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AGNOSTIC DIAGNOSIS
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HISTOINDEX – BRINGING DIAGNOSIS INTO BIOPSY
World’s first suite of fully-automated, 3-D, quantitative, laser-
based imaging system for tissue imaging
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WHAT ARE CUSTOMERS LOOKING FOR?
PRICE
SPEED
TARGET
CUSTOMER
ACCURACY
SPECIFIC
OBJECTIVE
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Tissue-Specific Image Analysis and Quantification
for Research and Clinical Applications
WHAT DO WE OFFER?
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• How did the
disease
progress/re
gress?
• Why did
that happen?
• When is
treatment
needed?
• What
treatment
to give?
CLOUD-BASED
GENESIS®
LAENNEC™
DISEASE-SPECIFIC ASSESSMENT
HOW IT WORKS
LASER
cells
ECM
Improvement in accuracy of tissue diagnosis from 65%
to more than 95%
Bedossa et al., Hepatology 20, 15-20 (1994); Gronbaek et al., Journal of Viral Hepatitis 9, 443-
449 (2002); Theodossi et al., Gastroenterology 79, 232-241 (1980); Theodossi et al., Gut 35,
961-968 (1994); Westin et al., Liver 19, 183-187 (1999)
He et al., Journal of Biomedical Optics, 15(5) 056007, 2010.
Bredfeldt et al., Journal of Pathology Informatics, 5(1), 28, 2014
Raja et al., Journal of Biomedical Optics 15(5) 056016, 2010.
Gailhouste et al., Journal of Hepatology 52, 398-406, 2010.
Asselah et al, Journal of Hepatology 61, 193-195, 2014.
Tai et al., Hepatology 50(4) 1093, 2009.
Tai et al., Journal of Biomedical Optics, 14(4) 044013, 2009.
Xu et al., Journal of Hepatology, 61, 260-269, 2014.
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HOW IT WORKS
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REVOLUTIONARY TECHNOLOGY
Stage 1 Stage 2 Stage 3 Stage 4
HistoIndex Stain-Free
Stage 1.2 Stage 2.5 Stage 3.1 Stage 4.7
Current Method
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KEY BENEFITS
1 – 3 days
Sample Staining Imaging Staging Diagnosis
0.5 – 1 hr
Diagnosis
HistoIndex
Stain-free Technology
Sample
 Patients (Hospitals and Clinics):
Same day results – greater accuracy & efficiency
 Users (Researchers, Drug companies & CROs):
• Higher specificity & sensitivity
• A "translational" program to measure drug efficacy from
the start of preclinical studies to the end of the clinical
trial
• Assessment of incremental improvement in treatment
efficacy
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WHAT IS THIS NEW STANDARD?
Hardware Genesis®200
Multi-photon microscope
utilizing a high power laser
Customized optics
Fully automated
One-touch operation
Unstained tissues
Multi-organ capabilities
Computer-assisted
tissue diagnostic
system
HISTOINDEX
is setting a
NEW STANDARD!
Software FibroIndex™ +
LiverCloud™
Quantification for decision
support database
3D visualization
Cloud-based database & online
assessment
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GLOBAL PRESENCE
Physical units placement
Clinical/Research sites with samples sending to HistoIndex’s global
Imaging Service Centres
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TISSUE-SPECIFIC IMAGE ANALYSIS &
QUANTIFICATION
FIBROSIS
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Research Development Validation Commercial
Liver
Kidney
Lung
Bone Marrow
Eye – AMD, Glaucoma
Heart
Brain – AD
Skin
Hair
Launch 2Q2016
Launch 2Q2016
Published
Explorations
In
Partnerships
TISSUE-SPECIFIC IMAGE ANALYSIS &
QUANTIFICATION
ONCOLOGY
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Research Development Validation Commercial
Breast
Prostate
Bladder
Vs Genomic Markers
3Q2016 3Q2018
Vs Genomic Markers
3Q2016 3Q2018
Vs Genomic Markers
3Q2016 3Q2018
Target Intent of Use:
To provide Physicians (e.g.
Urologists) with adjunctive
information to subclassify tumor
stages
FIBROSIS IN LIVER VALIDATION PATHWAY
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HistoIndex Pte.Ltd. property. All Rights Reserved
IMAGE ANALYSIS & QUANTIFICATION TOOL
Quantification of
Cell Damage
Quantification of
Collagens
Hepatocytes’s NAD(P)H and
Flavins intrinsic florescence.
Areas containing nucleus, lipid droplets, and the vacuoles
formed by degenerated hepatocytes appeared dark in the
TPEF image( lack of the fluorescent molecules)
Aggregated and
distributed collagens
are revealed and then
quantified
FIBROSIS
LIVER FIBROSIS
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• A SHG may open new opportunities in the quantification of collagen content in different
organs, which is of main importance in providing diagnostic information and evaluation
of therapeutic efficiency
Morphological changes at different stages 1 to 4 of liver fibrosis recorded with (a) to (d)
conventional Masson Trichrome staining, as well as (e) to (h) SHG and TPAF microscopies.
In stage 1 liver fibrosis, there was presence of pericellular collagen without the septa formation in
(a) and (e).
In livers with stage 2 fibrosis, (b) collagen aggregations formed incomplete septa from the portal
tract to central
vein, and (f) the bile duct proliferation was seen as dim regions in the SHG image.
For stage 3 liver fibrosis, profuse bile duct proliferation
was observed all over the tissue sample, where complete but thin collagen septa interconnected
with each other in (c) and (g).
