External Microbial Cleansing Device (EMCD)

Annually, microbial pathogens and toxins in the bloodstream cause millions of deaths

worldwide, in the form of diseases such as sepsis and AIDS, or bacterial infections from

transplants. Current treatments only include broad antibiotic therapies and are ineffective

because of increasing antibiotic resistance and the lack of nuanced treatment. Therefore we

propose an external microbial cleansing device (EMCD) which functions with the aid of

magnetic nanobeads attached to artificially engineered human opsonin-mannose-binding lectins

(MBLs) that have the capability to capture a wide variety of pathogens in the bloodstream. The

EMCD will quickly and efficiently remove bacteria, fungi, viruses, and toxins in the blood and

enable therapy without the need to first identify the infectious agents. With the ability to deliver

enriching nutrients, monitor blood, and develop medical reports, this revolutionary technology

will drastically improve the outcome of numerous patients with pathogenic diseases.

External Microbial Cleansing Device (EMCD)

Present Technology

The current solution for pathogenic diseases such as sepsis is antibacterial medication.

However, in order for the antibiotic medications to work in a patient with sepsis, the pathogen

must be detected first to know the appropriate antibiotic to administer (Microbiology Online,

2015). Also, the antibacterial medication must be modified annually to combat the new strains of

bacteria that have developed resistance to old drugs. Modern medicine includes various

antibiotics that destroy cell walls, target metabolic pathways, and inhibit DNA replication and

protein synthesis (Mobley, 2006). However, due to the overuse of antibiotics, the amount of

antibacterial-resistant bacteria has significantly increased. This spread occurs when the bacteria

with acquired resistance to medications multiply and pass on the resistant genes to their offspring

(Microbiology Online, 2015). Occasionally, however, the growth of antibiotic resistance

outpaces the development of antibiotics, resulting in increased deaths from previously treatable

illnesses, and extended recovery (Mayo Clinic, 2014).

Furthermore, a current solution for human immunodeficiency virus (HIV) is Anti-

Retroviral Therapy (ART), which is a more effective treatment for HIV. Also known as

combination therapy, ART requires taking three or more drugs daily that prevent the HIV virus

from reproducing, but does not eliminate the virus from the body (National AIDS Manual, 2014).

Multiple drugs are needed simultaneously to treat HIV because the virus easily develops a

resistance to one or two drugs, but has a difficult time getting around three or more (AIDS

InfoNet, 2014). However, for some people, taking ART is still difficult due to side effects that

may arise. Over time ART has become less effective, so solely relying on it is dangerous. The

treatment could stop working in the long term, allowing the virus to proliferate (U.S. Department

of Veterans Affairs, 2014).

History

The first treatments of pathogenic induced diseases during ancient times included molds

and other plants by the Greeks and Indians, soil by the Russians, and other natural materials by

others (Explorable, 2010). From the 1640s to the 1930s, numerous scientists looked for a cure to

microbial diseases, but it was not until the 1940s when one was actually found (BBC, 1999).The

use of antibiotics was first introduced in the 20th century when Alexander Fleming discovered

penicillin in 1928 and discovered its full potential in 1940, resulting in widespread use, which is

still developing today (Davies and Davies, 2010). In many ways, antibiotics have revolutionized

medical care, offering a solution for treating numerous bacteria-induced diseases.

However, bacteria have quickly developed resistance towards antibiotics, creating the

need to constantly develop new medications to fight off the evolving pathogens (Davies and

Davies, 2010). Four years after Penicillin became mass produced, the first bacterium with

resistance was discovered (Science Daily, n.d.). This bacterium is known as Staphylococcus

aureus (Staph aureus) and remains one of the major resistant pathogens (Science Daily, n.d.). A

rise in antibiotic use has spurred increasing bacterial resistance, with current sepsis therapy

options actually exacerbating the problem (CDC, 2013). The World Health Organization’s 2014

report on global surveillance of antimicrobial resistance reveals that antibiotic resistance is

happening internationally and is endangering our ability to treat simple diseases (WHO, 2014).

Joseph Lister then found that antibiotics could be used to combat sepsis. Sepsis was first

identified by Hippocrates (ca. 460-370 BC) (NEJM, 2013). Louis Pasteur then identified

bacterial microbes as a cause of sepsis. However, with increasing rates of antibiotic resistance,

sepsis has once again become a problem (Wyss Institute, 2014). Since ancient times pathogenic

diseases such as the Black Death and the Plague killed numerous people around the world

(Wassenaar, 2013). In the United States, bacterial infections are leading causes of death in

children and the elderly (BBC, 1999). The first primary immunodeficiency disease discovered

was agammaglobulinemia in 1952 (Ochs and Hitzig, 2012). Now, there are a multitude of

immunodeficiency diseases including HIV/AIDS (Ochs and Hitzig, 2012).

