Volume 26 Number 2

Introduction

Wound management is a significant and growing issue not only in Australia but worldwide. This increase can be attributed to the rise in prevalence of diabetes and obesity as well as the increasing geriatric population; leading to large numbers of pressure ulcers (PUs), venous leg ulcers (VLUs) and other chronic wounds. The cost to the Australian health care system has been estimated at A$2.85 billion and globally it is expected to reach US$13.07 billion by 2022¹. The costs attributable to a new foot ulcer are estimated at $17,500². Lower extremity amputation is a common complication, affecting some 15% of diabetics with foot ulcers, with direct costs escalating to up to US$60,000 per patient². In the US alone, some 80,000 lower extremity amputations are performed on diabetic patients each year. Furthermore, it costs approximately US$60,000 for lower limb amputation, and hospitalisation can cost a further US$16,000–20,000 for patients with diabetic ulcers so effective non-surgical treatments that improve healing is providing an incentive for the biopharmaceutical industry to focus on this area of unmet medical need². This has led to the development of a multitude of new approaches and products undergoing trials or in clinics and whilst moist wound healing with topical dressings remains the core of wound healing therapeutics, there is increasing interest and need for more advanced wound therapies.

This review has focussed on some of the new approaches and therapies which are currently under development or in clinical use. Some of these new approaches have only been assessed in animal studies, while others have had more rigorous assessment in human clinical trials and are currently on the market. This is not an exhaustive list but provides an insight into the breadth of research and development currently being performed to improve healing of people with wounds.

Skin substitutes

Skin substitutes were first developed as xenografts in 1871 by Reverdin³. They are bioengineered products which are able to replace the function and form of skin. Skin substitutes have been used traditionally for burns and wounds which require large areas of skin replacement. Currently, advanced skin substitutes are utilised universally for deep and chronic wounds as they are able to reduce infection, decrease body fluid loss, improve cytokine and growth factor production as well as acting as a covering to help protect the healing wound⁴. Several types of skin substitutes that are currently available and are used for wound management are shown in Figure 1⁵.

 

Figure 1: The structure of some common skin substitutes. Modified from reference 5.
Vig K et al. Advances in skin regeneration using tissue engineering. Int J Mol Sci 2017; 18(4):789.

 

Acellular skin substitutes

Acellular or synthetic skin substitutes are composed of different matrices without the inclusion of any cells in order to minimise any foreign body response. These substitutes can be designed for specific purposes by changing the composition of the scaffold. They mainly prevent body fluid loss and microbial infection.

Biobrane consists of porcine collagen type 1 on a silicone membrane⁶ and has been shown to decrease the pain, length of hospital stay and wound healing time of partial thickness burns in several prospective randomised controlled trials (RCTs)^7-9.

Integra, a bilayer skin equivalent, consists of an epidermal substitute layer on a chondroitin-6 sulphate and collagen-based dermis¹⁰. Integra facilitates the migration of macrophages to the wound and promotes angiogenesis and granulation tissue formation¹¹. RCT studies have shown that burn patients treated with Integra healed faster and have elevated amounts of serum constitutive protein and lower resting energy compared to patients treated with standard grafts^12-14. Moreover, patients with a diabetic foot ulcer (DFU) demonstrated greater complete wound closure with no infection and recurrent ulcer during the 12-week study¹⁵.

AlloDerm is an allograft skin in which all the epidermal and dermal cells are removed and the human dermal matrix acts as a template for soft tissue regeneration¹⁶ and promotes the functional performance in burn patients¹⁷. Use of AlloDerm on patients with major burns resulted in reduction in post-burn joint contracture¹⁸.

Graftjacket is a micro-ionised human dermal collagen matrix, which has been shown to increase the number of healed ulcers in a treated DFU group while decreasing the healing time and ulcer size¹⁹. Moreover, treatment of lower extremity wounds with Graftjacket in diabetic patients led to a significant increase in the rate of healing²⁰.

Omnigraft is composed of a matrix layer made of collagen and the glycosaminoglycan chondroitin-6 sulphate with a layer of silicone. Recently, the Food and Drug Administration (FDA) has approved Omnigraft, which previously had approval for burn therapy, for the treatment of DFUs²¹.

