Enhancing wound healing dressing development through interdisciplinary collaboration

Abstract The process of wound healing includes four phases: Hemostasis, inflammation, proliferation, and remodeling. Many wound dressings and technologies have been developed to enhance the body's ability to close wounds and restore the function of damaged tissues. Several advancements in wound healing technology have resulted from innovative experiments by individual scientists or physicians working independently. The interplay between the medical and scientific research fields is vital to translating new discoveries in the lab to treatments at the bedside. Tracing the history of wound dressing development reveals that there is an opportunity for deeper collaboration between multiple disciplines to accelerate the advancement of novel wound healing technologies. In this review, we explore the different types of wound dressings and biomaterials used to treat wounds, and we investigate the role of multidisciplinary collaboration in the development of various wound management technologies to illustrate the benefit of direct collaboration between physicians and scientists.


| INTRODUCTION
A glossary of terms found in the introduction is provided in Table 1.

| Overview of wound healing
Wound healing involves four phases: Hemostasis, inflammation, proliferation, and remodeling. 1 Wound healing begins with transient vasoconstriction of injured vessels. 2 In the initial phase, damage to the skin exposes the subendothelial collagen and tissue factor, leading to platelet aggregation. 3 In this process, Von Willebrand factor (vWF) binds to both the subendothelial collagen and the platelet receptor glycoprotein Ib/IX/V. 4 This adhesion, as well as thrombin generated by tissue factor, results in platelet activation, degranulation, and conformational change. 5 Conformational change in glycoprotein IIB/IIIA allows the binding of fibrinogen, a crucial step in platelet aggregation and formation of the platelet plug. Tissue factor and phosphatidylserine, located on the surface of platelets and endothelial cells, form a complex with circulating activated Factor VII, leading to activation of a coagulation cascade which results in the cleavage of fibrinogen to fibrin. 5

Fibrin activates
Factor XIII, which acts to crosslink the fibrin monomers. The final result is a strong blood clot. 6 The hemostasis process of wound healing leads to the inflammatory process in multiple ways. Platelets can activate the complement cascade, leading to inflammation and the formation of the membrane attack complex (MAC). 7 Activated complement proteins C3a and C5a cause the degranulation of mast cells, which releases factors, such as histamine, heparin, and proteases. 8 Mast cells express the enzymes T A B L E 1 Glossary of terms found in introduction Natural killer cell A type of white blood cell of the innate immune response. This type of lymphocyte plays a major role in the direct early host rejection of both tumors and virally infected cells.

Neutrophil
Polymorphonuclear granulocytes abundant in acute phase of inflammation.

Phagocytize
Engulfment or "eating" of cells and foreign material Phosphatidylserine Phospholipid located in cell membrane Platelet derived growth factor Glycoprotein produced by platelets and activated macrophages that acts as a chemoattractant for neutrophils and can induce cell division in mesenchymal cell types T cells A type of white blood cell seen in the adaptive immunity responsible for cell mediated immunity. T cells, along with B cells, are the two primary types of lymphocytes that determine the specificity of immune response to antigens.

