Good luck to me.

Recently, I applied for the Whitaker International Fellows and Scholars program (I'd be a Fellow). It's a great opportunity for me to travel abroad and conduct biomedical engineering related research at an international institution. I don't know what my chances are of getting it, but I think I have a decent enough shot at it. I worked hard on my essays and talked with my host professor a lot too. She was very receptive towards my own ideas and seemed like she wanted me in her lab. Each applicant has to identify a host institution and write a research proposal for their application. I chose the Skeletal Tissue Engineering group at the Institute for Biomechanics at Swiss Federal Institute of Technology in Zurich, Switzerland (ETHZ). They do a lot of interesting work with mostly bone tissue engineering and a bit with cartilage. Their research centers around scaffold design, 3D printing of structures with defined architecture, and utilization of advanced bioreactors (perfusion/compression or combination).

My proposal was titled, "Mechanobiological feedback-loops in bone tissue engineering". It was interesting to write about it and learn a different sort of approach to engineering bone than we do in our lab. It involves some of the same techniques, but this lab goes more into the mechanobiology of stem cells, osteoblasts, and bone formation. This is the type of research that I'd like to eventually work on since load-bearing tissues such as bone are able to sense and react to various types of mechanical stimuli whether from one's own physiology, natural movement, or external forces. Even if I don't get it, I'd like to try and apply again next year. It was also a good experience going through the process, writing essays, and thinking about possible avenues of research I could pursue. Anyways the project, in a nutshell, is implementing a fluid flow sensor system for a perfusion bioreactor that senses changes in culture conditions and alters flow rate accordingly. The idea is that since scaffolds are initially a porous structure, the mesenchymal stem cells that are seeded on them will eventually start to secrete extracellular matrix and mineralize the scaffold by filling in the pores. When these pore sizes shrink, this invariably alters the shear stress experienced by the cells. In order to understand how these cells are able to react to a mechanical stimuli, it is best to understand "optimal" shear stress and maintain constancy. Were an osteoblast to be subjected to a harmful shear stress regimen, cell death or tissue necrosis could occur. I will also be using micro-computed tomography (micro CT) to image the constructs temporally to visualize mineralization over time. It should be an interesting project that I can hopefully tie into my eventual dissertation research.

So that's all done with for now, just submitted it on Wednesday. I should hear back in a few months. If I don't talk about this again, it probably means I didn't get it and I'm too sad to bring up again. Also have a molecular imaging training grant interview on Tuesday that I really want to get. I may not be a traditional player in the imaging field as I think there are a lot of great imaging students and the department here is very strong. But I think I have a lot to offer and I can make a very good case for the use of imaging modalities in my research that is possibly underrated. Basically I have two chances to take big steps in my grad school life and I hope I don't strike out on both of them.

Another quarter.

I've been keeping busy, but I should've found time to update. Winter break would have been a good time to do that, I suppose. When you're writing essays and emails all the time, it's a little tough to relax by writing a blog entry. That's my excuse. There's always something more urgent priority-wise. I do need the practice though, so even if I don't have much content to write about, I'll try to write SOMETHING. I'll stop short of saying that's a New Year's Resolution because I don't make resolutions (and I know I'll probably break it), but hopefully I'll find more time this quarter to enhance my internet presence.

I recently joined the Leach Lab here at UC Davis. I've been doing a "rotation" there for the past few months and I really like it so I just figured I'd stick around. There are several reasons why I chose it, so maybe I'll talk a little about why I did. 

Research is the first thing that comes to mind but I wouldn't necessarily categorize it as the main factor in choosing a lab. I found that I love bone tissue engineering and load bearing tissues like cartilage. It's important work, like most areas of research in the sciences. There's a fantastic lab at UC Davis, the Athanasiou Lab, that does work in biomechanics of cartilage tissue engineering. I thought that's where I would find a place before I got to Davis, but I figured out that it wasn't really right for me. I did like the research and I think I could have potentially found a great project for myself. A few other factors swayed me towards a different direction. I'd like to eventually pursue mechanobiology, like how stem cells or differentiated cells sense and react to mechanical signals. I want eventually work on a project that can tie this into bone tissue engineering using novel biomaterials and biomolecule delivery approaches. So by joining the Leach Lab, I think I can go a variety of different directions in a field that is really exciting.