Future Technology

he EMCD, inspired by the microarchitecture of the spleen and current dialysis technology,

functions as an advanced immune system for immunodeficient patients. While current

technology focuses on attacking the pathogens within the bloodstream, the EMCD completely

eliminates the pathogens with the assistance of magnetic nanoparticles and artificially engineered

opsonin-mannose-binding lectins (MBLs). MBLs are C-type lectins that bind to the

carbohydrates on a variety of pathogens including viruses, fungi, bacteria and protozoa

(Davidson College, 2006). However, they cannot bind to the carbohydrates on human cells as the

carbohydrate geometry of body cells does not permit multipoint attachment (Parham, 2005). In

the EMCD, many artificially engineered MBLs coat each magnetic nanobead. The nanoparticle

then serve as the basic pathogen-capturing device (Figure 1). The pathogens in the blood are

eventually filtered out through a magnetic force which draws out the magnetic nanobeads, and

therefore the pathogens as well. Because patients with immunodeficiency disorders are

extremely weak, nutrients and a nanobot will also be discharged into the bloodstream to monitor

the patient’s blood (Grant, n.d.). Through this technology, a patient in critical condition can

undergo a simple, easy process to remove the pathogens in the blood, as opposed to strenuous

surgery.

First, the patient’s blood will be channeled from the body into the first compartment of

the EMCD: the integration station. Here, thousands of magnetic nanobeads are periodically

released into the bloodstream, proportional to the amount of blood flowing through. Each

nanoparticle is coated with numerous artificially engineered MBLs, ensuring that no pathogen is

left behind (Parham, 2014). Naturally occurring MBLs are shown to bind to the carbohydrates on

hundreds of pathogens (Davidson College, 2006). The MBL, in its innate state, can activate

clogging and organ damage under conditions of a cytokine storm due to the MBL’s tail which

will bind to other immune system proteins (Wyss Institute, 2014). Therefore, for the EMCD,

these MBLs will be genetically engineered through cutting off their tails and grafting similar

ones from other antibody proteins onto the MBL bodies that do not pose the same problems.

Figure 1

Figure 2

These artificial MBLs will also now be small enough and capable of attaching to the magnetic

nanoparticles. The coated nanoparticles will therefore be able to bind to the harmful pathogens;

the binding process occurs in the channel to the filtration system.

The filtration system itself is modeled after the vascular structure of the spleen, which

utilizes a series of increasingly complex micro channels to filter out defective blood cells (Cesta,

2006). The filtration system consists of two fluidic channels, one with the flowing blood and one

with slow flowing saline, like the spleen’s venous sinusoids (SUNY Medical Center, 2008). The

channels are vertically stacked, connected by a series of rectangular slits as shown in Figure 3.

The saline channel is topped with a magnet that pulls the pathogens out of the blood stream and

ejects them, effectively cleansing the blood of the unknown pathogens. The ejected pathogens

can then be studied for identification so more comprehensive treatments can be carried out. In

most cases of septic shock, the causative agent is never identified which is still one of the

greatest problems sepsis patients face today (Laboratory Talk, 2014).

The last component of the EMCD is the reintegration. In this segment, the cleansed blood

returns back to the patient. However, because sepsis patients and patients with other

immunodeficiency disorders are extremely weak, the EMCD will also release nutrients into the

bloodstream to help the patient. Numerous studies conducted by Emory University, Guangxi

Medical University, and many others have found that Vitamin D is capable of lowering bacterial

infection rates (Chen et al., 2014). This occurs because Vitamin D fights bacterial infections by

Figure 3

producing proteins called cathelicidin and defensins (Grant, n.d.). Vitamin D is necessary for the

optimal functioning of the innate immune system. It produces antimicrobial peptides (AMP)

such as LL-37 and acts to modulate the pro-inflammatory endothelial response to

lipopolysaccharides (LPS). AMPs are peptides that stave off bacterial infection by increasing the

permeability of the bacterial membrane once inside a phagosome. However, this process is