TGF-β Transforming growth factor-beta Cytokine that stimulates proliferation of epithelial cells and inhibits inflammation
Thrombin Protease that cleaves inactive fibrinogen to fibrin in coagulation cascade TNF-α Tumor necrosis factor-alpha Proinflammatory cytokine Transforming growth factor beta Inhibits function of immune cells such as T cells, B cells, and monocytes/macrophages 173 Type III collagen Collagen predominantly found in skin, blood vessels, and granulation tissue VEGF Vascular endothelial growth factor A signaling protein that stimulates vasculogenesis and angiogenesis VonWillebrand Factor Glycoprotein produced by endothelial cells that stimulates platelet adhesion and aggregation Abbreviations: TGF, transforming growth factor; TNF-α, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor. cyclooxygenase (COX) 1 and 2, which generate prostaglandins from the arachidonic acid precursor. 8 The histamine and prostaglandins that are released as a result of mast cell activation lead to increased vascular permeability 9 causing the sign localized swelling, 10 which can be visualized. In addition to increasing vascular permeability, prostaglandins sensitize pain receptors, 9 act as a neutrophilic chemoattractant, and cause vasodilation. 11 Prostaglandin induced receptor sensitization leads to pain, 11 while vasodilation leads to redness and heat 10 ; all of which can be appreciated by the patient.
Platelet aggregation leads to the release of neutrophil chemotactic factors such as platelet derived growth factor (PDGF) and transforming growth factor (TGF) beta. 12 Neutrophils migrate to the site of injury and become trapped in the platelet plug. 12 There, the neutrophils phagocytize dead tissue and release reactive oxygen species that create an unfavorable environment for bacteria. 12 13 The proinflammatory macrophages phagocytize microbes and cellular debris as well as secrete proinflammatory cytokines and chemokines that increase the number of natural killer cells, helper T cells, and macrophages at the site of injury. 13 Some macrophages will differentiate into antiinflammatory and pro-regenerative M2 macrophages. 15 The M2 subset of macrophages assist in wound healing by stimulating fibroblasts, stimulating angiogenesis (e.g., PDGF and VEGF), producing collagen precursors, producing factors that attenuate inflammation (e.g., IL-10 and TGF-β), and producing of metalloproteinases (MMPs). 15 The proliferative phase consists of the epithelization, revascularization, and formation of granulation tissue. 16,17 Epithelial cells located at the wound edges, upon stimulation by the epidermal growth factor (EGF) and TGF-α produced by the platelets, begin to proliferate. Stimulated fibroblasts secrete factors, such as keratinocyte growth factor (KGF)-2, which induce keratinocyte migration. 16 Keratinocytes migrate along the fibrin blood clot by lamellipodial crawling, until they begin to contact each other. 17 Growth factors bind to endothelial cells and set off a signaling cascade that results in secretion of proteolytic enzymes that break down the basal lamina, allowing the endothelial cells to proliferate and migrate into the wound to form blood vessels. 17 Fibroblasts initially synthesize a provisional matrix consisting of collagen, fibronectin, and other substances. In the final step of the proliferation phase, granulation tissue replaces the provisional matrix. 17 Granulation tissue mainly consists of fibroblasts, new blood vessels, and type III collagen. 18 Some fibroblasts will differentiate into myofibroblasts, which contract to bring the wound edges closer together. 18 The remodeling phase (also referred to as the maturation phase) is the longest phase of wound healing and is dependent on a delicate balance between synthesis and degradation. 18 The type III collagen is lysed by collagenases and subsequently denatured and digested by various proteases. 19 The type III collagen is replaced by type I collagen, which orients itself in an organized manner that gives it maximal strength against stress forces. Fibroblasts begin to decrease in number, resulting in a relatively acellular scar. 20 Reduced biological activity leads to apoptosis of vascular tissue, 19 which can be visualized clinically as a reduction in redness. 19 21 Much later, a Greek physician known as Galen of Pergamum, emphasized the importance of keeping the wound moist. 21 Prior to the late 1800s, dressings were prepared from unsterilized materials that could be reused, such as old linens, rags, and rope. 22 In the late 1800s, Gamgee of Birmingham had the idea to combine absorbent cotton with compressing gauze in an aseptic manner for use in wound care. 22 The concept of keeping the wound moist was not scientifically proven until 1962 when George D. Winter published research that showed epithelization of wounds occurs more rapidly in a moist environment, as opposed to wounds that are exposed to air. 21,23 According to Weir

| TYPES OF WOUND DRESSING
There are a variety of different types of wound dressings available.
Each wound dressing has unique properties that can be exploited to fit the needs of a patient. Furthermore, wound dressings can be combined to enhance wound healing. The major types of occlusive wound dressings are described below. Table 2 summarizes the advantages and disadvantages of the following wound dressings.