Cellular skin substitutes

Cellular or natural skin substitutes contain living cells which are predominantly skin cells contained within a matrix. Incorporation of cells within a matrix makes them more effective than acellular substitutes; however, they are more expensive, require specific storage conditions and are more difficult to use. Cellular skin substitutes are classified in two groups: Autologous substitutes which contain the patient’s own cells and allogeneic substitutes in which cells are obtained from donors.

TransCyte is a temporary skin substitute that consists of fibroblasts, from neonatal foreskins, seeded over a nylon mesh scaffold¹⁶. Several clinical studies have shown that TransCyte improves the rate of re-epithelialisation and reduces healing times of partial and full-thickness burns. It also decreased the daily wound care time, length of stay and need for autografts in burn patients.

Dermagraft is made from viable neonatal foreskin fibroblasts with a collagen mesh made from polyglycolic acid¹¹. Administration of Dermagraft has been shown to result in faster wound closure, fewer ulcers and reduced infection in chronic DFU, suggesting that this is a safe and effective treatment²². The healing of VLUs has also been shown to be improved when treated with Dermagraft and compression therapy^23-25.

Apligraf, a bilayered skin equivalent, contains allogenic keratinocytes on a type 1 bovine collagen gel and has been studied clinically in chronic wounds²⁶. Patients with VLUs treated with apligraf were significantly more effective in reaching complete wound healing²⁷. Apligraf was also found to improve vascularity, pigmentation, wound height and scar scores in burn patients²⁸ as well as shortening the healing time of donor site wounds²⁹.

OrCel is a product produced by culturing human allogeneic keratinocytes and dermal fibroblasts in two separate layers onto the different sides of a sponge made of type I collagen³⁰. A prospective, randomised, multicentre study comparing OrCel with Biobrane for the treatment of donor site injuries revealed shorter healing times and less scarring in wounds that were treated with OrCel³¹.

Epicel is made from human keratinocytes and murine fibroblasts that are placed onto petroleum gauze³² and has been investigated for the treatment of patients with a large burn area (37% ± 17% TBSA) in which about 90% of patients survived³³.

Vivoderm or laser skin is composed of cultured autologous keratinocytes on laser-perforated hyaluronic acid³⁴. A number of studies have confirmed the safety and effectiveness of this dressing for the treatment of deep leg ulcers³⁵ and DFUs^36-38.

Keratinocyte dressings

Keratinocytes are specialised epidermal cells and are the main cells that participate in the re-epithelialisation process and contribute to wound healing by secreting several cytokines and growth factors³⁹. These cells were first cultured successfully in 1975 and were first used as grafts for burns treatment five years later⁴⁰. Keratinocytes have been used widely as allografts and autografts for the treatment of various wounds including acute, chronic and burn wounds⁴¹. Treatment of burns with autologous keratinocytes minimised the morbidity for patients with severe burns. Several clinical studies (a case study and a study on 55 patients) which assessed the effects of autologous keratinocytes on burns and chronic wounds demonstrated that these cells have remarkable therapeutic value^42,43. Moustafa et al. used an autologous keratinocyte dressing as a therapy for non-healing diabetic neuropathic foot ulcers which showed promising results⁴⁴. Treatment with cultured autologous keratinocytes resulted in the complete healing in 6 of 9 ulcers and one improved ulcer in 6 weeks⁴⁵. Treatment of 51 chronic VLUs with allogenic keratinocyte sheets for a month also resulted in accelerated wound healing⁴⁶. A pilot study on patients with DFUs indicated that all patients treated with allogenic keratinocyte sheets achieved complete wound healing in 12 weeks⁴⁷.

Keratin-derived dressings

Keratinocytes enhance wound healing by facilitating re-epithelialisation through the up-regulated expression of keratins⁴⁸. It has been shown that keratin-based dressings are able to improve the function of keratinocytes in terms of proliferation and migration⁴⁹. An RCT confirmed that treatment of partial-thickness wounds with keratin-derived dresses caused an increase in re-epithelialisation after seven days⁵⁰. In a case study conducted on three patients with mixed venous and arterial leg ulcers, faster healing rates in were also observed in ulcers⁵¹.