In stage 4 fibrosis, thick collagen septa were observed, forming complete cirrhosis in (d) and (h).
Red: TPAF
Green: SHG
RENAL FIBROSIS
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• Combined SHG and TPAF imaging can provide simultaneous three-dimensional visualization
of collagen synthesis and assembly sites in transgenic animal models expressing GFP
constructs
• SHG is used to image collagen fibers in human and mouse unstained kidneys. This
approach allows quantitative 3-D imaging of interstitial fibrosis and arterial remodelling with
high accuracy.
SHG TPAF Overlay
SHG imaging showing increased tubulointerstitial
fibrosis and disrupted extracellular matrix in tissue
inhibitor of metalloproteinase-3 (TIMP3)
SHG and TPAF imaging in unfixed and unstained kidneys
showing the fibrillar collagen network (magenta) and tubular
endogenous autofluorescence (green) in wild-type (WT) and
TIMP3−/− kidneys at 3 days after unilateral urethral
obstruction (UUO)
PULMONARY FIBROSIS
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• Using TPAF, we can characterize normal and fibrotic pulmonary tissue in the bleomycin
model, and show that SHG by fibrillar collagen reveals the micrometer-scale three-
dimensional spatial distribution of the fibrosis
• TPAF is able to differentiate neoplastic from nonneoplastic lung tissue and identify
tumour subtypes. In the future larger studies, we foresee real time intraoperative
applications of TPAF
TPAF and hematoxylin and eosin (H&E) images of
progression from atypical lesion to various
patterns of invasive adenocarcinoma of lung
a) and b) Images of atypical adenomatous hyperplasia shows a focus of pneumocyte
proliferation along the alveolar wall
c) and d) Images of adenocarcinoma of lung with lepidic-predominant pattern and a few
clusters of free-floating tumour cells
e) and f) Images of adenocarcinoma of lung with acinar-predominant pattern
g) and h) Images showing solid pattern (arrows) with suggestion of gland formation
i) and j) Images showing papillary pattern
k) And l) Images showing micropapillary pattern, with complete destruction of normal
lung parenchyma
MYELOFIBROSIS
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• TPAF or SHG is a promising novel technology to be applied in quantification of
myelofibrosis, with performance equivalent to a stereology-based approach.
Further studies with large sample size are needed to validate the utility of this
method.
Fibrosis score = 0 Fibrosis score = 2+ Fibrosis score = 3+
Myelofibrosis is the proliferation of an abnormal clone of Hematopoetic Stem Cell (HSC) which results in fibrosis.
0 represents the least damage, while 3+ represents the most damage on the myeloproliferative neoplasm.
Green: SHG
Red: TPAF
DERMAL FIBROSIS
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• SHG is used to measure the significant differences in thickness of epidermis
and stratum corneum, and modified degrees of fibrosis in dermis, are clearly
demonstrated in in vitro studies
Transversal optically sectioned ex-vivo skin sample of healthy dermis
(a) SHG, (b) TPAF, (c) merge between the two images
Transversal optically sectioned ex-vivo sample of normal scar (NS)
(d) SHG, (e) TPAF, (f) merge between the two images
Area with fibroblastic proliferation inside a transversal optically sectioned ex-vivo
skin sample of keloid
(g) SHG, (h) TPAF, (i) merge between the two images
Area with keloidal fibers inside a transversal optically sectioned ex-vivo skin
sample of keloid
(j) SHG, (k) TPAF, (l) merge between the two images
Blue: TPAF
Green: SHG
SUBEPITHELIAL FIBROSIS ON CORNEA
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• Using SHG, we detected the presence of subepithelial fibrosis at the anterior stroma
and disorganized collagen lamellae at the posterior stroma of the bullous keratopathy
cornea
• SHG imaging of the anterior segment of edematous corneas revealed a normal
appearance of interwoven collagen lamellae in the anterior stroma
SHG images of the anterior segment of the stroma in
normal (A) and edematous corneas (B).
