Copyright © 1996 by the Biomedical Engineering Society
As 1996 comes to an end and the leadership of our Society changes, it is a good time to reflect on the state of the BMES. Over the last several years, the Society has essentially doubled in membership. With the growth of BMES has come increased responsibilities, opportunities and need to supply services. Communications between our various constituents have become more complex. As an example, our Annual Fall Meeting has grown rapidly to become an outstanding technical event. However, the increased size and scope make the meeting very difficult now to fit on one University campus, taking away some of the special atmosphere and making attendance more expensive, a particular drawback for students.
A second example is the development of our Society Journal -- the Annals of Biomedical Engineering. We would like to move the ABE into the first rank of engineering and science journals. To this end, the Board authorized four years ago an increase in funds to the editorial office from approximately $10,000 a year to $50,000 a year currently. In addition, we now require essentially all non-student members to subscribe to ABE. However, increasing the level of recognition of ABE in ways that encourage University librarians to purchase the journal (such as "Impact Factor") has proven difficult and requires large investments of intellectual energy, fiscal resources, and time. The broad scope of biomedical engineering can also lead to a lack of scientific focus within the journal articles. Specialty journals abound, with new ones appearing nearly every month [for example, the new journals Tissue Engineering and Cellular Engineering - both begun in 1995]. Attracting first-rate articles and maintaining readership will be a continuing challenge for ABE.
Students comprise approximately half of BMES membership. Student involvement has been and continues to be a very strong point for our Society. As the number of Biomedical Engineering Departments and programs expands over the next several years, we will need to maintain and improve our communications with BME student chapters. This will place increased demands on the Central BMES office, and will probably require increasing the staff from our current size of one. Increased fiscal resources will also have to be invested to develop this BMES infrastructure.
Our Biomedical Engineering Society interactions with the BME industry have been relatively few. Promoting these interactions with the growing number of companies that employ our biomedical engineering graduates and utilize our bioengineering expertise is a BMES goal -- but has proven difficult. The workshop held at the Penn State Annual Meeting this year was a good beginning and put forward some ideas -- but we need to nurture and build this relationship.
As our Society grows, we need to make our voice heard in the public policy arena. Biomedical Engineering should be seen as developing solutions for low cost, high quality health care technology -- not as the major problem in this area. Federal and private funding for biomedical engineering research needs to be aggressively promoted. The fiscal 1997 Federal Budget is very good for NIH (~7% overall increase). How that will translate into increased funding for biomedical engineering research is unclear. The consultants' report from the recently completed survey of Bioengineering within NIH is published in this issue of the BMES Bulletin. Some specific recommendations are put forward. Please read it and help to see that they are acted upon through contacts with your Congressman.
Each of these areas discussed generates both challenges and opportunities. How BMES progresses as a Society will be determined by how well we manage these challenges and convert them to opportunities. The Board of BMES needs your input on creative approaches to these and other potential problems the BMES will face over the next several years. These are tremendously exciting times for Biomedical Engineering. The opportunities for the BMES to be the leading Society for incorporating the new biological science into innovative biomedical engineering education and research are there if we have the will to meet the impressive challenges.
A Report Prepared for the National Institutes of Health by the External Consultants Committee
Robert M. Nerem, Ph.D. (Chair)
Kenneth D. Taylor, Ph.D. (Vice-Chair)
Frances Arnold, Ph.D.
Shu Chien, M.D., Ph.D.
Peter G. Katona, Sc.D.
Candace Littell
William D. Young
Fred G. Heinekin, Ph.D. (Liaison Member)
Executive Summary
Basic bioengineering research advances the Nation's health by increasing biological knowledge through the use of engineering principles and techniques. It also contributes methodologies that have enabled the development of novel devices, drugs, and systems. It has been instrumental in establishing the U.S. as the world leader in health care technology, as evidenced by a $4.6 billion trade surplus for this sector in 1993.
NIH is the major federal sponsor of bioengineering research, with total expenditures of over $300 million in fiscal year 1993. Less than $80 million of this, however, is dedicated to basic research. Such research, which concentrates on concepts and technologies rather than on specific diseases, is an essential ingredient for advancing health care and bringing innovations and new medical technologies to market.
To ensure that limited governmental funds for basic bioengineering research are spent in an optimal manner, the following five recommendations are made.
Recommendation 1: NIH should establish a central focus for basic bioengineering research. This central focus should be at the highest level and should include resources for the collaborative support of extramural research.
Recommendation 2: The NIH should significantly expand representation of the medical and biological engineering community on advisory groups and in the peer review process.
Recommendation 3: NIH should establish an intramural bio-engineering research program. This program would focus on cutting-edge research of national significance that complements ongoing intramural and extramural programs.
Recommendation 4: Communication and cooperation should be enhanced among governmental agencies with significant research activities in health-related bioengineering.
Recommendation 5: The public sector should increase efforts to foster greater private sector participation in determining basic research needs and in facilitating technology transfer.
With increased commitment and effective cooperation among governmental agencies and with industry, our country's investment in bioengineering will continue to yield important advances in health care through technology, while containing health care costs. The recommendations presented here are directed at not only maintaining our current edge over other countries, but widening that lead. The ultimate outcome will be improving the health and welfare of our fellow citizens and maintaining U.S. leadership in the worldwide marketplace.
1. Introduction
Section 1912 of the National Institutes of Health Revitalization Act of June 10, 1993, directed the Secretary of Health and Human Services to conduct a study on support for bioengineering research. The legislation calls for the study to be done through the Director of the National Institutes of Health, with a focus on basic research in bioengineering. To conduct the study, the NIH established a Working Group, with representation from all NIH Institutes and Centers. Executive direction was provided by an NIH Steering Committee. The study has been coordinated by Dr. John T. Watson, chief of the Devices and Technology Branch at the National Heart, Lung, and Blood Institute. An External Consultants Committee was appointed that includes representatives of academia, industry and professional organizations.
The External Consultants Committee met six times between November 1993 and May 1994, including two telephone conference calls. The committee also arranged two focus group meetings, one with representatives from industry and the other from academia. The process culminated with a workshop on April 21-22, 1994, to which more than 100 individuals were invited. The workshop allowed time for three smaller breakout groups to meet and develop specific recommendations for the External Consultants Committee. This report is an outgrowth of this workshop and the deliberations of the Committee.
The next section of this report describes bioengineering and how research in this field is improving health care in the United States. Section 3 discusses the role of bioengineering research in helping the United States maintain its leadership in health care technology. Section 4 reviews an NIH inventory of the current investment in bioengineering research in the United States. Finally, Section 5 presents the recommendations of the External Consultants Committee.
2. Bioengineering and Its Benefits to Society
Bioengineering has made enormous contributions to the advancement of health care in the United States. The field has given us such devices as the pacemaker, orthopaedic implants, and non-invasive diagnostic imaging. Bioengineers have developed new processes for manufacturing products in the pharmaceutical and biotechnology industries. An example is the manufacturing of Humulin, i.e. human insulin, the first product based on recombinant DNA technology, where bioengineering was critical to the ability to commercialize the product. Many more biotechnology products have followed human insulin.
For the purposes of this report, bioengineering refers to a discipline that uses engineering principles and quantitative methods to improve human health. (The report does not deal with other areas of bioengineering, such as the development of high-yield agricultural processes, that do not address the prevention, diagnosis, or treatment of disease.) Bioengineering spans the spectrum from basic research to the development of processes and products.
