# Presentation: 279042

## Translating Optical Technologies from Benchtop to Bedside

***Laser Microbeam and Medical Program (LAMMP)***
***Beckman Laser Institute and Medical Clinic***
***Department of Biomedical Engineering and Surgery***
- University of California, Irvine
*http://www.bli.uci.edu/lammp*

- Bruce J. Tromberg

**BLI**

## Beckman Laser Institute and Medical Clinic

- _[http://www.](http://www.bli.uci.edu/)__[bli](http://www.bli.uci.edu/)__[.](http://www.bli.uci.edu/)__[uci](http://www.bli.uci.edu/)__[.](http://www.bli.uci.edu/)__[edu/](http://www.bli.uci.edu/)_

## Five Beckman Institutes in U.S.

- Univ. of Illinois

- UC Irvine (1982)

- Caltech

- Stanford

- City of Hope
- Nat. Med. Ctr.

- Co-founders  Michael Berns and Arnold Beckman

- LAMP formed 1979; initiated BLI in 1982

## P41 Optics Centers

**Regional Laser and Biomedical Technology Laboratories (RLBTL)**
- PI, Robin Hochstrasser, University of Pennsylvania
- Multi-Dimensional infrared spectroscopy, _[http://rlbl.chem.upenn.edu/](http://rlbl.chem.upenn.edu/)_
**The Center for Fluorescence Spectroscopy (CFS)**
- PI, Joe Lackowicz, University of Maryland
- Fluorescence spectroscopy/sensing, _[http://cfs.umbi.umd.edu/cfs/](http://cfs.umbi.umd.edu/cfs/)_
**Laboratory for Fluorescence Dynamics (LFD)**
- PI, Enrico Gratton, University of California, Irvine, (formerly UIUC)
- Multi-dimensional fluorescence microscopy/correlation spectroscopy, _http://www.lfd.uiuc.edu/_
**Laser Biomedical Research Center (LBRC)**
- PI: Michael Feld, MIT
- Multimodal spectroscopy applied to human disease, _http://web.mit.edu/spectroscopy/_
- NIBIB
**Developmental Resource for Biophysical Imaging Opto-Electronics (DRBIO)**
- PI, Watt Webb, Cornell University
- Multi-photon microscopy and fluorescence correlation spectroscopy, _[http://www.](http://www.drbio.cornell.edu/)__[drbio](http://www.drbio.cornell.edu/)__[.](http://www.drbio.cornell.edu/)__[cornell](http://www.drbio.cornell.edu/)__[.](http://www.drbio.cornell.edu/)__[edu/](http://www.drbio.cornell.edu/)_

## Optics Across Spatial Scales

**0.1 ********m**

**1.0 ********m**

**10 ********m**

**1 cm**

**10 cm**

**500 ********m**

**5mm**

**1mm**

- {

**Transport**
**Sub-cellular structure**
**Development**
**Migration**
**Cell Death**

- {

**Proliferation**
**Hypoxia**
**Fibrosis**
**Edema**
**Necrosis**
**Inflammation**
**Angiogenesis**
**Degeneration**
**	**

- {

**	**

**0.1 nm**

**Bio-Molecular Dynamics**
**Diffusion**

- Light-tissue interactions, photon transport
*	**• ****Phototherapeutics***
***	******• ******Functional Imaging***
***	******• ******Modeling and Computation  ***

- LAMMP Core Expertise

## Light Tissue Interactions

**0.1 ********m**

**1.0 ********m**

**10 ********m**

**1 cm**

**5 cm**

**500 ********m**

**5mm**

**1mm**

*l**

- Diffuse

- Coherent

## 1st LAMP 

- Courtesy of National Geographic, 158:373  (1976)

**1****st**** LAMP **
**Laser Microbeam**

- CW beam: MW/cm2
- Pulsed: GW/cm2

## 1981 LAMP Technology

**Science** (1981) 213:505 – 513
- First use of NASA  digital image processing technology  in microscope imaging
- Laser damage spot is less than theoretical focal spot size (because of Gaussian).
- Technology applied to microsurgery in cell and developmental biology

