Improving Wound Healing and Trauma Recovery

The body undergoes profound physiological responses to injury and physical trauma. Injuries may be accidental or intentional (as with surgery), but all wound healing is complex with multiple stages. Much ongoing research is actively seeking improved methods to treat wounds.

Wound treatment always involves promoting the closing of the injury, as well as preventing infection. Also, maintaining good nutrition is critical during the wound healing process because several nutrients are critical to this process.

Many natural integrative interventions such as whey protein, omega-3 fatty acids, trace elements, and vitamins may be useful in supporting successful wound healing.

What Factors Can Compromise Wound Healing?

• Infection
• Foreign bodies in the wound
• Advanced age
• Stress
• Diabetes
• Venous insufficiency
• Obesity
• Certain medications, including non-steroidal anti-inflammatory drugs (NSAIDs)
• Alcohol and smoking
• Poor nutrition

How are Wounds and Trauma Conventionally Treated?

• Debridement ‒ the removal of foreign debris and/or dead tissue from the wound
• Infection control, including oral and/or topical antibiotics
• Wound closure with staples, sutures, or adhesives
• Dressings to keep the wound in a moist environment ideal for healing
• Mechanical offloading to remove pressure from the wound (eg, orthotics, padding)
• Parenteral or enteral nutrition

What Emerging Strategies May Improve Wound Healing?

• Wound biomarkers and diagnostics
• Novel antimicrobial therapies, including bacteriophages (viruses that attack bacteria), antimicrobial peptides, and wound dressings containing chitosan
• Other interventions, including hyperbaric oxygen therapy, negative-pressure wound therapy, cryopreserved placental membrane, and ultrasound or electrical stimulation to stimulate cells

What Dietary and Lifestyle Changes Can Improve Trauma and Wound Healing?

• Eating enough calories to support healing
• Caloric needs during wound healing are estimated to be 30–35 kcal/kg of body weight, or up to 40 kcal/kg for an underweight patient.
• Eating enough protein to meet the demand for amino acids required for cell growth and tissue repair
• The Agency for Healthcare Research and Quality recommends protein intake of 1.25 to 1.5 g/kg of body weight per day for patients with healing wounds.
• Proper hydration
• Exercise, to the level appropriate to the patient’s physical condition
• Quitting smoking

What Natural Interventions May Be Beneficial for Trauma and Wound Healing?

• Amino acids. Amino acids, such as glutamine and arginine, are important for promoting wound healing.
• Omega-3 fatty acids. Omega-3 fatty acids may promote wound healing and reduce infection throughout the healing process.
• Copper, selenium, and zinc. These trace elements are cofactors of enzymes essential to the wound-healing process.
• Vitamin A. Topical vitamin A can stimulate growth of cells involved in tissue and skin repair.
• Vitamin C. Low vitamin C levels are associated with delayed wound healing. Vitamin C can reduce oxidative stress and inflammation, and is a cofactor for collagen synthesis.
• Diosmin and hesperidin. Diosmin and hesperidin are citrus flavonoids that have been studied for their effects on venous insufficiency, including healing venous ulcers.
• Many plants and their extracts, including aloe vera,calendula, arnica, and pycnogenol can be beneficial in wound healing.

Physical trauma elicits profound physiological responses (Goldman 2016). Whether the cause of injury is accidental or intentional, such as in the case of surgery, the healing process is complex and frequently imperfect. For example, the body’s attempt to maximize tissue integrity after an injury often results in scar formation. In addition, wounds such as pressure ulcers can occur in immobilized or hospitalized patients, and may persist for months without healing (Sidgwick 2015). Improving wound care outcomes is a focal point of much ongoing research.

Conventional wound care relies heavily on topical treatment with antimicrobials, protective barriers, and tissue-growth-promoting agents, as well as tissue grafts. Nutrition plays an important and sometimes underappreciated role in successful wound healing. During the healing process, some nutrients important for wound repair, such as glutamine, may become conditionally essential. Furthermore, suboptimal nutrition and malnourishment, which are common in those with chronic or slow healing wounds, can undermine the physiological processes that promote wound closure and tissue regeneration. Thus, a well-balanced diet providing adequate protein, along with targeted nutritional supplementation, may improve wound healing (Quain 2015).

Ongoing wound care research continues to identify novel modalities for enhancing wound healing. For instance, bacteriophages, which are viruses that infect bacteria, represent an intriguing approach to treating wound infections while minimizing antibiotic resistance (Fish 2016), and temporary use of locally applied insulin may be an affordable alternative to expensive growth factors sometimes used to promote wound healing (Oryan 2017).

Several integrative interventions may also be useful in supporting wound healing. Omega-3 fatty acids may help regulate the inflammatory response at the site of injury, thereby enhancing tissue repair while reducing inflammatory tissue damage (Kiecolt-Glaser 2014). The citrus flavonoids diosmin and hesperidin have been shown in several studies to help heal chronic ulcers related to circulatory problems in the legs (Coleridge-Smith 2005).

This protocol summarizes usual wound-treatment strategies and reviews several important dietary and nutritional considerations to further support healthy wound healing. It also describes a number of novel and emerging wound-treatment techniques.

There are several ways wounds are classified. In the hospital setting, surgeons often classify wounds according to their degree of apparent contamination and infection risk (CDC 2017):

• Clean wounds are generally surgical wounds in which no inflammation or infection are encountered.
• Clean-contaminated wounds, also typically surgical wounds, are those in which the gastrointestinal, respiratory, genital, or urinary tract are entered without resulting in unusual contamination.
• Contaminated wounds include fresh accidental wounds as well as surgical wounds in which acute inflammation is encountered or sterile procedure is not properly followed.
• Dirty wounds include accidental wounds that retain dead tissue or are infected, and surgical wounds complicated by existing infection or organ perforation.