Basic research in bioengineering advances knowledge at the genetic, molecular, cellular, tissue, organ and system levels through the use of engineering principles and methods. Such knowledge is a prerequisite for the prevention and conquering of disease. Basic bioengineering research also seeks methodologies that enable the development of novel biologicals, devices, materials, processes, and systems. It concentrates on concepts and technologies that are generic, rather than being oriented toward any specific disease, product, or device. It includes the advancement of knowledge in the basic engineering sciences, e.g. materials science and engineering, robotics, and information science, as they relate to basic health care technologies.
Once the basic methodologies are available, applied research adapts the technologies to solve specific health problems. Bioengineering research, basic and applied, thus includes such areas of activity as artificial organs, bioinstrumentation, biomechanics, biomaterials, bioprocess engineering, cellular bioprocessing, clinical engineering, medical informatics, rehabilitation engineering, tissue engineering. The fruits of bio-engineering research are improved health care and restoration of function to those with physical impairments.
While technology has been primarily utilized for improving the quality of care, it is clear that the appropriate use of technology can also contribute to the containment of health care costs. Replacing invasive procedures with non-invasive ones, delivering care at home rather than in the hospital, and allowing the disabled to lead a productive life are examples where technology is part of the solution to escalating health care costs.
Universities started to establish bioengineering departments in the 1960s; since then the field has undergone enormous growth. Twenty-one universities now have accredited undergraduate bioengineering programs; a number of other institutions offer courses at the undergraduate level. More than 40 universities offer formal graduate programs; another 40 conduct research or teach graduate courses in bioengineering. In 1993, 147 Ph.D.s in bioengineering were awarded. It is estimated that at least an equal number of doctorates were granted through more traditional engineering departments based on bioengineering doctoral research. There are more than 20,000 bioengineers working in universities, hospitals, and industry in the United States. There are at least 30 professional bioengineering societies and an equivalent number of journals in the field.
3. Maintaining the Nation's Leadership in Health Care Technology
Basic bioengineering research can lead to the commercialization of new health care technology. New products from biotechnology and novel devices for diagnosis and treatment are brought to market through interactions between universities, medical centers, small start-up firms, and larger, more established companies.
Generally, the academic community devotes significant resources to basic research, thereby adding to the body of scientific knowledge and discovering novel techniques and approaches. These discoveries are typically refined and transformed into nascent products by small start-up companies, which eventually pique the interest of larger companies. Larger firms in general then devote the necessary resources to navigate the regulatory maze, complete product development, and manufacture and distribute the product.
The funding of research and development differs significantly between the various entities. Basic bioengineering research, primarily performed by the academic community, is funded largely by the government. Applied research and development are performed primarily by the private sector. Small start-up companies typically raise funding from non-traditional sources such as venture capital investors, while larger companies typically obtain funding through more traditional investment channels such as their own ongoing product sales, the stock market, and commercial banks.
The U.S. healthcare technology industries have built a leadership position in the worldwide healthcare technology products market, with 49 percent of the global production in 1993. Growing industry exports have led to a $4.6 billion trade surplus. Commitment to basic bioengineering research, coupled with an environment that is supportive of technology transfer and commercialization, was instrumental to achieving this success.
The ability of U.S. industry to maintain its preeminence in the global market will be a function of dealing with many difficult issues. One essential ingredient is steadfast support for basic bioengineering research, which is critical for the spawning of new technologies. Industry looks to the federal government to support basic research, not only as a source of new ideas, but as part of training the workforce required by the commercial sector. Active government support of basic bioengineering research, and enhancing research and technology partnerships, are imperative for bringing innovations and new medical technologies to market.
The increasingly stringent U.S. regulatory environment can adversely affect the private sector's ability to commercialize basic research results. The regulatory climate and uncertainty about healthcare reform have resulted in the tightening of criteria by venture capital investors, affecting mainly small start-up companies. The litigious legal environment provides a disincentive to invest in new technologies and has led to an alarming recent shortage of materials used in implantable medical devices. A U.S. tax law that provides financial incentives for manufacturing in foreign countries promotes the relocation of research and product development as well.
In response to these environmental forces, companies are increasingly forming alliances with foreign institutions. In a recent survey of medical technology companies, one third of those responding indicated that they were moving manufacturing facilities to other countries. Close monitoring of these developments will be necessary to determine the extent to which they will affect future innovations and ultimately the U.S. leadership in world markets.
4. Current Funding of Basic Bioengineering Research
NIH has conducted a detailed inventory of sources and amounts of public and private funding devoted to medically oriented bioengineering research in FY 1993. This inventory included a number of different agencies. For each agency, the support for bioengineering research was divided into three categories: basic research, applied research, and development. Preliminary numbers were reported at the April 21-22 workshop and final figures were made available later to the Committee.
It has not been possible for the Committee to verify the reported figures. Agencies may interpret definitions differently and it is unclear whether the responses have been prepared using a uniform interpretation. It is recommended that future inventories ask that bioengineering research be classified into different categorical areas. This would provide a more comprehensive view of the different agencies, help in the identification of voids in research funding, and also would allow at least partial verification of the reported figures.
The government-wide total support for bioengineering has been reported to be just under $500 million. Less than one third of this is for basic bioengineering research. The three lead organizations in the support of basic bioengineering research are the NIH, NSF, and The Whitaker Foundation, a private foundation. NIH by far provides the most support for bioengineering research: more than $300 million in FY 1993. Yet less than $80 million of the total, or 25 percent, was directed towards basic research. This is out of line with NIH as a whole. Across the board, NIH devotes 60 percent of their funding to basic research. NSF provided $15 million in FY 1993, $10 million of which was for basic research. Within the non-profit private sector, the Whitaker Foundation stands out in its commitment to biomedical engineering. In 1993, its total support of bioengineering research was $23 million, including $14 million for basic research.
The total support for basic bioengineering research provided by federal agencies and The Whitaker Foundation should be considered in the context of an estimated $3-5 billion in support from the commercial private sector for applied research and development. The leverage of research is extraordinary since the gross revenue of the bioengineering industry, i.e. the private sector involved with manufacturing health care products, already exceeds $40 billion.
The funds devoted to basic bioengineering research are relatively small, and the Committee is further concerned that these limited funds may not be spent in an optimum manner. There seems to be little coordination among the federal agencies, and even within the NIH, there is no coordination of the bioengineering activities scattered among its Institutes. For these reasons, the following recommendations focus on organizational issues.
5. Recommendations
The External Consultants Committee agreed on the five recommendations presented in this section. These may be divided into three categories. Recommendations 1-3 apply directly to the NIH. The focus is on NIH because it provides more support for bioengineering research than any other federal agency. As important as NIH is, there also are a number of other agencies that support bioengineering research. Recommendation 4 thus addresses the enhancement of cooperation among these agencies. Finally, Recommendation 5 focuses on improving the partnership between the public and private sectors.
Recommendation 1: NIH should establish a central focus for basic bioengineering research. This central focus should be at the highest level and should include resources for the collaborative support of extramural research.