## LAMP Impact

**Laser Microbeam Commercial Impact:**
- Cell Robotics
- PALM (Zeiss)
- Hamilton-Thorne
- Molecular Machines and Industries
- Arcturus (LCM)

## Developing LAMMP Technologies

- 	Subcellular Inactivation, Photodynamic Therapy and micro PDT
**1985-1990:** Laser Tweezers, Laser tissue ablation (dental, corneal, bone), multi-		photon mechanisms, ultra-fast ablation, photothermolysis
**1990-1995:** Dose Fractionation PDT, Photon Migration, Laser Zona Drilling, 		Optical Coherence Tomography, Doppler and polarization 	OCT, 			Photothermal Radiometery/Tomography, Dynamic Cooling
**1995-2000:** Multi-photon Microscopy, Laser Micropipette, OCT micro-endoscopy,
**	**Ovarian and Brain PDT
**2000-present:** Second Harmonic Tomography, Broadband Diffuse Optical 		Spectroscopy and Imaging, Combined optics and MRI, Spectral domain 		OCT, Second harmonic OCT, Combined MPM-OCT, Opto-elastic Imaging, 	Spatially-Modulated Tomography

**LAMP**

**LAM****M****P**

## Translational Technology

**Phase 0:** design, calibration, testing**Phase 1:** feasibility, safety (pilot)**Phase 2:** efficacy (limited trial)**Phase 3:** standardization, validation (multi-center)

**~10 yrs**

**~5 yrs**

- Blackboard to Bedside

**Low **
**barrier**

**Continuous feedback loop: humans, animals, cells **

## LAMMP Facilities

- Animal OR
- Clinic/ OR
- Modeling/Computation
- Cell/Tissue Engineering Biochem.
- Histopathology
- Photonic Incubator

*Reduce Translational Barrier*

## Facilitate Translational Technology 

**Optical technologies: ideal for bench to bedside**
- 	• Advanced Technology Suite: ~1000 sqft in BLI clinic
- 	• ~20 protocols; 2 Clinical Coordinators, ~400 subjects/yr
- 	• Clinic: ~4000/yr patient visits
**Multiple Portable Instruments**
- 	• UCIMC (cancer center/GCRC)
- 	• UCSF, UCLA
- 	• Army ISR
- 	• (UPenn, MGH, Dartmouth)

## Translational Technology

**Dynamic Cooling Device (DCD)**

**Licensed to Candela Laser (>12,000 units worldwide)**
**Selectively cools outermost layers of human skin during laser surgery allowing higher light dosages**
**More effective treatment with less pain, post-operative scarring**
**#3 revenue producer for UC**

- (Phase 0 ~1995)

## Translational Technology

**Dynamic Cooling Device (DCD)**

*J. Stuart Nelson, M.D., Ph.D*

## OCT Airway Diagnostics

- 133 patients
- 22 with laryngeal cancer
- Endoscopic photodocumentation
- The OCT device
- 1.3 m broadband light source
- frame rate of 1 Hz
- 1.6 mm x 6 mm image size
- Correlation of OCT images with histology

- Brian Wong, Zhongping Chen

*Z. Chen, B.Wong, M. Brenner*

- (OCT Phase 0 ~1993, endoscopy ~1999)

**Notes:**
JDS Uniphase
Broadband coherent light source
Axial scan frequency: 8khz
Custom fiberoptic OCT system
1310 nm Superluminescent diode
Axial and lateral resolution: <12m
Imaging depth: 1-2mm
Frame rate:  1 frame/sec
Custom sensing probe
Subjects Patients undergoing operative endoscopy for laryngeal pathology 
Correlation of endoscopic images, OCT images and pathologic specimens

## SCC Left Glottis rT2 

**500 ****μm**

**bm**

**slp**

**ca**

**tz**

**e**

- e: epithelium, bm: basement membrane, slp: superficial lamina propria, tz: transition zone, ca: cancer

## Optical Imaging in Thick Tissues

**800 nm NIR light**

## New Technology for Tissue Spectroscopy and Imaging

- Based on broadband modulation of semiconductor diode lasers, “photon diffusion” models
- Quantitatively separates absorption from scattering
- Tomography of biochemical composition and structure

***Time and Frequency-Domain Photon Migration***

- Tromberg et al.*  *Neoplasia 2, (2000).