| Contact layer dressings
Contact layer wound dressings are single layer dressings that are in direct contact with the wound surface. Contact layer wound dressings typically have low adherence with the wound bed thus preventing trauma to the wound bed upon removal. 24 They function to allow exudate to pass through to a secondary wound dressing 24,26 and can be used in conjunction with other wound therapies. 24 Some contact layer dressings, such as gauze impregnated with paraffin, may trap water vapor and lead to maceration, a condition in which exposure to moisture causes the surrounding skin to breakdown. 27,28 If contact dressings such as gauze impregnated with paraffin and tulle dry out, they may adhere to the wound bed, leading to trauma and pain upon removal of the dressing. 27,29 Because of these problems, gauze traditionally has attempted to control these factors by the closeness of its weave and the addition of other moisturizing agents. Gauze can be described as having a fine or coarse cotton mesh, depending upon the thread count per inch. 30 Gauze with a thread count of 41-47, referred to as "fine mesh gauze," 31 has been empirically determined to prevent granulation ingrowth through the contact layer, thus enhancing epithelial growth beneath it. When coated with Vaseline™ (Vaseline™ Petrolatum Gauze), or petrolatum, it allows moisture vapor to escape preventing maceration but retains enough moisture to prevent drying. Contact layer • Low adherence 24 • Used with secondary dressing 24,26 • May adhere to wound bed when dry 29 • Permeable to bacteria 27 Semipermeable film • Permeable to gases 27 • Effects growth of anaerobic bacteria 24 • Facilitates autolytic debridement 24 • Impermeable to bacteria 27 • Can be used with secondary dressing • Maintains moist wound environment  33 ). This extremely tight weave allows no cellular penetration, but wound exudate quickly incorporates the layer and it becomes part of the more quickly forming, thinner scab when this dressing is used. Contact layer dressings are permeable to bacteria. 27 Figure 1 illustrates the usage of a contact layer dressing on a wound. Interprofessional cooperation on the front end and review afterward would help problems like the fact that the above information on contact layer dressings does not appear in any one published description.

| Semipermeable films
Semipermeable films ( Figure 2) are transparent films that are permeable to gases and impermeable to liquids and bacteria. 27 The transparency of the films permits visualization of the wound, without requiring removal of the dressing. 27 Semipermeable films allow enough oxygen to penetrate and affect growth of anaerobic bacteria, but not enough to support the underlying tissue growth. 24 The waterproof nature of the films trap the bodily fluids in the wound, supporting autolytic debridement. 24

| Hydrocolloids
Hydrocolloid wound dressings are usually composed of two layers: An outer semi-occlusive layer and a hydrocolloid layer. 27,34 The outer occlusive layer is usually a foam or film. The hydrocolloid layer consists of a crosslinked polymer matrix that, in the presence of exudate, absorbs fluid to form a gel. 27 This reaction results in a moist environment for the wound bed and stimulates autolytic debridement. 27 Evidence suggests that hydrocolloid wound dressings are more effective for complete wound healing of chronic wounds than saline or paraffin gauze. 35 Hydrocolloid dressings are usually opaque, which complicates wound inspection. 36 Upon contact with wound exudate, hydrocolloids form a thick, yellow malodorous gel that can be mistaken for infection upon removal of the dressing. 36 Though the gel both looks and smells unpleasant, it provides a cushioning effect and prevents the dressing from sticking to the wound, facilitating painless removal. 37 Patients should be educated that this is a normal effect believed to be due to the breakdown products of gelatin. 38 Clinicians should use other parameters such as warmth and erythema to assess for wound infection when using hydrocolloid wound dressings. 38 See Figure 3 for an illustration of a hydrocolloid dressing.