Vitamin D-dependent, as vitamin D response elements (VDRE) induce genes for the AMPs. LPS

is a substance produced by gram-negative bacteria and stimulates the sepsis inflammatory

cascade. Vitamin D has important modulatory effects on the innate immune response to LPS-

induced sepsis. The cells in the body have vitamin D-dependent cellular responses to LPS,

therefore a supplement of Vitamin D can help the cells better suppress inflammatory responses to

sepsis (Kempker et al., 2012) .The EMCD utilizes this and injects Vitamin D into the blood flow

so that when the blood returns to the body, it carries Vitamin D in it, allowing the vitamin D to

enter the body and travel to the liver where it can be absorbed (Grant, n.d.). In this way, not only

will the EMCD be able to filter the blood and cleanse it of all pathogens, but will also help

strengthen a recovering patient and prevent further incidents.

When the last of the blood enters the reintegration component of the EMCD, a nanorobot

is inserted into the blood flow (shown in figure 4), allowing for it to flow into the bloodstream

along with the filtered blood. Once in the bloodstream, the nanorobot flows throughout the

circulatory system, flowing along with the rapid blood flow rate (ABC News, 2012). This

nanorobot contains a nanochip that will be able to determine whether or not there is another

influx of pathogens in the blood stream (Murray, 2014). If there is a sudden rise in pathogen

levels, the nanochip will be able to alert the doctor, and the EMCD or antibiotics (if the pathogen

is identified) can be used to stabilize the patient. The nanorobot itself proves vital to the

treatment of sepsis patients because diseases like sepsis frequently become lethal as they go

undetected (McKenna, 2013).

Through EMCD technology, millions of patients around the world will be able to survive

sepsis along with many other pathogenic diseases. Each year in the United States alone, more

than one million people are diagnosed with sepsis (Grant, n.d.). Around eight million people die

from sepsis globally each year, causing sepsis to be ranked as the leading cause of hospital

deaths (Wyss Institute, 2014). Sepsis patients are not the only ones who need the EMCD though;

people with weak immune systems also need this simple, fast process to help them filter the

pathogens out of their blood (Grant, n.d.). Patients undergoing organ transplants often have their

immune systems weakened for surgery (Pellegrino, 2013). However, immunosuppression can be

extremely dangerous. Fortunately, the EMCD eliminates all pathogens and therefore reduces the

eisk of infection (Pellegrino, 2013). Premature or low birth-weight infants with a weak immune

system are also susceptible to these pathogenic diseases and could also greatly benefit from the

EMCD (Grant, n.d.). Additionally, patients with viral diseases such as HIV or AIDS could

benefit from this as the EMCD filters and cleanses the blood so that the patient may survive

attacks even with a very weak immune system. MBLs have also been shown to bind to the HIV

Figure 4

virus itself, drastically reducing proliferation and progression to AIDS. The EMCD has an

extremely wide application, specifically though, to the countless unnecessary deaths from sepsis.

Breakthroughs

Although the EMCD will be feasible in the future, several technological breakthroughs

are needed before it can be fully realized. As of today, the dialysis process that the EMCD is

inspired by often takes up to four hours per session (National Kidney Foundation, 2014), which

is critical time for septic patients and others. This process would need to be expedited for optimal

results (Hall et al., 2011). Another vital part of the EMCD are the artificially engineered MBLs.

Genome modifying technology would also need to focus on deleting some of the triple helixes

that compose MBLs (Parham, 2005), while ensuring that the MBLs would still retain their

function.

The nanorobot that will be inserted into the bloodstream as the dialysis process comes to

an end will also need significant technological advancement. Although nanorobots exist today,

most are primitive, and cannot conduct effective scans for pathogen levels in the bloodstream in

vivo (Loscrí, Mannara, Aloi and Natalizio, n.d.). The nanorobots chosen for the EMCD must be

constructed with extreme precision, be able to constantly scan the patient’s blood for pathogen

levels, and alert the doctor when the situation becomes critical. In order to construct such robots,

microfiltration and blood scanning technology must be heavily advanced. Specifically, the

technology currently used in complete blood count tests (CBCs) must be shrunken (Figure 5)

(Moores, 2012). If the nanorobot observes an elevated amount of white blood cells, it will

contact extra help, as increased white blood cells are a sign of infection. However, that is not the

only route. The nanorobot could also contain an advanced 3D scanner that images and then

records the amount of white blood cells per liter of blood. This scanner could be based off of

current MRI technology, and then minimized. This type of nanorobot would not simply take one

image, but would detect the amount of white “spots” on its images, counting and always

recording the white blood cell count (Murray, 2014).

