Nanobubble Articles Summary

The following is a repository of important nanobubble studies and notes on the studies.

Summary of Important Nanobubble Studies

  • Nanobubble benefits:

Reducing Tumor Hypoxia via Oral Administration of Oxygen Nanobubbles

  • Discusses how tumor hypoxia has been decreased in mice as a result of oxygen therapy
    • Attributes this decrease to a decrease in the HIF1a protein as measured by PCR and Western Blotting
  • Interestingly, also measured the decrease in change in HIF1a protein and found that it was greatest among O2 gas when compared to argon gas or oxygenated water
    • This is advantageous because we plan to saturate water with nanobubbles, which theoretically offers a higher oxygen content capacity.
    • Also, these changes in particle count, HIF1a mRNA, partial pressure, and partial pressure over time were measured, all indicating O2 as the superior method.

Ultrasound beam steering of oxygen nanobubbles for enhanced bladder cancer therapy

  • Nanobubbles proved effective in treating bladder cancer tumors, enabling imaging and drug delivery when directed by an ultrasound beam
    • Precise targeting is possible: Nanobubble velocity can be controlled by altering the power of the ultrasound Doppler beam, while nanobubble direction can be adjusted to different desired angles by altering the angle of the beam.
  • Led to lower tumor progression rates and ability to use imaging via the nanobubbles. Thus, oxygen nanobubbles were found to be multimodal (imaging and oxygen delivery) and multifunctional (targeting and hypoxia programming) properties.

Nanobubbles: A Promising Efficient Tool for Therapeutic Delivery

  • Review of studies: concluded that nanobubbles are an effective tool for targeted drug delivery to tissues and blood vessels because of their stability, ability to circulate, and minimal invasiveness
  • The researchers propose the way to get nanobubbles to target specific is by designing nanobubble systems with specific ligands attached to their shell surface.

Influence of Nanobubble Concentration on Blood–Brain Barrier Opening Using Focused Ultrasound Under Real-Time Acoustic Feedback Control

  • Nanobubbles have the ability to penetrate the blood-brain barrier (BBB), a physiologic barrier that separates the central nervous system from circulating blood. BBB maintains brain homeostasis
  • Used acoustic imaging which found that nanobubbles were able to successfully move through the BBB
    • This has applications for drugs that want to deliver therapeutic value to the brain via the BBB, nanobubbles can help facilitate this

Nested Nanobubbles for Ultrasound-Triggered Drug Release

  • Nanobubbles useful for drug delivery
    • Can target specific locations and be specifically triggered by ultrasound waves by way of their permeability and retention
  • This would be specifically used, according to the authors, in chemotherapy treatment for cancer as these methods allow for controlled release
  • ANOTHER important application: Using lasers of light to trigger release of therapy in the body

Oxygen and Air Nanobubble Water Solution Promote the Growth of Plants, Fishes, and Mice

  • First study to demonstrate oxygen nanobubble’s ability to encourage growth in animals
  • Essentially, by facilitating O2 nanobubble treatment in plants, fish and mice, the researchers grew and added weight to the respective animals
  • No abnormalities reported when weight and size was increased (ie these were positive benefits shown)

Oxygen Ultra-Fine Bubbles Water Administration Prevents Bone Loss of Glucocorticoid-Induced Osteoporosis in Mice by Suppressing Osteoclast Differentiation

  • Nanobubbles led to a decrease in bone loss in mice– attributed to inhibiting osteoclastogenesis
    • Most likely due to oxygenation of tissue, since O2 is known to cause oxygen tension in bone metabolism
  • Bubbles were all < 200 nm in diameter (skin botches, visceral fat) (wound healing)

Oxygen’s Benefits: (peer reviewed article on specific places where O2 can benefit the body) (general article from NIH)

2019 Nobel Prize in Medicine

How cells sense and adapt to oxygen availability

  • Discussed HIF (a type of transcription factor regulating oxygen-dependent responses in cells) and HIF-1a (a subunit of HIF). Essentially, hydroxylation regulates HIF-1a.
  • Extrapolation: HIF, a transcription factor heavily involved in tumor growth and cancer, relies on oxygenation in cells. Nanobubble therapy, supported by several studies, emerges as a potentially effective treatment for cancer/tumors in the body.

Article 2:

-zeta potential, size, concentration??

On the Existence and Stability of Bulk Nanobubbles

  • How to increase efficacy of nanobubbles (Existence):
    • less salt (b/c it decreases zeta potential)
    • more anionic surfactants –>find one that’s skin friendly etc. (has to be drinkable in theory as well)
    • basic liquids increase efficacy because they make the nanobubbles more stable by way of zeta potential
  • diameter, zeta potential, charge all stay the same over a period of several months indicating that the efficacy does not decrease overtime (important in terms of shelf life instead of the pod)

The Optimized Fabrication of a Novel Nanobubble for Tumor Imaging

  • Discusses how to optimize nanobubble production for tumor imaging (also tests different gases)


Combination of phototherapy and nanobubbles has been extensively studied with positive results:

Taken out from article 2:

  • Several chemical reagents, including glucose, ethylenediaminetetraacetic acid, Na+, dimethyldioctadecylammonium bromide, Al3+, and Fe3+, have been studied (4). Chlorine is also considered (5).
  • Numerous studies investigate the effects of altering concentrations of these chemicals, revealing notable outcomes. Implementing such chemical reagents could pose challenges on our end; nevertheless, some, such as glucose and chlorine, could be more viable.
  • Another aspect to consider is employing additional ionic surfactants, which can produce relatively substantial outcomes. However, integrating them presents challenges, particularly in the context of nanobubble immersion.
  • Graphs:
The effects of SDS (Sodium Dodecyl Sulfate) on nanobubble Zeta Potential.
The effects of MIBC (Methyl Isobutyl Carbinol) on nanobubble Zeta Potential.
(2, methyl isobutyl methanol, MIBC, is a surfactant)