| Hydrogels
Hydrogel wound dressings consist of insoluble polymers in matrix with up to a 96% water content. 36 Hydrogels are available in a F I G U R E 1 Contact layers. Contact layer dressings provide a cover over of the wound that allows wound fluid such as blood and exudate to flow through to a secondary dressing multitude of physical forms: amorphous ( Figure 4), sheets, and impregnated within gauze, 36 nanoparticles, films, and coatings. 39 Hydrogel properties can be manipulated by a developer's choice of polymeric materials and the method of crosslinking. 40 They are also being explored as drug delivery systems. 39 For example, Yan et al 41 compared the effects treating deep partial thickness burns with a hydrogel containing recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) to a hydrogel without additives and found that the hydrogel containing GM-CSF had a faster healing time than hydrogel alone.
Researchers at Xi'an Jiaotong University have actively been engineering hydrogels capable of self-healing, hemostasis, antibacterial, and antioxidant capabilities. [42][43][44][45] Hydrogels maintain a moist environment in the wound bed and even provide a cooling effect when applied, which can act to soothe and reduce inflammation. 28,36 Hydrogels tend to have a low absorptive capacity due to its inherent high water content. 28 34 They have low adherence to the wound bed, which necessitates use of a secondary dressing such as film or foam. 36 Hydrogels have small pore sizes which can impede cell migration and the diffusion of proteins, waste products, nutrients, and oxygen. 38 Cryogels are able to overcome the limitations imposed by the nanoporous hydrogel.
Cryogels are a subtype of hydrogel that are formed at sub-zero temperatures, resulting in a macroporous structure. 38 Cryogels have been used in various applications, such as tissue engineering, cosmetics, cell transplantation, and immunotherapy. 38 Cryogels are able to be compressed at over 90% strain and regain their original configuration. 46 The macroporous nature and injectability of the cryogels make them excellent candidates for hemostatic application. 47-49

| Foam
Foam wound dressings ( Figure 5) are absorbent dressings that come in sheets and cavity filling chips. 50 Foam's ability to absorb large amounts of exudate is dependent upon the composition and vapor transmission rate of the foam. 51 Foam dressings provide protection from trauma and thermal insulation to the wound. 26  with these materials as dressings (e.g., Lyofoam). 52,53 It is recommended that highly absorbent foam dressings be avoided in patients with little to no exudate due to the risk of drying. 28

| Antimicrobial dressings
Antimicrobial agents can be added to wound dressings to prevent wound contamination. To prevent microbial wound invasion, wound dressings have incorporated substances, such as antibiotics, nanoparticles, and natural products. 54 Simões et al 54 excellently summarized recent investigations of antimicrobial wound dressings in a review. Table 3 provides a list of these antimicrobial agents and respective mechanisms of action that have been used in wound dressings.

| Wound dressings by injury
There is currently insufficient evidence to draw conclusions about the best use of specific wound dressings in treating burns. 55 The dressings that are typically used for Stage 1 and 2 pressure ulcers are polyurethane films, hydrocolloid wafers, and foam dressings. 56 For full thickness ulcers (Stage 3 and 4 pressure ulcers) that are highly exudative, absorptive dressings, such as those consisting of calcium alginate, and F I G U R E 4 Hydrogels. A transparent amorphous hydrogel filling a cavitary wound is illustrated above. Hydrogels provide moisture to a wound and deliver soothing relief with via a cooling sensation gauze packing are recommended. 56 Table 4 provides a quick reference for suitable wound dressings based upon wound types.

| Other wound management techniques
NPWT is a system that utilizes subatmospheric pressure to enhance wound healing. NPWT devices consist of a semipermeable film covering a wound filler, most commonly polyurethane foam though gauze and polyvinyl foam can also be used, which either directly contacts the wound bed or rests on top of a low adherent contact layer. 57,58 The dressing is connected to a drainage tube which is also connected to a device responsible for generating the negative pressure. 58 Figure 6 demonstrates an example of a NPWT system. NPWT pulls wound edges together, removes edematous fluid, stimulates fibroblast proliferation, and, with the use of a liner or contact layer, stimulates epithelial cell proliferation. 57 Some contraindications of NPWT include malignancy, osteomyelitis, and the presence of necrotic tissue. 59 Another wound management technique is shock wave therapy, which is hypothesized to utilize external deformations to the cytoskeleton via mechanotransduction. 60 Shock wave therapy involves the absorption of biphasic high energy acoustic waves by tissue through electrohydraulics. 60  Hyperbaric oxygen is being investigated as a treatment modality to promote wound healing. Hyperbaric oxygen therapy (HBOT) involves patients breathing 100% oxygen while being exposed to increased atmospheric pressure. 62

