ProTech

10/30/2016
W. Cully Hession
Professor of Biological Systems Engineering
200 Seitz Hall
Blacksburg, VA 24060

Dear Dr. Hession,

Enclosed is the requested technology review for the following Biological Systems Engineering
Senior Design project Design of Bioreactor to Produce Drug-Loaded PLGA to Combat Breast
Cancer. This technology review contains information regarding the current state of knowledge
revolving bioreactors involved in protein purification, PLGA usage in cancer therapeutics, and drug
loading nanoparticles. In addition, it presents an overview of a range of possible solutions to the
design problem, related engineering standards applicable to the problem, and an appendix complete
with brainstorming results, challenges encountered, a project timeline, and outlined responsibilities
for each team member.

Please contact us with any questions, comments or concerns. We look forward to

working with you!

Kind Regards,

Sara Peterson, Sarah Chaikind, Emily Gee, Stephanie Lundgren

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Design of Bioreactor to Produce Drug-Loaded PLGA to Combat
Breast Cancer

Technology Review, BSE 4125 Senior Design

October 30, 2016

Team Name: ProTech

Team Members: Sara Peterson, Sarah Chaikind, Stephanie Lundgren, Emily Gee

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1. Introduction and Scope of Project
Our project is centered around the design and further development of a nanoparticle
compatible bioreactor for use in cancer therapeutics.
The most common cancer worldwide has been cited as breast cancer for females with
approximately 246,660 estimated new cases for 2016 (What is Breast Cancer, 2016). Breast
cancer refers to an uncontrolled growth of breast cells and the growth of a malignant tumor in the
breast. One of the reasons it can be such a dangerous disease is due to its likelihood to spread to
lymph nodes which pass information throughout the rest of the body (Breast Cancer, 2016).
Traditionally, the treatment for breast cancer is based upon the stage at which the cancer is when
it is found. If the cancer has not metastasized to other parts of the body, local treatments can be
used, such as radiation therapy or surgery to remove the tumor. However, if the cancer has
spread, a systemic approach must be taken, which can oftentimes be chemotherapy (Krucik,
2014). Chemotherapy is the use of drugs that are intended to specifically target cancer cells, but
often affect healthy cells causing significantly negative side effects (Danhier, 2016). With our
design, we hope to eradicate these side effects by proposing an alternative solution: utilizing our
bioreactor design to produce drug-loaded nanoparticles that can specifically target only cancer
cells, leaving healthy cells entirely alone.
Because it is our goal to design a bioreactor to create these drug-loaded nanoparticles, we
will first discuss the bioreactor itself. A bioreactor can be defined as any vessel in which
biological conversion occurs (Williams, 2002). This conversion can be anything from enzymes,
microorganisms, human cell lines, to plant and animal cells (Williams, 2002). Bioreactor
designs vary greatly based on industrial or research setting and intended purpose in each setting.
However, there are several governing principles of bioreactor designs, such as size of target
market, required kinetic fluid flow conditions, and type of biological materials used (Williams,
2002). In our specific case we are looking to apply these principles to breast cancer cells for
large scale production.
Next we discuss nanoparticles and their role in the therapeutic process. The nanoparticle
we have chosen to focus on is Poly(lactic-coglycolic acid), or PLGA because it is one of the
most successfully used biodegradable polymers. It is often utilized in many biomedical
applications because of its breakdown into lactic and glycolic acid, both natural byproducts of
the body (Gutierrez, 2011). These nanoparticles can be modified to overcome biological barriers,

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which oftentimes are some of the most significant challenges of nanoparticle-based drug
delivery. For example, the reticulo-endothelial system recognizes hydrophobic particles and
eliminates them from the bloodstream, but surface modifications such a the addition of a
hydrophilic layer, can be added to PLGA to enable it to pass through the RES. Surface
modifications are just one example of how these nanoparticles can be used to selectively target
specific organs, tissues, or cells.
The ultimate goal of the design project is to create a bioreactor that will produce
drug-loaded nanoparticles that can be modified to specifically target breast cancer cells. These
nanoparticles would only attack the cancer cells, leaving the healthy cells alone, and thus
reducing and hopefully altogether eliminating the negative side effects that patients experience
from chemotherapy.
The project has included semi-monthly meetings with Dr. Zhang and weekly meetings as
a group to discuss progress and compare ideas. We have adopted a rotational leadership
approach to allow each group member to capitalize on her strengths and experience the team
from the perspectives of both a leader and a supporter. In regards to the research portion of our
project, we have divided the information evenly and equally to ensure all team members are
contributing ideas and proposing solutions.