Amniotic membrane

Amniotic membrane (AM) is a widely used and cost-effective wound dressing which contains cytokines, growth factors and progenitor cells. AM has unique properties, including being antibacterial, anti-inflammatory, anti-scarring, providing pain relief, as well as low immunogenicity^52,53. AM grafts have been trialled clinically for diabetic neurovascular ulcers, VLUs, and many other types of wounds^54,55. For example, in a pilot study, AM graft treatment of patients with VLUs caused a significant increase in granulation tissue formation and led to a reduction in ulcer size and pain level⁵⁶. Evaluating the effects of dehydrated human amnion/chorion membrane (EpiFix) on the treatment of VLUs showed a significant improvement in time of the healing⁵⁷. In another RCT on patients with diabetes, lower extremity ulcers treated with EpiFix demonstrated complete healing and a rapid reduction in wound size, compared to wounds treated with other grafts⁵⁸. All the clinical studies revealed that the use of AM for covering wounds contributed to reduced scarring, infection and pain and accelerated wound closure.

Oxygen

Oxygen is a vital component of the wound healing process and is necessary for modulation of cell responses and angiogenesis⁵⁹. Providing additional external oxygen has been shown to contribute to improved wound healing in chronic wounds⁶⁰ and has been demonstrated to be valuable to wound healing since the 1960s⁶¹.

In topical oxygen therapy, oxygen is provided to the wound area using portable devices which create external pressure and increase the oxygen concentration. A clinical trial on 20 patients with DFUs receiving topical oxygen revealed an increase in healing rate compared to those receiving standard care⁶². Currently, commercially available systems based on pressurised oxygen have been reported to be effective and safe dressings for severe DFUs and VLUs in several case reports and clinical studies^63-65. Topical oxygen therapy is a cheap and flexible method without any marked side effects related to systemic oxygen therapy, which makes it preferable to hyperbaric oxygen therapy (HBOT)^60,66,67. HBOT is a procedure in which patients are placed in a chamber with greater oxygen pressure — two to three times greater than normal atmospheric pressure — that results in an elevated amount of pure oxygen in wound tissues⁶⁸. While local hypoxia results in impaired wound healing, the growth in oxygen concentration has a number of physiologic and cellular benefits related to collagen deposition, angiogenesis and wound closure rate. A number of clinical trials on patients with a DFU demonstrated a rise in the rate of ulcer healing at six weeks but not at longer term. In another trial conducted on VLUs, the wound size reduction was shown by week 6. To the best of our knowledge, there are no clinical studies investigating HBOT and arterial ulcers.

However, there are some adverse effects of systemic oxygen including central nervous toxicity, ear barotrauma, pulmonary barotraumas and seizures^69,70. A recent sponsored consensus round table meeting supported the use of topical oxygen therapy to promote wound healing, particularly with DFUs⁷¹.

Topical negative pressure

Topical negative pressure (TNP) or vacuum-assisted closure (VAC) has been used classically for open wound care for over two decades. In this therapy, a polyurethane foam is applied to the wound surface and is sealed with an adhesive dressing⁷². The negative pressure given by a vacuum pump results in the promotion of wound healing, which is probably caused by an increase in local body fluid and new tissue formation along with a reduction in infection, mechanical stress and pain⁷³. In the treatment of DFUs, TNP has promoted wound healing and granulation tissue formation and decreased wound size and bacterial infections⁷⁴. Patients with PUs treated by TNP, in several RCTs, had a significant reduction in the wound size, depth, healing time and length of hospital stay^75,76. A number of other clinical studies have demonstrated the beneficial effects of TNP on non-healing chronic wounds including necrotic ulcers, arterial ulcer, PUs, DFUs and VLUs^77-82. However, the dressing should be replaced every two or three days to prevent tissue ingrowth, infection and pain. Recently, an extra polymeric membrane dressing has been used to overcome this replacement barrier. This RCT study indicated that the use of additional polymeric membrane dressing in patients with chronic wounds was a cost-effective, safe and efficient method which decreases the need for dressing changes⁸³.