Despite nanobubbles being considered an emerging therapy, allowing oxygen to pass through the skin transdermally is a concept that has existed and been studied for years. Below we will explore two important peer-reviewed, scientific studies which explore these concepts in depth:

Topical oxygen therapy & micro/nanobubbles: a new modality for tissue oxygen delivery

  • This article explored and synthesized the findings of several studies looking into the wound healing results in hyperbaric oxygen therapy/topical oxygen therapy (TOT) and micro/nanobubble therapy (MNB).
  • The authors found that while both are effective in dealing with wound healing of the skin, MNB had several advantages over TOT and HBOT including
    • Ability to remain in an aqueous solution for long periods of time; 
    • Ability to serve as a reservoir/cavity for oxygen (aka can increase oxygen concentration of water w/o contributing to saturation point)
    • The charged surface of bubbles attracts debris from the surrounding environment
  • MNBs also offer the ability to be engineered. You can deliver drugs through them and deliver antibiotics to skin wounds specifically. For skin this means that MNB’s can
    • Increase wound oxygen tension
    • Provide debridement
    • Promote healing
  • MNBs also are more cost efficient, require less infrastructure, and do not possess some of the risks that TOT and HBOT have

Topical Dissolved Oxygen Penetrates Skin: Model and Method

  • This article looked into delivering oxygen through the skin versus delivering oxygen though (traditional) gaseous means in human skin samples
  • The authors of the study found that oxygen that was topically dissolved penetrated the skin faster and deeper than oxygen delivered via gas. They posit that the reasons behind this were because in order for gaseous oxygen to be transferred and used by the body, it must change phases, and usually the body resists elements crossing phase boundaries within it.
    • The transfer of oxygen in the body follows Graham’s Law of Diffusion, which states that gases can move independent of factors such as pressure. Importantly, however, it indicates that delivering a greater concentration of oxygen initially will lead to greater penetration through the tissues, which was confirmed in this study.
  • Dissolved oxygen surpasses gaseous oxygen, overcoming barriers that the latter encounters, indicating superior therapeutic value. Furthermore, the substantial depth of 700 micrometers that dissolved oxygen traversed was adequate for macro-scale effects.
  • Although the study utilized human skin samples, the authors express confidence in similar in vivo results, particularly within a clinical context for treating skin wounds and facilitating wound healing.
  • This study holds significance for our objectives by demonstrating the superiority of topical dissolved oxygen through micro-nanobubbles over alternative gaseous oxygen therapy methods, like hyperbaric oxygen therapy. It suggests that our model would likely outperform in a theoretical head-to-head clinical trial.

A dissolved oxygen dressing: a pilot study in an ischemic skin flap model

  • We assessed skin flap failure rates in four pigs following surgery, involving two groups of pigs (two each, totaling 16 samples). One group received dissolved oxygen to the skin, while the other served as a control.
  • In the group with skin flaps treated with dissolved oxygen, only 25% of the samples experienced skin flap failure, in contrast to the 75% in the untreated group. Additionally, histological parameters of the skin directly treated with dissolved oxygen showed improvement compared to the skin of untreated pigs.
  • This study is significant for our purposes because it demonstrates the effectiveness of dissolved oxygen on the skin. The direct application to the skin and the clear changes observed make the findings of this study positive.

Topically delivered dissolved oxygen reduces inflammation and positively influences structural proteins in healthy intact human skin

  • Administered topical dissolved oxygen to 50 healthy subjects through the skin with the goal of enhancing skin health and outward appearance. Localized the delivery to specific skin regions for comparison with non-treated areas.
  • Within 8 weeks (and at 0-4 weeks and 4-8 weeks), significant improvements occurred in skin hydration, desquamation, roughness, and texture. The p-values for these variables (refer to table 1 for more detail) after 8 weeks were all <0.001, with skin hydration having a notably low p-value of 0.010 and 0.025 for 0-4 and 4-8 weeks, respectively. The study also demonstrated a reduction in inflammatory response markers and transcription products (IL-6, IL-8, TNF-alpha, MMP-1, and MMP-12), alongside an increase in structural skin proteins (collagen I, elastin, and filaggrin).
  • The study uncovered no negative effects. It’s crucial to note that this study specifically targeted healthy, intact, and non-wounded skin in vivo.
  • This study supports our findings, highlighting the positive outcomes of direct therapeutic treatment using dissolved oxygen on the skin.

New insights into oxygen therapy for wound healing

  • This is a really good article about oxygen therapy in general. It discusses it in the realm of wound healing, however
  • Talks about the benefits of HBOT over topical oxygen therapy (cost, side effects, ease of use, etc.) and the benefit of oxygen in general (benefits, historical usage, etc.) all things we already know
  • The insightful thing about this article is that it shows the mechanisms by which oxygen enters the body when looking at oxygen bubbles.
    • “Methods that deliver topical dissolved oxygen include those which catalytically produce dissolved oxygen at the wound surface, those which contain diffusible dissolved oxygen bound to a carrier such as a fluorocarbon, or those which allow a reservoir of gaseous oxygen to diffuse through the vehicle.”
    • Essentially oxygen diffuses (goes through) the surface of the skin as a gas. It is the oxygen going into the body, not the bubbles themselves. Could not find any information on replenishing abilities
  • It also emphasizes that the advantages of dissolved oxygen is that it is immediately available for biological use in the body, without going through any sort of resistance.


  • There are even studies that show the positive and even synergistic effects of red light and nanobubbles.

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