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| Jan
Boublik |
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Home
Institution
Medizinische Hochschule Hannover
Host
Institution
Massachusetts Institute of Technology (MIT), Division of Health Sciences
and Technology (HST)
Mentors: Lisa E. Freed MD, PhD; Gordana Vunjak-Novakovic, PhD
E-Mail
jan.boublik@web.de
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Research
Topic
see Abstract |
Personal
Reactions to the U.S. Experience
At a party, somebody said to me that only now do we get to see the "real
America" that is not hyped by the boom on Wall Street, and only concerned
with the way their stock funds are going. I don't know whether it is true,
but on Sept. 11 I was happy to have somebody whom I knew and I could talk
to. I cannot speak for anyone else, but I was certainly changed by these
months, and it made me appreciate a lot of things more than before.
On one side, the US was the country of contradictions and paradoxes I expected
it to be. Then again, it proves to have many opportunities for you, if you
are educated and know the right people. I also discovered things that I
had never expected to find, and met people I never thought I'd meet.
I was also fortunate to meet people who helped me to create my own little
"micro cosmos" that makes me consider pursuing my clinical training / further
research career in the US. Just like the president, I am "really, really
happy" - he to be president, I to have come here. |
Greatest
Difficulties Encountered
Housing in Boston: My first landlady didn't allow one to have guests over
for dinner, as this was considered a "social gathering," (this was @ $850
for 12 sqm, which was ignored by all roommates). However, she was very happy
when Florian visited as my "cousin, a neurosurgeon from Yale" (we were not
allowed to have overnight guests). |
Most
humorous incident
1) "What is appropriate?" (a phrase often used by Soenke Bartling, a wonderful
friend, kind-hearted human being, source of good spirit, and an "unconventional,
open-minded" character)
2) Being on my way from San Diego to Anaheim to a conference and realizing
that I had forgotten my suits and shirts in San Diego. (Thanks Payam -P.
Akhyari, BMEP AY2000 - for saving me by supplying me with spare ties and
shirts... funnier when you know that he is about 4" shorter than I am.)
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Helpful
Hints for Future Students
- Get your (right) visa early!
- Follow the pleasure principle - enjoy yourself, go out and just do it!
- Be careful playing basketball.
- For Bostonians: Check out MIT off-campus housing (E32-216), the MIT Euroclub
(Housing/furniture/pub tours), Café Vittoria in Boston's North End for tiramisu,
and the fruit market in Haymarket Square on Saturdays. |
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Abstract
on Research Topic:
Multifactorial Stimulation of an engineered cardiac tissue |
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Heart failure
is the leading cause of death in the US and the Western World. There is
an ever-growing shortage of donor organs for Transplantation: as of Jan.
2002 79,446 patients were waiting for heart, lung, liver, kidney, pancreas
and intestine transplantation. In 2000, 22,953 transplantations were performed
while 5,800 people died on the waiting list according to the United Network
for Organ Sharing (UNOS). Moreover, there is a lack of adequate material
for surgical repair/reconstruction of congenital heart defects such as
atrial septum defects or pulmonary hypertension. Potential alternatives
for heart transplantation (HTx) are either mechanical devices, such as
left ventricular assist devices (LVADs) and completely artificial hearts
(Abiocor®) or biological transplants including tissues (Xenotransplantation,
i.e. transplantation of organs from another species, e.g. pig) and cells
(cellular cardiomyoplasty, CCM, i.e. transplantation of cells to improve
the contractile functions of the heart).