Electrical stimulation

Human intact skin has an electrical potential due to the ATPase pumps present in the epidermal cells. Following damage to the skin, an additional electrical current, referred to as the “current of injury”, is generated to facilitate wound healing⁸⁴. It has been shown that administration of external electrical currents leads to an enhancement in the immunity of cells, a reduction in infection and improvement of wound healing⁸⁵. Therefore, electrical stimulation (ES) therapy for wounds, particularly chronic wounds, has gained interest in clinical trials. ES devices vary due to the different voltages, length of application time and currents. Three types of ES including alternating current (AC), direct current (DC), and pulsed current (PC) have been used for wound healing⁸⁶. The majority of clinical trials using ES for wound healing have used PC. In an RCT, patients with chronic dermal ulcers treated using PC electric stimulation showed a significant reduction in wound area⁸⁷. Gentzkow et al. in a prospective study has also shown complete healing in 43% of patients with PUs⁸⁸. Several RCTs using PC ES on PUs have resulted in accelerated wound healing rate^89,90. In terms of DFUs, treatment with PC ES has led to enhanced wound healing⁹¹. Recently, in a pilot RCT, positive effects of PC ES on reduction of VLUs size was observed⁹² and a much larger RCT is in progress with three arms: ES, ES + compression and compression alone. If shown to be effective, it will be an attractive therapy for those who cannot tolerate compression or where compression is contra-indicated.

Extracorporeal shock wave therapy (ESWT)

Extracorporeal shock wave therapy (ESWT) is based on shock waves which are transient acoustic pulses and are applied with high pressure to the wound site. ESWT has been used as an efficient therapy method for treatment of urinary and kidney stones for about three decades⁹³. Several clinical trials investigating the effects of ESWT on wound healing have achieved very encouraging outcomes. One study conducted on 208 patients with acute and chronic wounds demonstrated safety and potential efficacy for ESWT applied to the wounds; in which 75% of patients showed complete wound healing (with 100% epithelialisation) in a mean time of 44 days after therapy⁹⁴. A prospective, single-blind, placebo-controlled study was conducted to assess the effects of ESWT on scar pain which confirmed the scar pain reducing effect of ESWT⁹⁵. A number of clinical studies have also evaluated the use of ESWT on deep second- and third-degree burns. The results revealed an increase in complete wound healing rate and a decrease in burn-pruritus^96,97. Another randomised, single-blind, controlled study compared the effects of HOBT and ESWT on DFUs. The results revealed that the number of patients with complete wound healing or improved wound healing was greater in the ESWT-treated group after daily treatment for 20 times⁹⁸. A case series in VLUs was also supportive of a benefit of ESWT⁹⁹.

Growth factor therapy

Wound healing processes rely on cytokines and growth factors to regulate cellular signalling pathways to alter the proliferation and migration of cells in a wound bed. These proteins contribute to every step of the wound healing process and have been suggested as effective therapies for acute and chronic wounds.

Granulocyte-macrophage colony stimulating factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multipotent cytokine which plays a vital role in wound healing. In vivo studies using GM-CSF have suggested its effects on skin cell proliferation and migration and recruitment of immune cells to the wound bed^100,101. A number of in vivo and clinical studies have shown significant effects of GM-CSF treatment on the healing of chronic wounds and burns. In one study of chronic VLUs, 50% of patients treated with GM-CSF completely healed by two months as compared to 11% of the control, non-treated group¹⁰². In another double-blind, randomised, placebo-controlled study, chronic VLUs patients receiving GM-CSF demonstrated significant improvement in the healing of wounds in the treatment group¹⁰³. Two randomised controlled studies confirmed the therapeutic effects of a GM-CSF hydrogel on second-degree burns and indicated that early application achieved the best outcome^104,105. However, studies of GM-CSF on PUs have yielded diverse results. Topical GM-CSF did not have a marked effect on PUs, compared to the placebo group in a study by Robson et al.¹⁰⁶; while other case studies have demonstrated enhanced healing rate and increased granulation tissue formation in PUs¹⁰⁷. One randomised controlled study on diabetic patients with infected foot ulcers did, however, show improved outcomes on receiving GM-CSF along with insulin therapy¹⁰⁸.