2. Review of Current State of Technology and Possible Design Solutions

A. Review of Literature Related to Design
In order to confirm our design solution, we must first comprehensively consider
multiple bioreactor possibilities, including more traditional batch or continuous stir
reactors, microfluidic based reactors, and even the use of transgenic animals as
bioreactors. We will review current literature that presents each of these options to
determine advantages and disadvantages of each.

Traditional batch bioreactor

Nanoparticles may be produced in a batch bioreactor by first charging the
reactants into the bioreactor, insuring the materials are well-mixed, and then leaving them
to react for a period of time (Montgomery, 2004). Product properties such as particle size,
morphology and agglomeration can be controlled by parameters including reactant

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concentration in the feed and reaction temperature (Montgomery, 2004). For the most
part, small scale batch reactors are mostly used in lab settings to test the effectiveness of
new processes, work with expensive materials not ready for scale up, or for processes
difficult to convert to continuous applications (Montgomery, 2004). Some downsides to
batch processes are limited control on the size range of particles and high labor costs
associated with production (Montgomery, 2004). The use of a semi-batch may allow
some of these obstacles to be avoided. In a semi-batch reactor instead of all reactants
being charged into the reactor at once, one reactant is fed into the reactor containing the
other reactant, allowing for better control over the reaction temperature and reaction
speed and therefore better control over particle size and shape (Montgomery, 2004).

Microfluidics
Microfluidics is an emerging technology for targeted drug delivery of
nanoparticles with a large focus on cancer therapeutics (Gu, 2007). Microfluidics is
defined as manipulating very small volumes in microscale fluidic channels (Gu, 2007).
Research has shown that a single microfluidic device has the potential to complete
multiple time-consuming steps, including sample preparation, purification, mixing,
reactions, separations, and detection, making microfluidic devices a feasible form of
bioreactors (Manz). Microfluidic devices excel at dissolving nanoparticles precursors,
such as drugs and polymers (Gu, 2007). This is extremely important when creating
nanoparticles with drug loading capabilities because the rate of mixing and concentration
of precursors critically affect the size and drug loading capabilities of the synthesized
nanoparticles (Good Lab Practice, 2016). Microfluidic devices excel in creating
conditions that allow for the ideal manipulation of small volumes in millisecond and
microsecond timescales (Gu, 2007).

Transgenic Animals
Although the idea for utilizing a transgenic animal as a bioreactor for the creation
of protein-based drug was proposed many years ago, it hadnt been put into action until
21st century when significant advances were made in the use of a transgenic chicken. A
unique option for our bioreactor would be to utilize an egg-laying chicken in that these

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eggs will contain drug-loaded proteins that might have advantages for specific target
drugs including appropriate glycosylation for human patient application, lower cost than
cell culture and transgenic mammalian systems, and faster scale up (Montgomery, 2004).
Egg-laying hens typically produce eggs on a 20-24 hour cycle with albumen
protein being the main constituent of dried egg white and a complex mixture making up
the egg yolk. Albumens simple biochemistry facilitates simple purification of
recombinant proteins. By using the regulatory sequences of egg white genetics,
transgenic expression of therapeutic proteins can be achieved by targeting two specific
protein genes, ovalbumin and lysozyme. (Montgomery, 2004). The egg yolk proteins
accumulate via a receptor-mediated process (Montgomery, 2004). Therefore, synthesis
of recombinant antibodies in transgenic hens and recovery from yolk could be exploited
specifically for therapeutic antibody production, (Morrison, 2002) as long as they are
designed to be sequestered in the yolk using an internal recognition sequence.