Acute Versus Chronic Wounds

Acute wounds can result from surgery or accidental trauma (Ubbink 2015; Bowler 2001). Examples include clean incisions and common uncomplicated traumatic lacerations, abrasions, and punctures that heal with standard care (Ghafouri 2012; Worster 2015; Anderson 2016).

An acute injury can become a chronic wound (Sood 2014). Chronic wounds are defined by their persistence, often failing to heal for weeks or months (Nunan 2014; Kyaw 2017; Gould 2015).

Chronic wounds often fail to progress through the normal healing stages because of an underlying disease process. Common causes include reduced oxygen supply to the wound site due to poor blood flow, prolonged inflammation, poor cellular response to reparative stimuli, and infection (Guo 2010; Demidova-Rice 2012). Infections from chronic wounds can spread to surrounding tissues or enter the bloodstream and become widespread (Gardner 2008; Leaper 2015; Wolcott 2016).

Mitochondrial dysfunction may also impair wound healing. Because they provide energy for all cellular metabolic processes, including cell division, mitochondria play a critical role in the healing process. They also produce reactive oxygen species, which kill bacteria and participate in cell signaling during wound healing (Gould 2015).

Common types of chronic wounds include (Sen, Chandan 2009):

• Diabetic foot ulcers
• Venous ulcers (such as from venous insufficiency)
• Arterial ulcers (such as from atherosclerosis)
• Bedsores (pressure ulcers)

Primary and Secondary Intention

Wounds can also be classified by the way they are managed:

• Primary intention involves closure of the wound or surgical incision such that the edges of the wound are in direct contact and can reconnect with minimal need for new tissue synthesis. Primary intention best preserves the integrity of tissues surrounding the wound and reduces scarring, but can only be performed on surgical and some limited other wounds soon after they are inflicted (Mercandetti 2017; Velnar 2009).
• Secondary intention is used for wounds with edges that cannot be brought together because of extensive tissue loss. This is a longer process in which the open wound heals through the formation of new connective tissue and small blood vessels (granulation tissue) and the laying down of new superficial (epithelial) cells (Velnar 2009). Healing by secondary intention results in more inflammation and susceptibility to infection than healing by primary intention (Simon 2016). Examples of wounds generally left to heal by secondary intention include pressure ulcers and diabetic ulcers. Secondary intention healing leads to more scar formation.
• Delayed primary intention (sometimes called tertiary intention) is a technique used for contaminated wounds, in which the wound edges are not brought together right away. This allows time for the cells of the immune system to remove dead and contaminated tissue from the wound before it is closed (Mercandetti 2017). Delayed primary intention involves aspects of both primary and secondary wound management.

Local Factors

Infection. Infection caused by normal bacteria of the body or those from the external environment can trigger significant inflammation and impair the wound healing process (Guo 2010; Demidova-Rice 2012). Poor oxygenation or immune compromise can inhibit the natural antibacterial defenses of the healing wound and increase infection risk (Daley 2017). Infection is a significant cause of delayed healing in chronic wounds (Leaper 2015). Local wound infection has the potential to extend into deeper soft tissue and bone, or progress to potentially life-threatening systemic infection called sepsis (Healy 2006; Leaper 2015; Daley 2017).

Low oxygenation. Oxygen is critical for virtually all phases of the healing process. It is necessary for the prevention of infection in early stages of healing, efficient cellular energy production, and to support the increased metabolic needs of healing tissues. While temporary hypoxia (low oxygenation) stimulates the initial stages of healing, prolonged oxygen deprivation impairs healing and is a hallmark of chronic wounds. Hypoxia becomes more common with poor circulation, which can occur during aging or with medical conditions such as diabetes and cardiovascular disease (Sen 2009; Guo 2010).

Foreign body. Foreign debris in the wound can interfere with the restoration of tissue structure, promote inflammation, and serve as a reservoir for infection-causing bacteria (Daley 2017; Leaper 2015).

Venous insufficiency. Increased pressure and permeability in the venous system, as seen in chronic venous insufficiency, may lead to accumulation of fibrin around the small blood vessels. It is thought that deposits of fibrin, a protein normally involved in blood clotting, create a barrier to movement of nutrients and oxygen across the blood vessel wall and disrupt wound healing (Demidova-Rice 2012; Vasudevan 2014).

Systemic Factors

Age and gender. In older individuals, increased platelet adherence to the inner lining of blood vessels and higher levels of inflammatory chemicals from platelets can compromise wound healing. Reduced or altered immune cell movement and function, growth factor production, collagen synthesis, remodeling, and wound strength are also seen with advancing age (Gosain 2004). Women may have slightly faster wound healing capability than men because estrogens promote healing by modulating tissue regeneration, inflammation, matrix production, and skin function (Guo 2010).

Stress. Mental and physical stress can lead to increased production of the hormone cortisol, which reduces inflammatory and cell-activating cytokines necessary for the initial phases of wound healing. Cortisol also impairs healing by reducing immune cell development, connective tissue formation, and collagen synthesis (Tiganescu 2013; Saito 1997; Godbout 2006). Stressed individuals may also suffer from poor sleep, inadequate nutrition and exercise, and alcohol or drug abuse, which can further contribute to poor wound healing (Gouin 2011).

Diabetes. Diabetes poses several challenges to wound healing. Poor circulation, which is common in those with diabetes, leads to poor tissue oxygenation (Guo 2010). Diabetic wounds also have impaired blood vessel growth following injury (Brem 2007) and contain higher levels of compounds that negatively affect new tissue formation (Muller 2008; Ayuk 2016; Sibbald 2008). Persistently elevated blood glucose levels and a pro-oxidative state favor glycation, the bonding of glucose to proteins and fats, interfering with their function. Molecules damaged through glycation, known as advanced glycation end products (AGEs), have been shown to slow healing in animal models (Huijberts 2008).