Short, narrow bundles of linear structures in random
orientations are apparent in both corneas. (C, D)
Image of Subepithelial Fibrosis Associated
with Corneal Stromal Edema by SHG
RETINAL PIGMENT EPITHELIUM
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• Dysfunction Retinal Pigment Epithelium (RPE) will cause damages to the retina. Hence,
TPAF is used because it is an elegant and highly efficient tool to delineate the thick, fragile,
and opaque retina-choroid complex, and may provide clues to the trigger events of age-
related macular degeneration
TPAF signals from the 19-year-old macular RPE cells were acquired with two
spectral windows colour coded in (a) green and (b) red
(c) Merged TPAF images of the 19-year-old RPE cells
(d), (e) and (f) Corresponding TPAF images of the 64 year-old macular RPE
cells respectively
ARTERIAL FIBROSIS
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SHG and TPAF provides label-free molecular imaging of atherosclerotic lesions with 3-D
submicrometric resolution suggests its potential application to the diagnosis of
atherosclerotic plaques, determination of their rupture risk, and design of individualized
drug therapy based on plaque composition
D SHG E TPAF SHG/TPAFF
SHG TPAF SHG/TPAFCA B
Healthy Arteries
Atherosclerotic Iliac Arteries
a) SHG image of collagen
b) TPAF image of elastin in a healthy artery
c) Overlaid image of a and b
d) SHG image of collagen
e) TPAF image of elastin in an atherosclerotic artery
f) Overlaid image of d and e
Green: SHG
Red: TPAF
CARDIAC FIBROSIS
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• By using SHG to analyze the arrangement of collagen fibers, we can provide explicit information about the
relationship between myocardial fibrosis and Atrial Fibrillation (AF)
• A significant increase in the density of collagen fibres between hypertrophic and control tissues was evident
using SHG. Similar increases and patterns of staining were observed using parallel traditional picrosirius red
staining of collagen
Co-localized SHG (shown in white) and TPAF (shown in blue)
images visualize collagen fibril organization and cardiac muscle
cell nuclei, respectively, in the histological section of infarcted
myocardium of
(a) an untreated infarcted rat heart;
(b) an ASCs-treated infarcted rat heart;
(c) an image obtained from a histological section of a non-MI rat
heart
ALZHEIMER’S DISEASE (AD)
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• Using SHG and TPAF, the results suggest that tissues from AD transgenic
models contain distinct intrinsic emissions, which can provide valuable
information about the disease mechanisms
TPAF
a) TPAF
b) SHG
c) overlay of the hippocampus of a 17-month old mouse
d) Senile plaques emit TPAF that were morphologically distinct
from other sources of intrinsic emissions and were missing from
wild type
Images from acute hippocampal brain slice
of transgenic Alzheimer’s disease mouse
models
FIBROSIS IN DUCHENNE MUSCULAR
DYSTROPHY (DMD)
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• Second harmonic generation (SHG) imaging may soon be available in routine
clinical diagnostics, and in this work we provide valuable imaging tools to track
and quantify ultrastructural worsening in Duchenne Muscular Dystrophy (DMD),
and to judge the beneficial effects of possible drug or gene therapies
Co-imaging of TPAF and SHG shows that
the fascicle with abnormal sarcomere
angles sticking out of the main trunk is fully
covered by membrane
Red: TPAF
Green: SHG
CONTRACTION MODEL OF WOUND REPAIR
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• Since structural remodelling of collagen is important in fibrosis, SHG and Two
Photon Auto Fluorescence (TPAF) signals can be used in tandem to provide
spatially resolved 3-dimensional structural remodelling of a collagen matrix
A) SHG image of collagen matrix
B) TPAF image of contracted fibroblasts
C) Overlaid image of collagen matrix and contracted fibroblast
A) SHG image of collagen matrix
B) TPAF image of non-contracted fibroblasts
C) Overlaid image of collagen matrix and non-contracted fibroblasts
Gray: SHG signal strength
Green: Elongated Cell Peripheries
ONCOLOGY
PROSTATE CANCER
POSITIVE SAMPLE NEGATIVE SAMPLE
Benign Region
Cancerous Region
Benign Region
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PROSTATE CANCER
Gleason score 3+3
Cancerous region
Benign region
Patches within region
are randomly chosen
POSITIVE SAMPLE
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RESULTS IN 3D FEATURE SPACE
• 3+3 cancerous
• 4+3 cancerous
• Negative sample
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CO-LOCALIZATION
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=+
CO-LOCALIZATION
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Zoom on overlay image
BREAST CANCER
DCIS DCIS I I I I II II
T2N0M0 T2N0M0 T2N0M0 T2N1M0 T3N3M0 T3N0M0
II II III III III III III III
T1N0M0 T2N0M0 T2N0M0 T3N0M0 T3N1M0 T3N1M0 T2N0M0 T3N0M0
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BLADDER CANCER
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BLADDER CANCER
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SKIN CANCER (BOWEN’S DISEASE)
Bowen‘s Disease Normal
Patch
Patch
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NUMERICAL FEATURE
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OTHER CANCERS
BLADDER CANCER
(A) & (B) TPAF and H&E image of Bladder Cancer image
at low magnification showing demarcation between
normal urothelium (a) and lamina propria (b).
[Lamina propria is composed of collagen bundles (red)
and elastin fibers (green)]
(C) & (D) TPAF and H&E image at high magnification
showing multi-layered urothelium and superficial umbrella
cells.
Umbrella cells in each image are boxed and shown at
higher digital zoom in the inset.
(E) & (F) TPAF image and H&E image at low
magnification showing von Brunn nests, some with cystic
dilatation
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OESOPHAGEAL CANCER
The content and distribution of collagen, elastic fibers and cancer cells in normal and
cancerous submucosa layer can determine the early stages of early oesophageal
cancer by using multiphoton technology
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a) SHG and TPAF images of normal tissues
b) SHG and TPAF images of oesophageal cancer tissues
Green: Collagen Fibres (SHG)
Red: Cellular Structure (TPAF)
SHG TPAF SHG/TPAF
(a)
Normal
(b)
Cancer
RECTAL CANCER
 Multiphoton Technology is used to image mucosa layer, goblet cells, intestinal
glands, and collagen fibers of human rectal mucosa and submucosa. Results
shows that it can monitor early rectal cancer
 Multiphoton Technology has the potential to provide real-time, non-invasive
optical diagnosis for surgical margins in rectal cancer
a) SHG image of colorectal carcinoma
b) TPAF image of colorectal carcinoma
c) SHG/TPAF image of colorectal carcinoma
d) Hemotoxylin and eosin (H&E) staining of
colorectal carcinoma
Green: Collagen Fibres (SHG)
Red: Cellular Structure (TPAF)
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LUNG CANCER
By using Two Photon Auto Fluorescence (TPAF) and SHG, it can capture
3D structural organization of ECM as well as cellular morphologies in lung
or airway tissue with spectral specificity and sensitivity
Representative SHG image originating from fibrillar collagen in C
Overlaid with the TPAF image of healthy alveolar tissue is shown in D
C) SHG D) SHG + TPAF
a) SHG image shows normal collagen matrix
b) TPAF image shows normal alveolar tissue
c) Spirally wound form of collagen band around the elastic fibers
d) and e) Representative SHG image originating from the collagen matrix (D) overlaid with
the TPAF image of lung undergoing emphysematous destruction is shown E
f) The size of the ECM structures, particularly collagen, showed considerable variations as
evident from highly optically magnified image
A) 3D [SHG] B) 3D [SHG+TPAF] C) XY Plane [SHG + TPAF]
D) 3D [SHG] E) 3D [SHG+TPAF] F) XY Plane [SHG + TPAF]
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GASTRIC CANCER
TPAF has the ability to exhibit not only the mucosal and submucosal
microstructures of normal and cancerous gastric tissues but also the
distribution and content of abnormal cells in these 2 layers
Rows 1 and 2 represent microstructures of the mucosa epithelium and lamina
propria.
