans.  Xylitol has been shown to reduce dental caries and incidence of otitis media.32

 

Essential oils have also been used for millennia in wounds.  Oils of frankincense, myrrh, lavender, clove, and many others are recorded in ancient manuscripts.33 Essential oils have antimicrobial effects;  some also have anti-oxidant and/or anti-inflammatory effects.  The most important is the antimicrobial effect.

 

Essential oils disrupt cell membranes and cause leakage of ATP, nucleic acids, enzymes, and hydrogen ions.  Besides being effective, this mechanism is not susceptible to resistance by pathogens.  Essential oils are effective at low concentrations, and when combined, can have a synergistic effect.  They are effective against bacteria, fungi, and viruses.  They are obviously safe at or below concentrations found in foods.

 

So, currently used intraoral products contain drugs or other agents that are designed to prevent or treat infection, or provide pain relief.  Unfortunately, they can also produce toxic effects, or inhibit wound healing because of their cytotoxic characteristics.  Chlorhexidine has already been mentioned.  The topical anesthetic agent, benzocaine, which is used in many products for intraoral pain relief, also carries potential toxicities.  Benzocaine can cause methemoglobinemia, a serious condition in which oxygen availability to tissues is significantly reduced.  Therefore, benzocaine should be used with caution and should be avoided where multiple sites are involved, such as multiple extractions or generalized ulcerations of the mouth.  Again, it is worth mentioning that almost all products on the market for oral hygiene or general mouth care should not be swallowed.

 

Certain food ingredients, on the other hand, can provide pain relief, help protect wounds from contamination, and enhance the healing process, all with no toxicity.   Foods, after all, were designed to be swallowed.

 

An oral hydrogel wound dressing composed of acemannan, essential oils, and xylitol has been developed to be used for all oral wounds, injuries, and lesions.  After its initial application in the dental office at the time of the procedure, it is sent home with the patient to use as a pain gel and a wound dressing.  This test article was shown to provide significant pain relief after tooth extraction within 1 minute of application, above that provided by narcotic alone (see fig).34 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pain relief results from the gel protecting the wound from the environment, and by its interfering with the generation of the pain impulse.  The result is pain relief without a numbing effect.

 

This test article is also very effective in protecting wounds from contamination.  In-vitro tests showed that the gel was as effective as chlorhexidine against 17 pathogens (14 bacterial species, 3 Candida species) commonly found in the mouth (see figure below).  This test demonstrated the effectiveness of the all-natural nutrient preservative system in the gel.  As mentioned earlier, xylitol and acemannan also inhibit bacterial colonization.  Acemannan enhances macrophage activities such as phagocytosis and wound healing.  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

This unique test article provides three important benefits to oral wounds.  It:

 

PROMOTES OPTIMAL HEALING

PROVIDES FAST PAIN RELIEF, WITHOUT NUMBNESS

PROTECTS WOUNDS FROM CONTAMINATION

 

In summary, wounds should be cared for; in other words, they should be dressed.  Intraoral wounds should, and can be, treated with the same respect as any other wound of the body.  The topical application of a combination of all-natural nutrients can provide safe, non-toxic, effective pain relief, protection from microbial contamination, and enhanced healing for oral wounds.  Intraoral wound care - providing better care for our patients and our practices.

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VERIFICATION CODE: 5001

 

REFERENCES

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2. Medical Dictionary.  The Free Dictionary (online)

3. Cutting KF. Wound dressings: 21st-century performance requirements.  J Wound Care May 2010 Suppl:4-9

4. Bryant, RA, ed. Acute and Chronic Wounds: Nursing Management  St. Louis: Mosby; 1992.

5. Mosby’s Dental Dictionary. 2nd ed.

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8. Lodi G, et al. Antibiotics to prevent complications following tooth extractions.  Cochrane Database Sys Rev Nov 14, 2012;11:CD003811

9. Daly B, et al. Local interventions for the management of alveolar osteitis (dry socket). Cochrane Database Sys Rev Dec 12, 2012;12:CD006968