Other disorders. Conditions associated with poor wound healing include previous scarring, hereditary healing disorders, liver and kidney diseases, hypertension, peripheral vascular disease, cardiovascular disease, pulmonary disease, and gastrointestinal diseases that cause malnutrition (Guo 2010; Ahmed 2011; Young 1988; Sorensen 2005). Wound healing is also impaired in immunocompromised individuals, such as those with HIV or cancer (Aird 2011; Burns 2000; Payne 2008; Pyter 2016). Sleep disorders trigger a stress response, and obstructive sleep apnea may lead to intermittently low oxygen levels, which can impair healing of chronic wounds. In a report on three cases of obstructive sleep apnea in patients with non-healing diabetic ulcers, correction of the apnea with continuous positive airway pressure (CPAP) therapy led to significant improvements in wound healing in two of the patients (Vas 2016).

Obesity. Obesity has many negative effects on wound healing. Adipose (fat) tissue has relatively low blood and oxygen supply, and pressure from the weight of excess adipose tissue can reduce oxygen levels around sites of injury. Tension on surgical wounds due to excess adipose tissue can lead to reduced tissue oxygenation or failure of wound closure (Wilson 2004; Anaya 2006; Fantuzzi 2005). Skin folds in overweight individuals can harbor moisture or bacteria that increase risk of infection. Fat tissue secretes inflammatory chemicals that can hamper healing. Finally, obesity is associated with conditions such as cardiovascular disease, hypertension, and type II diabetes that have recognized negative effects on wound healing (Hellmann 2012; Klein 2014; Ahmed 2011).

Medications. Systemic glucocorticoid steroids can have a negative effect on healing via a mechanism similar to that of cortisol (Guo 2010). Studies suggest use of non-steroidal anti-inflammatory drugs (NSAIDs) might impair wound and ulcer healing (Jones 1999). Also, a meta-analysis of data from 17 studies comprising over 20,000 participants found that use of non-selective NSAIDs after colorectal surgery led to increased risk of leakage at the interface of conjoined tissue (anastomotic dehiscence) compared with non-NSAID treatment and selective NSAID treatment (Huang 2017). Some chemotherapy drugs interfere with wound healing by inhibiting cell division and blood vessel formation (Erinjeri 2011).

Alcohol and smoking. Alcohol increases risk of wound infection. Acute alcohol consumption suppresses inflammatory cytokine release, reducing the inflammatory phase of healing and preventing immune cell movement to the wound. It also reduces tissue regrowth in animal models of wound healing (Guo 2010). Smoking, in addition to its negative vascular effects and reduction of tissue oxygenation, can increase risk of infection, wound rupture, and tissue death (Guo 2010; Sorensen 2012).

Poor nutrition. The higher metabolic needs of healing tissues require increased energy and nutrient availability. Inadequate protein intake is especially detrimental during wound healing (Wolfe 2008). Moreover, deficiencies in total energy and several nutrients have been associated with impaired healing; these deficiencies including (Shepherd 2003; Arnold 2006; Campos 2008; Burgess 2008):

Wounds are treated both locally (at the site of injury) and systemically (Ubbink 2014). One common approach to wound treatment preparation, known by the acronym TIME, involves the following (Harries 2016):

• Removal of dead Tissue, a process known as debridement
• Controlling Inflammation and Infection with antibiotics and anti-inflammatories as needed
• Maintaining Moisture balance with appropriate wound dressings
• Re-assessing wound Edges or Epithelialization to determine if new superficial skin cells are forming and the wound is healing

Debridement

Debridement is the removal of foreign debris and nonliving tissue from the site of injury to improve wound closure (Steed 2004). Surgical debridement uses sharp instruments to remove dead tissue (Cardinal 2009; Attinger 2000). Enzymatic debridement involves the application of enzymes (papain, bromelain, or collagenase) to the site of injury to break down dead tissue (McCallon 2014). Autolytic debridement is similar to enzymatic debridement, but relies on enzymes produced by the tissue itself. Autolytic debridement is enhanced by using dressings that maintain moisture (Reyzelman 2015; Konig 2005). Biological debridement involves the application of sterilized green bottle fly maggots to consume dead tissue and bacteria within the wound (Tanyuksel 2005; Pereira 2016). Although some patients and physicians may find maggot therapy distasteful, this approach has been used successfully for centuries and there is abundant evidence for the efficacy of maggots in wound debridement. Emerging research even suggests that the biologic secretions of the maggots may promote wound healing. For these reasons, maggot therapy is a treatment option for chronic, non-healing, and infected wounds, despite the possible need to overcome prejudice (Nigam 2016).

Infection Control

It is not uncommon for opportunistic bacteria to populate a wound site. Immune cells from circulation and the natural antibacterial properties of fluids draining from wounds usually keep these pathogens in check; however, immunosuppression can allow bacterial colonies in the wound to expand, leading to infection (Wilgus 2013; Daley 2017). Progression of infection can lead to the formation of a biofilm, in which bacteria form a coating that protects them from immune and antibiotic attack, allowing them to persist in the wound site. Biofilms are especially prevalent in chronic non-healing wounds (Percival 2015; Domenech 2013; Lebeaux 2014; Clinton 2015).

Localized indications of wound infection include: increased, foul-smelling, and cloudy or colorful drainage; increased or spreading inflammation, pain, and redness; weak tissue and wound enlargement; and spontaneous bleeding (Halim 2012; Daley 2017; Leaper 2015). Systemic signs of infection include fever, chills, and increased white blood cell count (Daley 2017; Leaper 2015).

Prevention and treatment of infection is paramount in managing traumatic wounds and surgical sites. Methods of infection control involve proper surgical set-up (Harold 2017); copious rinsing of the wound with appropriate fluids (Nicks 2010); use of topical antiseptics, antibacterial compounds, and antimicrobial silver dressings (Pereira 2016; Murphy 2012); and use of photodynamic therapy, in which a light-sensitizing compound is applied to the infection site and irradiated with visible light causing formation of free radicals that damage bacteria (Yin 2013).