| Introduction to synthetic biomaterials
The biomaterials that are used to make wound dressings can be classified as either synthetic or natural. Synthetic biomaterials usually have good mechanical properties, thermal stability, and a shape that can be manipulated. 69 Synthetic biomaterials can be further classified into metals, polymers, ceramics, and composites. 70 Polymeric and composite materials will be considered below.

| Polyurethane
Polyurethane is a synthetic polymer consisting of repetitive urethane groups that is, used as a biomaterial in both semipermeable films and foam wound dressings. 71 It is synthesized through polymerization of diisocyanates and polyols. 72  Polyurethane is viewed as a desirable biomaterial for wound dressings due to its biocompatibility, strength, and lack of toxicity. 71

| Silicone
Silicone is a biomaterial used in foam dressings and low adherent contact wound dressings, such as Adaptic™ and Mepitel ® . 74 It is a polymer of repeating units of siloxane, which is composed of silicon, oxygen, and an alkane. 75 Most medical products that contain silicone utilize the organic polymer polydimethylsiloxane. 75 Silicone is nontoxic, biocompatible, and resistant to biodegradation in the short term. 70  were more effective than traditional methods, such as regular repositioning and skin care, at preventing pressure ulcers. 76

| Carboxymethylcellulose
Carboxymethylcellulose is a derivative of cellulose that contains a carboxymethyl group bound to the hydroxyl groups found in the backbone of the cellulose molecule. 70 It is synthesized in a two-step reaction that consists of the alkalization of cellulose, followed by carboxymethylation using chloroacetic acid. 77 Carboxymethylcellulose is a nontoxic, nonimmunogenic, and biocompatible polymer. 78 It is hydrophilic and rapidly undergoes gelation in an aqueous environment. 79 Examples of wound dressings that carboxymethylcellulose is used for include hydrocolloids, hydrogels, and hydrofibers. DuoDERM ® is a hydrocolloid wound dressings offered by the company ConvaTec Inc that contains a proprietary mix of carboxymethylcellulose, gelatin, and pectin.

| Poly (vinyl alcohol)
Poly (vinyl alcohol) is a synthetic polymer synthesized from vinyl acetate by controlled free radical polymerization. 80 Subsequently, the acetate group is removed from the resultant poly (vinyl acetate) via ester hydrolysis. 80 The degree of hydrolysis, tacticity, and average molecular weight of the poly (vinyl alcohol) determine its solubility, biodegradability, and mechanical strength. 81 Poly (vinyl alcohol) is biocompatible, easily prepared, odorless, and has a low permeability to oxygen and aroma. 81 Due to poly (vinyl alcohol) having poor stability in water, inadequate elasticity, and a rigid structure, 81 it is usually blended with synthetic polymers, such as polyvinylpyrrolidone, polyethylene glycol, poly (N-isopropylacrylamide), and montmorillonite, or natural polymers, such as chitosan, alginate, starch, dextran, glucan, gelatin, and hyaluronan. An example of such a dressing would be Hydrofera Blue ® , which is composed of polyurethane and poly (vinyl alcohol). 82