Rows 3 and 4 are from the submucosa.
Row 1 represents the abnormal epithelial cells
In row 2, pink circles indicate the boundary locations of representative
gastric glands; red circles indicate the nuclei of representative cells; blue
circles indicate the position of the gland cavity.
In row 3, blue arrows, pink arrows, red circles, and the blue circle
indicate collagen bundles, elastic fibers, abnormal cell nuclei, and the
lumen of the blood vessel, respectively.
In row 4, red circles indicate the nuclei of abnormal cells and blue circles
indicate the cavity of glandular tissue
TPAF Image SHG Image Overlay Image
Row 1
Row 2
Row 3
Row 4
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COLON CANCER
SHG microscopy has the potential in label-freely imaging the changes of
basement membranes for effectively distinguishing between normal,
precancerous, and cancerous colonic tissues
Image of SHG on colon cancer tissues
Green: Collagen Fibres (SHG)
Red: Cellular Structure (TPAF)
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KIDNEY CANCER
SHG and TPAF gave a detailed insight in cancer morphology and composition,
enabling to discern between normal kidney tissue, tumour and necrosis. Several
features can be seen clearly without the use of staining. It also greatly improves
speed and quality of the analyses.
(a) Image of the superficial kidney renal cortex shows dark renal
interstitium (RI), dark cellular nuclei (N) and bright intrinsic fluorescent
cytoplasm (CY) that form the epithelial cells in the renal tubules (RT), SHG
signal from the tough fibrous layer that forms the renal capsule (RC), and
the dark blood filled lumen (L) inside the renal tubules.
(b) Image of the inner colon wall shows bright intrinsic fluorescent signal
from entrocytes (E) surrounding dark circular crypts (C).
(c) Image of the rat liver showing ~20 µm diameter hapatocytes (coarse
dashed line) with dark nuclei (N, solid line) chained together to form hepatic
chords (HC), a dark bile duct (BD, fine dashed line) and bright intrinsically
fluorescent bile salts (BS), as well as SHG emission from the septa (S) a
fibrous tissue bands that separates hapatocyte nodules.
(d) Image of the rat liver without labels shown for clarity
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PANCREATIC CANCER
SHG and TPAF is used in a non-invasive manner and it provides real-time
histological evaluation of pancreatic cancer. Both of it also has ability to visualize
the morphology of fresh tissues associated with histology.
The pancreatic tumor xenografts harvested at different stages.
(A) 5 days after implantation
(B) 10 days after implantation
(C) 20 days after implantation
(D) 30 days after implantation
The SHG images (red color-coded), the TPAF images (green
color-coded), and the 3-D superimposed SHG/TPAF images are
shown in the first three columns respectively.
H&E images and the Masson's trichrome images are displayed in
the last two columns.
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GENESIS IMAGING SERVICES
(GLASGOW, UK)
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Services Capabilities
 On Demand Tissue Imaging Services
 Imaging System Shared access time
 Tissue Imaging Solutions development
 Grants Partnership:
o EU grants e.g. H2020
o UK national grants e.g. SBRI, MRC
grants, InnovateUK grants, etc
o University internal grants e.g. P2D
 Breakthrough non-destructive tissue
imaging technologies including:
o Non-Linear Microscopy
Two Photon Excited Fluorescence
Second Harmonic Generation
o Image Processing and Analysis
capabilities
o Co-localization of stain and unstain
images

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HistoIndex slidedeck

  • 1. AGNOSTIC DIAGNOSIS HistoIndex Pte.Ltd. property. All Rights Reserved
  • 2. HISTOINDEX – BRINGING DIAGNOSIS INTO BIOPSY World’s first suite of fully-automated, 3-D, quantitative, laser- based imaging system for tissue imaging HistoIndex Pte.Ltd. property. All Rights Reserved
  • 3. WHAT ARE CUSTOMERS LOOKING FOR? PRICE SPEED TARGET CUSTOMER ACCURACY SPECIFIC OBJECTIVE HistoIndex Pte.Ltd. property. All Rights Reserved Tissue-Specific Image Analysis and Quantification for Research and Clinical Applications
  • 4. WHAT DO WE OFFER? HistoIndex Pte.Ltd. property. All Rights Reserved • How did the disease progress/re gress? • Why did that happen? • When is treatment needed? • What treatment to give? CLOUD-BASED GENESIS® LAENNEC™ DISEASE-SPECIFIC ASSESSMENT
  • 5. HOW IT WORKS LASER cells ECM Improvement in accuracy of tissue diagnosis from 65% to more than 95% Bedossa et al., Hepatology 20, 15-20 (1994); Gronbaek et al., Journal of Viral Hepatitis 9, 443- 449 (2002); Theodossi et al., Gastroenterology 79, 232-241 (1980); Theodossi et al., Gut 35, 961-968 (1994); Westin et al., Liver 19, 183-187 (1999) He et al., Journal of Biomedical Optics, 15(5) 056007, 2010. Bredfeldt et al., Journal of Pathology Informatics, 5(1), 28, 2014 Raja et al., Journal of Biomedical Optics 15(5) 056016, 2010. Gailhouste et al., Journal of Hepatology 52, 398-406, 2010. Asselah et al, Journal of Hepatology 61, 193-195, 2014. Tai et al., Hepatology 50(4) 1093, 2009. Tai et al., Journal of Biomedical Optics, 14(4) 044013, 2009. Xu et al., Journal of Hepatology, 61, 260-269, 2014. HistoIndex Pte.Ltd. property. All Rights Reserved