Wound Closure

Soft tissue injuries and surgical sites can be closed with staples, sutures, or specialized adhesives, alone or in combination, to limit mobility and aid in healing. For heavily contaminated traumatic injuries, closure is often delayed to allow for monitoring for infection. Any dead tissue is cleared and the wound is covered in the time before final closure (Nicks 2010).

Dressings

Covering superficial wounds in an appropriate bandage can maintain a moist environment for optimal healing, reduce pain, and prevent scarring (Nicks 2010). Specialized dressings that hold in fluid yet are impermeable to microorganisms allow air movement and promote autolytic debridement. Skin substitutes and biological dressings that incorporate collagen structures and tissue-forming cells may also be used to promote healing (Murphy 2012; Dreifke 2015).

Antibiotics

Systemic antibiotics are an important consideration for highly contaminated wounds, deep puncture wounds, and bites, as well as in patients who are immunocompromised, take steroid medications, or have prosthetic joints (Nicks 2010).

Mechanical Offloading

Removing pressure or tension on the wound is necessary to maintain blood flow and oxygenation in the healing tissue. This is especially important for chronic wounds. Methods for offloading include padding, orthotics, and compression hose. In addition, immobilized and bed-bound patients should be moved or turned frequently and pressure points should be carefully monitored (Klein 2014; Nicks 2010).

Parenteral and Enteral Nutrition

Parenteral (intravenous) or enteral (via tube to the digestive tract) nutrition may be needed to ensure adequate protein and nutrient intake and prevent loss of muscle mass (Genton 2011; Molnar 2014). Although parenteral nutrition was widely used in the past in burn patients, studies have shown that it is associated with a three-fold higher mortality rate than enteral nutrition. Parenteral nutrition continues to be important in critical trauma patients for whom regular eating is not possible; however, enteral nutrition is now preferred in most other cases (Clark 2017).

Additional Treatments for Chronic Wounds

Chronic wounds often require repeated rounds of debridement and greater attention to mechanical offloading and decompression strategies (Nicks 2010). Skin from other sites can be grafted onto chronic wound sites to improve blood vessel growth. Cultured skin cells from the patient or a donor may also be used to improve chronic wound healing (Dreifke 2015).

Wound Biomarkers and Diagnostics

Research into wound biomarkers that can be measured to predict outcomes and guide treatment may one day provide a more individualized approach to wound treatment. For example, high levels of compounds called matrix metalloproteases (MMPs) in wound fluid can indicate a chronic non-healing wound that may benefit from MMP-absorbent wound dressings (Lindley 2016). Systemic markers such as MMPs, cytokines, and circulating stem cells can be measured in the blood and show promise in predicting wound healing outcomes (Thom 2016).

The use of rapid DNA sequencing methods may improve the efficiency of diagnosing wound infection, identification of specific pathogens in the wound microbial community, and the selection of appropriate antimicrobials for treatment. These newer methods are more likely to identify infection-causing bacteria present in the wound but have low survival in standard bacterial culture conditions (Lindley 2016).

Bacteriophages

Antimicrobial therapy using bacteriophages, or phages (viruses that specifically infect bacteria), is not a new concept: studies from the 1920s led to their use in wound healing in Germany and the Soviet Union during the second World War (Cisek 2017). Phage therapy research was largely abandoned with the advent of antibiotics, but the growing problem of antibiotic resistance has renewed interest in bacteriophages, which do not appear to promote resistance. Naturally occurring phages are very specific in the bacteria they attack. Although they lack the broad-spectrum coverage of antibiotics, they can be supplied in "cocktails" to kill multiple strains of bacteria (Young 2015).

In one report, the cases of 6 diabetic patients with chronic, non-healing, infected toe ulcers were described. The infections in these cases were due to Staphylococcus aureus, had spread into the bone and soft tissues, and failed to respond to antibiotic therapy. Although these patients were facing likely amputation, weekly treatment with a topical solution containing a strain-specific bacteriophage resulted in healing of the ulcers in an average of seven weeks (Fish 2016). The remarkable success reported in these cases lays the groundwork for clinical trials that will prospectively assess the efficacy of phage treatment on a larger scale.

Antimicrobial Peptides

Antimicrobial peptides are immune chemicals that control microbial presence and signal cells to respond to injury. Thousands of antimicrobial peptides have been identified across various species; most are short (10‒50 amino acid), positively charged molecules that are thought to bind to and damage microbial cell membranes (Mangoni 2016). They are also thought to enhance wound healing by promoting inflammation, tissue regeneration, and blood vessel growth. Several animal studies have investigated the use of antimicrobial peptides and related biological peptides such as snake venom peptides and lantibiotics (peptide antibiotics) in animal models of skin and burn infections. Toxicity remains a concern, and further research is needed to identify lantibiotics with substantive roles in human wound healing (Otvos 2015).

Chitosan Preparations

Chitosan is a chemically modified preparation of chitin, the common polysaccharide found in insect and arthropod shells (Azuma 2015). Chitosan’s properties as a topical antimicrobial agent are possibly due to its positive charge, which may disrupt bacterial cell membranes. In animal models, chitosan preparations have improved healing of surgical incisions, burns, respiratory wounds, experimental wounds in the liver and kidneys, and corneal ulcers (Dai 2012). Several human studies have shown that chitosan preparations can shorten healing time at skin graft donor sites (Azad et al. 2004; Biagini 1991; Stone 2000) and reduce adhesions in surgical wounds (Valentine 2010). These preparations may also be useful in promoting healing in chronic wounds. In a randomized controlled trial of a chitosan wound dressing in 90 patients with chronic wounds (pressure ulcers, diabetic ulcers, and infected wounds), use of the chitosan dressing led to greater reductions in wound area and depth compared with a control gauze dressing (Mo 2015). In addition to its intrinsic antimicrobial properties, chitosan has been investigated as a drug delivery vehicle for local delivery of antibiotics and growth factors (Dai 2012).