- (Phase 0 ~1990)

## The Laser Breast Scanner

- -50-500 MHz (FDPM)-Full NIR (600-1000nm) ~ 30 s-Point-point scan measurement

- The LBS

- handheld probe

- Pham, TH., et al.  Review of Scientific Instruments, 71 , 1 – 14, (2000). Bevilacqua, F., et al. Applied Optics, 39, 6498-6507, (2000).

**LBS Phase 0 ~1997**

## Linescan Geometry

## Diffuse Optics Technologies

**Diffuse Optical Imaging (DOI)**
**Diffuse Optical Spectroscopy (DOS)**
**Humans**
- Breast, Brain, Bone, Muscle
**Small animal models**
- Whole body

## 
Quantitative Measurements, Biochemical Composition

Hemoglobin
Oxy-, Deoxy-, Met-, Total, Tissue oxygen saturation
% Water
Protein bound, deep tissue temperature
% Lipid
Cytochrome oxidase
Oxidized, reduced forms
Tissue Scatter Power
Density of cells, collagen, lipid
Exogenous probes
ICG, Methylene Blue, Evans Blue...NIR fluorescent probes, etc.

*Quantitative Measurements, Biochemical Composition*
**Hemoglobin**
- Oxy-, Deoxy-, Met-, Total, Tissue oxygen saturation
**% Water**
- Protein bound, deep tissue temperature
**% Lipid**
**Cytochrome oxidase**
- Oxidized, reduced forms
**Tissue Scatter Power**
- Density of cells, collagen, lipid
**Exogenous probes**
- ICG, Methylene Blue, Evans Blue...NIR fluorescent probes, etc.

- Diffuse Optical Imaging/Spectroscopy

## <40 Yr. Olds, BrCa diagnosis

- N = 16

- Based on Quantitative Optical Biomarker Measurements

## Pathology Response Predictions

| ITEM | Hb | O2Hb | H2O | LIPID | SP |
| --- | --- | --- | --- | --- | --- |
| SENSITIVITY (%) | 86 | 57 | 71 | 43 | 43 |
| SPECIFICITY (%) | 100 | 50 | 100 | 75 | 75 |

| Hb
& H2O |
| --- |
| 100 |
| 100 |

- Based on Optical Biomarker Measurements at day 6
- 11 patients, AC Therapy, 4 months

## MRI-Optics Co-Registration

- Coronal Slices

- Computation, visualization, hardware integration

## Network for Translational Research in Optical Imaging

- Univ. of Illinois

- UC Irvine

- UPenn

- Siemens Corporate Research

- MGH

- Dartmouth

**N**etwork for **T**ranslational **R**esearch in **O**ptical **I**maging

*>600 BrCA subjects NTROI-wide*

- http://www.bli.uci.edu/NTROI

**Breast Cancer “Multi-Dimensional Diffuse Optical Imaging”**

- UCSF

## Small Animal (drug discovery)
Xenogen, GE/ART, Siemens/VisEn, Kodak, CRI... 

Human
Philips, Hamamatsu, ISS, NIRx, Spectros, IDSI...

- Xenogen, GE/ART, Siemens/VisEn, Kodak, CRI...
***Human***
- Philips, Hamamatsu, ISS, NIRx, Spectros, IDSI...