High Gravity Reactive Precipitation Technology

High Gravity Reactive Precipitation (HGRP) is a process that utilizes a rotating
packed bed (RPB) to create drug nanoparticles. Altering the temperature, rotating speed,
overall flow rate and drug concentration can be utilized to control the particle size and
shape (Zhang, 2016). This allows for much more control over the particle size than many
other technologies, making it a feasible process for the production of breast cancer drug
nanoparticles.The rotating packed bed relies on a large centrifugal force to intensify the
mass transfer and micro-mixing of the drug particles. When the particles travel through
the packing, they are split into nanoparticles (Chen, 2003). This is a multistep process
that includes the packed rotator (2), the motor (3), liquid distributors (4), two pumps (8)
and two tanks (9,10) shown in figure 1.

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Figure 1. Schematic of High Gravity Reactive Precipitation process. (Zhang, 2016)

Due to the multiple parts required to use this technology, this process is relatively more
expensive on a small scale, but becomes more profitable due to productivity when
scaled-up (Chen, 2003).
B. Review of Possible Solutions for Problem
Traditional batch bioreactor
Batch reactors are considered the most commonly used system in the wet
production of nanoparticles; however, batch reactors have longer nucleation times, lesser
mixing capability, and will produce particles with higher surface area-to-volume ratios
than their micro-scale counterparts (Kim, 2002). Batch reactors are difficult to scale up
due to the inherent lack of uniformity of the component distribution inside (Kim, 2002).
Also the poor product control found in bioreactors makes post-production steps necessary
to create a pure product (Kim, 2002). One area where batch reactors excel is their cost
efficiency. Micro-reactors are often expensive and the transition from a large-scale
process to a micro-scale is commonly not straight-forward making extra labor necessary,
whereas batch reactors are generally inexpensive and easy to operate (Kim, 2002). As far
as applicability with our chosen nanoparticle PLGA, we are still unsure as to whether or
not batch reactors will be capable to produce PLGA nanoparticles, but we are hopeful
that a batch reactor may be able to be modified to handle the specificity needed to
produce these particles.

Microfluidics

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 Microfluidic devices come in multiple forms, made of different types of materials.
They are currently being used in research laboratories to study a variety of cancer
therapies, anywhere from brain to breast cancers (Gu, 2007). One example of a potential
microfluidic device that could be applicable to our design problem is the one shown
below in figure 2. This particular microfluidic device could be adapted to our project by
seeding breast cancer cells within the holes of the microfluidic device. Perfusion inlet and
perfusion outlet can be used to create appropriate flow through the microfluidic device to
mimic the breast tumor microenvironment. Furthermore the top two concentration
gradient generator valves at the top can be used to manage input of PLGA nanoparticles
loaded with treatment, allowing for controlled release in terms of time and concentration.
This solution could provide high accuracy nanoparticles in well managed conditions.
Thus, in typical laboratory settings the small scale design maximizes drug efficacy,
making microfluidics a useful research tool. However, in considering scale-up
possibilities, microfluidic devices do not have the ability to serve as an option for
producing large amounts of therapeutic drugs. The lack of scale-up possibility is a major
downfall of this design as a potential solution given our focus on scaling up. It is
important to keep in mind this example microfluidic design is one of many potential
microfluidic solutions that apply to our design problem.

Figure 2. Microfluidic device for generating concentration gradients. Potential to be used

for drug loaded nanoparticle production with desired drug loading capacity (Gu, 2007).

Transgenic Animal
The use of a transgenic animal, specifically a chicken, could be applied to our
design project through the exploitation of the dried egg. As stated above, proteins can be

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extracted by utilizing the regulatory sequence of the dried egg white or by manipulating
the more complex lipid makeup of the egg yolk. The known advantages that would
greatly aid in our design project include significant scale up possibilities (Kim, 2002), in
that one hen could produce up to 30g of protein yearly, large scale production of
posttranslationally modified and complex proteins and a lower production cost when
compared against traditional large-scale bioreactors (Morrison, 2002). Conversely, the
downfalls include lack of definite costs to developing a transgenic production flock for a
specific therapeutic protein (Montgomery, 2004), lack of specific regulations on living
conditions for the transgenic flock (Montgomery, 2004), and the technical difficulty of
modifying chicken embryos as they develop (Sang, 1994). One of the most important
factors to keep in mind is that the transgenic animals compatibility with PLGA is widely
unknown because the studies examined demonstrated the ability to alter genetic code in
order to produce recombinant proteins and thus therapeutic antibodies. Therefore, we
might have to modify our design statement if we were to proceed with this option. The
usage of transgenic animals to create vaccines is currently utilized (Houdebine, 2009),
and thus if we were to proceed with a vaccine method of drug injection, drugs to combat
breast cancer could be created from the dried egg protein extraction method.