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| At present,
LVADs serve as a bridge to HTx or recovery, and Abiocor® only recently
started its first clinical trial in mid-2001. Xenotransplantation faces
as yet unanswered questions ethical questions and still struggles with potential
hazards, such as the porcine endogenous retrovirus (PERV) that could lead
to infections of the host and the b-1,3-gal-epitope, a sugar that could
lead to rejection of the graft as humans do not posses it on their cell
surface. In the latter, one of the recent milestones of transplantation
was achieved only recently when two teams were able to clone piglets using
nuclear transfer who had one of the alleles knocked out (Lai et al. and
Kaiser, both in Science, 2002). CCM is currently being studied in clinical
trials using myoblasts (Menaschee et al. Lancet, 2001) with promising results,
but more long-term data are needed. As for the lack of adequate materials
for surgical repair of cardiac defects, commercially available synthetic
materials are non-viable, do not contract, do not grow with the patient,
and if out-grown can cause significant problems such as the need for re-operation
if the patches create stenosis or obstruction. Synthetic material also constitutes
a "foreign body" prone to infection and thrombus formation. Natural materials
such as autologous pericardium are fibrous tissues with limited elasticity
(in part due to the preservation process) and can be complicated by shrinkage,
calcification, dilatation or formation of an aneurysm (Li et al., J Thorac
Cardiovasc Surgery, 2001). |
| A prospective
alternative approach is the young field of tissue engineering that started
approximately fifteen years ago and offers the promise of organogenesis
in vitro. The basic concept involves the cultivation of immunologically
acceptable cells on three dimensional (3-D)biomaterial scaffolds. M.I.T.-based
researchers (Carrier et al., Biotechnol Bioeng, 1999; Bursac et al., Am
J. Physiol Heart Circ, 1999;Papadaki et al. Am J Physiol Heart Circ, 2001;
Carrier et al., Tissue Engineering 2002) and others (Li et al., Circulation
1999 and J Thorac Cardiovasc Surgery 2000 and 2001; Eschenhagen et al.,
FASEB 1997; Zimmermann et al. Biotechnol Bioeng, 2000 and Circ Res 2002;
Fink et al., FASEB J, 2000; Kofidis et al., Journal Thorac Cardiovasc Surgery,
in press) have studied the generation of cardiac tissue using cells in conjunction
with a 3-D biomaterials scaffolds and in some cases bioreactors. It is proposed
that the resulting engineered tissue provides some minimal level of function
immediately post-implantation and then continues to develop in vivo until
normal heart tissue structure/function has been established. Possible biomaterials,
scaffolds and construct cultivation systems are under investigation. |
| Current models
of engineered cardiac tissue have only marginally addressed factors such
as electrical, mechanical and neurohormonal stimulation normally present
in vivo that are likely to generate heart muscle constructs that more closely
resemble the native heart muscle, and in some cases use components that
are not FDA-approved for clinical use such as Matrigel®, a tumor-derived
substance that contains collagen and growth factors. |
To address
some of the above-mentioned unresolved issues, I am studying the in vitro
generation of engineered cardiac tissues in a bioreactor system designed
to provide multifactorial stimulation: a) mechanically stimulation by dynamic,
cyclical strain and b) simultaneous perfusion to enhance convective mass
transfer. My studies will use three cells types: 1. C2C12 cells (a myogenic
cell line), 2. neonatal rat cardiomyocytes (CM) and 3. bone marrow-derived
cardiogenic precursor cells. My scaffold will be a novel woven, elastic
semi-synthetic polymer. The cells will be attached to the scaffold using
a hydrogel of fibrin (Ye et al. Eur J Cardio-Thoracic Surg; Joeckelhoevel
et al., 2001, Ameer et al., J Orthop Res, 2002) or e.g. collagen type I.
During construct cultivation I will apply dynamic strain using a magnetically-driven
system(BIO-STRETCH®, ICCT, Markham, Ontario, Canada) and provide perfusion
to enhance mass transfer, using a custom-built perfused bioreactor within
a closed loop consisting of a reservoir for medium, a gas exchanger and
a peristaltic pump. Constructs cultured without perfusion, both with and
without mechanical stimulation will serve as controls. Construct analysis
will include morphological (histology, immunohistochemistry, confocal microscopy,
electron microscopy, FACS), molecular (RT-PCR, W. Blot), metabolic (lactate/glucose
ratio, LDH, MTT) and functional (HPLC, electrophysiology) methods.
To date, I have constructed and tested a bioreactor system that provides
multifactorial stimulation by simultaneous perfusion and dynamic mechanical
strain. |
| I have also
generated constructs based on C2C12 cells and a new, elastic woven polymer
and cultured them for several days in the presence of dynamic mechanical
strain. |
| An ideal
cell source is a replicating/renewable cell that can be obtained in sufficiently
large numbers, which in the case of the heart is a major challenge. A recent
study reports some replicative capacity and potential "stem cells" in the
adult human heart (Anversa et al., NEJM, 2002), but it remains unclear as
to where these cells come from, and whether they are obtainable in sufficient
numbers to compensate for lost/damaged myocardium. Alternative cell types
such as bone marrow-derived caridogenic precursor cells and embryonic stem
cells are currently being investigated. |