Justification: Basic bioengineering aims to develop concepts and technologies common to a wide variety of diseases and devices. Consequently, the current disease-oriented NIH structure is not conducive to the support of basic bioengineering research. A central focus for bioengineering at NIH will foster basic bioengineering research that, while not directed to a specific disease, is critical to the translation of advances in basic biology into clinical application and commercializable technology. A central focus will facilitate coordination and cooperation within NIH, as well as with other federal agencies and industry.
The Committee believes that there is great need for a central focus, or a "champion" for bioengineering within NIH. The current fragmentation of bioengineering at NIH is evidenced by considerable difficulty that was encountered in conducting the research inventory. Of particular concern is the lack of mechanisms within NIH to identify and support important bioengineering research needs, particularly those leading to new generic technologies.
As NIH has evolved, a wide variety of organizational forms have been used to provide focus on specific areas of emerging interest. These have included new administrative positions, offices, centers, and institutes. While the Committee makes no recommendation for a specific structure, it believes that the central focus needs to be established at the highest NIH level. It must be trans-NIH in nature, and it must have resources to provide coordination, facilitation and collaborative support of extramural bioengineering research within the Institutes and Centers. That this can be accomplished is illustrated by the recently established Office of Research on Women's Health.
Recommendation 2: The NIH should significantly expand representation of the medical and biological engineering community on advisory groups and in the peer review process.
Justification: Only 36 study section members out of a total of 1,650 are bioengineering researchers. Twenty-two percent of bioengineering proposals require ad hoc or special review, compared to less than 5 percent NIH-wide. Substantially increased representation of bio-engineering researchers on study sections will improve the quality of the review process for bioengineering and other technologically-related proposals. This in turn will improve the quality of funded research, while reducing the burden of special study sections. If there were to be a restructuring of study sections at NIH, this could provide the opportunity for implementing a more appropriate framework for the review of bioengineering research proposals
In 1993, 320 individuals served on NIH senior advisory councils, participating in the formulation of research policies. Only two of these individuals could be identified as bioengineering researchers. The number of bioengineers on advisory councils should be expanded, and should include engineers and researchers from both academia and industry.
Recommendation 3: NIH should establish an intramural bioengineering research program. This program would focus on cutting-edge research of national significance that complements ongoing intramural and extramural programs.
Justification: While the extramural research community is developing programs in bioengineering, at the NIH there is no intramural program in bioengineering that would complement its intramural research in the life and clinical sciences. Not only does science drive technology, but technology also drives science. Thus, improvements in materials, measurement techniques, and information technology are often the key elements that result in revolutionary advances in the biological sciences.
Currently there is a lack of any commitment by NIH to an intramural bioengineering research program. The only identifiable intramural biomedical engineering activity is the Biomedical Engineering and Instrumentation Program (BEIP) of the National Center for Research Resources. This program, organized along traditional engineering disciplines, is the outgrowth of what has been primarily a service activity, and it is funded by a "tax" on the other institutes and centers. In its present form BEIP does not represent the type of intramural research program envisioned by the Committee; however, BEIP does contain several outstanding researchers who could form the core of such a program.
The Committee recognizes that there is considerable pressure to reduce and reorganize existing NIH intramural programs. A reorganization may provide an unusual opportunity to establish an intramural research program in bioengineering, where world-class researchers would focus on problems of special interest to the life science and medical community. The result could be a unique research environment available nowhere but the NIH.
Recommendation 4: Communication and cooperation should be enhanced between governmental agencies with significant research activities in health-related bioengineering.
Justification: The inventory of health-related bioengineering research shows broad participation of various governmental agencies. It is highly desirable for these agencies to form information linkages to exchange data on programs and their progress, as well as to identify unmet needs. Furthermore, a standing committee of agency representatives should be formed to further enhance cooperation between their agencies, and to provide a means of establishing personal contacts that could lead to further interagency collaboration. Such a committee could be a subcommittee of one of the existing National Science and Technology Council (NSTC) Committees (e.g., the Committee on Health, Safety and Food). This would give such a committee the stature needed to be effective.
Possible benefits of interagency coordination and cooperation include optimizing the use of resources, identifying important areas not being funded or which are underfunded, and developing joint new initiatives. Currently, there are isolated examples of the potential effectiveness of such interagency interactions. These include a joint program of the National Heart, Lung, and Blood Institute (NHLBI), and the National Science Foundation (NSF) on "Cardiovascular Device-Centered Infections." Additional joint programs are being discussed. NIH and NSF also have held a joint Workshop on Tissue Engineering, and have co-sponsored conferences on this topic. However, there are many other areas into which cooperation could be expanded.
Recommendation 5: The public sector should increase efforts to foster greater private sector participation in determining basic research needs and in facilitating technology transfer.
Justification: The private sector commercializes new product innovations made possible by basic and applied bioengineering research. This sector thus has a unique perspective on the direction of basic bioengineering research. Health care technology firms can provide valuable advice that will both improve health care and provide for continued leadership in global markets.
The level of industry input and participation in public sector research efforts is variable. For example, some segments of industry are closely involved in the Advanced Technology Program of the National Institute of Standards and Technology, and industry representatives also participate in groups advising the National Science Foundation. NIH as well as other agencies could benefit significantly from industry input.
Private sector input could be increased through a variety of mechanisms. These include but are not limited to the following: participation on policy-making bodies such as the NIH Advisory Councils; identification of topics for SBIR program research solicitations; and implementation of a public sector outreach program with activities such as periodic mailings to health care technology companies. Such mailings may describe research activities, government participation in health care technology meetings, and collaboration with various groups associated with health care technology companies.
Conclusion: With increased commitment and effective cooperation among governmental agencies and with industry, our country's investment in bioengineering will continue to yield important advances in health care through technology, while containing health care costs. The recommendations presented here are directed at not only maintaining our current edge over other countries, but widening that lead. The ultimate outcome will be improving the health and welfare of our fellow citizens and maintaining U.S. leadership in the worldwide marketplace.
Forms to renew chapter charters for 1997 were recently mailed to all BMES student chapters. Chapters that fail to renew are not listed in the BMES Membership Directory and are dropped from our "active" roster. Submit the name of the faculty advisor, a list of chapter officers, a roster of student chapter members who are members of the national Society (minimum of 10), an e-mail address, and a permanent mailing address for the chapter.
We hope that this will be a productive and rewarding year for your chapter and your individual student members.
The Society offers Meritorious Achievement Awards to those chapters judged to have outstanding activities and achievements. These awards are engraved plaques and are presented at the BMES Fall Meeting to representatives from the chapters. To compete for a Meritorious Achievement Award, a BMES chapter must submit a Chapter Development Report by March 1, 1997.
A detailed description of the report sections and types of activities to be described are outlined in the Student Chapter Operations Manual, as well as officers' duties and deadlines. Plan your yearly events and fundraising activities early to ensure their success. Keep duplicate copies of minutes, announcements, budgets, etc. for your Chapter Development Report. Photographs of picnics, awards banquets, parties and other events are encouraged.
The Biomedical Engineering Society welcomes two new student chapters.
Washington University, St. Louis, Missouri: Julius M. Guccione, Faculty Advisor; Eric Boulogne, chapter officer; Vinayek Kini, chapter officer.
University of Rochester, Rochester, New York: Diane Dalecki, Faculty Advisor; Nathan Brown, President; Matthew Vessa, Vice-President; Ekene Udeoji and Jessica Svatek, Secretaries; Jason Smith, Treasurer.