High Gravity Reactive Precipitation Technology Justification

There are many major advantages and disadvantages to HGRP technology. While
the start-up costs and ongoing costs are slightly higher due to the larger number of unit
operations, the high level of productivity and the quality of the nanoparticles make up for
this. The only source of environmental impact is the high level of consumption of energy
during the process. This technology works well on a small scale, but has also proven to
be easy to scale up (Chen, 2003). The one major downside to HGRP is that there has
been no research done on the use of this technology in combination with the production
of PLGA, an important factor in our design.

C. Review of Design Standards

In order to successfully complete our design several design standards must be
used as guidelines.

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 The first is good laboratory practices (GLP). GLPs are determined and
maintained by the Federal Drug Administrations (FDA) office of regulatory affairs.
GLPs outline principles that should be followed to ensure high quality and reliable test
data is acquired (Good Lab Practice, 2016). This also relates to the safety of industrial
chemical substances and preparations. GLPs are incredibly important in the preparation
of therapeutic drugs and in the completion of clinical studies to maintain the integrity and
safety of the drug throughout the entire development and testing process.
Additionally FDA Title 21 is important to our design process and solution. The
Code of Federal Regulations (CFR) is a code of rules published and updated by the FDA
executive departments. Title 21 is specific to food and drugs regulations within the
United States (Code of Federal Regulations, 2016). Within title 21 the 600 series covers
biological products such as vaccines and blood and the 800 series covers medical devices
(Management of Regulated Medical Waste, 2016). Both series detail regulations in the
development and marketing processes of the respective end product (Management of
Regulated Medical Waste, 2016).
The treatment and disposal of medical wastes as well as the management of
pharmaceutical hazardous waste set forth by the state of Virginia must also be
considered. The Virginia Department of Environmental Quality (DEQ) maintains laws
and regulations for the proper disposal of medical and contaminated waste, which our
design has the potential to create (Management of Regulated Medical Waste, 2016).
Finally, a standard operating procedure (SOP) must be developed and
documented to ensure safe use of the final design of our bioreactor on a large scale.

3. Summary and Conclusions

From this technical review, we learned the importance of comparative research,
the benefits of proposing a variety of diverse solutions, and how to appropriately and
effectively define an engineering problem and analyze a solution.
When completing our research on various bioreactor design, it was important to
remain unbiased and present only the facts. By providing specific information on each
designs advantages and disadvantages, it was possible to compare each design based
purely on fact.

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 The benefit of proposing a variety of solutions was that it allowed us to broaden
the scope of our project to allow for a thorough consideration of all possible options.
Instead of simply looking at batch vs continuous stir reactors, both of which are very
traditional fermentors, we decided to include solutions that are less common and more
outside the obvious realm. Not only did we learn a significant amount about each of the
options, but we also learned the importance of trying new ideas and experimentation.
Although the solution we think we will most likely go with is a more traditional reactor,
it was interesting and a good learning experience to offer diverse solutions.
One of the most important lessons we learned was how to define a broad problem
and apply engineering solutions. We were given a very general problem statement and
the goal was to create a design from it. One thing that we learned was the importance of
accurately and specifically defining the problem. We had a preliminary meeting with Dr.
Zhang to learn about his vision for the project and as time went on and we completed
more independent research on the topics he presented to us, we determined that we had
many more questions arise. Therefore, we had subsequent meetings where we were able
to hone in on the specifics of the project and determine the crucial next steps. By
determining specific constraints and criteria for the design, we were able to better guide
our research and ideas.
Looking forward, we still have significant work to do on our design project. First,
we must solidify our design solution by confirming that the traditional reactor is the best
option for our problem statement. Then we must do more expansive research on the cost
and design of our reactor, creating a second decision matrix for specific details about the
bioreactor itself. We must finally complete additional research on the materials and
processes needed for successfully engineering drug loaded nanoparticles within the
bioreactor to ensure our design is functional and successful. Once we have estimated
costs and materials needed, we will submit a budget request and begin preliminary
designs.