- Diffuse Optics Commercialization

## Phase 0/1 Technologies

**BLI**

- ~ 5-10 in “Pipeline”

## Modulated Imaging

**Digital Light Projector**

**Structured light pattern**

*D. Cuccia et al., Opt Let 30 (2005)*

## Slide 32

## Slide 33

## Summary of LAMMP Impact

***Technology Transfer***
- 	• ~12-15 disclosures/yr, ~15 patents, ~15 pending
- 	• 4 startups, ~12 licenses
- 	• >$25 Million royalty revenue
***Training/dissemination***
- 	• >50 graduate students, postgraduate fellows
- 	• ~18 in academic positions around world
- 	• >2/3 from physical sciences/engineering
- 	• Trainees developing/applying LAMMP technologies

## Summary of LAMMP Impact

***LAMMP in Cancer***
- 	• First NCI Cancer Center with “Optical Biology”, “Photomedicine” (1992)
- 	• U54 Network for Translational Research in Optical Imaging: 4 P41 centers, 4 Cancer Centers
- 	• Multi-modality (optics+) imaging
***LAMMP in GCRC/CTSC***
***	***• Translational technologies core
- 	• Doris Duke Award (Metabolic Syndrome)

## Summary of LAMMP Impact

***LAMMP in Biomedical Engineering***
- 	• Core of Whitaker Foundation Grant
- 	• Formation of Department in 2003, Undergrad 	concentration in BioPhotonics
- 	• 500 UG majors, 90 Graduate students
***LAMMP in Systems Biology***
- 	• Core in HHMI/NIH training grant
- 	• Graduate program, fall 2006

## Conclusions

- Translation takes time:
- Overcome ***technical*** and ***cultural*** barriers
- Feasibility, validation, acceptance of new paradigm
- P41 ideal: promotes technology, dissemination, training
- Multiple Pathways: Traditional licensing vs. investigator initiated
- Having both is healthy, ensures pursuit of “true solutions”
- Optimize technology impact
- Time to find best match for ideal solutions
- Proportional to collaboration, dissemination

## Conclusions

**Broad Impact of Optics in Medicine**
- High risk, difficult to access subjects
- Frequent scans/procedures, longitudinal studies
- Bedside, field: technology to patient
- Multi-modality imaging: *low $$ add on*
- Imaging therapy
- Monitoring/predicting drug response
- Understanding mechanisms
- Feedback for surgical guidance

## Acknowledgments

**LAMMP Coordinator, Webmaster:** *Jennifer Dorwachter, Brian Hill*
**LAMMP Clinical Coordinators:** *Montana Compton, Debbi Gordon*
**LAMMP Core Managers:** Translation: *Albert Cerussi *
*	**	**	**    *Microbeam:* Tatiana Krasieva*
**LAMMP Faculty:** *Zhongping Chen, Vasan Venugopalan, Tony Durkin, Bernard Choi*
**Collaborators:** *Stuart Nelson, Brian Wong, Matt Brenner, Petra Wilder-Smith, Michael Berns, Vickie LaMorte, Ron Frostig, Lydia Su, Orhan Nalcioglu, David Hsiang, John Butler, Rita Mehta*

## Acknowledgments

**NCRR*** P41 Laser Microbeam and Medical Program*
**NCI*** U54 NTROI, Chao Family Comprehensive Cancer Center*
*CA-Breast Cancer Research Program *
*Arnold and Mabel Beckman Foundation*
*AFOSR MFEL Program*

## Light Propagation in Tissue

**Multiple Light Scattering **

## Hand-held Scanner

- 10 mm

- +30

- -30

- -10

- 0

- -20

- +10

- +20

- SCAN DIRECTION

- -Y

- +Y

- x

- y

## Cortical Spreading Depression:Chromophore Maps vs. Time

- Cortical Spreading Depression:Chromophore Maps vs. Time

**Average Chromophores vs. Time, using ****λ****=740, 770, ****800 and 830 nm**

**(full data set acquired every**
**6 seconds for 30 min****)**

## Modulated Imaging: Wide Field Tomography

**x**

**z**

**y**

- lens

- mirror

-  bandpass filter

- condenser

- mercury lamp

- spatial light modulator

- digital projector

- tissue or phantom

- CCD

- Reflected Intensity

- Demodulated AC

- Input Intensity

*D. Cuccia et al., Opt Let 30 (2005)*