Platelet-derived growth factor

Platelet-derived growth factor (PDGF) that is released from platelets following injury has important functions in all phases of the wound healing process. In vitro and in vivo animal studies have confirmed the positive effects of this growth factor on inflammation initiation, fibroblast proliferation, re-epithelialisation and recruitment of other cells to the wound site^109-111. The amount of PDGF has been shown to decrease in chronic wounds, which implicates it as a therapeutic factor. Promoted wound healing was observed in patients with chronic PUs treated with Becaplermin, an FDA-approved human PDGF, in RCTs¹¹². A phase II study conducted on patients with advanced PUs demonstrated a reduction in wound size in the PDGF-treated group compared to the control group¹¹³. DFUs treated have shown accelerated closure in an RCT¹¹⁴. Although the clinical trials are promising, the use of PDGF is limited owing to the need for dressing replacement. Moreover, applying Becaplermin to the wound site caused erythematous rashes and a burning sensation at the site of application¹¹⁵ and using three tubes or more increased the risk of malignancy in a 20-month follow-up study from two RCTs^116,117.

Opal A

Opal A is an alkalinised compound which is derived from paw paw fruit. In a case study conducted on patients with PUs, treatment with Opal A cream promoted wound healing¹¹⁸. Treatment of arterial ulcers in a woman with arteriopathy resulted in improved wound healing and quicker wound closure. Furthermore, application of Opal A to a patient with an arterial leg ulcer decreased the pain and time of healing to half. Overall, arterial ulcers are resistant to common standard therapies but have shown improvement after Opal A treatment, which suggests that this compound may be an effective and safe method for wound healing¹¹⁹.

Monoclonal antibody therapy

Monoclonal antibodies are mono-specific antibodies which are able to bind to target proteins and neutralise their activity. Some proteins has been shown to be elevated in acute and chronic wounds; targeting these proteins with monoclonal antibodies may contribute to improved wound healing.

Transforming growth factor ß CAT-152

A number of studies have suggested that transforming growth factors contribute to hypertrophic scarring¹²⁰. CAT-152 is a human monoclonal antibody that neutralises the activity of transforming growth factor ß2. Several in vitro and in vivo animal studies have shown the anti-scarring effects of CAT-152 on post-surgery wounds¹²¹. However, not enough success was observed in an RCT conducted on the effectiveness and safety of CAT-152 on people undergoing trabeculectomy and other surgeries¹²².

TNF-α

Several studies implicated tumour necrosis factor-α (TNF-α) as a pivotal contributing factor in impaired healing in human and animal models¹²³. The levels of TNFα elevate in chronic wounds, suggesting its association with different chronic ulcers¹²⁴.

Infliximab is a therapeutic monoclonal antibody that is able to neutralise the activity of TNF-α. In a number of case studies, Infliximab was applied topically to the patients with chronic ulcers for 16 weeks. A significant reduction of ulcer surface area and improvement in healing rates was observed¹²⁵.

Adalimumab is another human monoclonal antibody that inhibits the TNF-α function and is clinically used for the treatment of autoimmune diseases¹²⁶. VLUs have higher TNF-α levels compared with normal skin. Treatment of 4 patients with VLUs for 4 weeks reduced the level of TNF-α in the wound site and decreased the ulcer size in a clinical pilot study¹²⁷.

These case and pilot studies indicated that future RCTs of TNF-α antibodies are viable and may further reveal the safety and efficacy of these new therapies on wound healing.

