Biophotonics Technology Center (BTC)

Co-Directors:

Rationale

Biophotonics has been identified by the U.S. National Academy of Sciences (NAS) as a critical area that should be considered a high national priority (see NAS 2012 report: Optics and Photonics: Essential Technologies for our Nation). In addition, the White House has announced a competition to establish a National Center for Photonics. More recently, the President announced a national priority in “precision medicine,” an area where biophotonic technologies will play a key role. Thus, an internal (within the campus) establishment of a center/program that focuses on biophotonics seems appropriate. UCSD already has a strong representation of faculty from several departments whose research embodies the use or study of photons and their interaction with biological systems. These interests and applications extend from the basic science of molecular imaging and biophysics of photon interaction with cells and tissue, to the clinical realm of drug delivery, non-invasive diagnostics, and therapy. The combination of these sub-disciplines into a focus area in the IEM will provide a strong interface of engineering and medicine that would attract students, top faculty, and funding. The result will be a unique and high-caliber focus that would further distinguish the IEM and UCSD nationally and internationally.

Objectives

The primary focus of the Biophotonics Technology Center (BTC) is to foster research collaboration amongst its members, as well with non-member faculty who collaborate with a BTC member. The translation to the private sector of discoveries made by member of the BTC is also a major objective. Several mechanisms are used to achieve these goals.

First, the BTC will provide funding for innovative pilot projects that are too early to garner funding from conventional venues (government, foundations, industry, etc.). These “spark” awards will be in the range of $50K-100K/year direct costs for one or two years. It is anticipated that 2-4 awards can be made each year. The funds can be used for graduate student and postdoctoral fellow support, but not for faculty salaries. The type of projects funded will generally deal with mechanisms of photon interaction with biological systems, the use of photons to manipulate cells and or tissues, and the application of photons in clinical diagnostic or therapeutics systems.

Second, to foster collaboration and interchange, there will be an annual one-day symposium devoted to oral presentations in the field of biophotonics. The speakers will be a mix of internal (UCSD) and external presenters from industry and other San Diego area research institutions. The intention of the symposium is to foster collaboration.

Third, mechanisms to foster collaboration will unfold with the success of the BTC program and will be in the form of either program project grants, IGERT awards, or grants from agencies where multidisciplinary collaboration is emphasized.

In summary, the formation of a Biophotonics Technology Center under the umbrella of the Institute for Engineering in Medicine (IEM) will establish a campus focus that matches a national priority, foster collaboration between faculty, faculty and the surrounding private sector, attract top students and post docs, and eventually garner funds from other sources (government, foundations, industry, and donors).

Cell Manipulation by Light: Cell Surgery/Nanosurgery and Optical Tweezers

Photons have been successfully applied to study and manipulate live cells and organelles since the Russian Tchakotine first used UV radiation to ablate areas of single cell marine organisms in the 1920’s. Lasers became available in the 1960’s and within ten years “laser partial cell irradiation” (laser scissors) became a widely accepted method to study cell and organelle structure and function. The application of laser scissors/nano-ablation to manipulate embryos to improve fertility, to facilitate the application of PCR for pathological molecular diagnosis, and to study basic cell biology questions of motility as well as DNA manipulation (DNA repair), are growing areas of application  and ones in which UCSD have strong faculty representations.

The ablation/alteration processes are still not well understood in living systems. This also is  a focus of this sub-discipline. In this regard, problems such as single and multiphoton ablation, as well as nonlinear microplasma and shockwave alteration of cells (and tissue), are important.  For example, shockwaves can be generated with a short pulsed laser beam and the mechanism of impact as well as the signal transduction of this impact can be studied in neurons from rats, mice, and iPS stem cells. This system provides a unique model for traumatic brain and spinal cord injury.

Complementing cell surgery/nanosurgery is the use of optical traps to study and manipulate whole cells, their organelles/structures, and materials that may interact with cells. This field was spear-headed in the late 1980’s with Arthur Ashkin’s seminal work demonstrating the use of light to trap cells and subsequently organelles outside and within cells (including the DNA molecule itself). This field has grown exponentially and includes study of the DNA molecule, the interactions between cells, motility of structures within cells, isolation of normal from cancer cells, and light-tweezer induced mechanotransduction.  In addition, the introduction of circular polarized laser tweezers as well as multiple tweezers has spawned research involving the study of torques and 3-D optical traps.

UCSD has a strong faculty representation in the areas of cell ablation and optical trapping. A major objective of the BTC will be to facilitate/stimulate interactions between these as well as with other faculty and students in the UCSD and surrounding community.