10. Wade, WG. The oral microbiome in health and disease. Pharmacol Res 2013;69(1):137-43

11. Cho M, Hunt TK. The overall clinical approach to wounds.  Falanga V; Cutaneous Wound Healing London, Martin Dunitz Ltd; 2001:141-54

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13. Forbes JA, et al. Evaluation of two opioid-acetaminophen combinations and placebo in postoperative oral surgery pain. Pharmacotherapy 1994;14(2): 139-46

14. Chambers F, et al. Antimicrobial agents. Hardman JG, Limbird LE. Goodman and Gilman’s the Pharmacological Basis of Therapeutics New York, McGraw-Hill; 1996:1029-56

15. World Health Organization.  Prevention and management of wound infection (online)

16. Gette MT, et al. Frequency of postoperative allergic contact dermatitis to topical antibiotics. Arch Dermatol 1992;128(3):365-67

17. Hidalgo E, et al. Cytotoxicity mechanisms of sodium hypochlorite in cultured human dermal fibroblasts and its bactericidal effectiveness. Chem Biol Interact 2002 Mar 20;139(3):265-82

18. Cabral CT, Fernandes MH. In vitro comparison of chlorhexidine and povidone-iodine on the long-term proliferation and functional activity of human alveolar bone cells. Clin Oral Investig 2007 Jun;11(2):155-64

19. Hidalgo E, Dominguez C. Mechanisms underlying chlorhexidine-induced cytotoxicity. Toxicol In Vitro 2001 Aug-Oct;15(4-5):271-6

20. Butcher M, White R. Reviewing the evidence for advanced dressings. Nurs Stand 2013 Jul 10-16;27(45):51-4

21. Patange VS, et al. Dressing wounds with potato peel. Indian J Dermatol Veneriol Leprol 1996 Sept-Oct;62(5):286-8

22. Gore MA, Akolekar D. Evaluation of banana leaf dressing for partial-thickness burn wounds. Burns 2003 Aug;29(5):487-92

23. Reynolds T, Dweck AC. Aloe vera leaf gel: a review update. J Ethnopharmacol 1999 Dec 15;68(1-3):3-37 

24. Acemannan, Budavari S, et al. The Merck Index.1996, 12th edition:6

25. Kristen R, et al. Influence of two guar preparations on glucose and insulin levels during a glucose tolerance test in healthy volunteers. Int J Clin Pharmacol Ther Toxicol 1991 Jan;29(1):19-22

26. Gulliford MC, et al. Evaluation of guar biscuits for use in the management of diabetes: tests of physiological effects and palatability in non-diabetic volunteers. Eur J Clin Nutr 1988 May;42(5):425-35

27. Hunt TK, et al. Wound Microenvironment. Cohen K, Diegelmann RF, Lindblad WJ; Wound Healing: Biochemical and Clinical Aspects Philadelphia, WB Saunders Co; 1992:274-81

28. Schepetkin IA, Quinn MT. Botanical polysaccharides: macrophage immunomodulation and therapeutic potential. Int Immunopharmacol 2006 Mar;6(3):317-33

29. Jettanacheawchankit S, et al. Acemannan stimulates gingival fibroblast proliferation, expressions of keratinocyte growth factor-1, vascular endothelial growth factor, and type I collagen, and wound healing. J Pharmacol Sci 2009 Apr;109(4):525-31

30. Mulder GD, et al. A controlled, randomized study of an amorphous hydrogel to expedite closure of diabetic ulcers. Paper presented at: 4th Euro Conf on Advances in Wound Management; 1994

31. Azghani AO, et al. A beta-linked mannan inhibits adherence of Pseudomonas aeruginosa to human lung epithelial cells. Glycobiology 1995 Feb;5(1):39-44

32. Vernacchio L, et al. Tolerability of oral xylitol solution in young children: implications for otitis media. Int J Pediatr Otorhinolaryngol 2007;71(1):89-94

33. Essential Oils. Essential Oils Desk Reference 2002 June; 2nd ed

34. Kennedy TJ, Hall, JE. A drug-free oral hydrogel wound dressing for pain management in immediate denture patients. Gen Dent 2009 Jul-Aug;57(4):   420-7