  • 6. HOW IT WORKS HistoIndex Pte.Ltd. property. All Rights Reserved
  • 7. REVOLUTIONARY TECHNOLOGY Stage 1 Stage 2 Stage 3 Stage 4 HistoIndex Stain-Free Stage 1.2 Stage 2.5 Stage 3.1 Stage 4.7 Current Method HistoIndex Pte.Ltd. property. All Rights Reserved
  • 8. KEY BENEFITS 1 – 3 days Sample Staining Imaging Staging Diagnosis 0.5 – 1 hr Diagnosis HistoIndex Stain-free Technology Sample  Patients (Hospitals and Clinics): Same day results – greater accuracy & efficiency  Users (Researchers, Drug companies & CROs): • Higher specificity & sensitivity • A "translational" program to measure drug efficacy from the start of preclinical studies to the end of the clinical trial • Assessment of incremental improvement in treatment efficacy HistoIndex Pte.Ltd. property. All Rights Reserved
  • 9. WHAT IS THIS NEW STANDARD? Hardware Genesis®200 Multi-photon microscope utilizing a high power laser Customized optics Fully automated One-touch operation Unstained tissues Multi-organ capabilities Computer-assisted tissue diagnostic system HISTOINDEX is setting a NEW STANDARD! Software FibroIndex™ + LiverCloud™ Quantification for decision support database 3D visualization Cloud-based database & online assessment HistoIndex Pte.Ltd. property. All Rights Reserved
  • 10. GLOBAL PRESENCE Physical units placement Clinical/Research sites with samples sending to HistoIndex’s global Imaging Service Centres HistoIndex Pte.Ltd. property. All Rights Reserved
  • 11. TISSUE-SPECIFIC IMAGE ANALYSIS & QUANTIFICATION FIBROSIS HistoIndex Pte.Ltd. property. All Rights Reserved Research Development Validation Commercial Liver Kidney Lung Bone Marrow Eye – AMD, Glaucoma Heart Brain – AD Skin Hair Launch 2Q2016 Launch 2Q2016 Published Explorations In Partnerships
  • 12. TISSUE-SPECIFIC IMAGE ANALYSIS & QUANTIFICATION ONCOLOGY HistoIndex Pte.Ltd. property. All Rights Reserved Research Development Validation Commercial Breast Prostate Bladder Vs Genomic Markers 3Q2016 3Q2018 Vs Genomic Markers 3Q2016 3Q2018 Vs Genomic Markers 3Q2016 3Q2018 Target Intent of Use: To provide Physicians (e.g. Urologists) with adjunctive information to subclassify tumor stages
  • 13. FIBROSIS IN LIVER VALIDATION PATHWAY HistoIndex Pte.Ltd. property. All Rights Reserved
  • 14. HistoIndex Pte.Ltd. property. All Rights Reserved IMAGE ANALYSIS & QUANTIFICATION TOOL Quantification of Cell Damage Quantification of Collagens Hepatocytes’s NAD(P)H and Flavins intrinsic florescence. Areas containing nucleus, lipid droplets, and the vacuoles formed by degenerated hepatocytes appeared dark in the TPEF image( lack of the fluorescent molecules) Aggregated and distributed collagens are revealed and then quantified
  • 16. LIVER FIBROSIS HistoIndex Pte.Ltd. property. All Rights Reserved • A SHG may open new opportunities in the quantification of collagen content in different organs, which is of main importance in providing diagnostic information and evaluation of therapeutic efficiency Morphological changes at different stages 1 to 4 of liver fibrosis recorded with (a) to (d) conventional Masson Trichrome staining, as well as (e) to (h) SHG and TPAF microscopies. In stage 1 liver fibrosis, there was presence of pericellular collagen without the septa formation in (a) and (e). In livers with stage 2 fibrosis, (b) collagen aggregations formed incomplete septa from the portal tract to central vein, and (f) the bile duct proliferation was seen as dim regions in the SHG image. For stage 3 liver fibrosis, profuse bile duct proliferation was observed all over the tissue sample, where complete but thin collagen septa interconnected with each other in (c) and (g). In stage 4 fibrosis, thick collagen septa were observed, forming complete cirrhosis in (d) and (h). Red: TPAF Green: SHG
  • 17. RENAL FIBROSIS HistoIndex Pte.Ltd. property. All Rights Reserved • Combined SHG and TPAF imaging can provide simultaneous three-dimensional visualization of collagen synthesis and assembly sites in transgenic animal models expressing GFP constructs • SHG is used to image collagen fibers in human and mouse unstained kidneys. This approach allows quantitative 3-D imaging of interstitial fibrosis and arterial remodelling with high accuracy. SHG TPAF Overlay SHG imaging showing increased tubulointerstitial fibrosis and disrupted extracellular matrix in tissue inhibitor of metalloproteinase-3 (TIMP3) SHG and TPAF imaging in unfixed and unstained kidneys showing the fibrillar collagen network (magenta) and tubular endogenous autofluorescence (green) in wild-type (WT) and TIMP3−/− kidneys at 3 days after unilateral urethral obstruction (UUO)