Introduction
Cardiovascular disease represents the leading cause of death in the Western world. Treatment of heart disease often involves bypass surgery or angioplasty coupled with drug therapy to reduce plasma cholesterol and improve heart function. Synthetic grafts of expanded polytetrafluoroethylene (ePTFE, Goretex@) and polyethylene terephthalate (PET, Dacron@) function well when used to replace large blood vessels, but fail when used to replace vessels with inner diameters less than 6 mm. Endothelial cell seeding of synthetic vascular grafts represents a promising approach to reduce thrombogenicity and intimal hyperplasia. Endothelial cell function on synthetic grafts can be improved by insert ing genes to reduce or inhibit thrombus formation. The graft can be modified to release agents which inhibit smooth muscle cell growth and promote endothelial cell adhesion and function. In addition to providing blood downstream to a blockage, vascular grafts seeded with endothelial cells can be used as therapeutic vehicles to reduce the complications of atherosclerosis.
For synthetic grafts with diameters less than 6 mm, vascular graft acceptance requires an endothelial monolayer on the graft's luminal surface to reduce thrombosis. To encourage the development of a monolayer, grafts are seeded with endothelial cells prior to insertion. Seeding and implantation must occur quickly to minimize the likelihood of infection (1). Otherwise, a confluent monolayer will not form and a subconfluent layer of endothelium will be exposed to fluid shear stresses.
Endothelial cell adhesion to a synthetic surface involves a defined set of molecular interactions that influence subsequent cell division and/or protein synthesis. The focal contact is the site of closest approach between endothelium and a surface (Figure 1). Focal contacts are typically 0.5-2 µm wide and 5-10 µm long with separation distances between 10 and 40 nm (Figure 1). At focal contacts, adhesion proteins such as fibronectin (Fn) and vitronectin (Vn) bind to integrins, which are transmembrane protein dimers consisting of an a and b chain. Binding induces a conformational change to the cytoplasmic side of the integrin b chain which causes the cytoplasmic side of the integrin to bind with talin and a-actinin. Association of focal adhesion kinase (FAK) with the developing focal contact results in activation of FAK and phosphorylation of FAK, vinculin and paxillin. Phosphorylation of focal contact proteins stimulates actin binding to the integrins via vinculin and a-actinin, resulting in actin polymerization (Figure 2). Tyrosine phosphorylation is associated with the assembly and disassembly of focal contacts (2). Tyrosine phosphorylation appears to activate mitogen-activated protein (MAP) kinase (3) which ultimately stimulates the cell to divide.
In addition to focal contacts, several other regions of contact between the cell and surface are known. Close contacts represent membrane separations of 15-50 nm. Close contacts may function in cell migration since migrating cells lack focal contacts but exhibit extensive close contacts (4). Extracellular matrix contacts refer to regions separated from the surface by 100 nm or more. Extracellular matrix contacts arise after 24 h or more of adhesion and contain fibrils of Fn.
Endothelial cell adhesion to vascular grafts involves attachment and spreading on a rough synthetic surface, maintenance of attachment following exposure to flow, and normal function. Although considerable detail is known about cellular structures involved in adhesion, our understanding about how these structures resist and respond to fluid shear forces is poorly understood. In this article we review studies of cell adhesion and discuss mechanisms involved in adhesion and cell detachment.
Methods to Study Endothelial Cell Adhesion to Polymers
Adhesion can be characterized qualitatively by measuring cell spreading or the presence of focal contacts. Quantitative measurements of adhesion involve application of a known force to a cell in order to detach the cell. Several methods are available to measure strength of adhesion, including flow channels, micropipet aspiration, laser tweezers, and atomic force microscopy. In general, the choice of technique is influenced by the particular study objectives and the specific measurements planned. Atomic force microscopy or micropipet techniques are ideal to study loading of a small number of bonds located in a small contact area. Data on bond forces and bond failure rates can be obtained (5). However, studies in which a small number of bonds are loaded cannot be related in a straightforward manner to the case of spread endothelial cells adherent to polymers. Spreading and well-spread endothelial cells have bonds located in a number of small contacts distributed over the basal surface of the cell. In vivo, these bonds would see a very different loading history than the normal forces applied by biointerface probes and micropipet techniques. The measured adhesion strength depends upon the bond loading (6). In vitro laminar flow studies faithfully reproduce the loading on endothelial cells and the distribution of loading is important to properly interpret experimental results. A limitation to flow chambers is that the stresses are nonuniformly distributed over the cell.
A variety of flow chambers are available. Parallel plate flow chambers expose cells to a single shear stress. A range of shear stresses in a single experiment can be generated with radial flow chambers, variable width chambers, and variable height flow chambers. Due to heterogeneities in cell properties, cells detach over a range of shear stresses. Using a range of shear stresses in a single experiment reduces experimental variability. The critical shear stress (tc), which is the shear stress required to detach 50% of the cells from the surface, is determined by nonlinear regression of the log-normal distribution to cell detachment data. Others (7) have defined the critical shear stress as the shear stress at which cells begin to detach from a surface. The critical shear stress is used to compare the effect of various treatments to the cells or the surfaces upon adhesion.
Strength of adhesion data and the cell-substrate contact area permit calculation of the bond forces involved in adhesion and the mode of detachment. Contact areas and cell-substrate separation distances can be measured by electron microscopy, interference reflection microscopy (IRM) and related techniques, and total internal reflection fluorescence microscopy (TIRFM). Only IRM- and TIRFM-based techniques can be applied to living cells. Both IRM and TIRFM provide qualitative data on focal and close contacts. TIRFM is significantly more sensitive than IRM to small fluctuations in the contour of the membrane/substrate contact regions (8).
Based upon these considerations, we have developed the following strategy to study endothelial cell adhesion to polymeric surfaces. We measure the critical shear stress using a variable height flow chamber. We use confocal microscopy to reconstruct the three-dimensional shape of cells. Others have obtained higher resolution results with atomic force microscopy (9). Computational fluid dynamics is then applied to determine the stresses acting on the cells. We developed real time total internal reflection fluorescence microscopy (TIRFM) to measure changes in membrane separation distances. TIRFM provides important information to properly interpret flow experiments and can be used to evaluate loading on bonds.
TIRFM derives its surface sensitivity from the evanescent wave of a totally reflected monochromatic light beam that preferentially illuminates the ventral side of an adherent cell to a depth of a few tenths of a micron (Figure 3). In the case of a fluorescently labeled lipid membrane (e.g., diI-C18), the brightest regions of the cell image would be those regions closest to the interface. Quantitative TIRFM relies on the conversion of the spatial TIRFM intensity pattern into the spatial distribution of cell-substrate separations. Numerical calculations show that one can neglect the refractive index discontinuity presented by the 4 nm thick cell membrane, assign an effective cellular refractive index to the interfacial region, and use expressions for a simple dielectric interface to accurately approximate the evanescent intensity penetrating the surface-adherent cell (10). From this analysis the relative cell-substrate separation distance (D in Figure 3) is obtained from the TIRFM intensity of a dye-labeled cell membrane using the following relation:
where Do is the minimum cell-substrate separation distance, Fm(x,y) is the local fluorescence intensity, Fm(Do) is the fluorescence intensity at Do, and deff is the effective depth of penetration
where: Io is the wavelength of light; n1 and q1 are the refractive index and propagation angle of light in the incident phase (Figure 3); and neff is the effective refractive index of the cell/substrate interface. The effective cellular refractive index in Eqn. 2 is determined from Snell's law neff = n1sinqc where qc is the experimentally observed critical angle for total internal reflection (= 64 degree). Experiments are performed at an incident angle of 70degree, for which the depth of penetration is 101.41 nm. At such an incident angle, fluorescence from the dorsal surface is a small fraction of the total fluorescence and can be neglected (11).