| Poly (ethylene glycol)
Poly (ethylene glycol), also referred to as poly(ethylene oxide) when the molecule weight exceeds 20,000 is a neutral polyether used in for a wide range of biomedical and biotechnical applications. 83 Poly (ethylene glycol) is a nonimmunogenic and biocompatible hydrophilic polymer. 84 Poly (ethylene glycol) is soluble in water and many organic solvents, but becomes insoluble in water when exposed to temperatures above 100 C. 83 Though poly (ethylene glycol) is bioinert in nature, it can be modified to incorporated bioactive moieties. 85,86 Poly (ethylene glycol) can be functionalized by either replacing the terminal hydroxyl groups with a functional group or by reacting the poly (ethylene glycol) with a molecule that has two functional groups, one of which will be replaced with poly (ethylene glycol). 87 Poly (ethylene glycol) modifies both the solubility and size of a molecule to which it is attached. 87

| Composites
Composite wound dressings consist of two or more distinct elements.
A biocomposite material consists of two or more matrices. 88

| Introduction to natural biomaterials
Biomaterials that are derived from animals, plants, and microbes are considered to be natural. 70 Natural biomaterials are typically biocompatible, biodegradable, and possess similar properties to the extracellular matrices found in connective tissues. 90 In addition, natural biomaterials are advantageous because of their ability to interact at the molecular level with tissues, thereby playing an active role in the wound healing process. 70

| Collagen
Collagen is the most abundant protein found in mammals, comprising a third of one's total protein content. 91 The collagen polypeptide is rich in proline, hydroxyproline, and glycine that displays a characteristic triple helix conformation. 92 The enzyme lysyl oxidase crosslinks the lysine and hydroxylysine residues, providing strength and stability to mature collagen fibrils. 92 Collagen affects all phases of wound healing; collagen acts as a matrix for blood clot formation thereby promoting hemostasis, scavenges reactive oxygen and reactive nitrogen species, acts as a sacrificial substrate for collagenases, and promotes migration of fibroblasts, macrophages, and epithelial cells into the wound area. 93 Collagen wound dressings are flexible, nontoxic, biodegradable, and have low immunogenicity. 93 Collagen wound dressings are absorbent and can decrease the pH of wound fluid, decreasing the likelihood of bacterial colonization as well as the activity of proteases. 93 Collagen wound dressings are recommended for full and partial thickness wounds with little-to-moderate exudate. 70 Collagen wound dressings are available in various forms, such as powder (e.g., Stimulen™) that dissolves in wound fluid to form a gel, matrices (e.g., Biostep™ by Smith & Nephew), and freeze dried composites (e.g., Promogran Prisma).

| Alginate
Alginate is derived from brown seaweed in the Phaeophyceae class. 94 It is composed of linear copolymers of (1,4)-linked β-Dmannuronate and α-L-guluronate blocks. 94 Alginate forms gels in the presence of acid and divalent and trivalent cations through an ionotropic mechanism. 95 In the case of sodium alginate gelation, sodium alginate exchanges its sodium cation that was bonded to guluronate with the divalent or trivalent cations, which link the polymers together. 94 The proportion of mannuronic and guluronic acid determines alginate's physical and chemical properties; a greater mannuronate content promotes gelation while a greater guluronate content promotes fiber integrity. 96 Alginates can be used to form many different types of wound dressings including hydrogels, semipermeable films, foams, and nanofibers. 95 According to a chapter in

| Chitin and chitosan
Chitin is the second most abundant natural polysaccharide, and consists of polymers of β (1, 4) linked N-acetylglucosamine units. 97 The main source of chitin used for commercial purposes are the shells of crustaceans, though it can also be found in the exoskeletons of other arthropods as well as in the cell walls of fungi and yeast. 98 Chitosan can be synthesized by partial deacetylation of chitin. 98 Chitin and chitosan are both biocompatible, biodegradable, nontoxic, and nonimmunogenic. 97 When chitin and chitosan are degraded by lysozymal activity they form N-acetyl-β-D-glucosamine which has been found to stimulate (a) fibroblast proliferation, (b) ordered collagen deposition, and (c) hyaluronic acid synthesis. 97 Both chitosan and chitin can be used as a biomaterial for various types of wound dressings, including hydrogels, sponges, films, and porous membranes. 99