  • 18. PULMONARY FIBROSIS HistoIndex Pte.Ltd. property. All Rights Reserved • Using TPAF, we can characterize normal and fibrotic pulmonary tissue in the bleomycin model, and show that SHG by fibrillar collagen reveals the micrometer-scale three- dimensional spatial distribution of the fibrosis • TPAF is able to differentiate neoplastic from nonneoplastic lung tissue and identify tumour subtypes. In the future larger studies, we foresee real time intraoperative applications of TPAF TPAF and hematoxylin and eosin (H&E) images of progression from atypical lesion to various patterns of invasive adenocarcinoma of lung a) and b) Images of atypical adenomatous hyperplasia shows a focus of pneumocyte proliferation along the alveolar wall c) and d) Images of adenocarcinoma of lung with lepidic-predominant pattern and a few clusters of free-floating tumour cells e) and f) Images of adenocarcinoma of lung with acinar-predominant pattern g) and h) Images showing solid pattern (arrows) with suggestion of gland formation i) and j) Images showing papillary pattern k) And l) Images showing micropapillary pattern, with complete destruction of normal lung parenchyma
  • 19. MYELOFIBROSIS HistoIndex Pte.Ltd. property. All Rights Reserved • TPAF or SHG is a promising novel technology to be applied in quantification of myelofibrosis, with performance equivalent to a stereology-based approach. Further studies with large sample size are needed to validate the utility of this method. Fibrosis score = 0 Fibrosis score = 2+ Fibrosis score = 3+ Myelofibrosis is the proliferation of an abnormal clone of Hematopoetic Stem Cell (HSC) which results in fibrosis. 0 represents the least damage, while 3+ represents the most damage on the myeloproliferative neoplasm. Green: SHG Red: TPAF
  • 20. DERMAL FIBROSIS HistoIndex Pte.Ltd. property. All Rights Reserved • SHG is used to measure the significant differences in thickness of epidermis and stratum corneum, and modified degrees of fibrosis in dermis, are clearly demonstrated in in vitro studies Transversal optically sectioned ex-vivo skin sample of healthy dermis (a) SHG, (b) TPAF, (c) merge between the two images Transversal optically sectioned ex-vivo sample of normal scar (NS) (d) SHG, (e) TPAF, (f) merge between the two images Area with fibroblastic proliferation inside a transversal optically sectioned ex-vivo skin sample of keloid (g) SHG, (h) TPAF, (i) merge between the two images Area with keloidal fibers inside a transversal optically sectioned ex-vivo skin sample of keloid (j) SHG, (k) TPAF, (l) merge between the two images Blue: TPAF Green: SHG
  • 21. SUBEPITHELIAL FIBROSIS ON CORNEA HistoIndex Pte.Ltd. property. All Rights Reserved • Using SHG, we detected the presence of subepithelial fibrosis at the anterior stroma and disorganized collagen lamellae at the posterior stroma of the bullous keratopathy cornea • SHG imaging of the anterior segment of edematous corneas revealed a normal appearance of interwoven collagen lamellae in the anterior stroma SHG images of the anterior segment of the stroma in normal (A) and edematous corneas (B). Short, narrow bundles of linear structures in random orientations are apparent in both corneas. (C, D) Image of Subepithelial Fibrosis Associated with Corneal Stromal Edema by SHG
  • 22. RETINAL PIGMENT EPITHELIUM HistoIndex Pte.Ltd. property. All Rights Reserved • Dysfunction Retinal Pigment Epithelium (RPE) will cause damages to the retina. Hence, TPAF is used because it is an elegant and highly efficient tool to delineate the thick, fragile, and opaque retina-choroid complex, and may provide clues to the trigger events of age- related macular degeneration TPAF signals from the 19-year-old macular RPE cells were acquired with two spectral windows colour coded in (a) green and (b) red (c) Merged TPAF images of the 19-year-old RPE cells (d), (e) and (f) Corresponding TPAF images of the 64 year-old macular RPE cells respectively
  • 23. ARTERIAL FIBROSIS HistoIndex Pte.Ltd. property. All Rights Reserved SHG and TPAF provides label-free molecular imaging of atherosclerotic lesions with 3-D submicrometric resolution suggests its potential application to the diagnosis of atherosclerotic plaques, determination of their rupture risk, and design of individualized drug therapy based on plaque composition D SHG E TPAF SHG/TPAFF SHG TPAF SHG/TPAFCA B Healthy Arteries Atherosclerotic Iliac Arteries a) SHG image of collagen b) TPAF image of elastin in a healthy artery c) Overlaid image of a and b d) SHG image of collagen e) TPAF image of elastin in an atherosclerotic artery f) Overlaid image of d and e Green: SHG Red: TPAF
  • 24. CARDIAC FIBROSIS HistoIndex Pte.Ltd. property. All Rights Reserved • By using SHG to analyze the arrangement of collagen fibers, we can provide explicit information about the relationship between myocardial fibrosis and Atrial Fibrillation (AF) • A significant increase in the density of collagen fibres between hypertrophic and control tissues was evident using SHG. Similar increases and patterns of staining were observed using parallel traditional picrosirius red staining of collagen Co-localized SHG (shown in white) and TPAF (shown in blue) images visualize collagen fibril organization and cardiac muscle cell nuclei, respectively, in the histological section of infarcted myocardium of (a) an untreated infarcted rat heart; (b) an ASCs-treated infarcted rat heart; (c) an image obtained from a histological section of a non-MI rat heart
