The Outline of a Lit Review

Hey readers!

Now that I have compiled about 15 sources about HemaDrop, it's time to start actually outlining my literature review -- it's all business. In case you forgot, I have been using the following subtopics to classify my sources: (1) Blood diagnostics, (2) Superhydrophilic films, (3) Blood Properties, (4) Substrates, (5) Analysis Techniques, and (6) Key Illnesses/Conditions.

Here's what I envision for my literature review:

Subtopic 1: Blood Diagnostics

I have to discuss blood diagnostics in general to introduce the general field of research I am investigating and describe its importance before talking about mechanisms behind blood analysis. Additionally, by explaining the current technology used for blood testing, I can highlight its evolution, needs, and limitations -- basically the gap.

• Premise 1: Blood testing is crucial for diagnosing illnesses, monitoring the conditions of patients, and providing healthcare to patients.
• Barthels, et al: Blood testing is the cornerstone of medicine, as it has allowed for diagnosing of many conditions based on markers in the blood.
• UK National Health Service Database of Illnesses and Blood Markers: E.g., conditions like diabetes, anemia, cancers, heart attacks, etc. all alter blood composition in a specific way, including increased glucose content, lack of Fe, presence of specific biomarkers, elevated troponin concentrations.
• Premise 2: Current blood tests require 7 mL of blood on average.
• Barthels, et al & Hamerling
• Examples include high-performance liquid chromatography (HPLC), spectroscopy of liquid vials of blood, testing conductivity of blood for hematocrit levels, etc.
• Premise 3: The current volume of blood required for testing (7 mL) causes patients discomfort, complications including hospital-acquired anemia (HAA), and can limit the number of tests possible for ill patients (thereby preventing diagnoses too).
• Bom, et al: Better testing procedures and advancements in diagnostics is necessary to stop HAA and unnecessary costs on the healthcare system.
• Thakkar, et al: Current blood diagnostic testing causes HAA, incurs unnecessary cost on the healthcare system, and reduces the quality of patient care. 
• Premise 1 + Premise 2 + Premise 3 --> Conclusion 1: A need exists for blood diagnostic technology that uses smaller volumes of blood to improve patient care, prevent HAA in critically ill patients, and reduce costs.
• Premise 4: Due to the importance of blood analysis, need for standardization, and ease of use needed for doctors and nurses, blood analysis techniques must: "use whole blood and a small sample volume, provide results in less than 1-15 min, maintain high accuracy (at least at current levels), have simple operation and inbuilt quality control, require minimal maintenance,  and use an IT interface."
• Barthels, et al: Point-of-care testing with glucose monitors and similar devices that can provide real-time and accurate monitoring of conditions are part of the next generation of medical devices.
• Premise 5: Previous attempts at blood analysis with smaller volumes (e.g., Theranos) have been unsuccessful.
• Kidd, et al: Theranos had errors of over 10%, the standard for biomedical testing
• Potentially could find more examples?
• Conclusion 1 + Premise 4 + Premise 5 --> Conclusion 2: If implemented, small volume blood analysis (microliter) must meet the aforementioned criteria.
• Premise 6: Both solid and liquid types of blood analysis exist, with liquid requiring little processing and potential lack of uniformity, but with solid allowing for vacuum-based analysis techniques and use of smaller volumes.
• Pershad, et al
• UK National Health Service Database of Illnesses and Blood Markers
• Conclusion 2 + Premise 6 --> Conclusion 3: Potentially a solid-based blood analysis technique, if it overcomes issues with processing time and uniformity, could use small volumes of blood for analysis with vacuum-based techniques.

Subtopic 2: Superhydrophilic Films

The mechanism behind the uniform, thin, solid film that HemaDrop creates is superhydrophilic films (or hyper-hydrophilic if you wish). The explanation of this technology follows naturally after the potential of solid-based blood diagnostics is introduced, since this property is what makes HemaDrop create a uniform film. 

• Premise 7: Superhydrophilic films are created by applying superhydrophilic coatings on surfaces to make them attract water.
• Wen, et al: Superhydrophilicity characterized by high contact angle and high CA hysteresis change by sliding angle -- SHFs can be created by high surface energy coatings and reducing surface roughness (relates to substrates) 
• Hosokawa, et al: "Extremely high receptivity to water adhesion" 

• Premise 8: Superhydrophilic films, because of the importance of polarity have a wide range of biomedical applications
• Hosokawa, et al
• Drelich, et al:
• "For example, surfaces of hydrophilic materials were roughened in the past to improve adhesion in composites, biocompatibility in implant devices, or simply to enhance spreading of liquid, even so these activities were not linked yet to superhydrophilicity" 
• Premise 9: The wettability/hydroaffinity of the surface on which a blood drop affects its uniformity and phase separation.
• Need more support for this -- maybe look at chromatography methods which use a polar mobile phase. (Note: I didn't think of this claim earlier, so good thing I'm outlining!)
• Subpremise 3.1: Since some elements of blood (e.g., the lipid cholesterol) are non-polar, phase separation will occur on hydrophilic samples between non-polar and polar elements.
• Premise 7 + Premise 8 + Premise 9 + Conclusion 3 --> Conclusion 4: The hydroaffinity of a surface can be manipulated to make it superhydrophilic before a small drop of blood is applied. The surface's properties (e.g., surface energy from hydrophilicity) will affect how the blood dries, potentially making the film uniform and analyzable (combatting a major problem with solid analysis of blood)
• Potential Gap -- Determining the optimal degree of wettability to minimize phase separation and heterogeneity, maximize analyzability