Insulin – Temporary Topical Application and Local Injection

One approach to improving wound healing is to temporarily apply local growth factors that promote cellular recruitment and tissue regeneration. A limitation of this technique is that many growth factors that may work in this context are expensive. Insulin represents a low-cost growth factor that may facilitate wound healing when applied topically as part of wound dressing or via local injection (Oryan 2017).

A randomized, double-blind, placebo-controlled trial found that a topically applied insulin spray improved the wound-healing rate in 45 participants with non-infected acute or chronic wounds on their extremities. The participants applied the insulin spray twice daily to their wounds until complete wound closure. The rate of healing in the insulin group was about 46 mm²/day compared with about 32 mm²/day in the placebo group. Importantly, glucose levels did not differ before and after the topical insulin application, demonstrating a lack of a systemic effect (Rezvani 2009). Animal studies have shown that topical insulin increases immune cell activation in wound sites and helps promote the release of local inflammatory chemicals that participate in wound healing. Human trials have shown that local insulin injections can promote healing of both acute and chronic wounds. However, insulin injections have the potential for systemic side effects (eg, hypoglycemia), so careful monitoring by a qualified healthcare provider is necessary. Newer methods of local insulin delivery that may mitigate potential side effects and maximize benefits in the context of wound healing are being explored (Oryan 2017).

Hyperbaric Oxygen Therapy

Hyperbaric oxygen therapy (HBOT) involves exposure to 100% oxygen in a pressurized (1.4 atmospheres or higher) full-body chamber. The combination of high oxygen concentration and pressure may restore oxygen to tissues with poor blood supply, reduce tissue edema, increase new blood vessel formation, and provide antimicrobial activity (Klein 2014; Anderson 2016).

Although findings from clinical trials have been inconsistent, several studies point to the potential efficacy of HBOT in treatment of acute and chronic wounds. In a randomized controlled trial, HBOT was more effective than sham HBOT for treating crush wounds, resulting in more healed wounds, less need for surgical interventions, and less tissue death (Bouachour 1996). HBOT has been shown to speed the healing of burns and improve survival of skin grafts compared with usual therapies (Eskes 2011; Eskes 2013). In uncontrolled research, the use of HBOT in conjunction with usual care was associated with lower than expected rates of complications and deaths due to soft tissue infections (Escobar 2005). HBOT is a recommended treatment for chronic diabetic foot ulcers that have failed to respond to 30 days of standard wound care and show evidence of deep soft-tissue infection, infection spreading to bone, or tissue death (Anderson 2016).

Negative-Pressure Wound Therapy

In negative-pressure wound therapy, a sealed dressing is applied to the wound site and a vacuum applies negative pressure. The mechanism of action is unclear (Argenta 1997; Gould 2015; Murphy 2012; Anderson 2016). In a structured analysis of 21 studies of negative-pressure wound therapy applied preventively to surgical sites, local infections were reduced by 44‒70% (De Vries 2016). A second review of 10 studies (several of which were not included in the first review) estimated a 46% reduction in infection with the use of negative pressure in closed surgical incisions when compared with standard dressings (Hyldig 2016).

Cryopreserved Placental Membrane

Human placental membranes are a rich source of connective tissue stem cells that can differentiate into a variety of cell types, as well as collagen and growth factors (Gibbons 2015). Grafix is a product made from human cryopreserved placental membrane (CPM) that is reported to have over 80% cell viability after thawing. In a randomized, controlled, multicenter trial, 50 and 47 patients with diabetic foot ulcers were treated with Grafix or standard of care, respectively. By the end of the trial, 62% of patients treated with Grafix had complete wound closure compared with only 21% in the standard of care group. Additionally, patients treated with Grafix had their wounds heal nearly four weeks faster, on average, compared with standard wound care (Lavery 2014).

In a randomized controlled trial, 62 patients with diabetic foot ulcers were enrolled in an evaluation of the efficacy of a CPM graft versus a human fibroblast-derived dermal substitute (hFDS) (Ananian 2018). At the end of treatment, 48.4% of patients in the CPM group compared with 38.7% in the hFDS group achieved a complete wound closure. Importantly, CPM was more cost-effective: the average per-patient cost was $3,846 for CPM and $7,968 for hFDS.

Dehydrated Human Amniotic/Chorion Membrane Allograft

The dehydrated human amniotic/chorion membrane (dHACM) allograft is another grafting technique to induce wound healing from a cryopreserved placental membrane. The dHACM allograft contains several components, including growth factors, collagen, fibronectin, laminin, cytokines, miRNA, and exosomes (Lei 2017; Wei 2020). In comparison with several commercially available CPM grafts, the dHACM is a richer source of beneficial components at significantly greater levels, and is prepared with a dehydration process that inhibits the viability of potential microorganisms. It has demonstrated the ability to promote the migration of stem cells in vitro and recruit stem cells to a wound site in vivo (Lei 2017). dHACM has also been evaluated in randomized controlled clinical trials as a treatment for plantar fasciitis, an inflammatory foot condition, aside from diabetic foot ulcers (Hanselman 2015; Cazzell 2018). It has had noteworthy success in these trials; however, more research is needed. Most of the research conducted thus far has shown dHACM to be successful in treating diabetic foot ulcers (Joshi 2020).