Design Process

In opposition to the EMCD, there were several preliminary ideas that were systematically

ruled out for practical and scientific reasons. The first idea that was proposed was a device that

would attach to one specific spot on a vein and filter the blood as the blood flowed through that

vein. However, this proposal was eliminated as the device would not be able to find the place at

which it needed to be. Although sepsis, like many other pathogenic diseases, begins in one area,

by the time the disease is discovered, the problem has already spread throughout the entire body

(NIGMS, 2014). The EMCD however, is an extracorporeal device and therefore needs no

specific position inside the body. Also, the EMCD is able to filter through all of the blood so that

all of the pathogens and toxins spread throughout the patient’s body can be extracted.

The next idea was a gel composed of positively and negatively charged magnetic

nanobeads that would be injected into the blood stream and flow throughout the circulatory

system, cleansing the blood and therefore ridding the problem of needing to find its position in

the body. However, this idea posed its own problems. There was no method to extract the

Figure 5

pathogens bound to the magnetic nanobeads or for the gel of collected magnetic nanobeads and

pathogens to travel around the entire circulatory system to filter through all the blood. In contrast,

the EMCD has a perfect solution to this problem as the architecture of the device is designed in a

way in which the magnetic nanobeads bound to the pathogens will be pulled out of the

bloodstream and into the saline channel and ejected out. Because the EMCD is composed of two

fluidic channels running parallel to each other, the nanobeads along with the pathogens may be

extracted from the bloodstream, fully cleansing the blood of toxins and a variety of pathogens.

Another preliminary idea was an artificial spleen to be inserted into the body. However,

the problem that it was near impossible to place the artificial spleen inside the patient’s body

arose. A patient diagnosed with sepsis would be far too weak to handle organ transplant surgery

(U.S. National Library of Medicine, 2014). The EMCD however, needs no surgery for it to cure

the patient of sepsis or of any other critical pathogenic diseases. The EMCD is external and only

requires that the patient be hooked up to it for the patient’s blood to be filtered.

Consequences

An estimated 1.5 million people are affected with HIV/AIDs (WHO, 2015) per year.

Sepsis kills at least eight million people worldwide annually and is the leading cause of hospital

deaths, as at least 30% of infected patients in the ICU die (Wyss Institute, 2014). Sepsis is a

bacterial infection that the EMCD can cure. The magnetic nanobeads will be able to filter out the

harmful microbes in the sepsis patient’s blood, thus curing the patient of infection. In addition to

killing millions, sepsis reigns as the single most expensive condition in U.S. hospitals, as $20

billion annually are invested in treating the 1.6 million U.S patients diagnosed with the condition

(Holland, 2013). The EMCD saves the patient from copious medicine costs and prolonged

hospitalization (NIGMS, 2014). Also, the ability of the EMCD to filter out foreign pathogens

will apply to many viral infections that weaken the immune system, such as Ebola and Malaria.

Furthermore, the use of the EMCD will slow down antibiotic resistance of pathogens in

the body. This method does not use any antibiotics, which prevents resistance by eliminating the

possibility of antibiotic overuse (Palumbi, 2001). People born with immunodeficiency and

people who are at risk for pathogenic diseases will also benefit from the EMCD. By visiting their

local hospitals, these people can have their blood filtered for harmful pathogens that may outstrip

their immune systems. This decreases their susceptibility to diseases. Additionally, after an organ

transplant, the patient is given an immunosuppressant, which blocks the effects of the body’s

natural defenses, to prevent the body from rejecting the transplanted organ. However, this leaves

the patient vulnerable to many diseases and infections that could occur during this period

(WebMD, 2014). An EMCD filtration would clean any unwelcome pathogens from the blood

and allow patients who have gone through an organ transplant to live without any infections or

pathogen-induced complications. Human immunodeficiency virus (HIV) is a virus that can be

cleansed out of the blood by the magnetic nanoparticles in the EMCD. This prevents the virus

from attacking and destroying the T-cells in the immune system, which also helps to prevent

Acquired Immunodeficiency Syndrome (AIDS), which usually results in death (Holland, 2013).

However, this technology does still have its drawbacks. In order to get their blood filtered,

patients must go to a hospital and wait while their blood is cleansed. Genetically engineering the

MBLs could be costly as well, given the precise, advanced technology needed to split an MBL

and graft at such a microscopic level. It will require specialized scientists and machinery to

produce this technology. Although there are some negative consequences, the positives far

outweigh.

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