| Pectin
Pectin is a heteropolysaccharide consisting of several different structural elements, such as homogalacturonan and rhamnogalacturonan, that can be found in the cell walls of dicotyledons. 91 Pectins that have greater than 50% methylation in the homogalacturonan region will gel in an acidic environment (pH <4.0) in the presence of a high concentration of sugar while pectins with a lower degree of methylation gel in the presence of divalent cations regardless of the presence of soluble solids. 91 Pectin is useful in biomedical applications due to its biocompatibility, biodegradability, low cost of production, and availability. 100 Pectin has been used as a biomaterial for hydrocolloids, 91 hydrogels, and films. 100 Two examples of wound dressings that contain pectin are ConvaTect Ltd.'s DuoDERM ® and GranuGEL ® . 101

| Hyaluronan
Hyaluronan (also known as hyaluronic acid) is a polysaccharide consisting of D-glucuronic acid and N-acetyl-D-glucosamine disaccharide. 102 Hyaluronan is highly absorbent; when hydrated, it forms stiff helices that can contain as much as 1,000-fold more water than polymer. 103 Hyaluronan is naturally found in the extracellular matrix, vitreous humor, cartilage, synovial fluid, epidermis, and dermis. 91 It is able to stimulate wound healing through multiple mechanisms. Hyaluronan modulates the inflammatory process, which may contribute to granulation tissue stabilization. 104 It is able to soften the fibrin clot, facilitating cell colonization. 104 In addition, hyaluronan modulates angiogenesis and stimulates fibroblasts. 104

| Gelatin
Gelatin is a protein derived from type I collagen present in bones and skin. 91 Gelatin contains an amino acid sequence similar to arginylglycylaspartic acid, which is known to promote cell adhesion and migration. 105 Gelatin forms a thermoreversible gel; it gels at lower temperatures and melts when the temperature increases. 106 145 The patent was recently issued by USPTO in June of 2019.
This patent cites many resources, including research publications primarily written by physicians.

| 3M
One of the patents cited was filed in 1981 for a polytetrafluoroethylene wound dressing coated with a silicone film, designed to prevent wound desiccation. 25 It was issued by the USPTO  [158][159][160][161] One of the patents was filed by an inventor with a background in engineering. 160 Two of the patents were filed by an inventor with a background in biochemistry. 158,159 The other patent was filed by an inventor with a background in farming and engineering. 161 Multiple publications were cited in each of the patents, which were authored by primarily by biochemists, physicians, and chemists. 162-169

| DISCUSSION
One question that should be explored is if early collaboration with different fields leads to a better wound dressing. A great example of this dynamic is seen with the product Tegaderm. It cannot be ignored that this product discovery was influenced by an engineer physically visiting a hospital and interacting with health care professionals that harbored a need. That engineer worked with a team of scientists to build a product that met those needs. Even though OpSite had been introduced around 6 years prior to Tegaderm's introduction to the US market, Tegaderm was able to surpass OpSite as a US market share leader in transparent films.
Another example of early collaboration leading to a better wound Early collaboration between those in different fields is also seen with the development of the Medihoney products. The backgrounds of the Medihoney product inventors were diverse, including fields, such as business, farming, biochemistry, and engineering. One of the inventors even collaborated with physicians on research involving using honey as a dressing for leg ulcers and included the resulting publication on the patent application. 166 Medihoney has since grown into the global leading medical honey-based product line.
Early collaboration between professionals in different disciplines has been shown to be advantageous for innovations in wound management technologies. One possible reason could be that representatives of separate disciplines can bring different perspectives that can be brought together to solve a problem. Another possible reason is that early input from medical professionals that will be using the technologies or have firsthand experience of the problem that the product is designed to solve can help shape the development in a way that

ACKNOWLEDGMENTS
Authors would like to sincerely thank the entire R3 lab for their support, feedback, and encouragement.

CONFLICT OF INTEREST
Ms. Hawthorne

DATA AVAILABILITY STATEMENT
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.