In an interim analysis of a randomized controlled trial, 60 patients with chronic lower extremity diabetic ulcers had superior healing from treatment with a dHACM allograft product called EpiFix compared with an allogeneic bi-layered cultured skin substitute product called Apligraf or standard of care (Zelen 2015). After six weeks of weekly application, 95% of patients in the EpiFix group had a complete wound closure, whereas this was only achieved in 45% and 35% of the patients in the Apligraf and standard care group, respectively. Once 100 patients completed the study another analysis was conducted (Zelen 2016). Within 12 weeks, 97% of those in the EpiFix group achieved complete closure compared with 73% and 51% in the Apligraf and standard of care groups, respectively. Also of noteworthy importance, the median cost to heal for the Apligraf was $8,918, but only $1,517 for the EpiFix.

In another randomized controlled trial, treatment with a non-commercialized dHACM allograft was compared with standard of care in 98 patients with diabetic foot ulcers (Tettelbach 2019). Within 12 weeks of weekly applications, those treated with the amniotic allograft were more than twice as likely to have complete wound closure than standard of care patients. At the final follow-up at 16 weeks, 95% of patients in the dHACM allograft group and 85% of the standard of care group had complete wound closure.

Ultrasound

Low-frequency ultrasound (20‒40 kHz) provides direct physical stimulation of cells and activates tissue repair (Anderson 2016). When applied to wounds, it can rapidly debride the wound surface, and may work synergistically with antibiotics to kill resistant bacteria and disrupt biofilms better than antibiotics alone (Gould 2015; Anderson 2016).

Electrical Stimulation

There is an electrical charge difference between the skin surface and tissues under the skin. When the skin is wounded, a natural electrical current is generated that has been shown to stimulate cells to begin healing (Anderson 2016; Torkaman 2014). Application of external low-intensity electrical current has been investigated in several animal studies of wound closure (Torkaman 2014) with mixed results. A review of 15 studies in humans determined that electrical stimulation used in conjunction with standard wound care for chronic wounds (pressure ulcers, diabetic foot ulcers, and venous leg ulcers) improved healing, with an average 27% additional reduction in the ulcer area after four weeks. For pressure ulcers alone, the effect was a nearly 43% reduction in the ulcer area (Koel 2014).

Proper nutrition is a very important factor in all phases of the wound healing process. During the recovery period, suboptimal nutrition can affect collagen synthesis, strength of wound tissue, and the body's ability to fight off infection (Quain 2015).

Wound healing is a metabolically demanding process that requires sufficient energy, in the form of calories, to proceed (Molnar 2014). Additionally, the reconstruction of injured tissue depends on the presence of protein as well as metabolic precursors and cofactors, including some vitamins, that sustain cell growth and division and new tissue synthesis (Molnar 2014; Posthauer 2007). Important nutritional factors for wound healing include:

• Eating sufficient calories from a well-balanced diet
• Consuming optimum amounts of protein
• For diabetic patients, controlling blood sugar levels
• Staying well hydrated

Total Energy (Calories)

Caloric needs during wound healing are estimated to be 30–35 kcal/kg of body weight, or up to 40 kcal/kg for an underweight patient. Distribution of calories should be similar to a traditional diet, with 45‒60% of calories from carbohydrate, 25‒30% from fat, and 15‒20% from protein, although more protein may be needed to support increased amino acid demands. Chronic wounds can increase caloric requirements by up to 50% and protein needs up to 250% in order to prevent loss of muscle (Molnar 2014).

Carbohydrates and Fats

Carbohydrate consumption must be sufficient for energy production. Simple carbohydrates (sugar) should be low enough not to exacerbate hyperglycemia, which can occur in critically injured patients and can suppress healing and increase inflammation (Mecott 2010; Rowan 2015). Fat and carbohydrate consumption are especially critical to monitor in burn patients as they are in an immunosuppressed state, and excess fat consumption can accentuate immunosuppression (Rowan 2015); in these patients, fat intake should represent <20% of non-protein calories, and carbohydrate intake should be less than 7g/kg/day in adults (Abdullahi 2014).

Protein

Elevated protein demands during wound healing come from increased amino acid requirements for cell growth and tissue repair, protein loss in fluids seeping from the wound, and breakdown of amino acids by the liver for energy (Breslow 1993; Molnar 2014). Chronic wounds can increase protein requirements by up to 250%. Protein requirements for patients under metabolic stress or recovering from surgical procedures can range from 1.0 to 2.0 g/kg of body weight depending on the diagnosis (Molnar 2014); the Agency for Healthcare Research and Quality recommends protein intake of 1.25 to 1.5 g/kg of body weight per day for patients with healing wounds.

Fluids

Preventing dehydration is a very important part of the wound healing process. Without proper hydration, wounds will not receive the oxygen and nutrients needed for healing. A lack of moisture at the wound's surface can halt cellular migration, decrease oxygenation of blood, and delay the wound healing process. The goal for fluid intake in wound patients is approximately 1mL/kcal/day. However, more fluid may be required for patients with significant drainage or less for patients with heart or kidney failure (Quain 2015).

Exercise

It has been hypothesized that the anti-inflammatory effects of exercise may be beneficial for tissue repair, especially in those with chronic inflammatory conditions (Pence 2014). In a study of 28 healthy older adults who underwent experimental wounding by punch biopsy, those assigned to an exercise group had faster healing compared with those in a sedentary control group (average of 29.2 days vs. 38.9 days, respectively) (Emery 2005). Animal studies also showed that exercise can improve wound healing (Pence 2012; Keylock 2008). Based on this evidence and the positive impact of exercise on overall health, it appears that exercise at a level appropriate to the patient's physical condition can be recommended to improve healing outcomes.

Amino Acids

Certain amino acids or their metabolites may provide additional benefits to wound healing aside from their role as building blocks for proteins.