I also feel like I'll be given a lot of freedom to conduct research that I want, without being assigned something to work on or be given strict boundaries. Of course, that's only true to some extent; it has to be reasonable and of interest/benefit to the lab. But I know that if I'm interested in an aspect of bone tissue engineering (or other tissues), then I will be given every opportunity to work on it, even if it's uncharted territory for the lab. After all, isn't that the point of research? To discover? The plus side of that is that it could open up the doors for potential collaborations with other labs, either on campus or elsewhere. It would be great if I could work with some people in the Orthopedic Surgery research unit at the med center.

It's important that I like the people in the lab too, since I'll be seeing them all the time, and I've been fortunate in that respect. I enjoy being around everyone, and I'm very much looking forward to our time together further on down the road. It usually takes me a little while to warm up to people but I like the environment that I'm in right now. Not way too many people in the lab, but just enough. And everyone is an excellent resource so I'm always learning a lot, even if I ask stupid questions sometimes. I like Dr. Leach as well, he's what I was looking for in an advisor. I wanted someone who fully embraced the mentorship aspect of being a professor and wanted what was best for me in addition to his own lab. While he's a nice guy, I know he is willing to challenge me in order to make me a better scientist, and that's a good thing.

Those are just a few quick thoughts. Everyone's different in terms of what they look for in a lab, so it's best to judge on an individual basis. There's more stuff going on, so hopefully it won't take another 3-4 months before the next update.

Graduate School Begins

As a respite from all the research papers, textbooks, and Wikipedia pages that I've been reading, I'd like to talk a little bit about graduate school as it starts to kick into gear. Classes haven't started yet (officially started Thursday, but I have classes on Monday and Wednesday), so I'm not yet encumbered with assignments and deadlines.

I'm currently enrolled in 3 classes and 2 seminars. The classes are:

BIM 173 - Cell and Tissue Engineering

BIM 204 - Physiology for Biomedical Engineers

BIM 284 - Mathematical Methods for Biomedical Engineers

The two seminars are "Meet the Faculty" and a "Distinguished Speaker Series". The faculty seminar involves a different professor each week who talks about his/her research. This is also helpful for current graduate students who are still unsure about whose lab they want to join. Along the same lines, the Distinguished Speaker Series invites guest speakers to present on their current research. The seminars should be very interesting, as it's generally a good idea to gain knowledge in any sort of area, even if it's not immediately pertinent to your specific research goals. It's similar to picking up a book to read. I don't read solely biomedical engineering books. That would be ridiculous. Here's a list of the books I'm currently reading on my Kindle:

1. Storm of Swords - George R.R. Martin
2. East of Eden - John Steinbeck
3. Contact - Carl Sagan
4. Incognito: The Secret Lives of the Brain - David Eagleman
5. The Big Short: Inside the Doomsday Machine - Michael Lewis

That'll actually take me a little while to get through since I won't have that much time for leisure reading (I usually bring out the Kindle now when I'm eating, when I have some downtime, or right before bed). I have 3 fiction books, but even from those you can still learn a lot. Maybe it's not about science (though Contact is heavily science based), but that doesn't mean you can't pick up new things and improve yourself. It could come in handy in future conversation, it could influence your vocabulary and writing style, or serve as a point of inspiration on a project. But mostly you're in it for a great story. Regardless, it's never a detriment to pick up a book to read (unless you really should be doing something else). I read a lot of non-fiction as well. I like reading about new ideas/concepts, memoirs, personal accounts, history, etc. I've had my eye on the John Adams biography by David McCullough for a while now. I might buy it.

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The books I really like (or if they're cheap), I'll purchase. Some are just nice to handle and to have on the bookshelf. Reading on the Kindle, sometimes I forget what it's like to read an actual paperback, i.e. how to flip pages, what real ink looks like on a page. Each format has its merits. I just really appreciate the Kindle for sheer volume and efficiency. I've read many books that I would never have read otherwise.