  • 25. ALZHEIMER’S DISEASE (AD) HistoIndex Pte.Ltd. property. All Rights Reserved • Using SHG and TPAF, the results suggest that tissues from AD transgenic models contain distinct intrinsic emissions, which can provide valuable information about the disease mechanisms TPAF a) TPAF b) SHG c) overlay of the hippocampus of a 17-month old mouse d) Senile plaques emit TPAF that were morphologically distinct from other sources of intrinsic emissions and were missing from wild type Images from acute hippocampal brain slice of transgenic Alzheimer’s disease mouse models
  • 26. FIBROSIS IN DUCHENNE MUSCULAR DYSTROPHY (DMD) HistoIndex Pte.Ltd. property. All Rights Reserved • Second harmonic generation (SHG) imaging may soon be available in routine clinical diagnostics, and in this work we provide valuable imaging tools to track and quantify ultrastructural worsening in Duchenne Muscular Dystrophy (DMD), and to judge the beneficial effects of possible drug or gene therapies Co-imaging of TPAF and SHG shows that the fascicle with abnormal sarcomere angles sticking out of the main trunk is fully covered by membrane Red: TPAF Green: SHG
  • 27. CONTRACTION MODEL OF WOUND REPAIR HistoIndex Pte.Ltd. property. All Rights Reserved • Since structural remodelling of collagen is important in fibrosis, SHG and Two Photon Auto Fluorescence (TPAF) signals can be used in tandem to provide spatially resolved 3-dimensional structural remodelling of a collagen matrix A) SHG image of collagen matrix B) TPAF image of contracted fibroblasts C) Overlaid image of collagen matrix and contracted fibroblast A) SHG image of collagen matrix B) TPAF image of non-contracted fibroblasts C) Overlaid image of collagen matrix and non-contracted fibroblasts Gray: SHG signal strength Green: Elongated Cell Peripheries
  • 29. PROSTATE CANCER POSITIVE SAMPLE NEGATIVE SAMPLE Benign Region Cancerous Region Benign Region HistoIndex Pte.Ltd. property. All Rights Reserved
  • 30. PROSTATE CANCER Gleason score 3+3 Cancerous region Benign region Patches within region are randomly chosen POSITIVE SAMPLE HistoIndex Pte.Ltd. property. All Rights Reserved
  • 31. RESULTS IN 3D FEATURE SPACE • 3+3 cancerous • 4+3 cancerous • Negative sample HistoIndex Pte.Ltd. property. All Rights Reserved
  • 33. CO-LOCALIZATION HistoIndex Pte.Ltd. property. All Rights ReservedConfidential Zoom on overlay image
  • 34. BREAST CANCER DCIS DCIS I I I I II II T2N0M0 T2N0M0 T2N0M0 T2N1M0 T3N3M0 T3N0M0 II II III III III III III III T1N0M0 T2N0M0 T2N0M0 T3N0M0 T3N1M0 T3N1M0 T2N0M0 T3N0M0 HistoIndex Pte.Ltd. property. All Rights Reserved
  • 35. HistoIndex Pte.Ltd. property. All Rights Reserved
  • 36. BLADDER CANCER HistoIndex Pte.Ltd. property. All Rights Reserved
  • 37. BLADDER CANCER HistoIndex Pte.Ltd. property. All Rights Reserved
  • 38. SKIN CANCER (BOWEN’S DISEASE) Bowen‘s Disease Normal Patch Patch HistoIndex Pte.Ltd. property. All Rights Reserved
  • 39. NUMERICAL FEATURE HistoIndex Pte.Ltd. property. All Rights Reserved
  • 41. BLADDER CANCER (A) & (B) TPAF and H&E image of Bladder Cancer image at low magnification showing demarcation between normal urothelium (a) and lamina propria (b). [Lamina propria is composed of collagen bundles (red) and elastin fibers (green)] (C) & (D) TPAF and H&E image at high magnification showing multi-layered urothelium and superficial umbrella cells. Umbrella cells in each image are boxed and shown at higher digital zoom in the inset. (E) & (F) TPAF image and H&E image at low magnification showing von Brunn nests, some with cystic dilatation HistoIndex Pte.Ltd. property. All Rights Reserved
  • 42. OESOPHAGEAL CANCER The content and distribution of collagen, elastic fibers and cancer cells in normal and cancerous submucosa layer can determine the early stages of early oesophageal cancer by using multiphoton technology HistoIndex Pte.Ltd. property. All Rights Reserved a) SHG and TPAF images of normal tissues b) SHG and TPAF images of oesophageal cancer tissues Green: Collagen Fibres (SHG) Red: Cellular Structure (TPAF) SHG TPAF SHG/TPAF (a) Normal (b) Cancer
  • 43. RECTAL CANCER  Multiphoton Technology is used to image mucosa layer, goblet cells, intestinal glands, and collagen fibers of human rectal mucosa and submucosa. Results shows that it can monitor early rectal cancer  Multiphoton Technology has the potential to provide real-time, non-invasive optical diagnosis for surgical margins in rectal cancer a) SHG image of colorectal carcinoma b) TPAF image of colorectal carcinoma c) SHG/TPAF image of colorectal carcinoma d) Hemotoxylin and eosin (H&E) staining of colorectal carcinoma Green: Collagen Fibres (SHG) Red: Cellular Structure (TPAF) HistoIndex Pte.Ltd. property. All Rights Reserved