Factors Influencing Endothelial Cell Adhesion
Experimentally, cell adhesion to polymers is influenced by manipulation of the following variables:
a. the surface properties which influence nonspecific and specific interactions (e.g., hydrophobicity, surface charge, presence of oxygen and amine groups);
b. the density and affinity of adhesion molecules on the surface;
c. covalent and noncovalent interactions between the cell and surface molecules;
d. the time of interaction between the cell and surface; and
e. signaling events within the cell to promote or inhibit cell spreading.
Cell attachment and spreading on artificial surfaces is mediated by bonds formed between cell adhesion proteins at the substrate surface and protein receptors embedded in the cell membrane. The role of adsorbed proteins in cell adhesion was reviewed recently (12). Adhesion is enhanced by incubating the graft with the recipient's plasma, adsorbing adhesion proteins such as Fn, Vn, or laminin, chemically modifying the culture substrate to promote adsorption of adhesion proteins, or covalently immobilizing peptides containing the cell binding domains of Fn (Arg-Gly-Asp or RGD) or laminin (Tyr-Ile-Gly-Ser-Arg or YIGSR) (13). Most animal studies to date indicate significant cell loss after implantation of vascular grafts seeded with endothelium, even after preadsorption of adhesion proteins.
Cell attachment and spreading do not simply depend upon the total surface density of adhesion proteins. The density of adsorbed adhesion proteins with accessible cell binding sites appears to be the important variable. Adhesion proteins undergo conformational changes upon adsorption. Conformational changes to the cell binding domain influence bovine aortic endothelial cell (BAEC) spreading, focal contact formation, and strength of adhesion (14). Differences in adhesion on glass and dimethyloctadecylchlorosilane treated glass were statistically significant at low Fn surface concentrations, and this difference in adhesion was primarily due to a difference in the affinity of Fn for its receptor. At higher Fn surface concentrations, a sufficient number of Fn-receptor bonds form to resist detachment on either surface, reducing the significance of differences in affinity. In addition to conformational changes upon adsorption, Fn may adsorb in a variety of orientations, some of which render the cell binding domain inaccessible to its receptor.
Conformational changes after protein adsorption may represent changes in the strength of the interaction between the adsorbed protein and the surface. For example, outgrowth of corneal epithelial cells from explant cultures appears to depend upon the amount of adsorbed protein as well as the resistance of adsorbed Fn to elution from the surface with sodium dodecyl sulfate and the exposure of the RGD binding site (15). Cell adhesion and migration may also be affected by how tightly the protein is adsorbed onto the surface.
Although adsorbed adhesion proteins promote cell adhesion, proteins may desorb and be displaced by other plasma proteins not involved in adhesion. Even greater control of protein attachment to surfaces is achieved with heterobifunctional crosslinkers. Cell attachment, spreading and proliferation of endothelial cells, fibroblasts, epithelial cells and osteoblasts were more extensive on polystyrene (PS) surfaces when the cell adhesion protein (type IV collagen and Fn) was photoimmobilized to the surface rather than adsorbed (16).
An alternative to immobilizing proteins is to attach peptides covalently. Covalently attached peptides containing the Fn cell binding domain sequence RGDS promote endothelial cell and fibroblast spreading and focal contact formation on polyethylene terephthalate (17) and polyurethane surfaces (18). The specificity of different integrins for these proteins may result from the local conformation of the RGD sequence (19). The sequence YIGSR on laminin is recognized by non-integrin receptors in the endothelial cell membrane and promotes adhesion and spreading (20). Other peptide sequences have also been implicated in cell adhesion, for example Arg-Glu-Asp-Val (REDV) from the alternately spliced type III connecting segment of Fn and Pro-Asp-Ser-Gly-Arg (PDSGR) from laminin (21). RGDS peptides bind to the Vn receptor (avb3) and not the Vn receptor (a5b1) (22).
Specificity can be introduced by changing the conformation of the peptide sequence, changing the specific amino acids flanking the cell adhesion sequence, or identifying unique receptors on the endothelial cell. Cyclization of RGD peptides constrains their adhesion sequence, resulting in increased affinity (23). Fibroblasts, endothelial cells, and smooth muscle cells attached and spread on RGD and YIGSR covalently coupled to either glycophase glass or polyethylene glycol modified polyethylene terephthalate (13). Only human endothelial cells spread on REDV peptides since these cells express the integrin a4b1 to which REDV binds (13). Surprisingly, RGD immobilized via the terminal amine does not promote attachment and spreading of quiescent or activated human platelets even though platelets contain receptors which bind to the RGD sequence (21).
Although soluble Fn and Vn have greater affinities for their receptors than soluble RGD peptide, RGDS covalently linked to hydrophobic glycophase glass induces spreading and focal contact formation at surfaces densities 100 times lower than those reported for adsorbed Fn and Vn (22). A possible explanation for this observation is that most of the adsorbed Fn and Vn are not in conformations or orientations favorable for binding to their respective receptors.
Mechanisms of Cell Detachment
Following exposure to flow, cells can detach by two mechanisms: failure of ligand-receptor bonds between membrane and the substratum (adhesive failure), and the mechanical rupture of the cell membrane (cohesive failure). Evidence to support receptor-ligand dissociation is the increase in the strength of adhesion when surfaces contain preadsorbed adhesion proteins as well as the correlation between the amount of adhesion protein adsorbed with the extent of cell spreading and the strength of adhesion (24). Studies with model cells (25) or endothelial cells (26) indicate that adhesion strength is logarithmically dependent upon the receptor-ligand affinity constant, as predicted by theoretical models (27).
The strength of adhesion increases as the contact time between the cell and surface increases (28, 29). Cell detachment of subconfluent cells is biphasic, with significant cell loss immediately following imposition of flow (29). Following long-term exposure to flow, subconfluent endothelial cells and fibroblasts detach either by progressive rounding or by the sequential detachment of cellular processes (28, 29). Adhesion strength is greatest on charged hydrophilic surfaces such as glass (28) as well as moderately hydrophobic polyethylmethacrylate (30), suggesting that adhesion is controlled by other factors besides hydrophobicity.
We examined whether smaller, rounder cells were preferentially detached by laminar flow, and whether cell detachment occurred by dissociation of adhesion proteins and their membrane receptors or rupture of the membrane (24). Shear-induced detachment from glass and silane was similar after 0.5h static attachment to the surfaces, even though 3T3 fibroblasts had a greater projected area on silane. No particular cell size was preferentially detached by fluid shear stresses. After 2 h attachment and spreading, 3T3 fibroblasts were more easily detached from the silane surface even though the cells were more spread than on glass. On glass, smaller cells were preferentially detached below 30 dyn e cm^-2. Above 30 dyne cm^-2, larger cells also detached from the surface. Cell detachment from the silane surfaces did not show any size preference. The strength of adhesion and projected areas on both surfaces increased significantly when the surfaces were preincubated with Fn. These results suggest a complex relation between spreading and the strength of adhesion.