Microscopy and Molecular Imaging

The discovery and development of genetically-encoded fluorescent proteins (FPs) have revolutionized the biology and medicine by allowing the visualization of molecular localization in live cells and animals (Nobel Prize in Chemistry, 2008). Biosensors based on FPs and fluorescence resonance energy transfer (FRET) could further transform our ability to visualize subcellular molecular and signaling activities in live cells with high spatiotemporal resolutions. In this center, we will integrate the imaging technologies, including cutting edge optical microscopy, and molecular biosensors to establish an unprecedented and state-of-the-art multi-scale imaging capability that will enable scientific breakthroughs in life sciences. The strategy developed can be readily extended for the study of, in principle, any signaling molecule and network. Therefore, this microscopy and molecular imaging study will not only advance our fundamental and in-depth understanding of molecular mechanisms regulating cellular functions but it will also provide a general platform and strategy for the correlative molecular imaging of different signaling molecules to translate between the molecular structures, functions, and physiological consequences. Hence, the success of the proposed project will revolutionize the ability to perform live cell imaging and study molecular functions, and have transformative impact on cell biology and medicine.

The above two areas (Cell Manipulation and Microscopy/Molecular Imaging) are the initial main areas of activities. Other areas to be developed are:

MEM/Microscale Interfaces

MEMs and other micro and nano-scale systems are important in biology, engineering, and medicine. The BTC, through its interdisciplinary focus around photonics and engineering will be ideally positioned to contribute to the area and strengthen contacts with the private sector, as most of these systems have commercial value. Some examples are:  optically interfaced chips for cell analysis and separation (Professors Lo and Esener). This area also would encompass drug screening because of the ability to have high thru-put drug screening on a multi-channeled chip. In addition, this area will be a major player in the “personalized medicine” arena, where optical analysis of drug response on an individual patient basis will behave a major future in medicine as well as the Pharma industry.

Tissue Imaging, Diagnostics and Therapy

  • Drug delivery/Therapy: the use of light in association with photodynamic terapy and diagnosis of cancer is rapidly evolving and important area.
  • Nano-tumor biology: nanoscale systems is an important are in cancer treatment and diagnostics as well as in other  areas, such as in ophthalmology
  • Endoscopic applications (OCT): OCT in the eye is well establishes, but it is now being developed via miniaturization of the imaging systems for insertion through a channel of an endoscope,. This is opening up applications in the airways, digestive system, urogenitoal systems, and through catheters for imaging of the heart and many internal organs.
  • Diffuse optical spectroscopy (DOS): This is a relatively new area that is being developed particularly in the areas of breast and skin cancer. It has the potential to provide tissue differentiation based on  blood chemistry in the tumor as well as different tissue types within the tissue (ie benign versus malignant lesions). DOS is also being developed as a way to assess how a particular is responding to therapy (chemo, radiation etc).
  • Dermatologic applications: Other than ophthalmology, dermatology uses light (photons) more than any other discipline. It is sued for treatment of pigmented and vascular lesions which are quite common. However, there is a need to improve on the optical delivery and monitoring (while treating). Understanding the physics of the light interaction is important to use the light most effectively. This is an area that has a very strong applied clinical relevance. Hiring Dr. Arisa Ortiz to direct the laser clinical studies in the department of dermatology presents a strong opportunity for interface with the BTC.

Interactions with other Centers

The BTC provides the expertise and resources for other IEM Centers in biophotonics research on cardiovascular (CBSEC), musculoskeletal (CMSR), neuroengineering (CANE), retina (REC),   and perinatal (CPNH) research. The BTC also will interact with CNME in nano-medicine/engineering, CMDT for medical devices, and WCBE for industrial relations. Biophotonics will play a key role in the President’s recent announcement of a national push in “precision medicine.” Many of these systems will be optically based.

Medical Benefits

A fundamental motivation for the BTC is to foster collaboration between clinicians, engineers, and basic scientists in the quest for new knowledge that leads to applications that benefit human health. This will be achieved by not only understanding the basic mechanisms of photon interaction with living systems, but also on how to use that knowledge  to engineer systems to gain a better understanding of the normal and diseased/altered state. This will lead to development of new biomedical technologies and procedures for diagnosis and treatment, and will be fundamental to newly developed technologies in “precision medicine.”

Interface with Private Sector

San Diego is a hub for biotech and health-related corporations and foundations, as well as healthcare delivery organizations.  Many of the diagnostic, pharma, and device development companies in the San Diego area employ photonic technologies in their R&D or product line devices. In addition, many of the BTC faculty already have established relationships with these companies The BTC will serve as a photonic resource focal point as well a catalyst for  the development of new photonic-based technologies, and as an expanded interface between UCSD and the technology community. 

Funding

Members of the BTC will have their own funding form the traditional government and private sources (NIH, NSF, DoD, Private Foundations, etc). As members of the BTC this should help in obtaining their grants because of the additional expertise and resources that will be available through the BTC. Examples are the four laser manipulation microscopes in my lab, and the state-of-the-art fluorescence lifetime microscopy and macroscropy in the co-director, David Hall's lab. In addition, the availability of the “spark” awards as seed money for projects, will allow feasibility studies that will facilitate success in a subsequent major grant. The BTC will also be eligible for program project awards, equipment grant awards, and training grants from either the NIH or the NSF (IGERT). One the center is established and operating for a year or two, applications will be considered to these various entities. Finally, the BTC may partner with the private sector for SBIR grants.

Centers