  • 44. LUNG CANCER By using Two Photon Auto Fluorescence (TPAF) and SHG, it can capture 3D structural organization of ECM as well as cellular morphologies in lung or airway tissue with spectral specificity and sensitivity Representative SHG image originating from fibrillar collagen in C Overlaid with the TPAF image of healthy alveolar tissue is shown in D C) SHG D) SHG + TPAF a) SHG image shows normal collagen matrix b) TPAF image shows normal alveolar tissue c) Spirally wound form of collagen band around the elastic fibers d) and e) Representative SHG image originating from the collagen matrix (D) overlaid with the TPAF image of lung undergoing emphysematous destruction is shown E f) The size of the ECM structures, particularly collagen, showed considerable variations as evident from highly optically magnified image A) 3D [SHG] B) 3D [SHG+TPAF] C) XY Plane [SHG + TPAF] D) 3D [SHG] E) 3D [SHG+TPAF] F) XY Plane [SHG + TPAF] HistoIndex Pte.Ltd. property. All Rights Reserved
  • 45. GASTRIC CANCER TPAF has the ability to exhibit not only the mucosal and submucosal microstructures of normal and cancerous gastric tissues but also the distribution and content of abnormal cells in these 2 layers Rows 1 and 2 represent microstructures of the mucosa epithelium and lamina propria. Rows 3 and 4 are from the submucosa. Row 1 represents the abnormal epithelial cells In row 2, pink circles indicate the boundary locations of representative gastric glands; red circles indicate the nuclei of representative cells; blue circles indicate the position of the gland cavity. In row 3, blue arrows, pink arrows, red circles, and the blue circle indicate collagen bundles, elastic fibers, abnormal cell nuclei, and the lumen of the blood vessel, respectively. In row 4, red circles indicate the nuclei of abnormal cells and blue circles indicate the cavity of glandular tissue TPAF Image SHG Image Overlay Image Row 1 Row 2 Row 3 Row 4 HistoIndex Pte.Ltd. property. All Rights Reserved
  • 46. COLON CANCER SHG microscopy has the potential in label-freely imaging the changes of basement membranes for effectively distinguishing between normal, precancerous, and cancerous colonic tissues Image of SHG on colon cancer tissues Green: Collagen Fibres (SHG) Red: Cellular Structure (TPAF) HistoIndex Pte.Ltd. property. All Rights Reserved
  • 47. KIDNEY CANCER SHG and TPAF gave a detailed insight in cancer morphology and composition, enabling to discern between normal kidney tissue, tumour and necrosis. Several features can be seen clearly without the use of staining. It also greatly improves speed and quality of the analyses. (a) Image of the superficial kidney renal cortex shows dark renal interstitium (RI), dark cellular nuclei (N) and bright intrinsic fluorescent cytoplasm (CY) that form the epithelial cells in the renal tubules (RT), SHG signal from the tough fibrous layer that forms the renal capsule (RC), and the dark blood filled lumen (L) inside the renal tubules. (b) Image of the inner colon wall shows bright intrinsic fluorescent signal from entrocytes (E) surrounding dark circular crypts (C). (c) Image of the rat liver showing ~20 µm diameter hapatocytes (coarse dashed line) with dark nuclei (N, solid line) chained together to form hepatic chords (HC), a dark bile duct (BD, fine dashed line) and bright intrinsically fluorescent bile salts (BS), as well as SHG emission from the septa (S) a fibrous tissue bands that separates hapatocyte nodules. (d) Image of the rat liver without labels shown for clarity HistoIndex Pte.Ltd. property. All Rights Reserved
  • 48. PANCREATIC CANCER SHG and TPAF is used in a non-invasive manner and it provides real-time histological evaluation of pancreatic cancer. Both of it also has ability to visualize the morphology of fresh tissues associated with histology. The pancreatic tumor xenografts harvested at different stages. (A) 5 days after implantation (B) 10 days after implantation (C) 20 days after implantation (D) 30 days after implantation The SHG images (red color-coded), the TPAF images (green color-coded), and the 3-D superimposed SHG/TPAF images are shown in the first three columns respectively. H&E images and the Masson's trichrome images are displayed in the last two columns. HistoIndex Pte.Ltd. property. All Rights Reserved
  • 49. GENESIS IMAGING SERVICES (GLASGOW, UK) HistoIndex Pte.Ltd. property. All Rights Reserved Services Capabilities  On Demand Tissue Imaging Services  Imaging System Shared access time  Tissue Imaging Solutions development  Grants Partnership: o EU grants e.g. H2020 o UK national grants e.g. SBRI, MRC grants, InnovateUK grants, etc o University internal grants e.g. P2D  Breakthrough non-destructive tissue imaging technologies including: o Non-Linear Microscopy Two Photon Excited Fluorescence Second Harmonic Generation o Image Processing and Analysis capabilities o Co-localization of stain and unstain images