Changes in adhesion strength with time can be explained in terms of biochemical events occurring at the site of contact. Within 15 min after binding to adhesion receptors, integrins bind to the cytoskeleton increasing the cell stiffness (31). Talin and FAK (focal adhesion kinase) rapidly interact with the developing focal contact. Actin polymerization increases twenty fold within 30 min of attachment, followed by depolymerization as the cell spreads (32). The actin polymerization rate is greater at higher ligand densities. Over longer periods of time vinculin, tensin, paxillin and a-actinin interact with integrins, stabilizing the contact.
Theoretical models indicate that focal contacts increase the strength of adhesion (33). Two mechanisms appear to be responsible: the rigidity of mature focal contacts distributes the stress among the bonds in the contact region, and interactions between integrins and the cytoskeleton produces receptor aggregation. Application of this model to experiments suggests that focal contacts are more rigid than the surrounding membrane. Studies with transfected cells containing integrin mutants missing parts of the cytoplasmic portion of the b chain which bind to cytoskeleton proteins indicate that association of integrins with the cytoskeleton increases the strength of adhesion (34).
Cell adhesion strength is dependent upon the amount of cell-substrate contact area. Limited data are available on the effect of surface properties upon the strength of adhesion and actual area of contact between the cell and substrate. We used TIRFM to examine the effect of surface properties on focal contacts and results were correlated with the strength of adhesion (30). Homo- and copolymer films of hydrophobic ethylmethacrylate (EMA) and hydrophilic hydroxyethylmethacrylate (HEMA) were spun cast onto glass slides. After 2 h, the close contact area of BAEC increased with increasing EMA content of the substrate. After 24 h, focal contacts were observed on 80%EMA/20%HEMA and 100%EMA surfaces. BAEC plated for 2 h were subjected to a brief exposure of laminar flow in a variable height flow chamber. Cell adhesion increased with increasing contact area, but for contact areas greater than 65 µm^2/cell further increases in contact area had little effect on the strength of cell adhesion.
Changing receptor-ligand affinity can improve the strength of adhesion under flow, but only if the cell surface receptor is linked to the cytoskeleton. Otherwise, the receptor is easily extracted through the cell membrane (35). Higher receptor-ligand affinity can increase adhesion in several ways. If adhesion is limited by binding equilibrium, the bond force increases logarithmically with the affinity constant (27). Alternatively, high-affinity binding also represents rapid receptor-ligand association (25) and adhesion strength is increased due to rapid bond formation and formation of large contact areas.
In order to evaluate the relation among ligand density, contact area, and the receptor-ligand dissociation constant, the strength of adhesion of BAEC was measured 15 min after attachment to immobilized linear and cyclic RGD peptides and adsorbed Fn (26). Adhesion strength was determined by exposing adherent BAEC to steady laminar flow in a variable height flow channel. Cell contact area was determined as a function of separation distance using TIRFM. At the lowest ligand density, the cell contour was very irregular, with many small projections (Figure 4A). At higher ligand densities, the contour became smoother (Figure 4B). Surfaces containing immobilized RGD and adsorbed Fn exhibited similar shapes. The contact area increased with increasing ligand surface density. For a given separation distance and ligand density, contact areas were slightly larger for BAEC attached to immobilized linear RGD than to cyclic RGD. Contact areas were significantly larger on surfaces with adsorbed Fn than on surfaces with immobilized RGD peptides.
A net force imparted on the cell reduces adhesion by applying stress to bonds. Increased bond stress reduces the dissociation constant for integrin and immobilized adhesion molecules. Although dissociation constants are known for adhesion molecules in solution, values for immobilized ligands are not known. As a result, dissociation constants for BAEC adherent to immobilized RGD peptides or adsorbed Fn were determined by nonlinear regression of models which assumed either that bonds were uniformly stressed or only bonds on the periphery of the contact region were stressed (peeling model). Both models provided equally good fits for cells attached to immobilized peptides, whereas the peeling model produced a better fit of data for cells attached to adsorbed Fn. Cyclic RGD and linear RGD both bound to the integrin avb3, but immobilized cyclic RGD exhibited a greater affinity than did linear RGD. Receptor affinities of Fn adsorbed to glycophase glass and Fn adsorbed to glass were similar.
Based upon this analysis, the number of bonds was calculated assuming binding equilibrium. A linear relationship between bond force and bond number is expected from theory (27). The peeling model produced good linear fits between bond force and estimated number of bonds. Results of this study indicate that: (1) bovine aortic endothelial cells are more adherent on immobilized cyclic RGD peptide than linear RGD or adsorbed Fn; (2) increased adhesion is due to a greater affinity between cyclic RGD and its receptor; and (3) the affinity of RGD peptides and adsorbed Fn for their receptors is increased following immobilization.
Some cells detach by cohesive failure, leaving behind membrane fragments. Such fragments have been observed by phase contrast, fluorescence and electron microscopy. The longer the exposure time to flow, the greater likelihood that cells deform and membrane fragments are produced (7, 24, 28). Surface properties appear to influence whether cells detach by cohesive or adhesive failure. When fibroblasts adhered to glass, tissue culture polystyrene, polymethylmethacrylate and teflon for short times in the presence of serum, few fragments were observed (7, 24, 28). When Fn was preadsorbed to glass, or copolymers of polyethylmethacrylate and polyhydroxyethylmethacrylate for 2 h, fragments were produced at shear stresses above the critical shear stress, but membrane fragments were not observed when cells detached from silane which contained preadsorbed Fn (24).
Cell detachment by cohesive failure likely results from extraction of the receptor through the cell membrane. This could happen even if the integrin had begun to interact with the cytoskeleton, since the affinity of vinculin for talin and actin is low (Kd = 0.3-0.8 µM) (36) with bond forces similar to the force required to extract receptors through the membrane. If the cytoskeleton-integrin binding were arranged in series, then failure would arise from the weakest linkage (37). The integrin may not dissociate from the cytoskeleton in a mature focal contact because it is held in place by multiple weak linkages arranged in series and parallel.
Preliminary data indicate that above the critical shear stress, many cells detach by membrane rupture. Thus, cells detach from the surface by two mechanisms: (1) by breaking individual receptor-ligand adhesive bonds at low contact areas where the cumulative strength of the adhesive bonds is less than the strength of the membrane; and (2) by membrane rupture at higher contact areas where the cumulative strength of the adhesive bonds exceeds the strength of the membrane.
Exposure of endothelial cells to flow elicits a variety of responses which affect the strength of adhesion. Focal contacts undergo rapid remodeling (38). Focal contact remodeling is influenced by adhesion proteins (38). Actin depolymerizes during the first three hours after the onset of flow (39), which may make focal contact remodeling and cell reorientation easier. Actin depolymerization leads to FAK inactivation (40) which may destabilize the focal contact. Actin depolymerization depends upon extracellular and intracellular Ca++ and protein kinase C (39). Disruption of the actin cytoskeleton with cytochalasin B increases cell loss after exposure to laminar shear stresses, whereas disruption of microtubules with nocodazole does not change the amount of cells detached (41). Following exposure to flow for 24-48 h, the actin cytoskeleton is reorganized, the cell becomes stiffer, and endothelial cells align in the direction of flow. Following exposure to flow for 24 h, Fn receptor expression is stimulated and vinculin and the Vn receptor are concentrated upstream (42), but the contact area does not change (38). Exposure to flow reduces the variation in the height of endothelial cells which decreases the peak shear stresses acting on the cells (43).