Flightless I protein

Flightless I protein (Flii) is an inflammatory modulatory protein¹²⁸. Several studies have demonstrated that Flii is elevated in human chronic wounds and the action of Flii negatively regulates wound healing by affecting process such as inflammation, collagen I expression, migration of keratinocytes during re-epithelialisation and migration of fibroblasts^129-131. In preclinical models, Flii neutralising antibodies (FnAbs) have been shown to promote healing of acute and chronic wounds with wounds becoming smaller and more contracted in murine and porcine models^132-134. Clinical studies need to be conducted to further investigate the effects of FnAbs on human wounds.

Protease inhibitors

The activity of proteases and their inhibitors plays a critical role in maintaining the balance between extracellular matrix construction and deconstruction¹³⁵. Upregulation of proteases in chronic wounds contributes to abnormal degradation of extracellular matrix and proteins such as cytokines and growth factors¹³⁶. These findings implicate protease inhibitors as a potential therapeutic approach for improving wound healing. In an ex vivo study, the administration of protease inhibitors to wound fluid taken from patients with DFUs caused a marked decrease in the protease activity including matrix metalloproteinase, plasmin and elastase¹³⁷. Several dressings have been developed to address this imbalance in proteolytic activity.

Promogran is a dressing that is made of collagen I and oxidised regenerated cellulose. This dressing reduces the activity of proteases such as elastin and matrix metalloproteinase. In several case studies Promogran dressing has been shown to be effective in chronic wound healing¹³⁸. Applying this dressing to VLU resulted in improved wound healing^139,140. An RCT conducted to evaluate the treatment with Promogran on DFUs showed that this treatment led to a safe and faster wound healing in a 6-month study¹⁴¹.

UrgoStart is a dressing that contains a layer of polyester mesh, hydrocolloid polymers and nano-oligosaccharide factor, which is a matrix metalloproteinase inhibitor factor¹⁴². UrgoStart has been shown to reduce the ulcer size and time of healing compared with foam dressings in two RCTs^143,144.

Doxycycline is an antibiotic and matrix metalloproteinase inhibitor which has been shown to improve the healing of chronic diabetic ulcers mainly based on its protease inhibitor activity in a small pilot RCT¹⁴⁵. Evaluating the effects of doxycycline as an adjunct to compression therapy on patients with chronic VLUs demonstrated the positive effects of this inhibitor on reduction of ulcer size¹⁴⁶.

Connexin inhibitor

Connexin 43 (Cx43) is a protein in gap junction channels which has a role in inflammatory and fibrotic processes. The expression of Cx43 quickly decreases after wounding¹⁴⁷ but is elevated in chronic wound fluids¹⁴⁸, suggesting this protein may be a potential target for wound healing therapies. An in vivo study investigating the effect of Cx43 inhibition on a corneal wound confirmed the promotion of wound healing in superficial epidermal wounds in murine model¹⁴⁹. Another animal study conducted by Qiu et al. revealed that application of Cx43 antisense oligonucleotides led to accelerated wound healing¹⁵⁰. In a prospective, multicentre clinical trial conducted on patients with VLUs, connexin expression was inhibited by alpha connexin carboxyl-terminal 1 (ACT1) peptide gel. The treatment resulted in an increase in skin cell proliferation, migration and re-epithelialisation. A significant reduction in ulcer area was observed at 12 weeks, as compared with standard care, which indicates the safety and efficacy of using ACT1 gel on healing of skin wounds¹⁵¹. In another prospective, randomised, multicentre clinical trial the efficacy of ACT1 was evaluated on DFUs and also showed greater re-epithelialisation rate and accelerated healing when treated with ACT1, as compared with standard care¹⁵².

Platelet-rich plasma

Platelet-rich plasma (PRP) is a concentrated plasma which is derived from whole blood and contains platelets and elevated amounts of growth factors, cytokines and fibrin¹⁵³. PRP has been used for treating inflammatory diseases, including osteoarthritis and diabetes for three decades. Several clinical studies demonstrated that PRP treatment promotes wound healing by affecting the proliferation, angiogenesis and cell recruitment in the wound site. In a case study, the autologous PRP treatment of a diabetic patient with unhealed chronic lower extremity wounds was successful¹⁵⁴. PRP treatment applied using a spray gave rise to an improved rate of healing and less antibiotic consumption and pain on surgery wounds after one week in a prospective cohort study¹⁵⁵. Driver et al. have conducted RCTs to evaluate the effects of autologous PRP gel on DFUs in a 12-week study. The results showed an improvement in complete wound healing rate and shorter healing time in treated groups¹⁵⁶. Furthermore, it has been shown in a clinical study with 56 patients that autologous PRP gel increased the healing rate and decreased infection in diabetic ulcers¹⁵⁷.