Subtopic 3: Blood Properties

Now that we have looked at the coating, we have to investigate the properties of what is actually drying on the surface. Specifically, properties of blood which prevent uniform drying and solid state analysis should be investigated, as they could affect accuracy of measurements or even prevent them.

• Premise 10: Blood contains cells of varying types (e.g., RBCs, WBCs, etc.) that all separate by hydroaffinity and density.
• Palta, et al.
• Can stay unrefrigerated for 24 hrs without separating.
• Premise 11: Blood coagulates in vitro very differently than in vivo, as it uses a cascade of proteins including thrombin, fibrinogen, and protein S, which are activated by Ca ions.
• Acharya, et al.
• Premise 12: Superhydrophilic films limit the aforementioned effects on the blood while preparing a HemaDrop sample.
• Hosokawa, et al & Pershad, et al.
• Premise 10 + Premise 11 + Premise 12 --> Conclusion 5: SHFs can control the natural tendencies of blood to coagulate and separate on surfaces.

Subtopic 4: Substrates

Substrates, although they end up being coated, are extremely important, as many analysis techniques (including Rutherford Backscattering Spectrometry) are affected by conductivity of the sample. Additionally, for commercialization, cost and ease of use are necessary considerations when preparing a sample for analysis. Thus, the, cost, conductivity, and other properties of the sample must be compared to determine the optimal sample type.

• Premise 13 (branching off Premise 7): The hydroaffinity of a surface is affected by the surface topography (roughness). not just the coating, so the substrate affects the degree of superhydrophilicity we are able to achieve.
• Wen, et al.
• Hosokawa, et al.
• Premise 14: Tests have been conducted on TiN/Si(100) and Si(100) surfaces using canine blood with and without the superhydrophilic coatings.
• Pershad, et al: Results published demonstrated a clear difference and affect of the SHF, but the substrates were expensive to use due to their lack of major topographical features (they were smooth)
• Premise 13 + Premise 14 --> Conclusion 6: A more cost-effective alternative, including microscope slides (e.g., borosilicate), should be investigated and the resulting hydroaffinity should be compared after treatment with SHF.
• Potential Gap -- The effectiveness of these more rough surfaces should be tested as an alternative to smoother wafers as tested in Pershad, et al.

Subtopic 5: Analysis Technniques

After looking at the sample preparation mechanisms, it is natural to look into how the samples should be analyzed. A comparison of the limitations, strengths, and properties of various microscopies and spectroscopies will be undertaken to determine which ones to investigate with HemaDrop during experimentation.

• Premise 15: Solid blood samples that are prepared uniformly on substrates can be analyzed in a vacuum, allowing for many applicable microscopies and spectroscopies.
• Mukhopadhay, et al: Describes the conditions necessary for analyzing samples in vacuum
• Premise 16: Atomic Force Microscopy, Scanning/Tunneling Microscopy, IR Fourier Transform Spectroscopy, Ruthterford Backscattering Spectrometry, Particle-Induced X-Ray Emission, X-Ray Photoelectron Spectroscopy, etc. are possible analysis techniques.
• Here's where I realize I need more sources to compare them -- I was having trouble finding good sources that have comparable information about all of them.
• Gap -- which techniques to consider? -- no conclusion yet.

Subtopic 6: Key Illnesses & Conditions

Finally, I want to investigate the specific markers in the blood of several illnesses and potentially simulate the disease in samples to determine whether the difference would be detected. To do this, I found a large database from the UK National Health Service. There are over 1000 illnesses, so to finish off I need to select which illnesses I want to specifically. I don't really have premises here, as I have just looked at diabetes, anemia, various types of cancer, and the monitoring of specific antibiotic concentrations as specific paths to test. I need to find studies who investigated diseases in a similar way that I am, perhaps after they found a new method of analysis.

My research question will then be something along these lines: "Can HemaDrop successfully create a uniform, solid, thin film and accurately analyze blood composition from microliters of blood?” Due to issues with IP, I can look into testing HemaDrop's viability rather than developing the product itself.

Well, I started writing and got very into it. So, there it is. Also, I apologize for no humor. I got too focused on content. Hopefully, I can start attacking the question parts I have outlined. I think if I can fill in those gaps, I'll have a solid understanding of what's going on in my field of study.

Cheers,

YP

(1, 598 -- RIP word limit)