CBET Award Achievements
Notable Accomplishments from CBET Awards

A Miniaturized Probe for Combined Femtosecond Laser Microsurgery and Two-Photon Imaging (An Ultrafast Micro-Scalpel with Vision)

Adela Ben-Yakar  -  University of Texas at Austin

Background:  Lasers have found numerous applications as surgical tools in cell biology and the clinic for over four decades.  Traditional lasers, including both continuous wave and pulsed lasers, cut tissue by heating a small focused spot.  This linear thermal ablation mechanism limits the ultimate precision and safety of the technique, because heat dissipation often leads to cell death in the surrounding tissue.  On the other hand, femtosecond (fs) duration laser pulses (a femtosecond is a millionth of a billionth of a second), quickly vaporize the target volume of tissue.  Because of the ultrashort timescale, these lasers use much less energy to induce cutting than their conventional counterparts.  Taking advantage of near-infrared light wavelengths, they can provide greater penetration depth and make cuts within tissue without harming its surface.  For example, in previous work the Ben-Yakar group used femtosecond laser microsurgery (FLMS) to sever individual nano-scale neural pathways in a model organism, the nematode C. Elegans, opening the door to a wide range of heretofore impossible neurological studies.

Femtosecond laser pulses can thus extend surgical precision and reduce complications after surgery.  In addition, two-photon microscopy using the same lasers has proved itself as an ideal tool for deep-tissue imaging with a similar resolution and penetration depth to FLMS.  Despite the recent developments of several two-photon endoscopes, the delivery of high peak intensity pulses for FLMS leads to additional challenges and has prevented the realization of a combined FLMS/TPM endoscope.  To date, the combination of these two technologies has unfortunately been limited to large table-top systems in research laboratories.  With the recent advances of the Ben-Yakar group at the University of Texas at Austin, the benefits of fs-lasers for surgery and imaging have finally taken an important first step towards the clinical use.

The Ben-Yakar group has developed a unique miniaturized probe that combines fs-laser microsurgery (FLMS) with two-photon microscopy (TPM).  The successful development of the probe has been achieved thanks to an improved optical design and novel photonics devices such as photonic crystal fibers and MEMS scanning mirrors.  Using this probe, the Ben-Yakar group has demonstrated three-dimensional (3D) imaging of live cancer cells in tissue phantoms, which are 3D cell cultures engineered to mimic the optical properties of natural biological tissue.  In addition, selective ablation of individual cells was demonstrated inside the phantom with high precision.  Such a device constitutes a novel all-optical seek-and-treat tool, capable of diagnostics as well as microsurgery with unrivaled precision.  This combined FLMS/TPM device would be valuable in a variety of medical applications, from early cancer detection and removal, to dermatology.

Results:  The NSF-funded Ben-Yakar group has successfully created a small probe, smaller than a 9 volt battery, which uses low-energy femtosecond pulses for TPM imaging as well high-energy femtosecond pulses for FLMS.  This novel device incorporates a microstructured photonic crystal fiber which guides the laser pulses through an air core, thus overcoming the hurdles of self-phase modulation and material damage.  Inside the probe housing, the laser beam is scanned through a miniaturized relay optics system by a microelectromechanical systems (MEMS) scanning mirror, which allows for a maximum field of view of over 300 Ám in diameter and imaging speeds of 10 frames per second.  In addition, by incorporating a separate large-core collection fiber, the probe exhibits light collection efficiency comparable to that of our complex large-scale imaging system.

Using the probe, the Ben-Yakar Group has imaged and selectively ablated breast carcinoma cells fluorescently labeled within a 3D collagen-based medium.  In the experiments, the probe was used to image the cancer cells down to the working distance of the objective lens (210 Ám) and disintegrate single cells at this depth without disruption of neighboring cells.  This represents a significant achievement towards the development of a clinical all-optical ultrafast laser scalpel for diagnosis and treatment of numerous pathologies.

Ben-Yakar Image 1
Figure 1 - An Ultrafast Micro-Scalpel with Vision.
A three-dimensional rendering of the combined
femtosecond laser microsurgery and two-photon
imaging probe designed by the Ben-Yakar Group.
SEM micrographs of:
(1) the air-core photonic crystal fiber, and
(2) the MEMS scanning mirror design, are shown inset.