Focal Contact Dynamics
In order to maintain adhesion in the presence of flow, endothelial cells must maintain close contacts with the surface. A major unanswered question is how stresses are transmitted to cell/substrate contacts. According to the peeling model, the cell behaves as a membrane surrounding a liquid. For such a model stresses are transmitted through the membrane. The upstream portions of cell-substrate contacts are under tension and downstream cell-substrate contacts are compressed. More realistically, the cytoskeleton bears some of the load imposed by flow. If the stresses are transmitted along the cytoskeleton, the contact strain might be highest where hydrodynamic stresses are greatest. In order to investigate which mechanism best explains adhesion under flow, we used TIRFM to examine the short-term responses of cell adhesion sites of subconfluent cells to fluid forces. Prior to exposure to flow, there were small changes in cell-substrate contacts. Following exposure to flow, the basal surface of BAEC underwent dramatic reorganization. At 20 and 30 dyne cm-2, the total contact area increased initially. This change in contact area represented a change in the size and number of discrete contacts. This phase was followed by a decrease in contact area to static levels. In spite of these changes, the cells were not migrating. Mean contact location, which tracks focal contact movement as well as gain or loss of contacts, moved downstream initially but was oriented along the major axis of the cell, coincident with the cytoskeleton. After 15-20 min exposure to flow, the mean contact location recovered to its initial position. Similar results were obtained with confluent endothelium (38). The initial change in contact area and transients in mean contact location increased as the applied shear stress increased. These results cannot be explained in terms of a simple peeling model and are consistent with a model in which the stress is transmitted through the actin cytoskeleton.
Future Directions
Conclusions from recent studies about cell adhesion in the presence of flow are that: (1) adhesion strength is not simply proportional to the contact area; (2) cell/substrate contacts are not stressed uniformly after exposure of endothelial cells to flow; and (3) cohesive failure is a significant mode of cell detachment. In order to promote strong attachment, the failure site must be identified and strategies developed to produce rapid and strong spreading and adhesion of endothelial cells. Possible approaches include modulation of signaling pathways in focal contacts or the use of multiple ligands on the substrate surface. Alternatively, micropatterning technology could be applied to align cells prior to exposure to flow, possibly improving cytoskeletal linkage and reducing the force on cells (44). Finally, the function of adherent endothelial cells on vascular grafts must be examined. Important functions which need to be maintained include inhibition of thrombus formation, production of vasodilators and vasoconstrictors, and release of smooth muscle cell growth inhibitors.
Acknowledgments
Helpful discussions with Bruce Klitzman are gratefully acknowledged. We appreciate the assistance of Kevin Barber, Vinayak Bhat, Jeffrey Burmeister, Lauri Olivier, and Yao Xiao. This work was supported in part by grants NIH HL-44972, an American Heart Association Grant-in-Aid 93012390, and NSF grant BES-9421425.
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1997 April 6-9 Spring Meeting (with Experimental Biology) New Orleans, LA
1997 October 2-5 BMES Annual Fall Meeting, San Diego, CA
1998 October 9-11 BMES Annual Fall Meeting, Cleveland/Arkon,OH
1999 October 14-16 BMES Annual Fall Meeting(with EMBS) Atlanta, GA
2000 BMES Annual Fall Meeting, Seatle, WA
Faculty Positions in Magnetic Resonance Imaging
Department of Biomedical Engineering of the University of Virginia
Applications are invited for two tenure track positions in Biomedical Engineering at the Assistant/Associate Professor rank. Applicants should have expertise in: (1) development of high resolution 3D MRI for in vivo assessment, or (2) designing smart contrast agents for functional and morphometric measurement of the vasculature. The successful candidates are expected to participate in our biomedical imaging and vascular genetic engineering program. Applicants must hold a Ph.D. in relevant areas and industrial experience is viewed favorably. Please submit a curriculum vitae, a two-page description of future research plans, and names, addresses and phone numbers of three professional references to: Dr. J.S. Lee, Chair, Dept. of Biomedical Engineering, Box 377, Health Sciences Center, Univ. of Virginia, Charlottesville, VA 22908. www.med.virginia.edu/som-bas/biomed/BME.html Applications will be reviewed until the positions are filled. The University of Virginia is an Equal Opportunity Employer. Women and minorities are encouraged to apply.
Director/Head of Bioengineering Program/Department
The University of Illinois at Chicago, College of Engineering Announces a Position Opening For a New Director/Head of The Bioengineering Program/Department.
The University of Illinois at Chicago (UIC) has opened a search for a new Director/Head of the Bioengineering Program/Department. The University is adding new faculty resources to this area and has begun the process to move the program to department status. The individual chosen must qualify for the rank of Professor and have a strong record of sponsored research in his/her field of expertise. A doctorate in engineering or its equivalent is required. As Professor and Director/Head of Bioengineering, the individual selected will be expected to provide leadership to guide the growth of Bioengineering. A history of interaction with the medical sciences is desired. Bioengineering has strong interactions with the UIC Medical Center and Rush Presbyterian St. Luke's Medical Center. Currently, Bioengineering draws its faculty from the College of Engineering and the medical sciences and consists of 21 faculty, 8 adjunct faculty, 48 graduate students and 88 undergraduate students.
Bioengineering offers Ph.D., M.S., and B.S. degrees. Research thrusts are: biomedical imaging, biomechanics, biomedical microfluidics and sensors, biomaterials, rehabilitation, and biotransport.
Applications will begin to be reviewed February 15, 1997 but the position will remain open until filled. Applicants should submit their resumes with the names of four references to the following: Professor Daniel Graupe, Chairman, Bioengineering Program Director/Head Search Committee, c/o Office of the Dean, College of Engineering, The University of Illinois at Chicago, 851 S. Morgan, M/C 159, Chicago, IL 60607-7043, Phone (312) 996-3085 =95, Fax (312) 996-8664, E-mail graupe@eecs.uic.edu.
The University of Illinois at Chicago is an affirmative action/equal opportunity employer and encourages all qualified candidates to apply.
Tenure Track Faculty Position in Biomechanics
The Department of Biomedical Engineering in the School of Engineering at the University of Alabama at Birmingham has an immediate opening for a tenure-track faculty member with expertise in the area of bone biomechanics. The candidate should be able to collaborate with investigators in the UAB Biomedical Implant Center, the Metabolic Bone and Disease Center and in UAB's CDC-sponsored Injury Control Research Center (ICRC). A leadership position in the ICRC accompanies the appointment in Biomedical Engineering. Candidates must have a Ph.D. degree in an appropriate field, and must be a U.S. citizen or have permanent residency in the U.S. The search will be continued until the position is filled.
UAB is an autonomous campus within the University of Alabama system. UAB faculty currently are involved in approximately $200 million of externally funded grants and contracts, positioning UAB among the nation's leading research universities. Facilities for biomechanics research include instrumentation for mechanical testing, a drop tower, SGI workstations and software for finite element analysis, and laboratories outfitted for biomechanics experiments.
