Carbon Dioxide Therapy For Tissue Injury

Carbon Dioxide Therapy For Ttissue Injury

Richard Rivers, M.D., Ph.D
Microvascular Physiologist
Johns Hopkins University
Associate Professor
Baltimore, Maryland

This paper discusses carbon dioxide physiology in the body and how it can be a trigger for the development of new blood vessels, and increases tissue oxygenation. It also discusses how carbon dioxide can diffuse through the skin and reach diseased tissue that may be far away from the skin. 

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There is a new device on the market that will allow treatment with carbon dioxide. This device blends carbon dioxide with water to make a highly concentrated environment that will offer carbon dioxide therapy to affected tissues, through the skin. How does carbon dioxide help with healing and how can it be delivered through the skin?

Carbon dioxide is produced by all living animals as a by-product of cellular metabolism. Highly metabolic, aerobically active, tissues produce high amounts of carbon dioxide. There is a direct correlation between the amount of aerobic activity and the production of carbon dioxide. Continuous metabolic activity also requires the continuous delivery of oxygen from the blood. The amount of blood flow to the tissues is precisely regulated according to the metabolic demand. A persistently high ratio of carbon dioxide to oxygen is an indication that the blood being supplied is not balanced with the tissue needs. If the biological signals that identify the need for blood persist for a prolonged period, it triggers the cascade for the formation of new blood vessels and the surrounding tissue to supports it.

As a specific example, stimulating metabolic aerobic activity in skeletal muscle causes new blood vessel formation. In separate experiments, carbon dioxide increases in the muscle clearly demonstrate  increases in the biological factors that trigger  new muscle cell and new blood vessel formation. Thus, it would be consistent with the data to claim that carbon dioxide released by metabolic activity is critical for the generation of new blood vessels and new tissue that is so necessary for the healing process.

It is important to note that the mechanisms that build more blood vessels due to meet metabolic demand is different from the mechanisms that control blood vessel formation during ischemia (low oxygen) when there is anaerobic metabolic activity and lactic acid formation. During ischemia the anaerobic mechanisms generating new blood vessels compete with the mechanisms linked to cell death and apoptosis. This leads to fibrosis and scar formation. In sharp contrast, the creation of new blood vessels due to aerobic metabolic activity (carbon dioxide formation) stimulates new native tissue. 

Carbon dioxide is more than just a biological trigger for new blood vessel formation. It will also increase the oxygen concentration in the tissue and cause a direct increase in blood flow by dilating small blood vessels. As carbon dioxide is released from metabolically active tissue it enters the blood stream and is absorbed by the red blood cells.  In the red cells it partially converted into carbonic acid. Both carbon dioxide and carbonic acid bind to the hemoglobin to cause the release of oxygen from the hemoglobin. The release of oxygen due to carbon dioxide is known as the Bohr effect.

The Bohr effect was first described early last century. The effects of carbon dioxide on hemoglobin binding of oxygen has been studied in many animals and has been shown to be more sensitive in smaller animals. However, horse hemoglobin has a more sensitive Bohr effect than human hemoglobin.  

Studies also show carbon dioxide can stimulate endothelial cells to release nitric oxide. Nitric oxide relaxes vascular smooth muscle to dilate blood vessels and increase tissue blood flow. So increases in the concentration of carbon dioxide will also increase tissue blood flow directly.

Thus, there are three critical properties of carbon dioxide in the tissue. They are 1) the formation of new tissue and blood vessels, 2) increasing oxygen levels in the tissue because of enhanced release from hemoglobin, and 3) the increases in tissue blood flow. All three of these properties are important for healing tissue that has been damaged by trauma, disuse, or disease.  

How is it possible to increase tissue carbon dioxide and generate all these positive effects that help healing tissues? This device will make it possible to transfer carbon dioxide to the tissue through diffusion. Carbon dioxide as a gas is in the air in small amounts, it is soluble in liquid (i.e. soda), and it is a solid at very cold temperatures (dry ice). Carbon dioxide is a very small molecule that can diffuse rapid along its concentration gradient. It can pass through skin, fat, and tissues to reach the microcirculation where is it can have its therapeutic effects. 

The solubility of carbon dioxide in water is very high. Carbon dioxide is 30x more soluble than oxygen. By virtue of its dipole moments, in contrast to oxygen, it can bind and be stabilized by water molecules. In fat and muscle the solubility is even higher.  

This is the carbon dioxide solubility in water. Gm/100gm H2O by Temp (Celsius)


Solubility in muscle is even higher and depends on the amount of fat. A ballpark value is 600ml of CO2 per kg of muscle (4degrees C). There is sufficient solubility in muscle to cause collapse of the headspace in sealed containers holding limited amounts of gaseous CO2. The solubility of muscle makes it a sink for diffusion across the skin. The driving force for diffusion across the skin will not be inhibited by accumulation in the tissue during the proposed treatments times for tissue therapy.

In summary, there is clear biological evidence that carbon dioxide will diffuse across the skin according to the concentration gradient. Once it reaches the tissue, and eventually the microcirculation, carbon dioxide has important direct effects on blood vessel dilation, blood vessel formation, and blood cell release of oxygen to heal damaged tissue.

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© 2018 Respiderm Corporation



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