Some of my literature purchases go towards comic books (it counts as literature). I always feel like I have to defend my interest in comics because people always assume it's nerdy or immature. As I've read in a book recently (Justice: What's the Right Thing To Do? by Michael Sandel), there are different forms of pleasure, but who's to say which is higher than the other? By higher, I mean the more sophisticated, respected, preferred form. The example given in the book was The Simpsons vs. Shakespeare. In a survey, many students say they prefer watching The Simpsons, but rate a Shakespearean work as a qualitatively higher experience. Why is that? Is Shakespeare really that much more worthy and noble than a product of the present? That can be debated. The point is, just because comics may seem like a lesser work, there is a lot underneath the surface that can be just as valuable. I do enjoy the art in comics, I think they are hugely impressive. But I also appreciate the story, the development from issue to issue, the satire, the irony, the social and political commentary. That's what's wonderful about comics, their dual nature and universal appeal. I can read them as an adult, and enjoy them just as much as when I was a kid. As my friend Glenn said, "They're the modern day mythology." It's true. I believe that in order to appreciate literature, you should be able to enjoy them in all its forms. Sometimes, comics are the best medium to get your story or message across, much better than a regular old book would. 

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As I was saying, it's important to read non-fiction as well, to incorporate useful information into your daily life. Maybe it won't impact your research, but maybe it can impact the way you work, the way you live, or how you're motivated. Maybe it'll come in handy when you least expect it. Or, if you're like me, you just read because you have an avid curiosity about everything.

Now that I'm at UC Davis, I think I appreciate the University of Michigan a little more. Michigan's facilities and resources are incredible. And I'm talking about the entire campus. Not to say that I'm severely disadvantaged here, but there are a few things I miss. Most notably, accessible computer labs, fast printing, a centralized campus, lounge/work areas, and an efficient (and free) bus system. It might be that I'm just new here and I haven't discovered everything yet, but I'm having some severe Wolverine nostalgia. I am also not happy with the fact that I have to bike everywhere and cycle through (pun intended) 2-3 shirts a day due to sweating.

This quarter I'll be doing a rotation in a research lab. Hopefully everything works out and I'll be able to stay on but at this point I think it's too early for either of us (me and PI) to commit. So besides classes, I'll be stopping by the lab every now and then to ask questions, read papers, and watch experiments. I'm also hoping to apply for a few fellowships and training grants. This upcoming week will be my first full week in action. There are also several seminars and social events going on so it should be a busy week.

Edit: Also, for those wondering, I've archived all my old posts dating back to a year ago. I still have them, they're just not available for public viewing anymore since I don't think they're relevant within the scope of this blog. I kept the travel posts (to Argentina) because they're a little more interesting.

Bone Remodeling

Building off the last post, I'd like to segue into the mechanism of bone remodeling, or the process of removing old bone (resorption) and laying down new bone. This is a good transition because I already covered the 3 main cell types in bone: osteoblasts, osteocytes, and osteoclasts. Each has an important role in bone remodeling that I briefly touched on previously.

Why do bones need to remodel? 
What we think of when we hear 'remodeling' is a new kitchen, a living room, a basement, an office. A room wears down after continual use, gets old and outdated, and eventually needs a new look. The same sort of idea can be applied to bone matrix. Over time, bones sustain micro-damage and new bone matrix must be produced to maintain skeletal/structural integrity. In the case of injuries, such as fractures, remodeling can also replace bone that is damaged on a larger scale. Physiologically, this process also regulates blood calcium levels. There are 3 phases to bone remodeling: resorption, reversal, and formation.

Resorption: 
The cells responsible for resorption of bone are osteoclasts, which reside on the outer layer of bone. First, the osteoclasts bind to the osteons and induces an infolding of their cell membranes. They secrete enzymes that break down the matrix. This causes calcium, magnesium, phosphate, and collagen to be released into the extracellular fluid. Calcium is transferred into the blood to alter plasma calcium levels.

Reversal:
In the reversal phase, mononucleated cells appear on the surface of the bone or where the "resorption pit" is formed from osteoclast activity. These are most likely mesenchymal stem cells, which proliferate on site and then differentiate into osteoblasts.

Formation:
In the final phase, the osteoblasts fulfill their role by releasing osteoid, eventually hardens into bone matrix. The matrix mineralizes through the help of calcium and phosphorous.