The University of Alabama at Birmingham is an equal opportunity, affirmative action employer, and encourages applications from qualified women and minorities. To apply send a current curriculum vitae, a listing of past and current research support, a single page summary of research and teaching plans and interests, and the names and addresses of three references to: Linda C. Lucas, Ph.D., Chair, Department of Biomedical Engineering, BEC 256, University of Alabama at Birmingham, Birmingham, AL 35209. Internet: llucas@eng.uab.edu; Phone: (205) 934-8422, FAX: (205) 975-4919.
Faculty Position
Biomaterials/Tissue Engineering
Arizona State University
Department of Chemical, Bio and Materials Engineering
The Chemical, Bio and Materials Engineering Department at Arizona State University has an opening for a Bioengineering faculty member in the area of Biomaterials at the Assistant or Associate Professor level. Qualified candidates must have earned a PhD in Bioengineering, Materials Science and Engineering, Chemical Engineering, or a closely related engineering degree. The essential functions of a successful candidate must be able to teach existing undergraduate and graduate courses in biomaterials and related engineering courses and to develop new courses in the candidates area of expertise in biomaterials. The successful candidate at the Assistant Professor level must have a strong interest in teaching at the undergraduate and graduate level. The successful candidate at the Associate Professor level must have evidence of proficiency in teaching at the undergraduate and graduate level. At the Assistant Professor level, the successful candidate must also have a demonstrated potential to develop an independent, externally funded research program in the candidate's area of expertise in biomaterials. At the Associate Professor level, the successful candidate must have demonstrated evidence of developing an independent, externally funded research program in the candidate's area of expertise in biomaterials.
It is desirable for the candidate to have background and expertise in biomaterials with active research in molecular and cellular engineering, tissue engineering, or related areas. However all areas of biomaterials will be considered. A record of publications in scholarly journals in biomaterials and related journals is also desirable at both the Assistant and Associate level.
Applications must be received by February 1, 1997, or the first of each succeeding month until the position is filled. Candidates must send a formal application consisting of a letter expressing interest in the position, a current vitae, a summary of past activity and future plans for research, teaching and service activities, and the names, addresses and telephone numbers of four references to: Dr. Vincent Pizziconi, Chair of the Biomaterials Faculty Search Committee, Department of Chemical, Bio and Materials Engineering, Arizona State University, Tempe, Arizona, 85287-6006. For additional information contact Dr. Vincent Pizziconi at (602) 965-1071 or via e-mail:vincent.pizziconi@asu.edu.
Arizona State University is located in the rapidly growing metropolitan Phoenix area. The Chemical, Bio and Materials Engineering Department has 27 faculty members and offers undergraduate and graduate degrees in three areas: Chemical Engineering, Bioengineering, and Materials Science and Engineering. Strong externally funded research programs exist in all three departments. Excellent research facilities are available for use within the department and at various multidisciplinary research centers on campus and local medical research centers. ASU Is An Equal Opportunity / Affirmative Action Employer.
Faculty Positions in Bioengineering
The University of Pittsburgh is expanding its active Program in Bioengineering which has been designated as one of the thrust areas for the School of Engineering. The Bioengineering Program, which is jointly sponsored by the School of Medicine, offers B.S., M.S. and Ph.D. degrees in Bioengineering, as well as certificates in Rehabilitation Engineering and Clinical Cardiovascular Engineering.
Currently there are 25 faculty closely associated with Bioengineering. Their respective disciplines span the fields of biomechanical engineering, biochemical engineering, tissue engineering, rehabilitation engineering, ergonomics, control systems, and biomedical imaging.
We are seeking four individuals who will hold faculty positions in Bioengineering within the School of Engineering. Faculty appointments will be commensurate with the qualifications of the candidates, i.e., at the assistant, associate, or full professorial level. These faculty will have a key leadership role in the further enhancement of our research and educational programs, particularly in conjunction with our Medical Center which ranks in the top ten in NIH funding. Incumbents should hold a Ph.D. and have significant experience in an academic setting including a proven track record of leadership and scholarly accomplishment. These are full-time, tenure stream appointments. Full consideration of applications will begin on January 1, 1997, and will continue until the positions are filled. A complete dossier should be sent to: Dr. Jerome S. Schultz, Chairman, Bioengineering Program, The University of Pittsburgh, 300 Technology Drive, Pittsburgh, PA 15219. The University of Pittsburgh is an Affirmative Action, Equal Opportunity Employer.
Biological Resources Engineering
Chair Search at University of Maryland, College Park
The Department of Biological Resources Engineering of the University of Maryland at College Park is seeking applications for the position of Department Chair. The Chair is responsible for leadership and administrative oversight of all departmental programs. The successful candidate must have a Ph.D. in engineering with a strong background in biological sciences, and a distinguished record of research, teaching, and extension service sufficient to be tenurable as a full professor. The Department is committed to enhancing its international reputation for excellence through integrated programs of teaching, research, and extension. The successful candidate must demonstrate strong leadership ability and be an able representative for the Department. The position is a 12-month tenure track appointment. Salary will be commensurate with qualifications and experience, and include liberal fringe benefits. The University of Maryland is an equal opportunity, affirmative action employer.
Evaluations begin January 1, 1997. Search will continue until a suitable candidate is found. A letter of application, vita, and the names of three prospective referees should be submitted to Professor Gregory B. Baecher, Chairman ENBE Search Committee, Room 1173 -- Building 088, University of Maryland, College Park, MD 20742, gbaecher@eng.umd.edu;
Biomedical Engineering Faculty Positions
The Biomedical Engineering department at Virginia Commonwealth University is seeking two individuals to join the tenure track faculty. Areas of interest include biomaterials and cellular engineering. The Biomedical Engineering department presently offers both the M.S. and Ph.D. degrees with an undergraduate program expected with a start of fall 1998.
Biomedical Engineering is located on the Medical College of Virginia (MCV) Campus, which is the 5th largest medical academic complex in the country. Our faculty interact with hundreds of medical collaborators in both clinical and basic research settings. Virginia Commonwealth University and MCV are located in Richmond, Virginia in a beautiful small urban setting less than 2 hours from Washington, D.C.
Biomedical Engineering has openings at both the assistant and associate professor ranks. Faculty are expected to support the departmental curriculum and to develop externally funded research programs. Applicants should possess a Ph.D. in bioengineering or equivalent degree and specialty. Evidence of teaching experience or ability with excellent oral, written and interpersonal skills are preferred. Demonstrated excellence in teaching, research and scholarly activities is also preferred.
Interested individuals should send a curriculum vitae and three references to: Dr. Gerald Miller, Chairman, Biomedical Engineering Department, Virginia Commonwealth University, P.O. Box 980694, Richmond, VA 23298-0694. Information regarding our programs is available on the Web at the VCU School of Engineering homepage (http://www.vcu.edu/egrweb). Virginia Commonwealth University is an equal opportunity/affirmative action employer. Women, minorities and persons with disabilities are encouraged to apply. Applications will be accepted until May 1, 1997 or until these positions are filled.
Address questions, comments, and corrections to:
Pin Lu
plu@cc.memphis.edu
Rita Schaffer
bmes@netcom.com
Last Updated: December 7, 1996