Medications

A number of medications have been utilised in wound healing. Where there is an inflammatory or auto-immune dimension to the wound aetiology, agents targeting these mechanisms have been successfully utilised. Such wounds include vasculitis ulcers, pyoderma gangrenosum and necrobiosis lipoidica. The agents have variously been utilised topically, orally and systemically, in widely varying doses.

Immunosuppressive drugs: Drugs with immunomodulatory roles including Cyclosporine, Mycophenolate, Tacrolimus, Pimicrolimus, Corticosteroids and Azathioprine have been shown to have positive effects on pyoderma gangrenosum^158,159.

Other medications, including complementary and alternative medicines, have been used for specific wound conditions — mostly orally but in some cases topically. Examples include:

Rutosides (oxerutins): These drugs have been examined on wounds associated with lymphoedema. In two different RCTs, they increased the freedom, movement and decreased the pain in patients with arm and leg ulcers^160,161.

Horse chestnut: This drug has been found effective for chronic venous insufficiency and lower limb oedema from various causes^162,163. There is little evidence, however, to support its use in wound healing.

Phenytoin: Topical phenytoin has been used to promote chronic wound healing such as leg ulcers, PUs, and DFUs but there is a paucity of recent evidence^164,165.

Pentoxifylline: This agent improves oxygen delivery to ischaemic areas and has been successfully used for symptoms of peripheral vascular disease. It has also been utilised for arterial and DFUs¹⁶⁶. A Cochrane review demonstrated its efficacy when used in addition to compression, or where compression cannot be used, in VLUs¹⁶⁷.

Sodium thiosulphate: Administered intravenously, this has been shown to improve healing of ulcers caused by calciphylaxis¹⁶⁸.

Arginine: This amino acid is required for wound healing but the body has only limited capacity to produce it. Several trials have supported its use in assisting healing of stage 2 and above pressure injuries, in doses from 3 to 9 gm/day^169-171.

Other nutrients: Whilst extensively administered, there is little to support the role of vitamin C or zinc to promote wound healing, despite their importance to collagen formation and wound healing. If a clear deficiency is demonstrated, they should be administered in replacement doses.

Herbal: Many herbs have been promoted as assisting wound healing, but there is little to no evidence to support their benefit.

Conclusions

Advanced wound therapies offer the appropriately trained clinician a wide range of options to promote wound healing, particularly for certain wound types or where more standard therapies are failing. Some of these therapies have been investigated in animal trials and case studies and are not approved for use due to the lack of clinical evidence. More RCT studies need to be done to prove the efficiency and safety of these methods. They are often more expensive than standard therapies and have limited availability, but where they can be sourced and afforded, they should be considered. As in all therapeutic areas, they should only be used where cheaper therapies have been tried and failed, or are unlikely when used alone to assist wound healing and should be used with a full awareness of possible adverse effects. Due to space restrictions, it has not been possible to review all new advances in wound technologies. Others include stem cells, gene therapies, and honey and silver dressings, which also show promise as treatments for wounds. However, given the magnitude of interest at the moment by companies keen to enter the wound care market, the development of advanced wound therapies is on the rise and only time will tell what the next breakthrough will be for the treatment of chronic non-healing wounds.

Author(s)

Parinaz Ahangar
MSc
Future Industries Institute
University of South Australia
SA, Australia

Michael Woodward
OAM
Director, Wound Management Service and Director Aged Care Research,
Heidelberg Repatriation Hospital
Austin Health
VIC, Australia

Allison J Cowin*
PhD
Professor Regenerative Medicine
Future Industries Institute
University of South Australia
SA, Australia
Email Allison.Cowin@unisa.edu.au

* Corresponding author

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