Credit:  Adela Ben-Yakar, University of Texas at Austin

Ben-Yakar Image 2
Figure 2 - Combined two-photon microscopy and femtosecond laser microsurgery of
breast carcinoma cells in a collagen-based 3D media.  These images are vertical slices,
reconstructed from a series of lateral image slices taken at various depths within the
sample, as shown in the schematic.  The first image shows a collection of three cells,
with the bottom cell targeted for ablation.  Following femtosecond laser irradiation, the
bottom cell has been clearly destroyed while the neighboring cells remain unaffected.

Credit:  Adela Ben-Yakar, University of Texas at Austin

Scientific Uniqueness:  The FLMS/TPM probe represents the first fiber-based and miniaturized optical system for combined femtosecond laser microsurgery and multiphoton imaging.  In demonstrating the probe, the Ben-Yakar Group became the first to use femtosecond laser pulses to successfully image and ablate cancer cells through a miniaturized fiber-based system.  This provides the proof-of-concept for a flexible tool capable of all-optical diagnosis and treatment of small regions of cancerous tissue based on femtosecond laser technology.

Work is notable because because it represents a crucial step towards creating a medical device capable of sub-micron scale cuts, hundreds of microns within tissue, with no collateral damage to surrounding cells and the device provides the imaging to guide such surgery.  For example, such a device would be capable of diagnosing cancerous cells within brain tissue and then removing all the diseased cells without causing harm to valuable neural pathways or healthy brain cells.  The probe created by the Ben-Yakar Group is the first known fiber-based FLMS probe.

Work is multidisciplinary: The realization of the FLMS/TPM probe has required interdisciplinary efforts in the fields of optics, electronics, biomedical instrumentation, MEMS fabrication, and cellular biology.  Further development of the probe will also include increased involvement from medical practitioners to help tailor the device toward different applications.

This project addresses the strategic outcome goals, as described in the NSF Strategic Plan 2006-2011, of:

(1) Discovery:  The technology developed here has expanded the frontiers of photonics by discovering novel ways in which to deliver and manipulate high peak intensity femtosecond laser pulses.  More specifically, the research provides a novel tool to aid physicians in their fight against cancer and other tissue pathologies with the highest level of precision and greater penetration depth.  In addition, the research has led to greater understanding in the field of biophotonics due to the knowledge gained in the interaction of ultrashort laser pulses in tissue as well as the delivery of ultrashort laser pulses through micro- and fiber-optics.

(2) LearningThis research has provided education and experience to graduate and undergraduate students through hand-on experimentation and design in a highly multidisciplinary environment.  Specifically, students have gained not only laboratory experience, but also public speaking experience at several high-profile conferences, writing experience through the writing of manuscripts, and intellectual property experience through the writing of patents.

This Nugget represents transformative research.  This novel technology may provide physicians with an alternative to traditional surgery lasers for precise surgical work.  This technology offers greater precision and the ability to ablate sub-surface tissue without damage to surface cells.  In addition, this technology provides an increase in patient safety, as 2-3 orders of magnitude less energy are needed thus reducing the risk of fire and collateral cell damage.  These factors combined can lead to a greater efficacy in treatment of epithelial and brain carcinomas, as well as improvements in the treatment of many other forms of disease.

This Nugget represents Broadening Participation.  The Principal Investigator is a woman.

Impact on Industry and/or Society:  This research has far reaching impacts within the medical community.  While lasers have found a large number of applications as cutting tools in many medical fields, most notably ophthalmology, dermatology, and otolaryngology, their potential has yet to be realized largely due to the intense heat deposition that is required for ablation.  By taking femtosecond lasers from the laboratory to the hospital, physicians gain a new tool that will allow them to work in high-sensitivity areas such as the brain, spine, vocal chords, and so on.  This research will also have indirect impacts on the femtosecond laser industry, which is currently working to develop cheaper and smaller femtosecond laser systems.  As the applications for these lasers develop, new design goals for laser systems arise which provide the impetus for the next generation of ultrashort laser systems.

Program Officer:   Leon Esterowitz
NSF Award Number:   0548673
Award Title:   Biophotonics: In-Vivo Femtosecond Laser Micro-Surgery Combined with Two-Photon Imaging using Optical MEMS Components
PI Name:   Adela Ben-Yakar
Institution Name:   University of Texas at Austin
Program Element:   7236
CBET Nugget:   FY 2008

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This Nugget was Updated on 25 September 2008.