Glutamine can be used as an energy source by various cells, including connective tissue and immune cells, and provides nitrogen for synthesis of other non-essential amino acids (Bellon 1995; Karna 2001; Molnar 2014). Research suggests glutamine may promote healing in trauma patients with wound-healing disorders (Blass 2012). Three randomized controlled trials that collectively enrolled 118 patients with severe burns involving 20‒80% of the body surface area were included in a research review. In all three studies, enteral formulas enriched with glutamine (0.35‒0.5 g/kg body weight daily) increased the rate of healing compared with placebo. Another study in the review reported that glutamine supplementation at 1.0 g/kg body weight for six days preceding and five days after surgery lowered the incidence of wound infections in patients with colorectal cancer undergoing surgery (Ellinger 2014).

Arginine is used to make proline, which is needed for collagen synthesis, and nitric oxide, which contributes to wound healing. It improves immune function and can stimulate wound healing (Guo 2010; Molnar 2014). Arginine in doses ranging from 6 to 30 grams daily has been found to reduce surgical wound complications in patients undergoing several types of surgery (Ellinger 2014). Along with zinc and vitamin C, arginine has been shown to promote healing of pressure ulcers (Desneves 2005; Cereda 2009).

Ornithine is a metabolite of arginine that shares many of its pharmacological properties. Mice supplemented with ornithine as 0.5% of their diet showed improved wound healing (Shi 2002). In a study of 160 elderly patients with heel pressure ulcers, 10 grams of an ornithine compound (ornithine alpha-ketoglutarate) once daily for six weeks shortened the time to ulcer closure compared with placebo (Meaume 2009).

Beta-hydroxy beta-methylbutyrate (HMB) is a metabolite of the amino acid leucine. It has anti-catabolic properties, contributing to a positive protein balance by reducing protein breakdown and stimulating protein synthesis (Landi 2016). In a small trial of amino acid supplementation, nine participants with diabetic foot ulcers received a combination of arginine, glutamine, and HMB or placebo twice daily for two weeks. Tissue hydroxyproline concentration (a measure of collagen concentration) increased by an average of almost 68% in the supplemented group, and dropped by over 78% in the control group (Jones 2014). In a larger trial in 270 diabetics, a drink containing HMB plus arginine and glutamine led to better healing than a control drink in a subgroup of participants with poor blood flow in their limbs and/or low albumin levels (Armstrong 2014).

Omega-3 Fatty Acids

Omega-3 fatty acids have been shown to promote wound healing by several mechanisms and may reduce infection during the healing process (Guo 2010). Intriguing evidence suggests omega-3 fats may have immunomodulatory effects, promoting local inflammation at the site of injury (where it is needed), while at the same time promoting recovery of physical function after surgery (Kiecolt-Glaser 2014). In a study of 40 patients with pressure ulcers, those whose enteral or parenteral food formulas were enriched with the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as copper, zinc, manganese, and vitamins A, C, and E, had decreased ulcer progression and reduced inflammatory marker levels over two weeks compared with those receiving an unenriched formula (Theilla 2012).

Copper, Selenium, and Zinc

Trace element deficiencies are associated with delayed wound healing and infections (Abdullahi 2014). Copper is a cofactor for the oxidative stress-reducing enzyme superoxide dismutase, as well as an enzyme used to synthesize collagen (Rucker 1998; Guo 2010). Selenium is a cofactor for the oxidative stress-reducing enzyme glutathione peroxidase, which protects cell membranes from free radical damage (Baker 1993; Espinoza 2008). Zinc is a cofactor for enzymes that prevent oxidative damage and are involved in cell replication and tissue repair and growth (Molnar 2014). In a systematic review of several randomized controlled clinical trials in burn patients, parenteral and enteral micronutrient preparations containing copper, selenium, and zinc have been associated with positive treatment outcomes. These include improved wound healing, decreased protein breakdown, reduced incidence of respiratory infection, increased glutathione peroxidase activity, and shorter hospital stay (Adjepong 2016).

In a controlled study of 20 healthy men with surgical wounds, those who received 150 mg of zinc (in the form of 220 mg zinc sulfate) per day had an average healing time of approximately 46 days versus 80 days in those who did not receive zinc. The greatest improvements in healing were seen during closure of the superficial skin (Pories 1967). In patients with pressure ulcers, treatment with protein-rich supplements containing 18‒30 mg zinc, 500 mg ascorbic acid, and 6‒9 grams arginine resulted in reduced ulcer surface area and ulcer severity after three to eight weeks (Desneves 2005; Cereda 2009).

Vitamin and Multi-nutrient Supplements

Vitamin A is a fat-soluble vitamin that can stimulate growth of cells involved in tissue and skin repair when applied topically (Reichrath 2007). It has an anti-inflammatory effect in wounds, and animal models suggest it can reduce the negative impact of steroid medications on wound healing (Molnar 2014).

Vitamin C lowers oxidative stress levels, has anti-inflammatory activity, and is a cofactor for collagen synthesis. Vitamin C levels fall rapidly during inflammation and low levels are associated with delayed healing (Mohammed 2015). Vitamin C deficiency results in decreased tissue growth and blood vessel formation, increased capillary fragility, impaired immune response, and increased susceptibility to infection (Guo 2010). In patients with pressure ulcers, one gram of vitamin C daily reduced healing time and ulcer surface area (Taylor 1974; ter Riet 1995). In a randomized controlled trial in 20 trauma patients with evidence of wound healing disorders, taking a multi-nutrient drink with 500 mg vitamin C twice daily reduced time to wound closure by about half compared with a placebo drink. The multi-nutrient drink also contained glutamine (20 grams), vitamin E (166 mg), beta-carotene (3.2 mg), zinc (6.6 mg), and selenium (100 mcg) (Blass 2012). Studies of protein-rich supplements containing 18‒30 mg zinc, 500 mg ascorbic acid, and 6-9 grams arginine have been shown to reduce ulcer surface area and ulcer severity scores over a period of three to eight weeks (Desneves 2005; Cereda 2009).