Regulation
Signaling pathways of physiological processes can be intensely intricate and complicated, influenced by a variety of factors. The entire process of bone remodeling is still not fully fleshed out in detail, though much work is being done. Many hormones (parathyroid hormone, calcitrol, etc) and growth factors (TGF-βs, BMP, prostaglandins, etc) regulate bone remodeling. For example, how can osteoblasts form enough bone and tell osteoclasts to stop resorbing bone? After the reversal phase, when osteoblasts are differentiated, the cell presents a protein called receptor activator of NF-kB ligand (RANKL), which then binds to its receptor (RANK) found on osteoclasts. The binding of the RANKL upregulates osteoclast activity, meaning it increases it. Many degenerative bone diseases such as rheumatoid arthritis are caused by overproduction of RANKL (too much resorption of bone). However, osteoblasts can also produce a decoy RANKL protein that binds to the osteoclast receptor and inhibits the osteoclast's ability to bind to osteons and remove matrix, thus downregulating it's activity. Hormones can also affect RANKL (and other protein) expression. The osteoblast thus uses these methods to not only control bone matrix integrity, but also plasma calcium levels.


Sources:
Porter JR, Ruckh TT, Popat KC. Bone Tissue Engineering: A Review in Bone Biomimetics and Drug Delivery Strategies. Biotechnol Prog. 2009, Vol. 25, No. 6. 1539-1560. 
Wikipedia

The Anatomy of Bone

In order to understand the mechanism of osteogenesis, a basic understanding of bone anatomy is necessary. Here, I will provide information gathered from a variety of sources, though I'm keeping everything relatively simple. There are massive repositories of knowledge available on the world wide web that can easily be accessed. I will be showing some illustrations, as it helps to visualize things when it comes to grasping anatomy.

I think it's best to start from a microscopic scale and move upwards to macroscopic. In other words, from cells to tissues, building on each other like bricks of a house. First, why is bone important? Technically, bone is an organ, with the primary function of providing support for the body. However, it also has many other functions, such as protection of internal organs, production of red/white blood cells, mineral storage, release of metabolic factors, etc.

There are three main types of bone cells:

1. Osteoblast - These cells make a protein mixture called osteoid, made up primarily of Type I collagen, that mineralizes to form bone matrix. They also secrete different kinds of enzymes and proteins. Eventually, the immature osteoblast cell matures into an adult bone cell, the osteocyte.
2. Osteocyte - Mature osteoblasts that become trapped in their own secreted matrix proteins. Their functions are to form bone, and maintain matrix and calcium homeostasis.They are also involved in bone remodeling through their mechanosensory receptive properties.
3. Osteoclast - Bone cells that are responsible for bone resorption (removal of bone matrix). Unlike osteoblasts and osteocytes, these are multinucleated cells that work together with the osteoblast to control the amount of bone tissue.

Bone matrix makes up about 1/3 of bone mass, while the other 2/3s is bone mineral. It is made up of organic and inorganic material. The inorganic part is carbonated hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂) and the organic is Type I collagen along with various growth factors.The matrix is composed of two types:

• Cortical Bone: Also known as hard compact bone, this is found in the outer shell of bones, surrounding the inner marrow cavities. 
• An osteon is the fundamental unit of cortical bone. The structure of an osteon is a cylinder, involving concentric layers called lamellae. The central region is called the Haversian Canal. Inside the canal are the nerve and blood supplies. The osteocytes in osteons are connected to each other via a network of channels called canaliculi.
• Cancellous Bone: Also known as trabecular or spongy bone. It is less dense and softer than cortical bone. It is found at the end of long bones, in flat bones, and in vertebrae. The bone is highly vascularized, meaning there are lots of blood vessels. The red bone marrow conducts hematopoiesis, or creation of blood cells.
• The trabecula is the fundamental unit of cancellous bone. These are rod-like structures of connective tissue.

These features can be seen in the figure below, taken from Wikipedia.

Sources: 

http://www.uchospitals.edu/online-library/content=P00109

http://cal.vet.upenn.edu/projects/saortho/chapter_01/01mast.htm
Wikipedia