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Montgomery, S. A. (2004). Transgenic animals: walking bioreactors. BioProcess
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Morrison, S. L., Mohammed, M.S., Wims, L.A., Trinh. R., Etches, R. (2002). Sequences
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Appendices
Appendix A: Brainstorming Session - Potential Solutions
Zhangs vision for the project
Design a continuous stir-tank reactor to fabricate nanoparticles that can be used
for drug delivery in the treatment of cancer.

Considerations:
How are nanoparticles formed?
What feed streams do we need? Is there a rest time require?
What mechanisms are required for continuous production?
How large do we want our bioreactor? (note: the larger, the more difficult mixing
becomes, and it becomes overall more expensive)
What is the best nanoparticle to use? Biodegradable or non-biodegradable?
What are the FDA regulations concerning pharmaceutical production?

Where do we start?
Choose a specific type of cancer and medication Breast cancer has the largest
patient population, use this population as a basis for how many patients we need
to treat
Breast cancer has 4 common medications we can consider with documented
dosage and treatment frequencies
Research literature on current use of nanoparticles in cancer therapy
Provide justification for every decision that is made

Focus of project: fabricating the nanoparticle and creating the bioreactor

Assumptions
Assume simultaneous loading and creation of nanoparticle
Process may be one step or multistep
May compare dosage and application to current drugs on the market (e.g. nicotine
vaccine)
Although there is no current large scale application, assume that this is possible in
the future

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Appendix B: Challenges Encountered and Plans to Address
When we first began our project the guidelines were not very defined and the
problem statement was rather ambiguous. We found the design problem to be too large
and too broad. It took several weeks of research to really hone in on what we could
feasibly complete as a senior design project. Once we decided on a specific nanoparticle,
PLGA, a specific form of cancer to treat, breast cancer, we were able to complete better
research and ask Dr. Zhang more focused questions.
Our next big hurdle was finding relevant research that applied to our design
problem. The exciting part of our design project is that its entirely new, no one else has
yet figured out how to produce drug loaded nanoparticles in a bioreactor on a large scale.
This means we have a world of possibilities, but it also means that finding applicable
current research and technology is quite challenging.
As we move forward, we as a team are going to have to continue to rely on
research to judge the feasibility of our designs. We will have to do our best to apply
research with different nanoparticles or different drug therapies to our design problem in
order to synthesize a viable solution. We are also going to struggle with knowing whether
or not our design truly works. This we cannot test in its entirety but we should find a
way to test parts of the final design bioreactor in general, excluding the PLGA and breast
cancer drug involvement. We should test for controllable flow conditions, continuous
retrieval of liquid, waste removal, and interactive inputs/outputs.
Estimation of cost and understanding the overall cost is going to be challenging
and is going to require research and deductive problem solving skills. We will have to
work backwards to extrapolate the cost and then work forwards to scale up the cost, all of
which is going to require extensive problem solving and reasoning skills.

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Appendix C: Project Timeline for Key Tasks
Gantt Chart Shown Below

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Appendix D: Team Member and Partner Responsibilities and Accomplishments
All group members assist in maintaining up to date meeting notes the general
upkeep of the onenote notebook. All members communicate with Dr.Zhang and attend
meetings with him. Additionally all members have provided valuable input, relevant
ideas, and viable solutions. Every member has been actively involved in the research
process, providing multiple research papers that help widen the team's knowledge of
current technologies and issues.
The literature review aspect of the project was evenly split between team
members. Each team member was responsible for coming up with a possible solution for
a bioreactor design and presenting their research. This was beneficial in that each
member became the point of contact for each solution to provide inside for the decision
matrix as well as advantages and disadvantages for each. This process provided the team
with a variety of input and ideas and allowed for discussion and debate on the range of
possible solutions. Every other aspect of the paper from the introduction to the conclusion
and the appendices was split evenly among team members.
We have experienced significant collaboration and have evenly delegated tasks to
allow for the utmost efficiency in our design. At each meeting, we go over our individual
accomplishments to ensure every team member is up to date on our progress. We also
plan ahead together and assign tasks to stay on track with guidelines.

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