Diosmin and Hesperidin

Diosmin and hesperidin, citrus flavonoids that have been reported to increase venous tone and decrease capillary leakage, have been extensively studied for their effects on venous insufficiency (Shoab 1999). In a meta-analysis of five randomized controlled trials with a combined total of 723 patients with venous ulcers, the addition of 450 mg of diosmin plus 50 mg of hesperidin twice daily to conventional treatment (compression and local therapies) resulted in significantly better healing than conventional treatment alone or with placebo. Differences in healing were evident by the second month and, after six months of treatment, 32% more ulcers were healed in flavonoid-treated patients. The average time for complete healing was 16 weeks with citrus flavonoids and 21 weeks without flavonoids (Coleridge-Smith 2005).

Aloe Vera

Aloe vera gel contains several biologically active compounds, including polysaccharides, vitamins C and B complex, enzymes, minerals, and salicylic acids. These constituents give aloe vera anti-inflammatory and antimicrobial properties, as well as the ability to stimulate tissue regeneration, collagen synthesis, and new blood vessel formation (Pereira 2016). Several small studies have investigated the use of topical aloe vera in the treatment of acute and chronic wounds. A randomized controlled trial compared topical aloe prepared with olive oil to phenytoin cream for the treatment of chronic ulcers in 60 patients. Although both groups showed improvement, reduction in wound size, depth, edema, and pain scores were superior in the aloe group (Panahi 2015). In other research, treatment with aloe resulted in faster skin closure and quicker onset of pain relief in burn victims compared with 1% silver sulfadiazine cream (Shahzad 2013; Khorasani 2009).

Calendula

Calendula (Calendula officinalis, commonly known as pot marigold) is a familiar garden plant with traditional application as a wound-healing agent. Constituents extracted from calendula have been shown to possess anti-inflammatory, antibacterial, antifungal, and free radical-reducing properties, and to stimulate blood vessel growth and collagen synthesis (Khairnar 2013; Schmiderer 2015; Pereira 2016). In a pilot study in 32 patients with non-infected venous leg ulcers, 17 were treated with a topical alcoholic extract of calendula, while the remaining 15 were treated with a topical antibiotic. After seven weeks, the patients treated with calendula saw a nearly 43% decrease in ulcer surface area versus almost 36% in those treated with the antibiotic. Additionally, the number of different types of bacteria isolated from healing ulcers in the calendula-treated patients was significantly lower than in the antibiotic-treated patients (Binić 2010).

Arnica

Arnica (Arnica montana) is a member of the sunflower family with a history of use as a homeopathic remedy for relieving pain and bruising after physical trauma (Barkey 2012; Iannitti 2016). Post-surgical topical application of arnica cream around the nose and eyes in 36 patients following nose reconstruction significantly reduced bruising and edema at days 2, 5, and 7 post-surgery compared with 36 patients not treated with arnica cream (Simsek 2016). Topical use of a 20% arnica cream for 2 weeks reduced experimental laser-induced bruising in healthy volunteers when compared with placebo (Leu 2010).

Bromelain

Topical bromelain is used in the enzymatic debridement of wounds. In addition, several clinical trials have investigated the use of oral bromelain as a treatment to reduce edema, bruising, and pain following surgical or traumatic wounds (MacKay 2003). In a rat model of crush injury to the Achilles tendon, oral bromelain increased numbers of tendon structural cells (Aiyegbusi 2011).

Pycnogenol

Pycnogenol is an extract from Maritime pine bark that is rich in free radical-scavenging, anti-inflammatory polyphenolic compounds (Deger 2013; Grether-Beck 2016). A growing body of evidence suggests that pycnogenol may have positive effects on skin health, improving elasticity and hydration and protecting against damage related to sun exposure (Grether-Beck 2016). It may also have a role in supporting wound healing.

In a randomized clinical trial, 30 patients with venous ulcers were treated with surgery followed by 50 mg of pycnogenol three times daily or a flavonoid combination previously shown to enhance vascular healing for 90 days. Pycnogenol was found to be as effective as the flavonoid combination at promoting healing of surgically treated venous ulcers (Toledo 2017). In another trial, the use of both oral and topical pycnogenol worked better than oral pycnogenol alone at reducing venous ulcers and edema (fluid accumulation) in individuals with a condition called venous hypertension (Belcaro 2005). In chronic venous hypertension, high pressure in the veins causes vascular damage, inflammatory signaling, and movement of fluid out of the venous system into nearby tissues, leading to tissue damage that can result in skin ulceration (Raffetto 2014). Another clinical trial found that oral (systemic) and topical (local) pycnogenol preparations, alone and in combination, led to higher rates of complete healing of diabetic ulcers after six weeks of use compared with standard medications (Belcaro 2006).

Animal research further suggests pycnogenol may be helpful as an aid to healing various types of wounds. The use of topical 1%, 2%, and 5% pycnogenol solutions shortened wound healing time and reduced scar size compared with pycnogenol-free solution in rats subjected to experimental injury, and the benefits were amplified as pycnogenol concentration increased (Blazso 2004). Abdominal injections of a pycnogenol solution for ten days after abdominal surgery was found to reduce adhesions better than abdominal saline injections in rats that had undergone abdominal surgery (Sahbaz 2015). Another study in rats showed that a topical pycnogenol solution reduced tissue oxidative stress and improved healing of incision wounds, and a solution made with an extract from the bark of another type of pine tree had even stronger effects (Cetin 2013).

Diabetes is well known to impair skin healing, and one animal study showed that pycnogenol may counter this problem. In the study, topical treatment with pycnogenol powder reduced the size of wounds compared with no treatment three weeks after experimental skin wounding in diabetic rats (Dogan 2017). Findings from another study in rats suggest that oral pycnogenol may reverse the negative impact of prior radiation therapy on post-surgical healing time (Deger 2013).