Preliminary Study of Wound Oxygenation Comparing Skin Substitutes and Dressings

Wound healing remains a critically important evolving science, and numerous strategies have been employed to improve local wound healing with varying success. Optimizing oxygen delivery to the wound has shown promise, yet, interestingly, this objective has not been particularly well achieved in the development of topical wound dressings. Addressing inhibitory hypoxic conditions, particularly in the vascularly compromised wound, has gained ever more attention as it relates to tissue and vascular growth, epithelialization, and antimicrobial control.¹ Occlusive and impermeable dressings aid in the healing of clean, limited, and superficial wound types. Unfortunately, the resultant occlusive or low moisture vapor–transmissive environment also contributes to an accumulation of significant volumes of serosanguinous fluid and leakage.² Absorptive and semipermeable dressings are often favored to modulate moisture balance and control exudate but are often compromised by volume overload or occlusion, resulting in diminished efficacy, leakage, maceration, and impaired oxygen delivery to the wound with an increased potential for infection. 

Several therapeutic modalities, such as hyperbaric oxygen therapy and topical oxygen therapy, augment oxygen delivery to tissues and have been shown to aid in complex wound healing, especially in cases of hypovascularity and ischemia reperfusion.³ The challenge with these modalities, despite their promise and efficacy, remains cost, construct, and availability. A cost-effective membrane oxygenating material may prove particularly advantageous in the development of newer-generation wound dressings and biosynthetic dermal replacements, obviating several notable impediments to wound healing. 

Visual observational testing was performed to determine if liquid readily flowed through the materials of interest. A glass cylinder, 7.5 cm in diameter and 8.5 cm in height and containing 50 mL of water at 21°C ± 2°, was cover sealed by the materials of interest, and the vessel inverted. Observations were made of 2 membranes manufactured with holes or slits: a porcine collagen–bonded nylon and silicone dressing (CNS) (Mylan Pharmaceuticals), and a 3-dimensional silicone and nylon membrane coated with porcine gelatin and aloe vera (3D) (Stedical Scientific). These results were then contrasted with the 3D without slits and a polyurethane foam membrane (PFD) (PolyNovo). 

A subsequent set of visual observations evaluated whether carbon dioxide gas would penetrate the manufactured holes in porcine collagen–bonded nylon and silicone dressing membrane. To do so, 2 g of carbon dioxide was added to 50 mL of water and the container was immediately covered and sealed with Biobrane. 

A third set of experiments was performed at an independent laboratory (Expert Chemical Analysis) to quantify oxygen and carbon dioxide movement through the 3D, CNS, UBC (Integra LifeSciences), a polyurethane dressing (PD) (Smith+Nephew), and a PFD (PolyNovo). These experiments were performed in a closed system utilizing a 2000-mL stainless steel container fitted with a 0 to 30-psig pressure gauge and needle valve, which was pressurized to 15 psig with either carbon dioxide or oxygen. A gas sampling cassette equipped with a circular sample of each membrane measuring 37 mm in diameter and a cellulose backing for support was attached to the exit end of the 2000-mL stainless steel container. The exit end of the cassette was connected to another 1000-mL stainless steel container, which was also fitted with a 0 to 30-psig pressure gauge. At time 0 seconds, the outer valve on the 2000-mL container was opened and a stopwatch activated. The time it took for the gases to travel through the membrane from the 2000-mL container to the 1000-mL container was recorded and the pressure monitored. When the pressure on the 1000-mL container reached 10 psig, the stopwatch measured and recorded the time at which the pressure reached equilibrium in each cylinder, reflecting a zero-pressure gradient. Each membrane was treated identically for oxygen and carbon dioxide permeability, and the data were recorded. 

Finally, scanning electron microscopy was performed to quantify the thickness of the UBC, PF, and 3D dressings as well as the slit size of the 3D dressing. 

The material lots tested were as follows: 

·      Polyurethane foam dressing, 10 cm × 10 cm, Reference No. BTM-1010, Lot No. 200703L-6, Expiration 2023-07-03 

·      Polyurethane dressing, 12 cm × 12 cm, Reference No. 66000710, Lot No. 202140, Expiration 2026-10-01 

·      Unmeshed bovine collagen-glycosaminoglycan matrix dressing coated with medical grade silicone, 10 cm × 12.5 cm, Reference No. MDRT4051, Lot No. 4822650, Expiration 2022-06-30 

·      Porcine collagen–bonded nylon and silicone dressing, Lot No. 2645C, Expiration 9/2016 

·      3-dimensional silicone and nylon membrane coated with porcine gelatin and aloe vera, Lot No. 62110, Expiration 7/25/2017 

Observational studies confirmed the unimpeded flow of water through study materials manufactured with openings, whether holes, or slits. The quantitative results of oxygen and carbon dioxide movement through 3D, UBC, PD, and PF are shown in Table 1. 

Oxygen gas moved through the 3D dressing 5.63 times faster than through the UBC . Observations showed that oxygen and carbon dioxide moved faster through 3D (1.12 L/sec and 1.05 L/sec, respectively) than through either UBC (0.2 L/sec and 0.27 L/sec, respectively) or PF (0.56 L/sec and 0.56 L/sec, respectively). 

We evaluated commonly used and commercially available wound closure devices UBC, PF, and CNS dressing as well as a new solid membrane-oxygenating construct 3D for their ability to control fluid and gas movement. 

The rate of fluid movement through a synthetic membrane is related to several interrelated factors, such as pressure gradient and dimensional surface area, as well as available fenestrations and porosity.^4,5 Gases flow through a thin occlusive silicone or urethane membrane inversely proportional to the thickness of the membrane, and that rate is impacted by the inherent chemistry and composition of membrane. Silicone membranes, for example, enable gas movement at a much faster rate than those made of urethane. Solid membrane-oxygenating constructs, which can well serve as foundations to modern dressing development, allow gas (oxygen, carbon dioxide, and water vapor) to diffuse; this is driven by a concentration gradient, thereby providing oxygen to preferentially diffuse inward towards a hypoxic wound site while providing egress of carbon dioxide. In these passive designs, the flow of fluids and gases occurs via penetration or diffusion through established pores or holes. 

The effectiveness of a construct to function as a suitable membrane oxygenator depends upon both its synthetic as well as physical properties, and silicone is a particularly suitable synthetic material for both gas permeation into and diffusion across. As demonstrated in 2002 by Kawahito et al, the optimal silicone thickness of a membrane oxygenator is approximately 0.1 mm.⁶ The ability of the 3D to function well as a membrane oxygenator is therefore related to the thinness of its silicone layer (0.0076 mm). In oxygen-critical applications, such as coronary bypass, faster is better concerning rate of gas transfer through a membrane oxygenator. 

The movement of oxygen and carbon dioxide, as noted above, was much more rapid through the 3D. Both in its nonexpanded state and when stretched by 5%, the 3D was found to be 100% occlusive, yet the dressing uniquely allowed gas driven by a pressure gradient to move quickly through its thin solid silicone membrane. When stretched, as is done in clinical applications, the open slits facilitated fluid movement.⁷

It is interesting to note that the PFD, which has a porous polyurethane sealing membrane, transferred oxygen less efficiently than the 3D but was twice as efficient as the UBC dressing. This fact may be due to the foam structure of the PFD and the comparatively tighter architecture of the UBC dressing. Conceptually, this might also explain why many clinicians prefer to purchase already-meshed dressings or perform non-crush meshing of these sophisticated dressings themselves at the time of application to minimize fluid buildup, improve contouring of the dressing to the wound site, and augment antimicrobial transfer. 

Oxygen is vital for healing wounds.⁸ It is intricately involved in numerous biological processes, including cell proliferation, angiogenesis, and protein synthesis, all of which are required for the restoration of tissue integrity and organ function. Providing adequate wound tissue oxygenation has been shown to jump-start healing and favorably influence the outcomes of other treatment modalities. Chronic ischemic wounds often fail to heal appropriately due to hypoxia that leads to cellular demise.⁹ Wound tissue hypoxia is typically greater at the center of the wound; accordingly, the oxygen requirements of the regenerating tissue will vary. As oxygen levels decrease within the wound, cell response mechanisms like hypoxia-inducible factors (HIFs) trigger the transcription of genes that promote cell survival and angiogenesis.¹⁰ HIF stabilizers are in development and currently being evaluated to better understand their wound healing and augmented remodeling potentials. 

Providing optimal moisture balance at the wound site can prove particularly challenging in the ever-evolving states of wound healing. The requisite demands of balancing moisture vapor transmission while minimizing the potential for desiccation or maceration creates a great challenge for modern dressings, particularly because they must also manage wound exudate. Excessive exudate build-up impairs wound healing. Exudate constituents include pathogenic organisms, wound debris, and proteolytic enzymes, all of which promote excessive inflammation and damage the provisional extracellular matrix.^11-16 Through optimal management of the amount of fluid produced, the detrimental effects of the wound exudate can be minimized. 

Precedent studies have demonstrated cytologically friendly attributes of each of the modern biosynthetics cited. This science has added tremendously to our understanding of the biology of wound healing and has improved our ability to successfully manage and treat many devastating injuries and wound types. Economic realities of scale and our evolving appreciation of the practical challenges faced in treating complex and varied wound types mandate that we seek and incorporate realistic solutions to complex problems. The 3D dressing affords the user a unique set of characteristics that may well expand our ability to heal challenging wounds by facilitating oxygen delivery and gas exchange while allowing for tailored application to accommodate moisture balance. 

Observational studies, while quickly and easily describing the gross transit of fluid through materials of interest, are limited to qualitative interpretation. The independent and regulated laboratory data and the scanning electroscopic measurements, complement and objectify the data. Ultimately, in vivo clinical quantification of gas and fluid transfer at the wound proper, as well as the clinical efficacy of this evolving technology deserves further study and evaluation. 

The 3D functions in a fashion like that of a membrane oxygenator, potentially augmenting atmospheric oxygen delivery to help heal wounds.